PMID- 24400117 TI - Matrix stiffness affects endocytic uptake of MK2-inhibitor peptides. AB - In this study, the role of substrate stiffness on the endocytic uptake of a cell penetrating peptide was investigated. The cell-penetrating peptide, an inhibitor of mitogen-activated protein kinase activated protein kinase II (MK2), enters a primary mesothelial cell line predominantly through caveolae. Using tissue culture polystyrene and polyacrylamide gels of varying stiffness for cell culture, and flow cytometry quantification and enzyme-linked immunoassays (ELISA) for uptake assays, we showed that the amount of uptake of the peptide is increased on soft substrates. Further, peptide uptake per cell increased at lower cell density. The improved uptake seen on soft substrates in vitro better correlates with in vivo functional studies where 10-100 uM concentrations of the MK2 inhibitor cell penetrating peptide demonstrated functional activity in several disease models. Additional characterization showed actin polymerization did not affect uptake, while microtubule polymerization had a profound effect on uptake. This work demonstrates that cell culture substrate stiffness can play a role in endocytic uptake, and may be an important consideration to improve correlations between in vitro and in vivo drug efficacy. PMID- 24400118 TI - Diurnal microstructural variations in healthy adult brain revealed by diffusion tensor imaging. AB - Biorhythm is a fundamental property of human physiology. Changes in the extracellular space induced by cell swelling in response to the neural activity enable the in vivo characterization of cerebral microstructure by measuring the water diffusivity using diffusion tensor imaging (DTI). To study the diurnal microstructural alterations of human brain, fifteen right-handed healthy adult subjects were recruited for DTI studies in two repeated sessions (8?30 AM and 8?30 PM) within a 24-hour interval. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial (lambda//) and radial diffusivity (lambda?) were compared pixel by pixel between the sessions for each subject. Significant increased morning measurements in FA, ADC, lambda// and lambda? were seen in a wide range of brain areas involving frontal, parietal, temporal and occipital lobes. Prominent evening dominant lambda? (18.58%) was detected in the right inferior temporal and ventral fusiform gyri. AM-PM variation of lambda? was substantially left side hemisphere dominant (p<0.05), while no hemispheric preference was observed for the same analysis for ADC (p = 0.77), lambda// (p = 0.08) or FA (p = 0.25). The percentage change of ADC, lambda//, lambda?, and FA were 1.59%, 2.15%, 1.20% and 2.84%, respectively, for brain areas without diurnal diffusivity contrast. Microstructural variations may function as the substrates of the phasic neural activities in correspondence to the environment adaptation in a light-dark cycle. This research provided a baseline for researches in neuroscience, sleep medicine, psychological and psychiatric disorders, and necessitates that diurnal effect should be taken into account in following up studies using diffusion tensor quantities. PMID- 24400119 TI - Defining the ligand specificity of the deleted in colorectal cancer (DCC) receptor. AB - The growth and guidance of many axons in the developing nervous system require Netrin-mediated activation of Deleted in Colorectal Cancer (DCC) and other still unknown signaling cues. Commissural axon guidance defects are more severe in DCC mutant mice than Netrin-1 mutant mice, suggesting additional DCC activating signals besides Netrin-1 are involved in proper axon growth. Here we report that interaction screens on extracellular protein microarrays representing over 1,000 proteins uniquely identified Cerebellin 4 (CBLN4), a member of the C1q-tumor necrosis factor (TNF) family, and Netrin-1 as extracellular DCC-binding partners. Immunofluorescence and radio-ligand binding studies demonstrate that Netrin-1 competes with CBLN4 binding at an overlapping site within the membrane-proximal fibronectin domains (FN) 4-6 of DCC and binds with ~5-fold higher affinity. CBLN4 also binds to the DCC homolog, Neogenin-1 (NEO1), but with a lower affinity compared to DCC. CBLN4-null mice did not show a defect in commissural axons of the developing spinal cord but did display a transient increase in the number of wandering axons in the brachial plexus, consistent with a role in axon guidance. Overall, the data solidifies CBLN4 as a bona fide DCC ligand and strengthens its implication in axon guidance. PMID- 24400120 TI - Basal keratinocytes contribute to all strata of the adult zebrafish epidermis. AB - The epidermis of terrestrial vertebrates is a stratified epithelium and forms an essential protective barrier. It is continually renewed, with dead corneocytes shed from the surface and replaced from a basal keratinocyte stem cell population. Whilst mouse is the prime model system used for epidermal studies, there is increasing employment of the zebrafish to analyse epidermis development and homeostasis, however the architecture and ontogeny of the epidermis in this system are incompletely described. In particular, it is unclear if adult zebrafish epidermis is derived entirely from the basal epidermal stem cell layer, as in the mouse, or if the most superficial keratinocyte layer is a remnant of the embryonic periderm. Furthermore, a relative paucity of cellular markers and genetic reagents to label and manipulate the basal epidermal stem cell compartment has hampered research. Here we show that the type I keratin, krtt1c19e, is a suitable marker of the basal epidermal layer and identify a krtt1c19e promoter fragment able to drive strong and specific expression in this cell type. Use of this promoter to express an inducible Cre recombinase allowed permanent labelling of basal cells during embryogenesis, and demonstrated that these cells do indeed generate keratinocytes of all strata in the adult epidermis. Further deployment of the Cre-Lox system highlighted the transient nature of the embryonic periderm. We thus show that the epidermis of adult zebrafish, as in the mouse, derives from basal stem cells, further expanding the similarities of epidermal ontogeny across vertebrates. Future use of this promoter will assist genetic analysis of basal keratinocyte biology in zebrafish. PMID- 24400122 TI - Automatic realistic real time stimulation/recording in weakly electric fish: long time behavior characterization in freely swimming fish and stimuli discrimination. AB - Weakly electric fish are unique model systems in neuroethology, that allow experimentalists to non-invasively, access, central nervous system generated spatio-temporal electric patterns of pulses with roles in at least 2 complex and incompletely understood abilities: electrocommunication and electrolocation. Pulse-type electric fish alter their inter pulse intervals (IPIs) according to different behavioral contexts as aggression, hiding and mating. Nevertheless, only a few behavioral studies comparing the influence of different stimuli IPIs in the fish electric response have been conducted. We developed an apparatus that allows real time automatic realistic stimulation and simultaneous recording of electric pulses in freely moving Gymnotus carapo for several days. We detected and recorded pulse timestamps independently of the fish's position for days. A stimulus fish was mimicked by a dipole electrode that reproduced the voltage time series of real conspecific according to previously recorded timestamp sequences. We characterized fish behavior and the eletrocommunication in 2 conditions: stimulated by IPIs pre-recorded from other fish and random IPI ones. All stimuli pulses had the exact Gymontus carapo waveform. All fish presented a surprisingly long transient exploratory behavior (more than 8 h) when exposed to a new environment in the absence of electrical stimuli. Further, we also show that fish are able to discriminate between real and random stimuli distributions by changing several characteristics of their IPI distribution. PMID- 24400121 TI - miR-223 is a coordinator of breast cancer progression as revealed by bioinformatics predictions. AB - MicroRNAs are single-stranded non-coding RNAs that simultaneously down-modulate the expression of multiple genes post-transcriptionally by binding to the 3'UTRs of target mRNAs. Here we used computational methods to predict microRNAs relevant in breast cancer progression. Specifically, we applied different microRNA target prediction algorithms to various groups of differentially expressed protein coding genes obtained from four breast cancer datasets. Six potential candidates were identified, among them miR-223, previously described to be highly expressed in the tumor microenvironment and known to be actively transferred into breast cancer cells. To investigate the function of miR-223 in tumorigenesis and to define its molecular mechanism, we overexpressed miR-223 in breast cancer cells in a transient or stable manner. Alternatively we overexpressed miR-223 in mouse embryonic fibroblasts or HEK293 cells and used their conditioned medium to treat tumor cells. With both approaches, we obtained elevated levels of miR-223 in tumor cells and observed decreased migration, increased cell death in anoikis conditions and augmented sensitivity to chemotherapy but no effect on adhesion and proliferation. The analysis of miR-223 predicted targets revealed enrichment in cell death and survival-related genes and in pathways frequently altered in breast cancer. Among these genes, we showed that protein levels for STAT5A, ITGA3 and NRAS were modulated by miR-223. In addition, we proved that STAT5A is a direct miR-223 target and highlighted a possible correlation between miR-223 and STAT5A in migration and chemotherapy response. Our investigation revealed that a computational analysis of cancer gene expression datasets can be a relevant tool to identify microRNAs involved in cancer progression and that miR-223 has a prominent role in breast malignancy that could potentially be exploited therapeutically. PMID- 24400123 TI - Matrix metalloproteinase 7 is associated with symptomatic lesions and adverse events in patients with carotid atherosclerosis. AB - BACKGROUND: Atherosclerosis is a major cause of cerebrovascular disease. Matrix metalloproteinases (MMPs) play an important role in matrix degradation within the atherosclerotic lesion leading to plaque destabilization and ischemic stroke. We hypothesized that MMP-7 could be involved in this process. METHODS: Plasma levels of MMP-7 were measured in 182 consecutive patients with moderate (50-69%) or severe (>=70%) internal carotid artery stenosis, and in 23 healthy controls. The mRNA levels of MMP-7 were measured in atherosclerotic carotid plaques with different symptomatology, and based on its localization to macrophages, the in vitro regulation of MMP-7 in primary monocytes was examined. RESULTS: Our major findings were (i) Patients with carotid atherosclerosis had markedly increased plasma levels of MMP-7 compared to healthy controls, with particularly high levels in patients with recent symptoms (i.e., within the last 2 months). (ii) A similar pattern was found within carotid plaques with markedly higher mRNA levels of MMP-7 than in non-atherosclerotic vessels. Particularly high protein levels of MMP-7 levels were found in those with the most recent symptoms. (iii) Immunhistochemistry showed that MMP-7 was localized to macrophages, and in vitro studies in primary monocytes showed that the inflammatory cytokine tumor necrosis factor-alpha in combination with hypoxia and oxidized LDL markedly increased MMP 7 expression. (iv) During the follow-up of patients with carotid atherosclerosis, high plasma levels of MMP-7 were independently associated with total mortality. CONCLUSION: Our findings suggest that MMP-7 could contribute to plaque instability in carotid atherosclerosis, potentially involving macrophage-related mechanisms. PMID- 24400124 TI - The effects of a problem solving-based intervention on depressive symptoms and HIV medication adherence are independent. AB - Depression and depressive symptoms predict poor adherence to medical therapy, but the association is complex, nonspecific, and difficult to interpret. Understanding this association may help to identify the mechanism explaining the results of interventions that improve both medical therapy adherence and depressive symptoms as well as determine the importance of targeting depression in adherence interventions. We previously demonstrated that Managed Problem Solving (MAPS) focused on HIV medication adherence improved adherence and viral load in patients initiating a new antiretroviral regimen. Here, we assessed whether MAPS improved depressive symptoms and in turn, whether changes in depressive symptoms mediated changes in adherence and treatment outcomes. We compared MAPS to usual care with respect to presence of depressive symptoms during the trial using logistic regression. We then assessed whether MAPS' effect on depressive symptoms mediated the relationship between MAPS and adherence and virologic outcomes using linear and logistic regression, respectively. Mediation was defined by the disappearance of the mathematical association between MAPS and the outcomes when the proposed mediator was included in regression models. Although MAPS participants had a lower rate of depressive symptoms (OR = 0.45, 95% confidence interval 0.21-0.93), there was no evidence of mediation of the effects of MAPS on adherence and virological outcome by improvements in depression. Thus, interventions for medication adherence may not need to address depressive symptoms in order to impact both adherence and depression; this remains to be confirmed, however, in other data. PMID- 24400125 TI - HCV genomic RNA activates the NLRP3 inflammasome in human myeloid cells. AB - BACKGROUND: Elevated plasma levels of IL-1beta and IL-18 from patients with hepatitis C virus (HCV) infection indicate a possible activation of inflammasome by HCV. METHODOLOGY/PRINCIPAL FINDINGS: To demonstrate whether HCV infection activates the inflammasome, we investigated inflammasome activation from HCV infected hepatic Huh7 cells, or monocytic cells and THP-1 derived macrophages challenged with HCV virions, but no any inflammasome activation was detected in these cells. However, when we transfected HCV genomic RNA into monocytes or macrophages, IL-1beta was secreted in a dose-dependent manner. We also detected ASC oligomerization and caspase-1 cleavage in HCV RNA transfected macrophages. Using shRNA-mediated gene silencing or specific inhibitors, we found that HCV RNA induced IL-1beta secretion was dependent on the presence of inflammasome components such as NLRP3, ASC and caspase-1. Furthermore, we also found that RIG I was dispensable for HCV RNA-induced NLRP3 inflammasome activation, while reactive oxygen species (ROS) production was required. CONCLUSIONS: Our results indicate that HCV RNA activates the NLRP3 inflammasome in a ROS-dependent manner, and RIG-I is not required for this process. PMID- 24400126 TI - Inter- and intra-patient heterogeneity of response and progression to targeted therapy in metastatic melanoma. AB - BACKGROUND: MAPK inhibitors (MAPKi) are active in BRAF-mutant metastatic melanoma patients, but the extent of response and progression-free survival (PFS) is variable, and complete responses are rare. We sought to examine the patterns of response and progression in patients treated with targeted therapy. METHODS: MAPKi-naive patients treated with combined dabrafenib and trametinib had all metastases >=5 mm (lymph nodes >=15 mm in short axis) visible on computed tomography measured at baseline and throughout treatment. RESULTS: 24 patients had 135 measured metastases (median 4.5/patient, median diameter 16 mm). Time to best response (median 5.5 mo, range 1.7-20.1 mo), and the degree of best response (median -70%, range +9 to -100%) varied amongst patients. 17% of patients achieved complete response (CR), whereas 53% of metastases underwent CR, including 42% >=10 mm. Metastases that underwent CR were smaller than non-CR metastases (median 11 vs 20 mm, P<0.001). PFS was variable among patients (median 8.2 mo, range 2.6-18.3 mo), and 50% of patients had disease progression in new metastases only. Only 1% (1/71) of CR-metastases subsequently progressed. Twelve month overall survival was poorer in those with a more heterogeneous initial response to therapy than less heterogeneous (67% vs 93%, P = 0.009). CONCLUSION: Melanoma response and progression with MAPKi displays marked inter- and intra patient heterogeneity. Most metastases undergo complete response, yet only a small proportion of patients achieve an overall complete response. Similarly, disease progression often occurs only in a subset of the tumor burden, and often in new metastases alone. Clinical heterogeneity, likely reflecting molecular heterogeneity, remains a barrier to the effective treatment of melanoma patients. PMID- 24400127 TI - Combined therapy of iron chelator and antioxidant completely restores brain dysfunction induced by iron toxicity. AB - BACKGROUND: Excessive iron accumulation leads to iron toxicity in the brain; however the underlying mechanism is unclear. We investigated the effects of iron overload induced by high iron-diet consumption on brain mitochondrial function, brain synaptic plasticity and learning and memory. Iron chelator (deferiprone) and antioxidant (n-acetyl cysteine) effects on iron-overload brains were also studied. METHODOLOGY: Male Wistar rats were fed either normal diet or high iron diet consumption for 12 weeks, after which rats in each diet group were treated with vehicle or deferiprone (50 mg/kg) or n-acetyl cysteine (100 mg/kg) or both for another 4 weeks. High iron-diet consumption caused brain iron accumulation, brain mitochondrial dysfunction, impaired brain synaptic plasticity and cognition, blood-brain-barrier breakdown, and brain apoptosis. Although both iron chelator and antioxidant attenuated these deleterious effects, combined therapy provided more robust results. CONCLUSION: In conclusion, this is the first study demonstrating that combined iron chelator and anti-oxidant therapy completely restored brain function impaired by iron overload. PMID- 24400128 TI - Protective immunity against lethal F. tularensis holarctica LVS provided by vaccination with selected novel CD8+ T cell epitopes. AB - Recently we described an unbiased bacterial whole-genome immunoinformatic analysis aimed at selection of potential CTL epitopes located in "hotspots" of predicted MHC-I binders. Applying this approach to the proteome of the facultative intra-cellular pathogen Francisella tularensis resulted in identification of 170 novel CTL epitopes, several of which were shown to elicit highly robust T cell responses. Here we demonstrate that by DNA immunization using a short DNA fragment expressing six of the most prominent identified CTL epitopes a potent and specific CD8+ T cell responses is being induced, to all encoded epitopes, a response not observed in control mice immunized with the DNA vector alone Moreover, this CTL-specific mediated immune response prevented disease development, allowed for a rapid clearance of the bacterial infection and provided complete protection against lethal challenge (10LD50) with F. tularensis holarctica Live Vaccine Strain (LVS) (a total to 30 of 30 immunized mice survived the challenge while all control DNA vector immunized mice succumbed). Furthermore, and in accordance with these results, CD8 deficient mice could not be protected from lethal challenge after immunization with the CTL-polyepitope. Vaccination with the DNA poly-epitope construct could even protect mice (8/10) against the more demanding pulmonary lethal challenge of LVS. Our approach provides a proof-of-principle for selecting and generating a multi-epitpoe CD8 T cell-stimulating vaccine against a model intracellular bacterium. PMID- 24400129 TI - Full-genome analysis of a canine pneumovirus causing acute respiratory disease in dogs, Italy. AB - An outbreak of canine infectious respiratory disease (CIRD) associated to canine pneumovirus (CnPnV) infection is reported. The outbreak occurred in a shelter of the Apulia region and involved 37 out of 350 dogs that displayed cough and/or nasal discharge with no evidence of fever. The full-genomic characterisation showed that the causative agent (strain Bari/100-12) was closely related to CnPnVs that have been recently isolated in the USA, as well as to murine pneumovirus, which is responsible for respiratory disease in mice. The present study represents a useful contribution to the knowledge of the pathogenic potential of CnPnV and its association with CIRD in dogs. Further studies will elucidate the pathogenicity and epidemiology of this novel pneumovirus, thus addressing the eventual need for specific vaccines. PMID- 24400130 TI - Flavoprotein autofluorescence imaging of visual system activity in zebra finches and mice. AB - Large-scale brain activity patterns can be visualized by optical imaging of intrinsic signals (OIS) based on activity-dependent changes in the blood oxygenation level. Another method, flavoprotein autofluorescence imaging (AFI), exploits the mitochondrial flavoprotein autofluorescence, which is enhanced during neuronal activity. In birds, topographic mapping of visual space has been shown in the visual wulst, the avian homologue of the mammalian visual cortex by using OIS. We here applied the AFI method to visualize topographic maps in the visual wulst because with OIS, which depends on blood flow changes, blood vessel artifacts often obscure brain activity maps. We then compared both techniques quantitatively in zebra finches and in C57Bl/6J mice using the same setup and stimulation conditions. In addition to experiments with craniotomized animals, we also examined mice with intact skull (in zebra finches, intact skull imaging is not feasible probably due to the skull construction). In craniotomized animals, retinotopic maps were obtained by both methods in both species. Using AFI, artifacts caused by blood vessels were generally reduced, the magnitude of neuronal activity significantly higher and the retinotopic map quality better than that obtained by OIS in both zebra finches and mice. In contrast, our measurements in non-craniotomized mice did not reveal any quantitative differences between the two methods. Our results thus suggest that AFI is the method of choice for investigations of visual processing in zebra finches. In mice, however, if researchers decide to use the advantages of imaging through the intact skull, they will not be able to exploit the higher signals obtainable by the AFI-method. PMID- 24400131 TI - Outlier-based identification of copy number variations using targeted resequencing in a small cohort of patients with Tetralogy of Fallot. AB - Copy number variations (CNVs) are one of the main sources of variability in the human genome. Many CNVs are associated with various diseases including cardiovascular disease. In addition to hybridization-based methods, next generation sequencing (NGS) technologies are increasingly used for CNV discovery. However, respective computational methods applicable to NGS data are still limited. We developed a novel CNV calling method based on outlier detection applicable to small cohorts, which is of particular interest for the discovery of individual CNVs within families, de novo CNVs in trios and/or small cohorts of specific phenotypes like rare diseases. Approximately 7,000 rare diseases are currently known, which collectively affect ~6% of the population. For our method, we applied the Dixon's Q test to detect outliers and used a Hidden Markov Model for their assessment. The method can be used for data obtained by exome and targeted resequencing. We evaluated our outlier-based method in comparison to the CNV calling tool CoNIFER using eight HapMap exome samples and subsequently applied both methods to targeted resequencing data of patients with Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease. In both the HapMap samples and the TOF cases, our method is superior to CoNIFER, such that it identifies more true positive CNVs. Called CNVs in TOF cases were validated by qPCR and HapMap CNVs were confirmed with available array-CGH data. In the TOF patients, we found four copy number gains affecting three genes, of which two are important regulators of heart development (NOTCH1, ISL1) and one is located in a region associated with cardiac malformations (PRODH at 22q11). In summary, we present a novel CNV calling method based on outlier detection, which will be of particular interest for the analysis of de novo or individual CNVs in trios or cohorts up to 30 individuals, respectively. PMID- 24400133 TI - Suppression of the cough reflex by alpha 2-adrenergic receptor agonists in the rabbit. AB - The alpha 2-adrenergic receptor agonist clonidine has been shown to inhibit citric acid-induced cough responses in guinea pigs when administered by aerosol, but not orally. In contrast, oral or inhaled clonidine had no effect on capsaicin induced cough and reflex bronchoconstriction in humans. In addition, intravenous administration of clonidine has been shown to depress fentanyl-induced cough in humans. We investigated the effects of the alpha 2-adrenergic receptor agonists, clonidine and tizanidine, on cough responses induced by mechanical and chemical (citric acid) stimulation of the tracheobronchial tree. Drugs were microinjected (30-50 nL) into the caudal nucleus tractus solitarii (cNTS) and the caudal ventral respiratory group (cVRG) as well as administered intravenously in pentobarbital sodium-anesthetized, spontaneously breathing rabbits. Bilateral microinjections of clonidine into the cNTS or the cVRG reduced cough responses at 0.5 mmol/L and abolished the cough reflex at 5 mmol/L. Bilateral microinjections of 0.5 mmol/L tizanidine into the cNTS completely suppressed cough responses, whereas bilateral microinjections of 5 mmol/L into the cVRG only caused mild reductions in them. Depressant effects on the cough reflex of clonidine and tizanidine were completely reverted by microinjections of 10 mmol/L yohimbine. Intravenous administration of clonidine (80-120 MUg/kg) or tizanidine (150-300 MUg/kg) strongly reduced or completely suppressed cough responses. These effects were reverted by intravenous administration of yohimbine (300 MUg/kg). The results demonstrate that activation of alpha 2-adrenergic receptors in the rabbit exerts potent inhibitory effects on the central mechanism generating the cough motor pattern with a clear action at the level of the cNTS and the cVRG. PMID- 24400134 TI - Posttranslational regulation of tissue inhibitor of metalloproteinase-1 by calcium-dependent vesicular exocytosis. AB - Liver myofibroblasts derived from hepatic stellate cells (HSC) are critical mediators of liver fibrosis. Release of tissue inhibitor of metalloproteinase-1 (TIMP-1) advances liver fibrosis by blocking fibrinolysis. The mechanisms responsible for the posttranslational regulation of TIMP-1 by myofibroblastic HSC are unknown. Here, we demonstrate that TIMP-1 release by HSC is regulated in a posttranslational fashion via calcium-sensitive vesicular exocytosis. To our knowledge, this is the first article to directly examine vesicular trafficking in myofibroblastic HSC, potentially providing a new target to treat and or prevent liver fibrosis. PMID- 24400135 TI - Lysine deacetylase inhibition promotes relaxation of arterial tone and C-terminal acetylation of HSPB6 (Hsp20) in vascular smooth muscle cells. AB - There is increasing interest in establishing the roles that lysine acetylation of non nuclear proteins may exert in modulating cell function. Lysine deacetylase 8 (KDAC8), for example, has been suggested to interact with alpha-actin and control the differentiation of smooth muscle cells. However, a direct role of smooth muscle non nuclear protein acetylation in regulating tone is unresolved. We sought to define the actions of two separate KDAC inhibitors on arterial tone and identify filament-interacting protein targets of acetylation and association with KDAC8. Compound 2 (a specific KDAC8 inhibitor) or Trichostatin A (TSA, a broad spectrum KDAC inhibitor) inhibited rat arterial contractions induced by phenylephrine (PE) or high potassium solution. In contrast to the predominantly nuclear localization of KDAC1 and KDAC2, KDAC8 was positioned in extranuclear areas of native vascular smooth muscle cells. Several filament-associated proteins identified as putative acetylation targets colocalized with KDAC8 by immunoprecipitation (IP): cortactin, alpha-actin, tropomyosin, HSPB1 (Hsp27) and HSPB6 (Hsp20). Use of anti-acetylated lysine antibodies showed that KDAC inhibition increased acetylation of each protein. A custom-made antibody targeting the C-terminal acetylated lysine of human HSPB6 identified this as a novel target of acetylation that was increased by KDAC inhibition. HSPB6 phosphorylation, a known vasodilatory modification, was concomitantly increased. Interrogation of publicly available mass spectrometry data identified 50 other proteins with an acetylated C-terminal lysine. These novel data, in alliance with other recent studies, alert us to the importance of elucidating the mechanistic links between changes in myofilament-associated protein acetylation, in conjunction with other posttranslational modifications, and the regulation of arterial tone. PMID- 24400136 TI - The fetal sheep lung does not respond to cortisol infusion during the late canalicular phase of development. AB - The prepartum surge in plasma cortisol concentrations in humans and sheep promotes fetal lung and surfactant system maturation in the support of air breathing after birth. This physiological process has been used to enhance lung maturation in the preterm fetus using maternal administration of betamethasone in the clinical setting in fetuses as young as 24 weeks gestation (term = 40 weeks). Here, we have investigated the impact of fetal intravenous cortisol infusion during the canalicular phase of lung development (from 109- to 116-days gestation, term = 150 +/- 3 days) on the expression of genes regulating glucocorticoid (GC) activity, lung liquid reabsorption, and surfactant maturation in the very preterm sheep fetus and compared this to their expression near term. Cortisol infusion had no impact on mRNA expression of the corticosteroid receptors (GC receptor and mineralocorticoid receptor) or HSD11B-2, however, there was increased expression of HSD11B-1 in the fetal lung. Despite this, cortisol infusion had no effect on the expression of genes involved in lung sodium (epithelial sodium channel -alpha, -beta, or -gamma subunits and sodium potassium ATPase-beta1 subunit) or water (aquaporin 1, 3, and 5) reabsorption when compared to the level of expression during exposure to the normal prepartum cortisol surge. Furthermore, in comparison to late gestation, cortisol infusion does not increase mRNA expression of surfactant proteins (SFTP-A, -B, and -C) or the number of SFTP-B-positive cells present in the alveolar epithelium, the cells that produce pulmonary surfactant. These data suggest that there may be an age before which the lung is unable to respond biochemically to an increase in fetal plasma cortisol concentrations. PMID- 24400137 TI - Effects of long-term head-down-tilt bed rest and different training regimes on the coagulation system of healthy men. AB - Immobility plus preexisting chronic disease or acute trauma can activate the coagulation system, thus increasing the risk for thromboembolic events. The effects of long-term bed-rest immobility and microgravity on the coagulation system of healthy persons (e.g., during crewed Mars missions) have not yet been studied. The main objective of the second Berlin BedRest Study (BBR2-2) "Coagulation Part" was to investigate adaptations of the hemostatic system during long-term bed rest (60 days) under simulated microgravity (6 degrees head-down tilt [6 degrees HDT]) and after mobilization in three different volunteer groups (randomly assigned to CTR= inactive control group; RE= resistive exercise only group; and RVE= resistive exercise with whole-body vibration group). In 24 males (aged 21-45 years), before, during, and after long-term bed rest, key parameters of coagulation were measured from venous blood samples: D-dimer (DD), thrombin antithrombin III complex (TAT), and prothrombin fragment F1 + 2 (PT-F1 + 2). Additionally, modified rotational thrombelastometry (ROTEM ((r)) ) analysis was performed. Times of exploratory analyses were as follows: baseline data collection 2 days before bed rest (BDC-2); eight different days of 6 degrees HDT bed rest (HDT1-HDT60), and two different days after reambulation (R + 3 and R + 6). We found significant changes in DD, TAT, and PT-F1 + 2 over the total time course, but no consistent effect of physical interventions (RE, RVE) on these parameters. Notably, no parameter reached levels indicative of intravascular thrombin formation. All ROTEM(r) parameters remained within the normal range and no pathological traces were found. Sixty days of 6 degrees HDT bed rest are not associated with pronounced activation of the coagulation system indicative of intravascular thrombus formation in healthy volunteers independent of the training type during the bed rest. PMID- 24400138 TI - The human sodium-dependent ascorbic acid transporters SLC23A1 and SLC23A2 do not mediate ascorbic acid release in the proximal renal epithelial cell. AB - Sodium-dependent ascorbic acid membrane transporters SLC23A1 and SLC23A2 mediate ascorbic acid (vitamin C) transport into cells. However, it is unknown how ascorbic acid undergoes cellular release, or efflux. We hypothesized that SLC23A1 and SLC23A2 could serve a dual role, mediating ascorbic acid cellular efflux as well as uptake. Renal reabsorption is required for maintaining systemic vitamin C concentrations. Because efflux from nephron cells is necessary for reabsorption, we studied whether SLC23A1 and SLC23A2 mediate efflux of ascorbic acid in the human renal nephron. We found high gene expression of SLC23A1 but no expression of SLC23A2 in the proximal convoluted and straight tubules of humans. These data rule out SLC23A2 as the ascorbic acid release protein in the renal proximal tubular epithelia cell. We utilized a novel dual transporter-based Xenopus laevis oocyte system to investigate the function of the SLC23A1 protein, and found that no ascorbate release was mediated by SLC23A1. These findings were confirmed in mammalian cells overexpressing SLC23A1. Taken together, the data for SLC23A1 show that it too does not have a role in cellular release of ascorbic acid across the basolateral membrane of the proximal tubular epithelial cell, and that SLC23A1 alone is responsible for ascorbic acid uptake across the apical membrane. These findings reiterate the physiological importance of proper functioning of SLC23A1 in maintaining vitamin C levels for health and disease prevention. The ascorbate efflux mechanism in the proximal tubule of the kidney remains to be characterized. PMID- 24400139 TI - Mycophenolate mofetil prevents high-fat diet-induced hypertension and renal glomerular injury in Dahl SS rats. AB - We designed experiments to test the hypothesis that Dahl salt-sensitive (SS) rats are sensitive to high-fat diet (HFD)-induced hypertension and renal injury via an inflammatory mechanism. Twelve-week-old Dahl SS rats were maintained on a normal diet (ND; 14% fat), HFD (59% fat), or HFD supplemented with the lymphocyte immunosuppressive agent, mycophenolate mofetil (HFD + MMF; 30 mg/kg/day orally in diet), for a period of 4 weeks. Mean arterial pressure (MAP), metabolic parameters, T lymphocyte (CD3(+)) localization, and renal structural damage were assessed during the studies. Four weeks of HFD significantly elevated MAP and visceral adiposity without changing circulating levels of lipids or adipokines. Immunohistochemical analysis demonstrated that SS rats on HFD had significantly greater numbers of CD3(+) cells in renal glomerular and medullary areas compared to ND SS rats. Additionally, HFD led to increased glomerular injury, but did not alter renal medullary injury. Chronic MMF treatment in HFD-fed Dahl SS rats reduced MAP, visceral adiposity, infiltration of CD3(+) cells in the glomerulus, as well as glomerular injury. However, MMF treatment did not alter HFD-induced infiltration of CD3(+) cells in the renal medulla. In conclusion, Dahl SS rats are sensitized to HFD-induced hypertension and renal glomerular injury via infiltration of T lymphocytes. PMID- 24400140 TI - Abnormal tracheal smooth muscle function in the CF mouse. AB - Increased airway smooth muscle (ASM) contractility is thought to underlie symptoms of airway hyperresponsiveness (AHR). In the cystic fibrosis (CF) airway, ASM anomalies have been reported, but have not been fully characterized and the underlying mechanisms are largely unknown. We examined ASM in an adult CF mouse tracheal ring preparation, and determined whether changes in contractility were associated with altered ASM morphology. We looked for inherent changes in the cellular pathways involved in contractility, and characterized trachea morphology in the adult trachea and in an embryonic lung culture model during development. Results showed that that there was a reduction in tracheal caliber in CF mice as indicated by a reduction in the number of cartilage rings; proximal cross sectional areas of cftr (-/-) tracheas and luminal areas were significantly smaller, but there was no difference in the area or distribution of smooth muscle. Morphological differences observed in adult trachea were not evident in the embryonic lung at 11.5 days gestation or after 72 h in culture. Functional data showed a significant reduction in the amplitude and duration of contraction in response to carbachol (CCh) in Ca-free conditions. The reduction in contraction was agonist specific, and occurred throughout the length of the trachea. These data show that there is a loss in the contractile capacity of the CF mouse trachea due to downregulation of the pathway specific to acetylcholine (ACh) activation. This reduction in contraction is not associated with changes in the area or distribution of ASM. PMID- 24400141 TI - Subject-specific measures of Achilles tendon moment arm using ultrasound and video-based motion capture. AB - THE ACHILLES TENDON (AT) MOMENT ARM IS AN IMPORTANT BIOMECHANICAL PARAMETER MOST COMMONLY ESTIMATED USING ONE OF TWO METHODS: (A) center of rotation and (B) tendon excursion. Conflicting findings regarding magnitude and whether it changes with contraction intensity have been reported when using these methods. In this study, we present an alternate method of measuring the AT moment arm by combining ultrasound and video-based motion capture. Moment arms for 10 healthy male subjects were measured at five different joint angles in 10 degrees increments ranging from 20 degrees of dorsiflexion (DF) to 20 degrees of plantar flexion (PF). Moment arms were measured at rest and also during maximum voluntary contraction (MVC). For both conditions, the AT moment arm increased in magnitude as the ankle moved from DF to PF. In 20 degrees of DF, the moment arm at rest averaged 34.6 +/- 1.8 mm and increased to a maximum value of 36.9 +/- 1.9 mm when plantar flexed to 10 degrees . Moment arms during MVC ranged from 35.7 +/- 1.8 mm to 38.1 +/- 2.6 mm. The moment arms we obtained were much more consistent with literature values derived using ultrasound and tendon excursion compared to center of rotation or in vitro methods. This is noteworthy as the hybrid method is easy to implement and as it is less costly and timing consuming than other methods, including tendon excursion, it is well suited for large-scale studies involving many subjects. PMID- 24400142 TI - The truncated splice variants, NT-PGC-1alpha and PGC-1alpha4, increase with both endurance and resistance exercise in human skeletal muscle. AB - Recently, a truncated peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha) splice variant, PGC-1alpha4, that originates from the alternative promoter was shown to be induced by resistance exercise and to elicit muscle hypertrophy without coactivation of "classical" PGC-1alpha targets involved in mitochondrial biogenesis and angiogenesis. In order to test if distinct physiological adaptations are characterized by divergent induction of PGC-1alpha splice variants, we investigated the expression of truncated and nontruncated PGC-1alpha splice variants and PGC-1alpha transcripts originating from the alternative and the proximal promoter, in human skeletal muscle in response to endurance and resistance exercise. Both total PGC-1alpha and truncated PGC-1alpha mRNA expression were increased 2 h after endurance (P < 0.01) and resistance exercise (P < 0.01), with greater increases after endurance exercise (P < 0.05). Expression of nontruncated PGC-1alpha increased significantly in both exercise groups (P < 0.01 for both groups) without any significant differences between the groups. Both endurance and resistance exercise induced truncated as well as nontruncated PGC-1alpha transcripts from both the alternative and the proximal promoter. Further challenging the hypothesis that induction of distinct PGC-1alpha splice variants controls exercise adaptation, both nontruncated and truncated PGC-1alpha transcripts were induced in AICAR-treated human myotubes (P < 0.05). Thus, contrary to our hypothesis, resistance exercise did not specifically induce the truncated forms of PGC-1alpha. Induction of truncated PGC-1alpha splice variants does not appear to underlie distinct adaptations to resistance versus endurance exercise. Further studies on the existence of numerous splice variants originating from different promoters are needed. PMID- 24400143 TI - Bilateral sectioning of the anterior ethmoidal nerves does not eliminate the diving response in voluntarily diving rats. AB - The diving response is characterized by bradycardia, apnea, and increased peripheral resistance. This reflex response is initiated by immersing the nose in water. Because the anterior ethmoidal nerve (AEN) innervates the nose, our hypothesis was that intact AENs are essential for initiating the diving response in voluntarily diving rats. Heart rate (HR) and arterial blood pressure (BPa) were monitored using implanted biotransmitters. Sprague-Dawley rats were trained to voluntarily swim 5 m underwater. During diving, HR decreased from 480 +/- 15 to 99 +/- 5 bpm and BPa increased from 136 +/- 2 to 187 +/- 3 mmHg. Experimental rats (N = 9) then received bilateral AEN sectioning, while Sham rats (N = 8) did not. During diving in Experimental rats 7 days after AEN surgery, HR decreased from 478 +/- 13 to 76 +/- 4 bpm and BPa increased from 134 +/- 3 to 186 +/- 4 mmHg. Responses were similar in Sham rats. Then, during nasal stimulation with ammonia vapors in urethane-anesthetized Experimental rats, HR decreased from 368 +/- 7 to 83 +/- 4 bpm, and BPa increased from 126 +/- 7 to 175 +/- 4 mmHg. Responses were similar in Sham rats. Thus, 1 week after being sectioned the AENs are not essential for initiating a full cardiorespiratory response during both voluntary diving and nasal stimulation. We conclude that other nerve(s) innervating the nose are able to provide an afferent signal sufficient to initiate the diving response, although neuronal plasticity within the medullary dorsal horn may be necessary for this to occur. PMID- 24400144 TI - Effect of decompression-induced bubble formation on highly trained divers microvascular function. AB - We previously showed microvascular alteration of both endothelium-dependent and independent reactivity after a single SCUBA dive. We aimed to study mechanisms involved in this postdive vascular dysfunction. Ten divers each completed three protocols: (1) a SCUBA dive at 400 kPa for 30 min; (2) a 41-min duration of seawater surface head immersed finning exercise to determine the effect of immersion and moderate physical activity; and (3) a simulated 41-min dive breathing 100% oxygen (hyperbaric oxygen [HBO]) at 170 kPa in order to analyze the effect of diving-induced hyperoxia. Bubble grades were monitored with Doppler. Cutaneous microvascular function was assessed by laser Doppler. Endothelium-dependent (acetylcholine, ACh) and -independent (sodium nitroprusside, SNP) reactivity was tested by iontophoresis. Endothelial cell activation was quantified by plasma Von Willebrand factor and nitric oxide (NO). Inactivation of NO by oxidative stress was assessed by plasma nitrotyrosine. Platelet factor 4 (PF4) was assessed in order to determine platelet aggregation. Blood was also analyzed for measurement of platelet count. Cutaneous vascular conductance (CVC) response to ACh delivery was not significantly decreased by the SCUBA protocol (23 +/- 9% before vs. 17 +/- 7% after; P = 0.122), whereas CVC response to SNP stimulation decreased significantly (23 +/- 6% before vs. 10 +/- 1% after; P = 0.039). The HBO and immersion protocols did not affect either endothelial-dependent or -independent function. The immersion protocol induced a significant increase in NO (0.07 +/- 0.01 vs. 0.12 +/- 0.02 MUg/mL; P = 0.035). This study highlighted change in microvascular endothelial-independent but not dependent function in highly trained divers after a single air dive. The results suggest that the effects of decompression on microvascular function may be modified by diving acclimatization. PMID- 24400145 TI - Multimodal imaging reveals a role for Akt1 in fetal cardiac development. AB - Even though congenital heart disease is the most prevalent malformation, little is known about how mutations affect cardiovascular function during development. Akt1 is a crucial intracellular signaling molecule, affecting cell survival, proliferation, and metabolism. The aim of this study was to determine the role of Akt1 on prenatal cardiac development. In utero echocardiography was performed in fetal wild-type, heterozygous, and Akt1-deficient mice. The same fetal hearts were imaged using ex vivo micro-computed tomography (MUCT) and histology. Neonatal hearts were imaged by in vivo magnetic resonance imaging. Additional ex vivo neonatal hearts were analyzed using histology and real-time PCR of all three groups. In utero echocardiography revealed abnormal blood flow patterns at the mitral valve and reduced contractile function of Akt1 null fetuses, while ex vivo MUCT and histology unraveled structural alterations such as dilated cardiomyopathy and ventricular septum defects in these fetuses. Further histological analysis showed reduced myocardial capillaries and coronary vessels in Akt1 null fetuses. At neonatal age, Akt1-deficient mice exhibited reduced survival with reduced endothelial cell density in the myocardium and attenuated cardiac expression of vascular endothelial growth factor A and collagen Ialpha1. To conclude, this study revealed a central role of Akt1 in fetal cardiac function and myocardial angiogenesis inducing fetal cardiomyopathy and reduced neonatal survival. This study links a specific physiological phenotype with a defined genotype, namely Akt1 deficiency, in an attempt to pinpoint intrinsic causes of fetal cardiomyopathies. PMID- 24400146 TI - Concurrent muscle and bone deterioration in a murine model of cancer cachexia. AB - Cachexia is defined as an excessive, involuntary loss of fat and lean tissue. We tested the validity of the Lewis lung carcinoma (LLC) as a model of cancer cachexia and examined its effect on the two major lean tissue components, skeletal muscle and bone. LLC cells (0.75 * 10(6)) were injected into the left thigh of C57BL/6 mice. Control mice received an equal volume injection of growth media. Tumors were observed in all LLC-injected animals 21 and 25 days post inoculation. LLC-injected animals showed significant reductions in fat and lean mass despite having the same average daily caloric intake as media-treated mice. Global bone mineral density (BMD) had fallen by 5% and 6% in the LLC animals at 21 and 25 days, respectively, compared to a BMD increase of 5% in the 25-day media-treated animals. Extensor digitorum longus (EDL) muscles (isolated from the noninjected hindlimb) showed earlier and quantitatively greater losses in mass, physiological cross-sectional area (pCSA), and tetanic force compared to soleus muscles from the same hindlimb. By the 25th day post-LLC inoculation, EDL force/pCSA was reduced by 19% versus media treatment. This loss in specific force was not trivial as it accounted for about one-third of the reduction in EDL absolute force at this time point. Muscle strips dissected from the diaphragm of LLC mice also exhibited significant reductions in force/pCSA at day 25. We conclude that LLC is a valid model of cachexia that induces rapid losses in global BMD and in limb and respiratory muscle function. PMID- 24400147 TI - Differential regulation of nitric oxide synthase function in aorta and tail artery from 5/6 nephrectomized rats. AB - Chronic renal failure (CRF) is associated with hypertension and concomitant endothelial dysfunction, enhanced vasoconstriction, and nitric oxide synthase (NOS) dysfunction. Vascular function in patients is assessed in peripheral extremity arteries like the finger arteries, whereas animal studies often use the centrally located aorta. Therefore, we examined whether peripheral tail artery and aortic NOS function are differentially regulated by blood pressure in rats with CRF. Using wire myography, arterial function was assessed in 16-week-old Sprague-Dawley rats that were subjected to 5/6 nephrectomy (Nx; arterial ligation model) 8 weeks earlier or non-Nx (control) rats. In aortas from Nx rats, endothelial-dependent vasorelaxation response to acetylcholine (ACh) was blunted and there was enhancement of phenylephrine (PE)-mediated vasoconstriction. Inversely, tail arteries from Nx rats had no change in endothelial function and reduced response to PE. Studies where arterial segments were incubated with the nonspecific NOS inhibitor, L-NAME, showed that Nx reduced NOS function in the aorta but increased NOS function in tail artery for both ACh and PE responses. Furthermore, the observed alterations in NOS function in both aorta and tail artery were abolished when mean arterial blood pressure, as assessed by telemetry, was maintained at normal levels in the 5/6 Nx rats using triple therapy: hydralazine (30 mg/kg per day), hydrochlorothiazide (10 mg/kg per day), and reserpine (0.5 mg/kg per day). In conclusion, differential changes of NOS function in central versus peripheral arteries in CRF are dependent upon hypertension. PMID- 24400148 TI - Vascular effects of deletion of melanocortin-4 receptors in rats. AB - Obesity is a major cause of hypertension, but links between the obese and hypertensive states remain incompletely understood. A major component of cardiovascular function in obese individuals is a state of sympathoactivation. A postulated mechanism of this sympathoactivation is the activation of specific classes of neurons commonly associated with metabolic control, which also affect sympathetic outflow to cardiovascular targets. One class of neurons is characterized by expression of melanocortin-4 receptors (MC4R) which are activated by metabolic signals such as leptin and insulin. In this study, we examined the effects of deletion of MC4R in a novel rat model. MC4R knockout (KO) rats are obese and profoundly insulin resistant without frank diabetes. Despite these conditions, MC4R KO rats are normotensive. Moderate bradycardia and significant increases in peripheral resistance were evident in MC4R KO rats. To determine if the dissociation between hypertension and obesity was associated with changes in vascular function, in vitro reactivity to vasoactive agents and in vivo reactivity to sympathetic blockade were examined. Vasodilator function was not affected by obesity in MC4R KO rats. Reactivity to phenylephrine was reduced, suggesting desensitization of adrenergic signaling. In response to ganglionic blockade with mecamylamine, blood pressure and hindlimb resistance fell more in MC4R KO rats, suggesting that sympathoactivation of the vascular was still evident, despite the absence of hypertension. These findings suggest that obesity causes sympathoactivation of the vasculature despite the absence of MC4R. Dissociation of obesity from hypertension in this model may reflect more renal mechanisms of blood pressure control. PMID- 24400149 TI - Interaponeurosis shear strain modulates behavior of myotendinous junction of the human triceps surae. AB - Muscle fascicles insert into a sheet-like aponeurosis. Adjacent aponeuroses are structurally in contact with each other, and ultimately merge into a common tendon. Consequently, fascicle shortening in planes of tissue layers in adjacent compartments must cause sliding between aponeuroses parallel to the acting forces. In this study, we used velocity-encoded, phase-contrast, and water saturated spin-lattice relaxation time-weighted imaging to identify and track fascicle and aponeurosis behaviors of human medial gastrocnemius (MG) and soleus (Sol) during 15 degrees dorsiflexion to 30 degrees plantarflexion contractions of the ankle. Interaponeurosis shear strain, which was defined as the relative displacement of the aponeurosis at the fascicle end points (insertion) of the MG and Sol, was an average of 1.35 +/- 0.27% (range 1.12 ~ 1.87%), indicating that the strain is greater in the aponeurosis of MG fascicle insertion than the Sol. The myotendinous junction (MTJ) displacement increased significantly with decreasing interaponeurosis shear strain (P < 0.05). The magnitude of interaponeurosis shear strain had significant correlation with the temporal difference between the time at which the peak aponeurosis displacement of the MG and Sol occurred (P < 0.05). Our model also indicated that theoretical MTJ displacement varies in relation to temporal difference: no temporal difference caused the largest MTJ displacement and presence of temporal differences indicated a reduction in MTJ displacement. Therefore, we concluded that interaponeurosis shear strain is a mechanism enabling individual muscle contraction and thus specific loading of the tendon and joint. PMID- 24400150 TI - Multiple mechanisms underlying rectification in retinal cyclic nucleotide-gated (CNGA1) channels. AB - In cyclic nucleotide-gated (CNGA1) channels, in the presence of symmetrical ionic conditions, current-voltage (I-V) relationship depends, in a complex way, on the radius of permeating ion. It has been suggested that both the pore and S4 helix contribute to the observed rectification. In the present manuscript, using tail and gating current measurements from homotetrameric CNGA1 channels expressed in Xenopus oocytes, we clarify and quantify the role of the pore and of the S4 helix. We show that in symmetrical Rb(+) and Cs(+) single-channel current rectification dominates macroscopic currents while voltage-dependent gating becomes larger in symmetrical ethylammonium and dimethylammonium, where the open probability strongly depends on voltage. Isochronal tail currents analysis in dimethylammonium shows that at least two voltage-dependent transitions underlie the observed rectification. Only the first voltage-dependent transition is sensible to mutation of charge residues in the S4 helix. Moreover, analysis of tail and gating currents indicates that the number of elementary charges per channel moving across the membrane is less than 2, when they are about 12 in K(+) channels. These results indicate the existence of distinct mechanisms underlying rectification in CNG channels. A restricted motion of the S4 helix together with an inefficient coupling to the channel gate render CNGA1 channels poorly sensitive to voltage in the presence of physiological Na(+) and K(+). PMID- 24400151 TI - Interleukin-10 protects against aging-induced endothelial dysfunction. AB - Carotid and cerebrovascular disease increase markedly with age contributing to stroke and cognitive impairment. Inflammation is a key element of vascular disease. In these studies, we tested the hypothesis that interleukin-10 (IL-10), a potent anti-inflammatory cytokine, protects against aging-induced endothelial dysfunction. Responses of carotid arteries from adult (5 +/- 1 months) and old (22 +/- 1 months) wild-type and IL-10-deficient mice were examined in vitro. Acetylcholine (an endothelium-dependent agonist) produced relaxation in arteries from adult wild-type that was not altered in old mice. In contrast, relaxation to acetylcholine in arteries from old IL-10-deficient mice was reduced by ~50% (P < 0.05). Tempol, a scavenger of superoxide, did not affect responses in adult or old wild-type mice, but restored vasodilation to acetylcholine to normal in old IL-10-deficient mice. Responses of the carotid artery to nitroprusside (an endothelium-independent agonist) were not altered in any group. Vascular expression of IL-6 (a proinflammatory mediator of vascular disease) and components of NADPH oxidase (a major source of superoxide) was increased in old IL-10-deficient mice compared with wild-type (P < 0.05). These findings provide the first evidence that age-related and superoxide-mediated endothelial dysfunction occurs earlier with IL-10 deficiency. Our findings suggest a novel role for IL-10 to protect against age-related increases in expression of IL-6, oxidative stress, and endothelial dysfunction. PMID- 24400152 TI - Validation of SenseWear Armband and ActiHeart monitors for assessments of daily energy expenditure in free-living women with chronic obstructive pulmonary disease. AB - To provide individually adapted nutritional support to patients with chronic obstructive pulmonary disease (COPD), objective and reliable methods must be used to assess patient energy requirements. The aim of this study was to validate the use of SenseWear Armband (SWA) and ActiHeart (AH) monitors for assessing total daily energy expenditure (TEE) and activity energy expenditure (AEE) and compare these techniques with the doubly labeled water (DLW) method in free-living women with COPD. TEE and AEE were measured in 19 women with COPD for 14 days using SWAs with software version 5.1 (TEESWA5, AEESWA5) or 6.1 (TEESWA6, AEESWA6) and AH monitors (TEEAH, AEEAH), using DLW (TEEDLW) as the criterion method. The three methods were compared using intraclass correlation coefficient (ICC) and Bland Altman analyses. The mean TEE did not significantly differ between the DLW and SWA5.1 methods (-21 +/- 726 kJ/day; P = 0.9), but it did significantly differ between the DLW and SWA6.1 (709 +/- 667 kJ/day) (P < 0.001) and the DLW and AH methods (709 +/- 786 kJ/day) (P < 0.001). Strong agreement was observed between the DLW and TEESWA5 methods (ICC = 0.76; 95% CI 0.47-0.90), with moderate agreements between the DLW and TEESWA6 (ICC = 0.66; 95% CI 0.02-0.88) and the DLW and TEEAH methods (ICC = 0.61; 95% CI 0.05-0.85). Compared with the DLW method, the SWA5.1 underestimated AEE by 12% (P = 0.03), whereas the SWA6.1 and AH monitors underestimated AEE by 35% (P < 0.001). Bland-Altman plots revealed no systematic bias for TEE or AEE. The SWA5.1 can reliably assess TEE in women with COPD. However, the SWA6.1 and AH monitors underestimate TEE. The SWA and AH monitors underestimate AEE. PMID- 24400153 TI - Cardioprotective effects of angiotensin III against ischemic injury via the AT2 receptor and KATP channels. AB - Angiotensin III (Ang III) has similar effects on blood pressure and aldosterone secretion as Ang II, but cardioprotective effects are also proposed. In this study, we investigated whether Ang III protects the heart against ischemia/reperfusion (I/R) injury. After sacrificing Sprague-Dawley rats, the hearts were perfused with Krebs-Henseleit buffer for a 20 min preischemic period with and without Ang III followed by 20-min global ischemia and 50-min reperfusion. Pretreatment with Ang III (1 MUmol/L) improved an increased postischemic left ventricular end-diastolic pressure (LVEDP) and a decreased postischemic left ventricular developed pressure (LVDP) induced by reperfusion compared to untreated hearts. Ang III markedly decreased infarct size and lactate dehydrogenase levels in effluent during reperfusion. Ang III increased coronary flow and the concentrations of atrial natriuretic peptide in coronary effluent during reperfusion. Pretreatment with Ang II type 2 receptor (AT2R) antagonist or ATP-sensitive K(+) channel (KATP) blocker for 15 min before ischemia attenuated the improvement of LVEDP, LVDP, and +/-dP/dt induced by Ang III. Ang III treatment increased Mn-superoxide dismutase, catalase, and heme oxygenase-1 protein levels, which was attenuated by pretreatment with AT2R antagonist or KATP blocker. Ang III treatment also decreased Bax, caspase-3, and caspase-9 protein levels, and increased Bcl-2 protein level, which were attenuated by pretreatment with AT2R antagonist or KATP blocker. These results suggest that the cardioprotective effects of Ang III against I/R injury may be partly related to activating antioxidant and antiapoptotic enzymes via AT2R and KATP channels. PMID- 24400154 TI - The effects of exercise on dynamic sleep morphology in healthy controls and patients with chronic fatigue syndrome. AB - Effects of exercise on dynamic aspects of sleep have not been studied. We hypothesized exercise altered dynamic sleep morphology differently for healthy controls relative to chronic fatigue syndrome (CFS) patients. Sixteen controls (38 +/- 9 years) and 17 CFS patients (41 +/- 8 years) underwent polysomnography on baseline nights and nights after maximal exercise testing. We calculated transition probabilities and rates (as a measure of relative and temporal transition frequency, respectively) between sleep stages and cumulative duration distributions (as a measure of continuity) of each sleep stage and sleep as a whole. After exercise, controls showed a significantly greater probability of transition from N1 to N2 and a lower rate of transition from N1 to wake than at baseline; CFS showed a significantly greater probability of transition from N2 to N3 and a lower rate of transition from N2 to N1. These findings suggest improved quality of sleep after exercise. After exercise, controls had improved sleep continuity, whereas CFS had less continuous N1 and more continuous rapid eye movement (REM) sleep. However, CFS had a significantly greater probability and rate of transition from REM to wake than controls. Probability of transition from REM to wake correlated significantly with increases in subjective fatigue, pain, and sleepiness overnight in CFS - suggesting these transitions may relate to patient complaints of unrefreshing sleep. Thus, exercise promoted transitions to deeper sleep stages and inhibited transitions to lighter sleep stages for controls and CFS, but CFS also reported increased fatigue and continued to have REM sleep disruption. This dissociation suggests possible mechanistic pathways for the underlying pathology of CFS. PMID- 24400155 TI - Heparanase mediates renal dysfunction during early sepsis in mice. AB - Heparanase, a heparan sulfate-specific glucuronidase, mediates the onset of pulmonary neutrophil adhesion and inflammatory lung injury during early sepsis. We hypothesized that glomerular heparanase is similarly activated during sepsis and contributes to septic acute kidney injury (AKI). We induced polymicrobial sepsis in mice using cecal ligation and puncture (CLP) in the presence or absence of competitive heparanase inhibitors (heparin or nonanticoagulant N-desulfated re N-acetylated heparin [NAH]). Four hours after surgery, we collected serum and urine for measurement of renal function and systemic inflammation, invasively determined systemic hemodynamics, harvested kidneys for histology/protein/mRNA, and/or measured glomerular filtration by inulin clearance. CLP-treated mice demonstrated early activation of glomerular heparanase with coincident loss of glomerular filtration, as indicated by a >twofold increase in blood urea nitrogen (BUN) and a >50% decrease in inulin clearance (P < 0.05) in comparison to sham mice. Administration of heparanase inhibitors 2 h prior to CLP attenuated sepsis induced loss of glomerular filtration rate, demonstrating that heparanase activation contributes to early septic renal dysfunction. Glomerular heparanase activation was not associated with renal neutrophil influx or altered vascular permeability, in marked contrast to previously described effects of pulmonary heparanase on neutrophilic lung injury during sepsis. CLP induction of renal inflammatory gene (IL-6, TNF-alpha, IL-1beta) expression was attenuated by NAH pretreatment. While serum inflammatory indices (KC, IL-6, TNF-alpha, IL-1beta) were not impacted by NAH pretreatment, heparanase inhibition attenuated the CLP induced increase in serum IL-10. These findings demonstrate that glomerular heparanase is active during sepsis and contributes to septic renal dysfunction via mechanisms disparate from heparanase-mediated lung injury. PMID- 24400156 TI - Renal vasoconstriction is augmented during exercise in patients with peripheral arterial disease. AB - Peripheral arterial disease (PAD) patients have augmented blood pressure increases during exercise, heightening their cardiovascular risk. However, it is unknown whether patients have exaggerated renal vasoconstriction during exercise and if oxidative stress contributes to this response. Eleven PAD patients and 10 controls (CON) performed 4-min mild, rhythmic, plantar flexion exercise of increasing intensity (0.5-2 kg) with each leg (most and least affected in PAD). Eight patients also exercised with their most affected leg during ascorbic acid (AA) infusion. Renal blood flow velocity (RBFV; Doppler ultrasound), mean arterial blood pressure (MAP; Finometer), and heart rate (HR; electrocardiogram [ECG]) were measured. Renal vascular resistance (RVR), an index of renal vasoconstriction, was calculated as MAP/RBFV. Baseline RVR and MAP were similar while HR was higher in PAD than CON (2.08 +/- 0.23 vs. 1.87 +/- 0.20 au, 94 +/- 3 vs. 93 +/- 3 mmHg, and 72 +/- 3 vs. 59 +/- 3 bpm [P < 0.05] for PAD and CON, respectively). PAD had greater RVR increases during exercise than CON, specifically during the first minute (PAD most: 26 +/- 5% and PAD least: 17 +/- 5% vs. CON: 3 +/- 3%; P < 0.05). AA did not alter baseline RVR, MAP, or HR. AA attenuated the augmented RVR increase in PAD during the first minute of exercise (PAD most: 33 +/- 4% vs. PAD most with AA: 21 +/- 4%; P < 0.05). In conclusion, these findings suggest that PAD patients have augmented renal vasoconstriction during exercise, with oxidative stress contributing to this response. PMID- 24400157 TI - Renal effects of a novel endogenous natriuretic agent xanthurenic acid 8-o-beta-d glucoside in rats. AB - Xanthurenic acid 8-o-beta-d-glucoside is an endogenous derivative of tryptophan metabolism, isolated from urine of patients with chronic renal disease. This compound was suggested previously to act as a natriuretic hormone based on its ability to block short circuit currents in a frog skin assay and to induce a sustained natriuresis when injected into rats (C. D. Cain et al., Proc. Natl. Acad. Sci. USA 2007: 17873-17878). The present communication describes the effects of the compound on renal clearance and hemodynamic parameters in male Sprague-Dawley rats maintained on a normal salt (0.4-0.5%) diet. Intravenous administration of synthetic xanthurenic acid 8-o-beta-d-glucoside in two consecutive incremental doses (6.3 and 31.5 nmol) resulted in a significant increase (P < 0.05), in urine flow (43.91 +/- 6.31 MUL/min vs. 10.54 +/- 2.21 MUL/min), absolute rate of sodium excretion (3.99 +/- 0.95 MUEq/min vs. 1.15 +/- MUEq/min), and percentage sodium excretion (1.63 +/- 0.46% vs. 0.37 +/- 0.12%, peak response vs. baseline, respectively). The natriuretic/diuretic effect was associated also with a significant increase in potassium excretion. These effects were not related to changes in renal hemodynamics or in arterial blood pressure. Pretreatment with the sodium channel blocker, amiloride, completely abolished the natriuretic and kaluretic actions of the compound. Administration of the xanthurenic acid derivative caused a dose-related increase in urinary nitrite/nitrate excretion. Moreover, under chronic nitric oxide blockade by l-NG Nitro-Arginine-Methyl-Esther (l-NAME) sodium excretion was similar in rats treated or untreated with the compound. Our data demonstrate that xanthurenic acid 8-o-beta-d-glucoside has significant diuretic/natriuretic and kaluretic properties. An intact amiloride-sensitive sodium channel is required for the renal effects of the compound. The data further suggest that the natriuretic effect is mediated in part by a nitric oxide-dependent mechanism. PMID- 24400158 TI - Maternal-to-fetal allopurinol transfer and xanthine oxidase suppression in the late gestation pregnant rat. AB - Fetal brain hypoxic injury remains a concern in high-risk delivery. There is significant clinical interest in agents that may diminish neuronal damage during birth asphyxia, such as in allopurinol, an inhibitor of the prooxidant enzyme xanthine oxidase. Here, we established in a rodent model the capacity of allopurinol to be taken up by the mother, cross the placenta, rise to therapeutic levels, and suppress xanthine oxidase activity in the fetus. On day 20 of pregnancy, Wistar dams were given 30 or 100 mg kg(-1) allopurinol orally. Maternal and fetal plasma allopurinol and oxypurinol concentrations were measured, and xanthine oxidase activity in the placenta and maternal and fetal tissues determined. There were significant strong positive correlations between maternal and fetal plasma allopurinol (r = 0.97, P < 0.05) and oxypurinol (r = 0.88, P < 0.05) levels. Under baseline conditions, maternal heart (2.18 +/- 0.62 mU mg(-1)), maternal liver (0.29 +/- 0.08 mU mg(-1)), placenta (1.36 +/- 0.42 mU mg(-1)), fetal heart (1.64 +/- 0.59 mU mg(-1)), and fetal liver (0.14 +/- 0.08 mU mg(-1)) samples all showed significant xanthine oxidase activity. This activity was suppressed in all tissues 2 h after allopurinol administration and remained suppressed 24 h later (P < 0.05), despite allopurinol and oxypurinol levels returning toward baseline. The data establish a mammalian model of xanthine oxidase inhibition in the mother, placenta, and fetus, allowing investigation of the role of xanthine oxidase-derived reactive oxygen species in the maternal, placental, and fetal physiology during healthy and complicated pregnancy. PMID- 24400159 TI - Temperature and transmural region influence functional measurements in unloaded left ventricular cardiomyocytes. AB - Intact cardiomyocytes are increasingly being used to investigate the molecular mechanisms of contraction and to screen new therapeutic compounds. The function of the cardiomyocytes is often measured from the calcium transients and sarcomere length profiles. We studied the role of experimental temperature and transmural region on indices of function in freshly isolated, unloaded cardiomyocytes. Intact cardiomyocytes were isolated from the subendocardium, midmyocardium, and subepicardium of 3-month-old Sprague-Dawley rats. Myocytes from each region were studied at 25 degrees C, 31 degrees C, and 37 degrees C. Cytosolic calcium transients were measured using Fura-2 fluorescence, whereas sarcomere length shortening and relengthening profiles were measured using high-speed video capture. For both the calcium transients and sarcomere length profiles, the time to peak and the time to half relaxation decreased significantly with increasing temperature. Increasing temperature also raised the minimum and maximum calcium levels of all cells. Of note, there was a reduced coefficient of variation (standard deviation divided by the mean) at higher temperatures for calcium fluorescence amplitudes, time to peak calcium, and rates of sarcomeric shortening and relengthening. The amplitudes and minimum of the calcium transients were significantly dependent on transmural region, and several sarcomere length parameters exhibited statistical interactions between temperature and transmural region. Together, these results show that biological variability can be reduced by performing experiments at 37 degrees C rather than at room temperature, and by isolating cells from a specific transmural region. Adopting these procedures will improve the statistical power of subsequent analyses and increase the efficiency of future experiments. PMID- 24400160 TI - Cardiac power integral: a new method for monitoring cardiovascular performance. AB - Cardiac power (PWR) is the continuous product of flow and pressure in the proximal aorta. Our aim was to validate the PWR integral as a marker of left ventricular energy transfer to the aorta, by comparing it to stroke work (SW) under multiple different loading and contractility conditions in subjects without obstructions in the left ventricular outflow tract. Six pigs were under general anesthesia equipped with transit time flow probes on their proximal aortas and Millar micromanometer catheters in their descending aortas to measure PWR, and Leycom conductance catheters in their left ventricles to measure SW. The PWR integral was calculated as the time integral of PWR per cardiac cycle. SW was calculated as the area encompassed by the pressure-volume loop (PV loop). The relationship between the PWR integral and SW was tested during extensive mechanical and pharmacological interventions that affected the loading conditions and myocardial contractility. The PWR integral displayed a strong correlation with SW in all pigs (R (2) > 0.95, P < 0.05) under all conditions, using a linear model. Regression analysis and Bland Altman plots also demonstrated a stable relationship. A mixed linear analysis indicated that the slope of the SW-to-PWR integral relationship was similar among all six animals, whereas loading and contractility conditions tended to affect the slope. The PWR integral followed SW and appeared to be a promising parameter for monitoring the energy transferred from the left ventricle to the aorta. This conclusion motivates further studies to determine whether the PWR integral can be evaluated using less invasive methods, such as echocardiography combined with a radial artery catheter. PMID- 24400161 TI - Identification of compound heterozygous KCNJ1 mutations (encoding ROMK) in a kindred with Bartter's syndrome and a functional analysis of their pathogenicity. AB - A multiplex family was identified with biochemical and clinical features suggestive of Bartter's syndrome (BS). The eldest sibling presented with developmental delay and rickets at 4 years of age with evidence of hypercalciuria and hypokalemia. The second sibling presented at 1 year of age with urinary tract infections, polyuria, and polydipsia. The third child was born after a premature delivery with a history of polyhydramnios and neonatal hypocalcemia. Following corrective treatment she also developed hypercalciuria and a hypokalemic metabolic alkalosis. There was evidence of secondary hyperreninemia and hyperaldosteronism in all three siblings consistent with BS. Known BS genes were screened and functional assays of ROMK (alias KCNJ1, Kir1.1) were carried out in Xenopus oocytes. We detected compound heterozygous missense changes in KCNJ1, encoding the potassium channel ROMK. The S219R/L220F mutation was segregated from father and mother, respectively. In silico modeling of the missense mutations suggested deleterious changes. Studies in Xenopus oocytes revealed that both S219R and L220F had a deleterious effect on ROMK-mediated potassium currents. Coinjection to mimic the compound heterozygosity produced a synergistic decrease in channel function and revealed a loss of PKA-dependent stabilization of PIP2 binding. In conclusion, in a multiplex family with BS, we identified compound heterozygous mutations in KCNJ1. Functional studies of ROMK confirmed the pathogenicity of these mutations and defined the mechanism of channel dysfunction. PMID- 24400162 TI - Axonal projections of Renshaw cells in the thoracic spinal cord. AB - Renshaw cells are widely distributed in all segments of the spinal cord, but detailed morphological studies of these cells and their axonal branching patterns have only been made for lumbosacral segments. For these, a characteristic distribution of terminals was reported, including extensive collateralization within 1-2 mm of the soma, but then more restricted collaterals given off at intervals from the funicular axon. Previous authors have suggested that the projections close to the soma serve inhibition of motoneurons (known to be greatest for the motor nuclei providing the Renshaw cell excitation) but that the distant projections serve mainly the inhibition of other neurons. However, in thoracic segments, inhibition of motoneurons is known to occur over two to three segments (20-40 mm) from the presumed somatic locations of the Renshaw cells. Here, we report the first detailed morphological study of Renshaw cell axons outside the lumbosacral segments, which investigated whether this different distribution of motoneuron inhibition is reflected in a different pattern of Renshaw cell terminations. Four Renshaw cells in T7 or T8 segments were intracellularly labeled with neurobiotin in anesthetized cats and their axons traced for distances >=6 mm from the somata. The only morphological difference detected within this distance in comparison with Renshaw cells in the lumbosacral cord was a minimal taper in the funicular axons, where in the lumbosacral cord this is pronounced. Patterns of termination were virtually identical to those in the lumbosacral segments, so we conclude that these patterns are unrelated to the pattern of motoneuronal inhibition. PMID- 24400163 TI - Maintained expression of genes associated with metabolism in the ventromedial hypothalamic nucleus despite development of leptin resistance during pregnancy in the rat. AB - Hyperphagia and weight gain to acquire energy stores for development and growth of the fetus and to prepare for the demands of lactation are important adaptations to support a healthy pregnancy. As a consequence, hypothalamic leptin resistance develops to enable maintenance of a positive energy state. During pregnancy there is a decrease in leptin receptor expression and reduced leptin induced phospho signal transducer and activator of transcription 3 (pSTAT3) in the ventromedial nucleus of the hypothalamus (VMN), suggesting that the VMN is a key site of pregnancy-induced modification in the control of energy homeostasis. The aim of this study was to investigate expression levels of known gene targets, which are involved in metabolic regulation and glucosensing, within the VMN during pregnancy. Using in situ hybridization, pituitary adenylate cyclase activated polypeptide (Pacap), brain-derived neurotrophic factor (Bdnf), and glucokinase messenger ribonucleic acid (mRNA) expression were localized in the hypothalamus of nonpregnant and day 14 pregnant rats, then expression levels were compared by quantitative polymerase chain reaction (qPCR) using laser capture microdissection of the VMN and arcuate nucleus. Despite significantly elevated plasma leptin and insulin concentrations, and lower blood glucose levels, during pregnancy, no significant changes in gene expression of Pacap, Bdnf, or glucokinase were detected between nonpregnant and day 14 pregnant groups. These data suggest that loss of leptin and insulin sensitivity in the VMN might allow gene expression to be maintained at normal/control levels in this nucleus, despite marked changes in the levels of these important regulatory hormones. These data provide further evidence for development of leptin resistance in the VMN as an adaptive response during pregnancy. PMID- 24400164 TI - Pituitary adenylate cyclase-activating polypeptide prevents contrast-induced nephropathy in a novel mouse model. AB - We determined whether pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) prevents contrast-induced nephropathy using human renal proximal tubule epithelial (HK-2) cells and homozygous endothelial nitric oxide synthase deficient (eNOS(-/-)) mice as a novel in vivo model. Cultured HK-2 cells were pretreated with 10(-9)-10(-6) mol/L PACAP or vasoactive intestinal peptide (VIP) for 1 h, and then exposed to ionic (Urografin) or nonionic (iohexol) contrast media at 50 mg iodine/mL for 24 h. Male eNOS(-/-) mice received Urografin (1.85 g iodine/kg) intravenously after water deprivation for 24 h, and PACAP38 (10 MUg) intraperitoneally 1 h before and 12 h after Urografin injection. Urografin and iohexol increased lactate dehydrogenase and kidney injury molecule 1 in the culture medium, induced apoptosis, and inhibited cell proliferation in HK-2 cell cultures. PACAP38 and VIP reduced these changes in a dose-dependent manner. PACAP38 was more potent than VIP. In eNOS(-/-) mice, Urografin raised serum creatinine and cystatin C levels, caused renal tubule damage, induced apoptosis, and promoted neutrophil influx. Urografin also increased kidney protein levels of proinflammatory cytokines, and kidney mRNA levels of proinflammatory cytokines, kidney injury biomarkers, and enzymes responsible for reactive oxygen and nitrogen species. PACAP38 significantly reduced these Urografin-induced changes in eNOS(-/-) mice. This study shows that both Urografin and iohexol are toxic to HK-2 cells, but Urografin is more toxic than iohexol. Urografin causes acute kidney injury in eNOS(-/-) mice. PACAP38 protects HK-2 cells and mouse kidneys from contrast media and is a potential therapeutic agent for contrast-induced nephropathy. PMID- 24400165 TI - Inhibitory collaterals in genetically identified medium spiny neurons in mouse primary corticostriatal cultures. AB - Inhibitory collaterals between striatal medium spiny neuron (MSN) subtypes have been shown to critically influence striatal output. However, the low rate of inhibitory collateral detection between striatal MSNs in conventional ex vivo slice recordings has made the study of these connections challenging. Furthermore, most studies on MSN collaterals have been conducted either blind or in models, in which only one MSN subtype can be distinguished. Here, we describe a dissociated culture system using striatal and cortical neurons harvested from genetically modified mice at postnatal day 0. These mice express tdTomato and enhanced green fluorescent protein (EGFP) downstream of the dopamine D1 and D2 receptor promoters, respectively, allowing for simultaneous distinction between the two major subtypes of MSNs. In vitro, these neurons develop spines, hyperpolarized resting membrane potentials and exhibit up-and-down states, while also maintaining expression of both fluorophores through time. Using paired whole cell patch-clamp recordings from identified MSNs at 14 days in vitro, we are able to detect a much higher rate of inhibitory functional synapses than what has been previously reported in slice recordings. These collateral synapses release gamma Aminobutyric acid (GABA) and shape the firing patters of other MSNs. Although reduced in vitro models have a number of inherent limitations, the cultures described here provide a unique opportunity to study frequently observed functional collaterals between identifiable MSNs. Additionally, cultured neurons allow for control of the extracellular environment, with the potential to investigate pharmacological regulation of inhibitory MSNs collaterals. PMID- 24400166 TI - Role of tongue pressure production in oropharyngeal swallow biomechanics. AB - The tongue is important for orofacial movements, including swallowing. Although numerous studies have focused on tongue pressure against the palate, its physiological role has not been fully evaluated. The tongue pressure generation may have the temporal coordination with the swallowing relational organs. The aim of this study was to clarify the physiological mechanisms of tongue pressure and to investigate the temporal relationship among tongue pressure, supra-hyoid muscle activity, and videofluorographic (VF) images during swallowing. Fifteen healthy young subjects participated. Tongue pressure measured using a sensor sheet with five channels, electromyographic EMG, and VF was recorded synchronously during 4-ml barium swallowing. Swallowing behavior in VF images with and without the sensor sheet was compared. Furthermore, the temporal relationship between events measured from tongue pressure, EMG, and VF was evaluated. Swallowing behavior on VF images was not affected by placement of the sensor sheet. Tongue pressure at the posterio-lateral point of the hard palate tended to have biphasic peaks. Tongue pressure production with a monophasic pattern appeared during the same period as the second peak in the biphasic pattern. The onset of tongue pressure was later than the start of hyoid movement and onset of EMG, and offset was observed between the hyoid at the up-forward position and reposition. Onset of tongue pressure at the anterior area was correlated with the start of slight hyoid elevation. Offset of tongue pressure at the posterio-lateral points was strongly time locked with the hyoid at the up forward position. The present results suggested the temporal coordination of tongue pressure generation with the swallowing-related organs. That is, the tongue pressure was produced for bolus propulsion, and was closely related to hyoid movement temporally during swallowing. These results may contribute to clarify the clinical state with the disorder of tongue kinetics. PMID- 24400167 TI - Evidence for a common mechanism for spontaneous rhythmic contraction and myogenic contraction induced by quick stretch in detrusor smooth muscle. AB - Detrusor smooth muscle exhibits myogenic contraction in response to a quick stretch (QS) as well as spontaneous rhythmic contraction (SRC); however, whether the same population of actomyosin crossbridges with a common regulatory mechanism is responsible for these two types of contraction has not been determined. Detrusor strips from New Zealand white rabbit bladders were allowed to develop SRC at a reference muscle length (L ref), or rhythmic contraction (RC) was induced with tetraethylammonium (TEA). Multiple 10-msec stretches of 15% L ref were then imposed at L ref randomly during the rhythm cycle, and the nadir-to peak (NTP) tension amplitude of the resulting myogenic contraction was measured. The amplitude and period of the rhythm cycle were measured prior to each QS. NTP was larger when a QS was imposed during a portion the cycle when tension was smaller (n = 3 each SRC and TEA-induced RC). These data suggest that when the rhythmic mechanism was mostly inactive and tension was near a minimum, a larger portion of a shared population of crossbridges was available to produce a myogenic response to a QS. Rho kinase, cyclooxygenase-1, and cyclooxygenase-2 inhibitors (H-1152, SC-560, and NS-398) affected SRC amplitude and NTP amplitude following a QS to the same degree (n = 3 each drug), providing additional evidence to support the hypothesis that a common mechanism is responsible for SRC and myogenic contraction due to QS. If a common mechanism exists, then QS is a potential mechanical probe to study SRC regulation and its alteration in overactive bladder. PMID- 24400168 TI - Effects of hyperbaric oxygen preconditioning on cardiac stress markers after simulated diving. AB - Hyperbaric oxygen preconditioning (HBO-PC) can protect the heart from injury during subsequent ischemia. The presence of high loads of venous gas emboli (VGE) induced by a rapid ambient pressure reduction on ascent from diving may cause ischemia and acute heart failure. The aim of this study was to investigate the effect of diving-induced VGE formation on cardiac stress marker levels and the cardioprotective effect of HBO-PC. To induce high loads of VGE, 63 female Sprague Dawley rats were subjected to a rapid ambient pressure reduction from a simulated saturation dive (50 min at 709 kPa) in a pressure chamber. VGE loads were measured for 60 min in anesthetized animals by the use of ultrasonography. The animals were divided into five groups. Three groups were exposed to either diving or to HBO-PC (100% oxygen, 38 min at 303 kPa) with a 45 or 180 min interval between HBO-PC and diving. Two additional groups were used as baseline controls for the measurements; one group was exposed to equal handling except for HBO-PC and diving, and the other group was completely unexposed. Diving caused high loads of VGE, as well as elevated levels of the cardiac stress markers, cardiac troponin T (cTnT), natriuretic peptide precursor B (Nppb), and alphaB-crystallin, in blood and cardiac tissue. There were strong positive correlations between VGE loads and stress marker levels after diving, and HBO-PC appeared to have a cardioprotective effect, as indicated by the lower levels of stress marker expression after diving-induced VGE formation. PMID- 24400169 TI - The vortex formation time to diastolic function relation: assessment of pseudonormalized versus normal filling. AB - In early diastole, the suction pump feature of the left ventricle opens the mitral valve and aspirates atrial blood. The ventricle fills via a blunt profiled cylindrical jet of blood that forms an asymmetric toroidal vortex ring inside the ventricle whose growth has been quantified by the standard (dimensionless) expression for vortex formation time, VFTstandard = {transmitral velocity time integral}/{mitral orifice diameter}. It can differentiate between hearts having distinguishable early transmitral (Doppler E-wave) filling patterns. An alternative validated expression, VFTkinematic reexpresses VFTstandard by incorporating left heart, near "constant-volume pump" physiology thereby revealing VFTkinematic's explicit dependence on maximum rate of longitudinal chamber expansion (E'). In this work, we show that VFTkinematic can differentiate between hearts having indistinguishable E-wave patterns, such as pseudonormal (PN; 0.75 < E/A < 1.5 and E/E' > 8) versus normal. Thirteen age-matched normal and 12 PN data sets (738 total cardiac cycles), all having normal LVEF, were selected from our Cardiovascular Biophysics Laboratory database. Doppler E-, lateral annular E'-waves, and M-mode data (mitral leaflet separation, chamber dimension) was used to compute VFTstandard and VFTkinematic. VFTstandard did not differentiate between groups (normal [3.58 +/- 1.06] vs. PN [4.18 +/- 0.79], P = 0.13). In comparison, VFTkinematic for normal (3.15 +/- 1.28) versus PN (4.75 +/- 1.35) yielded P = 0.006. Hence, the applicability of VFTkinematic for diastolic function quantitation has been broadened to include analysis of PN filling patterns in age-matched groups. PMID- 24400170 TI - Baroreceptor reflex control of heart rate in angiotensin type 1A receptor knockout mice. AB - The baroreceptor reflex dampens the short-term fluctuations in blood pressure by feedback modulation of heart rate (HR) and vascular resistance. Impairment of this reflex has been observed in hypertension and heart failure. Angiotensin II, a blood borne hormone, acts via its type 1A receptor to attenuate the baroreceptor reflex and this reflex is reported to be dramatically altered in angiotensin type 1A receptor knockout mice. This study sought to further investigate changes in the arterial and cardiopulmonary baroreceptor reflex control of HR in angiotensin II type 1A receptor knocked out mice. In artificially ventilated, isoflurane anesthetized mice, the arterial and cardiopulmonary baroreceptor reflexes were activated via injection or slow infusions, respectively, of phenylephrine and sodium nitroprusside through the jugular vein. We observed no impairment of either the arterial or cardiopulmonary baroreceptor reflex control of HR in angiotensin type 1A receptor knockout mice. PMID- 24400171 TI - Spinal plasticity in stroke patients after botulinum neurotoxin A injection in ankle plantar flexors. AB - The effect of botulinum neurotoxin A (BoNT-A) in stroke patients' upper limbs has been attributed to its peripheral action only. However, BoNT-A depressed recurrent inhibition of lumbar motoneurons, likely due to its retrograde transportation along motor axons affecting synapses to Renshaw cells. Because Renshaw cells control group Ia interneurons mediating reciprocal inhibition between antagonists, we tested whether this inhibition, particularly affected after stroke, could recover after BoNT-A. The effect of posterior tibial nerve (PTN) stimulation on tibialis anterior (TA) electromyogram (EMG) was investigated in 13 stroke patients during treadmill walking before and 1 month after BoNT-A injection in ankle plantar flexors. Before BoNT-A, PTN stimuli enhanced TA EMG all during the swing phase. After BoNT-A, the PTN-induced reciprocal facilitation in TA motoneurons was depressed at the beginning of swing and reversed into inhibition in midswing, but at the end of swing, the reciprocal facilitation was enhanced. This suggests that BoNT-A induced spinal plasticity leading to the recovery of reciprocal inhibition likely due to the withdrawal of inhibitory control from Renshaw cells directly blocked by the toxin. At the end of swing, the enhanced reciprocal facilitation might be due to BoNT-induced modification of peripheral afferent inputs. Therefore, both central and peripheral actions of BoNT-A can modify muscle synergies during walking: (1) limiting ankle muscle co contraction in the transition phase from stance to swing, to assist dorsiflexion, and (2) favoring it from swing to stance, which blocks the ankle joint and thus assists the balance during the single support phase on the paretic limb. PMID- 24400172 TI - Modification by KCNE1 variants of the hERG potassium channel response to premature stimulation and to pharmacological inhibition. AB - human Ether-a-go-go-Related Gene (hERG) encodes the pore-forming subunit of cardiac rapid delayed rectifier K(+) current (I Kr) channels, which play important roles in ventricular repolarization, in protecting the myocardium from unwanted premature stimuli, and in drug-induced Long QT Syndrome (LQTS). KCNE1, a small transmembrane protein, can coassemble with hERG. However, it is not known how KCNE1 variants influence the channel's response to premature stimuli or if they influence the sensitivity of hERG to pharmacological inhibition. Accordingly, whole-cell patch-clamp measurements of hERG current (I hERG) were made at 37 degrees C from hERG channels coexpressed with either wild-type (WT) KCNE1 or with one of three KCNE1 variants (A8V, D76N, and D85N). Under both conventional voltage clamp and ventricular action potential (AP) clamp, the amplitude of I hERG was smaller for A8V, D76N, and D85N KCNE1 + hERG than for WT KCNE1 + hERG. Using paired AP commands, with the second AP waveform applied at varying time intervals following the first to mimic premature ventricular excitation, the response of I hERG carried by each KCNE1 variant was reduced compared to that with WT KCNE1 + hERG. The I hERG blocking potency of the antiarrhythmic drug quinidine was similar between WT KCNE1 and the three KCNE1 variants. However, the I hERG inhibitory potency of the antibiotic clarithromycin and of the prokinetic drug cisapride was altered by KCNE1 variants. These results demonstrate that naturally occurring KCNE1 variants can reduce the response of hERG channels to premature excitation and also alter the sensitivity of hERG channels to inhibition by some drugs linked to acquired LQTS. PMID- 24400173 TI - Arthroscopic suture bridge fixation of tibial intercondylar eminence fractures. AB - Tibial intercondylar eminence fractures that are displaced and non-reducible require open or arthroscopically assisted repair. Ideally, fracture reduction and fixation would be performed with a technique that has low morbidity, allows easy visualization and reduction, provides firm fixation, does not violate the proximal tibial physis, avoids metal hardware, and does not require a second procedure for implant removal. The suture bridge technique, used in the shoulder for rotator cuff tears and greater tuberosity fracture repair, has the ability to produce high contact pressures with rigid fixation. We describe an all-inside and all-epiphyseal arthroscopic suture bridge technique for tibial intercondylar eminence fracture repair performed with PushLock anchors (Arthrex, Naples, FL). One or 2 anchors preloaded with No. 2 FiberWire (Arthrex) are placed in the posterior fracture bed, followed by fracture reduction. The suture limbs are shuttled through and around the anterior cruciate ligament and over the fracture fragment in crossing fashion and are secured by use of additional anchors placed at the anteromedial and anterolateral fracture margin. The anchors are placed obliquely to avoid the proximal tibial physis in the pediatric population. Anatomic reduction and secure fixation allow more aggressive rehabilitation and faster restoration of joint function. PMID- 24400174 TI - Anatomic anterior cruciate ligament reconstruction with a flexible reamer system and 70 degrees arthroscope. AB - Anterior cruciate ligament (ACL) reconstruction techniques continue to evolve as surgeons seek to improve surgical process and outcome measures. On the basis of published data showing improved biomechanics, many surgeons now attempt to better re-create native ACL anatomy in reconstruction. Use of flexible reamer technology and a 70 degrees arthroscope allows for excellent visualization of the native ACL anatomy, as well as precise and independent drilling of the tibial and femoral reconstruction tunnels, while offering several surgical and technical advantages compared with other drilling techniques. This technical note with accompanying video describes our use of the Smith & Nephew Clancy anatomic cruciate guide/flexible drill system (Smith & Nephew, London, England) with a 70 degrees arthroscope. PMID- 24400175 TI - Arthroscopic posterior labral repair and capsular shift with a lateralized posterior portal. AB - Arthroscopic techniques for posterior shoulder subluxation with labral injuries in athletes have shown good results. The difficulty with the procedure is gaining appropriate access to the posteroinferior quadrant of the glenoid at a steep enough angle that allows for safe anchor placement. Various portals have been described that can be used as accessory portals for anchor placement. Although the use of additional portals to create appropriate access to the joint is always encouraged, preoperative planning can minimize the need for their use. The video shows a simple technique for posterior labral repair with capsular plications through a lateralized posterior portal in the lateral decubitus position. This technique allows the surgeon to address posterior labral tears and capsular laxity without the need for accessory portals. PMID- 24400176 TI - Arthroscopic acetabular rim resection in the treatment of femoroacetabular impingement. AB - Appropriate identification and precise resection of the pincer lesion are integral parts of the arthroscopic surgical treatment of femoroacetabular impingement. Preoperative radiographic planning of the bone resection, as well as executing the plan intraoperatively using both fluoroscopic and arthroscopic cues, is critical to adequately removing the pincer lesion. We present our surgical technique of removing the impinging bone by defining the focal acetabular rim overcoverage, accessing the pincer lesion with labral detachment, and then performing acetabular rim resection. PMID- 24400177 TI - Arthroscopic labral repair in the treatment of femoroacetabular impingement. AB - Labral repair has become an essential technique in the arthroscopic surgical management of femoroacetabular impingement. Several clinical studies suggest that labral repair results in superior patient outcomes in comparison to labral debridement alone. The repair procedure requires accurate evaluation of labral tissue quality, precise placement of sutures and anchors, and careful re tensioning of the labrum. We present our preferred technique for labral repair. PMID- 24400178 TI - Modified anterior portal for hip arthroscopy. AB - Routine portal placement for the central compartment should be based on minimizing iatrogenic injury and maximizing access. Anchor placement for labral repair/refixation requires a more distal entry position to accomplish sufficient divergence to avoid perforating the articular surface of the acetabulum. If a standard portal for joint access is moved more distal, this can compromise its utility for addressing intra-articular pathology. In addition, it can be difficult to position this portal sufficiently distally to ensure adequate divergence. Moving the anchor away from the rim to avoid perforation, due to suboptimal portal placement, can result in nonanatomic labral repair. Thus a percutaneous anchor delivery system is advantageous in ensuring adequate divergence without compromising routine portal placement for the central compartment. PMID- 24400179 TI - ORV Arthroscopic Reduction and Internal Fixation of Tibial Eminence Fractures. AB - Tibial eminence fractures are an uncommon but well-described avulsion of the anterior cruciate ligament. Treatment principles are based on the amount and pattern of fracture displacement. Management has evolved from closed reduction and immobilization to arthroscopic reduction and internal fixation followed by early rehabilitation. Various fixation methods have evolved, ranging from arthroscopic reduction and percutaneous screw fixation to arthroscopic suture repair. We present a technique for arthroscopic reduction and internal fixation using a cannulated drill bit and high-strength suture. This technique facilitates anatomic reduction with uncomplicated tunnel placement and suture passing in an effort to allow strong fixation and early rehabilitation. PMID- 24400180 TI - The "cup-shaped" technique for uncontained osteochondral lesion of the talus. AB - The arthroscopic bone marrow stimulation technique is defined as the first-line procedure for an osteochondral lesion of the talus. The containment of the lesion has been reported as 1 of the prognostic factors for clinical outcomes of arthroscopic bone marrow stimulation. It was surmised that lesions without a stable rim lose the protective border, thereby making stable formation of fibrocartilage less likely. The purpose of the cup-shaped technique is to improve the stability of blood clots after arthroscopic bone marrow stimulation in an uncontained lesion. The geometry of the lesion changes from "uncontained" to "contained like," which improves the stability of the blood clots. PMID- 24400181 TI - Treatment of a patellar chondral defect using juvenile articular cartilage allograft implantation. AB - Focal articular cartilage defects of the knee commonly occur. Various arthroscopic and open procedures have been developed to address these lesions when they are symptomatic, all aimed at defect filling. Juvenile cartilage transplantation procedures have recently been described as an option for managing symptomatic cartilage lesions. We present a technique using transfer of juvenile cartilage allograft transplantation into the defect with subsequent second-look arthroscopy and biopsy results after implantation. PMID- 24400182 TI - Easy and Safe All-Inside Suture Technique for Posterior Horn Tears of Lateral Meniscus Using Standard Anteromedial and Anterolateral Portals. AB - The importance of the lateral meniscus in weight bearing, distribution of force, shock absorption, articular cartilage protection, proprioception, stabilization of the joint, and joint lubrication is well known. Surgeons currently agree on the importance of preserving the menisci. Different suture techniques have been standardized. These include outside-in, inside-out, and all-inside techniques. The all-inside technique can be used to repair lesions of the posterior horn of the lateral meniscus. However, this technique presents important disadvantages, such as the necessity for an accessory portal and a high risk of neurovascular damage. For these reasons, we have developed a technique in which a suture hook and a shuttle relay are used to pass the suture wire through the meniscal lesion of the posterior horn of the lateral meniscus with an all-inside technique, without the use of accessory portals and cannulas, with a standard 30 degrees arthroscopic camera. PMID- 24400183 TI - Modified arthroscopic latarjet procedure with coracoid exteriorization for treatment of anterior glenohumeral instability. AB - The Latarjet procedure for treating anterior glenohumeral instability includes transfer of the coracoid and biceps tendon to the anterior glenoid. A modified method for the arthroscopic procedure was developed to facilitate the procedure and minimize the risk of injury to the brachial plexus. The detached coracoid was exteriorized through the anteroinferior portal for drilling and shaping. A Coracoid Drill Guide (Arthrex, Naples, FL) was used to help cut the coracoid to the desired size and make 2 drill holes in the coracoid for fixation to the glenoid. The Coracoid Transfer Instrument (Acierart, Masku, Finland) was designed to facilitate coracoid transfer and serve as a pin guide for fixation. Ten patients with severe anterior glenohumeral instability were treated with this technique. They had only mild to moderate postoperative pain. There were no postoperative infections or recurrent dislocations. The safety of this operation was similar to that of other operations on the coracoid process in the proximity of the brachial plexus. The modified arthroscopic Latarjet procedure may be applied successfully to the treatment of anterior glenohumeral instability, with good patient satisfaction and functional outcome. PMID- 24400184 TI - Arthroscopic treatment of labral tears and concurrent avascular necrosis of the femoral head in young adults. AB - Avascular necrosis (AVN) of the femoral head is a progressive disease affecting young adults that results in collapse of the femoral head and subsequent degenerative joint disease. Although precollapse stages of AVN can be successfully treated with core decompression, making the diagnosis is often difficult given alternative sources of hip pain in this age group. We propose that arthroscopic-assisted core decompression of the femoral head offers an effective method of addressing AVN of the femoral head as well as coexistent hip disorders in the same operation. This article describes in detail the technique used to perform an arthroscopic-assisted core decompression of the femoral head, and a companion video demonstrating the procedure is included. Our experience suggests that arthroscopic-assisted core decompression can be used as an alternative to open core decompression, while simultaneously addressing other sources of hip pain, with successful outcomes. PMID- 24400185 TI - Arthroscopic recognition and repair of the torn subscapularis tendon. AB - Although the subscapularis has historically received less attention than posterosuperior rotator cuff tears, repair of a torn subscapularis tendon is critically important to restoring anatomy and achieving the best functional outcome possible. Arthroscopic repair begins with proper recognition of the tear. A systematic approach can then be used to arthroscopically repair all types of subscapularis tendon tears, from partial tears to full-thickness tears, as well as those which are retracted and have adhesions medially. Subscapularis footprint restoration can be accomplished with a variety of repair techniques that must be matched to the extent of the tear and mobility of the tendon. PMID- 24400186 TI - TransMedial All-Inside Posterior Cruciate Ligament Reconstruction Using a Reinforced Tibial Inlay Graft. AB - Surgical reconstruction of the posterior cruciate ligament (PCL) is technically demanding. Potential challenges include visualization of the tibial footprint and drilling of the tibial tunnel without damaging posterior neurovascular structures, as well as graft selection, deployment, tensioning, and fixation. We present a novel TransMedial all-inside arthroscopic technique (technique designed by A. J. Wilson with support from Arthrex) using a single hamstring tendon graft, fixed with adjustable cortical suspensory devices. The technique simplifies the difficult steps encountered during PCL reconstruction and is safe and reproducible. All arthroscopic viewing is accomplished from the lateral portal, and femoral socket preparation is performed from the medial side with specially contoured instruments, which allow accurate marking, measuring, and anatomic positioning of the graft. The quadrupled semitendinosus graft can be augmented with composite polymer tape for increased strength and initial stability. We use outside-in drilling to create retrograde femoral and tibial sockets. Cortical suspensory fixation on the tibial side can be supplemented with anchor fixation. We use an arthroscopic tibial inlay technique that better approximates native knee anatomy. This also avoids the "killer turn," a problem seen in transtibial PCL reconstruction techniques, which theoretically induces graft laxity due to abrasion with cyclic loading. This technique can be further adapted to allow a modified double-bundle or TriLink graft (technique designed by A. J. Wilson with support from Arthrex.). PMID- 24400187 TI - Anterior cruciate ligament femoral socket drilling with a retrograde reamer: lessons from the learning curve. AB - Whereas "anatomic" anterior cruciate ligament reconstruction may improve clinical results, the technique has introduced new technical challenges. The purpose of this technical note and video is to explore tips and tricks that improve femoral socket drilling with a retrograde reamer, bone-patellar tendon-bone graft passage, and interference screw fixation. The techniques for retrograde femoral socket drilling in an inside-out direction, bone-patellar tendon-bone graft passage, and interference screw fixation are described and demonstrated. Pitfalls, troubleshooting tips, and possible solutions are discussed. With the retrograde reamer, the femoral socket can be placed in the footprint of the anterior cruciate ligament with a longer and more vertical tunnel. By modifying the size of the patellar bone plug, graft passage is improved. With care and technique, interference screw fixation in the femoral socket over a guidewire is possible. PMID- 24400188 TI - "Retrograde technique" for drilling the femoral tunnel in an anterior cruciate ligament reconstruction. AB - Recent literature has led some surgeons to drill the femoral tunnel in an anterior cruciate ligament reconstruction through an accessory anteromedial portal. Several techniques have been reported for the safe, effective drilling of the femoral tunnel by this approach. This technical note presents a new "retrograde technique" in which all instruments are passed independently into the notch and across the medial compartment. This technique is safe and reproducible and allows for meticulous evaluation and creation of the femoral tunnel(s) while minimizing steps. PMID- 24400189 TI - Double-bundle medial patellofemoral ligament reconstruction with a single patellar tunnel. AB - Medial patellofemoral ligament (MPFL) reconstruction is an established method to prevent patellofemoral instability. Nevertheless, the anatomy and the biomechanical behavior of native MPFL are still under investigation, but in recent years they have become more defined. We propose a technique for MPFL reconstruction based on the results of recent anatomic studies regarding the patellar insertion of the MPFL. A double-bundle MPFL is reconstructed by use of the semitendinosus tendon passed through a single patellar tunnel, which crosses the patella from the midpoint of its medial border until its superolateral corner is reached. This method permits a strong patellar fixation, potentially reducing the risk of patellar fracture compared with double-patellar tunnel techniques. Moreover, it requires no fixation devices at the patella and only a single interference screw on the femoral side. PMID- 24400190 TI - Arthroscopic distal tibial allograft augmentation for posterior shoulder instability with glenoid bone loss. AB - Glenoid bone loss is commonly associated with recurrent shoulder instability. Failure to recognize and appropriately address it can lead to poor outcomes. Numerous studies have found anterior-inferior glenoid bone loss in the setting of recurrent anterior instability. Though much less common, posterior shoulder instability can be seen in the setting of acute trauma, epilepsy, electrocution, and alcoholism. Heightened awareness has led to recognition in collision athletes as well. Posterior glenoid bone loss must be addressed in a similar fashion to anterior glenoid bone loss to prevent recurrent instability. Open bone augmentation procedures have been described with successful results. In this technical note, we describe an arthroscopic technique using fresh distal tibial allograft for posterior glenoid augmentation. In addition, a current review regarding the diagnosis and management of recurrent posterior shoulder instability is provided. PMID- 24400191 TI - Arthroscopic treatment of medial femoral condylar coronal fractures and nonunions. AB - Nonunion of medial femoral condylar coronal fractures are uncommon. In neglected Hoffa fractures despite nonunion, there is a risk of missing accompanying ligamentous and intra-articular injuries. Neither preoperative clinical examination nor magnetic resonance imaging showed these injuries before arthroscopy. Arthroscopy before internal fixation gives additional information and changes the surgical protocol for these fractures and nonunions. PMID- 24400192 TI - Medial patellofemoral ligament reconstruction with semitendinosus autograft. AB - Patellar instability is a common complaint after traumatic dislocation of the patella. Traumatic dislocation always leads to tearing of the medial patellofemoral ligament (MPFL). Treatment consists of recovery from the traumatic injury, followed by reconditioning and physical therapy to strengthen the dynamic stabilizers of the patella. In patients with recurrent instability, detailed evaluation of the cause is required to determine the needed interventions. In patients with an incompetent MPFL and recurrent instability, reconstruction is indicated, along with other procedures to address other contributing factors. This article details our technique for MPFL reconstruction using semitendinosus autograft, which can be performed alone or in concert with other realignment procedures. PMID- 24400193 TI - Arthroscopic reduction of a chronically dislocated reversed shoulder arthroplasty. AB - We present the case of a 64-year-old female patient who had a traumatic dislocation of a reversed shoulder arthroplasty that was unnoticed for 5 weeks and that was reduced arthroscopically. Arthroscopy of the shoulder, as in other joints with prostheses, can facilitate the treatment of conditions that would otherwise require the use of open surgery to solve them and that might become more frequent because of the widespread use of reversed shoulder arthroplasties, which have a high rate of dislocation. PMID- 24400194 TI - "Central" quadriceps tendon harvest with patellar bone plug: surgical technique revisited. AB - The objective of this article is to review the surgical technique for quadriceps tendon graft harvest while highlighting an additional technical note that has not been previously emphasized. The quadriceps tendon typically inserts eccentrically on the superior pole of the patella. By shifting the soft-tissue harvest to a location just off the medial edge of the tendon, the adjoining patellar bone plug will be centered on the superior pole of the patella, reducing the risk of an iatrogenic patellar fracture. PMID- 24400195 TI - Ultrasonography-assisted arthroscopic proximal iliotibial band release and trochanteric bursectomy. AB - We describe arthroscopic iliotibial band release and trochanteric bursectomy assisted by intraoperative ultrasonography for accurate placement of arthroscopic portals and to ensure adequate decompression of the peritrochanteric space. We have found ultrasonography for endoscopic iliotibial band release a useful tool to assist with localizing the site and length of decompression. PMID- 24400196 TI - Dry arthroscopy of the shoulder. AB - A technique to perform glenohumeral arthroscopy without using arthroscopic fluid for visualization or instrumentation is presented. The patient is placed in the beach-chair position. No traction is applied. Portal placement is performed as usual. Water flow is used only sporadically to wash the joint cavity, and then it is immediately aspirated with a synoviotome suction pump. The entire exploration and instrumentation occur within a pressure-free dry joint. We have applied this technique in more than 50 patients, and in none of these cases was there a need to switch from the dry to the wet technique. By use of this surgical technique, intra-articular shoulder pathology treatment can be performed in a more accurate biomechanical and physiological scenario. It avoids many visualization and instrumentation inconveniences, as well as the risk of some major complications. Joint distension with fluid becomes unnecessary, making it possible to use medium sized incisions to perform and simplify complex procedures. PMID- 24400197 TI - Free biceps tendon autograft to augment arthroscopic rotator cuff repair. AB - Arthroscopic rotator cuff repairs have become the standard of treatment for all sizes of tears over the past several years. Current healing rates reported in the literature are quite good, but improving the healing potential of rotator cuff repairs remains a challenging problem. There has been an increase recently in the use of augmentation of rotator cuff repairs with xenografts or synthetics for large and massive tears. Biceps tenodesis is often indicated as part of the treatment plan while one is performing rotator cuff surgery. A subpectoral biceps tenodesis provides a source of autograft to augment rotator cuff repairs of all sizes. Two techniques are presented to augment rotator cuff repairs with a free biceps tendon autograft. This is a novel idea in an attempt to improve healing rates and long-term results of rotator cuff repairs of all sizes. PMID- 24400198 TI - All-arthroscopic patch augmentation of a massive rotator cuff tear: surgical technique. AB - Surgical management of massive rotator cuff tears remains challenging, with failure rates ranging from 20% to 90%. Multiple different arthroscopic and open techniques have been described, but there is no current gold standard. Failure after rotator cuff repair is typically multifactorial; however, failure of tendon footprint healing is often implicated. Patch augmentation has been described as a possible technique to augment the biology of rotator cuff repair in situations of compromised tendon quality and has shown promising short-term results. The purpose of this article is to describe our preferred surgical technique for arthroscopic rotator cuff repair with patch augmentation. PMID- 24400199 TI - Inside-out meniscus repair. AB - Meniscus repair over resection, when feasible, should be strongly considered in an effort to preserve meniscus integrity and function, especially in younger patients. Currently, a number of techniques and implants may be used to achieve a successful result. Although all-inside meniscus repair devices have evolved significantly since their introduction and have become the repair technique of choice for many surgeons, the classic inside-out repair technique is still very useful to have in one's armamentarium. Though less popular because of the ease of current-generation fixators, the inside-out technique can still offer advantages for those surgeons who are proficient. With the versatility to address most tear patterns, the ability to deliver sutures with smaller needle diameters, and proven long-term results, it has been considered the gold standard in meniscus repair. We review the inside-out repair technique for both a medial and lateral meniscus tear with some helpful tips when performing the technique, and we present a video demonstration of the lateral meniscus repair technique. PMID- 24400200 TI - Cloud publishing of scientific medical journals: current status and future direction. PMID- 24400201 TI - How to relate diastolic left ventricular dysfunction to the results of stress echocardiography in aortic stenosis? AB - In aortic stenosis (AS), altered functional capacity may be not only a result of impaired systolic performance but likewise of diastolic left ventricular (LV) dysfunction. In asymptomatic severe AS, in borderline severe AS and in low flow, low gradient AS with reduced ejection fraction (EF), assessment of systolic and diastolic LV function should be completed by evaluation of functional capacity using low dose dobutamine stress echocardiography (SE). PMID- 24400202 TI - Focus on non-communicable diseases: an important agenda for the African continent. AB - In Africa together with risk factors for cardiovascular diseases such as systemic hypertension, diabetes, tobacco smoking, alcohol consumption and overweight, there is an important role of poverty-related conditions in determining the burden of cardiovascular diseases. The management of common diseases such as untreated congenital heart disease, rheumatic heart valve disease and cardiomyopathies, highly prevalent in Sub-Saharan Africa, imposes an unsustainable burden to the health systems in this continent, and may hamper the efforts towards Africa's alignment with the Global Agenda for non-communicable diseases (NCDs). Thus to prevent death and disability by cardiovascular disease in Africa specific approaches need to be designed focusing not only on the global risk factors addressed by the United Nations Declaration, but also on the prevention and control of infections and poverty-related diseases. PMID- 24400203 TI - Prevalence and factors associated with false positive suspicion of acute aortic syndrome: experience in a patient population transferred to a specialized aortic treatment center. AB - STUDY OBJECTIVE: Acute aortic syndrome (AAS) is a medical emergency that requires prompt diagnosis and treatment at specialized centers. We sought to determine the frequency and etiology of false positive activation of a regional AAS network in a patient population emergently transferred for suspected AAS. METHODS: We evaluated 150 consecutive patients transferred from community emergency departments directly to our Cardiac Intensive Care Unit (CICU) with a diagnosis of suspected AAS between March, 2010 and August, 2011. A final diagnosis of confirmed acute Type A, acute Type B dissection, and false positive suspicion of dissection was made in 63 (42%), 70 (46.7%) and 17 (11.3%) patients respectively. RESULTS: Of the 17 false positive transfers, ten (58.8%) were suspected Type A dissection and seven (41.2%) were suspected Type B dissection. The initial hospital diagnosis in 15 (88.2%) patients was made by a computed tomography (CT) scan and 10 (66.6%) of these patients required repeat imaging with an ECG synchronized CT to definitively rule out AAS. Five (29.4%) patients had prior history of open or endovascular aortic repair. Overall in-hospital mortality was 9.3%. CONCLUSIONS: The diagnosis of AAS is confirmed in most patients emergently transferred for suspected AAS. False positive activation in this setting is driven primarily by uncertainty secondary to motion-artifact of the ascending aorta and the presence of complex anatomy following prior aortic intervention. Network-wide standardization of imaging strategies, and improved sharing of imaging may further improve triage of this complex patient population. PMID- 24400204 TI - Exercise stress echocardiography in patients with aortic stenosis: impact of baseline diastolic dysfunction and functional capacity on mortality and aortic valve replacement. AB - BACKGROUND: Patients with aortic stenosis (AS) often undergo exercise echocardiography. Diastolic dysfunction (DD) is frequently associated with AS but little is known about its impact on functional capacity (FC). We sought to determine the relationship between DD and FC and their impact on mortality and need for aortic valve replacement (AVR) in patients with AS. METHODS AND RESULTS: Data was analyzed for consecutive patients with any degree of AS undergoing exercise stress echocardiography between 2000 and 2010 at our institution. The primary endpoint was a composite of death or need for AVR. We identified 1,267 patients [mean age 67+/-11 years, ejection fraction (56+/-7)%, mean aortic valve gradient 19+/-12 mmHg, mean maximal metabolic equivalents (METs) achieved 8+/ 2.6]. The proportion with normal, stage 1, and >= stage 2 diastology was 195 (15%), 928 (73%), 144 (12%). A total of 475 (37.5%) patients had a primary outcome with 164 deaths (mean follow up 5.6+/-4.1 years) and 341 AVR (mean follow up 2.4+/-2.6 years). Predictors of FC were age, gender, body mass index, Bruce protocol, heart rate recovery (HRR), ejection fraction, mean aortic valve gradient, and diabetes but not baseline DD. Baseline DD [HR 1.82, 95% CI (1.17, 2.82), P=0.008] and FC [HR 0.93, 95% CI (0.88, 0.98), P=0.003] were independent predictors of death or AVR. CONCLUSIONS: For patients with AS undergoing exercise echocardiography, baseline DD was not predictive of FC. However, both baseline DD and FC were independent predictors of death or need for AVR. PMID- 24400205 TI - Improved diagnosis and prognosis using Decisions Informed by Combining Entities (DICE): results from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE). AB - OBJECTIVES: To introduce an algorithmic approach to improve the interpretation of myocardial perfusion images in women with suspected myocardial ischemia. BACKGROUND: Gated single photon emission computed tomography (SPECT) and magnetic resonance (MR) myocardial perfusion imaging (MPI) approaches have relatively poor diagnostic and prognostic value in women with suspected myocardial ischemia. Here we introduce an approach: Decisions Informed by Combining Entities (DICE) that forms a mathematical model utilizing MPI and cardiac dimensions generated by one modality to predict the perfusion status of another modality. The effect of the model is to systematically incorporate cardiac metrics that influence the interpretation of perfusion images, leading to greater consistency in designation of myocardial perfusion status between studies. METHODS: Women (n=213), with suspected myocardial ischemia, underwent MPI assessment for regional perfusion defects using two modalities: gated SPECT (n=207) and MR imaging (n=203). To determine perfusion status, MR data were evaluated qualitatively and semi quantitatively while SPECT data were evaluated using conventional clinical criteria. These perfusion status readings were designated "Original". Four regression models were generated to model perfusion status obtained with one modality [e.g., semi-quantitative magnetic resonance imaging (MRI)] against another modality (e.g., SPECT) and a threshold applied (DICE modeling) to designate perfusion status as normal or low. The DICE models included perfusion status, left ventricular (LV) chamber volumes and myocardial wall thickness. Women were followed for 40+/-16 months for the development of first major adverse cardiovascular event (MACE: CV death, nonfatal myocardial infarction (MI) or hospitalization for congestive heart failure). Original and DICE perfusion status were compared in their ability to detect high-grade coronary artery disease (CAD) and for prediction of MACE. RESULTS: Adverse events occurred in 25 (12%) women and CAD was present in 34 (16%). In receiver-operator characteristic (ROC) analysis for CAD detection, the average area under the curve (AUC) for DICE vs. Original status was 0.77+/-0.03 vs. 0.70+/-0.03, P<0.01. Similarly, in Kaplan Meier survival analysis the average log-rank statistic was higher for DICE vs. the Original readings (10.6+/-5.2 vs. 3.0+/-0.6, P<0.05). CONCLUSIONS: While two data sets are required to generate the DICE models no knowledge of follow-up results is needed. DICE modeling improved diagnostic and prognostic value vs. the Original interpretation of the myocardial perfusion status. PMID- 24400206 TI - The reversal of cardiology practices: interventions that were tried in vain. AB - Medical reversal happens when new trials-better powered, designed or controlled than predecessors--contradict current standard of care. The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial and CAST study are notable examples of investigations that overturned current practice by demonstrating that these interventions offered no survival benefits. In this mini-review, we summarize our experience reviewing a decade of original articles in the New England Journal of Medicine with an eye towards investigations that reversed cardiology practice. From the management of arrhythmias to lipids to percutaneous coronary intervention (PCI) and finally, hemodynamics, reversals in the cardiology literature cover a broad set of practices. These reversals are instructive in that many of the therapies overturned were widely adopted and based on either sound physiologic reasoning or observational trials. PMID- 24400207 TI - Profile of cardiac disease in Cameroon and impact on health care services. AB - BACKGROUND: Cardiovascular diseases (CVD) have emerged as a major public health problem and impose an escalating burden on the health care system in Cameroon. The aim of the study was to investigate the preparedness of health care services for patients presenting with CVD in general and specifically, in St. Elizabeth catholic general hospital Shisong, cardiac centre. PATIENTS AND METHODS: Between November 2009 and November 2011, a population of 8,389 adults and 706 children consulted the referral cardiac centre of St. Elizabeth Catholic General Hospital. The patients' age ranges between 5 days and 103 years old, with a mean of 48.7+/ 18 years. Female represented 54.2% of the total population. RESULTS: Hypertension was diagnosed in 41.5% of patients. Isolated systolic hypertension was rarely found (4.2%) and 45.2% of patients were classified as class II according to the JNC7. Congestive heart failure was diagnosed in 29.6%. Forty-four percent of patients were in class III and 7% in class IV heart failure (NYHA). Arrhythmia was seen in 12.2% cases, with atrial fibrillation in 35.2%, followed by ventricular ectopic beats in 20.3%. Stable angina was diagnosed in 1.5%, and acute myocardial infarction 0.9%. In children, the prevalence of congenital heart disease was (4.3%). The disease the most detected was isolated ventricular septal defect, followed by tetralogy of Fallot. Post rheumatic valvulopathies were the main cause of heart failure in teenagers and young adults. Valve replacement with a mechanical valve was performed in 110 patients, valvuloplasty in eight patients, and surgical correction of congenital heart diseases in 105 cases. CONCLUSIONS: Our data, collected in a rural area, shows the high prevalence of hypertension in rural sub-Saharan Africa. Congestive heart failure mainly due to post rheumatic valvulopathies is common amongst children and young adults. PMID- 24400208 TI - Conservative treatment of iatrogenic left main coronary artery dissection: report of two cases. AB - Revascularization treatment is mostly recommended for iatrogenic left main coronary artery dissection because of potential for catastrophic sequel, even in case of initial TIMI 3 flow and hemodynamic stability. However, conservative treatment seems to be feasible in asymptomatic and hemodinamically stable patient with low-grade dissection. We report two cases of iatrogenic left main coronary dissection managed conservatively. PMID- 24400209 TI - Engineered humanity. PMID- 24400210 TI - Glass microbiology. PMID- 24400211 TI - Mitochondrial dynamics in the heart as a novel therapeutic target for cardioprotection. AB - Traditionally, mitochondria have been regarded solely as energy generators for cells; however, accumulating data have demonstrated that these complex organelles play a variety of roles within the cardiomyocyte that extend beyond this classic function. Mitochondrial dynamics involves mitochondrial movements and morphologic alterations by tethering, fusion, and fission, which depend on cellular energy requirements and metabolic status. Many studies have indicated that mitochondrial dynamics may be a fundamental component of the maintenance of normal cellular homeostasis and cardiac function. Mitochondrial dynamics is controlled by the protein machinery responsible for mitochondrial fusion and fission, but cardiomyocytes are densely packed as part of an intricate cytoarchitecture for efficient and imbalanced contraction; thus, mitochondrial dynamics in the adult heart are restricted and occur more slowly than in other organs. Cardiac mitochondrial dynamics is important for cardiac physiology in diseased conditions such as ischemia-reperfusion (IR) injury. Changes in mitochondrial morphology through modulation of the expression of proteins regulating mitochondrial dynamics demonstrates the beneficial effects on cardiac performance after IR injury. Thus, accurately defining the roles of mitochondrial dynamics in the adult heart can guide the identification and development of novel therapeutic targets for cardioprotection. Further studies should be performed to establish the exact mechanisms of mitochondrial dynamics. PMID- 24400212 TI - Increased Phosphorylation of PI3K/Akt/mTOR in the Obstructed Kidney of Rats with Unilateral Ureteral Obstruction. AB - The present study aimed to investigate changes in the mammalian target of rapamycin (mTOR) signaling pathway in the obstructed kidney of rats with unilateral ureteral obstruction (UUO). Male Sprague-Dawley rats were unilaterally obstructed by ligation of the left proximal ureter for 7 days. Control rats were treated in the same way except that no ligature was made. The expression levels of phosphorylated phosphatidylinositol 3-kinase (PI3K), Akt, and mTOR were determined in the kidney by semiquantitative immunoblotting. The protein expression levels of transforming growth factor (TGF)-beta1, Bax, and Bcl-2 were also determined in the kidney. The phosphorylation of PI3K, Akt, and mTOR was increased in the kidney of ureteral obstruction rats compared with the control. In the obstructed kidney, the protein expression of TGF-beta1 and Bax was also increased, whereas Bcl-2 expression was decreased. In conclusion, the phosphorylation of PI3K/Akt/mTOR was increased in the obstructed kidney of rats with UUO. PMID- 24400213 TI - Factors related to catheter-induced hemorrhage after brain parenchymal catheterization. AB - This article aimed to investigate the incidence rate and possible risk factors for catheter-induced hemorrhage (CIH) after brain parenchymal catheterization. Between January 2011 and March 2013, 381 patients (572 punctures) who underwent brain parenchymal catheterization were retrospectively evaluated. All patients were checked by computerized tomography scan for the detection of hemorrhage within 48 hours after catheter insertion. CIH was defined as any evidence of new hemorrhage on the post-procedural computerized tomography scan. The incidence rate and the possible risk factors were analyzed by surgeon (4 different surgeons performed the procedures), characteristics of the catheter device, and patient background. Of 381 patients, 572 punctures were performed and CIH developed in 122 puncture cases (122/572, 21.3%). The risk factors related to CIH were Glasgow Coma Scale (GCS) score <=8 (p<0.01) and prothrombin time international normalized ratio (PT INR) >=1.3 (p=0.038). The amount of hemorrhage was minimal without additional operations. A low GCS score and high PT INR are implicated as potential risk factors for CIH after brain parenchymal catheterization. Careful and delicate operative technique can help to reduce postoperative complications in these patients. PMID- 24400214 TI - Effect of atorvastatin-eluting stents in a rabbit iliac artery restenosis model. AB - Statins have pleiotropic effects, which include the inhibition of neointima hyperplasia, the inhibition of vascular inflammation, and platelet inhibition. The aim of this study was to examine the effect of an atorvastatin-eluting stent (AES) in a rabbit iliac artery overstretch restenosis model. Ten rabbits were used in this study (10 rabbits, 10 iliac arteries for each stent). An AES and paclitaxel-eluting stent (PES) were implanted in the left and right iliac arteries in a rabbit (2 stents in each rabbit). The stents were deployed with oversizing (stent/artery ratio 1.3:1), and histopathologic analysis was assessed at 28 days after stenting. There were no significant differences in the injury score, lumen area, or inflammation score. There were significant differences in the neointimal area (0.7+/-0.18 mm(2) in the AES group vs. 0.4+/-0.25 mm(2) in the PES group, p<0.01), in the percentage stenosis area (14.8+/-5.06% in the AES group vs. 10.5+/-6.80% in the PES group, p<0.05), and in the fibrin score (0.4+/ 0.51 in the AES group vs. 2.7+/-0.48 in the PES group, p<0.001). Although the AES did not suppress neointimal hyperplasia compared with the PES, it showed a superior arterial healing effect in a rabbit iliac artery overstretch restenosis model. PMID- 24400215 TI - Parathyroid cyst presenting as acute pancreatitis: report of a case. AB - We report the first case of hypercalcemia-induced acute pancreatitis caused by a functioning parathyroid cyst in a 67-year-old man. Laboratory investigation revealed increased serum amylase and lipase, increased serum ionized calcium and parathyroid hormone (PTH) levels, and decreased serum phosphate, indicating pancreatitis and primary hyperparathyroidism (PHPT). Abdominal computed tomography (CT) revealed mild swelling of the pancreatic head with peri pancreatic fat infiltration and fluid collection around the pancreatic tail. Ultrasonography and CT of the neck showed a cystic lesion at the inferior portion of the left thyroid gland, suggesting a parathyroid cyst. There was no evidence of parathyroid adenoma by 99mTc sestamibi scintigraphy. PHPT caused by a functioning parathyroid cyst was suspected. The patient underwent surgical resection of the functioning parathyroid cyst owing to his prolonged hypercalcemia. At 3 weeks after the operation, his serum levels of PTH, total calcium, ionized calcium, inorganic phosphate, amylase, and lipase were normalized. At the follow-up examinations, he has remained asymptomatic. PMID- 24400216 TI - Percutaneous treatment of an injured coronary stent using the looping wire technique. AB - Drug-eluting stent implantation is an effective treatment for coronary artery disease, yet unexpected serious complications during stent implantation are possible. A 70-year-old man with unstable angina presented with a left main bifurcation lesion. Two drug-eluting stents were successfully deployed at the left main bifurcation lesion by the mini-crush technique under intravascular ultrasound guidance. However, after removal of the wire and intravascular ultrasound catheter, the stent of the proximal left circumflex artery was damaged and shortened at the distal edge. We used a looping wire technique to cross the injured stent and we successfully re-dilated the damaged portion of the stent. Finally, we deployed an additional drug-eluting stent at the left circumflex artery over the damaged stent. Our case illustrates the importance of gentle handling of devices during coronary intervention. Furthermore, interventionists should keep in mind the role of intravascular ultrasound when treating this kind of serious complication. PMID- 24400217 TI - A case of gastric cancer manifesting as a solitary brain metastasis in the cerebellopontine angle that mimicked acoustic neuroma. AB - At the time of diagnosis, about 20% of patients with gastric cancer have stage IV disease involving the liver, lung, and bone. Brain metastasis from gastric cancer is exceedingly rare, with an incidence of <1% of clinical cases. A 59-year-old man was admitted with hearing loss in the left ear and left facial palsy for 1 month. A magnetic resonance imaging scan revealed a tumor in the cerebellopontine angle that extended to the inner auditory canal and that was clinically diagnosed as acoustic neuroma. After complete resection, histological examination showed metastatic poorly differentiated carcinoma. Further investigation revealed advanced gastric cancer involving the antrum with no evidence of the involvement of other sites except the brain parenchyma. Palliative total gastrectomy was performed and the surgical specimen revealed a poorly cohesive carcinoma that was histopathologically identical to that of the resected brain tumor. Here we report this rare case of gastric cancer that initially presented as a solitary brain metastasis mimicking acoustic neuroma. PMID- 24400219 TI - Alpha-fetoprotein-L3: Useful or Useless for Hepatocellular Carcinoma? PMID- 24400218 TI - Biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy: a novel strategy in drug development. AB - Cancer is a leading cause of mortality worldwide and matters are only set to worsen as its incidence continues to rise. Traditional approaches to combat cancer include improved prevention, early diagnosis, optimized surgery, development of novel drugs, and honing regimens of existing anti-cancer drugs. Although discovery and development of novel and effective anti-cancer drugs is a major research area, it is well known that oncology drug development is a lengthy process, extremely costly and with high attrition rates. Furthermore, those drugs that do make it through the drug development mill are often quite expensive, laden with severe side-effects and unfortunately, to date, have only demonstrated minimal increases in overall survival. Therefore, a strong interest has emerged to identify approved non-cancer drugs that possess anti-cancer activity, thus shortcutting the development process. This research strategy is commonly known as drug repurposing or drug repositioning and provides a faster path to the clinics. We have developed and implemented a modification of the standard drug repurposing strategy that we review here; rather than investigating target-promiscuous non cancer drugs for possible anti-cancer activity, we focus on the discovery of novel cancer indications for already approved chemotherapeutic anti-cancer drugs. Clinical implementation of this strategy is normally commenced at clinical phase II trials and includes pre-treated patients. As the response rates to any non standard chemotherapeutic drug will be relatively low in such a patient cohort it is a pre-requisite that such testing is based on predictive biomarkers. This review describes our strategy of biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy, taking the repurposing of topoisomerase I (Top1) inhibitors and Top1 as a potential predictive biomarker as case in point. PMID- 24400220 TI - Rescue Living-donor Liver Transplantation for Liver Failure Following Hepatectomy for Hepatocellular Carcinoma. AB - Liver failure following major hepatectomy for hepatocellular carcinoma is a known but uncommon mode of early treatment failure. When post-hepatectomy liver failure becomes progressive, the only effective treatment for rescuing the patient is liver transplantation. Deceased-donor liver transplantation in this situation is often not feasible because of the shortage of deceased-donor liver grafts. Proceeding with living-donor liver transplantation is an ethical challenge because of the possibility of donor coercion. In addition, tumor status, as confirmed by histopathological examination of the resected specimen, may indicate aggressive cancer that warns against rescue transplantation because of the increased chance of tumor recurrence. Here we describe four cases of rescue living-donor liver transplantation for liver failure after hepatectomy for hepatocellular carcinoma. The patients all survived the transplantation and were free from tumor recurrence after follow-up periods ranging from 6 months to 9 years. Our experience has shown that rescue living-donor liver transplantation for post-hepatectomy liver failure is feasible. Tumor status should be considered carefully because large tumors and tumors with macrovascular invasion are strong contraindications to rescue living-donor liver transplantation. PMID- 24400221 TI - Liver transplantation for hepatocellular carcinoma. AB - Hepatitis B is endemic in many regions of Asia, including China, Korea and India. This results in a heavy burden of hepatocellular carcinoma (HCC) because hepatitis B virus is a major risk factor in the development of the disease. In addition, the incidence of hepatitis-C-related HCC is on the rise in the United States. HCC patients with poor liver function reserve are not suitable candidates for resection, and liver transplantation (LT) has emerged as the treatment of choice for small unresectable HCCs. To treat more HCC patients with LT, the standard patient selection criteria have been expanded at a number of centers. Careful and well-considered selection of patients is the key to success in LT for HCC. Although tumor size and tumor number are used to predict whether transplantation is likely to be successful, the weighting that should be attached these two parameters has not been determined. In addition to the size and number of lesions, the morphology of HCC is also predictive of its behavior. Well circumscribed lesions, in general, are less aggressive than those with poorly defined borders. On the waiting list for LT, HCC patients compete with liver failure patients. It is essential that the criteria used for selecting HCC patients for LT should be easily applicable and fair to other transplant candidates. In the face of the scarcity of deceased-donor livers and the inevitable risks for living liver donors, a predictably low rate of recurrence of HCC after LT is mandatory. PMID- 24400222 TI - Clinical trials in hepatocellular carcinoma: an update. AB - The success of sorafenib has spurred an explosive increase of clinical trials testing novel molecular targets and other agents in the treatment of hepatocellular carcinoma (HCC). The paradigm of the studies has been characterized by three noticeable changes. First, the molecular targets of interest have expanded from angiogenesis to cancer cell-directed oncogenic signaling pathways for advanced HCC treatment. Agents targeting EGFR, FGFR, PI3K/Akt/mTOR, TGF-beta, c-Met, MEK, IGF signaling, and histone deacetylase have been actively explored. Second, the target indication has shifted from advanced stage to early or intermediate stages of disease. The feasibility of combining locoregional therapies and targeted agents, and the use of novel agents after curative treatments are currently under active investigation. Finally, the therapeutic strategy has shifted from monotherapy to combination targeted therapy. We aim to provide a comprehensive overview of newly disclosed and ongoing clinical trials for the treatment of HCC. PMID- 24400223 TI - Molecular Link between Liver Fibrosis and Hepatocellular Carcinoma. PMID- 24400224 TI - From cirrhosis to hepatocellular carcinoma: new molecular insights on inflammation and cellular senescence. AB - Sequential progression from chronic liver disease to fibrosis and to cirrhosis culminates in neoplasia in hepatocellular carcinoma (HCC). The preneoplastic setting of the cirrhotic background provides a conducive environment for cellular transformation. The role of classical inflammation in cirrhosis is widely known, but the exact mechanism linking inflammation and cancer remains elusive. Recent studies have elucidated roles for NF-kappaB, STAT3 and JNK as possible missing links. In addition, the "inflammasome" (a multiprotein complex and sensor of cellular damage) is a recently identified player in this field. The hallmarks of cirrhosis include necroinflammation, deposition of extracellular matrix and shortening of telomeres, leading to senescence and regeneration. Additionally, the accumulation of genetic/epigenetic changes propels atypical cells toward a malignant phenotype. This review provides recent information on the classical inflammatory pathway, together with a spotlight on inflammasomes and the immunomodulatory role of cellular senescence during the progression from cirrhosis to HCC. Moreover, lacunae in the current knowledge were identified and key questions raised on whether the observed adaptive responses are beneficial or detrimental to tissue homeostasis in a complex organ like liver. PMID- 24400225 TI - Shared mechanisms in stemness and carcinogenesis: lessons from oncogenic viruses. AB - A rise in technologies for epigenetic reprogramming of cells to pluripotency, highlights the potential of understanding and manipulating cellular plasticity in unprecedented ways. Increasing evidence points to shared mechanisms between cellular reprogramming and the carcinogenic process, with the emerging possibility to harness these parallels in future therapeutics. In this review, we present a synopsis of recent work from oncogenic viruses which contributes to this body of knowledge, establishing a nexus between infection, cancer, and stemness. PMID- 24400226 TI - Yersinia pestis: mechanisms of entry into and resistance to the host cell. AB - During infection, Yersinia, a facultative intracellular bacterial species, exhibits the ability to first invade host cells and then counteract phagocytosis by the host cells. During these two distinct stages, invasion or antiphagocytic factors assist bacteria in manipulating host cells to accomplish each of these functions; however, the mechanism through which Yersinia regulates these functions during each step remains unclear. Here, we discuss those factors that seem to function reversely and give some hypothesis about how bacteria switch between the two distinct status. PMID- 24400227 TI - Genetic characterization of trh positive Vibrio spp. isolated from Norway. AB - The thermostable direct hemolysin (TDH) and/or TDH-related hemolysin (TRH) genes are carried by most virulent Vibrio parahaemolyticus serovars. In Norway, trh+ V. parahaemolyticus constitute 4.4 and 4.5% of the total number of V. parahaemolyticus isolated from blue mussel (Mytilus edulis) and water, respectively. The trh gene is located in a region close to the gene cluster for urease production (ure). This region was characterized in V. parahaemolyticus strain TH3996 and it was found that a nickel transport operon (nik) was located between the first gene (ureR) and the rest of the ure cluster genes. The organization of the trh-ureR-nik-ure gene cluster in the Norwegian trh+ isolates was unknown. In this study, we explore the gene organization within the trh-ureR nik-ure cluster for these isolates. PCR analyses revealed that the genes within the trh-ureR-nik-ure gene cluster of Norwegian trh+ isolates were organized in a similar fashion as reported previously for TH33996. Additionally, the phylogenetic relationship among these trh+ isolates was investigated using Multilocus Sequence Typing (MLST). Analysis by MLST or ureR-trh sequences generated two different phylogenetic trees for the same strains analyzed, suggesting that ureR-trh genes have been acquired at different times in Norwegian V. parahaemolyticus isolates. MLST results revealed that some pathogenic and non pathogenic V. parahaemolyticus isolates in Norway appear to be highly genetically related. PMID- 24400228 TI - Competition for zinc binding in the host-pathogen interaction. AB - Due to its favorable chemical properties, zinc is used as a structural or catalytic cofactor in a very large number of proteins. Despite the apparent abundance of this metal in all cell types, the intracellular pool of loosely bound zinc ions available for biological exchanges is in the picomolar range and nearly all zinc is tightly bound to proteins. In addition, to limit bacterial growth, some zinc-sequestering proteins are produced by eukaryotic hosts in response to infections. Therefore, to grow and multiply in the infected host, bacterial pathogens must produce high affinity zinc importers, such as the ZnuABC transporter which is present in most Gram-negative bacteria. Studies carried in different bacterial species have established that disruption of ZnuABC is usually associated with a remarkable loss of pathogenicity. The critical involvement of zinc in a plethora of metabolic and virulence pathways and the presence of very low number of zinc importers in most bacterial species mark zinc homeostasis as a very promising target for the development of novel antimicrobial strategies. PMID- 24400229 TI - The role of inflammatory mediators in the development of prostatic hyperplasia and prostate cancer. AB - Benign prostatic hyperplasia and prostate cancer remain the most prevalent urologic health concerns affecting elderly men in their lifetime. Only 20% of benign prostatic hyperplasia and prostate cancer cases coexist in the same zone of the prostate and require a long time for initiation and progression. While the pathogenesis of both diseases is not fully understood, benign prostatic hyperplasia and prostate cancer are thought to have a multifactorial etiology, their incidence and prevalence are indeed affected by age and hormones, and they are associated with chronic prostatic inflammation. At least 20% of all human malignancies arise in a tissue microenvironment dominated by chronic or recurrent inflammation. In prostate malignancy, chronic inflammation is an extremely common histopathologic finding; its origin remains a subject of debate and may in fact be multifactorial. Emerging insights suggest that prostate epithelium damage potentially inflicted by multiple environmental factors such as infectious agents, dietary carcinogens, and hormones triggers procarcinogenic inflammatory processes and promotes cell transformation and disease development. Also, the coincidence of chronic inflammation and tumorigenesis in the peripheral zone has recently been linked by studies identifying so-called proliferative inflammatory atrophy as a possible precursor of prostatic intraepithelial neoplasia and prostate cancer. This paper will discuss the available evidence suggesting that chronic inflammation may be involved in the development and progression of chronic prostatic disease, although a direct causal role for chronic inflammation or infection in prostatic carcinogenesis has yet to be established in humans. Further basic and clinical research in the area, trying to understand the etiology of prostatic inflammation and its signaling pathway may help to identify new therapeutic targets and novel preventive strategies for reducing the risk of developing benign and malignant tumors of the prostate. PMID- 24400230 TI - Kidney stone composition in overweight and obese patients: a preliminary report. AB - OBJECTIVE: To report preliminary information on urinary stone composition in patients who are either overweight or obese with kidney stone disease. METHODS: A cohort of patients (n = 138) with nephrolithiasis were prospectively followed from January 2011 for 18 months. Of those, 64 (46%) were found to be overweight with body mass index >= 25 kg/m(2) and 74 (54%) were obese with body mass index >= 30 kg/m(2). Stone characteristics including size, location, and composition were studied in detail, and patients' age, weight, height, and gender were all documented. The stone size and location were studied radiologically while semiquantitative stone analysis was carried out using the DiaSys method, which involves titrimetric determination of calcium, colorimetric determination/visual assessment of oxalate, phosphate, magnesium, ammonium, uric acid, and cystine, and qualitative determination of carbonate. RESULTS: Eighteen stones were collected from overweight and obese patients. Those obtained were either spontaneously passed (n = 2), fragments passed following shockwave lithotripsy (n = 11), extracted ureteroscopically (n = 2), or extracted by percutaneous nephrolithotomy (n = 3). About 95% of the stones contained calcium oxalate and more than half contained uric acid. CONCLUSION: This report confirms that kidney stones are mainly composed of calcium oxalate and uric acid in overweight and obese patients with nephrolithiasis. PMID- 24400231 TI - Current and emerging treatment options for Peyronie's disease. AB - Peyronie's disease (PD) is a condition of the penis, characterized by the presence of localized fibrotic plaque in the tunica albuginea. PD is not an uncommon disorder, with recent epidemiologic studies documenting a prevalence of 3-9% of adult men affected. The actual prevalence of PD may be even higher. It is often associated with penile pain, anatomical deformities in the erect penis, and difficulty with intromission. As the definitive pathophysiology of PD has not been completely elucidated, further basic research is required to make progress in the understanding of this enigmatic condition. Similarly, research on effective therapies is limited. Currently, nonsurgical treatments are used for those men who are in the acute stage of PD, whereas surgical options are reserved for men with established PD who cannot successfully penetrate. Intralesional treatments are growing in clinical popularity as a minimally invasive approach in the initial treatment of PD. A surgical approach should be considered when men with PD do not respond to conservative, medical, or minimally invasive therapies for approximately 1 year and cannot have satisfactory sexual intercourse. As scientific breakthroughs in the understanding of the mechanisms of this disease process evolve, novel treatments for the many men suffering with PD are anticipated. PMID- 24400232 TI - Effect of pretreatment prostate volume on urinary quality of life following intensity-modulated radiation therapy for localized prostate cancer. AB - BACKGROUND: The aim of this study was to describe the effect of pretreatment prostate volume on urinary quality of life after intensity-modulated radiation therapy (IMRT) for clinically localized prostate cancer. METHODS: A total of 368 men treated with prostate IMRT (77.4-81 Gy) were stratified into three gland volume groups, ie, <30 g (group 1), 30-60 g (group 2), and >60 g (group 3). Post IMRT urinary function was evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 genitourinary guidelines at one year post-IMRT, and surveyed by the International Prostate Symptom Score (IPSS) before treatment, and then at one month and one year post IMRT. RESULTS: Late (one year post-IMRT) CTCAE version 4.0 genitourinary toxicity occurred in 11/368 (3.0%) men, but was not severe (grade >= 3); total toxicity was similar between the prostate volume groups (P = 0.86). Continuous prostate volume neither correlated with (P = 0.50) nor predicted late genitourinary toxicity (univariate odds ratio 0.99, 95% confidence interval 0.96-1.02). The total IPSS cohort, group 1 (<30 g) and 2 (30-60 g), showed a similar IPSS trend of elevation from pretreatment baseline to one month post-IMRT (each P < 0.01), then a reduction to baseline at one year (each P < 0.01). Group 3 (>60 g) had the highest pretreatment IPSS, but uniquely showed a better urinary symptom trend than the smaller volume groups, with similar IPSS from baseline to one month post IMRT (P = 0.88) and improved post-treatment IPSS from baseline at one year (P = 0.003). CONCLUSION: Pretreatment prostate volume and initial IPSS scores were not associated with increased late genitourinary toxicity after IMRT in our series. Patients with smaller prostates had an initial increase in urinary symptoms, but returned to baseline at one year. Larger prostate glands (>60 g) had comparatively worse pretreatment symptoms, but at one year showed an overall improvement in IPSS versus baseline. PMID- 24400233 TI - Efficacy and safety of the phytotherapeutic drug Canephron(r) N in prevention and treatment of urogenital and gestational disease: review of clinical experience in Eastern Europe and Central Asia. AB - This review evaluates 17 clinical studies from 18 selected publications concerning the safety, tolerability, and additional effects of the phytotherapeutic drug, Canephron(r) N (CAN, containing the medicinal plants, Centaurium erythraea, Levisticum officinale, and Rosmarinus officinalis) as standard therapy in various clinical settings. Its role in the prophylaxis and treatment of urinary tract infections in adults and in children, therapy and prophylaxis in adult patients with renal stones, treatment and prevention of urinary tract infections and other gestational diseases in pregnancy, and also its safety and tolerability. The dosage was as recommended and over a varying duration. Overall, CAN was shown to be effective in the treatment and prophylaxis of UTI compared with standard therapy, both in adults and children, and there was a reduced number of relapses. Children undergoing surgical correction of vesicoureteral reflux benefited from a prophylactic course of CAN. Ten-day add on therapy increased the rate of spontaneous elimination of kidney stones compared with standard therapy alone and may also have had a positive effect on stone prevention. Pregnant women showed earlier relief of symptoms and normalization of pyuria on additional treatment with the herbal combination. Only one adverse effect was reported (skin rash) in the 3115 patients included in this review. No teratogenic, embryotoxic, or fetotoxic effects, or negative interference with the psychological development or health of children born of mothers treated with the drug were reported. Because some of the studies were not well designed, their statistical significance remains unclear. PMID- 24400234 TI - Short-term outcomes of the surgical management of acquired rectourethral fistulas: does technique matter? AB - BACKGROUND: Acquired rectourethral fistulas are uncommon and challenging to repair. Most arise as a complication of prostate cancer treatment. Several procedures have been described to repair rectourethral fistulas with varying outcomes. We review the etiology, management, and outcomes of patients with rectourethral fistulas at our institution. MATERIALS AND METHODS: A retrospective review of patients undergoing repair of rectourethral fistulas was undertaken. Data were collected on patient demographics, fistula etiology, operative procedure, fecal and urinary diversion, and clinical outcome. Patients with urinary and/or fecal diversion underwent radiographic evaluation to confirm closure of the fistula prior to reversal of the diversion. RESULTS: Fistula repair was performed on 22 patients from 1999 to 2009. All the patients were male of an average age of 69 years (range: 39-82 years). All patients, except one, had prostate cancer. Fistula formation was associated with radiotherapy in 54.4% of patients, brachytherapy in 36.4% of patients, and with external beam radiation therapy in 18.2% of patients. Other causes included prostatectomy (seven patients, 31.8%), cryotherapy (two patients, 9.1%), and perianal abscess (one patient, 4.5%). Procedures performed for fistula repair included transanal repair (eleven patients, 50%), transperineal repair (five patients, 22.7%), transabdominal repair (three patients, 13.6%), and York-Mason repair (three patients, 13.6%). Fourteen patients (63.6%) had urinary diversion. Fecal diversion was performed in 16 (72.7%) patients. Five (22.7%) patients had had previous attempts at fistula repair. Of the 22 patients treated, repair was successful in 20 patients (91%). The average follow-up time was 6 months (range: 3-13 months). CONCLUSION: The success rate of treatment of rectourethral fistulas is high, regardless of the procedure type. Patients with previous repair attempts tend to have less favorable outcomes. With high success rates, less invasive procedures should be attempted first. PMID- 24400236 TI - Perioperative management of classic bladder exstrophy. AB - The exstrophy-epispadias complex is a rare congenital malformation of the genitourinary system, abdominal wall muscles, and pelvic structures. Modern surgical repairs focus on reconstruction of the bladder and its adjacent structures, with the goal of achieving urinary continence, a satisfactory cosmetic result, and a high quality of life. Complex surgery in neonates and young children, as well as a prolonged postoperative course require close collaboration between surgeons, anesthesiologists, intensivists, pediatricians, and an experienced nursing staff. This article will review the spectrum of bladder exstrophy anomalies, the surgical repair, and the perioperative interdisciplinary management. PMID- 24400237 TI - Procalcitonin as an indicator of urosepsis. AB - BACKGROUND: Procalcitonin has been advocated as a marker of bacterial infection, so this study was carried out to determine the usefulness of serum procalcitonin in the early diagnosis of urosepsis. METHODS: The subjects were 37 febrile patients with urinary tract infection in whom we examined the serum procalcitonin concentration at the start of treatment. RESULTS: Thirty patients had acute pyelonephritis (16 simple, 14 complex), one had emphysematous pyelonephritis, five had acute prostatitis, and one had acute epididymitis. The procalcitonin level was <0.5 ng/mL in 18 patients, >=0.5 ng/mL in one patient, >=2 ng/mL in seven patients, and >=10 ng/mL in 11 patients. Five of the 11 patients with procalcitonin levels >= 10 ng/mL had disseminated intravascular coagulation. All patients with urinary tract obstruction and disseminated intravascular coagulation had procalcitonin levels >= 10 ng/mL. CONCLUSION: Although this retrospective study comprised a small number of patients, we found that procalcitonin was a useful marker for urinary tract infection. PMID- 24400235 TI - New therapeutic targets in the management of urothelial carcinoma of the bladder. AB - Urothelial carcinoma of the bladder, despite the myriad of treatment approaches and our progressively increasing knowledge into its disease processes, remains one of the most clinically challenging problems in modern urological clinical practice. New therapies target biomolecular pathways and cellular mediators responsible for regulating cell growth and metabolism, both of which are frequently overexpressed in malignant urothelial cells, with the intent of inducing cell death by limiting cellular metabolism and growth, creating an immune response, or selectively delivering or activating a cytotoxic agent. These new and novel therapies may offer a potential for reduced toxicity and an encouraging hope for better treatment outcomes, particularly for a disease often refractory or not amenable to the current therapeutic approaches. PMID- 24400239 TI - Involvement of magnitude of ambient temperature change in nonspecific effect in perceived placebo effect on lower urinary tract symptoms: study on switching of naftopidil in patients with benign prostatic hyperplasia. AB - PURPOSE: To determine if switching from one brand of the alpha1-adrenoceptor antagonist naftopidil (AvishotTM) to another brand (FlivasTM) under the same conditions causes the same changes in lower urinary tract symptoms (LUTS) and quality of life (QOL) as the perceived placebo effect, and if ambient temperature as a nonspecific factor is related to those changes in benign prostatic hyperplasia (BPH) patients. PATIENTS AND METHODS: A retrospective study was carried out on 217 BPH patients who had received AvishotTM for more than 6 months and then were switched to FlivasTM at the same dose and timing. The two drugs contain the same principal ingredient and display the same pharmacokinetic properties. The International Prostate Symptom Score (IPSS), QOL score, and average monthly ambient temperature at the patients' residence area from the Automated Meteorological Data Acquisition System in Japan were used for the evaluation. RESULTS: A significant change in urinary storage symptoms (P = 0.006), and especially in nighttime frequency (P< 0.001), was observed by switching drugs, suggesting the perceived placebo effect. There was significant improvement of daytime frequency (P< 0.05), nighttime frequency (P< 0.001), storage symptoms (P< 0.001), and total IPSS (P< 0.05) when the magnitude of ambient temperature change from before and 3 months after switching drugs was higher than 10 degrees C, while no significant improvement was noted in any of the parameters examined when the same was lower than 10 degrees C. CONCLUSION: The present study showed the nonspecific effect of magnitude of ambient temperature change was involved in the perceived placebo effect on LUTS, especially on storage symptoms, by switching drugs. The nonspecific effect on LUTS with BPH needs to be considered when evaluating subjective treatment efficacy of drugs for LUTS with BPH in routine clinical practice. The present study supports the lifestyle advice "avoid exposing the lower body to cold temperature" or "keep warm when it is cold" for LUTS with BPH. PMID- 24400240 TI - The effect of obesity and components of metabolic syndrome on urinary and sexual functions in Saudi men. AB - OBJECTIVE: To establish a possible association between obesity, measured by waist circumference (WC) and body mass index (BMI), and voiding and sexual functions in a random cohort of Saudi men. MATERIALS AND METHODS: An outpatient men's health clinic was set up at King Abdulaziz University Hospital in Jeddah, Saudi Arabia and men were invited to discuss their sexual and urinary functions. The data collected included age, WC, weight, height, blood pressure, history of diabetes, hypertension, and smoking. The International Prostate Symptom Score (IPSS) and the International Inventory of Erectile Function (IIEF-5) questionnaire were used to assess urinary tract symptoms and sexual function, respectively. Serum testosterone, prostate-specific antigen and cholesterol levels were measured and documented. Data were analyzed using the Statistical Package for the Social Sciences. RESULTS: We recruited 113 participants. The mean WC and BMI of the men were 104 +/- 14.599 cm and 29.706 kg/m(2), respectively. Thirty-seven men (32.7%) had an IPSS >= 8 points. Sexual disorders were reported in 19 men; 16 men had erectile dysfunction, while three had premature ejaculation. Of the whole cohort, 37 men were diabetic, of which 15 (40.5%) had an IPSS >= 8 and 13 (35%) were either overweight or obese. CONCLUSION: Increased WC and BMI were associated with diabetes mellitus and large percentages of voiding and sexual disorders. PMID- 24400242 TI - Therapeutic efficacy and anti-inflammatory effect of ramelteon in patients with insomnia associated with lower urinary tract symptoms. AB - OBJECTIVES: This study was conducted to examine the therapeutic efficacy and anti inflammatory effect of ramelteon in elderly patients with insomnia associated with lower urinary tract symptoms (LUTS), who visited our urology department. METHODS: The study included 115 patients (102 men, 13 women) who scored >=4 on the Athens Insomnia Scale and who wished to receive treatment. The assessment scales for therapeutic efficacy included the International Prostate Symptom Score (IPSS) for LUTS and the Insomnia Severity Index (ISI) for sleep disorders. The high-sensitivity C-reactive protein (hs-CRP) test was used to an objective assessment. The patients were treated with ramelteon (8 mg/day) for an average of 10 weeks and were then reexamined using the questionnaires and hs-CRP test to evaluate therapeutic efficacy. RESULTS: IPSS total scores declined significantly from 11.39 +/- 8.78 to 9.4 +/- 7.72. ISI total scores improved significantly from 11.6 +/- 5.2 to 9.2 +/- 5.3 (P < 0.0001). The levels of hs-CRP decreased significantly from 0.082 (standard deviation [SD] upper limit, 0.222; SD lower limit, -0.059) to 0.06 (SD upper limit, 0.152; SD lower limit, -0.032). The ISI scores >= 10 (n = 51) showed a weak correlation with the hs-CRP levels. CONCLUSION: Ramelteon had a systemic anti-inflammatory effect and improved sleep disorders and LUTS, suggesting that it may be a useful treatment for patients with LUTS-associated insomnia. PMID- 24400241 TI - The use of a single daily dose of tadalafil to treat signs and symptoms of benign prostatic hyperplasia and erectile dysfunction. AB - A strong and independent association between lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) and erectile dysfunction (ED) has been widely evidenced in several clinical epidemiologic studies. Preclinical animal models have provided a great deal of information on potential common pathogenic mechanisms underlying these two clinical identities. Although the efficacy of the most commonly used treatments for LUTS/BPH is well defined, the negative impact of these treatments on sexual function - in particular, on ED - has triggered the search for new treatment options. In this regard, a new role for phosphodiesterase type 5 inhibitors in the treatment of LUTS/BPH and ED has been claimed. Tadalafil is one of the most extensively investigated phosphodiesterase type 5 inhibitors for this new indication. All evidence reported to date suggests that tadalafil 5 mg once daily is a safe and effective treatment option for both LUTS/BPH and ED. PMID- 24400243 TI - Pelvic lymph node dissection in the context of radical cystectomy: a thorough insight into the connection between patient, surgeon, pathologist and treating institution. AB - Pelvic lymph node dissection (PLND) in patients with bladder cancer varies widely in extent, technique employed, and pathological workup of specimens. The present paper provides an overview of the existing evidence regarding the effectiveness of PLND and elucidates the interactions between patient, surgeon, pathologist, and treating institution as well as their cumulative impact on the final postoperative lymph node (LN) staging. Bladder cancer patients undergoing radical cystectomy with extended PLND appear to have better oncologic outcomes compared to patients undergoing radical cystectomy and limited PLND. Attempts have been made to define and assess the quality of PLND according to the number of lymph nodes identified. However, lymph node counts depend on multiple factors such as patient characteristics, surgical template, pathological workup, and institutional policies; hence, meticulous PLND within a defined and uniformly applied extended template appears to be a better assurance of quality than absolute lymph node counts. Nevertheless, the prognosis of the patients can be partially predicted with findings from the histopathological evaluation of the PLND specimen, such as the number of positive lymph nodes, extracapsular extension, and size of the largest LN metastases. Therefore, particular prognostic parameters should be addressed within the pathological report to guide the urologist in terms of patient counseling. PMID- 24400244 TI - The conceptualization and development of a patient-reported neurogenic bladder symptom score. AB - BACKGROUND: There is no single patient-reported instrument that was developed specifically to assess symptoms and bladder-related consequences for neurogenic bladder dysfunction. The purpose of this study was to identify and consolidate items for a novel measurement tool for this population. METHODS: Item generation was based on a literature review of existing instruments, open-ended semistructured interviews with patients, and expert opinion. Judgment-based item reduction was performed by a multidisciplinary expert group. The proposed questionnaire was sent to external experts for review. RESULTS: Eight neurogenic quality of life measures and 29 urinary symptom-specific instruments were identified. From these, 266 relevant items were extracted and used in the creation of the new neurogenic symptom score. Qualitative interviews with 16 adult patients with neurogenic bladder dysfunction as a result of spinal cord injury, multiple sclerosis, or spina bifida were completed. Dominant themes included urinary incontinence, urinary tract infections, urgency, and bladder spasms. Using the literature review and interview data, 25 proposed items were reviewed by 12 external experts, and the questions evaluated based on importance on a scale of 1 (not important) to 5 (very important). Retained question domains had high mean importance ratings of 3.1 to 4.3 and good agreement with answer hierarchy. CONCLUSION: The proposed neurogenic bladder symptom score is a novel patient-reported outcome measure. Further work is underway to perform a data based item reduction and to assess the validity and reliability of this instrument. PMID- 24400245 TI - Effectiveness of epidural versus alternate analgesia for pain relief after radical prostatectomy and correlation with biochemical recurrence in men with prostate cancer. AB - OBJECTIVES: Our objectives were to analyze the effectiveness of epidural anesthesia in patients who underwent open retropubic radical prostatectomy (RRP) at our institution over the past decade, and to examine subsequent oncologic outcomes, comparing those receiving with those not receiving epidural anesthesia. METHODS: A comprehensive database of all patients undergoing RRP from November 1996 to December 2006 was analyzed; 354 patients underwent RRP at our institution and were divided into those receiving or not receiving an epidural. An independent pain management team scoring technical success found epidural technique to be consistent. Oncological outcome was an endpoint of our study, comparing both analysis groups. We classed prostate-specific antigen (PSA) recurrence after RRP as a serum PSA >= 0.2 ng/mL at any stage of postoperative follow-up. Complications were recorded to 30 days using the modified Clavien system, and full statistical analyses were undertaken. RESULTS: Records were available for 239 men; we observed a decreased trend in the use of epidural for pain management, along with a decrease in average hospital stay and an overall epidural success rate of 64%. When dividing data into RRP with and without epidural, we found a median hospital stay of 7 days for patients receiving an epidural compared with 6 days for those not receiving an epidural. The differences were statistically significant (P < 0.048) and remained so after adjusting for complications (P < 0.0001). Regarding oncological outcome, PSA recurrence was further analyzed in this cohort. Percentage of recurrence was higher (14.8%) for patients receiving an epidural than for the non-epidural group (4.8%). The differences were statistically significant (P = 0.012). CONCLUSION: Epidural analgesia increased length of hospital stay and technical problems related to the epidural. Furthermore, men receiving an epidural showed an increased recurrence of PSA. In light of our findings, epidurals are probably not indicated for men undergoing RRP. However, as minimally invasive techniques are becoming more widespread, and epidural analgesia is being used less frequently, large randomized controlled trials to definitively support our hypotheses are unlikely to be undertaken. PMID- 24400246 TI - Impact of mirabegron extended-release on the treatment of overactive bladder with urge urinary incontinence, urgency, and frequency. AB - Overactive bladder is a highly prevalent disorder with a significant impact on quality of life. Antimuscarinic agents are commonly used, but persistence is limited due to unsatisfactory efficacy and/or tolerability. Mirabegron is the first beta-3 adrenoceptor agonist approved for the treatment of overactive bladder syndrome. This paper reviews the pharmacology, mechanism of action, efficacy, and safety of mirabegron. A PubMed search of all English articles pertaining to mirabegron was performed. An alternative to antimuscarinics, mirabegron has a unique mechanism, improves overactive bladder symptoms and quality of life, and has limited adverse effects and few contraindications. PMID- 24400247 TI - Sensorimotor polyneuropathy and foot-drop as result of a prostate cancer paraneoplastic syndrome. AB - Paraneoplastic syndromes (PNS) vary in incidence and manifestation based on tumor histology. PNS secondary to urologic malignancies have an extremely low incidence. Most reported cases of PNS from urologic malignancies are associated with adenocarcinoma. Peripheral neuropathy-associated PNS from urologic malignancy are exceedingly rare. An 80-year-old male developed a paraneoplastic sensorimotor polyneuropathy and foot-drop after a diagnosis of clinical stage T2cN0M0, Gleason grade 5+4 prostate cancer. A thorough workup is needed in order to adequately assess and treat PNS. Careful analysis must be used to determine the root cause of a patient's symptoms. PMID- 24400248 TI - Pharmacotherapy of overactive bladder in adults: a review of efficacy, tolerability, and quality of life. AB - INTRODUCTION: Overactive bladder (OAB) is a prevalent condition that has a significant impact on quality of life. The usual treatment approach is both behavioral and pharmacological. The first-line pharmacological treatment commonly utilizes anticholinergic agents, which may be limited by their tolerability, efficacy, and long-term compliance. Developments in elucidating the pathophysiology of OAB and alternative targets for pharmacological therapy have led to newer agents being developed to manage this condition. These agents include mirabegron and botulinum toxin, which have alternate mechanism of action and avoid the anticholinergic side effects. OBJECTIVES: To provide an update for clinicians managing OAB with an overview of the existing and newer medical options for OAB, including pharmacology, efficacy, side-effect profile, tolerability, and impact on patient quality of life. METHODS: PubMed and Medline were searched for randomized controlled drug trials in adults with OAB, meta analyses of medical therapy for OAB, and individual drug names, including the keywords efficacy, tolerability, quality of life, and compliance. Nonhuman studies, pediatric trials, and those involving patients with neurogenic bladder dysfunction (with the exception of studies involving botulinum toxin A) were excluded. RESULTS: There is level 1, Grade A evidence to support the efficacy of anticholinergic drugs, botulinum toxin, and mirabegron for OAB. Long-term compliance with anticholinergic medications is limited. The mechanism of action, effectiveness, and side effects of these drugs are discussed, and where the data are available compared with other OAB medications. CONCLUSION: Most of the anticholinergic agents have comparative efficacies and core side-effect profiles, with individual variations relating to their muscarinic receptor selectivity, pharmacokinetics, and metabolism. Newer agents, with alternative sites of action, such as mirabegron and botulinum toxin, provide additional treatment options for patients intolerant to or inadequately treated with anticholinergics. PMID- 24400250 TI - Pediatric Gastroenterology-challenges great and small. PMID- 24400249 TI - Systemic venous anomalies in the Middle East. AB - INTRODUCTION: Systemic venous anomalies are quite rare and can be associated with congenital heart disease requiring surgery. MATERIALS AND METHODS: All consecutive patients (pts) undergoing surgery for congenital heart defects were retrospectively analyzed for presence of systemic venous anomalies: (a) Persistent left superior vena cava (PLSVC)(b) Inferior vena cava (IVC) interruption(c) Retro-aortic innominate vein Results: From 9/2010 to 5/2012 155 pts, median age 7 months, mean age 1.3 years (3 days-50 years), median weight 4 kg, mean weight 7.2 kg (0.6-110 kg) underwent congenital heart surgery. Twenty nine systemic venous anomalies were identified in 28/155 patients (=18.1%). PLSVC was present in 21 pts (=13.5%), median age 4 months, mean age 2.7 years (3 days 22 years), median weight 6 kg, mean weight 10.1 kg (2.4-43.0 kg). IVC interruption was identified in 5 pts (=3.2%), median age 2 months, mean age 5.4 years (30 days-26 years), median weight 3.7 kg, median weight 17 kg (2.3-68.0 kg). Retro-aortic innominate vein was diagnosed in 3 pts (=1.9%), median age 5 years, mean age 3.7 years (10 months-5 years), median weight 12 kg, mean weight 10.1 kg (4.5-14 kg). Complete pre-operative diagnosis was obtained in 14/28 (=50%) pts with echocardiography and in other 8/28 (=28.6%) only after computed tomography (CT) scan, for a total of 22/28 (=78.6%) correct pre-operative diagnosis. In 6/28 (=21.4%) patients the diagnosis was intra-operative. Total incidence of systemic venous anomalies was 18.1% (vs. 4% in the literature, P = 0.0009), with presence of PLSVC = 13.5% (vs. 0.3-4.0%, respectively P = 0.0004 and P = 0.0012), IVC interruption = 3.2% (vs. 0.1-1.3%, N.S.), and retro-aortic innominate vein = 1.9% (vs. 0.2-1%, N.S.). CONCLUSIONS: Our study showed an incidence of systemic venous anomalies in Middle Eastern pts with congenital heart defects higher than previously reported. In 78.6% of pts the diagnosis was correctly made before surgery (echocardiography or CT scan), with 21.4% of complete diagnosis made at surgery. A careful pre-operative screening should be performed in all pts with congenital heart defects from this region to better identify all systemic venous anomalies for a more accurate surgical planning. PMID- 24400251 TI - Frontiers in pediatric cardiology-specialty grand challenge. PMID- 24400252 TI - Great challenges in pediatrics. PMID- 24400253 TI - Biomarkers of pediatric brain tumors. AB - Background and Need for Novel Biomarkers: Brain tumors are the leading cause of death by solid tumors in children. Although improvements have been made in their radiological detection and treatment, our capacity to promptly diagnose pediatric brain tumors in their early stages remains limited. This contrasts several other cancers where serum biomarkers such as cancer antigen (CA) 19-9 and CA 125 facilitate early diagnosis and treatment. AIM: The aim of this article is to review the latest literature and highlight biomarkers which may be of clinical use in the common types of primary pediatric brain tumor. METHODS: A PubMed search was performed to identify studies reporting biomarkers in the bodily fluids of pediatric patients with brain tumors. Details regarding the sample type [serum, cerebrospinal fluid (CSF), or urine], biomarkers analyzed, methodology, tumor type, and statistical significance were recorded. RESULTS: A total of 12 manuscripts reporting 19 biomarkers in 367 patients vs. 397 controls were identified in the literature. Of the 19 biomarkers identified, 12 were isolated from CSF, 2 from serum, 3 from urine, and 2 from multiple bodily fluids. All but one study reported statistically significant differences in biomarker expression between patient and control groups. CONCLUSION: This review identifies a panel of novel biomarkers for pediatric brain tumors. It provides a platform for the further studies necessary to validate these biomarkers and, in addition, highlights several techniques through which new biomarkers can be discovered. PMID- 24400254 TI - De-politicizing youth suicide prevention. AB - Despite a large volume of research literature on suicide, the approach to suicide prevention is still firmly based on a medical model. Recently, the Chief Coroner in New Zealand expressed the view that current techniques have failed to reduce the suicide rate and a new approach is needed. However, the call for a new approach is often interpreted as disparities in access to mental health services so resources are directed to increase public access to them. Current evidence suggests that persisting with depression and mental illness as a rationale for suicide prevention is unwise and is highly politicized. For example, over the last decade or so, despite a sustained awareness campaign on depression and mental illness and the doubling of prescriptions for anti-depressants, suicide rates maintained an increasing trend over the same period. It is argued that a new approach must redefine the suicide prevention problem holistically so that the whole community may share ownership of the problem. This paper argues that in order to move forward with a new approach, suicide prevention must be de politicized - and describes a grassroots approach to de-politicization. Initial results suggest that with the grassroots approach there is potential to save lives, and it is cost-effective and sustainable. PMID- 24400255 TI - A review of the use of complementary and alternative medicines by children with inflammatory bowel disease. AB - The Inflammatory Bowel Diseases (IBDs) are diagnosed more commonly in children and adolescents. Following diagnosis, the key objectives are to achieve and then maintain remission. Although some therapies are able to effectively modify and modulate inflammatory events, none of the available interventions cure these conditions. Consequently, children and their parents face uncertainty and may look to alternative management options as ways to help their child, which may include various complementary and alternative medicines (CAMs). A number of studies have shown that many children with IBD receive or are given CAM agents. This article reviews the rates and patterns of CAM use in children with IBD, and emphasizes the increasing importance of these aspects of the management of children with IBD. PMID- 24400256 TI - Grand challenges in pediatric otolaryngology. PMID- 24400259 TI - Neonatology specialty grand challenge. PMID- 24400257 TI - Transposition of great arteries: new insights into the pathogenesis. AB - Transposition of great arteries (TGA) is one of the most common and severe congenital heart diseases (CHD). It is also one of the most mysterious CHD because it has no precedent in phylogenetic and ontogenetic development, it does not represent an alternative physiological model of blood circulation and its etiology and morphogenesis are still largely unknown. However, recent epidemiologic, experimental, and genetic data suggest new insights into the pathogenesis. TGA is very rarely associated with the most frequent genetic syndromes, such as Turner, Noonan, Williams or Marfan syndromes, and in Down syndrome, it is virtually absent. The only genetic syndrome with a strong relation with TGA is Heterotaxy. In lateralization defects TGA is frequently associated with asplenia syndrome. Moreover, TGA is rather frequent in cases of isolated dextrocardia with situs solitus, showing link with defect of visceral situs. Nowadays, the most reliable method to induce TGA consists in treating pregnant mice with retinoic acid or with retinoic acid inhibitors. Following such treatment not only cases of TGA with d-ventricular loop have been registered, but also some cases of congenitally corrected transposition of great arteries (CCTGA). In another experiment, the embryos of mice treated with retinoic acid in day 6.5 presented Heterotaxy, suggesting a relationship among these morphologically different CHD. In humans, some families, beside TGA cases, present first-degree relatives with CCTGA. This data suggest that monogenic inheritance with a variable phenotypic expression could explain the familial aggregation of TGA and CCTGA. In some of these families we previously found multiple mutations in laterality genes including Nodal and ZIC3, confirming a pathogenetic relation between TGA and Heterotaxy. These overall data suggest to include TGA in the pathogenetic group of laterality defects instead of conotruncal abnormalities due to ectomesenchymal tissue migration. PMID- 24400258 TI - Dendritic cell vaccination in pediatric gliomas: lessons learnt and future perspectives. AB - Immunotherapy of malignant gliomas with autologous dendritic cells (DCs) in addition to surgery and radiochemotherapy has been a focus of intense research during the past decade. Since both children and adults are affected by this highly aggressive brain tumor, 10-15% of the several hundred vaccinated patients represent children, making pediatric glioma patients the largest uniform pediatric vaccination cohort so far. In general, DC vaccination in malignant gliomas has been shown to be safe and several studies with a non-vaccinated control group could clearly demonstrate a survival benefit for the vaccinated patients. Interestingly, children and adolescents below 21 years of age seem to benefit even more than adult patients. This review summarizes the findings of the 25 clinical trials published so far and gives a perspective how DC vaccination could be implemented as part of multimodal therapeutic strategies in the near future. PMID- 24400260 TI - Specialty grand challenge - pediatric pulmonology. PMID- 24400261 TI - Frontiers in pediatric urology - specialty grand challenge. PMID- 24400262 TI - Multiple ventricular septal defects: a new strategy. AB - INTRODUCTION: A multicenter prospective study was conducted to evaluate a new strategy for multiple Ventricular Septal Defects (VSDs). MATERIALS AND METHODS: From 2004 to 2012 17 consecutive children (3 premature, 14 infants), mean age 3.2 months (9 days-9 months), mean body weight 4.2 kg (3.1-6.1 kg), with multiple VSDs underwent Pulmonary Artery Banding (PAB) with an adjustable FloWatch PAB((r)). Associated cardiac anomalies included patent ductus arteriosus (1), aortic coarctation (2), hypoplastic aortic arch (2), and left isomerism (3). Five patients (5/17 = 29.4%) required pre-operative mechanical ventilation, with a mean duration of 64 days (7-240 days) RESULTS: There were no early or late deaths during a mean follow-up of 48 months (7-98 months), with either FloWatch removal or last observation as end-points. FloWatch-PAB((r)) adjustments were required in all patients: a mean of 4.8 times/patient (2-9) to tighten the PAB, and a mean of 1.1 times/patient (0-3) to release the PAB with the patient's growth. After a mean interval of 29 months (8-69 months) 10/17 (59%) patients underwent re operation: 7/10 PAB removal, with closure of a remaining unrestrictive VSD in 6 (peri-membranous in 3 patients, mid-muscular in 2, and inlet in 1) and Damus-Kaye Stansel, bi-directional Glenn, and atrial septectomy in 1; 3/9 patients required only PAB removal. All muscular multiple VSDs had closed in all 10 patients. PA reconstruction was required in 1/10 patient. In 5/7 of the remaining patients with the PAB still in situ, all muscular VSDs had already closed. The only 2 patients with persistent muscular multiple VSDs are the 2 patients with the shortest follow-up. CONCLUSION: This reproducible new strategy with an adjustable PAB simplifies the management of infants with multiple VSDs and provides the following advantages: (a) good results (0% mortality), delayed surgery with a high incidence (15/17 = 88%) of spontaneous closure of multiple muscular VSDs, and facilitated closure of residual unrestrictive VSD (peri-membranous, mid muscular, or inlet) at an older age and higher body weight; PAB with FloWatch PAB((r)) and its subsequent removal can potentially be the only procedure required for Swiss cheese multiple VSDs without an associated peri-membranous unrestrictive VSD. PMID- 24400263 TI - Pulmonary Artery Banding is Still a Valuable Option. PMID- 24400264 TI - Positive youth development, life satisfaction, and problem behaviors of adolescents in intact and non-intact families in Hong Kong. AB - This study investigated whether Chinese adolescents living in intact and non intact families differed in their positive development, life satisfaction, and risk behavior. A total of 3,328 Secondary 1 students responded to measures of positive youth development (such as resilience and psychosocial competencies), life satisfaction, and risk behavior (substance abuse, delinquency, Internet addiction, consumption of pornographic materials, self-harm, and behavioral intention to engage in problem behavior). Findings revealed that adolescents growing up in intact families reported higher levels of positive developmental outcomes and life satisfaction as compared with adolescents from non-intact families. Adolescents in non-intact families also reported higher levels of risk behaviors than those growing up in intact families. PMID- 24400265 TI - Physical therapy for young children diagnosed with autism spectrum disorders clinical frameworks model in an israeli setting. AB - Recent research findings suggest that many children with Autism Spectrum Disorders (ASD) demonstrate delayed and atypical motor achievements. It has now become clear that a more holistic, integrative and multi-disciplinary intervention is required to effectively address the motor-related impairments of this population. It is also crucial to ensure that this group of clients has access to early physical therapy (PT) interventions. Despite accumulating research on physical interventions, little is known about intervention model for implementation at a national level. This report introduces a model that uniquely illustrates implementation of PT services for a large number of children with ASD. The model has been operating for the past 2 years in one country (Israel), and includes an optional implementation model of PT practice settings for young children diagnosed with ASD. The Israeli setting offers a unique opportunity for implementing PT services for a multitude of children with ASD on a regular basis as an accepted/needed service. The initial outcomes of the present implementation suggest that an intensive PT intervention program might enhance therapeutic outcomes for this population, and contribute to our knowledge on the potential of PT for individuals with ASD. PMID- 24400266 TI - Tobacco or healthy children: the two cannot co-exist. AB - Tobacco exposure increases mortality and morbidity of the fetus, the child, the adolescent, and their children in turn. Nearly half the children in the world are exposed. Smoking is not merely personal choice or personal responsibility; those subtle phrases undermine those who have no choice in the matter. Tobacco control must take a multi-pronged attack. Smoking cessation by adults in childbearing years must take center stage of these efforts, because it is the only way to ensure a smoke-free environment for children. Smoke-free parents provide a role model for smoke-free young people, and erode the image of smoking as a desirable adult behavior to emulate. Pediatricians and pediatric pulmonologists have a key role to play here. This goal will reduce morbidity and mortality among adults and children. Legislation regarding taxation, environments, tobacco constituents, product placement and display, packaging, and media education are all key to this core goal. Smoke-free policy must be protected from attack based on trade agreements. Research is needed into more effective ways to attract and help people give up smoking, and into educating and re-deploying tobacco industry workers in emerging and developed countries. PMID- 24400267 TI - Associations between Infant Feeding Practices and Length, Weight, and Disease in Developing Countries. AB - The health benefits of exclusive breastfeeding are well-known, but the relative detrimental impacts of other foods on infant health are unknown. Because infants in developing countries are fed a wide range of food, quantifying the burden of these diverse feeding practices on infant health is essential for public health policy. We used data from the Demographic Health Survey from 20 developing countries over multiple years to examine the independent association of six different types of food (exclusive breastfeeding, non-exclusive breastfeeding, infant formula, milk liquids, non-milk liquids, and solid foods) with five measures of infant health (length, weight, diarrhea, fever, and cough). We estimated associations with regression analysis, controlling for confounding factors with infant, mother, and household factors and community-year fixed effects. We used these estimates in a simulation model to quantify the burden of different combinations of food on infant health. We show that for an infant younger than 6 months old, following current guidelines and exclusively breastfeeding instead of giving the infant solid foods may increase length by 0.75 cm and weight by 0.25 kg and decrease diarrhea, fever, and cough prevalence by 8, 12, and 11%, respectively. We found that the burden on infant health of some feeding practices is less than others. Although all other feeding practices are associated with worse health outcomes than exclusive breastfeeding, breastfeeding supplemented with liquids has a lower burden on infant health than solid foods and infant formula has a lower burden than milk or non-milk liquids as measured by four of five health metrics. Providing specific quantified burden estimates of these practices can help inform public health policy related to infant feeding practices. PMID- 24400268 TI - Preventing germinal matrix layer rupture and intraventricular hemorrhage. AB - The etiology of intraventricular hemorrhage (IVH) in extremely low birth weight preterm infants is multifactorial with circulatory instability and hemostasis being preeminent. This study sought to determine if the germinal matrix layer remained intact when platelets were above 200 * 10(9)/L, a near normal level, and fell below that when IVH occurred. This was a retrospective study of platelets and head ultrasounds (HUS) in infants 23-28 weeks gestation. Analyses were descriptive, one way analysis of variance, Pearson Chi-square tests, and t-tests. Platelet counts and HUS were linked in 114 infants during the first 3 days when 90% of IVHs occur. Mean platelet levels were >200 * 10(9)/L in 68% of infant 23 24 weeks gestation and 78% of those 25-26 weeks when there were no IVHs. These findings, if confirmed, suggest that improving hemostasis in high risk preterm infants by keeping platelet levels >200 * 10(9)/L may maintain the integrity of the germinal matrix layer and prevent IVHs. PMID- 24400269 TI - Pathophysiology, management, and outcome of persistent pulmonary hypertension of the newborn: a clinical review. AB - Persistent Pulmonary Hypertension of the Newborn (PPHN) results from the failure of relaxation of the pulmonary vasculature at birth, leading to shunting of non oxygenated blood from the pulmonary to the systemic circulation. More often, full term and near-term infants are affected, however it is not uncommon to see PPHN in preterm infants who have respiratory distress syndrome. In some infants pulmonary vascular remodeling is present at birth, pointing toward the prenatal onset of the disease process. Regardless of the etiology, PPHN should be diagnosed and treated as soon as possible to avoid hypoxia related short term and long-term morbidities. The mainstay therapy is the treatment of the underlying condition along with several promising therapeutic modalities such as oxygen supplementation, mechanical ventilation, nitric oxide, phosphodiesterase inhibitors, prostaglandins analogs, endothelin receptor antagonists, and extracorporeal membrane oxygenation. The optimal approach to the management of PPHN remains controversial. After discharge from the NICU, infants with PPHN warrant long-term follow up since they are at risk for neurodevelopmental disabilities and chronic health conditions. PMID- 24400270 TI - The challenges facing training in pediatric surgery worldwide. AB - Like most specialties, pediatric surgery is becoming more complex, and changes to health systems have not always been in the best interests of trainees or their surgical teachers. This paper outlines four of the current challenges faced by training boards in pediatric surgery worldwide, and documents their implications for the future training of pediatric surgeons. PMID- 24400271 TI - Alternatives to conventional enterocystoplasty in children: a critical review of urodynamic outcomes. AB - Alternatives to conventional enterocystoplasty have been developed in order to avoid the most common complications derived from contact of the urine with intestinal mucosa. In this article critically we review the literature on the topics: ureterocystoplasty, detrusorectomy, detrusorotomy, seromuscular gastroenterocystoplasty, use of off the shelf biomaterials, and bladder augmentation by bioengineering. Recognizing the difficulty of deciding when a child with a history of posterior urethral valves requires and augmentation and that the development of a large megaureter in cases of neurogenic dysfunction represents a failure of initial treatment, we conclude that ureterocystoplasty can be useful in selected cases when a large dilated ureter is available. Seromuscular colocystoplasty lined with urothelium (SCLU) has been urodynamically effective in several series when the outlet resistance is high and no additional intravesical procedures are necessary. Seromuscular gastrocystoplasty lined with urothelium seems to offer no distinct advantages and involves a much more involved operation. The use of seromuscular segments without urothelial preservation, with or without the use of an intravesical balloon has been reported as successful in two centers but strict urodynamic evidence of its effectiveness is lacking. The published evidence argues strongly against the use of detrusorectomy or detrusorotomy alone because of the lack of significant urodynamic benefits. Two recent reports discourage the use of small intestinal submucosa patches because of a high failure rate. Finally, research into the development of a bioengineered bladder constructed with cell harvested from the same patient continues but is fraught with technical and conceptual problems. In conclusion of the methods reviewed, only ureterocystoplasty and SCLU have been proven urodynamically effective and reproducible. PMID- 24400272 TI - Studying the microanatomy of the heart in three dimensions: a practical update. AB - The structure and function of the heart needs to be understood in three dimensions. We give a brief historical summary of the methods by which such an understanding has been sought, and some practical details of the relatively new technique of micro-CT with iodine contrast enhancement in samples from rat and rabbit. We discuss how the improved anatomical detail available in fixed cadaveric hearts will enhance our ability to model and to understand the integrated function of the cardiomyocytes, conducting tissues, and fibrous supporting structures that generate the pumping function of the heart. PMID- 24400273 TI - Autonomic nervous system function following prenatal opiate exposure. AB - In utero exposure to opiates may affect autonomic functioning of the fetus and newborn. We investigated heart rate variability (HRV) as a measure of autonomic stability in prenatal opiate-exposed neonates (n = 14) and in control term infants (n = 10). Electrocardiographic data during both non-nutritive and nutritive sucking were evaluated for RR intervals, heart rate (HR), standard deviation of the consecutive RR intervals (SDRR), standard deviation of the differences of consecutive RR intervals (SDDRR), and the power spectral densities in low and high frequency bands. In controls, mean HR increased significantly, 143-161 per min (p = 0.002), with a trend toward a decrease in RR intervals from non-nutritive to nutritive sucking; these measures did not change significantly among exposed infants. Compared to controls, exposed infants demonstrated significantly greater HRV or greater mean SDRR and SDDRR during non-nutritive period (p < 0.01), greater mean SDDRR during nutritive sucking (p = 0.02), and higher powers in the low and high frequency bands during nutritive feedings. Our findings suggest that prenatal opiate exposure may be associated with changes in autonomic nervous system (ANS) functioning involving both sympathetic and parasympathetic branches. Future studies are needed to examine the effects of prenatal opiate exposure on ANS function. PMID- 24400274 TI - Assessment Disparities among Pediatric Patients: Advantages of Pictorial Descriptions. PMID- 24400275 TI - Improving the Diagnosis, Management, and Outcomes of Children with Pneumonia: Where are the Gaps? AB - Pneumonia is the greatest contributor to childhood mortality and morbidity in resource-poor regions, while in high-income countries it is one of the most common reasons for clinic attendance and hospitalization in this age group. Furthermore, pneumonia in children increases the risk of developing chronic pulmonary disorders in later adult life. While substantial advances in managing childhood pneumonia have been made, many issues remain, some of which are highlighted in this perspective. Multiple studies are required as many factors that influence outcomes, such as etiology, patient characteristics, and prevention strategies can vary between and within countries and regions. Also, outside of vaccine studies, most randomized controlled trials (RCTs) on pneumonia have been based in resource-poor countries where the primary aim is usually prevention of mortality. Few RCTs have focused on medium to long-term outcomes or prevention. We propose different tiers of primary outcomes, where in resource rich countries medium to long-term sequelae should also be included and not just the length of hospitalization and readmission rates. PMID- 24400276 TI - Cough and exhaled nitric oxide levels: what happens with exercise? AB - Cough associated with exertion is often used as a surrogate marker of asthma. However, to date there are no studies that have objectively measured cough in association with exercise in children. Our primary aim was to examine whether children with a pre-existing cough have an increase in cough frequency during and post-exercise. We hypothesized that children with any coughing illness will have an increase in cough frequency post-exercise regardless of the presence of exercise-induced broncho-constriction (EIB) or atopy. In addition, we hypothesized that Fractional exhaled nitric oxide (FeNO) levels decreases post exercise regardless of the presence of EIB or atopy. Children with chronic cough and a control group without cough undertook an exercise challenge, FeNO measurements and a skin prick test, and wore a 24-h voice recorder to objectively measure cough frequency. The association between recorded cough frequency, exercise, atopy, and presence of EIB was tested. We also determined if the change in FeNO post exercise related to atopy or EIB. Of the 50 children recruited (35 with cough, 15 control), 7 had EIB. Children with cough had a significant increase in cough counts (median 7.0, inter-quartile ranges, 0.5, 24.5) compared to controls (2.0, IQR 0, 5.0, p = 0.028) post-exercise. Presence of atopy or EIB did not influence cough frequency. FeNO level was significantly lower post exercise in both groups but the change was not influenced by atopy or EIB. Cough post-exertion is likely a generic response in children with a current cough. FeNO level decreases post-exercise irrespective of the presence of atopy or EIB. A larger study is necessary confirm or refute our findings. PMID- 24400277 TI - Modeling single ventricle physiology: review of engineering tools to study first stage palliation of hypoplastic left heart syndrome. AB - First stage palliation of hypoplastic left heart syndrome, i.e., the Norwood operation, results in a complex physiological arrangement, involving different shunting options (modified Blalock-Taussig, RV-PA conduit, central shunt from the ascending aorta) and enlargement of the hypoplastic ascending aorta. Engineering techniques, both computational and experimental, can aid in the understanding of the Norwood physiology and their correct implementation can potentially lead to refinement of the decision-making process, by means of patient-specific simulations. This paper presents some of the available tools that can corroborate clinical evidence by providing detailed insight into the fluid dynamics of the Norwood circulation as well as alternative surgical scenarios (i.e., virtual surgery). Patient-specific anatomies can be manufactured by means of rapid prototyping and such models can be inserted in experimental set-ups (mock circulatory loops) that can provide a valuable source of validation data as well as hydrodynamic information. Such models can be tuned to respond to differing the patient physiologies. Experimental set-ups can also be compatible with visualization techniques, like particle image velocimetry and cardiovascular magnetic resonance, further adding to the knowledge of the local fluid dynamics. Multi-scale computational models include detailed three-dimensional (3D) anatomical information coupled to a lumped parameter network representing the remainder of the circulation. These models output both overall hemodynamic parameters while also enabling to investigate the local fluid dynamics of the aortic arch or the shunt. As an alternative, pure lumped parameter models can also be employed to model Stage 1 palliation, taking advantage of a much lower computational cost, albeit missing the 3D anatomical component. Finally, analytical techniques, such as wave intensity analysis, can be employed to study the Norwood physiology, providing a mechanistic perspective on the ventriculo arterial coupling for this specific surgical scenario. PMID- 24400278 TI - Results of Treatment of Grades IV and V Vesicoureteral Reflux with Endoscopic Injection of Polyacrylate Polyalcohol Copolymer. AB - PURPOSE: Here we report the results of a review of a prospectively maintained database of the use polyacrylate polyalcohol copolymer (PPC) injection to correct grades IV and V VUR. MATERIALS AND METHODS: All children with grades IV and V primary VUR that presented with febrile urinary tract infection while on prophylaxis, in a 3-year period, were treated with a sub-ureteral injection of PPC. Institutional ethical approval was obtained. Exclusion criteria were incomplete bladder emptying documented on videourodynamic study, ureteral duplication, paraureteral diverticula, and poor ureteral emptying observed during fluoroscopy and previous open surgical or endoscopic treatment. Pre- and post operative evaluation included urinalysis, renal and bladder ultrasonography, DMSA scan, and videourodynamic studies. RESULTS: Thirty-three children [36 renal units (RU)] were included with a median age of 57 months (range 7-108). There were 18 boys and 15 girls. Thirty RU had grade IV and 6 grade V VUR. Median follow-up time was 32 months (range 7-58). Reflux was cured in 32/36 RU with the first injection, but another two patients were reimplanted because of dilatation. Complications included early urinary tract infection in seven children, transient lower urinary tract symptoms in five children. Progressive ureteral dilatation was noted in four children and was treated with insertion of a double J stent. Two of these children eventually required an ureteroneocystostomy. CONCLUSION: The use of PPC to treat grades IV and V vesicoureteral reflux in young children has an overall success rate of 83.3%. Persistent ureteral dilatation was present in 11% associated with high injection volume. Future studies will attempt to maintain a high success rate reducing the volume of injection and the incidence of dilatation. PMID- 24400279 TI - Congestive heart failure: experimental model. AB - INTRODUCTION: Surgically induced, combined volume and pressure overload has been used in rabbits to create a simplified and reproducible model of acute left ventricular (LV) failure. MATERIALS AND METHODS: New Zealand white male rabbits (n = 24, mean weight 3.1 +/- 0.2 kg) were randomly assigned to either the Control group (n = 10) or to the Heart Failure group (HF, n = 14). Animals in the Control group underwent "sham" procedures. Animals in the HF group underwent procedures to induce LV volume overload by inducing severe aortic valve regurgitation with aortic cusp disruption and pressure overload using an occlusive silver clip positioned around the pre-renal abdominal aorta. RESULTS: Following Procedure-1 (volume overload) echocardiography confirmed severe aortic regurgitation in all animals in the HF group, with increased mean pulse pressure difference from 18 +/ 3 to 38 +/- 3 mmHg (P < 0.0001). After Procedure-2 (pressure overload) all animals in the HF group showed clinical and echocardiographic signs of constriction of the abdominal aorta and echocardiography confirmed progressively declining LV function. At the end of the protocol there was a significant increase of the heart/body weight ratio in the HF group vs. Control group (4.6 +/ 0.2 vs. 2.9 +/- 0.1 g/kg, P < 0.05), and echocardiography showed in HF group significant increase of the LV end-diastolic diameter (2.15 +/- 0.09 vs. 1.49 +/- 0.03 cm, P < 0.001) and reduction of the LV shortening fraction (26.3 +/- 3.8 vs. 41.3 +/- 1.6%, P < 0.001). CONCLUSION: This experimental model: (a) consistently produces LV hypertrophy/dilatation and subsequent congestive heart failure, (b) provides new data on the time course of LV dilatation, hypertrophy and failure, (c) allows study of the progress and evolution of LV systolic and diastolic dysfunction in the presence of induced LV failure, (d) is suitable to study intervention or pharmacological administration to reduce the negative effects of acute LV failure. PMID- 24400280 TI - Changing incidence of inflammatory bowel disease: environmental influences and lessons learnt from the South asian population. AB - Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder of the gastrointestinal tract associated with significant morbidity. While IBD occurs in genetically susceptible individuals, the etiology is multifactorial, involving environmental influences, intestinal dysbiosis, and altered immune responses. The rising incidence of IBD in industrialized countries and the emergence of IBD in countries with traditionally low prevalence underscore the importance of environmental influences in the pathobiology of the disease. Moreover the high incidence of IBD observed in the South Asian immigrant population in the United Kingdom and Canada further supports the influence of environmental factors. PMID- 24400281 TI - Anterior urethral valves: not such a benign condition.... AB - PURPOSE: Anterior urethral valves (AUVs) is an unusual cause of congenital obstruction of the male urethra, being 15-30 times less common than posterior urethral valves (PUVs). It has been suggested that patients with congenital anterior urethral obstruction have a better prognosis than those with PUV, with less hydronephrosis, and a lower incidence of chronic renal insufficiency (5 vs. 30%). The long-term prognosis of AUVs is not clear in the literature. In this report we describe our experience and long-term follow up of patients with anterior urethral valve. MATERIALS AND METHODS: We retrospectively identified 13 patients who presented with the diagnosis of AUVs in our institutions between January 1994 and June 2012. Two patients were excluded: one patient had no follow up after intervention; the other had a follow up <1 year. From the 11 patients included, we evaluated the gestational age, prenatal and postnatal ultrasound findings, voiding cystourethrogram findings, age upon valve ablation, micturition pattern, creatinine, and clinical follow up. RESULTS: Between 1994 and 2012 we evaluated 150 patients with the diagnosis of urethral valves. Of this group, 11 patients (7.3%) had AUVs and an adequate follow up. Mean follow up is 6.3 years (2.5-12 years). Five (45.4%) patients had prenatal diagnosis of AUV. The most common prenatal ultrasonographic finding was bilateral hydronephrosis and distended bladder. One patient showed a large perineal cystic mass, which was confirmed to be a dilated anterior urethra. The mean gestational age was 37.6 weeks (27-40 WGA). Postnatally, 90% had trabeculated bladder, 80% hydronephrosis, and 40% renal dysplasia. The most common clinical presentation was urinary tract infection in five patients (45.4%), followed by weak urinary stream found in four patients (36.3%). The age at initial surgical intervention ranged between 7 days and 13 years. Seven (63.6%) patients had primary transurethral valve resection or laser ablation and three patients (27.2%) had primary vesicostomies. One boy (9.1%) had penile urethrostomy with excision of urethral diverticulum. Two (18.2%) patients developed end-stage renal disease. CONCLUSION: Anterior urethral valve is a rare congenital entity affecting the genitourinary system in males. Early urinary tract obstruction resulted in end-stage renal disease in 18% of our patient population. In our series, the complication rate and the evolution to renal failure are high and similar to patients with PUV. In patients with AUVs we recommend long-term follow up and close evaluation of patient's bladder and renal function. PMID- 24400282 TI - Specialty grand challenge - genetic disorders. PMID- 24400284 TI - Understood consent versus informed consent: a new paradigm for obtaining consent for pediatric research studies. AB - All too often the informed consent process is viewed by members of research teams as a challenge of getting a parent or young person's signature on a form. Informed consent is, however, much more than a signed form. Rather, it is a process, often iterative, in which the parent or young person is given sufficient information about a study in order that they can make a truly informed decision about participation. Substantial effort is required in producing appropriately formatted and readable documents using plain language at about Grade 6 or 12-year old reading level. Achieving truly understood consent involves the researcher spending significant one-on-one time with the parent or young person explaining in simple language what is proposed and then using so-called repeat-back techniques to test the understanding of the participants. This is critically important if the research involves randomization to different treatments or use of a placebo arm and, in particular if the research involves more than minimal risk. PMID- 24400283 TI - Right ventricular failure and pathobiology in patients with congenital heart disease - implications for long-term follow-up. AB - Right ventricular dysfunction represents a common problem in patients with congenital heart defects, such as Tetralogy of Fallot or pulmonary arterial hypertension. Patients with congenital heart defects may present with a pressure or volume overloaded right ventricle (RV) in a bi-ventricular heart or in a single ventricular circulation in which the RV serves as systemic ventricle. Both subsets of patients are at risk of developing right ventricular failure. Obtaining functional and morphological imaging data of the right heart is technically more difficult than imaging of the left ventricle. In contrast to findings on mechanisms of left ventricular dysfunction, very little is known about the pathophysiologic alterations of the right heart. The two main causes of right ventricular dysfunction are pressure and/or volume overload of the RV. Until now, there are no appropriate models available analyzing the effects of pressure and/or volume overload on the RV. This review intends to summarize clinical aspects mainly focusing on the current research in this field. In future, there will be increasing attention to individual care of patients with right heart diseases. Hence, further investigations are essential for understanding the right ventricular pathobiology. PMID- 24400286 TI - The Importance of General Self-Efficacy for the Quality of Life of Adolescents with Diabetes or Juvenile Rheumatoid Arthritis Over Time: A Longitudinal Study among Adolescents and Parents. AB - PURPOSE: To (i) investigate the influence of general self-efficacy on quality of life outcomes over time among adolescents with type I diabetes or juvenile rheumatoid arthritis (JRA), (ii) investigate parents' perceptions of general self efficacy and quality of life of adolescents with diabetes or JRA over time, and (iii) identify possible differences in the evaluations of adolescents and parents. METHODS: This study included adolescents aged 12-25 years with type I diabetes or JRA and their parents. At T1, 171/573 (30% response rate) adolescents with diabetes or JRA and 229/563 (41% response rate) parents completed the questionnaire. At T2, 230/551 (42% response rate) adolescents and 220/559 (39% response rate) parents still participating in the study completed the questionnaire. A total of 112 adolescents and 143 parents filled in the questionnaires at both T1 and T2. RESULTS: Adolescents perceived significant improvement in their general self-efficacy and reduced quality of life over time, whereas parents' perceptions did not change. According to adolescents and parents, physical functioning was better among adolescents with diabetes than among those with JRA. Regression analyses of adolescents' data showed that general self-efficacy at T1 (beta = 0.13; p <= 0.10) and changes in general self efficacy (beta = 0.22; p <= 0.01) predicted quality of life at T2. Parents' responses revealed that adolescents' general self-efficacy at T1 (beta = 0.16; p <= 0.05) and changes in adolescents' general self-efficacy (beta = 0.18; p <= 0.05) predicted adolescents' quality of life at T2. CONCLUSION: General self efficacy and changes therein positively affected quality of life in adolescents with diabetes or JRA over time, as perceived by adolescents and parents. These findings emphasize the need for the implementation of interventions aiming to improve general self-efficacy in these populations. PMID- 24400285 TI - Congenital Long QT Syndrome: An Update and Present Perspective in Saudi Arabia. AB - Primary cardiac arrhythmias are often caused by defects, predominantly in the genes responsible for generation of cardiac electrical potential, i.e., cardiac rhythm generation. Due to the variability in underlying genetic defects, type, and location of the mutations and putative modifiers, clinical phenotypes could be moderate to severe, even absent in many individuals. Clinical presentation and severity could be quite variable, syncope, or sudden cardiac death could also be the first and the only manifestation in a patient who had previously no symptoms at all. Despite usual familial occurrence of such cardiac arrhythmias, disease causal genetic defects could also be de novo in significant number of patients. Long QT syndrome (LQTS) is the most eloquently investigated primary cardiac rhythm disorder. A genetic defect can be identified in ~70% of definitive LQTS patients, followed by Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) and Brugada syndrome (BrS), where a genetic defect is found in <40% cases. In addition to these widely investigated hereditary arrhythmia syndromes, there remain many other relatively less common arrhythmia syndromes, where researchers also have unraveled the genetic etiology, e.g., short QT syndrome (SQTS), sick sinus syndrome (SSS), cardiac conduction defect (CCD), idiopathic ventricular fibrillation (IVF), early repolarization syndrome (ERS). There exist also various other ill-defined primary cardiac rhythm disorders with strong genetic and familial predisposition. In the present review we will focus on the genetic basis of LQTS and its clinical management. We will also discuss the presently available genetic insight in this context from Saudi Arabia. PMID- 24400287 TI - The Surgical Correction of Urogenital Sinus in Patients with DSD: 15 Years after Description of Total Urogenital Mobilization in Children. AB - Total urogenital sinus mobilization has been applied to the surgical correction of virilized females and has mostly replaced older techniques. Concerns have been raised about the effect of this operation on urinary continence. Here we review the literature on this topic since the description of the technique 15 years ago. Technical aspects and correct nomenclature are discussed. We emphasize that the term "total" refers to an en-bloc dissection and not to the extent of the proximal dissection. No cases of urinary incontinence have been reported following this operation. It is yet too early to evaluate results regarding sexual function but it is likely that the use of a posterior skin flap to augment the introitus will minimize the development of introital stenosis. PMID- 24400288 TI - Renal transplant outcome in children with an augmented bladder. AB - OBJECTIVE: Studies evaluating renal transplant (RT) outcome in children who underwent an augmentation cystoplasty (AC) are contradictory and the current knowledge is based on studies with a limited number of patients. The aim of this study is to compare RT outcome between children who underwent AC and those without augmentation. PATIENTS AND METHODS: A total of 20p who underwent an AC prior to the RT (12 with ureter and 8 with intestine) were enrolled in the study and were compared to a control group of 24p without AC, transplanted in the same time period (1991-2011). Data including; age at transplant, allograft source, urological complications, urinary tract infections (UTI) incidence, the presence of VUR, and patient and graft survival were compared between the groups. RESULTS: Mean age at RT and mean follow-up were 9.7 vs. 7.9 years and 6.9 vs. 7.9 years in the AC group and control group, respectively (NS). The graft originated in living donors for 60% of AC patients and 41.6% of the control RT patients. The rate of UTI were 0.01 UTI/patient/year and 0.004 UTI/patient/year in the augmented group and controls, respectively (p = 0.0001). In the AC group of 14p with UTIs, 10 (71%) had VUR and 5p out of 8 (62.5%) in the control group had VUR. In the AC group, of the 7p with >=3 UTIs, 3 (43%) were non-compliant with CIC and the incidence of UTIs was not related with the type of AC or if the patient did CIC through a Mitrofanoff conduit or through the urethra. Graft function at the end of study was 92.9 +/- 36.85 ml/min/m(2) in the AC group and 88.17 +/- 28.2 ml/min/m(2) in the control group (NS). Graft survival at 10 years was also similar 88% in the AC group and 84.8% in controls. In the AC group 3p lost their grafts and 5 in the control group with respective mean follow-up of 10.6 +/- 4.3 and 7.1 + 4.7 years. CONCLUSION: There are no significant differences in the RT outcome between children transplanted with AC or without. However, recurrent UTIs are more frequent in the former group and these UTIs are related with non compliance with CIC or the presence of VUR but, even so, UTIs will not lead to impaired graft function in most of the patients. PMID- 24400289 TI - Myelination of the postnatal mouse cochlear nerve at the peripheral-central nervous system transitional zone. AB - In the nerve roots of vertebrates, the peripheral nervous system (PNS) and central nervous system (CNS) interface at the PNS-CNS transitional zone (PCTZ), which consists of cell boundaries with various myelin components. We have recently shown that the mouse cochlear nerve presents an exceptionally long segment of the CNS tissue extending into the PNS using light microscopy. However, it is unclear how oligodendrocytes and Schwann cells contribute to the formation of myelin components of the PCTZ. It is undetermined how myelination is initiated along the cochlear nerve, and when it adopts a mature pattern. In this study, immunofluorescence using antibodies specific to oligodendrocyte marker myelin oligodendrocyte glycoprotein (MOG) and Schwann cell marker myelin protein zero (MPZ) were used to detail the expression of myelin components along the postnatal mouse cochlear nerve. We found that the expression of MPZ was initially observed in the soma of bipolar spiral ganglion neurons at postnatal day 0 (P0) and progressed to the central and peripheral processes after P8-P10. Myelination of the CNS tissue was initiated in close proximity to the PCTZ from P7 to P8 and then extended centrally. Myelination of the PCTZ reached a mature style at P14, when the interface of the expression of MOG and MPZ was clearly identified along the cochlear nerve. This knowledge of PCTZ formation of the cochlear nerve will be essential to future myelination research, and it will also gain clinical interest because of its relevance to the degeneration and regeneration of the auditory pathway in hearing impairment. PMID- 24400290 TI - Reflections on five decades of the fontan kreutzer procedure. AB - The first successful total right heart bypass via atriopulmonary anastomosis (APA) were reported in 1971 for patients with tricuspid atresia. At the Children's Hospital of Buenos Aires, the cohort of such procedures started in July, when the first fenestrated right heart by pass was performed, with the interposition of a homograft between the right atrial appendage and the main pulmonary artery. In the second patient, instead of placing a homograft, the APA was achieved with the patient's own pulmonary root harvested from the outflow tract of the right ventricle. These techniques were soon replaced in 1978 with the development of the direct valveless posterior APA. Since the very beginning the principle was that the right atrium only functions as a pathway rather than a pump (reason why no inferior vena cava valves were ever used), and the diastolic properties of the systemic ventricle regulate the only real "pump" of this system. The late hemodynamic problems inherent of the APA diminished with modern surgical techniques like the lateral tunnel (LT) or the extracardiac conduit (EC). In spite of the improvement in prognosis and quality of life that the modern techniques have brought for univentricular hearts (UH), with the passing of time, deterioration of this system is frequently seen, due to chronic low cardiac output, elevated central venous pressure making heart transplantation the final stage of treatment. Progressive increase in pulmonary vascular resistances and ventricular dysfunction result in a decline in quality of life and survival. However, the timing of this occurrence is variable, and many survivors enjoy today a satisfactory clinical status. The challenge is to develop a better solution for UH, but in the mean time the Fontan Kreutzer palliation represents the best and only surgical option. It is undoubtedly one of the triumphs of cardiac surgery in congenital heart disease. PMID- 24400291 TI - Transumbilical multiport laparoscopic nephroureterectomy for congenital renal dysplasia in children: midterm follow-up from a single institution. AB - OBJECTIVE: To assess the clinical utility and efficiency of transumbilical multiport laparoscopic nephroureterectomy (TMLN) for the treatment of congenital renal dysplasia in children by analyzing consecutive cases from a single institution. METHODS: Sixteen children underwent TMLN procedure due to dysplastic kidney between January 2010 and December 2011. The surgery was transperitoneally performed through three transumbilical incisions for two 5-mm and one 3-mm ports, which duplicated the standard laparoscopic steps with the usual laparoscopic instruments. Demographic, perioperative, and follow-up data were analyzed. RESULTS: TMLN was performed in all patients, without additional ports or conversion to open surgery. The mean operation time was 108.4 min (range 90-125), and the blood loss was minimal. There were no severe intraoperative or post operative complications. The post-operative recovery was uneventful in all patients. No urinary incontinence or umbilical hernias occurred. The cosmetic result was excellent as the incision scar was hidden inside the belly button. CONCLUSION: TMLN is a safe and efficient procedure for the management of congenital renal dysplasia in children with good cosmesis. Future randomized studies with a larger number of cases and a longer follow-up are warranted to elucidate the benefits and limitations of TMLN in children. PMID- 24400292 TI - Neurodevelopmental Outcomes after Pediatric Cardiac ECMO Support. AB - PURPOSE: To characterize the neurodevelopmental outcomes and identify factors associated with poor outcomes in pediatric patients undergoing cardiac extracorporeal membrane oxygenation (ECMO). METHODS: Five year retrospective review, including demographics, cardiac lesion, and surgical complexity, reason for ECMO, ECMO complications, and neurodevelopmental status at discharge and latest follow-up. Neurodevelopmental status was determined through the Pediatric Overall Performance Category and Pediatric Cerebral Performance Category Scales. RESULTS: Overall ECMO survival was 73% at hospital discharge and 66% a t the latest follow-up. Most patients underwent cardiopulmonary resuscitation (CPR) (43%), and the majority (53%) had a significant disease complexity (Aristotle = 4). Complications occurred in 42% of the ECMO runs, of which 12% were intracranial injuries. At hospital discharge, 75% of patients had normal to mild disability, improving to 81% at 2 years follow-up. At hospital discharge, moderate to severe disability was associated with CPR, plasma exchange or intracranial insults. After discharge, 23% showed improvement in neurologic status and 4% showed deterioration. Cerebral infarction was the only parameter associated with deterioration at the later follow-up stage. CONCLUSION: Extracorporeal membrane oxygenation was successfully used in children with cardiac disease with 73 and 66% short and long-term survival respectively. Majority of the survivors had normal to mild neurodevelopmental disability and a significant portion showed neurologic improvement by the latest follow-up. Nevertheless, despite the grossly favorable outcomes standardized comprehensive neuropsychological testing is of paramount importance in all these patients. PMID- 24400293 TI - Pediatric genitourinary oncology. AB - Tumors of the kidney, bladder, prostate, testis, and adrenal represent a large part of the adult urologic practice, but are relatively infrequent in children. The natural history and management of these tumors in the pediatric age is different from that of the adults. As result of the successful work of several clinical trial groups in recent decades, there has been a significant improvement in their cure rates. The aim of this article is to review their most significant clinical aspects, as well as to present an update in their management. PMID- 24400294 TI - Assessing the need for a specialist service for people with intellectual disabilities and mental health problems living in Israel: a qualitative study. AB - BACKGROUND: It is well established that people with intellectual disabilities are at higher risk of developing mental illnesses. This study aimed to assess the need for a specialized service for people (children and adults) with intellectual disabilities and mental health problems living in Israel. METHODS: Our research question was: is there a need for a specialist mental health service for people with intellectual disabilities living in Israel and, if so, what type of service would be most appropriate? We conducted a qualitative study using semi-structured interviews with 14 major stakeholders to identify key themes in response to our research question. The data were coded and themes were identified. RESULTS: Participants were generally not satisfied with current mental health care for people with intellectual disabilities and there was a general agreement that services are in need of improvement. We identified three major themes from the data. These were: current services, future services, and ways to facilitate change. CONCLUSION: We hope that our findings will be instrumental in shaping the ongoing debate about the best form of delivery of services to this population in Israel. Specifically, we suggest the development of a more specialized system, with the formation of multidisciplinary regional assessment and treatment units in parallel with improved relevant training for all mental health workers and the possibility of referral to specialized teams in more complex cases. PMID- 24400295 TI - Mechanical forces in fetal lung development: opportunities for translational research. PMID- 24400296 TI - New paradigms in the pathogenesis of otitis media in children. AB - Acute otitis media (AOM) is a multifactorial disease with a significant socioeconomic impact. The pathogenesis of AOM is attributed to a variety of well established internal and extrinsic factors. Recent evidence strongly points to bacterial biofilm formation as an important contributor to this disease entity. The nasopharynx is a likely reservoir for infection with subsequent seeding of pathogens to the middle ear via planktonic shedding. Various modalities have been used to directly detect biofilm formation in the middle ear mucosa of children with AOM. Further insights into this disease may lead to new strategies for prevention and treatment. PMID- 24400297 TI - Cleft lip - a comprehensive review. AB - Orofacial clefts comprise a range of congenital deformities and are the most common head and neck congenital malformation. Clefting has significant psychological and socio- economic effects on patient quality of life and require a multidisciplinary team approach for management. The complex interplay between genetic and environmental factors play a significant role in the incidence and cause of clefting. In this review, the embryology, classification, epidemiology, and etiology of cleft lip are discussed. The primary goals of surgical repair are to restore normal function, speech development, and facial esthetics. Different techniques are employed based on surgeon expertise and the unique patient presentations. Pre-surgical orthopedics are frequently employed prior to definitive repair to improve outcomes. Long term follow up and quality of life studies are discussed. PMID- 24400298 TI - Congenital Adrenal Hyperplasia: Review from a Surgeon's Perspective in the Beginning of the Twenty-First Century. AB - Congenital adrenal hyperplasia (CAH) most commonly due to 21-hydroxylase deficiency is the most common type of disorder of sex development. This review will focus on CAH addressing historical and current surgical techniques with their anatomical foundations, with special attention to long-term results and outcomes on sexual function, patient satisfaction, patient attitude toward surgery, and ongoing controversies in management of these patients. PMID- 24400299 TI - Somatic Symptoms among Children and Adolescents in Poland: A Confirmatory Factor Analytic Study of the Children Somatization Inventory. AB - The aim of the present study was to examine the factor structure and psychometric properties of the short version of the Children's Somatization Inventory (CSI-24) in Poland. The CSI-24 is a self-report questionnaire designed to assess somatic symptoms in children and adolescents. A total of 733 children and adolescents, aged 12-17 years, participated in this research. The participants for this study were recruited from urban and suburban schools of Opole province in South Western Poland. In addition to the CSI-24, all participants completed the Spence Children's Anxiety Scale (SCAS) and the Strength and Difficulties Questionnaire (SDQ). The correlated four-factor model that included four-correlated dimensions (pain/weakness, gastrointestinal problems, cardiovascular symptoms, and pseudoneurological problems) showed a better fit compared to the single-factor model. The Cronbach's Alpha for the CSI-24 was 0.91. Somatic symptoms correlated significantly highly with the SCAS total scores and the SDQ emotional subscale, suggesting good construct validity. Somatic symptoms had low correlation with the SDQ behavioral problems symptoms, suggesting adequate discriminant validity. The CSI-24 reliably measured somatic symptoms in children and adolescents in Poland. PMID- 24400301 TI - Active gaming as a mechanism to promote physical activity and fundamental movement skill in children. PMID- 24400300 TI - A Positive Association between T. gondii Seropositivity and Obesity. AB - Obesity is a global public health problem that is linked with morbidity, mortality, and functional limitations and has limited options for sustained interventions. Novel targets for prevention and intervention require further research into the pathogenesis of obesity. Consistently, elevated markers of inflammation have been reported in association with obesity, but their causes and consequences are not well understood. An emerging field of research has investigated the association of infections and environmental pathogens with obesity, potential causes of low grade inflammation that may mediate obesity risk. In this study, we estimate the possible association between Toxoplasma gondii (T. gondii) infection and obesity in a sample of 999 psychiatrically healthy adults. Individuals with psychiatric conditions, including personality disorders, were excluded because of the association between positive serology to T. gondii and various forms of serious mental illness that have a strong association with obesity. In our sample, individuals with positive T. gondii serology had twice the odds of being obese compared to seronegative individuals (p = 0.01). Further, individuals who were obese had significant higher T. gondii IgG titers compared to individuals who were non-obese. Latent T. gondii infection is very common worldwide, so potential public health interventions related to this parasite can have a high impact on associated health concerns. PMID- 24400303 TI - An exaltation of offshore islands. PMID- 24400302 TI - Memory feats. PMID- 24400304 TI - Morning report in Kigali - November 20, 2013. PMID- 24400305 TI - Secure email communication between patient and physician associated with better glycemic control. PMID- 24400306 TI - Pediatric Emergency Medicine: from small beginnings, a subspecialty emerges and evolves in RI, nationwide. PMID- 24400307 TI - Pediatric resuscitation: lessons learned and future directions. AB - The science of resuscitation has had significant and meaningful advances over the past fifty years, with resultant improvements in outcomes for both adult and pediatric populations. This article aims to describe some of the recent advances in pediatric resuscitation, including aspects of care affecting the management of cardiac arrest and sepsis, and to give a glimpse into technologies and methodologies that may be utilized to improve outcomes for children in the near future. PMID- 24400308 TI - Going with the flow: respiratory care in the pediatric emergency department. AB - Providers in pediatric emergency departments (ED) frequently encounter a variety of life-threatening respiratory illnesses. This article reviews current updates on the management and unique adjuncts for 3 common respiratory illnesses. Discussed first is bronchiolitis and the impact of high flow nasal cannula on reducing the need for intubation. Next, the current therapy for croup and the adjunctive use of Heliox and finally, the ED approach to asthma and treatment with breath actuated nebulizers. PMID- 24400309 TI - 'Not just little adults' - a pediatric trauma primer. AB - This article describes pediatric trauma care and specifically how a pediatric trauma center, like Hasbro Children's Hospital, provides specialized care to this patient population. The authors review unique aspects of pediatric trauma patients broken down into anatomy and physiology, including Airway and Respiratory, Cardiovascular Response to Hemorrhage, Spine Injuries, Traumatic Brain Injuries, Thoracic Injuries and Blunt Abdominal Trauma. They review certain current recommendations for evaluation and management of these pediatric patients. The authors also briefly review the topic of Child Abuse/Non-accidental Trauma in pediatric patients. Although Pediatric Trauma is a very broad topic, the goal of this article is to act as a primer and describe certain characteristics and management recommendations unique to the pediatric trauma patient. PMID- 24400310 TI - Fear and loathing in the ER: managing procedural pain and anxiety in the Pediatric Emergency Department. AB - The pediatric emergency department can be frightening for children. Visits are unplanned, and frequently accompanied by significant emotional and physical distress. While treatment of pain and anxiety in children have been historically inadequate, the barriers to their treatment have largely been overcome through increased awareness, child- and family-focused care, standardized assessment, institutional safety protocols, and newer pharmacologic agents. The pediatric emergency physician is now a primary advocate for treatment of children's pain and anxiety and for the safe and appropriate use of procedural sedation. This article focuses on the treatment spectrum available for providing safe and effective procedural sedation, analgesia and anxiolytic therapy. PMID- 24400311 TI - Multicenter pediatric emergency medicine research and Rhode Island. AB - Multicenter clinical research studies are often needed to address issues of generalizability, conditions with low incidence, adequate statistical power, and potential study bias. While pediatric research networks began work in the 1950s, and Rhode Island physicians have contributed to many of these studies, pediatric emergency medicine (PEM) collaboratives are relative newcomers. Since the mid 1990s, Rhode Island pediatricians have contributed to multicenter studies of diabetic ketoacidosis, bronchiolitis, asthma, quality of PEM care, meningitis, brief interventions for substance use disorders, point-of-care ultrasound, and pre-hospital triage protocols. In 2011, Rhode Island Hospital joined the Pediatric Emergency Care Applied Research Network, the first federally funded pediatric emergency medicine network of its kind. Its mission is to perform high quality, high impact PEM research. Since joining the network, Rhode Island Hospital has quickly become a productive and valued member of the network, portending a bright future for multicenter PEM research in the Ocean State. PMID- 24400312 TI - Driving policy after seizures and unexplained syncope: a practice guide for RI physicians. AB - Physicians in Rhode Island sometimes find it difficult to advise patients about returning to driving after they present with a seizure or syncopal episode due to lack of statutory or professional guidance on the issue. We provide an overview of the medical literature on public policies and recommendations regarding driving after seizures or syncope. We also present the laws in Rhode Island regarding physician notification of the medical advisory board of the Department of Motor Vehicles, legal obligations, and immunity from prosecution for those who report. Finally, we present the results of a survey of current practice by Rhode Island neurologists when they advise patients who have had a recent seizure or unexplained syncopal event. Based upon this information, we hope local practitioners are empowered in their decision making on driving restrictions and we hope this data informs future public policy efforts. PMID- 24400313 TI - Age and consumer product-related eye injuries in the United States. AB - PURPOSE: The purpose of this study was to describe the epidemiology of consumer product (CP) related eye injuries presenting to US emergency departments (EDs) stratified by age. METHODS: The Consumer Product Safety Commission's National Electronic Injury Surveillance System (CPSC-NEISS) database was used to derive national, weighted estimates of nonfatal Emergency Department visits for eye injuries by patients' age, gender, diagnosis, injured body part, locale of incidence, and related CP. RESULTS: The CPs causing the highest proportion of injury visits varied among the different age groups: chemicals in the very young (0-4 yr), household items in 5-9 year olds, sports products in 10-24 year olds, cutting and construction tools in 25-64 year olds, and chemicals in the elderly (65+). Patients aged 0-4 also represented the age interval with the highest rate of injury visits (92 visits per 10,000). CONCLUSION: This study identified the CPs responsible for the most eye injury visits by age groups. Further research is needed on how to effectively change the behavior of individuals and their environment so that we can minimize preventable eye injuries from consumer products. PMID- 24400314 TI - Youth homicide deaths in Rhode Island, 2004-2012. PMID- 24400315 TI - Detection of biomarkers with graphene nanoplatelets and nanoribbons. AB - Well-defined graphene nanosheets have become increasingly popular in the electrochemical detection and quantification of small molecules. In this work, the electrochemical oxidation of biomarkers such as uric acid, ascorbic acid, dopamine, NADH and DNA bases, namely guanine and adenine, was performed using cyclic voltammetry and differential pulse voltammetry to compare the electrochemical properties of electrochemically reduced nanoplatelets (ENPs) and electrochemically reduced nanoribbons (ENRs). The graphene materials displayed better electrochemical performances than the bare glassy carbon surface. Between the two graphene materials, the oxidation of biomarkers occurred at lower oxidation potentials on the ENP surface. The sensitivities of the two graphene surfaces varied when different biomarkers were studied. The ENP surface showed enhanced sensitivities for ascorbic acid, while the ENR surface exhibited higher sensitivities for uric acid and dopamine. As for the DNA bases analysed, both guanine and adenine were oxidised at lower potentials on the ENP surface than the ENR surface. The ENP surface displayed a better sensitivity for guanine, whereas the oxidation of adenine was more sensitive on the ENR surface. PMID- 24400316 TI - Measurements of local chemistry and structure in Ni(O)-YSZ composites during reduction using energy-filtered environmental TEM. AB - Energy-filtered transmission electron microscopy images are acquired during the reduction of a NiO-YSZ composite in H2 up to 600 degrees C. Temperature-resolved quantitative information about both chemistry and structure is extracted with nm spatial resolution from the data, paving the way for the development of detailed reduction models. PMID- 24400317 TI - H2O2-dependent substrate oxidation by an engineered diiron site in a bacterial hemerythrin. AB - The O2-binding carboxylate-bridged diiron site in DcrH-Hr was engineered in an effort to perform the H2O2-dependent oxidation of external substrates. A His residue was introduced near the diiron site in place of a conserved residue, Ile119. The I119H variant promotes the oxidation of guaiacol and 1,4 cyclohexadiene upon addition of H2O2. PMID- 24400318 TI - A near-infrared colorimetric fluorescent chemodosimeter for the detection of glutathione in living cells. AB - A novel near-infrared (NIR) and colorimetric fluorescent molecular probe based on a dicyanomethylene-4H-pyran chromophore for the selective detection of glutathione in living cells has been developed. The fluorescence OFF-ON switch is triggered by cleavage of the 2,4-dinitrobenzensulfonyl (DNBS) unit by the interaction with GSH. PMID- 24400319 TI - A novel nickel-thiourea-triethylamine complex adsorbed on graphitic C3N4 for low cost solar hydrogen production. AB - A low-cost photocatalytic system composed of earth-abundant elements has been synthesized, with the nickel-thiourea-triethylamine catalyst in situ formed on the C3N4 photocatalyst, which exhibits a comparable H2 production with a C3N4-Pt photocatalytic system and a long term photocatalytic activity. PMID- 24400320 TI - Enantioselective 1,4-additions of ClMeAl(CH=CHR) (R = alkyl, alkenyl, Ph) to cyclohexenones. AB - Chloromethylvinyl alanes (E)-ClMeAl(CH=CHR) prepared directly from terminal alkynes undergo 1,4-addition to cyclohexenone and 3-methylcyclohexenone in moderate to good yield (30-70%) and good to excellent stereoselectivity (80-98% ee) using readily available copper(I) sources and chiral ligands. PMID- 24400321 TI - A white-light-emitting LnMOF with color properties improved via Eu3+ doping: an alternative approach to a rational design for solid-state lighting. AB - The intrinsic white-light-emitting properties of a lanthanide metal-organic framework that approach requirements for solid-state lighting are easily improved by incorporating minute quantities of red-emitting Eu(3+) into the host framework by virtue of the isostructural character of the La(3+) and Eu(3+) compounds and efficient sensitization of ligands toward Eu(3+) ions. PMID- 24400322 TI - Pharmaceutical hydrates under ambient conditions from high-pressure seeds: a case study of GABA monohydrate. AB - The monohydrate form of the neurotransmitter gamma-amino butyric acid (GABA) has been crystallised in the 0.4-0.8 GPa pressure range, recovered to ambient pressure and then used as a seed. Theoretical calculations indicate that this hydrate is only thermodynamically favoured over the two anhydrous forms at high pressures. PMID- 24400323 TI - Oxovanadium-salen and -salan complexes as effective labels for electrochemical immunosensing: a case study for estradiol detection. AB - Oxovanadium complexes are presented as new labels for the development of electrochemical immunosensors. The concept was successfully applied to the accurate detection of estradiol, an emerging environmental pollutant, at concentrations ranging from 4 ng L(-1) to 5 MUg L(-1). PMID- 24400324 TI - Palladium[II] catalysed C(sp3)-H oxidation of dimethyl carbamoyl tetrahydrocarbazoles. AB - Dimethyl carbamoyl tetrahydrocarbazoles undergo directed oxidation using standard conditions to exclusively provide products from C(sp(3))-H oxidation. This result is in contrast to recent studies on the directed C-H olefination of hydrocarbazoles, which result in selective aromatic functionalisation. PMID- 24400325 TI - The authors respond. PMID- 24400326 TI - Elements of consciousness in animals. PMID- 24400327 TI - Gyorgy Buzsaki. PMID- 24400328 TI - [If the blood pressure does not drop. . ]. PMID- 24400329 TI - [How to reduce prescription rates of antibiotics?]. PMID- 24400330 TI - Stratified three-dimensional fusion imaging of delayed enhancement magnetic resonance and multi-detector computed tomography to identify a ventricular tachycardia focus,. PMID- 24400331 TI - Democratic responsiveness and the sources of public opinion. PMID- 24400332 TI - Ghana's mental health patients confined to prayer camps. PMID- 24400333 TI - England's HIV services face complex new environment. PMID- 24400334 TI - Taking a narrative turn in psychiatry. PMID- 24400335 TI - Summaries for patients. Does exposure to low or moderate levels of arsenic increase the risk for cardiovascular disease? PMID- 24400336 TI - Summaries for patients. Using medications to decrease the risk for breast cancer in women: recommendations from the U.S. Preventive Services Task Force. PMID- 24400337 TI - Dendrites: Dendritic processors. PMID- 24400338 TI - Cell fate: The patterns of fate. PMID- 24400339 TI - Pain: A wandering brain reduces pain? PMID- 24400341 TI - The effect of an advanced glycation end-product crosslink breaker and exercise training on vascular function in older individuals: a randomized factorial design trial. AB - Aging leads to accumulation of irreversible advanced glycation end-products (AGEs), contributing to vascular stiffening and endothelial dysfunction. When combined with the AGE-crosslink breaker Alagebrium, exercise training reverses cardiovascular aging in experimental animals. This study is the first to examine the effect of Alagebrium, with and without exercise training, on endothelial function, arterial stiffness and cardiovascular risk in older individuals. Forty eight non-exercising individuals (mean age 70 +/- 4 years) without manifest diseases or use of medication were allocated into 4 groups for a 1-year intervention: Exercise training & Alagebrium (200 mg/day); exercise training & placebo; no exercise training & Alagebrium (200 mg/day); and no exercise training & placebo. We performed a maximal exercise test (VO2max) and measured endothelial function using venous occlusion plethysmography and intra-arterial infusion of acetylcholine, sodium nitroprusside and NG-monomethyl-l-arginine. Arterial stiffness was measured using pulse wave velocity. Cardiovascular risk was calculated using the Lifetime Risk Score (LRS). In the exercise training groups, LRS and VO2max improved significantly (23.9 +/- 4.5 to 27.2 +/- 4.6mLO2/min/kg, p < 0.001). Endothelial response to the vasoactive substances did not change, nor did arterial stiffness in any of the four groups. In conclusion, one year of exercise training significantly improved physical fitness and lifetime risk for cardiovascular disease without affecting endothelial function or arterial stiffness. The use of the AGE-crosslink breaker Alagebrium had no independent effect on vascular function, nor did it potentiate the effect of exercise training. Despite the clinical benefits of exercise training for older individuals, neither exercise training nor Alagebrium (alone or in combination) was able to reverse the vascular effects of decades of sedentary aging. PMID- 24400340 TI - Temporal fate specification and neural progenitor competence during development. AB - The vast diversity of neurons and glia of the CNS is generated from a small, heterogeneous population of progenitors that undergo transcriptional changes during development to sequentially specify distinct cell fates. Guided by cell intrinsic and -extrinsic cues, invertebrate and mammalian neural progenitors carefully regulate when and how many of each cell type is produced, enabling the formation of functional neural circuits. Emerging evidence indicates that neural progenitors also undergo changes in global chromatin architecture, thereby restricting when a particular cell type can be generated. Studies of temporal identity specification and progenitor competence can provide insight into how we could use neural progenitors to more effectively generate specific cell types for brain repair. PMID- 24400342 TI - Amyloid precursor protein expression is enhanced in human platelets from subjects with Alzheimer's disease and frontotemporal lobar degeneration: a real-time PCR study. AB - Frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) represent the most frequent causes of early-onset and late-onset degenerative dementia, respectively. A correct diagnosis entails the choice of appropriate therapies. In this view the present study aimed to identify biomarkers that could improve the differential diagnosis. We recently found an overexpression of platelet amyloid precursor protein (APP) in AD; furthermore, recent studies have suggested the presence of changes in APP processing in FTLD. In this context, we analyzed the mRNA expression level of Total APP (TOT) and APP containing a Kunitz-type serine protease inhibitor domain (KPI) in platelets obtained from AD patients, subjects with FTLD, and healthy subjects. In addition, we evaluated the correlation between platelet APP mRNA expression levels and cognitive impairment.Differential gene expression measurements revealed a significant up-regulation of APP TOT and APP KPI in both AD and FTLD patients compared to the controls (being AD/Controls: 1.67 for APP TOT and 1.47 for APP KPI; FTLD/Controls: 1.62 for APP TOT and 1.51 for APP KPI; p < 0.05), although it is interesting to note that in FTLD patients this expression did not correlate with the severity of cognitive impairment.This could be related to a reduced beta-amyloid (Abeta) formation, caused by an alteration of secretase enzymatic activity, even though a post-transcriptional regulation of APP mRNAs in FTLD cannot be excluded. PMID- 24400343 TI - Intracardiac extra-cavitary primary effusion lymphoma in an HIV-infected patient. PMID- 24400344 TI - 2012 European guideline on the diagnosis and treatment of gonorrhoea in adults. AB - Gonorrhoea is a major public health concern globally. Of particularly grave concern is that resistance to the extended-spectrum cephalosporins has emerged during the most recent years. This guideline provides recommendations regarding the diagnosis and treatment of gonorrhoea in Europe. Compared to the outdated 2009 European gonorrhoea guideline, this 2012 European gonorrhoea guideline provides up-to-date guidance on, broader indications for testing and treatment of gonorrhoea;the introduction of dual antimicrobial therapy (ceftriaxone 500 mg and azithromycin 2 g) for uncomplicated gonorrhoea when the antimicrobial sensitivity is unknown; recommendation of test of cure in all gonorrhoea cases to ensure eradication of infection and identify emerging resistance; and recommendations to identify, verify and report failures with recommended treatment regimens. Optimisations of the testing, diagnostics, antimicrobial treatment and follow-up of gonorrhoea patients are crucial in controlling the emergent spread of cephalosporin-resistant and multidrug-resistant gonorrhoea. PMID- 24400345 TI - Not so different after all? Comparing patients attending general practice-based locally enhanced services for sexual health with patients attending genitourinary medicine. AB - We did a cross-sectional survey of patients attending genitourinary (GU) medicine clinics (n = 933) and general practice-based Locally Enhanced Services for Sexual Health (GP-LESSH, n = 111) in Cornwall, England, in 2009/2010, to compare patients' characteristics and experiences. Patients completed a pen-and-paper questionnaire that was then linked to an extract of their clinical data. GP-LESSH patients took longer both to seek and to receive care: medians of nine and seven days, respectively, versus GU medicine patients: medians of seven and one day, respectively. GP-LESSH patients were less likely than GU medicine patients to report symptoms (19.6% versus 30.6%) and sexual risk behaviours (33.3% versus 44.7% reported new partners) since recognizing needing to seek care; 5.0% versus 10.2% were men who have sex with men). However, they were equally likely to have sexually transmitted infections (STIs) diagnosed (23.3% versus 24.8%). As GP LESSH may operate infrequently, local services must work collaboratively to ensure that those seeking care for suspected STIs receive it promptly. Failing to do so facilitates avoidable STI transmission. PMID- 24400346 TI - An unexpected cause for aplastic anaemia in an elderly woman. AB - Aplastic anaemia is a rare clinical syndrome associated with diminished or absent precursors in the bone marrow. Acquired aplastic anaemia secondary to human immunodeficiency virus (HIV) is very rare. We present a 71-year-old woman with severe aplastic anaemia secondary to HIV infection, which was after extensive exclusion of other causes. She achieved undetectable viral load after 5 months of combination antiretroviral therapy but remains profoundly pancytopenic, complicated by recurrent infectious and bleeding complications. HIV infection should be considered in patients with pancytopenia. PMID- 24400347 TI - Immune reconstitution inflammatory syndrome Kaposi sarcoma in the liver manifesting as acute obstructive hepatitis: another potential role for montelukast? AB - Immune reconstitution inflammatory syndrome has been described in Kaposi sarcoma, but does not usually manifest as acute hepatitis. We describe a case of rapid obstructive jaundice after initiation of antiretroviral therapy, in which the liver biopsy confirmed hepatic Kaposi sarcoma, and the clinical course was altered by the addition of montelukast. PMID- 24400348 TI - Acquired microcyst in the paraurethral glands of a male patient. PMID- 24400350 TI - A woman with didanosine retinopathy and non-cirrhotic portal hypertension. PMID- 24400349 TI - Starting treatment according to guidelines evaluation: a multicentre audit of HIV patients in the UK. AB - The aim of this audit was to assess whether HIV patients are being started on antiretroviral therapy (ART) according to British and European guidelines. Data were collected from the Survey of Prevalent HIV Infections Diagnosed (SOPHID) return for 2010 at five major HIV management centres in the UK. Data from this 3873 patient cohort revealed 52 patients who should have been receiving ART according to the guidelines but were not. Of these, 23 patients elected not to start ART despite clinical advice to the contrary. Information required to assist in the decision for earlier ART initiation (CD4 count 350-500 cells/mL) was missing for some patients. Clinicians must pay attention to the regular assessment of patients with a CD4 count of 351-500 cells/mL so that all those who may benefit from earlier treatment are identified. Future research should investigate patient barriers to initiating therapy following recommendation by a clinician. PMID- 24400351 TI - The effect on Neisseria gonorrhoeae screening rates in an integrated clinic following the introduction of dual nucleic acid amplification tests. PMID- 24400352 TI - Trans-atlantic debate: should young patients with good risk factors be treated with EVAR? PMID- 24400353 TI - From RICE to PRICE. PMID- 24400354 TI - Bedside report: look at the big picture. PMID- 24400355 TI - When eligibility is a disadvantage: changing federal guidelines could lead to declining investment in pediatric emergency department infrastructure. PMID- 24400356 TI - Baby boomers and the hepatitis C boom. PMID- 24400357 TI - Traffic safety facts 2011 data--pedestrians. PMID- 24400358 TI - The role of motor response in implicit encoding: evidence from intertrial priming in pop-out search. AB - Perception and motor control jointly act to meet our current needs. Recent evidence shows that the generation of motor action significantly affects perception. Here, we examined the role of motor response in inter-trial priming, namely, in Priming of Pop-out (PoP): when searching for a singleton target, performance is improved when the target and distractors features repeat on consecutive search trials than when they switch. Although recent studies have shown an interaction between motor response and PoP, the role of motor action on priming has not been fully characterized. Here we investigated whether motor action is necessary during encoding, for PoP to be observed. On go trials, observers searched for a color singleton target and responded to its shape, while on no-go trials they passively watched the display instead of responding to the target. We observed PoP even when the previous trial had been a no-go trial, suggesting that encoding of search-relevant attributes in pop-out displays is not contingent on motor response. Nevertheless, the repetition effect was larger after a go trial than after a no-go trial, supporting the dual-stage model of PoP, according to which this effect involves both a perceptual and a motor component. PMID- 24400359 TI - $ 1.4 billion funding shortfall for tuberculosis control. PMID- 24400361 TI - Auer on the top! PMID- 24400362 TI - Circulating proplatelet. PMID- 24400363 TI - An interview with Jonas Capelli Junior. PMID- 24400364 TI - Personal experiences of emigre cardiologist Paolo G. Camici. Get the most out of a foreign country by learning the system. PMID- 24400365 TI - The Croatia Cardiac Society and its two educational resources, the journal Cardiologia Croatica and the web portal Kardio.hr. PMID- 24400366 TI - Cardiac arrhythmia challenge: a new App. PMID- 24400367 TI - Philips launches new ultrasound technology. PMID- 24400368 TI - Author's reply: To PMID 23261803. PMID- 24400369 TI - Author's reply: To PMID 23228972. PMID- 24400370 TI - Winning the battle for greater efficiency. AB - The keynote speeches at this year's Healthcare Estates conference, which was themed 'Putting positive energy into healthcare', included a rousing address by former Welsh Guardsman, and Falklands War veteran, Simon Weston, describing his extraordinary recovery after suffering extensive burns when his troop ship was hit by an Argentinian bomb in June 1982, as well three estates and facilities orientated presentations from senior sector players, on topics ranging from public sector energy procurement, to how those English NHS Trusts still seeking Foundation Trust status can 'raise the bar' sufficiently to achieve this. HEJ editor, Jonathan Baillie reports. PMID- 24400371 TI - Changing times, similar challenges. AB - With IHEEM celebrating its 70th Anniversary this month, HEJ editor, Jonathan Baillie, recently met the Institute's oldest surviving Past-President, Lawrence Turner OBE, who, having in 1964 established a small engineering business producing some of the NHS's earliest nurse call systems from the basement of his three-storey West Midlands home, has since seen the company, Static Systems Group, grow to become one of the U.K. market-leaders in its field. The Institute's President from 1979-1981, he looked back, during a fascinating two hour discussion, at his time in the role, talked through some of the key technological and other changes he has seen in the past five decades, reflected on an interesting and varied career, and considered some of the very different current-day challenges that today's IHEEM President, and the Institute as a whole, face. PMID- 24400372 TI - [Diagnostic imaging Q & A: co-existence of interrupted aortic arch type A, aorto pulmonary window and intact ventricular septum]. PMID- 24400373 TI - A survey on readiness and needs regarding the transition from ICD-9-CM to ICD-10 CM. AB - The New York State Congenital Malformations Registry (CMR) conducted a Web-based survey to assess reporting hospitals readiness and needs with regards to the transition from the ICD-9-CM to ICD-10-CM for diagnoses and ICD-10-PCS for procedure coding system (PCS). The survey contains 8 questions focusing on the transition to collect information about case reporting methods, anticipated plan and date for the transition, and the needs from the CMR for the process. In September 2012, a link to the Web-based survey was sent to all 158 CMR reporting hospitals requesting completion of the online survey. By October 31, 2012, 91 (60 percent) out of 158 reporting hospitals completed the survey. For the question "When will your facility be ready to report to the CMR using the ICD-10 coding system?", a majority (71 percent) of the respondents answered October 1, 2014. With regard to the method they plan to use for converting from ICD-9-CM to ICD-10 CM/PCS, 51 percent will rely on a crosswalk provided by vendors and 7 percent will use the general equivalence mapping method. Nearly half (45 percent) of the respondents were interested in implementing a dual reporting system (accepting both ICD-9-CM and ICD-10-CM/ PCS by the CMR). For the question, "What specific information would you like the Congenital Malformations Registry to provide in regards to reporting to this registry using ICD-10?", 30% of the respondents requested a list of reportable ICD-10-CM/PCS codes and related descriptions, 10 percent requested an ICD-9-CM to ICD-10-CM/PCS crosswalk, and 19 percent requested keeping them updated with information about the transition and implementation of ICD-10-CM/PCS. Among the respondents who provided comments at the end of the survey, more than half (55 percent) stated that they are in the process of transition and 27 percent expressed thanks and appreciation for CMR's leading effort on the transition project. This online survey enabled the CMR staff to assess readiness and identify the needs of the hospitals regarding the transition. This information will help the CMR with appropriate planning for our own transition and enable us to meet the needs of hospital reporters PMID- 24400374 TI - Raising the bar: busyness does not equal competence. PMID- 24400375 TI - Removal of penalty for breaking appointments. Final rule. AB - The Department of Veterans Affairs (VA) amends its regulations to remove an outdated regulation that stated that a veteran who misses two medical appointments without providing 24 hours' notice and a reasonable excuse is deemed to have refused VA medical care. VA removes this penalty because we believe it is incompatible with regulatory changes implemented after the regulation was promulgated, is not in line with current practice, and is inconsistent with VA's patient-centered approach to medical care. PMID- 24400376 TI - Raising the bar: how to become a standout cancer registrar. PMID- 24400377 TI - Reality check: data are not always plentiful. PMID- 24400379 TI - Raising the bar: 4 secrets to a meaningful life. PMID- 24400378 TI - Exploring the cost-effectiveness of unit-based health promotion activities for nurses. AB - The Stepping Stones to Wellness program, offered on one hospital unit by the organization's wellness team and nurse practitioner students, was evaluated for its return on investment (ROI), level of participation, and satisfaction among staff and students. Interventions included (1) biometric screening, (2) participation incentives, and (3) education delivered by staff and nurse practitioner students on the unit. Using the hours of unscheduled absence as a proxy for staff wellness, ROI was calculated using 75% of the difference between the mean hours of unscheduled absence during the intervention compared to the previous 3 years. Average hourly rate (including benefits) was multiplied by unscheduled absence ($11,409.17). The total cost of program delivery ($7,662.50) for 80 employees yielded an ROI of $3,746.67. Participation improved and satisfaction increased. Graduate nursing students and an employer wellness team can deliver a successful unit-based health promotion program and possibly affect absenteeism. PMID- 24400380 TI - [The optimizing influence of melatonin on the behavioral activity of cognitive enhancers]. AB - The pineal hormone melatonin (0.1 mg/kg) differently changed the behavioral shifts induced by piracetam, bilobil, and ginseng in the open-field and elevated plus-maze tests in rats. Melatonin more effectively optimized memory in the model of passive avoidance conditioned reflex. It is suggested that the observed enhancement of the specific activity of nootropic drugs is related to the melatonin-induced changes in the hippocampal activity. PMID- 24400381 TI - [Neurotensin NT (8- 13) dipeptide analog dilept increases the pain threshold and decreases the severity of morphine withdrawal syndrome in rats]. AB - The pain threshold effects of a neurotensin NT (8 - 13) dipeptide analog (dilept), morphine, and their combination have been studied using the tail flick test in rats. The animals of another experimental group were administered with morphine in increasing doses (10 - 20 mg/kg, i.p.) for 5 days in order to induce the state of dependence. The physical dependence on morphine was evaluated in the open-field test by monitoring 16 specific behavioral signs of withdrawal syndrome (WS) induced by the opioid receptor antagonist naloxone, after which the WS total index was calculated. It was established, that dilept (1.6 mg/kg, i.p.) produced a mild analgesic effect via increasing the pain threshold by 34% (p < 0.01), did not effect on the morphine analgesic effect, and decreased the expression of morphine WS by 29.1 and 37.5% (p < 0.01) after a single or subchronic administration, respectively. These behavioral effects of dilept were accompanied by normalization of dopamine and serotonin turnover in the hypothalamus, frontal cortex, and striatum of experimental animals. PMID- 24400382 TI - [Effects of melaxen and valdoxan on the activity of glutathione antioxidant system and NADPH-producing enzymes in rat heart under experimental hyperthyroidism conditions]. AB - The effects of melaxen and valdoxan on the activity of glutathione antioxidant system and some NADPH-producing enzymes have been studied under conditions of experimental hyperthyroidism in rat heart. Under the action of these drugs, reduced glutathione (GSH) content increased as compared to values observed under the conditions of pathology. It has been established that the activities of glutathione reductase (GR), glutathione peroxidase (GP), glucose-6-phosphate dehydrogenase, and NADP isocitrate dehydrogenase (increased under pathological conditions) change toward the intact control values upon the introduction of both drugs. The influence of melaxen and valdoxan, capable of producing antioxidant effect, leads apparently to the inhibition of free-radical oxidation processes and, as a consequence, the reduction of mobilization degree of the glutathione antioxidant system. PMID- 24400383 TI - [Using meglumine acridonacetate for the treatment of gastroenteritis caused by rotavirus in children]. AB - The study was aimed at an analysis of the influence of meglumine acridonacetate- the inductor of endogenous interferon synthesis--on the clinical course of gastroenteritis caused by rotavirus in children. A group of 100 patients aged from 3 months to 14 years were involved on retrospective comparative randomized study. The obtained data showed the advantages of meglumine acridonacetate administration during early terms of treatment of the gastroenteritis caused by rotaviruses. This treatment leads to fast regression of the main clinical symptoms such as fever, diarrhea, and intoxications, which results in reduction of the clinical course duration. PMID- 24400384 TI - [Relationship between the anticoagulant activity of sulfated plant polysaccharides and the area of their precipitation with polycations during biospecific electrophoresis]. AB - Polyanions (in an amount within 1.5 - 6.0 mg), including cellulose sulfates (excreted from Gossipium hirsutum L., molecular weight 22.0 kDa, degree of sulfation within 0.8 - 1.8), inulin sulfates (excreted from Helianthus tuberosus, molecular weight 8.0 kDa, degree of sulfation within 0.6 - 1.6), pectin sulfates (excreted from Abies sibirica L., molecular weight 24.0 kDa, degree of sulfation within 0.8 - 1.1), give rise to peaks of precipitation with polycations of protamine sulfate. Only cellulose sulfates (in amount within 0.38 - 6.00 mg) give the peaks of precipitation with chitosan polycations (molecular weight 10 kDa, degree of deacetylation 85%) during horizontal biospecific electrophoresis. The height of the peak of precipitation with protamin sulfate was found to grow with increasing antithrombin activity of cellulose sulfates and pectin sulfate (for polyanions in an amount within 1.5 - 6 mg). The size of the area of precipitation with chitosan was found to decrease with increasing antithrombin activity of cellulose sulfates. PMID- 24400385 TI - [Comparative study of the effects of 4-chlorophenyl-2-hydroxy-4-oxo-2-butenoate and heparin on blood coagulation]. AB - The purpose of this work investigation to study the effect of 4-chlorophenyl-2 hydroxy-4-oxo-2-butenoate (thiazoline ammonium butenoate, compound FS 169) and heparin on the coagulation of whole rabbit blood in vitro and in vivo. The effects of heparin and FS 169 were investigated using a Minilab 701 coagulometer. Citrated (3.8%) blood of outbred rabbits was used in a volumetric ratio of 9 : 1. In the experiments in vivo, heparin and FS 169 were introduced subcutaneously. The results showed that FS 169 in vitro reduced the blood clotting time 3.8 times; in vivo, this compound in a dose of 1/40 LD50 decreased the clotting time 2 times within 30 min after introduction. The drug effect upon subcutaneous administration lasted for 2 h. The activity of FS 169 both in vitro and in vivo was comparable with the activity of heparin. PMID- 24400386 TI - [Experience of using reamberin for detoxification therapy at the stage of deworming in children with chronic opisthorchiasis]. AB - The study presents data on the reversible aggregation of erythrocytes in 50 children with chronic opisthorchiasis and 45 children with inflammatory diseases of the upper digestive tract without opisthorchiasis (chronic gastroduodenitis, duodenal ulcers), all patients aged from 7 to 17 years. The results of using reamberin for detoxification therapy at the stage of deworming in children with chronic opisthorchiasis are assessed. PMID- 24400387 TI - [Evaluation of manganese-trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetate complex (Cyclomang) as paramagnetic contrast agent for magnetic resonance imaging]. AB - Preclinical evaluation of a 0.5 M solution of the manganese(II)- trans-1,2 diaminocyclohexane-N,N,N',N'-tetraacetate complex (Mn-DCTA, Cyclomang) has been carried out with a view to substitution of potentially toxic gadolinium containing paramagnetic contrast agents for clinical MRI routines. The toxicological tests of Mn(II)-DCTA were performed on mice and rats. Liquid phantoms were used for evaluating the relaxivity of Mn(II)-DCTA in comparison to that of Gd(III)-DTPA and Mn-DTPA. The diagnostic imaging properties of Mn(II) DCTA were quantitatively assessed on dogs with cerebral meningeomas (n = 10). The LD50 upon single administration in rats was above 17 ml/kg, thus slightly exceeding the corresponding values for of Gd(III)-DTPA and Mn-DTPA. The relaxivity of Mn(II)-DCTA amounted to R1 = 3.68 (mM(-1) x s(-1)) and did not differ significantly from the values known for Gd-DTPA and Mn-DTPA. Mn(II)-DCTA ensured high-intensity contrast of tumor areas in brain of dogs. It is concluded that Mn(II)-DCTA can be employed as a paramagnetic contrast agent in routine MRI studies and is worth further clinical evaluation. PMID- 24400388 TI - [Pathophysiological grounds of reamberin application in complex treatment of disintegrated factures of pelvic bones]. AB - The investigation showed that reamberin application in the complex treatment of patients with severe disintegrated fractures of pelvic bones is pathogenetically grounded. Despite polyetiological origin of critical conditions in the organism in this case, all these have a common pathophysiological basis of three main processes: hypoxia, intoxication, and immunosuppression. Succinic acid, which is contained in reamberin, is a substrate antihypoxant that stimulates the synthesis of restorative equivalents in the cell. A modifying effect of succinic acid on the processes of tissue metabolism, including cell respiration, LPO/AOS system, and synthesis of proteins, is the basis of pathophysiological ground of reamberin application in a complex treatment of patients with disintegrated fractures of pelvic bones. PMID- 24400389 TI - [Evaluation of the effectiveness of immunomodulating therapy in children with chronic gastroduodenitis]. AB - The article assesses the effectiveness of administering immunomodulating drug cycloferon in patients aged 10 to 16 years with chronic gastroduodenitis. It is established that the use of cycloferon in children with virus-associated chronic gastroduodenitis leads to a significant increase in T- and B-lymphocyte populations in mucous membranes of the stomach and duodenum, and contributes to the elimination of viruses. This results in reduced severity and activity of inflammation in the mucous membranes and decreases clinical manifestations of the disease. PMID- 24400390 TI - Complementary and alternative medicine (CAM) use in advanced cancer: a systematic review. AB - This systematic review synthesizes knowledge about the use of complementary and alternative medicine (CAM) among advanced cancer patients. EBSCO and Ovid databases were searched using core concepts, including advanced cancer, CAM, integrative medicine, and decision-making. Articles included in the final review were analyzed using narrative synthesis methods, including thematic analysis, concept mapping, and critical reflection on the synthesis process. Results demonstrate that advanced cancer patients who are younger, female, more educated, have longer duration of disease, and have previously used CAM are more likely to use CAM during this stage of illness. Key themes identified include patterns of and reasons for use; and barriers and facilitators to informed CAM decision making. Knowledge regarding the use of CAM in advanced cancer remains in its nascent stages. Findings suggest a need for more research on understanding the dynamic process of CAM decision-making in the advanced cancer population from the patients' perspective. PMID- 24400391 TI - Best practices for pediatric palliative cancer care: a primer for clinical providers. AB - Cancer is the leading cause of disease-related death in children and adolescents. Pediatric patients with cancer suffer greatly at the end of life. However, palliative care interventions can reduce suffering and significantly improve the care of these patients and their families. A large percentage of pediatric deaths occur outside of the hospital setting where pediatric palliative resources may not be readily available. Patients in the home setting may be cared for by community hospice programs, which are typically staffed for adult populations. Increasingly, nonpediatric providers are asked to provide palliative care for children and adolescents at the end of life, yet they receive little formal training in this area. This review focuses on the principles of best practice in the provision of palliative care for children and adolescents with cancer. Our intent is to aid clinical providers in delivering optimal care to this patient population. Topics unique to pediatric palliative care that are addressed include: providing pain and symptom management in the broad pediatric range from neonate to adolescent; caring for and interacting with developmentally distinct groups; engaging in shared decision making with parents and adolescents; providing accommodations for prognoses that are often more uncertain than in adult patients; and delivering concurrent disease-directed therapy with palliative care. PMID- 24400392 TI - Gender differences in the evolution of illness understanding among patients with advanced cancer. AB - BACKGROUND: Patient understanding of advanced metastatic disease is central to decisions about care near death. Prior studies have focused on gender differences in communication style rather than on illness understanding. OBJECTIVES: : To evaluate gender differences in terminal illness acknowledgement (TIA), understanding that the disease is incurable and the advanced stage of the disease. To evaluate gender differences in patients' reports of discussions of life expectancy with oncology providers and its effect on differences in illness understanding. METHODS: Coping with Cancer 2 patients (N = 68) were interviewed before and after a visit with their oncology providers to discuss scan results. RESULTS: At the prescan interview, there were no statistically significant gender differences in patient measures of illness understanding. At the postscan interview, women were more likely than men to recognize that their illness was incurable (Adjusted Odds Ratio, [AOR] = 5.29; P = .038), know that their cancer was at an advanced stage (AOR = 6.38; P = .013), and report having had discussions of life expectancy with their oncologist (AOR = 4.77; P = .021). Controlling discussions of life expectancy, women were more likely than men to report that their cancer was at an advanced stage (AOR = 9.53; P = .050). Controlling for gender, discussions of life expectancy were associated with higher rates of TIA (AOR = 4.65; P = .036) and higher rates of understanding that the cancer was incurable (AOR = 4.09; P = .085). CONCLUSIONS: Due largely to gender differences in communication, women over time have a better understanding of their illness than men. More frequent discussions of life expectancy should enhance illness understanding and reduce gender differences. PMID- 24400393 TI - A feasibility study of caregiver-provided massage as supportive care for Veterans with cancer. AB - PURPOSE: To assess the feasibility of using a multimedia program to teach caregivers of Veterans with cancer how to offer basic massage for supportive care at home. METHODS: Feasibility was assessed according to partner availability, compliance with watching training materials and practicing massage regularly, compliance with data collection; perceived study materials burden; clarity of instructional and other study materials. Pre- and post-massage changes in patients' symptom scores were measured using a numerical rate scale. A semistructured exit interview was answered by patient and caregiver at the end of the study. RESULTS: A total of 27 dyads were recruited. Veterans were 78% male. Forty-eight percent were diagnosed with hematologic malignancies (85%, advanced stage); 52% were diagnosed with solid tumors (64% advanced stage). Caregivers were 78% female; 81% were spouses. Out of the 27 pairs, 11 completed 8 weeks of data and practiced massage weekly. The majority of attrition (69%) was due to caregivers' burden. Caregivers reported instructional materials were clear, high quality, and easy to use. Patients were highly satisfied with receiving touch from their partners regularly. Post-massage symptom scores showed statistically significant decreases in pain, stress/anxiety, and fatigue. Perceived burden of data collection instruments was high, particularly for patients. CONCLUSION: It is feasible to use the TCC program to train caregivers of Veterans with cancer to offer massage for supportive care at home. Future studies should evaluate ways of providing support to caregivers, including offering massage to them, and easing the burden of data collection for patients. PMID- 24400394 TI - Chlorpromazine bioavailability from a topical gel formulation in volunteers. AB - BACKGROUND: Symptom management medications are often compounded into topical gel formulations providing an alternative route of administration for hospice and palliative care patients. Though commonly used, transdermal absorption and bioavailability studies of these gel products are lacking. Chlorpromazine was studied because it is FDA approved for treatment of nausea and vomiting and is used off-label for treatment of agitation and delirium. OBJECTIVE: The objective of this study is to determine the transdermal absorption of chlorpromazine PLO gel in healthy adults. METHODS: Twenty-five milligrams of chlorpromazine in PLO gel was applied to 10 subjects' wrists and 100 mg was applied to 1 subject's wrist. Blood draws were completed preapplication and 1, 2, and 4 hours postapplication. This single-center unblinded study recruited healthy adults between 18 and 70 years of age. Participants were not pregnant, did not have an allergy to any component of the study medication, and were not taking a phenothiazine medication. RESULTS: Chlorpromazine was undetected in any of the 11 subjects' blood samples. LIMITATIONS: There is an assumption of equivalent medication absorption in healthy patients and palliative care or hospice patients. CONCLUSION: Rapid relief of symptoms at end of life is essential. Chlorpromazine in PLO gel may not be an effective treatment option since blood levels were undetectable at 1, 2, and 4 hours after topical application. PMID- 24400395 TI - [A course for a safe and generation equitable health care]. PMID- 24400396 TI - [Structure, contents and findings of an expert report prepared by a medical professional (I)]. AB - The second section in this report on accident-related injuries is concerned with the development and result of the report. Criteria which are generally valid for the preparation of the expert report are developed. The priorities here are the previous history obtained from the medical files, the accident report, description of injuries and pain, determination of the result, evaluation of diagrams and procedures and the diagnoses emerging from the overall picture. Results are assessed in line with the scientific reference literature. The standardised method of result determination and the assessment improve the quality of the expert report. The second section is intended for experts and insurance company employees. PMID- 24400397 TI - [Psychological aspects of "reasonable efforts" for the prediction of mental disorder-related disability]. AB - Current standards by which socio-medical expert opinions are furnished and how they forecast the effects of mental disorder on the individual level of performance are discussed. Expert reports generally focus on assessing how the impact of mental illness can be overcome by reasonable "efforts of volition", using a number of criteria within the scope of psychiatric and psychosomatic models of explanation. The article reasons that prognoses concerning impaired performance due to health problems should to a lesser degree be based on illness related parameters and analyses which are not subject to will and intention. Instead, it asks for a clear distinction between controlled coping processes on the one hand and psychodynamic defence mechanisms and illness-related processes on the other. Forecasts should take into greater consideration to what extent the effects of mental disorder on individual behaviour can also be attributed to a wide range of deliberate, non-pathological factors. Psychological motivation and action theories should become an integral part of expert reports, as they offer some useful tools for differentiating between those disabilities that are caused by controlled action and others that can be attributed to disorder-related factors. PMID- 24400398 TI - [Forensic assessment of DSM-5 posttraumatic stress disorder: a commentary on the transition from DSM-IV-TR (I)]. AB - In May 2013 the American Psychiatric Association (APA) has released the latest and fifth edition of the diagnostic and statistical manual of mental disorders (DSM-5). Like its predecessor, the DSM-IV-TR, it will have considerable impact on the science of Psychiatry. The DSM-5 describes - actually available in English - the present medical knowledge about mental disorders. In the short run, German medical science and scientific medicolegal expertises will continue to rely on the German version of the DSM-IV-TR, however, they will be difficult to defend without bearing in mind the changes that DSM-5 brings about. This report discusses the transition from DSM-IV-TR to DSM-5 with regard to posttraumatic stress disorder (PTSD) and provides suggestions, how the criteria might be evaluated. PMID- 24400399 TI - [Is vocational reintegration of young cancer patients possible?]. AB - BACKGROUND: Besides an improvement in quality of life, one of the major targets of rehabilitation programmes is to preserve the ability to work and to integrate the patient into working life again. Cancer in particular is often associated with a loss of employment and joblessness, frequently caused by incomplete rehabilitation. METHODS: The programme is aimed at young cancer patients aged between 18 and 40 years. In addition to medical rehabilitation, they undergo a specially developed programme which they complete in groups of no more than 5 persons. At baseline and at the end of the 3 weeks rehabilitation, tests on physical and mental capacity are conducted. During rehabilitation, different training programmes concerning mobility at work, fine motor skills and cognitive abilities are held, complemented by an intensive psycho-social training programme. Additionally, patients receive individual social counselling. RESULTS: So far, 34 patients with an average age of 31.8 years have participated in the programme, 65% of them suffering from malignant haematological diseases. The combination of a medical and a vocational rehabilitation programme was judged extremely positively by the participants, which remained the case 6 months after completion of the programme. The rehabilitation programme significantly reduced work incapacity periods: at baseline, only 6% of the participants had not experienced such periods, but after 3 and 6 months, this rate had increased to 61% and 62% respectively. This was accompanied by an increased health-related quality of life and reduced fatigue. CONCLUSION: With our pilot project we were able to show that such a programme is feasible, can be well integrated into clinical routine and is successful. PMID- 24400400 TI - [Prevalence of HIV treatment in PHI]. AB - The importance of HIV in PHI is examined on the basis of the "AIDS statistics" of the Association of PHI and pharmaceutical data from PHI. The observation period is from 2007 to 2011. We define a HIV case if a private insured person has submitted at least one HIV-related invoice (e.g., an antiretroviral drug) for reimbursement during the observation period. In 2011, 7,624 people in PHI received HIV therapy, that is 32% (+1888) more than in 2007. The number of new HIV cases in 2011 was 673, and thus 12% (-92) lower than in 2007. The proportion of people receiving antiretroviral therapy in PHI is higher than in the general population in Germany. HIV infections occur in all age groups, but peaks in the age group 41 to 50 years old. Men are affected more than women. In contrast, the number of HIV cases among 11- to 15-year-old girls is higher compared to boys of the same age. PMID- 24400401 TI - [Extensive speech therapy of a child growing up trilingual]. PMID- 24400402 TI - [New images, new markers in risk evaluation]. PMID- 24400403 TI - [Neurologic stress profile in nonspecific intestinal complaints and treatment with thymus, vitamins and trace elements]. PMID- 24400404 TI - [AWMF: basic principles of medical expert assessment]. PMID- 24400405 TI - [Letters to G.-M. Ostendorf: What is Medical Insurance? In: Versicherungsmedizin 65 (2013) Heft 2, S. 65]. PMID- 24400406 TI - [Letters to G.-M. Ostendorf: What is Medical Insurance? In: Versicherungsmedizin 65 (2013) Heft 2, S. 65]. PMID- 24400407 TI - [Letters to G.-M. Ostendorf: What is Medical Insurance? In: Versicherungsmedizin 65 (2013) Heft 2, S. 65]. PMID- 24400408 TI - [Letters to G.-M. Ostendorf: What is Medical Insurance? In: Versicherungsmedizin 65 (2013) Heft 2, S. 65]. PMID- 24400409 TI - [Letter to E. Pickering, J. Becher, A. Regenauer: Is family history dispensable? In: Versicherungsmedizin 65 (2013) Heft 2, S. 73. ]. PMID- 24400410 TI - [Final word]. PMID- 24400411 TI - Our great professors. PMID- 24400412 TI - Oral and maxillofacial pathology. Case of the month. Multiple odontogenic keratocysts in association with nevoid basal cell carcinoma syndrome (NBCCS). PMID- 24400413 TI - Dentistry's watershed moment. PMID- 24400414 TI - The 2013 Gold Medal for Distinguished Service--Dr Paul E. Stubbs. PMID- 24400415 TI - In patients with peri-implantitis, access flap surgery may be more effective than mechanical debridement in terms of clinical attachment gain although both treatments lead to improved clinical parameters (UT CAT #2432). PMID- 24400416 TI - Career transition and dental school faculty development program. AB - Academic dentistry, as a career track, is not attracting sufficient numbers of new recruits to maintain a corps of skilled dental educators. The Faculty Development Program (FDP) at the University of Texas Health Science Center at San Antonio Dental School received federal funds to institute a 7-component program to enhance faculty recruitment and retention and provide training in skills associated with success in academics including:(1) a Teaching Excellence and Academic Skills (TExAS)Fellowship, (2) training in research methodology,evidence based practice research, and information management, (3) an annual dental hygiene faculty development workshop for dental hygiene faculty, (4) a Teaching Honors Program and Academic Dental Careers Fellowship to cultivate students' interest in educational careers, (5) an Interprofessional Primary Care Rotation,(6) advanced education support toward a master's degree in public health, and (7) a key focus of the entire FDP, an annual Career Transition Workshop to facilitate movement from the practice arena to the educational arm of the profession.The Career Transition Workshop is a cap stone for the FDP; its goal is to build a bridge from practice to academic environment. It will provide guidance for private practice, public health, and military dentists and hygienists considering a career transition into academic dentistry. Topics will be addressed including: academic culture, preparation for the academic environment,academic responsibilities, terms of employment,compensation and benefits, career planning, and job search / interviewing. Instructors for the workshop will include dental school faculty who have transitioned from the practice, military, and public health sectors into dental education.Objectives of the Overall Faculty Development Program:* Provide training in teaching and research skills,career planning, and leadership in order to address faculty shortages in dental schools and under representation of minority faculty.* Provide resident and faculty training in cultural and linguistic competency.* Develop and conduct a collaborative inter professional education project with a Pediatric Medicine department, a nursing school, and other health professions' education programs.* Provide faculty and residents with financial support to pursue a master's degree in public health; and * Provide support and assistance for dental practitioners desiring to explore a transition into the educational environment. PMID- 24400417 TI - What dentists should know about sickle cell disease. AB - The medical history should be a communication between the patient and the dentist. A good history will reveal a patient's medical problems,concerns, ideas, and expectations. Understanding medical conditions on a patient's medical history is of up most importance in providing the patient with the best possible standard of care. Sickle cell disease is an inherited blood disorder that affects red blood cells. Normal red blood cells contain hemoglobin A. People with sickle cell disease have red blood cells containing mostly hemoglobin S, an abnormal type of hemoglobin. These mutated sickle cells do not have the smooth motion needed for oxygenation and deoxygenation. One of the main concerns in sickle cell disease is the reversible extreme pain episodes called "sickle cell crisis."Pain episodes occur when sickle cells clog small vessels, depriving the body of adequate blood and oxygen. Treatment of the sickle cell patient should be a team approach between dentist,patient, and physician. Dental treatments should be conservative and stress free for the patient.Prevention of dental disease and infections are of the up most importance to the sickle cell patient.If your patient has sickle cell disease, know about it and talk to your patient about the disease.Maintaining excellent oral health to decrease the possibility of oral infections will ensure the best care for these patients.Key words: communication, sickle cell disease (SCD), sickle cell anemia (SCA), blood inherited disorder, sickle cell trait, crisis, African Americans, deoxygenation, hemoglobin,supporting dentist, prophylactic antibiotics, and infection. PMID- 24400418 TI - Photographic images: a process for increased patient awareness and engagement. PMID- 24400419 TI - Value for your profession. Texas private practices gain the volume purchasing power of corporate practices. PMID- 24400420 TI - A seven-year intervention to diffuse economic innovations with safety benefits to Wisconsin dairy farmers. AB - The purpose of this study was to conduct a targeted information dissemination campaign to persuade agricultural managers to adopt more profitable practices that reduce injury hazards compared to traditional practices. The project disseminated information to northeast Wisconsin dairy managers about three production practices that were more profitable and had safety benefits (barn lights, silage bags, and calf feed mixing sites) using information sources that these managers were known to rely on. The project prospectively evaluated rolling, independent, community-based, probability samples (a different group of operations each year) at baseline and after each of seven intervention years. The project also evaluated comparison samples from either Maryland or New York dairy operations after intervention years two through seven. In baseline versus year seven comparisons, the Wisconsin dairy managers reported getting more information about the three practices. Compared to New York managers, Wisconsin managers reported getting more information after year seven about the three practices. Among Wisconsin managers, intervention year was associated with increased adoption of all three practices. Compared to New York managers, Wisconsin managers were more likely to report adopting two of the three practices after year seven. A targeted campaign that disseminated information to managers through traditional channels was associated with increases in manager reports of getting information about, being aware of and adopting profit-enhancing work practices with safety benefits in a high-hazard industry. PMID- 24400421 TI - Factors associated with agricultural work performed by adolescents from an immigrant farm worker population (MICASA study). AB - While studies have looked at the relationship of adolescent employment with health outcomes and risk behaviors, few have focused on children of hired farm workers. These children face unique challenges affecting their health and work environment. Exploring the frequency and nature of agricultural work characteristics among adolescent children of Hispanic hired farm workers is important for assessing the potential risks they face. METHODS: MICASA is a population-based study of settled immigrant Hispanic farm working families in Mendota, California. We selected a cross-sectional random sample of adolescents (ages 11 to 18). Interviews assessed work history, place of birth, and acculturation. RESULTS: 38% of participants were female and 62% were male; 55% were born in the U.S., 38% in Mexico, and 7% in El Salvador; and 49% worked for pay during the last year. Among those who worked, farm work was most frequently reported (73.5%). Among those who had done farm work, the mean age at initiation was 14 years, and they worked a mean of 4.3 weeks during the previous year. Hoeing, picking, and packing/sorting were the most common tasks. In models adjusted for age and sex, low-acculturated adolescents were more likely than moderately acculturated to have worked in the past 12 months, to start work younger than age 14 years, and to do farm work. SIGNIFICANCE: Farm work is common among adolescents in this Hispanic agricultural community and is strongly associated with foreign birth and low acculturation. PMID- 24400422 TI - Selecting target populations for ROPS retrofit programs in Pennsylvania and Vermont. AB - Agriculture has the highest injury and fatality rates when compared with other U.S. industries, and tractor overturns remain the leading cause of agricultural fatalities. Rollover protection structures (ROPS) are the only proven devices to protect a tractor operator in the event of an overturn. These devices are 99% effective when used with a seatbelt. Nearly 49% of tractors in the U.S. are not equipped with a ROPS. Interventions such as social marketing, community awareness campaigns, and financial incentives have been directed at encouraging farmers to install ROPS on their unprotected tractors. The purpose of this study was to conduct similar comparisons of ROPS protection and readiness to retrofit in different segments of the Vermont and Pennsylvania farm communities. A telephone survey was used to collect data on ROPS prevalence, farm demographic characteristics, and farmer's stage of change relative to installing ROPS on farm tractors. Our data provide new and unique information on the prevalence of ROPS equipped tractors relative to commodity, farm size, and a variety of other demographic variables. Extrapolating from these data, the commodities studied account for roughly 162,072 tractors across the two states. Of these, 85,927 (53%) do not have ROPS. Of these unprotected tractors, 77,203 are in Pennsylvania and 8,724 are in Vermont. Our other two research questions dealt with the farmer's stage of change and possible ways to segment this population. The stage of change portion of our work demonstrates that most Pennsylvania and Vermont farmers are not contemplating ROPS retrofitting in the near future. Since no major differences were found in the stage of change, the number of unprotected tractors was examined for each of the commodity groups. In Pennsylvania, 29% of all unprotected tractors were found on cash crop farms. This trend was even more apparent on smaller farms than large farms. This led to the selection of smaller cash crop farms as the target audience for social marketing messages. In contrast, researchers in Vermont found a bimodal distribution of unprotected tractors. Of all the commodity groups surveyed in Vermont, vegetable and cash crop farmers were least likely to have even one protected tractor to use on the farm. Probably the most encouraging finding from this study is that over 85% of Pennsylvania farms and over 87% of Vermont farms surveyed had at least one tractor available that had ROPS protection. Of those farms, 25.5% of the Pennsylvania farms and 46% of the Vermont farms have ROPS on all of their tractors. Both of these findings were greater than the findings from a 2006 survey of New York State farms, which found that 75% of surveyed New York farms have ROPS on at least one tractor and 18% have ROPS on all tractors. Even with these encouraging data, the goal of 100% of tractors with ROPS is far from being met. There are still an estimated 90,000 unprotected tractors on Pennsylvania and Vermont farms, and these farm owners are currently unmotivated to install ROPS. However as demonstrated in New York State, it may be possible to use social marketing that combines persuasive messages and cost-sharing to persuade these farmers that ROPS are indeed important and accessible. PMID- 24400423 TI - Characteristics of and risk factors for compensated occupational injury and disease claims in dairy farmers: a case-control study. AB - Research indicates that dairy farmers have an elevated risk of work-related adverse health outcomes. This case-control study evaluated the characteristics of and risk factors for compensated occupational injury and disease claims among Finnish dairy farmers. The cases consisted of 19 farm couples in which both spouses had a history of multiple claims. There were 283 claims in total, a rate of 26.6 claims per 100 person-years. The controls consisted of 12 couples in which neither spouse had compensated or rejected claims during their work history as insured farmers. A combined mail/telephone survey charted potential risk factors for compensated claims. These claims frequently involved work tasks and causes related to animal husbandry. Cattle were the most common cause for injuries in general and for serious injuries in particular. Gender differences in farm work and claims were observed. Using logistic regression analyses, we identified personal and work-related risk factors including long work history, small-scale dairy farm operation, and conventional stanchion barn for dairy cattle. Outdated working conditions, while not statistically significant, were positively associated with claims as well. Declined current work ability and musculoskeletal or respiratory conditions were significantly associated with claims where each of these outcomes may contribute to the other. Identified factors could be used to select subgroups of dairy farmers with either elevated or reduced risk of claims. Prevention of adverse health outcomes could be most effective when targeted to farmers at highest risk of occupational injury and disease. PMID- 24400424 TI - Molecular cloning and characterisation of the methionine sulphoxide reductase A (msrA) gene locus in Campylobacter lari organisms. AB - The methionine sulphoxide reductase A (msrA) gene and its adjacent genetic loci from urease-negative (UN) Campylobacter lari RM2100 and urease-positive thermophilic Campylobacter (UPTC)CF89-12 strains appear to be composed of a msrA structure gene (507 base pairs [bp]) and another five-gene cluster (approximately 6300 bp) in the same strand and direction. A primer pair (F1/R4-msrA) for polymerase chain reaction (PCR) amplification was designed to generate a product of approximately 900 bp of the msrA gene, including its adjacent genetic loci for the thermophilic Campylobacter organisms and generate an amplicon with 16 C. lari isolates (n = 4 for UN C. lari; n = 12 for UPTC). Following direct nucleotide sequencing, sequence analysis and nucleotide sequence alignment analysis, the putative full-length msrA gene from the 16 C. lari isolates showed high nucleotide sequence similarities (91.8-100%) to each other and relatively low similarity (69.3-71.8%) to three reference C. jejuni and C. coli strains. In addition, the msrA gene was transcribed in both the UPTC CF89-12 and NCTC12893 cells using reverse transcription PCR. An immunoreactively positive signal was identified in the UPTC CF89-12 and NCTC12893 cells with anti-UPTC MsrA synthetic peptide antibodies. PMID- 24400425 TI - Matrix-assisted laser desorption/ionisation-time of flight mass spectrometry: rapid identification of bacteria isolated from patients with cystic fibrosis. AB - Despite extensive research into the diagnosis and management of cystic fibrosis (CF) over the past decades, sufferers still have a median life expectancy of less than 37 years. Respiratory tract infections have a significant role in increasing the morbidity and mortality of patients with CF via a progressive decline in lung function. Rapid identification of organisms recovered from CF sputum is necessary for effective management of respiratory tract infections; however, standard techniques of identification are slow, technically demanding and expensive. The aim of this study is to asses the suitability of matrix-assisted laser desorption/ionisation-time of flight mass spectrometry (MALDI-TOF MS) in identifying bacteria isolated from the respiratory tract of patients with CF, and is assessed by testing the accuracy of MALDI-TOF MS in identifying samples from a reference collection of rare CF strains in conjunction with comparing MALDI-TOF MS and standard techniques in identifying clinical isolates from sputum samples of CF patients. MALDI-TOF MS accurately identified 100% of isolates from the reference collection of rare CF pathogens (EuroCare CF collection). The isolate identification given by MALDI-TOF MS agreed with that given by standard techniques for 479/481 (99.6%) clinical isolates obtained from respiratory samples provided by patients with CE In two (0.4%) of 481 samples there was a discrepancy in identification between MALDI-TOF MS and standard techniques. One organism was identified as Pseudomonas aeruginosa by MALDI-TOF but could only be identified by the laboratory's standard methods as of the Pseudomonas genus. The second organism was identified as P. beteli by MALDI-TOF MS and Stenotrophomonas maltophilia by standard methods. This study shows that MALDI-TOF MS is superior to standard techniques in providing cheap, rapid and accurate identification of CF sputum isolates. PMID- 24400426 TI - Rapid identification of bacteria from bioMerieux BacT/ALERT blood culture bottles by MALDI-TOF MS. AB - Several studies have reported poor results when trying to identify microorganisms directly from the bioMerieux BacT/ALERT blood culture system using matrix assisted laser desorption/ionisation-time of flight (MALDI-TOF) mass spectrometry. The aim of this study is to evaluate two new methods, Sepsityper and an enrichment method for direct identification of microorganisms from this system. For both methods the samples were processed using the Bruker Microflex LT mass spectrometer (Biotyper) using the Microflex Control software to obtain spectra. The results from direct analysis were compared with those obtained by subculture and subsequent identification. A total of 350 positive blood cultures were processed simultaneously by the two methods. Fifty-three cultures were polymocrobial or failed to grow any organism on subculture, and these results were not included as there was either no subculture result, or for polymicrobial cultures it was known that the Biotyper would not be able to distinguish the constituent organisms correctly. Overall, the results showed that, contrary to previous reports, it is possible to identify bacteria directly from bioMerieux blood culture bottles, as 219/297 (74%) correct identifications were obtained using the Bruker Sepsityper method and 228/297 (77%) were obtained for the enrichment method when there is only one organism was present. Although the enrichment method was simpler, the reagent costs for the Sepsityper method were approximately pound 4.00 per sample compared to pound 0.50. An even simpler and cheaper method, which was less labour-intensive and did not require further reagents, was investigated. Seventy-seven specimens from positive signalled blood cultures were analysed by inoculating prewarmed blood agar plates and analysing any growth after 1-, 2- and 4-h periods of incubation at 37 degrees C, by either direct transfer or alcohol extraction. This method gave the highest number of correct identifications, 66/77 (86%), and was cheaper and less labour-intensive than either of the two above methods. PMID- 24400427 TI - Emergence of carbapenem-resistant Acinetobacter in a temperate north Indian State. AB - This study aims to determine drug sensitivity, metallo-beta-lactamase (MBL) production and elaboration of bla(OXA)-type carbapenemases in Acinetobacter spp. in a temperate climate area in north India with a heavy influx of tourists. Antimicrobial sensitivity of 165 isolates was performed. Imipenem-resistant isolates were subjected to combined disk (CDT) and double-disk diffusion tests (DDT) for MBL detection. Minimum inhibitory concentration (MIC) and MBL production were tested by Etest. A multiplex polymerase chain reaction (PCR) was performed for the detection of genes encoding bla(OXA)-23 like, bla(OXA-24) like, bla(OXA-51) like and bla(OXA-58) like genes. Ninety-nine (60%) isolates were imipenem-resistant (MICs 2-96 microg/mL). Fifty (50.5%) of the 99 carbapenem resistant isolates were MBL producers by CDT and 26 (26.3%) by DDT. The majority (77%) of the isolates elaborated bla(OXA-23) and bla(OXA-51) like genes. Forty seven of the 50 MBL-positive isolates harboured bla(OXA-23) like and bla(OXA-51) like genes. MBL-producing Acinetobacter has emerged as a major pathogen in Kashmir with elaboration of bla(OXA-23) and bla(OXA-51) related carbapenemases. This poses a significant challenge for healthcare professionals and policy planners, and needs to be addressed immediately. Primary care physicians treating visitors to Kashmir need to be aware of the situation. PMID- 24400428 TI - Vitamin D in health and disease: a literature review. AB - Vitamin D, a fat-soluble prohormone, is synthesised in response to sunlight. Vitamin D requires two metabolic conversions, 25-hydroxylation in the liver and 1alpha-hydroxylation in the kidney, to become active hormone. The active form, 1alpha,25-(OH)2D, binds to the vitamin D receptor (VDR) to modulate gene transcription and regulate mineral ion homeostasis. Vitamin D plays several roles in the body, influencing bone health as well as serum calcium and phosphate levels. Furthermore, vitamin D may modify immune function, cell proliferation, differentiation and apoptosis. Vitamin D deficiency has been associated with numerous health outcomes, including risk of rickets in children or osteomalacia in adults, increased risk of fractures, falls, cancer, autoimmune disease, infectious disease, type 1 and type 2 diabetes, hypertension and heart disease, and other diseases such as multiple sclerosis. Here, vitamin D physiology and metabolism, its genomic action and association of polymorphisms in vitamin D pathway genes with different diseases are reviewed by focusing on new findings published in the literature. PMID- 24400429 TI - Increased susceptibility to antibiotics in gram-negative and gram-positive pathogens, including Pseudomonas aeruginosa, at lower temperature: is antibiotic resistance reversal possible? PMID- 24400430 TI - Evaluation of different methods to extract DNA from serum seeded with methicillin resistant Staphylococcus aureus. PMID- 24400431 TI - Non-beta-haemolytic variants of Streptococcus pyogenes: a challenge for the microbiology laboratory. PMID- 24400432 TI - Blood sample contamination by glucose-containing solutions: effects and identification. PMID- 24400433 TI - President's message. A year in review at the 2013 convention. PMID- 24400434 TI - Shed or You're Dead: 7 unconventional strategies that every nurse needs to know to stay alive & thrive! PMID- 24400435 TI - OpenNotes initiative aims to improve patient-clinician communication, care. PMID- 24400436 TI - Chronotherapy of hypertension with combination treatment. AB - In the last decade, a number of clinical studies identified an additional improvement of blood pressure control if the single drug treatment is time targeted in hypertensive individuals. On the other hand, only a few of them investigated whether any different antihypertensive effects with combination therapy can be confirmed between morning and evening dosing. This article reviews those studies employed various combinations of antihypertensive agents including calcium channel blocker with angiotensin-receptor blocker, calcium channel blocker with diuretic, angiotensin-receptor blocker with diuretic, angiotensin receptor blocker with angiotensin-converting enzyme inhibitor and angiotensin converting enzyme inhibitor with diuretic. Interestingly, the majority of studies confirmed that evening dosing is more effective in reducing asleep and/or mean systolic and/or diastolic blood pressure, one study found no difference and one study suggested that morning dosing could be more effective. Three studies showed a positive shift from non-dipping to dipping pattern with evening dosing and an opposite effect was found with morning dosing. Importantly, while the data strongly suggest that efficacy can be improved with evening dosing when drug combination is used, no thought was given to safety comparison. Thus, the complex benefit-risk ratio comparison between morning and evening dosing of blood pressure reducing drug combinations remains to be elucidated. PMID- 24400437 TI - Scaffold evaluation of liguzinediol analogs as novel cardiotonic agents. AB - Liguzinediol (LZDO) could mediate the positive inotropic effects through sarcoplasmic reticulum Ca2+ ATPase-dependent mechanism without the risk of arrhythmia. However, the pharmacophore of LZDO contributed to the activities was not clear. The aim of this work was to explore the relationship between positive inotropic effect and scaffold of LZDO as well as to check whether the pharmacophore of LZDO on anti-heart failure activity was located at the pyrazine ring. A series of LZDO analogs (3a-b, 4a-b, 9-19) were designed and synthesised, and their activities were evaluated on isolated heart contractility by Langendorff perfusion. The results showed that the efficacy of LZDO was reduced when the hydroxyl, carboxyl or ester moieties at the side chain position of LZDO were induced, and the para-dihydroxy in LZDO was necessary for its activity. Thus, the pharmacophore of the positive inotropic effect might be located at the whole scaffold of LZDO, but not at the pyrazine ring. The finding may provide an important clue of the pharmacophore for the development of novel cardiotonic agents. PMID- 24400438 TI - Simultaneous determination of aliskiren and hydrochlorothiazide in tablets and spiked human urine by ion-pair liquid chromatography. AB - An alternative method for analysis of aliskiren (ALI) and hydrochlorothiazde (HCT) in combined dosage forms by ion-pair reversed phase high performance liquid chromatography was developed and validated. The pharmaceutical preparations were analyzed using a C18 column (250 mm x 4.6 mm, 3 microm) with a mobile phase consisting of 25% methanol, 50% sodium monobasic phosphate aqueous solution containing 6 mM tetrabutylammonium bromide and 25% water at pH 7.2. Isocratic analysis was performed at a flow rate of 1 mL/min and a column temperature of 30 degrees C under direct UV detection at 210 nm. Paracetamol was used as internal standard. The validation was performed according to the ICH guidelines. The proposed method was linear over the concentration range of 0.250 to 60 and 0.1 to 10 microg/mL for ALI and HCT, respectively. The limits of detection and quantitation (LOD and LOQ) were 0.075 and 0.198 microg/mL, respectively, for ALI and 0.04 and 0.062 microg/mL, respectively, for HCT. The method proved to be specific, sensitive, precise and accurate with mean recovery values of 101.1 +/- 0.32% and 100.9 +/- 0.41% for ALI and HCT, respectively. The method robustness was evaluated by means of an experimental design. The proposed method was applied successfully to spiked human urine samples with mean recoveries of 98.8 +/- 0.36% and 98.1 +/- 0.21% for ALI and HCT, respectively. PMID- 24400439 TI - Preparation, characterization and antiproliferative activity of thymoquinone-beta cyclodextrin self assembling nanoparticles. AB - Thymoquinone (TQ) was complexed with beta-cyclodextrin (CD) to form nanosized aggregates. Various TQ:CD ratios were tested and it was found that the ratio of (1:0.25) TQ:CD formed distinguishable nanoparticles with minimum toxicity towards normal cells. These nanoparticles had an average size of 445 +/- 100 nm with a charge 21.8 mV using Zeta-sizer. Particle size measurement using scanning electron microscopy (SEM) showed an average size of 400 nm and it also revealed the presence of smaller structures, with an average size of 50 nm. The in vitro antiproliferative activity on MCF7 cells was determined using MTT assay and an IC50 of 4.70 +/- 0.60 microM for TQ-CD nanoparticles in comparison to 24.09 +/- 2.35 microM of free TQ solution after 72 h of incubation. Simultaneously, TQ-CD nanoparticles showed lesser toxicity than TQ solution using human periodontal fibroblasts as a model for normal cells. It could be concluded from the results that TQ loaded cyclodextrin nanoparticles might serve as a potential nanocarrier to improve TQ solubility as well as its antiproliferative activity with little toxicity to normal tissues. PMID- 24400440 TI - Arbidol exhibits strong inhibition towards UDP-glucuronosyltransferase (UGT) 1A9 and 2B7. AB - The aim of the present study was to investigate arbidol's inhibition towards UDP glucuronosyltransferase (UGT) 1A9 and 2B7. The nonspecific probe substrate 4 methylumbelliferone (4-MU) and recombinant UGT enzymes (UGT1A9, UGT2B7) were firstly used to evaluate the inhibition of arbidol towards UGT1A9 and UGT2B7. Furthermore, specific substrates of UGT1A9 and UGT2B7 propofol and zidovudine (AZT) were used to determine the inhibition of arbidol towards UGT1A9 and UGT2B7. Inhibition type and inhibition kinetic parameters (Ki) were determined. In vitro in vivo extrapolation (IV-IVE) was performed to predict in vivo DDI magnitude induced by arbidol. Arbidol was demonstrated to exhibit competitive inhibition towards UGT1A9 and UGT2B7 without substate-dependent behaviour. The inhibition kinetic parameters (Ki) were calculated to be 0.5 microM, 3.5 microM, 2.8 microM, 29.7 microM for UGT2B7-mediated 4-MU glucuronidation, UGT1A9-mediated 4-MU glucuronidation, UGT2B7-mediated AZT glucuronidation, and UGT1A9-mediated propofol glucuronidation, respectively. Using these parameters, the in vivo alteration of area under of concentration-time curve (AUC) was calculated to be 156%, 22%, 28% and 2.6%, respectively. Given that arbidol exhibits strong inhibition towards UGT1A9 and UGT2B7, clinical monitoring should be given when arbidol was co-administered with drugs mainly undergoing UGT1A9, UGT2B7-mediated metabolism. PMID- 24400441 TI - Proteomic analysis reveals that Adh1p is involved in a synergistic fluconazole and tetrandrine mechanism against Candida albicans. AB - We previously showed that Adh1p participates in fluconazole (FLC) resistance in Candida albicans through a mechanism that may involve efflux pumps. We also found that the concomitant use of tetrandrine (TET) and FLC provided a synergistic action against C. albicans and that the mechanism of action could be related to inhibition of a drug efflux system. To determine whether Adh1p participates in the synergistic antifungal activity of TET against C. albicans, we performed a comparative proteomic study comparing cells treated with FLC and/or TET in FLC sensitive CA-3 and untreated control cells. Proteins were analyzed using two dimensional polyacrylamide gel electrophoresis (2-D PAGE), and differentially expressed proteins were identified through matrix-assisted laser desorption/ionization time-of-flight (MALDI TOF/TOF) mass spectrometry. The resulting data were searched against a C. albicans protein database. Our analyses identified six differentially expressed proteins; four (Eno1p, Adh1p, Slb1p, and Tdh1p) were down-regulated, and two (Xyl2p, and Cdc19p) were up-regulated. The Adh1p mRNA levels were consistent with the Adh1p protein levels in all of the groups. The results suggest that Adh1p participates in the synergistic antifungal activity of TET against C. albicans. PMID- 24400442 TI - Let-7c sensitizes acquired cisplatin-resistant A549 cells by targeting ABCC2 and Bcl-XL. AB - Cancer cells that develop resistance to cisplatin (DDP) are a major clinical obstacle to the successful treatment of cancer, including non-small cell lung cancer (NSCLC). Recent studies have implicated dysregulation of microRNAs (miRNAs) function in chemoresistance. Here, we explored the role of let-7c in the acquisition of DDP-resistant phenotype in A549 cells. Let-7c was downregulated in A549/DDP cell compared with A549 cells. Modulation of let-7c altered the sensitivity of A549/DDP cells to DDP through regulating DDP-induced apopotis. Furthermore, ABCC2 and Bcl-XL were identified as targets of let-7c. ABCC2 and Bcl XL knockdown increased DDP sensitivity and DDP-induced apoptosis in A549/DDP cells. In conclusion, our findings suggested for the first time that let-7c modulate DDP response in A549/DDP cells, and one of the mechanisms was through targeting ABCC2 and Bcl-XL. Thus, let-7c could be considered for potential therapeutic application for modulating DDP-based therapy. PMID- 24400443 TI - Thiabendazole, a well-known antifungal drug, exhibits anti-metastatic melanoma B16F10 activity via inhibiting VEGF expression and inducing apoptosis. AB - Thiabendazole, an orally available antifungal drug, has been used in clinical practice for 40 years. Previous studies indicated its potential in inhibiting angiogenesis in both animal models and in human cells. Malignant melanoma is associated with angiogenesis and it is unknown whether thiabendazole is effective for malignant melanoma or not. In our research, the effects of thiabendazole on the proliferation of the murine metastatic melanoma cell line B16F10 in vitro and in vivo and the molecular mechanism were investigated. Assay of cell viability, chick embryo chorioallantoic membrane assay, quantitative real-time PCR, Western blot, wound healing assay, annexin V/propidium iodide (AV/PI) assay and B16F10 xenograft model were applied to elucidate the mechanism of thiabendazole on B16F10 cells. Thiabendazole inhibited B16F10 proliferation in vitro in a dose- and time-dependent manner with an IC50 of 532.4 +/- 32.6, 322.9 +/- 28.9, 238.5 +/- 19.8 microM at 24, 48, and 72 h, respectively. Moreover, thiabendazole inhibited the angiogenesis and the migration of B16F10 cells in vitro. Furthermore, thiabendazole restrained transcription and translation of the VEGF gene in B16F10 in vitro, and the apoptotic percentage of B16F10 cells was increased after exposure to thiabendazole. Finally, in the B16F10-bearing mice model, thiabendazole significantly suppressed tumor growth with inhibitory rates of 16.5%, 35.4% and 48.7% at the treatment of thiabendazole 20, 40 and 80 mg/kg, respectively. These results further indicated that thiabendazole may be a potential candidate for the treatment of malignant melanoma. PMID- 24400444 TI - Epidermal growth factor receptor localized to exosome membranes as a possible biomarker for lung cancer diagnosis. AB - Detection of drug-target proteins and biomarkers that are expressed in cancer tissue has significant potential for both diagnosis and treatment of cancer. However, current immuno-histochemical and cytogenetic analyses of biopsy specimens for pre-operational diagnosis are highly invasive and often difficult to apply to lung cancer patients. The purpose of this study was to evaluate the possible utility of determining epidermal growth factor receptor (EGFR) expression on exosomal membranes using a targeted ELISA with an anti-CD81 antibody as a capture antibody for lung cancer diagnosis. While soluble EGFR (sEGFR) levels in plasma were not remarkably different between lung cancer patients and normal controls, significantly higher exosomal EGFR expression levels were observed in 5/9 cancer cases compared to normal controls. These results suggest that measurement of exosomal protein levels could be useful for in vitro diagnosis, and that exosomal EGFR is a possible biomarker for characterization of lung cancer. PMID- 24400445 TI - Two potent cytochrome P450 2D6 inhibitors found in Rhodiola rosea. AB - OBJECTIVES: Throughout the world, in particular in Russia, Northern Europe and China, Rhodiola species are used as herb supplements. Previously, we found that the extract of Rhodiola rosea, one of the most widely used Rhodiola species, had an inhibitory effect on the catalytic activity of cytochrome P450 2D6. Here, its inhibitory components were identified. METHODS: A human liver microsomal in vitro system was used with dextromethorphan as substrate. The production rate of destrorphan, a metabolite of dextromethorphan, was used to measure enzyme activity. The concentration of destrorphan in the samples was measured using LC MS/MS. Inhibitory activity of eight main components from Rhodiola rosea was evaluated. RESULTS: Rhodiosin and rhodionin showed inhibitory activity with IC50 values of 0.761 microM and 0.420 microM, respectively. The other components showed no obvious inhibition (with a residual enzyme activity of more than 90%). Both rhodiosin and rhodionin were determined to be non-competitive inhibitors with Ki values of 0.769 microM and 0.535 microM. CONCLUSION: Two of the main Rhodiola rosea compounds, rhodiosin and rhodionin, can inhibit cytochrome P450 2D6 non-competitively with high specificity which could have implications for interactions with co-administered drugs. PMID- 24400446 TI - Impact of levofloxacin dose adjustments by dispensing pharmacists on adverse reactions and costs in the treatment of elderly patients. AB - Ensuring an appropriate dosage of renally eliminated drugs for patients with renal insufficiency is important for preventing adverse drug reactions. We investigated the effectiveness of interventions by pharmacists in a hospital pharmaceutical department. The comparative study was performed at Gifu Municipal Hospital in Japan from March to August 2011, and included an intervention (142 patients) and a control group (98 patients). Upon receiving a prescription of levofloxacin for patients aged > or = 75 years, pharmacists evaluated the patients' kidney function and adjusted the appropriate dosage at the time of dispensation. In the intervention and control groups, levofloxacin-induced adverse reactions developed in 6 of 142 (4.2%) and 13 of 98 (13.3%) patients, respectively (p < 0.05). The cost of reducing levofloxacin per patient was yen 191.1 and yen 0 in the intervention and control groups, respectively. The cost per patient for adverse reaction treatments and examinations was yen 15.5 and yen 290.0 in the intervention and control groups, respectively. The intergroup difference in the total cost per patient was yen 465.6. Dose adjustment of levofloxacin at the time of dispensation by the pharmacist for patients aged > or = 75 years resulted in a decrease in the incidence of adverse reactions and cost. These findings can be applied not only to hospitals, but also to community pharmacies, because the intervention, which is a manual system, is simply performed when pharmacists are dispensing drugs. PMID- 24400447 TI - Accountable care organizations: implications for nursing. PMID- 24400448 TI - The affordable care act and the role of nursing. PMID- 24400449 TI - Texas team: an update on goals, gala, and giving. PMID- 24400450 TI - Implementing SB 406. How APRNs get involved in the process. PMID- 24400451 TI - Nursing advocacy: issues for Texas nurses. PMID- 24400452 TI - The complex world faced daily by health care executives and ideas and direction to effectively deal with this complexity. PMID- 24400453 TI - Interview with John W Bluford III, FACHE, President and Chief Executive Officer, Truman Medical Centers. Interview by Dr. O'Connor. PMID- 24400454 TI - REAL data collection essential for care of vulnerable populations. PMID- 24400455 TI - Fewer, but tighter, payer relationships expected to underpin integrated health system strategies in the future. PMID- 24400456 TI - Healthcare employers' policies on nurse education. AB - The 2010 recommendation that the proportion of registered nurses with BSN (bachelor of science in nursing) degrees in the nursing workforce should increase from the current 40% to 80% by the year 2020 has shifted the focus on nurses educational progression from state legislatures-where changes in entry-level requirements were debated for decades-to the executive suites of large healthcare providers. The recommendation, contained in the report titled The Future of Nursing: Leading Change, Advancing Health, by the Robert Wood Johnson Foundation Initiative on the Future of Nursing at the Institute of Medicine, suggests that human resources policies for nurses have the potential to double the rates of college degree completions (IOM, 2010). We surveyed 447 nurse executives in hospitals, nurse-led clinics, and home and hospice companies to explore the current practices of healthcare employers with regard to this recommendation. Almost 80% of respondents reported that their institution either preferred or required newly hired nurses to have a bachelor's degree, and 94% of the facilities offered some level of tuition reimbursement. Only 25%, however, required their nurses to earn a BSN or offered salary differentials on the basis of educational attainment (9%). We conclude that if employers are serious about wanting a more highly educated nurse workforce, they need to adopt requirements for degree completion and wage differentials in the coming years. The likelihood that such policies will be widely adopted, however, is dramatically affected by the dynamics of nursing supply and demand. PMID- 24400458 TI - Engaging primary care physicians in quality improvement: lessons from a payer provider partnership. AB - A health insurer in Michigan, through its Physician Group Incentive Program, engaged providers across the state in a collection of financially incentivized initiatives to transform primary care and improve quality. We investigated physicians' and other program stakeholders' perceptions of the program through semistructured interviews with more than 80 individuals. We found that activities across five areas contributed to successful provider engagement: (1) developing a vision of improving primary care, (2) deliberately fostering practice-practice partnerships, (3) using existing infrastructure, (4) leveraging resources and market share, and (5) managing program trade-offs. Our research highlights effective strategies for engaging primary care physicians in program design and implementation processes and creating learning communities to support quality improvement and practice change. PMID- 24400457 TI - Reducing preventable emergency department utilization and costs by using community health workers as patient navigators. AB - Primary care-related emergency department (PCR-ED) utilization, including for conditions that are preventable or treatable with appropriate primary care, is associated with decreased efficiency of and increased costs to the health system. Many PCR-ED users experience actual or perceived problems accessing appropriate, ongoing sources of medical care. Patient navigation, an intervention used most often in the cancer care continuum, may help to address these barriers among medically underserved populations, such as those who are low income, uninsured, publicly insured, or recent U.S. immigrants. We examined a patient navigation program designed to promote appropriate primary care utilization and prevent or reduce PCR-ED use at Memorial Hermann Health System in Houston, Texas. The intervention is facilitated by bilingual, state-certified community health workers (CHWs) who are trained in peer-to-peer counseling and connect medically underserved patients with medical homes and related support services. The CHWs provide education about the importance of primary care, assist with appointment scheduling, and follow up with patients to monitor and address additional barriers. Our study found that the patient navigation intervention was associated with decreased odds of returning to the ED among less frequent PCR-ED users. Among patients who returned to the ED for PCR reasons, the pre/post mean visits declined significantly over a 12-month pre/post-observation period but not over a 24-month period. The savings associated with reduced PCR-ED visits were greater than the cost to implement the navigation program. Our findings suggest that an ED-based patient navigation program led by CHWs should be further evaluated as a tool to help reduce PCR-ED visits among vulnerable populations. PMID- 24400459 TI - Implementing high-performance work practices in healthcare organizations: qualitative and conceptual evidence. AB - Studies across industries suggest that the systematic use of high-performance work practices (HPWPs) may be an effective but underused strategy to improve quality of care in healthcare organizations. Optimal use of HPWPs depends on how they are implemented, yet we know little about their implementation in healthcare. We conducted 67 key informant interviews in five healthcare organizations, each considered to have exemplary work practices in place and to deliver high-quality care, as part of an extensive study of HPWP use in healthcare. We analyzed interview transcripts inductively and deductively to examine why and how organizations implement HPWPs. We used an evidence-based model of complex innovation adoption to guide our exploration of factors that facilitate HPWP implementation. We found considerable variability in interviewees' reasons for implementing HPWPs, including macro-organizational (strategic level) and micro-organizational (individual level) reasons. This variability highlighted the complex context for HPWP implementation in many organizations. We also found that our application of an innovation implementation model helped clarify and categorize facilitators of HPWP implementation, thus providing insight on how these factors can contribute to implementation effectiveness. Focusing efforts on clarifying definitions, building commitment, and ensuring consistency in the application of work practices may be particularly important elements of successful implementation. PMID- 24400460 TI - Test your knowledge of heart failure! PMID- 24400461 TI - Racism and cardiovascular disease: implications for nursing. AB - The social determinants of health (SDH) are recognized as a prominent influence on health outcomes across the lifespan. Racism is identified as a key SDH. In this article, the authors describe the concept of racism as an SDH, its impact in discriminatory actions and inactions, and the implications for cardiovascular nurses. Although research in Canada on the links among racism, stress, and cardiovascular disease is limited, there is growing evidence about the stress of racism and its long-term impact on cardiovascular health. The authors discuss how cardiovascular nursing could be enhanced through an understanding of racism related stress, and race-based differences in cardiovascular care. The authors conclude with strategies for action to address this nursing concern. PMID- 24400462 TI - [Links between perceptions of cardiovascular disease and participation in cardiac rehabilitation programs: an exploratory study]. AB - BACKGROUND: Cardiac rehabilitation programs (CRP) entail beneficial changes for the majority of participants with heart problems. However, only 21% to 41% of those patients participate in such programs. GOAL: The goal of this study was to identify modifable and non-modifiable cardiovascular risk factors, as well as perceptions of illness that affect the participation of patients with cardiovascular problems in CRPs. METHOD: Thirty individuals with a cardiovascular disease participated in this exploratory, quantitative study. RESULTS: The results suggest that the level of education as well as increases in the level of HDL cholesterol (high-density lipoprotein) and of anxiety predict the participation in CRPs. However, the perception of illness was not associated with participation in CRPs. DISCUSSION: The implications of these results are discussed. PMID- 24400463 TI - The cochrane collaboration: 20 years of improving access to evidence for cardiovascular nursing. PMID- 24400464 TI - Taking us there. PMID- 24400465 TI - Creativity and innovation: thought and action. AB - The purpose of this article is to discuss the significance of creativity and innovation in contemporary health care contexts, and to provide nurses and other health care professionals with models, resources, and ways of thinking about creativity that informs the development of an innovation-action and creative thinking mind-set. As the complexity of health care and nursing escalates, health care providers are challenged to think more creatively and develop innovations that advance the knowledge, learning, and service contributions of their discipline to the health care enterprise. Nursing requires creative thought and innovative action in service of the greater good. PMID- 24400466 TI - Buurtzorg: nurse-led community care. AB - Buurtzorg is a nurse-led, nurse-run organization of self-managed teams that provide home care to patients in their neighborhoods. Championing humanity over bureaucracy, autonomous teams work with primary care providers, community supports, and family resources to bring patients to optimal functioning as quickly as possible. The award-winning organization grew out of a common sense approach based on principles of trust, autonomy, creativity, simplicity, and collaboration. These organizational principles translate into highly effective and efficient care, satisfied patients, and enthusiastic nurses. The model is being replicated worldwide, with teams starting in Minnesota, Sweden, Japan, and other countries. PMID- 24400467 TI - Integration of innovative clinical reasoning pedagogies into a baccalaureate nursing curriculum. AB - The significance of good clinical reasoning skills relates to prevention of adverse patient outcomes from failure to diagnose problems, institute appropriate treatments, and/or manage complications. The clinical reasoning pedagogies described in this article are integrated across a baccalaureate curriculum designed to promote a beginner level of competence in solving patient problems. The faculty adopted the content, structure, and process model for integration that includes professional language and content, the Outcome-Present State Test (OPT) model of clinical reasoning, and reflective journaling. These strategies show promise for attaining higher levels of student thinking, focusing attention on patient problems, and promoting situated cognition. As students realize that situations are complex, faculty guidance can influence best judgments and facilitate clinical reasoning with feedback on assignments to promote student growth and competence in solving clinical problems. PMID- 24400468 TI - Social media in health care: benefits, concerns, and guidelines for use. AB - The use of social media and other electronic communication has exploded as the number of social media outlets and applications continue to increase. These are exciting and valuable tools when used wisely, but pose risks when inappropriately used. The purpose of this article is to consider what comprises social media, its benefits and concerns, and guidelines for use that protect patients, employees, and organizations. PMID- 24400469 TI - Grace and glory: how one can make a difference. AB - In 2010, a free clinic in northeast Oklahoma City opened its doors and began seeing nonemergent patients. This evidence-based article illustrates the impact of the clinic on its community. It discusses the benefits and financial implications and the operation of the free clinic through contributions and volunteerism, and highlights strengths and limitations. A survey conducted over a period of three months on 50 clinic patients concluded that one free clinic can make a difference by providing much-needed access to medical care, decreasing financial burdens on area hospitals, and enhancing public opinion of Advanced Practice Registered Nurses (APRNs) as primary care providers. PMID- 24400470 TI - Hourly rounding for falls prevention: a change initiative. AB - Fall-related injuries are a particular concern within the elderly population, and trends toward an aging demographic will keep this issue at the forefront in health care. We are challenged to develop creative strategies to significantly reduce harm and fall rates among the elderly. This article describes the process of establishing an hourly rounding initiative in a health care facility. Hourly rounding is supported by the literature as an effective strategy for falls prevention and patient safety. When the initiative was not successfully adopted initially, the implementation process was critically examined and an innovative sustainability plan was developed to ensure that the change would be embedded in the organization's culture. Through this opportunity, nurses and allied health members from all levels were able to collaborate on strategies for this patient safety initiative. PMID- 24400471 TI - Harold's story. PMID- 24400472 TI - The conversation in Albuquerque. PMID- 24400473 TI - To live as as men and women of good will. PMID- 24400474 TI - Pelvic synovial sarcoma of unknown primary origin: case report and literature review. AB - A case report of a 26-year-old woman with pelvic pain for one-month duration is presented. The physical exam was unremarkable, but a right pelvic mass was found on ultrasound. Computed tomography (CT) of the abdomen/pelvis confirmed a heterogeneous 6 x 4.4 cm mass within the right pelvis adjacent to the superior lateral aspect of the uterus. Laparoscopy was performed, and the mass was found to be friable and necrotic. The origin of the mass was not able to be determined due to the collapse of the mass upon instrumentation. Histology revealed spindle cells. Further studies, including immunochemical staining, revealed a synovial sarcoma. Patient underwent laparotomy for staging and in hopes of obtaining clear tumor margins. Surgery revealed subsequent tumors involving the mesentery of the small intestine and the peritoneal wall. Biopsies taken at surgery did not reveal the primary origin of the original pelvic tumor. PMID- 24400475 TI - Aloha, I'm back. PMID- 24400476 TI - About adult tuberculosis. PMID- 24400477 TI - [Epigenetics in cancer stem cells]. AB - According to the types of stem cells and considering tumor evolution, one of the most significant theories about stem cells is derived from cancer stem cells (CSCs), which, similar to normal adult stem cells, possess the capacity of self renewal and potential of differentiation. Over the past few years, compelling evidence has emerged in support of the CSC model for many tumors. The CSCs are posited to be responsible not only for tumor initiation but also for tumor metastasis, relapse and therapyresistance. Thus, understanding the mechanisms that govern the generation and maintenance of this special population of cells is of great importance. Despite the current progress in basic genetic research, the latest work implies that epigenetic mechanisms, from DNA methylation, histone modifications and chromatin-remodeling to the wide discovered miRNAs, play critical roles in the regulation of CSC features. This review focuses on the key epigenetic mechanisms that regulate and define the unique CSC properties. PMID- 24400478 TI - [Sonic Hedgehog signaling pathway and regulation of inner ear development]. AB - During inner ear development, Sonic Hedgehog (Shh) signaling pathway is involved in the ventral otic identity, cell fate determination of statoacoustic ganglion neurons and hair cell development. Shh protein, secreted from floor plate, antagonizes Wnt protein from roof plate, which refines and maintains dorsoventral axial patterning in the ear. Shh, served as a mitogen during neurogenesis, directly promotes the development of spiral ganglion neuron. After Shh signaling pathway is activated, Ngn1 is freed from Tbx1 repression. As a result, Shh indirectly upregulates the expression of Ngn1, thus regulating neurogenic patterning of inner ear. In addition, Shh regulates the differentiation of hair cells by influencing cell cycle of the progenitor cells located in the cochlea. The basal-to-apical wave of Shh decline ensures the normal devel- opment pattern of hair cells. It is confirmed by a quantity of researches conducted in both animals and patients with hereditary hearing impairment that abnormal Shh signaling results in aberrant transcription of target genes, disturbance of the proper development of inner ear, and human hearing impairment. In humans, diseases accompanied by hearing disorders caused by abnormal Shh signaling include Greig cephalopolysyndactyly syndrome (GCPS), Pallister-Hall syndrome (PHS), Waardenburg syndrome (WS) and medulloblastoma, etc. This review would provide a theoretical basis for further study of molecular mechanisms and clinical use of inner ear development. PMID- 24400479 TI - [Advances on gene-based association analysis]. AB - Genome-wide association studies (GWAS) have been widely used for hunting the susceptibility genes for common diseases in the past years; however, the abundant information for the disease mechanism based on the GWAS data has not been fully mined. Recently, some researchers focused on the biological network and pathway analysis for the GWAS data to explore the potential disease mechanism. Since genes are the basic units for the biological network and pathway, the genetic effects from all or part of single nucleotide polymorphisms (SNPs) in the genes should be integrated into genetic scores, which are so-called "gene-based association analysis". Gene-based association analysis takes into account some important factors such as genetic effects of the SNPs, the number of the SNPs in the genes and the linkage disequilibrium structure of the SNPs. In this review, we will focus on the progress, principle and application of gene-based association analysis. PMID- 24400480 TI - [Structure, distribution, classification, and function of C1q protein family: a review]. AB - The C1q protein family consists of many proteins containing a Clq domain, which exists widely within organisms from bacteria to mammals. The domain organization of these proteins mainly includes a leading signal peptide, a collagen-like region, and a globular Clq domain. According to their structural characteristics, the C1q protein family can be divided into three subgroups: C1q, C1q-like and ghC1q. C1q, as the first subcomponent of classical pathway in the complement system, has the ability to bind immune complexes and triggers activation of the classical complement pathway. In addition, it can be a pattern recognition receptor with the unique ability to sense an amazing variety of ligands. C1q-like protein contains a collagen-like region and a globular Clq domain which is similar to Clq molecule. It involves in leech central nervous system repair. However, in vertebrates, its function converts from a lectin to an immunoglobulin binding molecule and it involves in the activation of complement system. The structure of ghC1q protein is composed of a globular Clq domain and a short N terminal sequence. This protein contains secreted globular head C1q proteins and cellular globular head C1q proteins. The sghClq protein plays an important role in the innate immune system of invertebrates. The sghC1q proteins that belong to vertebrates may serve as a new class of transneuronal regulators of synapse development and synaptic plasticity in various brain regions. The earliest cghC1q gene can be traced back to bacteria of the genus Bacillus. Its stereotypical gC1q jelly roll topology substantiates that the gC1q domain has an ancient evolutionary history and a highly conserved structure. This review focuses on the structure, distribution, classification, and function of C1q family proteins, providing valuable clues for the future research in this field. PMID- 24400481 TI - [The influence of satellite cells on meat quality and its differential regulation]. AB - Satellite cell is a kind of myogenic stem cells, which plays an important role in muscle development and injury repair. Through proliferation, differentiation and fusion of muscle fiber can satellite cells make new myonuclear, leading to the hypertrophy of skeletal muscle and fiber type transformation, and this would further affect the meat quality. Here, we review the relationship between muscle fiber development and meat quality attributes as well as the influence of the satellite cell differentiation on muscle fiber character. Besides, we also summarize the classical signaling pathway (i.e., Notch etc.) and influence of epigenetic regulation (i.e. miRNA) on muscle quality. PMID- 24400482 TI - [miRNA in regulation of skin and hair follicle development]. AB - Epidermal development and cyclic hair follicle regeneration are governed by well balanced programs of gene activation and silencing. Recent researches demonstrated that the expression profiles of miRNA showed tissue-specific expression patterns in the epidermis and hair follicles and stage-specific in cyclical development of hair follicles. Furthermore, a large number of miRNAs are involved in the development of epidermis and hair follicles, pigmentation, and the cyclical development of hair follicles. miRNAs in different cell types formed a comprehensive, multi-level network system through interaction with signal pathway and regulation factors. This review summarizes the available progress on how miRNAs are involved in the control of epidermal homeostasis and hair follicle development to enrich the research of gene regulatory networks and contribute to disease treatment and molecular breeding. PMID- 24400484 TI - [Genetic analysis and gene mapping for a salt tolerant mutant at seedling stage in rice]. AB - A salt tolerant mutant at seedling stage was obtained from an M2 population of radiation mutagenesis of an indica rice cultivar R401. The mutant seedlings could survive under the treatment of sodium chloride solution at the concentration of 150 mmol/L, while the wild-type control seedlings withered and died. An F2 population was developed from a cross between a japonica cultivar Nipponbare and the salt tolerant mutant. By investigating the performance of the F2 population under the stress of 150 mmol/L NaCl solution, we found that the mutant phenotype was caused by the recessive mutation of a single gene, temporarily designated SST(t). Bulked segregant analysis (BSA) based on the F2 mapping population revealed that SST(t) is located on chromosome 6. By analyzing 137 typical salt tolerant F2 plants using molecular markers, SST(t) was mapped in a 2.3 cM (or 406 kb) interval between InDel markers ID26847 and ID27253, with genetic distances of 1.2 cM and 1.1 cM to the two markers, respectively. PMID- 24400483 TI - [Single nuclear polymorphisms in exon 3 of POMC gene and the association with growth traits in Hu sheep and East Friesian x Hu crossbred sheep]. AB - Pro-opiomelancortin (POMC) plays important roles in the regulation of food intake and energy expenditure. The sheep exon 3 of gene POMC was amplified and sequenced by screening the DNA pools to select single nuclear polymorphisms and analyze the association with the growth traits. Two silent SNP mutations (g.273 T/C and g.456 G/A) in Hu sheep were identified. PCR-restriction fragment length polymorphism (RFLP) was used to test the g.273 T/C and the association between the g.273 T/C polymorphism and some growth traits was analyzed in Hu sheep (n = 162) and East Friesian x Hu crossbred sheep (n=130). The results showed that three genotypes, TT, TC and CC, were detected in Hu sheep with the frequencies of 0.469, 0.438 and 0.093, respectively. Two genotypes, TT and TC, were detected in East Friesian x Hu crossbred sheep with the frequencies of 0.754 and 0.246, respectively. The association analysis showed that in Hu sheep the two-month weaning weight, four month rump height of genotype CC and the four-month body length, cannon circumference of genotype TC were significantly higher than those of genotype TT (P < 0.05); the four- and six-month weight of genotype CC were significantly higher than those of genotypes TT and TC (P < 0.01); the four-month body height and body length of genotype CC were significantly higher than those of genotypes TT (P < 0.01) and TC (P < 0.05); the four-month cannon circumference of CC genotype was significantly higher than that of TT genotype (P < 0.01). In East Friesian x Hu crossbred sheep the two-month weaning weight, four-month weight, body height, body length, chest depth and cannon circumference of genotype TC were significantly higher than those of genotype TT (P < 0.05); the six-month weight of genotype TC was significantly higher than that of genotype CC (P < 0.01). In conclusion, the exon 3 of gene POMC was associated with growth traits, and C allele was beneficial to the increase of body weight and body size traits of sheep, which potentially afford a good foundation for further study on POMC gene as aided breeding markers for growth traits in sheep. PMID- 24400485 TI - [Control of organ shape and size by YUAN1 in Arabidopsis thaliana]. AB - Control of organ shape and size by cell proliferationandcell expansion is a fundamental process in plant development. However, little is known about the molecular mechanisms that set the shape and size of determinate organs in plants. We have previously demonstrated that the Arabidopsis gene DA1 controls the final size of organs by restricting cell proliferation. Through an activation tagging screen for modifiers of da1-1, we have identified a semi-dominant mutant (yuan1 1D) with altered leaf shape and size. The yuan1-1D mutation results in reduced plant height, short and round leaves and short petioles due to defects in cell elongation. YUAN1 encodes a PHD zinc finger domain-containing protein. The GFP YUAN1 fusion protein is localized to the nucleus. Overexpression of YUAN1 leads to round leaves and short petioles. Genetic analyses show that YUAN1 acts independently of DA1, ROTUNDIFOLIA 3 (ROT3) and ROTUNDIFOLIA4 (ROT4) to influence leaf shape and size. Collectively, our findings show that Arabidopsis YUAN1, a PHD zinc finger domain-containing protein, controls organ shape and size by restricting cell elongation, and give insight into how plants control their organ shape and size. PMID- 24400486 TI - [Molecular evolution of Orf1 gene in plant LTR-retrotransposons]. AB - LTR-Retrotransposons are the major DNA components in plant genomes. They usually contain gag and pol, two genes necessary for transpositinal process. Our previous study on soybean genome annotation identified a SARE LTR-Retrotransposon family, which carries the third gene, Orf1. Using a bioinformatics approach, we here reported that 7 out of 33 sequenced genomes have some LTR-Retrotransposons with an extra Orf1 gene/gene fragment (approximately 1-2 kb) in the region between 5' LTR and gag gene, including Eucalyptus grandis, Populus trichocarpa, Gossypium raimondii, Glycine max, Lotus japonica, Linum usitatissimum, and Medicago truncatula. The majority of these elements were inserted into the genomes they reside within the last 3 million years, but their structures, frequencies, intensity, and activity in different host genomes are quite different. Phylogenetic analysis indicated that these unusual elements were clustered in a eudicot branch, suggesting that they may be generated in the evolution of some eudicot species. The relative conservation, transcriptional activity, and the presence of multiple potential conserved motifs suggest that Orf1 gene may still be functional. PMID- 24400487 TI - [Sequence variation and protein structure of pipo gene in Potato virus Y]. AB - The objectives of this study were to understand the sequence variation and the putative protein structure of pipo gene in the Potato virus Y (PVY) collected from Solanum tuberosum. The pipo gene in PVY was cloned using a pair of degenerate primers designed from its conserved region and its sequences were used to re-construct phylogenetic tree in Potyvirus genera by a Bayesian inference method. An expected fragment of 235 bp was amplified in all 20 samples by RT-PCR and the pipo genes in the 20 samples assayed shared more than 92% nucleotide sequence similarity with the published sequences of PVY strains. Among the 20 pipo gene sequences, 13 polymorphic sites were detected, including 4 parsimony informative sites and 9 singleton variable sites. These results indicate that PVY pipo gene is highly conserved but some sequence variations exist. Further analyses suggest that the pipo gene encodes a hydrophilic protein without signal peptide and transmembrane region. The protein has theoretical isoelectric points (pI) ranging from 11.26 to 11.62 and contains three highly conserved regions, especially between aa 10 and 59. The protein is likely located in the mitochondria and has a-helix secondary structure. Bayesian inference of phylogenetic trees reveals that PVY isolates are clustered in the same branch with high posterior probability, while Sunflower chlorotic mottle virus (SoCMoV) and Pepper severe mosaic virus (PepSMV) are closely related, consisting with the classification of Potyvirus genera using other approaches. Our analyses suggest that the pipo gene can be a new marker for phylogenetic analysis of the genera. The results reported in this paper provide useful insights in the genetic variation and the evolution of PVY and can stimulate further research on structure and function of the PIPO protein. PMID- 24400488 TI - [SAGA complex subunit Spt20 involves in the calcineurin-mediated Cl- homeostasis in Schizosaccharomyces pombe]. AB - SAGA (Spt-Ada-Gcn5 acetyltransferase) is a highly conserved protein complex in eukaryotes, which plays a role in many important cellular processes, including transcriptional activation and mRNA exportation. In order to investigate the potential biological function of SAGA subunit, we performed a yeast two-hybrid screen using a core structural subunit of SAGA in fission yeast, Spt20, as the bait. Ppbl, catalytic subunit of calcineruin was identified in the test. Calcineurin is a key regulator of signal transduction. The interaction between Spt20 and Ppb1 was confirmed by yeast two-hybrid assay and co immunoprecipitation. In S. pombe, ppb1delta was hypersensitive to high concentration of Cl-. In contrast, spt20delta could resist high concentration of Cl-, which maintained normal growth of cells. Fluorescent colocalization analysis showed that Ppb1 was translocated from cytoplasm to nucleus and colocalized with Spt20 upon the increase of extracellular Cl-. Further genetic analysis revealed that loss of spt20+ suppressed the hypersensitive phenotype to Cl- of ppbldelta. Thus, spt20+ and ppb1+ stayed in the same pathway of regulating Cl- homeostasis and spt20+ functioned downstream of ppb1+. Our data suggest that spt20delta is able to resist high concentration of extracellular Cl- and Spt20 involves in the calcineurin-mediated Cl- homeostasis. The aberrant up-regulation of intracellular Cl- is correlated with the diseases like myocardial ischemia reperfusion injury in higher organism. As Spt20 is highly conserved in eukaryotes, it might serve as a potential drug target in Cl- imbalance related diseases. PMID- 24400489 TI - Large effects of consumer offense on ecosystem structure and function. AB - Study of the role of within-species adaptation in ecological dynamics has focused largely on prey adaptations that reduce consumption risk (prey defense). Few, if any, studies have examined how consumer adaptations to overcome prey defenses (consumer offense) affect ecosystem structure and function. We manipulated two sets of genotypes of a planktonic herbivore (Daphnia pulicaria) in a highly productive ecosystem with abundant toxic prey (cyanobacteria). The two sets of consumer genotypes varied widely in their tolerance of toxic cyanobacteria in the diet (i.e., sensitive vs. tolerant). We found a large effect of tolerant D. pulicaria on phytoplankton biomass and gross primary productivity but no effect of sensitive genotypes, this result stemming from genotype-specific differences in population growth in the presence of toxic prey. The former effect was as large as effects seen in previous Daphnia manipulations at similar productivity levels. Thus, we demonstrated that the effect of consumer genotypes with contrasting offensive adaptations was as large as the effect of consumer presence/absence. PMID- 24400490 TI - Rethinking the linear regression model for spatial ecological data. AB - The linear regression model, with its numerous extensions including multivariate ordination, is fundamental to quantitative research in many disciplines. However, spatial or temporal structure in the data may invalidate the regression assumption of independent residuals. Spatial structure at any spatial scale can be modeled flexibly based on a set of uncorrelated component patterns (e.g., Moran's eigenvector maps, MEM) that is derived from the spatial relationships between sampling locations as defined in a spatial weight matrix. Spatial filtering thus addresses spatial autocorrelation in the residuals by adding such component patterns (spatial eigenvectors) as predictors to the regression model. However, space is not an ecologically meaningful predictor, and commonly used tests for selecting significant component patterns do not take into account the specific nature of these variables. This paper proposes "spatial component regression" (SCR) as a new way of integrating the linear regression model with Moran's eigenvector maps. In its unconditioned form, SCR decomposes the relationship between response and predictors by component patterns, whereas conditioned SCR provides an alternative method of spatial filtering, taking into account the statistical properties of component patterns in the design of statistical hypothesis tests. Application to the well-known multivariate mite data set illustrates how SCR may be used to condition for significant residual spatial structure and to identify additional predictors associated with residual spatial structure. Finally, I argue that all variance is spatially structured, hence spatial independence is best characterized by a lack of excess variance at any spatial scale, i.e., spatial white noise. PMID- 24400491 TI - Characterizing scale-dependent community assembly using the functional-diversity- area relationship. AB - Phenotypic traits mediate organisms' interactions with the environment and determine how they affect and are affected by their biotic and abiotic milieu. Thus, dispersion of trait values, or functional diversity (FD) of a community can offer insights into processes driving community assembly. For example, underdispersion of FD suggests that habitat "filtering" of species with unfavorable trait values restricts the species that can exist in a particular habitat, while even spacing of FD suggests that interspecific competition, or biotic "sorting," discourages the coexistence of species with similar trait values. Since assembly processes are expected to vary as a function of spatial scale, we should also expect patterns of FD to reflect scale dependence in filtering and biotic sorting. Here we present the concept of the functional diversity-area relationship (FAR), which is similar to the species-area relationship but plots a measure of phenotypic trait diversity as a function of spatial scale. We develop a set of null model tests that discriminate between FARs generated predominantly by filtering or biotic sorting and indicate the scales at which these effects are pronounced. The utility of the FAR for addressing long-standing issues in ecology is illustrated with several examples. A multi-scale examination of FD and its pattern relative to null expectations provides an important tool for ecologists interested in understanding the scale dependence of community assembly processes. PMID- 24400492 TI - The checkered history of checkerboard distributions. AB - To address the idea that the process of interspecific competition can be inferred from data on geographical distribution alone and that evidence from geographical distribution implies an important role for interspecific competition in shaping ecological communities, we reexamine the occurrence of "true checkerboard" distributions among the land and freshwater birds in three Melanesian archipelagoes: Vanuatu, the Bismarck Archipelago, and the Solomon Islands. We use the most recently published distributional records and explicitly include the geography of the distributions of species within each archipelago. We use the overlap of convex hulls to estimate the overlap in the geographic range for each pair of species in each of these archipelagoes. We define a "true checkerboard" to consist of a pair of species with exclusive island-by-island distributions, but that have overlapping geographical ranges. To avoid the "dilution effect," we follow Diamond and Gilpin in focusing only on congeneric and within-guild species pairs as potential competitors. Few, if any, "true checkerboards" exist in these archipelagoes that could possibly have been influenced by competitive interactions, and even "true checkerboards" can arise for reasons other than interspecific competition. The similarity between related species pairs (congeneric and within-guild pairs) and unrelated species pairs in their deviation from expectation of the number of islands shared and the overlap of their geographic ranges indicates that these are not distinct statistical populations, but rather a single population of species pairs. Our result, which is based on an examination of the distributional data alone, is consistent with the interpretation that, in these avifaunas, the distributions of congeneric, within-guild, and unrelated species pairs are shaped by a common set of biological and physical environmental processes. PMID- 24400493 TI - Seabirds modify El Nino effects on tree growth in a southern Pacific island. AB - Oceanic island ecosystems are particularly sensitive to El Nino effects due to their dependence on energy and nutrient inputs from marine systems. Seabirds play a key role in transporting resources of marine origin to insular ecosystems. We report tree-growth patterns showing how the effects of El Nino rainy events on tree species in a southern Pacific island depend on the presence of local seabird colonies. We performed manipulative experiments in order to assess the mechanisms underlying these patterns. Tree ring data showed that, in normal years, the growth of all tree species (Aextoxicon punctatum, Cryptocarya alba, and Pinus radiata) was significantly lower in seabird sites compared to adjacent patches without seabirds (control sites). In contrast, in El Nino years, trees formerly hosting seabird colonies grew more than those in control sites. Experiments showed that (1) pine plants on soil from seabird sites grew more than those on soil from control sites, (2) pine individuals with seabird feces on their leaves grew less than those sprayed with an aqueous solution, and (3) soil moisture had little effect on plant growth. The stress produced by massive cormorant nesting on trees, which impairs tree growth and physiological performance, is relieved during El Nino events because of seabird migration due to decreased prey availability and pouring rains that flood nests. Soils enriched by the seabird guano, together with the increased water availability associated with El Nino, foster the growth of trees from seabird sites. We suggest that El Nino may be a key determinant of tree performance in forest communities from island and coastal ecosystems of the Pacific Ocean. PMID- 24400494 TI - Multimillion-year climatic effects on palm species diversity in Africa. AB - Past climatic changes have caused extinction, speciation, and range dynamics, but assessing the influence of past multimillion-year climatic imprints on present day biodiversity patterns remains challenging. We analyzed a new continental scale data set to examine the importance of paleoclimatic effects on current gradients in African palm richness patterns. Using climate reconstructions from the late Miocene (-10 mya), the Pliocene (-3 mya), and the Last Glacial Maximum (0.021 mya), we found that African palm diversity patterns exhibit pronounced historical legacies related to long-term climate change. Notably, pre-Pleistocene paleoprecipitation variables differentially affected current diversity patterns of palms grouped by contrasting habitat requirements. Accounting for present-day environment, rain forest palms exhibit greater species richness in localities where Pliocene precipitation was relatively high, whereas open-habitat palms show higher species richness in areas of relatively low precipitation during the Miocene Epoch. Our results demonstrate that diversity-climate relationships among African palm species include multimillion-year lagged dynamics, i.e., with historical legacies persisting across much longer time periods than commonly recognized. PMID- 24400495 TI - Quantifying effects of habitat heterogeneity and other clustering processes on spatial distributions of tree species. AB - Spatially explicit consideration of species distribution can significantly add to our understanding of species coexistence. In this paper, we evaluated the relative importance of habitat heterogeneity and other clustering processes (e.g., dispersal limitation, collectively called the non-habitat clustering process) in explaining the spatial distribution patterns of 341 tree species in three stem-mapped 25-50 ha plots of tropical, subtropical, and temperate forests. Their relative importance was estimated by a method that can take one mechanism into account when estimating the effects of the other mechanism and vice versa. Our results demonstrated that habitat heterogeneity was less important in explaining the observed species patterns than other clustering processes in plots with flat topography but was more important in one of the three plots that had a complex topography. Meanwhile, both types of clustering mechanisms (habitat or non-habitat) were pervasive among species at the 50-ha scale across the studied plots. Our analyses also revealed considerable variation among species in the relative importance of the two types of mechanism within each plot and showed that this species-level variation can be partially explained by differences in dispersal mode and growth form of species in a highly heterogeneous environment. Our findings provide new perspectives on the formation of species clustering. One important finding is that a significant species-habitat association does not necessarily mean that the habitat heterogeneity has a decisive influence on species distribution. The second insight is that the large species-level variation in the relative importance of the two types of clustering mechanisms should not be ignored. Non-habitat clustering processes can play an important role on species distribution. PMID- 24400496 TI - Directed seed dispersal of Piper by Carollia perspicillata and its effect on understory plant diversity and folivory. AB - Directed dispersal occurs when seeds are differentially deposited to sites where offspring survivorship is higher than at randomly chosen sites. Traditionally, characteristics of the dispersal target sites that could increase survivorship of the dispersed plants are thought to be intrinsic to the sites. If directed dispersal is constant over extended periods of time, however, it is likely that nonrandom patterns of dispersal could modify the ecological characteristics of the target site in ways that could increase survivorship and fitness of the dispersed plants. Here we report patterns of Piper diversity (richness, equitability, and similarity) and Piper folivory within plots near natural or artificial roosts of Carollia perspicillata vs. similar plots without bat roosts. Plots with bat roosts, both natural and artificial, had significantly higher Piper species diversity. Additionally, we found that plots with a higher Piper species diversity showed less specialist folivory, higher generalist folivory, and lower total herbivore leaf damage than plots with low Piper diversity. Finally, plots with bat roosts also showed less specialist folivory, lower generalist folivory, and lower total folivory when compared to plots without roosts. We propose that long-lasting nonrandom patterns of seed dispersal can change the local ecological characteristics of target sites via changes in plant diversity, and that these changes are likely to reduce the local rates of folivory and, therefore, increase seed and adult plant survivorship. PMID- 24400497 TI - Fire drives functional thresholds on the savanna-forest transition. AB - In tropical landscapes, vegetation patches with contrasting tree densities are distributed as mosaics. However, the locations of patches and densities of trees within them cannot be predicted by climate models alone. It has been proposed that plant-fire feedbacks drive functional thresholds at a landscape scale, thereby maintaining open (savanna) and closed (forest) communities as two distinct stable states. However, there is little rigorous field evidence for this threshold model. Here we aim to provide support for such a model from a field perspective and to analyze the functional and phylogenetic consequences of fire in a Brazilian savanna landscape (Cerrado). We hypothesize that, in tropical landscapes, savanna and forest are two stable states maintained by plant-fire feedbacks. If so, their functional and diversity attributes should change abruptly along a community closure gradient. We set 98 plots along a gradient from open savanna to closed forest in the Brazilian Cerrado and tested for a threshold pattern in nine functional traits, five soil features, and seven diversity indicators. We then tested whether the threshold pattern was associated with different fire regimes. Most community attributes presented a threshold pattern on the savanna-forest transition with coinciding breakpoints. The thresholds separated two community states: (1) open environments with low diversity communities growing in poor soils and dominated by plants that are highly resistant to high-intensity fires; and (2) closed environments with highly diverse plant communities growing in more fertile soils and dominated by shade tolerant species that efficiently prevent light from reaching the understory. In addition, each state was associated with contrasting fire regimes. Our results are consistent with the hypothesis that forests and savannas are two coexisting stable states with contrasting patterns of function and diversity that are regulated by fire-plant feedbacks; our results also shed light on the mechanism driving each state. Overall, our results support the idea that fire plays an important role in regulating the distribution of savanna and forest biomes in tropical landscapes. PMID- 24400498 TI - High-performance genotypes in an introduced plant: insights to future invasiveness. AB - Maintaining high reproductive output in diverse conditions has consistently been found to promote invasiveness in introduced taxa. Following on this key observation, studies have compared the performance across environments of invasive vs. native congeners, and of introduced vs. native populations within invasive species. Performance differences among genotypes within introduced species have received far less attention, although such genetic variation could be critical to invasive potential. If an introduced species contains genotypes that can maintain high fitness across contrasting environments, such broadly adaptive, high-performance genotypes could promote and shape the species' immediate spread across multiple habitats. Furthermore, their presence could lead to the evolution of greater aggressiveness in the species, as these high performers increase in frequency. We investigated the existence and distribution of high-performance genotypes in Polygonum cespitosum, a newly invasive Asian annual. We raised 416 genotypes, collected from 14 North American populations, under resource-rich conditions to identify potential high-performance genotypes (the top 5% in total reproductive output). We then compared their fitness, life history, and functional traits to a random group of the remaining genotypes in three contrasting environments to ask the following: (1) Do consistently high performance genotypes (i.e., genotypes with high relative fitness in diverse conditions) exist within introduced-range populations? (2) If so, do these high performance genotypes possess distinctive life history and/or functional traits? (3) Do these genotypes occur in all populations or in only a subset of populations? Genotypes initially identified as high-performance in favorable conditions also had higher reproductive output in resource-limited environments. Their fitness advantage compared with control genotypes varied in magnitude from one environment to another but was significant within all three test environments. High-performance genotypes shared a developmental syndrome characterized by rapid and high germination, fast seedling growth, early reproductive onset, and high reproductive allocation, but they did not differ in other functional traits. P. cespitosum includes a subset of genotypes with accelerated development and significantly greater fitness in both favorable and stressful conditions. The nonrandom distribution of these high-performance genotypes among populations in the species' introduced range highlights the importance of genotypic and population-level variation for invasion dynamics. PMID- 24400499 TI - Influence of recent bark beetle outbreak on fire severity and postfire tree regeneration in montane Douglas-fir forests. AB - Understanding how disturbances interact to shape ecosystems is a key challenge in ecology. In forests of western North America, the degree to which recent bark beetle outbreaks and subsequent fires may be linked (e.g., outbreak severity affects fire severity) and/ or whether these two disturbances produce compound effects on postfire succession is of widespread interest. These interactions remain unresolved, largely because field data from actual wildfires following beetle outbreaks are lacking. We studied the 2008 Gunbarrel Fire, which burned 27 200 ha in Douglas-fir (Pseudotsuga menziesii) forests that experienced a bark beetle outbreak 4-13 years prefire ("gray stage," after trees have died and needles have dropped), to determine whether outbreak severity influenced subsequent fire severity and postfire tree regeneration. In 85 sample plots we recorded prefire stand structure and outbreak severity; multiple measures of canopy and forest-floor fire severity; and postfire tree seedling density. Prefire outbreak severity was not related to any measure of fire severity except for mean bole scorch, which declined slightly with increasing outbreak severity. Instead, fire severity varied with topography and burning conditions (proxy for weather at time of fire). Postfire Douglas-fir regeneration was low, with tree seedlings absent in 65% of plots. Tree seedlings were abundant in plots of low fire severity that also had experienced low outbreak severity (mean = 1690 seedlings/ha), suggesting a dual filter on tree regeneration. Although bark beetles and fire collectively reduced live basal area to < 5% and increased snag density to > 2000% of pre-outbreak levels, the lack of relationship between beetle outbreak and fire severity suggests that these disturbances were not linked. Nonetheless, effects on postfire tree regeneration suggest compound disturbance interactions that contribute to the structural heterogeneity characteristic of mid/lower montane forests. PMID- 24400500 TI - Ideal free distribution of fixed dispersal phenotypes in a wing dimorphic beetle in heterogeneous landscapes. AB - According to the ideal free distribution (IFD) theory, individuals that are able to perceive the quality of different patches in a landscape and disperse freely are expected to redistribute themselves proportionally to the carrying capacities of heterogeneous patches. Here, we argue that, when dispersal is unconditional and genetically fixed, a coalition of sedentary and dispersing phenotypes can attain an IFD under spatiotemporally uncorrelated variation in fitness. This not only leads to a stable polymorphism of both dispersal phenotypes, but also implies that the number of dispersing individuals should on average be equal among patches and determined by the carrying capacity of the smallest local populations in the landscape. Differences in carrying capacity among patches are thus only reflected by changes in the number of sedentary individuals. Individual based simulations show that this mechanism can be generalized over a wide range of spatiotemporal conditions and dispersal strategies. Moreover, these expectations are in strong agreement with empirical data on the density of both dispersal phenotypes of the wing dimorphic ground beetle Pterostichus vernalis within and among 10 different landscapes. Hence, for the first time, these results demonstrate that this mechanism serves as a plausible alternative to the competition-colonization model to explain the spatial distribution of fixed dispersal phenotypes in heterogeneous landscapes. Understanding of the frequency distributions of individuals expressing discrete dispersal morphs moreover improves our predictive and management capabilities for a broad range of species, for which we currently typically rely on using mean dispersal rates. PMID- 24400501 TI - Limits to the reproductive success of two insect parasitoid species in the field. AB - Debates on the relative importance of different factors in limiting the realized fitness of insect parasitoids and herbivores have continued for decades. One major reason for the duration of these debates is the paucity of empirical evidence regarding the reproductive success of minute insects under field conditions. We used a novel technique to estimate lifetime reproductive success in two Anagrus spp. parasitoids, whose hosts are eggs of leafhoppers that feed on grape leaves. Females were collected soon after they died naturally, and the number of eggs in their ovaries was counted. We used these data to estimate the lifetime oviposition success of individual females. We found that more than 10% of females from the field exhausted their entire supply of eggs before they died. The lifetime reproductive success of females was positively related to their body size and was higher at field sites with more abundant hosts, although we could not rule out a causal role for other site-specific factors. In addition, we found that females from habitats rich with hosts emerged with more eggs, suggesting that they might be adapted to local conditions. The results are consistent with theoretical predictions from models considering the risk of egg limitation. PMID- 24400502 TI - Resource limitation in a competitive context determines complex plant responses to experimental resource additions. AB - Almost all models of plant resource limitation are grounded in either one or both of two simple conceptual models: Liebig's Minimum Hypothesis (LMH), the idea that plants are limited by the resource in shortest supply, and the Multiple Limitation Hypothesis (MLH), the idea that plants should adjust to their environment so that all essential resources are equally limiting. Despite the differences in their predictions, experiments have so far failed to discriminate between them. In a simple factorial nitrogen and water addition experiment in a Minnesota grassland, we observed shifts in allocation that, as in previous studies, are not all explained by a single theory. We found that leaf biomass responded positively to nitrogen additions but did not respond to water additions. We found that fine-root biomass increased in response to water additions, but only at low nitrogen levels, and that fine-root biomass decreased in response to nitrogen additions, but only at high water levels. To understand these responses we built a physiologically based model of plant competition for water, nitrogen, and space to predict plant allocation to fine roots and leaves. Critically, we include in our model the inherent variability of soil moisture and treat light, water, and nitrogen as resources with distinct mechanistic roles. Experimental results showed that plants were nitrogen and water limited. The model explains the experimental results, under conditions of co-limitation, as follows. Foliage increases with nitrogen additions but not water additions because leaf construction is constrained by nitrogen uptake. When water is added, plants spend a larger fraction of the growing season limited by light (and effectively nitrogen) than by water. Thus, water additions cause fine-root biomass to increase because of the increased importance of nitrogen limitation. The response of fine-root biomass to water additions decreases with nitrogen additions because these additions reduce nitrogen limitation. In general, our results are explained by sequential resource limitation. The rate of carbon assimilation may be limited by a single resource at any one moment, but the identity of the limiting resource(s) changes throughout the growing season. PMID- 24400503 TI - Top-down control of soil fungal community composition by a globally distributed keystone consumer. AB - The relative contribution of top-down and bottom-up processes regulating primary decomposers can influence the strength of the link between the soil animal community and ecosystem functioning. Although soil bacterial communities are regulated by bottom-up and top-down processes, the latter are considered to be less important in structuring the diversity and functioning of fungal-dominated ecosystems. Despite the huge diversity of mycophagous (fungal-feeding) soil fauna, and their potential to reverse the outcomes of competitive fungal interactions, top-down grazing effects have never been found to translate to community-level changes. We constructed soil mesocosms to investigate the potential of isopods grazing on cord-forming basidiomycete fungi to influence the community composition and functioning of a complex woodland soil microbial community. Using metagenomic sequencing we provide conclusive evidence of direct top-down control at the community scale in fungal-dominated woodland soil. By suppressing the dominant cord-forming basidiomycete fungi, isopods prevented the competitive exclusion of surrounding litter fungi, increasing diversity in a community containing several hundred fungal species. This isopod-induced modification of community composition drove a shift in the soil enzyme profile, and led to a restructuring of the wider mycophagous invertebrate community. We highlight characteristics of different soil ecosystems that will give rise to such top-down control. Given the ubiquity of isopods and basidiomycete fungi in temperate and boreal woodland ecosystems, such top-down community control could be of widespread significance for global carbon and nutrient cycling. PMID- 24400504 TI - Phylogenetic distance and species richness interactively affect the productivity of bacterial communities. AB - Our understanding of how biodiversity influences ecosystem functioning is entering a new stage of its development through the incorporation of information about the evolutionary relatedness of species. Bacteria are prime providers of essential ecosystem services, representing an excellent model system to perform biodiversity-ecosystem function research. By using bacteria isolated from petroleum-contaminated sites, we show that communities composed of poorly related species were more productive than those containing highly related species. The nature of the forces controlling this positive effect of phylogenetic diversity on community productivity depended on the number of species in culture. In communities of two species the positive effect of phylogenetic diversity on productivity was driven by changes in the selection effect. Communities of two distantly related species were dominated by the most productive species in monoculture, whereas communities of two closely related species were dominated by the less productive species in monoculture. In communities of four species the positive effect of phylogenetic diversity on productivity was driven by changes in the complementarity effect. In communities composed of four distantly related species the influence of positive interactions such as facilitation, cross feeding, and niche partitioning seemed to outweigh the influence of negative interactions such as interference. As a consequence the proportion of species favored by the presence of other species increased as they became less related. Multiple facets of biodiversity may influence ecosystem functioning. Here, we present evidence of an interaction between phylogenetic and taxonomic diversity on community productivity, underlining the importance of considering multiple aspects of biodiversity when studying its impact on ecosystem functioning. PMID- 24400505 TI - Terrestrial distribution of pond-breeding salamanders around an isolated wetland. AB - Terrestrial habitats surrounding isolated wetlands are a critical resource for many pond-breeding amphibian species, yet few studies have examined the terrestrial distribution of post-metamorphic juveniles and adults. We used an encircling drift fence at a breeding pond in conjunction with partial fences at 90, 172, and 332 m from the wetland to estimate the terrestrial distribution of adult marbled salamanders (Ambystoma opacum; four breeding seasons) and mole salamanders (A. talpoideum; two seasons), as well as the dispersion of newly metamorphosed A. opacum (one summer). For newly metamorphosed A. opacum, 79% emigrated < 90 m from the wetland, and 8% moved beyond 172 m; movement distance was unrelated to body size. Distribution of adult A. opacum varied among years, with an average of 28% (range 23-31%) occurring beyond 172 m in all years. Averaged across two years, 51% of adult A. talpoideum occurred beyond 172 m. Lognormal models provided a good fit to both the juvenile and adult ambystomatid distributions, and parameters differed between age classes, sexes, species, and years within species. For adult A. opacum a buffer radius of 300 m or 340 m, depending on the year, is estimated to include 95% of adults; for A. talpoideum the estimate is 464 m or 501 m. A reanalysis of distribution data for seven ambystomatid species shows that a previous estimate of a 164-m radius to protect 95% of a population underestimates the needed buffer radius by 185 m. Because our study wetland requires a nearly 500 m wide radius to protect 95% of its ambystomatid adults, preservation of similar communities may require much more surrounding terrestrial habitat than previously thought. PMID- 24400506 TI - Disturbance regime alters the impact of dispersal on alpha and beta diversity in a natural metacommunity. AB - Disturbance and dispersal are two fundamental ecological processes that shape diversity patterns, yet their interaction and the underlying mechanisms are still poorly understood, and evidence from natural systems is particularly lacking. Using an invertebrate rock pool metacommunity in South Africa as a natural model system, we studied potential interactive effects of disturbance regime and patch isolation on diversity patterns of species with contrasting dispersal modes (passive vs. active dispersal). Isolation and disturbance regime had negative synergistic effects on alpha diversity: both directly, by excluding late successional species from isolated patches; and indirectly, by modulating establishment success of generalist predators in well-connected patches. Unimodal relationships between isolation and alpha diversity, as predicted by mass effects, were only detected for passive dispersers in frequently disturbed patches and not in active dispersers. For passive dispersers, indications for a positive effect of isolation and a negative effect of disturbance on beta diversity were found, presumably due to differences in deterministic succession and stochastic colonization-extinction dynamics among different patch types. Our findings illustrate that interactions between dispersal rates and disturbance regime are important when explaining species diversity patterns in metacommunities and support the idea that diversity in frequently disturbed habitats is more sensitive to effects of dispersal-based processes. PMID- 24400507 TI - How many founders for a biological invasion? Predicting introduction outcomes from propagule pressure. AB - Ecological theory on biological invasions attempts to characterize the predictors of invasion success and the relative importance of the different drivers of population establishment. An outstanding question is how propagule pressure determines the probability of population establishment, where propagule pressure is the number of individuals of a species introduced into a specific location (propagule size) and their frequency of introduction (propagule number). Here, we used large-scale replicated mesocosm ponds over three reproductive seasons to identify how propagule size and number predict the probability of establishment of one of world's most invasive fish, Pseudorasbora parva, as well as its effect on the somatic growth of individuals during establishment. We demonstrated that, although a threshold of 11 introduced pairs of fish (a pair is 1 male, 1 female) was required for establishment probability to exceed 95%, establishment also occurred at low propagule size (1-5 pairs). Although single introduction events were as effective as multiple events at enabling establishment, the propagule sizes used in the multiple introductions were above the detected threshold for establishment. After three reproductive seasons, population abundance was also a function of propagule size, with rapid increases in abundance only apparent when propagule size exceeded 25 pairs. This was initially assisted by adapted biological traits, including rapid individual somatic growth that helped to overcome demographic bottlenecks. PMID- 24400508 TI - Changes in algal community structure via density- and trait-mediated indirect interactions in a marine ecosystem. AB - In various terrestrial and aquatic ecosystems, predators affect resources indirectly via intermediate prey. Such indirect interactions involve reducing the density of the prey (density-mediated indirect interactions, DMIIs) or changing the behavioral, morphological, or life history traits of the prey (trait-mediated indirect interactions, TMIIs). Although the importance of TMIIs has been highlighted recently, the strengths of both DMIIs and TMIIs under natural conditions have rarely been evaluated, especially in the context of resource community structure. We studied a three-level marine food chain involving the carnivorous snail Thais clavigera, its limpet prey Siphonaria sirius, and the limpet's food sources, the algae Lithoderma sp. and Ulva sp. We measured the strengths of DMIIs and TMIIs and observed how the algal community changes under the pressure of natural predation by T. clavigera on S. sirius. Neither DMIIs nor TMIIs affected the total algal cover or chlorophyll content per unit area. However, both types of indirect interactions caused similar changes in algal composition by increasing the cover of Ulva and decreasing the cover of Lithoderma. This change in the algal community was caused by a reduction in the limpet's preferential consumption of the competitively dominant Ulva over Lithoderma. These results suggest that both DMIIs and TMIIs have similar effects on the changes in resource community structure under natural conditions. PMID- 24400509 TI - Adaptive paternal effects? Experimental evidence that the paternal environment affects offspring performance. AB - The ability of females to adaptively influence offspring phenotype via maternal effects is widely acknowledged, but corresponding nongenetic paternal effects remain unexplored. Males can adjust sperm phenotype in response to local conditions, but the transgenerational consequences of this plasticity are unknown. We manipulated paternal density of a broadcast spawner (Styela plicata, a solitary ascidean) using methods shown previously to alter sperm phenotype in the field, then conducted in vitro fertilizations that excluded maternal effects and estimated offspring performance under natural conditions. Offspring sired by males from low-density experimental populations developed faster and had a higher hatching success than offspring sired by males living in high densities. In the field, offspring survived relatively better when their environment matched their father's, raising the possibility that fathers can adaptively influence the phenotype of their offspring according to local conditions. As the only difference between offspring is whether they were artificially fertilized by sperm from males kept in high- vs. low-density cages, we can unequivocally attribute any differences in offspring performance to an environmentally induced paternal effect. Males of many species manipulate the phenotype of their sperm in response to sperm competition: our results show this plasticity can influence offspring fitness, potentially in adaptive ways, raising the possibility that adaptive nongenetic paternal effects may be more common than previously thought. PMID- 24400510 TI - A mechanism that maintains alternative life histories in a loggerhead sea turtle population. AB - Intrapopulation variation in habitat use is commonly seen among mobile animals, yet the mechanisms maintaining it have rarely been researched among untrackable species. To investigate how alternative life histories are maintained in a population of the loggerhead sea turtle (Caretta caretta), cumulative reproductive output was evaluated and compared between small planktivores inhabiting oceanic areas (with water depths > 200 m) and large benthivores inhabiting neritic areas (depths < 200 m) that sympatrically nested at Yakushima Island, Japan, from 1986 to 2011. In total, 362 nesting females sampled in three different years were classified into the two foraging groups based on stable isotope ratios in egg yolks. There were significant differences between the two foraging groups in most recorded life history parameters (clutch size, clutch frequency, breeding frequency, and remigration intervals), with the exception of emergence success. We did not find evidence of life history trade-offs, nor age related changes in fecundity. Over the 26-year study period, we calculated a 2.4 fold greater reproductive output for neritic foragers than for oceanic ones, accounting for breeding and clutch frequency. Temporal consistencies in stable isotope ratios and remigration intervals within females suggested that female Japanese loggerheads show fidelity to respective foraging habitats throughout the adult stage. The large difference in productivity between the two groups was unlikely to be offset by the difference in survival during the period from aboveground emergence to first reproduction, suggesting that oceanic foragers have a lower level of fitness than neritic ones. Together with an absence of genetic structure between foraging groups, we infer that alternative life histories in a loggerhead turtle population are maintained by a conditional strategy. PMID- 24400511 TI - Telemetry and random-walk models reveal complex patterns of partial migration in a large marine predator. AB - Animals are often faced with complex movement decisions, particularly those that involve long-distance dispersal. Partial migrations, ubiquitous among all groups of vertebrates, are a form of long-distance movement that occurs when only some of the animals in a population migrate. The decision to migrate or to be a resident can be dependent on many factors, but these factors are rarely quantified in fishes, particularly top predators, even though partial migrations may have important implications for ecosystem dynamics and conservation. We utilized passive acoustic telemetry, with a Brownian bridge movement model and generalized additive mixed models, to explore the factors regulating partial migration in a large marine predator, the tiger shark, throughout the Hawaiian Islands. Although sharks tended to utilize a particular "core" island, they also demonstrated inter-island movements, particularly mature females that would swim from the northwestern Hawaiian Islands to the main Hawaiian Islands (MHI). Immigration to another island was a function of season, sea surface temperature (SST), and chlorophyll a concentration. Our results predict that 25% of mature females moved from remote French Frigate Shoals atoll to the MHI during late summer/early fall, potentially to give birth. Females with core home ranges within the MHI showed limited movements to the NWHI, and immigration to an island was better explained by SST and chlorophyll a concentration, suggesting a foraging function. Dispersal patterns in tiger sharks are complex but can be considered a mix of skipped-breeding partial migration by mature females and individual-based inter-island movements potentially linked to foraging. Therefore, sharks appear to use a conditional strategy based on fixed intrinsic and flexible extrinsic states. The application of Brownian bridge movement models to electronic presence/absence data provides a new technique for assessing the influence of habitat and environmental conditions on patterns of movement for fish populations. PMID- 24400512 TI - Accommodating species identification errors in transect surveys. AB - Ecologists often use transect surveys to estimate the density and abundance of animal populations. Errors in species classification are often evident in such surveys, yet few statistical methods exist to properly account for them. In this paper, we examine biases that result from species misidentification when ignored, and we develop statistical models to provide unbiased estimates of density in the face of such errors. Our approach treats true species identity as a latent variable and requires auxiliary information on the misclassification process (such as informative priors, experiments using known species, or a double observer protocol). We illustrate our approach with simulated census data and with double-observer survey data for ice-associated seals in the Bering Sea. For the seal analysis, we integrated misclassification into a model-based framework for distance-sampling data. The simulated data analysis demonstrated reliable estimation of animal density when there are experimental data to inform misclassification rates; double-observer protocols provided robust inference when there were "unknown" species observations but no outright misclassification, or when misclassification probabilities were symmetric and a symmetry constraint was imposed during estimation. Under our modeling framework, we obtained reasonable apparent densities of seal species even under considerable imprecision in species identification. We obtained more reliable inferences when modeling variation in density among transects. We argue that ecologists should often use spatially explicit models to account for differences in species distributions when trying to account for species misidentification. Our results support using double observer sampling protocols that guard against species misclassification (i.e., by recording uncertain observations as "unknown"). PMID- 24400513 TI - Moving to stay in place: behavioral mechanisms for coexistence of African large carnivores. AB - Most ecosystems have multiple predator species that not only compete for shared prey, but also pose direct threats to each other. These intraguild interactions are key drivers of carnivore community structure, with ecosystem-wide cascading effects. Yet, behavioral mechanisms for coexistence of multiple carnivore species remain poorly understood. The challenges of studying large, free-ranging carnivores have resulted in mainly coarse-scale examination of behavioral strategies without information about all interacting competitors. We overcame some of these challenges by examining the concurrent fine-scale movement decisions of almost all individuals of four large mammalian carnivore species in a closed terrestrial system. We found that the intensity ofintraguild interactions did not follow a simple hierarchical allometric pattern, because spatial and behavioral tactics of subordinate species changed with threat and resource levels across seasons. Lions (Panthera leo) were generally unrestricted and anchored themselves in areas rich in not only their principal prey, but also, during periods of resource limitation (dry season), rich in the main prey for other carnivores. Because of this, the greatest cost (potential intraguild predation) for subordinate carnivores was spatially coupled with the highest potential benefit of resource acquisition (prey-rich areas), especially in the dry season. Leopard (P. pardus) and cheetah (Acinonyx jubatus) overlapped with the home range of lions but minimized their risk using fine-scaled avoidance behaviors and restricted resource acquisition tactics. The cost of intraguild competition was most apparent for cheetahs, especially during the wet season, as areas with energetically rewarding large prey (wildebeest) were avoided when they overlapped highly with the activity areas of lions. Contrary to expectation, the smallest species (African wild dog, Lycaon pictus) did not avoid only lions, but also used multiple tactics to minimize encountering all other competitors. Intraguild competition thus forced wild dogs into areas with the lowest resource availability year round. Coexistence of multiple carnivore species has typically been explained by dietary niche separation, but our multi-scaled movement results suggest that differences in resource acquisition may instead be a consequence of avoiding intraguild competition. We generate a more realistic representation of hierarchical behavioral interactions that may ultimately drive spatially explicit trophic structures of multi-predator communities. PMID- 24400514 TI - A complex relationship between moonlight and temperature on the foraging behavior of the Alabama beach mouse. AB - Most animal species forage with risk from an ensemble of predators, wherein some predators are themselves prey to the others. A forager's behavior should reflect a synthesis of the effect of environmental conditions on both marginal predation risk and rates of energy accumulation. Here, a forager's giving-up density [GUD] is analyzed for signs of these complex signals. Specifically, we hypothesized that temperature can reverse the effect of moonlight intensity on Alabama beach mouse (Peromyscus polionotus ammobates) GUD because changes in temperature change the ensemble of predators from homeothermic taxa with better vision than the mouse to ectothermic taxa with worse vision than the mouse. We fit several models to GUD measurements taken over a broad range of temperatures and nocturnal luminosities. We obtained strong information-theoretic support for a model that is consistent with our hypothesis of temperature-dependent reversal of the effect of nocturnal illumination on mouse GUD. Signals in GUDs can reveal complex effects of optimal foraging at multiple trophic levels, which is especially informative when direct measurement of taxonomic sources of predation is not feasible. PMID- 24400515 TI - A maladaptive intermediate form: a strong trade-off revealed by hybrids between two forms of a snail-feeding beetle. AB - Although trade-off curves between fitness components are essential in theoretical studies of ecological specialization, few empirical studies have actually determined these curves experimentally. Using the snail-feeding carabid beetle Damaster blaptoides, which is endemic to the Japanese archipelago, we estimated the trade-off curve for feeding success with alternative foraging behaviors that are linked to varying morphology. First, we crossed a stout-bodied and a slender bodied subspecies and produced their F1 and backcross hybrids, which exhibited intermediate body shapes. Then we compared the snail-feeding success of these beetles. Stout beetles could eat small snails by crushing shells, whereas slender beetles could eat large snails by inserting their heads into shells. Although hybrids with intermediate body shapes attempted to employ both strategies, they frequently failed at both. The relationship between feeding success rate and beetle body shape was represented by an inward bending curve, which implies a strong trade-off that can cause disruptive selection, leading to ecological specialization. We suggest that the intermediately shaped beetles were maladapted for snail-feeding and that disruptive selection may have played an important role in the morphological divergence of these beetles. PMID- 24400516 TI - Using citizen scientists to measure an ecosystem service nationwide. AB - The decomposition of dung constitutes an ecosystem service of massive proportions. Previous studies addressing how it depends on individual invertebrate taxa have been focused on small spatial scales, neglecting the impact of large-scale factors like climate. Here, we use the concept of "citizen science" to quantify taxon-specific contributions to dung decomposition at the level of a nation. Young people across Finland manipulated the decomposer communities of cow pats, then measured changes in pat mass over the grazing season. In southern Finland most (90%) of the cattle dung hitting pastures decomposed in just two months, whereas 1100 km to the north the corresponding fraction was smaller (74%). Of the total invertebrate-caused decomposition (13% of dung pat mass, independent of latitude), large tunneling dor beetles in the genus Geotrupes account for 61%, hence removing dung twice as fast as do smaller dung-dwelling beetles and earthworms. Overall, this paper illustrates how ecologists may direct citizen scientists to implement massive ecological experiments. Compared to an approach based purely on professional scientists, we saved three-quarters of the costs. Ultimately, citizen science may offer a key tool for testing current ecological theories at relevant spatial scales--and for disseminating these theories in the process. PMID- 24400517 TI - A similarity based learning framework for interim analysis of outcome prediction of acupuncture for neck pain. AB - Chronic neck pain is a common morbid disorder in modern society. Acupuncture has been administered for treating chronic pain as an alternative therapy for a long time, with its effectiveness supported by the latest clinical evidence. However, the potential effective difference in different syndrome types is questioned due to the limits of sample size and statistical methods. We applied machine learning methods in an attempt to solve this problem. Through a multi-objective sorting of subjective measurements, outstanding samples are selected to form the base of our kernel-oriented model. With calculation of similarities between the concerned sample and base samples, we are able to make full use of information contained in the known samples, which is especially effective in the case of a small sample set. To tackle the parameters selection problem in similarity learning, we propose an ensemble version of slightly different parameter setting to obtain stronger learning. The experimental result on a real data set shows that compared to some previous well-known methods, the proposed algorithm is capable of discovering the underlying difference among different syndrome types and is feasible for predicting the effective tendency in clinical trials of large samples. PMID- 24400518 TI - A medical diagnosis support system based on automatic knowledge extraction from databases through differential evolution. AB - An intelligent system for supporting medical diagnosis is presented in this paper. The system automatically extracts knowledge from databases as sets of IF THEN rules. The approach chosen to fulfil this task is based on the differential evolution (DE) algorithm and its implementation results in a tool called DEREx. This tool is aimed at supporting clinicians in their decision making in the diagnostic process, by providing them with clear explanations on the reasons why each item is assigned to a given class. Performance of the tool has been evaluated over seven medical databases and compared against that of fifteen well known classification tools. Numerical results in terms of classification accuracy and their statistical analysis, have evidenced the effectiveness of the proposed approach, so DEREx is preferable because of its added value, i.e. the knowledge extracted automatically and provided to users in an easily comprehensible form. PMID- 24400519 TI - Unsupervised corpus distillation for represented indicator measurement on focus species detection. AB - The gene ambiguity with the highest dimension is the species with which an entity is associated in biomedical text mining. Furthermore, one of the bottlenecks in gene normalisation is focus species detection. This study presents a method which is robust for all types of articles, particularly those without explicit species mentions. Since our method requires a training corpus, we developed an iterative distillation method to extend the corpus. Unsupervised corpus is therefore helpful for the detection of focus species. In experiments, the proposed method achieved a high accuracy of 85.64% and 84.32% in datasets with and without species mentions respectively. PMID- 24400520 TI - A robust hidden semi-Markov model with application to aCGH data processing. AB - Hidden semi-Markov models are effective at modelling sequences with succession of homogenous zones by choosing appropriate state duration distributions. To compensate for model mis-specification and provide protection against outliers, we design a robust hidden semi-Markov model with Student's t mixture models as the emission distributions. The proposed approach is used to model array based comparative genomic hybridization data. Experiments conducted on the benchmark data from the Coriell cell lines, and glioblastoma multiforme data illustrate the reliability of the technique. PMID- 24400521 TI - Evaluation of supervised and unsupervised 3D star visualisation algorithms. AB - The 3D Star Coordinate Projection (3DSCP) visualisation algorithm has been developed to address the following key issues: choosing the projection configuration autonomously. preserving the data topology after projection. enhancing resolution. A supervised version of 3DSCP (S3DSCP) is also introduced to improve the computational efficiency of 3DSCP. Comparison with other linear, non-linear and axis-based techniques is performed to illustrate the efficacy of the 3DSCP and S3DSCP methods. Empirical analyses indicate that the 3DSCP and S3DSCP algorithms find hidden patterns in data while overcoming limitations of other techniques. PMID- 24400522 TI - Improved short adjacent repeat identification using three evolutionary Monte Carlo schemes. AB - This paper employs three Evolutionary Monte Carlo (EMC) schemes to solve the Short Adjacent Repeat Identification Problem (SARIP), which aims to identify the common repeat units shared by multiple sequences. The three EMC schemes, i.e., Random Exchange (RE), Best Exchange (BE), and crossover are implemented on a parallel platform. The simulation results show that compared with the conventional Markov Chain Monte Carlo (MCMC) algorithm, all three EMC schemes can not only shorten the computation time via speeding up the convergence but also improve the solution quality in difficult cases. Moreover, we observe that the performances of different EMC schemes depend on the degeneracy degree of the motif pattern. PMID- 24400523 TI - Predictability of intracranial pressure level in traumatic brain injury: features extraction, statistical analysis and machine learning-based evaluation. AB - This paper attempts to predict Intracranial Pressure (ICP) based on features extracted from non-invasively collected patient data. These features include midline shift measurement and textural features extracted from Computed axial Tomography (CT) images. A statistical analysis is performed to examine the relationship between ICP and midline shift. Machine learning is also applied to estimate ICP levels with a two-stage feature selection scheme. To avoid overfitting, all feature selections and parameter selections are performed using a nested 10-fold cross validation within the training data. The classification results demonstrate the effectiveness of the proposed method in ICP prediction. PMID- 24400524 TI - The contribution of Trichoderma to balancing the costs of plant growth and defense. AB - Trichoderma is a fungal genus of cosmopolitan distribution and high biotechnological value, with several species currently used as biological control agents. Additionally, the enzyme systems of the fungus are widely applied in industry. Species of Trichoderma protect plants against the attack of soil-borne plant pathogens by competing for nutrients and inhibiting or killing plant pathogenic fungi and oomycetes, through the production of antibiotics and/or hydrolytic enzymes. In addition to the role of Trichoderma spp. as biocontrol agents, they have other beneficial effects on plants, including the stimulation of plant defenses and the promotion of plant growth. In this review, we focus on the complex plant defense signaling network that allows the recognition of fungi as non-hostile microbes, including microbial-associated molecular patterns (MAMPs), damage-associated molecular patterns (DAMPs) and secreted elicitors. We also examine how fungal interactions with plant receptors can activate induced resistance by priming and balancing plant defense and growth responses. Our observations are integrated into a model describing Trichoderma-plant hormone signaling network interactions. PMID- 24400525 TI - Staphylococcus aureus outbreak in the intensive care unit of the largest public hospital in Quito, Ecuador. AB - Staphylococcus aureus is a frequent cause of nosocomial pneumonia and bacteremia worldwide. Classical and molecular epidemiology approaches were used to study a S. aureus outbreak in the intensive care unit (ICU) of one of the largest public hospitals in Quito. Staphylococcus aureus isolates from 17 patients and 19 potential carriers from the staff were collected from March 2007 to February 2008 and analyzed by pulsed-field gel electrophoresis (PFGE) to determine their clonal relationships. During this period the hospital reported 16 cases of hospital acquired staphylococcal pneumonia and an apparent outbreak occurred from June to September 2007. DNA from these isolates formed six different PFGE patterns: four clonal groups, and two groups of clonally related isolates. Molecular typing failed to identify any staphylococcal reservoir among staff members. The current study suggested that a staphylococcal outbreak that occurred in the summer of 2007 was caused by different bacterial clones, although some clones were shared by two patients. Historical analysis of the staphylococcal infections in the ICU showed a higher incidence during the summer months, which coincided with the programmed personnel shift. This observation suggests that outbreaks might be produced by the introduction of improperly trained personnel. PMID- 24400526 TI - Increased bile resistance in Salmonella enterica mutants lacking Prc periplasmic protease. AB - Prc is a periplasmic protease involved in processing of penicillin-binding protein 3 (PBP3). Lack of Prc suppresses bile sensitivity in Dam-, Wec-, PhoP-, DamX-, and SeqA- mutants of Salmonella enterica, and increases bile resistance in the wild type. Changes in the activity of penicillin binding proteins PBP3, PBP4, PBP5/6 and PBP7 are detected in a Prc- background, suggesting that peptidoglycan remodeling might contribute to bile resistance. PMID- 24400527 TI - Cloning and expression of a codon-optimized gene encoding the influenza A virus nucleocapsid protein in Lactobacillus casei. AB - Lactic acid bacteria (LAB) species are envisioned as promising vehicles for the mucosal delivery of therapeutic and prophylactic molecules, including the development of oral vaccines. In this study, we report on the expression of a synthetic nucleocapsid (NP) gene of influenza A virus in Lactobacillus casei. The NP gene was re-designed based on the tRNA pool and the codon usage preference of L. casei BL23. The codon-optimized NP gene was then cloned and expressed in L. casei RCEID02 under the control of a constitutive promoter, that of the lactate dehydrogenase (ldh) gene. The synthetic NP gene was further expressed in L. casei EM116 under the control of an inducible promoter, that of the structural gene of nisin (nisA) from Lactococcus lactis. Based on Western blot analysis, the specific protein band of NP, with a molecular mass of 56.0 kDa, was clearly detected in both expression systems. Thus, our study demonstrates the success of expressing a codon-optimized influenza A viral gene in L. casei. The suitability of the recombinant LAB strains for immunization purposes is currently under evaluation. PMID- 24400528 TI - Identification and modeling of a novel chloramphenicol resistance protein detected by functional metagenomics in a wetland of Lerma, Mexico. AB - The exploration of novel antibiotic resistance determinants in a particular environment may be limited because of the presence of uncultured microorganisms. In this work, a culture-independent approach based on functional metagenomics was applied to search for chloramphenicol resistance genes in agro-industrial wastewater in Lerma de Villada, Mexico. To this end, a metagenomic library was generated in Escherichia coli DH10B containing DNA isolated from environmental samples of the residual arsenic-enriched (10 mg/ml) effluent. One resistant clone was detected in this library and further analyzed. An open reading frame similar to a multidrug resistance protein from Aeromonas salmonicida and responsible for chloramphenicol resistance was identified, sequenced, and found to encode a member of the major facilitator superfamily (MFS). Our results also showed that the expression of this gene restored streptomycin sensitivity in E. coli DH10B cells. To gain further insight into the phenotype of this MFS family member, we developed a model of the membrane protein multiporter that, in addition, may serve as a template for developing new antibiotics. PMID- 24400529 TI - Isolation, selection, and characterization of highly ethanol-tolerant strains of Oenococcus oeni from south Catalonia. AB - Twenty-one strains of Oenococcus oeni were isolated during the malolactic fermentation of wines from south Catalonia. Due to their high ethanol tolerance (14 %, or more), these strains may serve as promising starters. The strains were screened by assays in a wine-like medium and by their co-inoculation in wine, resulting in the selection of well-performing strains, subsequently shown not to produce the main biogenic amines and lacking the genes involved in their synthesis. The genetic diversity of the isolates was studied by multilocus sequence typing (MLST), in which seven housekeeping genes were sequenced. Although the concatenated allelic profile of some strains was the same, the profiles obtained by random amplification of polymorphic DNA together with the variable number of tandem repeats at several loci showed that none of the strains were identical. A phylogenetic tree was constructed based on MLST with the seven genes and clearly showed two phylogroups, in accordance with previous studies. The best-performing strains occurred in members of both subgroups, suggesting that the grouping of housekeeping genes is not directly related to adaptation and ethanol tolerance. PMID- 24400531 TI - [Serious organ damage and intractable clinical conditions in rheumatic and connective tissue disease--progress in pathophysiology and treatment. Editorial: Autoimmunity, inflammation, and organ damage]. PMID- 24400530 TI - Accessibility, sustainability, excellence: how to expand access to research publications. Executive summary. PMID- 24400532 TI - [Serious organ damage and intractable clinical conditions in rheumatic and connective tissue disease--progress in pathophysiology and treatment. Topics: I. Damage to important organs whose early treatment makes a big difference; 1. Central nervous system]. PMID- 24400533 TI - [Serious organ damage and intractable clinical conditions in rheumatic and connective tissue disease--progress in pathophysiology and treatment. Topics: I. Damage to important organs whose early treatment makes a big difference; 2. Cardiac involvement in connective tissue disease]. PMID- 24400534 TI - [Serious organ damage and intractable clinical conditions in rheumatic and connective tissue disease--progress pathophysiology and treatment. Topics: I. Damage to important organs whose early treatment makes a big difference; 3. Pulmonary disease]. PMID- 24400535 TI - [Serious organ damage and intractable clinical conditions in rheumatic and connective tissue disease--progress in pathophysiology and treatment. Topics: I. Damage to important organs whose early treatment makes a big difference; 4. Kidney]. PMID- 24400536 TI - [Serious organ damage and intractable clinical conditions in rheumatic and connective tissue disease--progress in pathophysiology and treatment. Topics: I. Damage to important organs whose early treatment makes a big difference; 5. Hepatic and gastrointestinal manifestations in collagen vascular diseases]. PMID- 24400537 TI - [Serious organ damage and intractable clinical conditions in rheumatic and connective tissue disease--progress in pathophysiology and treatment. Topics: I. Damage to important organs whose early treatment makes a big difference; 6. Hematopoiesis]. PMID- 24400538 TI - [Serious organ damage and intractable clinical conditions in rheumatic and connective tissue disease--progress in pathophysiology and treatment. Topics: I. Damage to important organs whose early treatment makes a big difference; 7. Vasculitis syndrome]. PMID- 24400539 TI - [Serious organ damage and intractable clinical conditions in rheumatic and connective tissue disease--progress in pathophysiology and treatment. Topics: I. Damage to important organs whose early treatment makes a big difference; 8. Skin and mucosa]. PMID- 24400541 TI - [Serious organ damage and intractable clinical conditions in rheumatic and connective tissue disease--progress in pathophysiology and treatment. Topics: I. Damage to important organs whose early treatment makes a big difference; 10. Eye]. PMID- 24400540 TI - [Serious organ damage and intractable clinical conditions in rheumatic and connective tissue disease--progress in pathophysiology and treatment. Topics: I. Damage to important organs whose early treatment makes a big difference; 9. Rheumatoid arthritis: the progress of pathology and therapeutic strategy]. PMID- 24400542 TI - [Serious organ damage and intractable clinical conditions in rheumatic and connective tissue disease--progress in pathophysiology and treatment. Topics: II. Clinical conditions special attention needed to be paid to; 1. Pulmonary hypertension associated with connective tissue diseases]. PMID- 24400543 TI - [Serious organ damage and intractable clinical conditions in rheumatic and connective tissue disease--progress in pathophysiology and treatment. Topics: II. Clinical conditions special attention needed to be paid to; 2. Antiphospholipid syndrome]. PMID- 24400544 TI - [Serious organ damage and intractable clinical conditions in rheumatic and connective tissue disease--progress in pathophysiology and treatment. Topics: II. Clinical conditions special attention needed to be paid to; 3. Opportunistic infections]. PMID- 24400546 TI - [Serious organ damage and intractable clinical conditions in rheumatic and connective tissue disease--progress in pathophysiology and treatment. Topics: II. Clinical conditions special attention needed to be paid to; 5. Pregnancy in autoimmune rheumatic diseases]. PMID- 24400545 TI - [Serious organ damage and intractable clinical conditions in rheumatic and connective tissue disease--progress in pathophysiology and treatment. Topics: II. Clinical conditions special attention needed to be paid to; 4. Macrophage activating syndrome and hemophagocytic syndrome]. PMID- 24400547 TI - [Organ damage in collagen vascular diseases: toward the understanding of the complicated conditions (discussion)]. PMID- 24400548 TI - [Case report; a case of methotrexate-associated lymphoproliferative disorders caused with multiple lung nodules]. PMID- 24400549 TI - [Case report; a case of lung and skin nocardiosis in a non-immunocompromised patient]. PMID- 24400550 TI - [Case report; drug-induced hypersensitivity syndrome following meningoencephalitis associated with human herpes virus-6]. PMID- 24400551 TI - [Case report; a case of hereditary angioedema with laryngeal edema leading to suffocation]. PMID- 24400552 TI - [Case report; acute respiratory distress syndrome associated with ovarian hyperstimulation syndrome due to hydatidiform mole]. PMID- 24400553 TI - [Cutting-edge of medicine; dysfunction of adipose tissue and insulin resistance]. PMID- 24400554 TI - [Cutting-edge of medicine; iron metabolism--recent findings]. PMID- 24400555 TI - [Cutting-edge of medicine; pandemic potential of H5N1 influenza virus]. PMID- 24400556 TI - [Cutting-edge of medicine; clinical epidemiology regarding clinical and pathophysiological features of Japanese patients with type 2 diabetes mellitus]. PMID- 24400557 TI - [Report from Kyushu Chapter Educational Seminar: what is cardiac rehabilitation? Case report and short lectures]. PMID- 24400558 TI - [Series: For attending physicians: seeking to understand the diversity of medicine; conflict of interest in medical practice and education]. PMID- 24400559 TI - [Using serial tachograms to measure the evoked impulse activity of isolated hippocampal neurons]. AB - In these studies, we investigated the phenomenon of change in impulse activity of isolated hippocampal neurons during longtime recording. We described the use of serial tachograms during registering the electrical activity of neurons, analysis of which can improve the reliability of data. An analysis of the data identified three phases of changes in impulse activity of isolated neurons in the experimental registrations: a phase of increased activity, phase of stable activity and the phase of declining activity. It is established that in conditions of the perforated patch-clamp the phase of stable activity started at 10-15 minutes after formation of the tight junction and had an average duration of 30 minutes. It is shown that the use of the serial tahograms and phases of activity improves the quality of assessment in the measurement of the electrical activity of neurons. PMID- 24400560 TI - [Changes in active cysteine cathepsins in lysosomes from tissues thyroid papillary carcinomas with various biological characteristics]. AB - To clarify possible role of cysteine cathepsin H, B and L in the proteolytic processes that contribute to the progression of tumor growth in the thyroid, we studied their activity in lysosomes isolated from the tissue of papillary carcinomas. It was shown that for these enzymes there is a dependence of the changes in their activity on a number of biological characteristics of the tumors. Thus, the sharp increase in the activity ofcathepsin H observed in lysosomes of tissue carcinomas category T2 and T3, with intra-and ekstrathyroid and lymphatic invasion of tumor cells. An increase in the activity of cathepsin B is set in the lysosomes of tissue heterogeneous follicular structure, especially in the presence of solid areas, in comparison with typical papillary tumors and in the lysosomes of tissue carcinomas in intrathyroid and cathepsin L-at extrathyroid invasion. A common feature of the enzymes is to increase the activity of cathepsins in lysosomes of tissue nonencapsulated papillary carcinomas. These enzymes probably do not take part in the invasion of tumor cells into blood vessels and in the mechanisms of tumor metastasis to regional lymph nodes. The latter shows no changes in the activity of cathepsins in lysosomes of tissue carcinomas category N1. The results indicate the different role of cathepsin H, B and L in thyroid carcinogenesis, where each enzyme has its specific function. PMID- 24400561 TI - [Peculiarities of sexual behavior of female rats with hyperandrogenia in pubertal and postpubertal periods]. AB - The parameters of female and male sexual behavior in 3- and 6- month old female rats which were exposed to an androgen excess (subcutaneous implantation of Silastic capsules containing 5 mg of crystalline testosterone) from the beginning of pubertal period (at the age of 35 days), or within postpubertal period (at the age of 4 months). Hyperandrogenia in pubertal period had no effect on female sexual behavior formation, but it led to appearance of male behavior components in 100% of animals. In female rats which were implanted with testosterone capsules in postpubertal period, sexual disturbances were more pronounced and were characterized by masculinization and defeminization, which was due to a higher degree of androgenic saturation. The data obtained suggest a leading role of hyperandrogenemia in the pathogenesis of sexual behavior disturbances in female rats in different periods of individual development. PMID- 24400562 TI - [Cerebral hemodynamics in children of 8-12 years old with alterations of the motor activity of central origin]. AB - In children with altered physical activity there is a lack of brain blood supply, which is the most pronounced in the system of the vertebral arteries right hemisphere, and a low volume speed of blood flow in the internal carotid artery and in the system of the vertebral arteries. Children of the main group have a decreased venous outflow from the cavity of the skull, which is accompanied by altered venous circulation in the sinuses of the brain. It is established that in the system of the vertebral arteries a hemispheric asymmetry of growth in the right hemisphere is observed, in contrast to the left hemisphere, indicators of vascular tone of arterial and venous type of small caliber. Children with altered physical activity have higher values of indicators of venous outflow, than the children of the control group, and they have better venous outflow from the carotid system and a slightly worse with vertebro-basilar. PMID- 24400563 TI - [The involvement of lidocaine and tetrodotoxin-sensitive current in the generation of action potentials with low DV/DT max in the cells of the mouse sinoauricular region]. AB - The effects of the specific blockers of the inward Na-current --lidocaine and tetrodotoxin (TTX) were studied with microelectrode technique on the spontaneously beating strips of the mouse sinoauricular (SA) area. Lidocaine (25 microM) and TTX (25 pM) increased the duration of the peak of the action potentials (AP) of true pacemaker cells by extending the plateau phase (phase 2 or APD 20), slowing the dV/dt max from 2.6 +/- 0.8 V/s (n = 25) to 1.4 +/- 0.3 V/s (n = 5, p < 0.05) and reducing the velocity of diastolic depolarization (DD) by 20%. The extend of the dV/dt max value decline depended on the lidocaine concentration. The experimental data fully meted to Hill equation. The lidocaine threshold concentration was 20 microM. The lidocaine effective concentration which decreased dV/dt max by 50% (EC50) was 35 microM. The TTX (25 microM) exposure decreased the dV/dt max from 1.6 V/s to 0.8 V/s and DD velocity slowed by 49%. It should be noted that TTX also increased the duration of APD20. Our data show that dV/ dt max of the true pacemaker cells was reduced by 35-45% after exposure to TTX and lidocaine. This fact confirms the involvement of Na-current in the generation of the upstroke true pacemaker cells AP. PMID- 24400564 TI - [Features of cortical activation processes in men during auditorimotor activity of different complexity]. AB - 104 health right-handers men at the age 17-21 y.o. were tested in the study. Based on the average value of the median distribution in all parts of the cortex of individual alpha frequency activity (IAF), men were divided into two groups: with high (n = 53, IAF > or = 10,04 Hz) and low (n = 51, IAF < 10,04 Hz) levels of IAF. In men with high levels of IAF, we observed more economical and local processes ascending nonspecific activation in the cortex and descending influences of the frontal zone, which is probably a mechanism to facilitate interaction between parts of the cortex. Men with the low levels of IAF have a higher intensity of use of non-specific activation strategies indicating greater subjective difficulties of targets and the involvement of additional mechanisms for information processing. PMID- 24400565 TI - [The activity of the interneuron pools of the spinal cord in experimental diabetes mellitus]. AB - We analyzed threshold, chronaxy and parameters of the potential of the dorsal surface (PDP) of the spinal cord (SC) in Wistar rats with experimental diabetes mellitus (DM) and intact animals. We found a decrease in the excitation threshold by 41.4% (P < 0.05), and an increase in chronaxia by 9.5% (P < 0.01), an increase of the amplitude of the N3-component by 15.8% (P < 0.05), and an increase in the duration of the afferent peak by 4.5 % (P < 0,05) and the N2-component by 10.9% (P < 0.01) responsively. We conclude that the metabolic changes under DM lead to modification of activity of the afferent pathways and interneuron pool of SC. PMID- 24400566 TI - [Influence of intranasal administration of dopamine on realization of cognitive processes and locomotor activity of rats during stress]. AB - In spontanepously hypertensive rats (SHR) we studied the influence of intranasal administration of dopamine (DA) on realization of food operant conditioned reflex (OCR) and motor activity (locomotion, bars, stopping beating, grooming) in a interstimulation period in a norm and in the conditions of stressed influences. The state of sharp stress was caused by application of intensive acoustic irritation is a loud sound operating during realization ofOCR. Stress caused a brake of conditioned reflex activity, immobilization ofanimals, weakening of attention to the conditional stimulus. On a background intranasal application DA (0.15 mgs/of kg) the effect of stress on voice irritation was eliminated, not rendering brake influence on OCR and motor activity. DA via oppressing the reactions of alarm and fear strengthened the focused attention that assisted the improvement of integrative function in the concrete situation of realization of OCR. PMID- 24400567 TI - [Influence of adenosine diphosphate on respiration of rat pancreatic acinar cells mitochondria in situ]. AB - The influence ofadenosine diphosphate (ADP) on respiration of pancreatic acinar cell mitochondria in situ was studied. The model of digitonin-treated pancreatic acini was used. It was found that succinate or a mixture of pyruvate, glutamate and malate intensified respiration ofpermeabilized cells. Low ADP concentration (100 microM) did not influence the rate of oxygen uptake, whereas at higher concentration (750 microM) brief intensification of respiration was observed when using nominally Ca(2+)-free medium. When the medium with 100 nM Ca2+ was used, ADP had no effect on oxygen uptake, while the rate of respiration stimulated by a mixture of pyruvate, glutamate and malate increased. Rate of succinate-stimulated respiration did not depend on Ca2+ content in medium. The presence of ATP in the medium reduced the stimulatory effect of ADP, but increased its duration. Intensification of respiration by ADP, occurred only at elevated Ca2+ content, was not associated with oxidative phosphorylation because oligomycin did not inhibit it. The effect ofADP might be a novel "functional marker" of development of pathological processes in the mitochondria of acinar pancreacytes. PMID- 24400568 TI - [Characteristics of antiischemic and nootropic properties of ademol in a rat model of acute brain ischemia]. AB - In experiments with the rat model of acute disorder of encephalic circulation (bilateral carotid occlusion) it was found that introduction of derivate of adamantan 1-adamantiloxy-3-morfolino-2 propanol (under conventional name ademol) in the dose 2 mg/kg intraabdominal in treatment regimen (in an hour after reconstruction of insult and further 1 time every 24 hours during 21 days) was accompanied by a recovery of mnemotropic properties and is more effective than cytikolin, resulting in a decreased lethality and neurological deficiency in acute and recovery periods of insults. The data received proved the usefulness of development of ademol based cerebroprotective remedy. PMID- 24400569 TI - [Immunobiological blood parameters in rabbits after addition to the diet suspensions of chlorella, sodium sulfate, citrate and chromium chloride]. AB - We studied the content of glycoproteins and their individual carbohydrate components, the phagocyte activity of neutrophils, phagocyte index, phagocyte number lizotsym and bactericidal activity of the serum concentration of circulating immune complexes and middle mass molecules in the blood of rabbits following administration into the diet chlorella suspension, sodium sulfate, chromium citrate and chromium chloride. The studies were conducted on rabbits weighing 3.7-3.9 kg with altered diet from the first day of life to 118 days old. Rabbits were divided into five groups: the control one and four experimental groups. We found that in the blood of rabbits of experimental groups recieved sodium sulphate, chromium chloride and chromium citrate, the content of glycoprotein's and their carbohydrate components was significantly higher during the 118 days of the study compared with the control group. Feeding rabbits with mineral supplements likely reflected the differences compared with the control parameters of nonspecific resistance in the blood for the study period, which was more pronounced in the first two months of life. PMID- 24400570 TI - [The role of NADPH-oxidase in paracrine and autocrine regulation of platelet functional activity]. AB - NADPH-oxidase (NOX) is a novel transmembrane enzyme that appears to have pivotal role in the control of platelet signal pathways. The NOX activity in platelets is controlled by agonist receptors activation, which, in turn are modulated by NOX. This review focuses on participation of NOX in autocrine and paracrine regulation of platelet activation, aggregation secretion, protein synthesis and cell recruitment processes during thrombus formation. Possible involving of NOX in the cell-to-cell communication and coordination in response to trombogenic stimulus is discussed. PMID- 24400572 TI - Offer personalized nursing care by getting up to speed on personalized medicine. PMID- 24400571 TI - [Contribution of academician MF Shuba in the understanding of mechanisms of synaptic transmission in smooth muscles]. PMID- 24400573 TI - Patients look to you as a leader in understanding new healthcare laws. PMID- 24400574 TI - Get the basics of genetic mutations in oncology. PMID- 24400575 TI - A calculated risk. PMID- 24400576 TI - How does bioethics affect your nursing practice? PMID- 24400577 TI - How has genetic testing affected your clinical practice? PMID- 24400578 TI - What models can help with decisions to refer patients for genetic testing? PMID- 24400579 TI - Aiming for the future: clinical trials study the personalized treatments of tomorrow. PMID- 24400580 TI - Medicine becomes even more personal when family is involved. PMID- 24400581 TI - Treatment complexity is a key factor in overadherence to oral oncolytics. PMID- 24400582 TI - Coalition educates patients with cancer about new health insurance options. PMID- 24400583 TI - The case of the pyrogenic platelet product. PMID- 24400584 TI - Web forums allow patients with colorectal cancer to share their real-world experiences. PMID- 24400586 TI - Oncology nurses continue to reinvent themselves for the future. PMID- 24400585 TI - Drug shortages, sequestration, and the government shutdown predict the future of drug development. PMID- 24400587 TI - Visibility in the community helps educate the public about nursing. PMID- 24400588 TI - New statistical approaches to semiparametric regression with application to air pollution research. PMID- 24400590 TI - Enhanced hepatoprotective activity of andrographolide complexed with a biomaterial. AB - CONTEXT: Humic acid (HA), a natural organic matter is recently being investigated for pharmaceutical purposes. Andrographolide (AGP), a potent hepatoprotective, possesses low aqueous solubility which results in a low bioavailability after oral administration, inappropriate tissue localization and consequently poor therapeutic application. OBJECTIVE: The present study investigates the complexation of AGP with HA to increase its solubility and hepatoprotective efficacy. MATERIALS AND METHODS: Complexes prepared by solvent evaporation in various weight ratios were characterized using differential scanning calorimetry, Fourier Transform InfraRed spectroscopy, X-ray diffraction, and scanning electron microscopy. RESULTS AND DISCUSSION: The complexed AGP demonstrated improved solubility, dissolution, and permeation across rat intestine. It also displayed better hepatoprotection against carbontetrachloride-induced liver toxicity than the free drug in rats. CONCLUSION: Complexation with HA is a valuable technique to improve solubility and bioavailability of pharmaceuticals. PMID- 24400589 TI - Functional analysis of the involvement of apurinic/apyrimidinic endonuclease 1 in the resistance to melphalan in multiple myeloma. AB - BACKGROUND: Melphalan resistance has been considered one of the major obstacles to improve outcomes in multiple myeloma (MM) therapy; unfortunately, the mechanistic details of this resistance remain unclear. Melphalan is a highly effective alkylating agent which causes many types of DNA lesions, including DNA base alkylation damage that is repaired by base excision repair (BER). We postulated that human apurinic/apyrimidinic endonuclease 1 (APE1), an essential BER enzyme, plays a vital role in acquired melphalan resistance. However, because APE1 is a multifunctional protein with redox activity and acetylation modification in addition to its major repair activity, the particular APE1 function that may play a more important role in melphalan resistance is unknown. METHODS: Two MM cell lines, RPMI-8226 and U266 were used to measure the difference in APE1 levels in melphalan-resistant and sensitive derivatives. APE1 functional mutants for DNA repair, redox and acetylation were employed to investigate the roles of individual APE1 activities in acquired melphalan resistance. RESULTS: Our results indicate that APE1 is overexpressed in both MM melphalan-resistant cells. Knocking down APE1 sensitizes the melphalan resistant MM cells to melphalan treatment. The exogenous expression of DNA repair mutant H309N and acetylation mutant K6R/K7R of APE1 failed to restore the melphalan resistance of the APE1 knockdown RPMI-8226 cells. The AP endonuclease activity and multidrug resistance protein 1 (MDR1) regulatory activity may play roles in the melphalan resistance of MM cells. CONCLUSIONS: The present study has identified that the DNA repair functions and the acetylation modification of APE1 are involved in melphalan resistance of MM cells and has also shed light on future therapeutic strategies targeting specific APE1 functions by small molecule inhibitors. PMID- 24400591 TI - Superselective targeting using multivalent polymers. AB - Despite their importance for material and life sciences, multivalent interactions between polymers and surfaces remain poorly understood. Combining recent achievements of synthetic chemistry and surface characterization, we have developed a well-defined and highly specific model system based on host/guest interactions. We use this model to study the binding of hyaluronic acid functionalized with host molecules to tunable surfaces displaying different densities of guest molecules. Remarkably, we find that the surface density of bound polymer increases faster than linearly with the surface density of binding sites. Based on predictions from a simple analytical model, we propose that this superselective behavior arises from a combination of enthalpic and entropic effects upon binding of nanoobjects to surfaces, accentuated by the ability of polymer chains to interpenetrate. PMID- 24400592 TI - Spatial trend, environmental and socioeconomic factors associated with malaria prevalence in Chennai. AB - BACKGROUND: Urban malaria is considered to be one of the most significant infectious diseases due to varied socioeconomic problems especially in tropical countries like India. Among the south Indian cities, Chennai is endemic for malaria. The present study aimed to identify the hot spots of malaria prevalence and the relationship with other factors in Chennai during 2005-2011. METHODS: Data on zone-wise and ward-wise monthly malaria positive cases were collected from the Vector Control Office, Chennai Corporation, for the year 2005 to 2011 and verified using field data. This data was used to calculate the prevalence among thousand people. Hotspot analysis for all the years in the study period was done to observe the spatial trend. Association of environmental factors like altitude, population density and climatic variables was assessed using ArcGIS 9.3 version and SPSS 11.5. Pearson's correlation of climate parameters at 95% and 99% was considered to be the most significant. Social parameters of the highly malaria prone region were evaluated through a structured random questionnaire field survey. RESULTS: Among the ten zones of Chennai Corporation, Basin Bridge zone showed high malaria prevalence during the study period. The 'hotspot' analysis of malaria prevalence showed the emergence of newer hotspots in the Adyar zone. These hotspots of high prevalence are places of moderately populated and moderately elevated areas. The prevalence of malaria in Chennai could be due to rainfall and temperature, as there is a significant correlation with monthly rainfall and one month lag of monthly mean temperature. Further it has been observed that the socioeconomic status of people in the malaria hotspot regions and unhygienic living conditions were likely to aggravate the malaria problem. CONCLUSION: Malaria hotspots will be the best method to use for targeting malaria control activities. Proper awareness and periodical monitoring of malaria is one of the quintessential steps to control this infectious disease. It has been argued that identifying the key environmental conditions favourable for the occurrence and spread of malaria must be integrated and documented to aid future predictions of malaria in Chennai. PMID- 24400593 TI - A self-administered method of acute pressure block of sciatic nerves for short term relief of dental pain: a randomized study. AB - OBJECTIVES: While stimulation of the peripheral nerves increases the pain threshold, chronic pressure stimulation of the sciatic nerve is associated with sciatica. We recently found that acute pressure block of the sciatic nerve inhibits pain. Therefore, we propose that, the pain pathology-causing pressure is chronic, not acute. Here, we report a novel self-administered method: acute pressure block of the sciatic nerves is applied by the patients themselves for short-term relief of pain from dental diseases. DESIGN: This was a randomized, single-blind study. SETTING: Hospital patients. PATIENTS: Patients aged 16-60 years with acute pulpitis, acute apical periodontitis, or pericoronitis of the third molar of the mandible experiencing pain >=3 on the 11-point numerical pain rating scale. INTERVENTIONS: Three-minute pressure to sciatic nerves was applied by using the hands (hand pressure method) or by having the patients squat to force the thigh and shin as tightly as possible on the sandwiched sciatic nerve bundles (self-administered method). OUTCOMES: The primary efficacy variable was the mean difference in pain scores from the baseline. RESULTS: One hundred seventy-two dental patients were randomized. The self-administered method produced significant relief from pain associated with dental diseases (P <= 0.001). The analgesic effect of the self-administered method was similar to that of the hand pressure method. CONCLUSIONS: The self-administered method is easy to learn and can be applied at any time for pain relief. We believe that patients will benefit from this method. PMID- 24400594 TI - Magnolia dealbata seeds extract exert cytotoxic and chemopreventive effects on MDA-MB231 breast cancer cells. AB - CONTEXT: Cancer prevention remains a high priority for the scientific world. Magnolia dealbata Zucc (Magnoliaceae), a Mexican endemic species, is used for the empirical treatment of cancer. OBJECTIVE: To evaluate the cytotoxic and cancer chemopreventive effects of an ethanol extract of Magnolia dealbata seeds (MDE). MATERIALS AND METHODS: The cytotoxic effect of MDE, at concentrations ranging from 1 to 200 ug/ml, on human cancer cells and human nontumorigenic cells was evaluated using the MTT assay for 48 h. The apoptotic activities of MDE 25 MUg/ml on MDA-MB231 breast cancer cells were evaluated using the TUNEL assay and the detection of caspase 3 using immunofluorescence analysis for 48 h, each. The chemopreventive effect was evaluated by administrating different doses of MDE, between 1 and 50 mg/kg, injected intraperitoneally daily into athymic mice which were implanted with MDA-MB231 cells during 28 days. The growth and weight of tumors were measured. RESULTS: MDE showed cytotoxic effects on MDA-MB231 cells (IC50 = 25 ug/ml) and exerted pro-apoptotic activities as determined by DNA fragmentation in MDA-MB231 cells. MDE 25 ug/ml also induces the activation of caspase 3 in MDA-MB231 cells. These results suggest that Magnolia dealbata may be an optimal source of the bioactive compounds: honokiol (HK) and magnolol (MG). MDE 50 mg/kg i.p. exerted chemopreventive effects by inhibiting the growth of MDA MB231 tumor by 75% in athymic mice, compared to the control group. CONCLUSIONS: MDE exerts cytotoxic, apoptotic and chemopreventive activities on MDA-MB231 human cancer cells. PMID- 24400595 TI - Measuring rate constants for reactions of the simplest Criegee intermediate (CH2OO) by monitoring the OH radical. AB - While generating the CH2OO molecule by reacting CH2I with O2, significant amounts of the OH radical were observed by laser-induced fluorescence. At least two different processes formed OH. A fast process was probably initiated by a reaction of vibrationally hot CH2I radicals. The second process appeared to be associated with the decay of the CH2OO molecule. The addition of molecules known to react with CH2OO increased the observed decay rates of the OH signal. Using the OH signals as a proxy for the CH2OO concentration, the rate constant for the reaction of hexafluoroacetone with CH2OO was determined to be (3.33 +/- 0.27) * 10(-11) cm(3) molecule(-1) s(-1), in good agreement with the value measured by Taatjes et al.1 The rate constant for the reaction of SO2 with CH2OO, (3.53 +/- 0.29) * 10(-11) cm(3) molecule(-1) s(-1), showed no pressure dependence over the range of 50-200 Torr and was in agreement with the value at 4 Torr reported by Welz et al. PMID- 24400596 TI - Reanalysis of study of pancreatic effects of incretin therapy: methodological deficiencies. AB - A recently published study by Butler et al. concluded that incretin treatment had adverse effects on the human type 2 diabetic pancreas including 'a marked expansion of the exocrine and endocrine pancreatic compartments, the former being accompanied by increased proliferation and dysplasia and the latter by alpha-cell hyperplasia with the potential for evolution into neuroendocrine tumours'. Incretin therapy has become widely used for type 2 diabetes, so these conclusions have instigated major concerns with regard to patient safety. We reassessed both the clinical case information and virtual microscopy images of the same 34 cases that were used in the Butler study as well as Network for Pancreatic Organ Donation (nPOD) cases that were not included. Whereas we would like to stress that it is important to investigate in depth any indication that incretin treatment may lead to inflammation or dysplasia in the pancreas, we find that the data presented in the Butler paper have serious methodological deficiencies that preclude any meaningful conclusions. PMID- 24400597 TI - The influence of hormonal replacement and growth hormone treatment on the lipids in Turner syndrome. AB - AIM: Women with Turner syndrome (TS) have a risk of developing cardiovascular diseases. We assessed the lipid and carbohydrate metabolism in TS-women in the context of current hormone replacement therapy (HRT) and growth hormone (GH) treatment during childhood. METHODS: The information were collected from medical documentation and anamnesis of 165 TS-women (24.9 +/- 7.7 yr) between 1995 and 2011. The patients underwent a pituitary-gonadal axis assessment together with measurements of total cholesterol (TC), high- (HDL) and low- (LDL) density lipoproteins, triglycerides (TG), and glucose levels. RESULTS: Only 58% of women were using HRT. No differences were found in the levels of the lipid components and glucose in women who were undergoing HRT compared to those without it. Compared to TS-women without (n = 113), prior GH treatment in 34 TS-women positively influenced the lipid parameters: TC 5.0 +/- 1.1 versus 4.6 +/- 0.9 mmol/l (p = 0.03), HDL 1.5 +/- 0.5 versus 1.4 +/- 0.4 mmol/l (p > 0.05), LDL 3.3 +/- 0.9 versus 2.9 +/- 0.7 mmol/l (p = 0.03), and TG 1.1 +/- 0.6 versus 0.8 +/- 0.3 g/l (p = 0.009), respectively. CONCLUSIONS: (1) HRT does not affect lipid metabolism in TS-women. (2) The use of GH in TS-children favorably influences their lipid profile in adulthood. PMID- 24400598 TI - Comparative cytogenetic analysis in two tissues with different lineage in Turner's syndrome patients: correlation with phenotype. AB - OBJECTIVE: To analyze karyotype of Turner's syndrome (TS) patients in two tissues of different lineage, and to correlate them with phenotype. STUDY DESIGN: An observational study was designed at the Gynaecological Endocrinology Unit of Hospital Clinic in Barcelona. Patients diagnosed with TS by blood karyotype were included, between 20 and 50 years of age. A new 50-cell count blood karyotype and a urethral cell karyotype from urine samples were performed. Data on some TS related comorbidities were collected. RESULTS: Twenty-seven TS patients were included. Urine cultures of 12 patients were contaminated by microorganisms. With 50-cell count blood karyotype, three cryptic mosaicisms were found. Six patients with mosaicism in blood karyotype showed pure monosomy in urine karyotype. Correlations exist between blood karyotype and phenotype where spontaneous menarche, height, dysmorphology, congenital malformations and hypothyroidism are concerned, whereas they did not appear in urine analysis. CONCLUSIONS: Karyotyping T-lymphocytes in blood samples is the gold standard technique. 50 cell count may be considered if TS or ovarian failure is suspected, in order to detect cryptic mosaicisms. Urethral cell culture from urine samples presents technical difficulties and some limitations, due to the easier lost of abnormal X chromosome. A partial correlation between blood karyotype and phenotype exists. PMID- 24400599 TI - Newborn LpL (Ser447Stop, Asn291Ser) genotypes and the interaction with maternal genotypes influence the risk for different types of preeclampsia: modulating effect on lipid profile and pregnancy outcome. AB - AIM: To establish that newborn Ser447Stop and Asn291Ser may have interactive effects with maternal genotypes on the plasma lipoprotein levels, risk of preeclampsia as well as on the prognosis of preeclampsia. MATERIALS AND METHODS: Seventy preeclamptic women and 94 normotensive pregnant women, and their newborns were genotyped using PCR-RFLP methods. RESULTS: The risk of mild and severe preeclampsia was 4 (p = 0.004) and 5.18 (p = 0.001), respectively, if both the mother and newborn were carriers of the Ser447/Ser477 genotype. If both the mother and newborn were carriers of the Asn291Ser variant, the risk to develop severe preeclampsia was 6.07 (p = 0.03). Women with mild and severe preeclampsia had higher TG (p < 0.001; p < 0.001) and LDL-C levels (p = 0.008; p < 0.001) if both the mother and newborn were carriers of the Ser447/Ser447 genotype. Women with severe preeclampsia had significantly higher TG (p = 0.03) and LDL-C levels (p = 0.037) if both the mother and newborn were carriers of Asn291Ser. Newborn/maternal LpL interaction had no statistically significant influence on pregnancy outcome. CONCLUSIONS: The newborn/maternal LpL interaction influences the severity of preeclampsia and modulates the lipid profile particularly in severe preeclampsia. PMID- 24400600 TI - A mechanistic investigation of the C-terminal redox motif of thioredoxin reductase from Plasmodium falciparum. AB - High-molecular mass thioredoxin reductases (TRs) are pyridine nucleotide disulfide oxidoreductases that catalyze the reduction of the disulfide bond of thioredoxin (Trx). Trx is responsible for reducing multiple protein disulfide targets in the cell. TRs utilize reduced beta-nicotinamide adenine dinucleotide phosphate to reduce a bound flavin prosthetic group, which in turn reduces an N terminal redox center that has the conserved sequence CICVNVGCCT, where CIC is denoted as the interchange thiol while the thiol involved in charge-transfer complexation is denoted as CCT. The reduced N-terminal redox center reduces a C terminal redox center on the opposite subunit of the head-to-tail homodimer, the C-terminal redox center that catalyzes the reduction of the Trx-disulfide. Variations in the amino acid sequence of the C-terminal redox center differentiate high-molecular mass TRs into different types. Type Ia TRs have tetrapeptide C-terminal redox centers of with a GCUG sequence, where U is the rare amino acid selenocysteine (Sec), while the tetrapeptide sequence in type Ib TRs has its Sec residue replaced with a conventional cysteine (Cys) residue and can use small polar amino acids such as serine and threonine in place of the flanking glycine residues. The TR from Plasmodium falciparum (PfTR) is similar in structure and mechanism to type Ia and type Ib TRs except that the C-terminal redox center is different in its amino acid sequence. The C-terminal redox center of PfTR has the sequence G534CGGGKCG541, and we classify it as a type II high molecular mass TR. The oxidized type II redox motif will form a 20-membered disulfide ring, whereas the absence of spacer amino acids in the type I motif results in the formation of a rare eight-membered ring. We used site-directed mutagenesis and protein semisynthesis to investigate features of the distinctive type II C-terminal redox motif that help it perform catalysis. Deletion of Gly541 reduces thioredoxin reductase activity by ~50-fold, most likely because of disruption of an important hydrogen bond between the amide NH group of Gly541 and the carbonyl of Gly534 that helps to stabilize the beta-turn-beta motif. Alterations of the 20-membered disulfide ring either by amino acid deletion or by substitution resulted in impaired catalytic activity. Subtle changes in the ring structure and size caused by using semisynthesis to substitute homocysteine for cysteine also caused significant reductions in catalytic activity, demonstrating the importance of the disulfide ring's geometry in making the C-terminal redox center reactive for thiol-disulfide exchange. The data suggested to us that the transfer of electrons from the N-terminal redox center to the C-terminal redox center may be rate-limiting. We propose that the transfer of electrons from the N terminal redox center in PfTR to the type II C-terminal disulfide is accelerated by the use of an "electrophilic activation" mechanism. In this mechanism, the type II C-terminal disulfide is polarized, making the sulfur atom of Cys540 electron deficient, highly electrophilic, and activated for thiol-disulfide exchange with the N-terminal redox center. This hypothesis was investigated by constructing chimeric PfTR mutant enzymes containing C-terminal type I sequences GCCG and GCUG, respectively. The PfTR-GCCG chimera had 500-fold less thioredoxin reductase activity than the native enzyme but still reduced selenocystine and lipoic acid efficiently. The PfTR-GCUG chimera had higher catalytic activity than the native enzyme with Trx, selenocystine, and lipoic acid as substrates. The results suggested to us that (i) Sec in the mutant enzyme accelerated the rate of thiol-disulfide exchange between the N- and C-terminal redox centers, (ii) the type II redox center evolved for efficient catalysis utilizing Cys instead of Sec, and (iii) the type II redox center of PfTR is partly responsible for substrate recognition of the cognate PfTrx substrate relative to noncognate thioredoxins. PMID- 24400602 TI - What's in this issue? PMID- 24400601 TI - Actin controls the vesicular fraction of dopamine released during extended kiss and run exocytosis. AB - The effect of latrunculin A, an inhibitor of actin cross-linking, on exocytosis in PC12 cells was investigated with single cell amperometry. This analysis strongly suggests that the actin cytoskeleton might be involved in regulating exocytosis, especially by mediating the constriction of the pore. In an extended kiss-and-run release mode, actin could actually control the fraction of neurotransmitters released by the vesicle. This scaffold appears to contribute, with the lipid membrane and the protein machinery, to the closing dynamics of the pore, in competition with other forces mediating the opening of the exocytotic channel. PMID- 24400603 TI - Making appropriate decisions about admission to critical care: the role of critical care outreach and medical emergency teams. PMID- 24400604 TI - Technological equipment in critical care: the cost of progress. PMID- 24400605 TI - South African critical care nurses' views on end-of-life decision-making and practices. AB - BACKGROUND: Care of patients at the end-of-life (EOL) may be influenced by the experiences, attitudes and beliefs of nurses involved in their direct care. AIM: To investigate South African critical care nurses' experiences and perceptions of EOL care. DESIGN: Cross-sectional survey. METHODS: South African critical care nurses completed a modified version of the 'VENICE' survey tool. Data were collected concerning: attitudes towards EOL care; involvement in EOL decision making; and beliefs about EOL practices. RESULTS: Of 149 surveys distributed, 100 were returned (response rate 67%). Seventy-six percent stated that they had had direct involvement in EOL care of patients, but a minority (29%) had participated in EOL decision-making processes. Whilst most nurses (86%) were committed to family involvement in EOL decisions, less than two thirds (62%) reported this as routine practice. When withdrawing treatment, around half (54%) of the respondents indicated they would decrease the inspired oxygen level to room air, and the majority (84%) recommended giving effective pain relief. Continued nutritional support (84%) and hydration (85%) were advocated, with most nurses (62%) indicating that they were against keeping patients deeply sedated. Most respondents (68%) felt patients should remain in intensive care at the end of life, with the majority (72%) supporting open-visiting, no restriction on number of family members visiting (70%), and the practising of religious or traditional cultural EOL rituals (93%). CONCLUSIONS: The involvement of Johannesburg critical nurses in EOL care discussions and decisions is infrequent despite their participation in care delivery and definite views about the process. RELEVANCE TO CLINICAL PRACTICE: Use of formal guidelines and education is recommended to increase the nurses' involvement in and their confidence in participating in EOL decisions. Educators, managers, senior nurses and other members of the multi disciplinary team should collaborate to enable critical care nurses to become more involved in EOL care. PMID- 24400606 TI - Knowledge levels of intensive care nurses on prevention of ventilator-associated pneumonia. AB - BACKGROUND: Ventilator-associated pneumonia constitutes a significant concern for ventilated patients in the intensive care unit. AIM: This study was planned to evaluate the knowledge of nurses working in general intensive care units concerning evidence-based measures for the prevention of ventilator-associated pneumonia. METHOD: This study design is cross-sectional. It was carried out on nurses working in the general intensive care units of anesthiology and re animation clinics. Collection of research data was performed by means of a Nurse Identification Form and a Form of Evidence-Based Knowledge concerning the Prevention of Ventilator-Associated Pneumonia. Characterization statistics were shown by percentage, median and interquartile range. Chi-square and Wilcoxon tests and Kruskal-Wallis tests were used as appropriate. RESULTS: The median value of total points scored by nurses on the questionnaire was 4.00 +/- 2.00. The difference between the nurses' education levels, duration of work experience and participation in in-service training programmes on ventilator-associated pneumonia prevention and the median value of their total scores on the questionnaire was found to be statistically significant (p < 0.05). CONCLUSION: The conclusion of the study was that critical care nurses' knowledge about ventilator-associated pneumonia prevention is poor. PMID- 24400607 TI - Clinical experience and incidence of ventilator-associated pneumonia using closed versus open suction-system. AB - BACKGROUND: Studies have shown a decreasing ventilator-associated pneumonia (VAP) incidence after prophylactic interventions bundles. The use of closed suction systems (CSS) has been suggested beneficial as a prophylactic measure. AIM: To investigate the effects of a CSS on VAP incidence, suction circuit contamination and adverse events (AEs) compared to an open suction system (OSS) approach in a general mixed intensive care unit (ICU). METHODS: Adult patients on mechanical ventilation were consecutively included. Data were collected during four 1-month periods where CSS and OSS were used on an alternating basis. Airway cultures were obtained at intubation, after 72 h and every Monday. After changing CSS and at extubation, the catheter tip was cultured. AEs and desaturation events during suction were monitored. ANALYSE: Descriptive analysis and differences between the groups were analysed using comparative methods. RESULTS: No differences in airway colonization at admission between the groups were detected (Table 2). The CSS group had a higher Simplified Acute Physiology Score (SAPS) III and also a non significant increase in VAP incidence. Positive cultures were obtained in 50% of all the retrieved CSS catheters. There was no inter-patient contamination in either group. Six AEs versus one (CSS/OSS) related to tube-occlusion and secretion clogging was seen. Desaturations at suctioning were rare in both groups. CONCLUSION: No beneficial effects were seen on VAP incidence or inter patient contamination compared to OSS. A high frequency of circuit contamination in the CSS group paralleled with experienced secretions clearance problems seem unfavourable and in concordance with previous studies. PMID- 24400608 TI - International overview of high-level simulation education initiatives in relation to critical care. AB - The use of simulation in health care education has become very topical across all professions and specialties in order to improve patient safety and quality of care. In the last decade, the adoption of more realistic simulation-based teaching methodologies, which serves as a bridge between the acquisition and application of clinical skills, knowledge, and attributes, has been accompanied by the development of a multitude of international and national simulation societies. These serve as important exchange fora for educators, clinicians, researchers, and engineers who desire to learn and share their experience and knowledge around simulation-based education. Several countries have derived their own strategy in order to promote the use of such training methodology. Current key national strategies will be presented in this paper alongside a discussion of their expected impact. Various approaches have been adopted and each has their own place and the potential to be adopted by other nations depending on their political, economic or even geographic context. Within the critical care arena, simulation has generated considerable interest and there is a growing evidence base for its use as a learning and teaching strategy within this environment. A number of critical care-related associations and societies are now recognizing simulation as an appropriate pedagogical approach and acknowledging its potential to improve patient care and clinical outcomes. Its implementation should be carefully considered to ensure that developments are based on current best educational practice to maximize the efficiency of these educational interventions. PMID- 24400609 TI - Nursing challenges with a severely injured patient in critical care: the importance of hypothermia mitigation. PMID- 24400610 TI - Reply to letter. PMID- 24400620 TI - Life cycle water footprints of nonfood biomass fuels in China. AB - This study presented life cycle water footprints (WFs) of biofuels from biomass in China based on the resource distribution, climate conditions, soil conditions and crop growing characteristics. Life cycle WFs including blue, green and gray water were evaluated for the selected fuel pathways. Geographical differences of water requirements were revealed to be different by locations. The results indicated that water irrigation requirements were significantly different from crop to crop, ranging from 2-293, 78-137, and 17-621 m(3)/ha, for sweet sorghum, cassava, and Jatropha curcas L., respectively. Four biofuel pathways were selected on this basis to analyze the life cycle WF: cassava based bioethanol in Guangxi, sweet sorghum based bioethanol in Northeast China, Jatropha curcal L. based biodiesel in Yunnan and microalgae based biodiesel in Hainan. The life cycle WFs of bioethanol from cassava and sweet sorghum were 3708, and 17 156 m(3) per ton of bioethanol, respectively, whereas for biodiesel produced from Jatropha curcas L. and microalgae, they were 5787, and 31 361 m(3) per ton of biodiesel, respectively. The crop growing stage was the main contributor to the whole life cycle of each pathway. Compared to blue and green water, gray water was significant due to the use of fertilizer during the growing of biomass. From the perspective of the WF, cassava based bioethanol in Guangxi and Jatropha based biodiesel in Yunnan were suitable for promotion, whereas the promotion for microalage based biodiesel in Hainan required improvement on technology. PMID- 24400621 TI - Preparation and characterization of high-surface-area Bi(1-x)/3V(1-x)Mo(x)O4 catalysts. AB - We report the successful application of a templating approach employing ordered mesoporous carbon to the synthesis of BiVO4, Bi2Mo3O12, and Bi0.85V0.55Mo0.45O4 and the performance of these materials as catalysts for the oxidation of propene to acrolein. Ordered mesoporous carbon templates were used to control the nucleation and growth of the mixed metal oxide crystals, allowing higher final surface areas to be obtained. The resulting materials were characterized by X-ray diffraction, Raman spectroscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, and BET surface area analysis. The surface area of the mixed metal oxide catalysts was found to depend on the type of mesoporous silica used to prepare the carbon template and on the conditions under which the carbon template was formed. Through an appropriate choice of template, the surface areas of the mixed metal oxides exceeded 15 m(2)/g. Catalytic testing revealed that materials produced via templating in ordered mesoporous carbon had per-gram activities that were up to 85 times higher than those produced by a conventional hydrothermal synthesis and exhibited stable catalytic activities over 24 h. PMID- 24400619 TI - Climate change. A global threat to cardiopulmonary health. AB - Recent changes in the global climate system have resulted in excess mortality and morbidity, particularly among susceptible individuals with preexisting cardiopulmonary disease. These weather patterns are projected to continue and intensify as a result of rising CO2 levels, according to the most recent projections by climate scientists. In this Pulmonary Perspective, motivated by the American Thoracic Society Committees on Environmental Health Policy and International Health, we review the global human health consequences of projected changes in climate for which there is a high level of confidence and scientific evidence of health effects, with a focus on cardiopulmonary health. We discuss how many of the climate-related health effects will disproportionally affect people from economically disadvantaged parts of the world, who contribute relatively little to CO2 emissions. Last, we discuss the financial implications of climate change solutions from a public health perspective and argue for a harmonized approach to clean air and climate change policies. PMID- 24400623 TI - Introduction: leading lesbians fight disease and disability. AB - This thematic issue of the Journal of Lesbian Studies focuses on the ways in which lesbian leaders have dealt with disease and disability. In the articles that follow, eight prominent lesbians describe what it means to cope with serious illness and medical treatment in the context of lesbian identity and community. This introduction provides an overview of some of the themes that arose in the various articles, focusing on lesbian support systems as well as best medical practices. PMID- 24400622 TI - RAFT aqueous dispersion polymerization yields poly(ethylene glycol)-based diblock copolymer nano-objects with predictable single phase morphologies. AB - A poly(ethylene glycol) (PEG) macromolecular chain transfer agent (macro-CTA) is prepared in high yield (>95%) with 97% dithiobenzoate chain-end functionality in a three-step synthesis starting from a monohydroxy PEG113 precursor. This PEG113 dithiobenzoate is then used for the reversible addition-fragmentation chain transfer (RAFT) aqueous dispersion polymerization of 2-hydroxypropyl methacrylate (HPMA). Polymerizations conducted under optimized conditions at 50 degrees C led to high conversions as judged by (1)H NMR spectroscopy and relatively low diblock copolymer polydispersities (M(w)/M(n) < 1.25) as judged by GPC. The latter technique also indicated good blocking efficiencies, since there was minimal PEG113 macro-CTA contamination. Systematic variation of the mean degree of polymerization of the core-forming PHPMA block allowed PEG113-PHPMA(x) diblock copolymer spheres, worms, or vesicles to be prepared at up to 17.5% w/w solids, as judged by dynamic light scattering and transmission electron microscopy studies. Small-angle X-ray scattering (SAXS) analysis revealed that more exotic oligolamellar vesicles were observed at 20% w/w solids when targeting highly asymmetric diblock compositions. Detailed analysis of SAXS curves indicated that the mean number of membranes per oligolamellar vesicle is approximately three. A PEG113-PHPMA(x) phase diagram was constructed to enable the reproducible targeting of pure phases, as opposed to mixed morphologies (e.g., spheres plus worms or worms plus vesicles). This new RAFT PISA formulation is expected to be important for the rational and efficient synthesis of a wide range of biocompatible, thermo-responsive PEGylated diblock copolymer nano-objects for various biomedical applications. PMID- 24400624 TI - Grand slam on cancer. AB - A winner of 59 Grand Slam championships including a record 9 Wimbledon singles titles, Martina Navratilova is the most successful woman tennis player of the modern era. Martina was inducted into the International Tennis Hall of Fame, named "Tour Player of the Year" seven times by the Women's Tennis Association, declared "Female Athlete of the Year" by the Associated Press, and ranked one of the "Top Forty Athletes of All-Time" by Sports Illustrated. Equally accomplished off the court, Martina is an author, philanthropist, TV commentator, and activist who has dedicated her life to educating people about prejudice and stereotypes. After coming out as a lesbian in 1981, Martina became a tireless advocate of equal rights for lesbian, gay, bisexual, and transgender (LGBT) people, and she has contributed generously to the LGBT community. Martina is the author of seven books, including most recently Shape Your Self: My 6-Step Diet and Fitness Plan to Achieve the Best Shape of your Life, an inspiring guide to healthy living and personal fitness. Martina was diagnosed with breast cancer in 2010. PMID- 24400625 TI - Live your life out loud. AB - Susan Love, MD, MBA, has dedicated her professional life to the eradication of breast cancer. Author of the bestselling Dr. Susan Love's Breast Book, Dr. Susan Love's Menopause and Hormone Book, and Live a Little, Susan is Chief Visionary Officer of the Dr. Susan Love Research Foundation where she oversees an active research program centered on breast cancer cause and prevention. Susan co-founded the National Breast Cancer Coalition in the early 1990s, and she served on President Clinton's National Cancer Advisory Board from 1998-2004. Her recent projects include recruiting 377,000 women for the Love Army of Women, an Internet program that partners women and scientists to accelerate breast cancer research; and the online Health of Women Study designed to identify the cause of breast cancer. A recipient of six honorary doctorate degrees, Susan is Clinical Professor of Surgery at the David Geffen School of Medicine at the University of California, Los Angeles. In June of 2012, Susan was diagnosed with acute myelogenous leukemia and was treated with an allogenic stem cell transplant. PMID- 24400626 TI - Living "anyway:" stories of access. AB - Elana Dykewomon's 1974 novel, Riverfinger Women, was among the first lesbian books with a "happy ending." Her seven books of fiction and poetry include the Lambda Award winner Beyond the Pale (now an audio and e-book) and Lambda nominee, Risk. She was an editor of the lesbian-feminist journal, Sinister Wisdom, for eight years. Her literary work foregrounds the lesbian heroic as integral to women's communities. As a social justice activist, she has organized and participated in anti-war, anti-racist, anti-classist, fat and disability rights work since the 1970s. She is now working with Old Lesbians Organizing for Change. She is happy to live embedded in dyke community as a lesbian radical committed to a loving justice. While she suffered psychiatric abuse at 13 (and acknowledges long-term adaptive behavior on that account), she has not experienced disabling mental illness since. Her primary disabilities are mobility impairment through severe, progressive arthritis and constant low-to-powerful pain, sometimes diagnosed as fibromyalgia. Her acute illnesses include pancreatitis and a rare-in adults kidney disease currently in remission. PMID- 24400627 TI - Chemo killed the small-talk gene. AB - Urvashi Vaid is a community organizer and writer active in the lesbian, gay, bisexual, and transgender (LGBT) and social justice movements for over three decades. She is currently Director of the Engaging Tradition Project at the Center for Gender and Sexuality Law at Columbia University Law School. She is founder of LPAC, the first lesbian political action committee, and sits on the Board of Directors of the Gill Foundation. Vaid's past positions include Executive Director of the Arcus Foundation, Deputy Director of Governance and Civil Society Unit for the Ford Foundation, Executive Director of the National Gay and Lesbian Task Force, and staff attorney for the ACLU National Prison Project. She is author of the books Irresistible Revolution: Confronting Race, Class and The Assumptions of Lesbian, Gay, Bisexual, and Transgender Politics, and Virtual Equality: The Mainstreaming of Gay & Lesbian Liberation, and co editor of the book Creating Change: Public Policy, Sexuality and Civil Rights. Urvashi has had thyroid cancer and stage III breast cancer. PMID- 24400628 TI - Looking outside the (voice)box. AB - Laura S. Brown, PhD, is a clinical and forensic psychologist in independent practice in Seattle, Washington. The bulk of her scholarly work has been in the fields of feminist therapy theory, trauma treatment, lesbian and gay issues, assessment and diagnosis, ethics and standards of care in psychotherapy, and cultural competence. She has authored or edited ten professional books, including the award-winning Subversive Dialogues: Theory in Feminist Therapy, as well as more than 140 other professional publications. She has also recently published her first book for general audiences, Your turn for care: Surviving the aging and death of the adults who harmed you. Laura has been featured in five psychotherapy training videos produced by the American Psychological Association. She was President of American Psychological Association Divisions 35 (Society for the Psychology of Women), 44 (Society for the Psychological Study of Lesbian, Gay and Bisexual Issues), and 56 (Trauma Psychology). Laura was also President of the Washington State Psychological Association. She is the founder and Director of the Fremont Community Therapy Project, a low-fee psychotherapy training clinic in Seattle. In the fall of 2000, she was the on-site psychologist for the reality show Survivor: The Australian Outback. In 1987, Laura lost her voice and was diagnosed with spasmodic dysphonia. In 1988, she found her voice again. PMID- 24400629 TI - Don't let your disease define you. AB - Vivian Stephenson directed information technology systems at numerous companies, including Target Corporation, as Executive Vice President and Chief Information Officer, and Williams-Sonoma, as Chief Operating Officer and Chief Information Officer. In 1994, Vivian was a recipient of the "Oscar" of information technology the Smithsonian Institution and Computerworld Award-for developing the Planned Store Inventory System at Mervyn's Corporation. Vivian is a former chair of the Board of Trustees at Mills College, from which she received a Doctor of Humane Letters Honorary Degree in 2005 for her "ethical and compassionate leadership" and for serving as "an inspired, unwavering advocate for women and the power of education to transform women's lives and society as a whole." Vivian survived two different types of breast cancer, diagnosed in 1980 and 1996. In 2009, she was diagnosed with stage IV ovarian cancer. PMID- 24400630 TI - Medical muddle. AB - Nanette Gartrell, MD, is a psychiatrist and researcher whose investigations have documented the mental health and psychological well-being of lesbian, gay, bisexual, and transgender (LGBT) people over the past four decades. Nanette is the principal investigator of an ongoing longitudinal study of lesbian families in which the children were conceived by donor insemination. Now in its 27th year, this project has been cited internationally in the debates over equality in marriage, foster care, and adoption. Previously on the faculty at Harvard Medical School and the University of California, San Francisco, Nanette is currently a Visiting Distinguished Scholar at the Williams Institute, UCLA School of Law. In 2013, Nanette received the Association of Women Psychiatrists Presidential Commendation Award for "selfless and enduring vision, leadership, wisdom, and mentorship in the fields of women's mental health, ethics, and gender research." At the age of 63, Nanette experienced a 3 1/2 month period of intractable, incapacitating dizziness for which there was never a clear diagnosis. PMID- 24400631 TI - Healthy barbs: activism confronts mortality. AB - Barbara Brenner, JD, was the Executive Director of Breast Cancer Action (BCA) from 1995-2010. Before that, she was a longtime activist in the anti-war movement and an attorney who, for most of her career, practiced public policy law. After she was diagnosed with breast cancer in 1993 at the age of 41, she took the helm of BCA. Under her leadership, the organization moved into a position of national advocacy-demanding research on the causes and prevention of breast cancer, including the role of industrial pollutants. Barbara started the "Think Before You Pink" campaign, encouraging people to question whether companies that display pink ribbons actually produce products that harm women's health or generate any funds to fight breast cancer. Her blog, "Healthy Barbs," challenged readers to critique routine healthcare practices and policies. Barbara received numerous awards, including a Jefferson Award for Public Service in 2007, the Smith College Medal in 2012, and the ACLU-Northern California's Lola Hanzel Courageous Advocacy Award in 2012. Barbara had a recurrence of breast cancer in 1996. She died of complications associated with amyotrophic lateral sclerosis, ALS, on May 10, 2013. PMID- 24400632 TI - The alligator woman's tale: remembering Nicaragua's "first self-declared lesbian". AB - Carmen Aguirre (1931-1971) was a young woman who lived as a self-made man in the 1960s under the brutal, yet populist, right-wing Somoza dictatorship in Nicaragua. Carmen was known as Carmelo or la Caimana (the alligator woman). This article sheds light not only on la Caimana's life, but on how he is remembered today in Nicaragua. It addresses dynamics of Nicaragua's sexual past, present, and future, as well as theoretical questions dealing with identity, sex, and politics. PMID- 24400633 TI - "Wham bam tap scratch screech": the brief-but proud-history of Lesbian London, 1991-1994. AB - During its time in circulation from 1991-1994, Lesbian London set out to provide a voice for lesbians, but also to resist what it saw as the creeping malaise of commercialization and depoliticization of lesbian, gay, bisexual, and transgender (LGBT) communities. Virtually every topic of relevance to its readership was covered within the pages of each monthly issue, available free of charge. Despite its standout contribution, the magazine has been all but forgotten. Moreover, its untimely demise raises important questions about the future prospects of radical, non-commercial publications as well as about the direction of LGBT politics. PMID- 24400634 TI - The genetic basis of natural variation for iron homeostasis in the maize IBM population. AB - BACKGROUND: Iron (Fe) deficiency symptoms in maize (Zea mays subsp. mays) express as leaf chlorosis, growth retardation, as well as yield reduction and are typically observed when plants grow in calcareous soils at alkaline pH. To improve our understanding of genotypical variability in the tolerance to Fe deficiency-induced chlorosis, the objectives of this study were to (i) determine the natural genetic variation of traits related to Fe homeostasis in the maize intermated B73 * Mo17 (IBM) population, (ii) to identify quantitative trait loci (QTLs) for these traits, and (iii) to analyze expression levels of genes known to be involved in Fe homeostasis as well as of candidate genes obtained from the QTL analysis. RESULTS: In hydroponically-grown maize, a total of 47 and 39 QTLs were detected for the traits recorded under limited and adequate supply of Fe, respectively. CONCLUSIONS: From the QTL results, we were able to identify new putative candidate genes involved in Fe homeostasis under a deficient or adequate Fe nutritional status, like Ferredoxin class gene, putative ferredoxin PETF, metal tolerance protein MTP4, and MTP8. Furthermore, our expression analysis of candidate genes suggested the importance of trans-acting regulation for 2' deoxymugineic acid synthase 1 (DMAS1), nicotianamine synthase (NAS3, NAS1), formate dehydrogenase 1 (FDH1), methylthioribose-1-phosphate isomerase (IDI2), aspartate/tyrosine/aromatic aminotransferase (IDI4), and methylthioribose kinase (MTK). PMID- 24400635 TI - Left ventricular strain reduction is not confined to the noncompacted segments in noncompaction cardiomyopathy-insights from the three-dimensional speckle tracking echocardiographic MAGYAR-path study. AB - INTRODUCTION: Noncompaction cardiomyopathy (NCCM) is a new clinical entity characterized by prominent trabecular meshwork and deep intertrabecular recesses communicating with the left ventricular (LV) cavity due to arrest of the normal embryogenesis of the endomyocardium. The aim of the present study was to evaluate different contributions of noncompacted and compacted LV segments to the global LV dysfunction by three-dimensional (3D) speckle tracking echocardiography (3DSTE)-derived strain parameters in NCCM. PATIENTS AND METHODS: The present study comprised 9 patients with typical features of NCCM. Due to the limited image quality, one patient was excluded from the evaluations. Finally, 128 segments of 8 NCCM patients were assessed. Their results were compared to 176 segments of 11 healthy volunteers. Complete two-dimensional Doppler echocardiography extended with 3DSTE has been performed in all cases. RESULTS: Fifty-five of 128 LV segments (43%) proved to be noncompacted in NCCM patients. All strain parameters of segments of NCCM patients were significantly lower as compared to segments of controls. Only radial strain (6.99 +/- 7.36% vs. 12.58 +/ 12.78% vs. 25.24 +/- 11.76%, P < 0.001 and P < 0.05, respectively) and 3D strain (7.79 +/- 7.59% vs. 14.67 +/- 14.04% vs. 27.78 +/- 12.57%, P < 0.001 and P < 0.05, respectively) showed further reduction in noncompacted segments as compared to compacted segments. CONCLUSIONS: Left ventricular strain reduction is not confined to the nocompacted segments in NCCM. Radial and 3D strain parameters show further reduction in noncompacted segments compared to compacted segments. PMID- 24400636 TI - Isolation of high-quality RNA from grains of different maize varieties. AB - The study of gene expression in maize varieties represents a powerful tool aiming to increase vitamin A precursors. However, the isolation of RNA from different maize varieties is challenging because these varieties show different levels of polysaccharides, and most methods available for RNA isolation are inappropriate for grain samples. The polysaccharides co-purify and co-precipitate with RNA during isolation, resulting in low-quality RNA, compromising the use of RNA in subsequent applications. Thus, a cetyltrimethylammonium bromide (CTAB)-based method was adapted in this study and compared with six methods for RNA isolation, including commercial reagents and RNA and DNA isolation kits, in order to identify the most appropriate for maize grains from different varieties. Most of the methods evaluated were considered inadequate due to limitations in terms of purity and/or quantity of the isolated RNA, which affected the efficiency of subsequent RT-qPCR analysis, resulting in nonamplification of beta-carotene hydroxylase gene (HYD3) or high deviation among replicates. However, the CTAB modified method allowed the study to obtain intact RNA, with high quality and quantity, from 25 maize varieties. Furthermore, this RNA was successfully used to evaluate the expression of HYD3 gene by real-time qualitative polymerase chain reaction (RT-qPCR), and thus represents a simple, efficient, and low-cost strategy. PMID- 24400637 TI - Flt3 ligand treatment modulates parasitemia during infection with rodent malaria parasites via MyD88- and IFN-gamma-dependent mechanisms. AB - We previously showed that treatment of mice with the Flt3 ligand (Flt3L) prevents development of lethal experimental cerebral malaria and inhibits parasitemia during Plasmodium berghei ANKA (PbA) infection. In this study, we investigated the mechanisms underlying the reduction of parasitemia in Flt3L-treated mice. Studies using gene knockout mice and antibody treatment indicated that the anti parasitemia effect of Flt3L was mediated by innate immune system and was dependent on MyD88, IFN-gamma, IL-12 and natural killer (NK) cells. The number of NK cells and their ability to produce IFN-gamma was enhanced in Flt3L-treated mice. Phagocytic activity of splenocytes was increased in Flt3L-treated mice after PbA infection when compared with that in untreated mice, and this activity was mainly mediated by the accumulation of F4/80(mid) CD11b(+) cells in the spleen. In both MyD88(-/-) and IFN-gamma(-/-) mice, the proportion of F4/80(mid) CD11b(+) cells was not increased in the spleen of Flt3L-treated mice after infection. These correlations suggest that NK cells produce IFN-gamma in Flt3L treated mice, and accumulation of F4/80(mid) CD11b(+) cells in the spleen is promoted by an IFN-gamma -dependent manner, culminating in the inhibition of parasitemia. These findings imply that Flt3L promotes effective innate immunity against malaria infection mediated by interplay among varieties of innate immune cells. PMID- 24400638 TI - Mutation spectrum in BBS genes guided by homozygosity mapping in an Indian cohort. AB - Bardet-Biedl syndrome (BBS), a ciliopathy disorder with pleiotropic effect manifests primarily as retinal degeneration along with renal insufficiency, polydactyly and obesity. In this study, we have performed homozygosity mapping using NspI 250K affymetrix gene chip followed by mutation screening of the candidate genes located in the homozygous blocks. These regions are prioritized based on the block length and candidature of the genes in BBS and other ciliopathies. Gene alterations in known BBS (22) and other ciliopathy genes such as ALMS1 (2) were seen in 24 of 30 families (80%). Mutations in BBS3 gene, inclusive of a novel recurrent mutation (p.I91T) accounted for 18% of the identified variations. Disease associated polymorphisms p.S70N (BBS2), rs1545 and rs1547 (BBS6) were also observed. This is the first study in Indian BBS patients and homozygosity mapping has proved to be an effective tool in prioritizing the candidate genes in consanguineous pedigrees. The study reveals a different mutation profile in the ciliopathy genes in Indian population and implication of novel loci/genes in 20% of the study group. PMID- 24400639 TI - Influence of a variable overall diameter hydrophilic acrylic sharp-edged single piece intra-ocular lens on capsule opacification one year after surgery. AB - BACKGROUND: To investigate the influence of the overall intraocular lens (IOL) diameter on posterior capsule opacification (PCO) formation. METHODS: In this prospective randomized clinical trial, 124 eyes of 62 patients with bilateral age related cataract were included. Each patient received a Corneal A501D IOL in one eye and a Corneal J501D IOL in the fellow eye. Best corrected visual acuity (BCVA) and digital slitlamp photographs were taken a 1 h, 1 week, 1, 3, 6 and 12 months postoperatively. The amount of PCO was assessed subjectively at the slitlamp and objectively using automated image-analysis software. RESULTS: We found a mean BCVA of 0.81 +/- 0.2 for the Corneal A501D group and 0.79 +/- 0.21 for the Corneal J501D group. There was no significant difference 12 months after surgery between the two IOLs (p > 0.05). Objective PCO assessment resulted in a mean PCO score (scale 0-10) of 1.65 +/- 1.71 was found for the Corneal J501D group and a score of 1.54 +/- 1.64 was found for the Corneal A501D group (p > 0.05). The subjective PCO assessment at 1 year resulted in a mean PCO score of 2.0 +/- 1.74 in the Corneal J501D group and 2.13 +/- 1.64 in the Corneal A501D group (p > 0.05). CONCLUSION: Both investigated IOLs showed good clinical performance regarding PCO and BCVA. Our study suggests that the use of an IOL with variable total diameter seems not to influence the rate of PCO formation. PMID- 24400640 TI - Long term follow-up in patients with initially diagnosed low grade Ta non-muscle invasive bladder tumors: tumor recurrence and worsening progression. AB - BACKGROUND: We evaluated the clinical outcome of low grade Ta bladder cancer followed-up for a long period using the 2004 WHO grading system. METHODS: We retrospectively reviewed 190 patients with primary, low grade Ta bladder cancer. We defined worsening progression (WP) as confirmed high grade Ta, all T1 or Tis/concomitant CIS of bladder recurrence, upper urinary tract recurrence (UTR), or progression to equal to or more than T2. The associations between clinicopathological factors and tumor recurrence as well as WP pattern were analyzed. We also evaluated the late recurrence of 76 patients who were tumor free for more than 5 years. RESULTS: Tumor recurrence and WP occurred in 82 (43.2%) and 21 (11.1%) patients during follow-up (median follow-up: 101.5 months), respectively. WP to high grade Ta, all T1 or Tis/concomitant CIS was seen in 17 patients, and UTR and progression to equal to or more than T2 were seen in 2 and 2 patients, respectively. Multivariate analyses demonstrated that multiple tumor (p < 0.001, HR: 2.97) and absence of intravesical instillation (IVI) (p < 0.001, HR: 2.88) were significant risk factors for tumor recurrence while multiple tumor was the only risk factor for WP (p = 0.001, HR: 5.26). After a 5-year tumor-free period, 9 patients experienced late recurrence in years 5 and 10 and were diagnosed at a follow-up cystoscopy, however, only 2 patients recurred beyond 10 years and were found by gross hematuria. There were no significant risk factors of late recurrence. CONCLUSIONS: Multiple tumor was a risk factor for both tumor recurrence and WP while IVI did not affect the occurrence of WP. Our results suggest that routine follow-up of patients with low grade Ta bladder cancer is needed up to 10 years from the initial diagnosis. PMID- 24400641 TI - Health literacy of common ocular diseases in Nepal. AB - BACKGROUND: Poor health literacy is often a key cause of lack of or delayed uptake of health care services. The aim of this study was to assess the health literacy of common ocular diseases, namely cataract, glaucoma, night blindness, trachoma and diabetic retinopathy in Nepal. METHODS: A cross sectional study of 1741 participants randomly selected from non-triaged attendants in the outpatient queue at Tilganga Institute of Ophthalmology, a semi urban general population of Bhaktapur district of Kathmandu Valley and patients attending rural outreach clinics. Participants responded to trained enumerators using verbally administered, semi structured questionnaires on their awareness and knowledge of cataract, glaucoma, diabetic retinopathy, night blindness, and trachoma. RESULTS: The awareness of cataract across the entire sample was 49.6%, night blindness was 48.3%, diabetic retinopathy was 29%, glaucoma was 21.3% and trachoma was 6.1%. Patients presenting to rural outreach clinics had poorer awareness of cataract, glaucoma, diabetic retinopathy, night blindness and trachoma compared to those from a semi-urban community and an urban eye hospital (p<0.05), Old age was directly associated with poorer awareness of cataract, glaucoma, night blindness, trachoma and diabetic retinopathy (p<0.05). Female gender was associated with lower awareness of cataract, glaucoma, night blindness and trachoma (p<0.05). Literacy was associated with greater awareness of cataract, glaucoma, diabetic retinopathy, night blindness and trachoma (p<0.05). Higher education was significantly associated with greater awareness of cataract, night blindness and trachoma (p<0.05). Multivariate analysis found that the awareness of common ocular diseases was significantly associated with level of education (p<0.05). Similarly, awareness of cataract, glaucoma, trachoma and night blindness was associated with female gender (p<0.05) whereas awareness of cataract, night blindness, trachoma and diabetic retinopathy was associated with age (p<0.05) but the awareness glaucoma and diabetic retinopathy was associated with camps. CONCLUSIONS: Low awareness of common ocular conditions is associated with factors such as female gender, old age, lower levels of education and rural habitation. A would be successful health promotion programs should specifically target health determinants to promote health literacy and to ensure timely utilization of eye care services. PMID- 24400642 TI - Simple, sensitive and quantitative bioluminescence assay for determination of malaria pre-patent period. AB - BACKGROUND: The first phase of malaria infection occurs in the liver and is clinically silent. Inside hepatocytes each Plasmodium sporozoite replicate into thousands of erythrocyte-infectious merozoites that when released into the blood stream result in clinical symptoms of the disease. The time between sporozoite inoculation and the appearance of parasites in the blood is defined as the pre patent period, which is classically analysed by time-consuming and labor intensive techniques, such as microscopy and PCR. METHODS: Luciferase-expressing Plasmodium berghei parasites were used to measure pre-patent period of malaria infection in rodents using a bioluminescence assay that requires only one microliter of blood collected from the tail-vein. The accuracy and sensitivity of this new method was compared with conventional microscopy and PCR based techniques, and its capacity to measure the impact of anti-malarial interventions against the liver evaluated. RESULTS: The described method is very sensitive allowing the detection of parasites during the first cycles of blood stage replication. It accurately translates differences in liver load due to inoculation of different sporozoite doses as well as a result of treatment with different primaquine regimens. CONCLUSIONS: A novel, simple, fast, and sensitive method to measure pre-patent period of malaria infection in rodents is described here. The sensitivity and accuracy of this new method is comparable to standard PCR and microscopy-based techniques, respectively. PMID- 24400643 TI - Strategy to recognize and initiate treatment of chronic heart failure in primary care (STRETCH): a cluster randomized trial. AB - BACKGROUND: Most patients with heart failure are diagnosed and managed in primary care, however, underdiagnosis and undertreatment are common. We assessed whether implementation of a diagnostic-therapeutic strategy improves functionality, health-related quality of life, and uptake of heart failure medication in primary care. METHODS/DESIGN: A selective screening study followed by a single-blind cluster randomized trial in primary care. The study population consists of patients aged 65 years or over who presented themselves to the general practitioner in the previous 12 months with shortness of breath on exertion. Patients already known with established heart failure, confirmed by echocardiography, are excluded. Diagnostic investigations include history taking, physical examination, electrocardiography, and serum N-terminal pro B-type natriuretic peptide levels. Only participants with an abnormal electrocardiogram or an N-terminal pro B-type natriuretic peptide level exceeding the exclusionary cutpoint for non-acute onset heart failure (> 15 pmol/L (~ 125 pg/ml)) will undergo open-access echocardiography. The diagnosis of heart failure (with reduced or preserved ejection fraction) is established by an expert panel consisting of two cardiologists and a general practitioner, according to the criteria of the European Society of Cardiology guidelines.Patients with newly established heart failure are allocated to either the 'care as usual' group or the 'intervention' group. Randomization is at the level of the general practitioner. In the intervention group general practitioners receive a single half-day training in heart failure management and the use of a structured up titration scheme. All participants fill out quality of life questionnaires at baseline and after six months of follow-up. A six-minute walking test will be performed in patients with heart failure. Information on medication and hospitalization rates is extracted from the electronic medical files of the general practitioners. DISCUSSION: This study will provide information on the prevalence of unrecognized heart failure in elderly with shortness of breath on exertion, and the randomized comparison will reveal whether management based on a half-day training of general practitioners in the practical application of an up titration scheme results in improvements in functionality, health-related quality of life, and uptake of heart failure medication in heart failure patients compared to care as usual. TRIAL REGISTRATION: ClinicalTrials.gov NCT01202006. PMID- 24400644 TI - Impact of prostate weight on perioperative outcomes of robot-assisted laparoscopic prostatectomy with a posterior approach to the seminal vesicle. AB - BACKGROUND: To determine the effect of prostate weight on the preoperative and postoperative outcomes of robotic-assisted laparoscopic radical prostatectomy with a posterior approach to the seminal vesicle. METHODS: This retrospective study examined prospectively collected data on 219 robotic-assisted laparoscopic radical prostatectomies performed from May 2011 to February 2013. Patients were divided into four groups based on pathologic prostate weight: <30 g, 30-49 g, 50 79 g, and >=80 g. Continence and sexual function were assessed using validated questionnaires. RESULTS: Of the 219 patients, 19, 143, 51, and 6 had prostates weighing <30 g, 30-49 g, 50-79 g, and >=80 g, respectively. Significant differences were found between the preoperative Gleason scores, total operative times, and robotic times of the groups. Both estimated blood loss and anastomosis time tended to be greater in the higher prostate weight groups, but the differences were not significant. No significant differences were observed in transfusion rate, length of catheterization, complication incidence, or positive surgical margins. The return of urinary function, as determined by questionnaire scores, was not affected by prostate weight. CONCLUSIONS: Robotic-assisted laparoscopic radical prostatectomy can be performed safely and with similar perioperative outcomes, regardless of prostate weight. Indeed, oncological outcome, urinary continence, and complications were similar across the prostate weight groups, suggesting that robotic-assisted laparoscopic radical prostatectomy with a posterior approach to the seminal vesicle may be performed effectively on men with large prostates, despite greater surgical times. PMID- 24400645 TI - Individual, family and environmental factors associated with pediatric excess weight in Spain: a cross-sectional study. AB - BACKGROUND: There is a growing worldwide trend of obesity in children. Identifying the causes and modifiable factors associated with child obesity is important in order to design effective public health strategies.Our objective was to provide empirical evidence of the association that some individual and environmental factors may have with child excess weight. METHOD: A cross sectional study was performed using multi-stage probability sampling of 978 Spanish children aged between 8 and 17 years, with objectively measured height and weight, along with other individual, family and neighborhood variables. Crude and adjusted odds ratios were calculated. RESULTS: In 2012, 4 in 10 children were either overweight or obese with a higher prevalence amongst males and in the 8-12 year age group. Child obesity was associated negatively with the socio-economic status of the adult responsible for the child's diet, OR 0.78 (CI95% 0.59-1.00), girls OR 0.75 (CI95% 0.57-0.99), older age of the child (0.41; CI95% 0.31-0.55), daily breakfast (OR 0.59; p = 0.028) and half an hour or more of physical activity every day. No association was found for neighborhood variables relating to perceived neighborhood quality and safety. CONCLUSION: This study identifies potential modifiable factors such as physical activity, daily breakfast and caregiver education as areas for public health policies. To be successful, an intervention should take into account both individual and family factors when designing prevention strategies to combat the worldwide epidemic of child excess weight. PMID- 24400646 TI - The interrelations of radiologic findings and mechanical ventilation in community acquired pneumonia patients admitted to the intensive care unit: a multicentre retrospective study. AB - BACKGROUND: We evaluated patients admitted to the intensive care units with the diagnosis of community acquired pneumonia (CAP) regarding initial radiographic findings. METHODS: A multicenter retrospective study was held. Chest x ray (CXR) and computerized tomography (CT) findings and also their associations with the need of ventilator support were evaluated. RESULTS: A total of 388 patients were enrolled. Consolidation was the main finding on CXR (89%) and CT (80%) examinations. Of all, 45% had multi-lobar involvement. Bilateral involvement was found in 40% and 44% on CXR and CT respectively. Abscesses and cavitations were rarely found. The highest correlation between CT and CXR findings was observed for interstitial involvement. More than 80% of patients needed ventilator support. Noninvasive mechanical ventilation (NIV) requirement was seen to be more common in those with multi-lobar involvement on CXR as 2.4-fold and consolidation on CT as 47-fold compared with those who do not have these findings. Invasive mechanical ventilation (IMV) need increased 8-fold in patients with multi-lobar involvement on CT. CONCLUSION: CXR and CT findings correlate up to a limit in terms of interstitial involvement but not in high percentages in other findings. CAP patients who are admitted to the ICU are severe cases frequently requiring ventilator support. Initial CT and CXR findings may indicate the need for ventilator support, but the assumed ongoing real practice is important and the value of radiologic evaluation beyond clinical findings to predict the mechanical ventilation need is subject for further evaluation with large patient series. PMID- 24400647 TI - The incidence of phrenic nerve injury during pulmonary vein isolation using the second-generation 28 mm cryoballoon. AB - INTRODUCTION: The second-generation cryoballoon (CB; Arctic Front Advance, Medtronic Inc., Minneapolis, MN, USA) has demonstrated greater procedural efficacy compared to the original CB. Whether increased efficacy translates into a higher incidence of phrenic nerve (PN) injury needs further evaluation. MATERIALS AND METHODS: In patients with drug-refractory paroxysmal atrial fibrillation (AF) or short-standing persistent AF, pulmonary vein isolation (PVI) was performed using the 28 mm second-generation CB. During cryoenergy delivery along the septal PVs, continuous PN pacing was performed. The freeze cycle was aborted in case of weakening or loss of diaphragmatic contraction. RESULTS: A total of 115 patients (42 female, mean age 61 +/- 11 years, mean LA-diameter 43 +/- 6 mm) with a history of paroxysmal AF (93/115 patients [81%]) or short standing persistent AF (22/115 patients [19%]) underwent CB-based PVI. A total 445 of 448 (99%) PVs were isolated successfully. PN palsy (PNP) occurred in 4 of 115 (3.5%) patients, while applying cryoenergy to the right superior PV. Despite prompt interruption of the freezing cycle, PN function failed to recover during the periprocedural phase. PN recovery was observed as late as 10 months postablation. CONCLUSIONS: Using the second-generation 28 mm CB, PNP occurred in 4 of 115 (3.5%) patients. While 1 of 4 PNP recovered 10 months after ablation, long-term outcome in the remaining 3 patients is currently unknown due to the rather short follow-up period. PMID- 24400648 TI - Can cardiac computed tomography predict cardiovascular events in asymptomatic type-2 diabetics?: results of a long term follow-up. AB - BACKGROUND: Doubts remain about atherosclerotic disease and risk stratification of asymptomatic type-2 diabetic patients (T2DP). This study aims to evaluate the usefulness of calcium score (CS) and coronary computed tomography (CT) angiography (CTA) to predict fatal and non fatal cardiovascular events (CVEV) in T2DP. METHODS: Eighty-five consecutive T2DP undergoing CT (Phillips Brilliance, 16-slice) with CS and CTA were prospectively enrolled in a transversal case control study. Patients were followed for 48 months (range 18 - 68) to assess CVEV: cardiovascular death, acute coronary syndrome, revascularisation and stroke. Potential predictors of CVEV were identified. Predictive models based on clinical features, CTA and CS were created and compared. RESULTS: Performing CT impacted T2DP treatment. Cardiovascular risk was lowered during follow-up but metabolic control remained suboptimal. CVEV occurred in 11.8% T2DP (3.1%/year). CS >=86.6 was predictor of CVEV over time, with a high negative predictive value, an 80% sensitivity and 74.7% specificity. Although its prognostic value was not independent of the presence/absence of obstructive CAD, adding CS and CTA data to clinical parameters improved the prediction of CVEV: the combined model had the highest AUC (0.888, 95%CI 0.789-0.987, p < 0.001) for the prediction of the study endpoints. CONCLUSIONS: CS showed great value in T2DP risk stratification and its prognostic value was further enhanced by CTA data. Information provided by CT may help predict CVEV in T2DP and potentially improve their outcome. PMID- 24400649 TI - Experimental design approach in recombinant protein expression: determining medium composition and induction conditions for expression of pneumolysin from Streptococcus pneumoniae in Escherichia coli and preliminary purification process. AB - BACKGROUND: Streptococcus pneumoniae (S. pneumoniae) causes several serious diseases including pneumonia, septicemia and meningitis. The World Health Organization estimates that streptococcal pneumonia is the cause of approximately 1.9 million deaths of children under five years of age each year. The large number of serotypes underlying the disease spectrum, which would be reflected in the high production cost of a commercial vaccine effective to protect against all of them and the higher level of amino acid sequence conservation as compared to polysaccharide structure, has prompted us to attempt to use conserved proteins for the development of a simpler vaccine. One of the most prominent proteins is pneumolysin (Ply), present in almost all the serotypes known at the moment, which shows an effective protection against S. pneumoniae infections. RESULTS: We have cloned the pneumolysin gene from S. pneumoniae serotype 14 and studied the effects of eight variables related to medium composition and induction conditions on the soluble expression of rPly in Escherichia coli (E. coli) and a 28-4 factorial design was applied. Statistical analysis was carried out to compare the conditions used to evaluate the expression of soluble pneumolysin; rPly activity was evaluated by hemolytic activity assay and served as the main response to evaluate the proper protein expression and folding. The optimized conditions, validated by the use of triplicates, include growth until an absorbance of 0.8 (measured at 600 nm) with 0.1 mM IPTG during 4 h at 25 degrees C in a 5 g/L yeast extract, 5 g/L tryptone, 10 g/L NaCl, 1 g/L glucose medium, with addition of 30 MUg/mL kanamycin. CONCLUSIONS: This experimental design methodology allowed the development of an adequate process condition to attain high levels (250 mg/L) of soluble expression of functional rPly in E. coli, which should contribute to reduce operational costs. It was possible to recover the protein in its active form with 75% homogeneity. PMID- 24400650 TI - Morphologic identification of atypical chronic lymphocytic leukemia by digital microscopy. AB - INTRODUCTION: Atypical chronic lymphocytic leukemia (aCLL) is a morphologic variant found in approximately 25% of patients with chronic lymphocytic leukemia (CLL). Although aCLL has a more aggressive course compared to typical CLL (tCLL), it is not usually reported. This retrospective study used digital microscopy to morphologically classify CLL patients as aCLL or tCLL, and determined the prevalence of prognostic markers in each group. METHODS: CellaVision AB (Lund, Sweden) was used to evaluate lymphocyte morphology on archived blood films of 97 CLL patients, and results of their prognostic marker analysis at diagnosis were obtained. The unpaired t-test, Chi-square, or Fisher's Exact test were used for statistical analysis. RESULTS: 27% of CLL cases were morphologically classified as aCLL. The aCLL group had a higher prevalence of trisomy 12, unmutated IgVH, and CD38 expression (markers associated with poor prognosis), and a lower prevalence of 13q14 deletions compared to tCLL; this was statistically significant. CONCLUSION: Using digital imaging to identify aCLL is feasible, economical, and may provide clinically relevant prognostic information at diagnosis and during periodic monitoring. Further study of a larger number of patients is needed to assess the clinical utility of reporting aCLL morphology. PMID- 24400651 TI - Maternal and paternal attributions in the prediction of boys' behavior problems across time. AB - We examined the extent to which mother and father attributions for child behavior problems predict child behavior problems over time, accounting for the other parent's attributions, initial child problems and the child's attention deficit/hyperactivity disorder (ADHD) status. Parents of 7- to 12-year-old boys with (n = 26) and without (n = 38) ADHD participated. Parents completed the Strengths and Difficulties Questionnaire (SDQ) as a measure of their son's behavior problems as well as the Written Analogue Questionnaire, reporting their attributions for child behavior problems. Parents completed the SDQ a second time 7 months later. Both mother and father attributions were associated with child behavior problems at Time 1 and again 7 months later. However, when ADHD status and the other parent's attributions for child behavior were controlled, only father attributions predicted child behavior problems, and continued to be uniquely predictive of child behavior problems at Time 2 even with initial child behavior problems controlled. Father attributions provide unique information above and beyond mother attributions when considering current and future child behavior problems. PMID- 24400652 TI - A visual or tactile signal makes auditory speech detection more efficient by reducing uncertainty. AB - Acoustic speech is easier to detect in noise when the talker can be seen. This finding could be explained by integration of multisensory inputs or refinement of auditory processing from visual guidance. In two experiments, we studied two interval forced-choice detection of an auditory 'ba' in acoustic noise, paired with various visual and tactile stimuli that were identically presented in the two observation intervals. Detection thresholds were reduced under the multisensory conditions vs. the auditory-only condition, even though the visual and/or tactile stimuli alone could not inform the correct response. Results were analysed relative to an ideal observer for which intrinsic (internal) noise and efficiency were independent contributors to detection sensitivity. Across experiments, intrinsic noise was unaffected by the multisensory stimuli, arguing against the merging (integrating) of multisensory inputs into a unitary speech signal, but sampling efficiency was increased to varying degrees, supporting refinement of knowledge about the auditory stimulus. The steepness of the psychometric functions decreased with increasing sampling efficiency, suggesting that the 'task-irrelevant' visual and tactile stimuli reduced uncertainty about the acoustic signal. Visible speech was not superior for enhancing auditory speech detection. Our results reject multisensory neuronal integration and speech specific neural processing as explanations for the enhanced auditory speech detection under noisy conditions. Instead, they support a more rudimentary form of multisensory interaction: the otherwise task-irrelevant sensory systems inform the auditory system about when to listen. PMID- 24400653 TI - Australian optometric and ophthalmologic referral pathways for people with age related macular degeneration, diabetic retinopathy and glaucoma. AB - BACKGROUND: This study investigated the referral pathways offered to patients with age-related macular degeneration (AMD), diabetic retinopathy (DR) or glaucoma (GL) by ophthalmologists and optometrists. METHODS: Australian ophthalmologists and optometrists were surveyed regarding referral decisions to other eye-care specialists (inter- or intra-professional), general medical practitioners (GPs), low vision rehabilitation (LVR) and support services. Thematic analysis and concept mapping were applied to highlight current and ideal referral pathways. RESULTS: The survey was completed by 155 optometrists and 50 ophthalmologists and deemed representative of their respective professions in Australia. Not surprisingly, the vast majority of the participating optometrists (97 to 99 per cent) referred to ophthalmologists regardless of the underlying condition. Clear differences (Chi-square: p < 0.05) were observed in the referral patterns of optometrists and ophthalmologists to GPs and support services. General medical practitioner services were almost exclusively used for patients with DR, while AMD triggered a significantly higher referral rate to low vision rehabilitation and support services than the other two disorders. CONCLUSION: While ophthalmologists predominantly referred patients with AMD, DR or GL to low vision rehabilitation services, optometrists' referrals were highly skewed toward ophthalmology. Referrals to other supporting services by the two groups were not greatly used. The perceived referral pathways by the two eye-care professionals suggested a unidirectional route, potentially highlighting the need for a more collaborative approach that facilitates optimal use of eye health care and allied services. PMID- 24400654 TI - Winners and losers in health insurance: access and type of coverage for women in same-sex and opposite-sex partnerships. AB - Using data from the American Community Survey, 2009 (N=580,754), we compared rates of health insurance coverage and types of coverage used between women in same-sex and opposite-sex partnerships. This large, national dataset also allowed us to investigate regional variation in insurance coverage for women in same-sex partnerships by comparing "gay-tolerant" states versus other states. Multivariate analyses revealed that women in same-sex partnerships consistently had lower rates of health insurance coverage than married women in opposite-sex partnerships, but always more than unmarried women in opposite-sex partnerships. We also found that state-level variation in gay tolerance did not contribute to the access or type of coverage used by women in same-sex partnerships. PMID- 24400655 TI - Efficacy and safety of initial combination therapy with alogliptin plus metformin versus either as monotherapy in drug-naive patients with type 2 diabetes: a randomized, double-blind, 6-month study. AB - AIM: To evaluate the efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin plus metformin (A + M) initial combination therapy versus either as monotherapy in drug-naive T2DM patients. METHODS: This international, randomized, double-blind, placebo-controlled, 26-week study involved T2DM patients with hyperglycaemia (HbA1c 7.5-10.0%) following diet/exercise therapy. Patients (N = 784) received placebo, alogliptin (A, 12.5 mg BID or 25 mg QD), metformin (M, 500 or 1000 mg BID) or A + M (12.5/500 or 12.5/1000 mg BID); placebo, A25 for secondary analyses only. ENDPOINTS: week 26 changes from baseline in HbA1c (primary), fasting plasma glucose (FPG) and 2-h postprandial glucose (PPG); incidences of clinical response and hyperglycaemic rescue. RESULTS: Week 26 mean HbA1c reductions from baseline (8.45%) were -1.22 and -1.55% with A + M 12.5/500 and 12.5/1000 versus -0.56, -0.65, and -1.11% with A12.5, M500 and M1000 (p<0.001, A + M vs. component monotherapies). FPG reductions were -1.76 and -2.55 mmol/L with 12.5/500 and 12.5/1000 versus -0.54, -0.64 and -1.78 mmol/L with A12.5, M500 and M1000 (p < 0.05, A + M vs. component monotherapies). Significantly more A + M-treated patients achieved HbA1c < 7% (47.1-59.5% vs. 20.2-34.3% with monotherapy), significantly fewer required hyperglycaemic rescue (2.6-12.3% vs. 10.8-22.9% with monotherapy). A + M caused only mild/moderate hypoglycaemia (1.9-5.3%) and weight loss (0.6-1.2 kg). CONCLUSIONS: Alogliptin plus metformin initial combination therapy was well tolerated yet more efficacious in controlling glycaemia in drug-naive T2DM patients than either as monotherapy. PMID- 24400656 TI - The efficacy and safety of novel oral anticoagulants for the preventive treatment in atrial fibrillation patients: a systematic review and meta-analysis. AB - BACKGROUND: Novel oral anticoagulants, including direct factor Xa inhibitors and direct factor IIa inhibitors, have been used to prevent stroke in patients with atrial fibrillation (AF) for a decade. In this study, the efficacy and safety of the novel oral anticoagulants were assessed in AF patients. METHODS: No language restrictions were applied. Study selection and data extraction were carried out by searching PubMed, EMBASE, OVID, the BIOSIS, the Web of Science, Clinical Trials Registers, Cochrane Central Register of Controlled Trials and the China Academic Library and Information System. Each database was searched from its inception date to June 2013. Using odds ratio (OR) as an indicator, we systematically evaluated the primary efficacy endpoints and safety endpoints, as well as 10 secondary endpoints. RESULT: Compared to the control drugs, the novel oral anticoagulants showed an OR decreased by 26% (OR: 0.74, 95% confidence interval (CI): 0.62-0.88) for stroke or systemic embolism, decreased by 24% (OR: 0.76, 95% CI: 0.64-0.90) for major bleeding, decreased by 10% (OR: 0.90, 95% CI: 0.84-0.95) for death from any cause, decreased by 27% for disabling or fatal stroke (OR: 0.73, 95% CI: 0.54-0.97), decreased by 31% (OR: 0.69, 95% CI: 0.60 0.8) for fatal bleeding, and decreased by 8% (OR: 0.92, 95% CI: 0.88-0.95) for serious adverse events. However, there was no significant difference in acute myocardial infarction, systemic embolism, major bleeding or clinically relevant non-major, all bleeding events, all adverse events and liver function disorder, between the novel oral anticoagulants and control drugs (p > 0.05). CONCLUSIONS: Compared to the control drugs, the novel oral anticoagulants showed higher efficiency and safety in patients with AF, as evidenced by their superior performance not only in reducing the risk of stroke or systemic embolism with a lower risk of major bleeding but also in decreasing the incidence of death from any cause, disabling or fatal stroke, serious adverse events and fatal bleeding. PMID- 24400657 TI - Exploration and classification of intensive care nurses' clinical decisions: a Greek perspective. AB - AIM: The recording, identification, coding and classification of clinical decisions by intensive care nurses. BACKGROUND: Clinical decision-making is an essential dimension of nursing practice as through this process nurses make choices to meet the goals of patient care. Intensive care nurses' decision-making has received attention because of the complexity and urgency associated with it, however, the types of nurses' clinical decisions have not been described systematically. METHODS: Qualitative content analysis of daily diaries of clinical decisions recorded during nursing work by 23 purposefully selected intensive care nurses from three major hospitals of Greece. The process of data collection and analysis continued until the point of theoretical saturation. FINDINGS: Eight categories of nursing clinical decisions emerged including decisions related to: (1) evaluation, (2) diagnosis, (3) prevention, (4) intervention, (5) communication with patients, (6) clinical information seeking, (7) setting of clinical priorities and (8) communication with health care professionals. Psychological assessment and support decisions were scarce, whereas patient input in care decisions appeared to be limited. The most frequent types of decisions were regarding intervention (29%), evaluation (25%) and clinical setting of priorities (17%), while clinical information seeking (3%) and communication with patients decisions (2%) were the least frequent. Additionally, recorded decisions were ranked in order of degree of urgency and of dependency on medical order. Non-urgent decisions were 78% of the total and 60% of nurses' intervention decisions were independent of medical order and were related to basic nursing care. CONCLUSIONS: Intensive care nurses make multiple decisions that seem to be in line with the nursing process, although the latter is not officially implemented in Greek ICUs. RELEVANCE TO CLINICAL PRACTICE: The types and frequency of clinical decisions made by intensive care nurses are related to features of ICU work environment, their professional autonomy and accountability, as well as their perceptions of their clinical role. PMID- 24400658 TI - Fusarium-damaged kernels and deoxynivalenol in Fusarium-infected U.S. winter wheat. AB - Fusarium head blight (FHB) is a devastating disease that threatens wheat (Triticum aestivum) production in many areas worldwide. FHB infection results in Fusarium-damaged kernels (FDK) and deoxynivalenol (DON) that dramatically reduce grain yield and quality. More effective and accurate disease evaluation methods are imperative for successful identification of FHB-resistant sources and selection of resistant cultivars. To determine the relationships among different types of resistance, 363 (74 soft and 289 hard) U.S. winter wheat accessions were repeatedly evaluated for FDK and DON concentration in greenhouse and field experiments. Single-kernel near-infrared (SKNIR)-estimated FDK and DON were compared with visually estimated FDK and gas chromatography-mass spectroscopy estimated DON. Significant correlations were detected between percentage of symptomatic spikelets and visual FDK in the greenhouse and field, although correlations were slightly lower in the field. High correlation coefficients also were observed between visually scored FDK and SKNIR-estimated FDK (0.72, P < 0.001) and SKNIR-estimated DON (0.68, P < 0.001); therefore, both visual scoring and SKNIR methods are useful for estimating FDK and DON in breeding programs. PMID- 24400659 TI - From the city to the Lake: loadings of PCBs, PBDEs, PAHs and PCMs from Toronto to Lake Ontario. AB - Loadings from Toronto, Canada to Lake Ontario were quantified and major sources and pathways were identified, with the goal of informing opportunities for loading reductions. The contaminants were polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), polycyclic aromatic hydrocarbons (PAHs) and polycyclic musks (PCMs). Loadings were calculated from measured concentrations for three major pathways: atmospheric processes, tributary runoff, and wastewater treatment plant (WWTP) effluents. Although atmospheric deposition to the Great Lakes has received the greatest attention, this was the dominant loading pathway for PCBs only (17 +/- 5.3 kg/y or 66% of total loadings). PCB loadings reflected elevated urban PCB air concentrations due to, predominantly, primary emissions. These loadings contribute to consumption advisories for nearshore fish. PBDE loadings to the lake, again from mainly primary emissions, were 48% (9.1 +/- 1.3 kg/y) and 42% (8.0 +/- 5.7 kg/y) via tributaries and WWTPs, respectively, consistent with emissions deposited and subsequently washed-off of urban surfaces and emissions to the sewage system. PAHs loadings of 1600 +/- 280 kg/y (71%) from tributaries were strongly associated with vehicle transportation and impervious surfaces. PCM loadings were 83% (+/-140 kg/y) from WWTP final effluent, reflecting their use in personal care products. Opportunities for source reduction lie in reducing the current inventories of in-use PCBs and PBDE containing products, reducing vehicle emissions of PAHs and use of PAHs in the transportation network (e.g., pavement sealants), and improving wastewater treatment technology. PMID- 24400660 TI - Quasi-isometric points for the technique of lateral suture placement in the feline stifle joint. AB - OBJECTIVE: To evaluate the quasi-isometric points (nearest isometric points) between the distal aspect of the femur and fabella and the proximal aspect of the tibia for placement of a lateral suture in cats. STUDY DESIGN: Radiographic study. ANIMALS: Cadaveric cat stifles (n = 7 cats; 14 stifles). METHODS: Specimens were secured in a mounting frame to maintain rigid fixation of the femur and allow free range of motion of the stifle joint and proximal tibia. Two anatomic landmarks were identified: the center of the lateral fabella (Ff) and a point 4 mm proximal to the insertion of the patellar tendon adjacent to the tibial cortex (Tt). Radiopaque spheres were placed at predefined landmarks in the femur (caudal aspect of the lateral femoral condyle distal [F1] and proximal [F2] to the lateral fabella) and in the tibia (caudal to the proximal aspect of the extensor groove [T1]; cranial to the proximal aspect of the extensor groove [T2]; 2 mm proximal and caudal to the insertion of the patellar tibial tendon [T3] and 3 mm caudal to the insertion of the patellar tibial tendon [T4]. For each stifle, 4 radiographic projections were made: in extension (166 degrees ), in flexion (45 degrees ), and 2 intermediate stance phases (90 degrees , 130 degrees ). ANOVA was used to compare means of the distance between the point pairs and means of the percent change in variation of distance (VOD%) using the 45 degrees measurement as a reference. RESULTS: Mean VOD% nearest to zero, over all the different angles tested, was produced by Ff-Tt, which was statistically significantly different from each of the other point pairs. CONCLUSION: Ff-Tt provides the best quasi-isometric points for placement of lateral sutures in cats, compared with all combinations tested. Further assessments with biomechanical studies are needed to evaluate the reproducibility of these landmarks for stabilization of CCL rupture in cats. PMID- 24400662 TI - Pressure induced phase transitions and metallization of a neutral radical conductor. AB - The crystal structure and charge transport properties of the prototypal oxobenzene-bridged 1,2,3-bisdithiazolyl radical conductor 3a are strongly dependent on pressure. Compression of the as-crystallized alpha-phase, space group Fdd2, to 3-4 GPa leads to its conversion into a second or beta-phase, in which F-centering is lost. The space group symmetry is lowered to Pbn21, and there is concomitant halving of the a and b axes. A third or gamma-phase, also space group Pbn21, is generated by further compression to 8 GPa. The changes in packing that accompany both phase transitions are associated with an "ironing out" of the ruffled ribbon-like architecture of the alpha-phase, so that consecutive radicals along the ribbons are rendered more nearly coplanar. In the beta-phase the planar ribbons are propagated along the b-glides, while in the gamma-phase they follow the n-glides. At ambient pressure 3a is a Mott insulator, displaying high but activated conductivity, with sigma(300 K) = 6 * 10(-3) S cm( 1) and E(act) = 0.16 eV. With compression beyond 4 GPa, its conductivity is increased by 3 orders of magnitude, and the thermal activation energy is reduced to zero, heralding the formation of a metallic state. High pressure infrared absorption and reflectivity measurements are consistent with closure of the Mott Hubbard gap near 4-5 GPa. The results are discussed in the light of DFT calculations on the molecular and band electronic structure of 3a. The presence of a low-lying LUMO in 3a gives rise to high electron affinity which, in turn, creates an electronically much softer radical with a low onsite Coulomb potential U. In addition, considerable crystal orbital (SOMO/LUMO) mixing occurs upon pressurization, so that a metallic state is readily achieved at relatively low applied pressure. PMID- 24400663 TI - Falls and EQ-5D rated quality of life in community-dwelling seniors with concurrent chronic diseases: a cross-sectional study. AB - BACKGROUND: Although recommended for use in studies investigating falls in the elderly, the European Quality of Life Group instrument, EQ-5D, has not been widely used to assess the impact of falls on quality of life. The aim of this study was to investigate the association of single and frequent falls with EQ-5D rated quality of life in a sample of German community-dwelling seniors in primary care suffering a variety of concurrent chronic diseases and conditions. METHODS: In a cross-sectional study, a sample of community-dwelling seniors aged >= 72 years was interviewed by means of a standardised telephone interview. According to the number of self-reported falls within twelve months prior to interview, participants were categorised into one of three fall categories: no fall vs. one fall vs. two or more falls within twelve months. EQ-5D values as well as other characteristics were compared across the fall categories. Adjustments for a variety of concurrent chronic diseases and conditions and further variables were made by using multiple linear regression analysis, with EQ-5D being the target variable. RESULTS: In total, 1,792 participants (median age 77 years; 53% female) were analysed. The EQ-5D differed between fall categories. Participants reporting no fall had a mean EQ-5D score of 81.1 (standard deviation [s.d.]: 15.4, median: 78.3), while participants reporting one fall (n = 265; 14.8%) and participants with two or more falls (n = 117; 6.5%) had mean total scores of 77.0 (s.d.: 15.8, median: 78.3; mean difference to participants without a fall: -4.1, p < 0.05) and 72.1 (s.d.: 17.6, median: 72.5; mean difference: -9.0, p < 0.05), respectively. The mean difference between participants with one fall and participants with two or more falls was -4.9 (p < 0.05). Under adjustment for a variety of chronic diseases and conditions, the mean decrease in the total EQ-5D score was about 1.0 score point for one fall and about -2.5 points for two or more falls within twelve months. In quantity, this decrease is comparable to other chronic diseases adjusted for. Among the variables with the greatest negative association with EQ 5D ratings in multivariate analysis were depression and fear of falling. CONCLUSIONS: The findings suggest that falls are negatively associated with EQ-5D rated quality of life independent of a variety of chronic diseases and conditions. PMID- 24400665 TI - Products from the oxidation of linear isomers of hexene. AB - The experimental study of the oxidation of the three linear isomers of hexene was performed in a quartz isothermal jet-stirred reactor (JSR) at temperatures ranging from 500 to 1100 K including the negative temperature coefficient (NTC) zone, at quasi-atmospheric pressure (1.07 bar), at a residence time of 2 s and with dilute stoichiometric mixtures. The fuel and reaction product mole fractions were measured using online gas chromatography. In the case of 1-hexene, the JSR has also been coupled through a molecular-beam sampling system to a reflectron time-of-flight mass spectrometer combined with tunable synchrotron vacuum ultraviolet photoionization. A difference of reactivity between the three fuels, which varies with the temperature range has been observed and is discussed according to the changes in the possible reaction pathways when the double bond is displaced. An enhanced importance of the reactions via the Waddington mechanism and of those of allylic radicals with HO2 radicals can be noted for 2- and 3-hexenes compared to 1-hexene. PMID- 24400664 TI - Presentation of BMP-2 mimicking peptides in 3D hydrogels directs cell fate commitment in osteoblasts and mesenchymal stem cells. AB - Many strategies for controlling the fate of transplanted stem cells rely on the concurrent delivery of soluble growth factors that have the potential to produce undesirable secondary effects in surrounding tissue. Such off target effects could be eliminated by locally presenting growth factor peptide mimics from biomaterial scaffolds to control stem cell fate. Peptide mimics of bone morphogenetic protein 2 (BMP-2) were synthesized by solid phase Fmoc-peptide synthesis and covalently bound to alginate hydrogels via either carbodiimide or sulfhydryl-based coupling strategies. Successful peptide conjugation was confirmed by (1)H NMR spectroscopy and quantified by fluorescently labeling the peptides. Peptides derived from the knuckle epitope of BMP-2, presented from both 2D surfaces and 3D alginate hydrogels, were shown to increase alkaline phosphatase activity in clonally derived murine osteoblasts. Furthermore, when presented in 3D hydrogels, these peptides were shown to initiate Smad signaling, upregulate osteopontin production, and increase mineral deposition with clonally derived murine mesenchymal stem cells. These data suggest that these peptide conjugated hydrogels may be effective alternatives to local BMP-2 release in directly and spatially eliciting osteogenesis from transplanted or host osteoprogenitors in the future. PMID- 24400666 TI - Comparative studies of N-glycans and glycosaminoglycans present in SIRC (Statens Seruminstitut rabbit cornea) cells and corneal epithelial cells from rabbit eyes. AB - PURPOSE: We compared cultured Statens Seruminstitut rabbit cornea (SIRC) cells and corneal epithelial cells from rabbit eyes by analyzing their N-glycans and glycosaminoglycans (GAGs). This work is a fundamental study on the efficacy of using cultured cells instead of animals for drug development. MATERIALS AND METHODS: N-Glycans and GAGs from SIRC cell monolayers and corneal epithelial cells of rabbit eyes were analyzed by capillary electrophoresis (CE) and a combination of high-performance liquid chromatography (HPLC) and mass spectrometry. RESULTS: High mannose-type glycans and a hybrid-type glycan were the common N-glycans in SIRC cells and corneal epithelial cells of rabbit eyes. Mono-fucosylated biantennary glycans with or without one N-acetylneuraminic acid residue were observed only in SIRC cells. Hyaluronic acid was the only measurable GAG in the corneal epithelial cells of rabbit eyes. In contrast, hyaluronic acid and chondroitin sulfates were abundantly present in SIRC cells. CONCLUSIONS: Profiles of both N-glycans and GAGs were conspicuously different between SIRC cells and corneal epithelial cells of rabbit eyes. This report will be useful for the evaluation of pharmaceutical candidates when animals or cultured cells are employed in drug development studies. PMID- 24400667 TI - Attitudinal concordance toward uptake and disclosure of genetic testing for cancer susceptibility in patient-family member dyads. AB - Decisions for cancer susceptibility genetic testing (CSGT) uptake and dissemination of results occur within the family context. A national survey was performed with 990 patient-family member dyads (participation rate:76.2%), with paired questionnaires examining attitudes toward CSGT uptake and disclosure of results in response to a hypothetical scenario in which a reliable CSGT was available for the specific cancer a patient was being treated. While most patients and family members responded they would uptake or recommend CSGT if available, concordance between the dyads was poor for both patient's testing (agreement rate 77.5%, weighted kappa=0.09) and first-degree relatives' testing(agreement rate 78.0%, weighted kappa=0.09). Most patients (93.2%) and family members (92.9%) indicated that patients should disclose positive CSGT results to family members, with dyadic agreement of 89.1% (kappa=0.15). However, there were substantial disagreement regarding when disclosure should take place, who should make the disclosure (the patient or the health care professionals), and to whom the results should be disclosed. Patients and family members may hold different attitudes toward CSGT uptake of and disclosure of results within the family. Our findings reinforce the need for a family system approach to incorporate perspectives of patients as well as their family members. PMID- 24400668 TI - Clinical characteristics, management, and prognosis of elderly patients with Brugada syndrome. AB - BACKGROUND: The clinical course and prognosis of Brugada syndrome (BS) in the elderly is unknown. The purpose of this study was to investigate the clinical characteristics, management, and prognosis of BS in an elderly population. METHODS AND RESULTS: A total of 437 patients with BS were included in this study. Patients were categorized in 2 groups according to the age at the time of diagnosis: <60 years (N = 363) and >=60 years (N = 74). Moreover, an elderly patients' subgroup analysis was performed between patients with an age between 60 and 70 years (N = 49) and subjects older than 70 years (N = 25). Among elderly patients (50% male, mean age: 67 +/- 6 years), family history of sudden death (SD) and induction of sustained ventricular arrhythmias during programmed ventricular stimulation were less frequent as compared to younger patients. Two patients (3%) had a previous episode of aborted SD. Elderly patients with BS presented more frequently with ECG conduction disturbances or previous transient advanced atrioventricular block as compared to younger patients. Of the elderly patients, 42% underwent implantable cardioverter defibrillator implantation and 7% received a pacemaker. After a mean follow-up time of 54 +/- 18 months, none of the elderly patients with BS older than 70 years experienced documented life threating ventricular arrhythmias. Family screening was performed in 58 family members and a BS diagnosis was confirmed in 49%. CONCLUSION: The clinical features and the benign prognosis of BS patients older than 70 years likely identify a lower risk category of patients as compared to younger individuals. The device-guided management in this setting remains individualized and sometimes controversial. Moreover, BS diagnosis in the elderly should not be missed, mainly due to the clinical impact on the family of elderly patients. PMID- 24400670 TI - Studies on supercapacitor electrode material from activated lignin-derived mesoporous carbon. AB - We synthesized mesoporous carbon from pre-cross-linked lignin gel impregnated with a surfactant as the pore-forming agent and then activated the carbon through physical and chemical methods to obtain activated mesoporous carbon. The activated mesoporous carbons exhibited 1.5- to 6-fold increases in porosity with a maximum Brunauer-Emmett-Teller (BET) specific surface area of 1148 m(2)/g and a pore volume of 1.0 cm(3)/g. Both physical and chemical activation enhanced the mesoporosity along with significant microporosity. Plots of cyclic voltammetric data with the capacitor electrode made from these carbons showed an almost rectangular curve depicting the behavior of ideal double-layer capacitance. Although the pristine mesoporous carbon exhibited a range of surface-area-based capacitance similar to that of other known carbon-based supercapacitors, activation decreased the surface-area-based specific capacitance and enhanced the gravimetric specific capacitance of the mesoporous carbons. A vertical tail in the lower-frequency domain of the Nyquist plot provided additional evidence of good supercapacitor behavior for the activated mesoporous carbons. We have modeled the equivalent circuit of the Nyquist plot with the help of two constant phase elements (CPE). Our work demonstrated that biomass-derived mesoporous carbon materials continue to show potential for use in specific electrochemical applications. PMID- 24400669 TI - Hospital case volume and outcomes among patients hospitalized with severe sepsis. AB - RATIONALE: Processes of care are potential determinants of outcomes in patients with severe sepsis. Whether hospitals with more experience caring for patients with severe sepsis also have improved outcomes is unclear. OBJECTIVES: To determine associations between hospital severe sepsis caseload and outcomes. METHODS: We analyzed data from U.S. academic hospitals provided through University HealthSystem Consortium. We used University HealthSystem Consortium's sepsis mortality model (c-statistic, 0.826) for risk adjustment. Validated International Classification of Disease, 9th Edition, Clinical Modification algorithms were used to identify hospital severe sepsis case volume. Associations between risk-adjusted severe sepsis case volume and mortality, length of stay, and costs were analyzed using spline regression and analysis of covariance. MEASUREMENTS AND MAIN RESULTS: We identified 56,997 patients with severe sepsis admitted to 124 U.S. academic hospitals during 2011. Hospitals admitted 460 +/- 216 patients with severe sepsis, with median length of stay 12.5 days (interquartile range, 11.1-14.2), median direct costs $26,304 (interquartile range, $21,900-$32,090), and average hospital mortality 25.6 +/- 5.3%. Higher severe sepsis case volume was associated with lower unadjusted severe sepsis mortality (R2 = 0.10, P = 0.01) and risk-adjusted severe sepsis mortality (R2 = 0.21, P < 0.001). After further adjustment for geographic region, number of beds, and long-term acute care referrals, hospitals in the highest severe sepsis case volume quartile had an absolute 7% (95% confidence interval, 2.4-11.6%) lower hospital mortality than hospitals in the lowest quartile. We did not identify associations between case volume and resource use. CONCLUSIONS: Academic hospitals with higher severe sepsis case volume have lower severe sepsis hospital mortality without higher costs. PMID- 24400671 TI - Lower estimated glomerular filtration rates in patients on long term lithium: a comparative study and a meta-analysis of literature. AB - BACKGROUND: Several studies have shown that long-term lithium use is associated with a subtle decline in estimated glomerular filtration rate. This study compared mean estimated glomerular filtration rates (eGFR) in patients on long term lithium, against matched controls. METHODS: Patients with bipolar affective disorder, who are on lithium (for at least a year), were compared against controls that were matched (1:1) for age, gender and presence or absence of diabetes or hypertension. The eGFR was calculated from creatinine values according to the 'modification of diet in renal disease study' (MDRD) formula and was compared between cases and controls. A meta-analysis was performed to compare our findings with similar studies in literature. RESULTS: Forty seven patients met the inclusion criteria. They were matched with 47 controls. The eGFR values of lithium users were significantly lower (p = 0.04) compared to controls. This difference persisted between the subgroup of lithium users without comorbidities (diabetes and hypertension) and their controls but disappeared for lithium users with comorbidities and their controls. Nonetheless, lithium users had lower eGFR values in both subgroups. A meta-analysis of 9 studies showed a significant lowering in the glomerular filtration rate in lithium users compared to controls [mean difference -10.3 ml/min (95% confidence interval: -15.13 to -5.55, p < 0.0001)]. CONCLUSIONS: Lithium causes a subtle decline in glomerular filtration rate; renal function needs to be monitored in patients on lithium treatment. PMID- 24400672 TI - Effectiveness of community forestry in Prey Long forest, Cambodia. AB - Cambodia has 57% forest cover, the second highest in the Greater Mekong region, and a high deforestation rate (1.2%/year, 2005-2010). Community forestry (CF) has been proposed as a way to reduce deforestation and support livelihoods through local management of forests. CF is expanding rapidly in Cambodia. The National Forests Program aims to designate one million hectares of forest to CF by 2030. However, the effectiveness of CF in conservation is not clear due to a global lack of controlled comparisons, multiple meanings of CF, and the context-specific nature of CF implementation. We assessed the effectiveness of CF by comparing 9 CF sites with paired controls in state production forest in the area of Prey Long forest, Cambodia. We assessed forest condition in 18-20 randomly placed variable radius plots and fixed-area regeneration plots. We surveyed 10% of households in each of the 9 CF villages to determine the proportion that used forest products, as a measure of household dependence on the forest. CF sites had fewer signs of anthropogenic damage (cut stems, stumps, and burned trees), higher aboveground biomass, more regenerating stems, and reduced canopy openness than control areas. Abundance of economically valuable species, however, was higher in control sites. We used survey results and geographic parameters to model factors affecting CF outcomes. Interaction between management type, CF or control, and forest dependence indicated that CF was more effective in cases where the community relied on forest products for subsistence use and income. PMID- 24400673 TI - Sexual coercion and behavior among a sample of sexual minority women. AB - Sexual coercion may affect the sexual experiences of sexual minority women differently. Women (n=445) aged 18 to 71 years (Mean=30.38) answered an online survey on sexual orientation, lifetime coercion, and sexual history. Sexual minority women (45.8%, n=204) were more likely to report having been coerced into unwanted sexual behavior (56.5%) than heterosexual women (44.8 %; p=0.010). Coerced sexual minority women reported earlier ages of initiation into performing oral sex (p=0.016), penile-vaginal (p=0.024), and penile-anal (p=0.027) intercourse. In multiple logistic regression models, currently being in a partnered relationship was the sole factor related to lifetime engagement in penile-vaginal intercourse and receiving oral sex from partners. Having at least a graduate degree was the only characteristic related to engagement in lifetime penile-anal intercourse. Sexual coercion was not related to any lifetime sexual behavior outcomes. The nature of sexual initiation and coercion should be explored further among sexual minority women, with the goal of incorporating their experiences into prevention and treatment initiatives. PMID- 24400674 TI - Approaches to the chemical synthesis of the chlorosulfolipids. AB - Since the initial discovery of the chlorosulfolipids in 1969, the chemical synthesis community largely ignored these compounds for nearly four decades, perhaps because they contain a high density of chlorine atoms, which suggested that these molecules and any projected synthetic intermediates might be unstable. Beginning in 2008, a sudden flurry of synthesis activity by several research groups, including our own, appeared in the literature. In this Account, we highlight our work from the last several years on the chemical synthesis of the chlorosulfolipids. Our work in this area began with attempts to stereoselectively generate the abundant dichloroalcohol functional group arrangements in these natural targets. In these early studies, we learned that many polychlorinated intermediates were far more stable than anticipated. We also developed a method for the diastereoselective dichlorination of allylic alcohol derivatives that permitted access to the syn,syn-dichloroalcohol stereotriad found in several chlorosulfolipids. Concurrently, we investigated an approach to mytilipin A that included multiple intermediates bearing aldehydes with beta-leaving groups, but this route proved intractable. However, we leveraged what we had learned from this approach into our first success in this area: we synthesized danicalipin A via a route that introduced all of the polar functional groups using alkene oxidation reactions. By adapting this relatively general strategy, we completed an enantioselective synthesis of malhamensilipin A. This body of work also resulted in the full stereochemical elucidation of danicalipin A and the structural revision of malhamensilipin A. Finally, with the advent of Z-selective alkene cross metathesis, we developed a second-generation synthesis that featured this strategy in place of a poorly performing Wittig olefination that plagued our first approach. In addition to this new convergent step, we developed a reliable protocol for diastereoselective addition to highly sensitive alpha,beta dichloroaldehydes and a method for kinetic resolution of complex vinyl epoxides. Altogether, these advances led to a synthesis of enantioenriched mytilipin A in only eight steps. In the context of this work, we discovered a number of highly stereoselective reactions that might offer new, broadly applicable lessons in acyclic stereocontrol. Moreover, this research testifies to the stability of polychlorinated molecules and should inspire confidence in the use of aliphatic chlorides in other applications, including in discovery chemistry. PMID- 24400675 TI - Effect of SGLT2 inhibitors in a murine model of urinary tract infection with Candida albicans. AB - AIMS: Urinary tract infection (UTI) is a common clinical problem in diabetic patients; however, the relationship between UTI and glucosuria remains uncertain. To investigate the relationship, we examined the effect of glucosuria induced by sodium glucose cotransporter 2 (SGLT2) inhibitors on the progression of UTI in mice. METHODS: From 1 day before transurethral inoculation with Candida albicans, female mice were treated orally once a day with an SGLT2 inhibitor in different treatment regimens: (i) dapagliflozin at 10 mg/kg for 2, 3 or 7 days, (ii) dapagliflozin at 0.1, 1 or 10 mg/kg for 3 days and (iii) dapagliflozin, canagliflozin or tofogliflozin at 10 mg/kg for 3 days. To evaluate the ascending UTI, the kidneys were removed 6 days after the inoculation, and the number of viable C. albicans cells in kidney was measured as colony-forming units (CFU). RESULTS: In mice treated with dapagliflozin, the number of C. albicans CFU in kidney increased in accordance with both treatment duration and dose. The number of CFU significantly increased when mice were treated with 10 mg/kg dapagliflozin or canagliflozin but not tofogliflozin. With dapagliflozin and canagliflozin, urine glucose concentration (UGC) significantly increased up to 24 h after drug administration; with tofogliflozin, UGC significantly increased only up to 12 h after drug administration. CONCLUSIONS: Our data indicate that increased susceptibility to UTI is associated with a persistent increase in UGC. PMID- 24400676 TI - Integrating a tailored e-health self-management application for chronic obstructive pulmonary disease patients into primary care: a pilot study. AB - BACKGROUND: Changes in reimbursement have been compelling for Dutch primary care practices to apply a disease management approach for patients with chronic obstructive pulmonary disease (COPD). This approach includes individual patient consultations with a practice nurse, who coaches patients in COPD management. The aim of this study was to gauge the feasibility of adding a web-based patient self management support application, by assessing patients' self-management, patients' health status, the impact on the organization of care, and the level of application use and appreciation. METHODS: The study employed a mixed methods design. Six practice nurses recruited COPD patients during a consultation. The e Health application included a questionnaire that captured information on demographics, self-management related behaviors (smoking cessation, physical activity and medication adherence) and their determinants, and nurse recommendations. The application provided tailored feedback messages to patients and provided the nurse with reports. Data were collected through questionnaires and medical record abstractions at baseline and one year later. Semi-structured interviews with patients and nurses were conducted. Descriptive statistics were calculated for quantitative data and content analysis was used to analyze the qualitative data. RESULTS: Eleven patients, recruited by three nurses, used the application 1 to 7 times (median 4). Most patients thought that the application supported self-management, but their interest diminished after multiple uses. Impact on patients' health could not be determined due to the small sample size. Nurses reported benefits for the organization of care and made suggestions to optimize the use of the reports. CONCLUSION: Results suggest that it is possible to integrate a web-based COPD self-management application into the current primary care disease management process. The pilot study also revealed opportunities to improve the application and reports, in order to increase technology use and appreciation. PMID- 24400677 TI - Counselor and client perspectives of Trauma-focused Cognitive Behavioral Therapy for children in Zambia: a qualitative study. AB - This study examined Zambian counselors, children, and caregivers' perceptions of an evidence-based treatment (EBT) for trauma (Trauma-Focused Cognitive Behavioral Therapy [TF-CBT]) utilized in Zambia to address mental health problems in children. Semistructured interviews were conducted with local counselors trained in TF-CBT (N = 19; 90% of those trained; 12 female) and children/caregivers who had received TF-CBT in a small feasibility study (N = 18; 86% of the children and N = 16; 76% of the caregivers) who completed TF-CBT (total completed; N = 21). Each client was asked six open-ended questions, and domain analysis was used to explore the data. Counselors were positive about the program, liked the structure and flexibility, reported positive changes in their clients, and discussed the cultural adaptation around activities and language. Counselors stated the training was too short, and the supervision was necessary. Challenges included client engagement and attendance, availability of location, funding, and a lack of community understanding of "therapy." Children and caregivers stated multiple positive changes they attributed to TF-CBT, such as better family communication, reduction of problem behaviors, and ability to speak about the trauma. They recommended continuing the program. This study brings a critical examination of providers' and clients' perspectives of the implementation of an EBT for children in a low-resource setting. Clinical implications include changing implementation methods based on responses. Research implications include future study directions such as an effectiveness trial of TF-CBT and an examination of implementation factors. PMID- 24400678 TI - Voluntary stopping of eating and drinking at the end of life - a 'systematic search and review' giving insight into an option of hastening death in capacitated adults at the end of life. AB - BACKGROUND: The terminally ill person's autonomy and control are important in preserving the quality of life in situations of unbearable suffering. Voluntary stopping of eating and drinking (VSED) at the end of life has been discussed over the past 20 years as one possibility of hastening death. This article presents a 'systematic search and review' of published literature concerned with VSED as an option of hastening death at the end of life by adults with decision-making capacity. METHODS: Electronic databases PubMed, EBSCOhost CINAHL and Ovid PsycINFO were systematically searched. Additionally, Google Scholar was searched and reference lists of included articles were checked. Data of the included studies were extracted, evaluated and summarized in narrative form. RESULTS: Overall, out of 29 eligible articles 16 were included in this review. VSED can be defined as an action by a competent, capacitated person, who voluntarily and deliberately chooses to stop eating and drinking with the primary intention of hastening death because of the persistence of unacceptable suffering. An estimated number of deaths by VSED was only provided by one study from the Netherlands, which revealed a prevalence of 2.1% of deaths/year (on average 2800 deaths/year). Main reasons for patients hastening death by VSED are: readiness to die, life perceived as being pointless, poor quality of life, a desire to die at home, and the wish to control the circumstances of death. The physiological processes occurring during VSED and the supportive care interventions could not be identified through our search. CONCLUSIONS: The included articles provide marginal insight into VSED for hastening death. Research is needed in the field of theory-building and should be based on qualitative studies from different perspectives (patient, family members, and healthcare workers) about physiological processes during VSED, and about the prevalence and magnitude of VSED. Based on these findings supportive care interventions for patients and family members and recommendations for healthcare staff should be developed and tested. PMID- 24400679 TI - A pitfall on postoperative radiographs in dogs after tibial plateau leveling osteotomy. AB - OBJECTIVE: To identify the cause of an occasional radiolucent line in the tibia on postoperative radiographs after tibial plateau leveling osteotomy (TPLO) in dogs. STUDY DESIGN: Retrospective case series and ex vivo experiment. SAMPLE POPULATION: Dogs (n = 80; 87 stifles) with cranial cruciate ligament (CCL) rupture that had TPLO; and 4 canine tibia specimens. METHODS: Medical records (2007-2010) and radiographs of dogs that had TPLO were reviewed and examined for presence of a radiolucent line on postoperative radiographs. The TPLO procedure was reproduced ex vivo to determine the origin of this line by use of metallic wires to identify bone contours. RESULTS: A curvilinear radiolucent line was visible in 14 (16%) tibias and was 5.4 times more likely to be visible with lateral misalignment of the tibial diaphysis relative to the plateau and 2.6 times more likely visible on caudocranial radiographs with the stifle in outward rotation. Fracture complication rate was higher in dogs with this radiolucent line (P = .02) and with lateral misalignment of the tibial diaphysis relative to the plateau (risk ratio, 3.8). The line could be reproduced ex vivo and caused by superimposition of the craniomedial border of osteotomy with the tibial plateau. CONCLUSIONS: The radiolucent line was a spurious fracture line created by the medial margin of the tibial osteotomy and confounding factors such as tibial misalignment may explain the apparently associated higher complication rate. PMID- 24400680 TI - Nonionic surfactant-based vesicular system for transdermal drug delivery. AB - OBJECTIVE: The objective of this study was to formulate and evaluate the Ibuprofen niosomal formulation as a transdermal drug delivery system. MATERIALS AND METHODS: Niosomes were prepared by a modified ethanol injection method, using Span 60, Tween 60 and Tween 65 as well as cholesterol with various cholesterol:surfactant molar ratios. The prepared vesicles were characterized for entrapment efficiency (EE), particle size, zeta potential and in vitro release study. Skin permeation studies were conducted using modified Franz diffusion cell, and excised rat skin was treated with niosomal, liposomal and conventional Carbopol 914 gel of Ibuprofen. RESULTS AND DISCUSSION: The results showed that the type of surfactant and molar ratio of cholesterol:surfactant altered the EE, size and in vitro drug release of niosomes. Higher EE was obtained with the niosomes prepared with cholesterol and Span 60 at molar ratio of 0.5:1. It has been observed that both niosomal and liposomal formulations enhanced the drug permeation and the percentage of accumulated dose in the skin compared to control conventional gel formulation. However, niosomes prepared by Span 60 and Tween 65 exhibited higher permeation and retention of Ibuprofen, respectively. CONCLUSION: Our results suggested that niosomal formulations could be used as a promising carrier for the Ibuprofen transdermal delivery system. PMID- 24400681 TI - The roles of reactive species in micropollutant degradation in the UV/free chlorine system. AB - The UV/free chlorine process forms reactive species such as hydroxyl radicals (HO(*)), chlorine atoms (Cl(*)), Cl2(*-), and O(*-). The specific roles of these reactive species in aqueous micropollutant degradation in the UV/chlorine process under different conditions were investigated using a steady-state kinetic model. Benzoic acid (BA) was chosen as the model micropollutant. The steady-state kinetic model developed fitted the experimental data well. The results showed that HO(*) and Cl(*) contributed substantially to BA degradation, while the roles of the other reactive species such as Cl2(*-) and O(*-) were negligible. The overall degradation rate of BA decreased as the pH increased from 6 to 9. In particular, the relative contributions of HO(*) and Cl(*) to the degradation changed from 34.7% and 65.3% respectively at pH 6 to 37.9% and 62% respectively at pH 9 under the conditions evaluated. Their relative contributions also changed slightly with variations in chlorine dosage, BA concentration and chloride concentration. The scavenging effect of natural organic matter (NOM) on Cl(*) was relatively small compared to that on HO(*), while bicarbonate preferentially reduced the contribution of Cl(*). This study is the first to demonstrate the contributions of different reactive species to the micropollutant degradation in the UV/chlorine system under environmentally relevant conditions. PMID- 24400682 TI - Interleukin 28B polymorphism predicts interferon plus ribavirin treatment outcome in patients with hepatitis C virus-related liver cirrhosis: A multicenter retrospective study in Japan. AB - AIM: This study evaluated the efficacy of interferon plus ribavirin and examined whether interleukin 28B (IL28B) polymorphism influenced treatment outcome in Japanese patients with hepatitis C virus (HCV)-related liver cirrhosis (LC). METHODS: Fourteen collaborating centers provided details of 261 patients with HCV related LC undergoing treatment with interferon plus ribavirin. Univariate and multivariate analyses were used to establish which factors predicted treatment outcome. RESULTS: Eighty-four patients (32.2%) achieved a sustained virological response (SVR). SVR rates were 21.6% (41/190) in patients with HCV genotype 1 with high viral load (G1H) and 60.6% (43/71) in patients with non-G1H. In patients with non-G1H, treatment outcome was effective irrespective of IL28B polymorphism. In those with G1H, SVR was achieved in 27.1% of patients with the IL28B rs8099917 TT allele compared with 8.8% of those with the TG/GG alleles (P = 0.004). In patients with G1H having TT allele, treatments longer than 48 weeks achieved significantly higher SVR rates than treatments less than 48 weeks (34.6% vs 16.4%, P = 0.042). In patients with G1H having TG/GG alleles, treatments longer than 72 weeks achieved significantly higher SVR rates than treatments less than 72 weeks (37.5% vs 4.1%, P = 0.010). CONCLUSION: Interferon plus ribavirin treatment in Japanese patients with non-G1H HCV-related LC was more effective than those with G1H and not influenced by IL28B polymorphism. In those with G1H, IL28B polymorphism may predict SVR and guide treatment duration: SVR rates were higher in those with the TT allele treated for more than 48 weeks and those with the TG/GG alleles treated for more than 72 weeks. PMID- 24400683 TI - The measurement properties of modified Rivermead mobility index and modified functional ambulation classification as outcome measures for Chinese stroke patients. AB - Valid, reliable, responsive and practical outcome measures are essential for treatment planning and outcome assessment. This study aimed to examine the measurement properties of Modified Rivermead Mobility Index (MRMI) and Modified Functional Ambulation Classification (MFAC) in Chinese stroke patients. The content validity, responsiveness, predictive validity, test-retest reliability, internal consistency and factor structure of the MRMI were examined. The content validity, discriminative power and inter-rater agreement of the MFAC were investigated. A total of 456 Chinese stroke patients were recruited. Evidence of good content validity, high responsiveness, adequate predictive validity, excellent test-retest reliability with 1.3-point as minimum detectable change in 95% confidence interval, high internal consistency and unidimensionality was obtained for the MRMI. Good content validity, sufficient discriminative power and excellent inter-rater agreement were demonstrated for the MFAC. Both the MRMI and MFAC have good to excellent measurement properties and are recommended as routine outcome measures for Chinese stroke patients. PMID- 24400684 TI - Retraction of "Synthesis of multivalent glycoconjugates containing the immunoactive LELTE peptide: effect of glycosylation on cellular activation and natural killing by human peripheral blood mononuclear cells". PMID- 24400685 TI - Impedimetric detection of pathogenic Gram-positive bacteria using an antimicrobial peptide from class IIa bacteriocins. AB - Real-time, label-free detection of Gram-positive bacteria with high selectivity and sensitivity is demonstrated using an interdigitated impedimetric array functionalized with naturally produced antimicrobial peptide from class IIa bacteriocins. The antimicrobial peptide, leucocin A, was chemically synthesized and covalently immobilized on interdigitated gold microelectrodes via the interaction between the C-terminal carboxylic acid of the peptide and free amines of a preattached thiolated linker. Exposing the peptide sensor to various concentrations of Gram-positive bacteria generated reproducible impedance spectra that detected peptide-bacteria interactions at a concentration of 1 cell/MUL. The peptide sensor also selectively detected Listeria monocytogenes from other Gram positive strains at a concentration of 10(3) cfu mL(-1). The study highlights that short peptide ligands from bacteriocin class offer high selectivity in bacterial detection and can be used in developing a robust, portable biosensor device to efficiently detect pathogenic Gram-positive bacteria in food samples. PMID- 24400686 TI - Collision tumor with inflammatory breast carcinoma and malignant phyllodes tumor: a case report and literature review. AB - There have been some reports of coincidental presentation of breast carcinoma and phyllodes tumor in the same breast. Most of the cases were carcinoma that arose from a phyllodes tumor with a histologically identified transitional area, and they behaved less aggressively than the usually encountered carcinoma. Collision tumors are rare clinical entities in which two histologically distinct tumor types show involvement at the same site. The occurrence of these tumors in the breast is extremely rare. Here, we report a case of 45-year-old woman who had both invasive ductal carcinoma as the finding of inflammatory carcinoma and a malignant phyllodes tumor in the same breast. There was no evidence of a transitional area between the phyllodes tumor and the invasive ductal carcinoma. To our knowledge, this is the first report of a collision tumor of inflammatory breast carcinoma coincident with a malignant phyllodes tumor in same breast. PMID- 24400687 TI - Coupled thermal and electromagnetic induced decomposition in the molecular explosive alphaHMX; a reactive molecular dynamics study. AB - We use molecular dynamics simulations with the reactive potential ReaxFF to investigate the initial reactions and subsequent decomposition in the high-energy density material alpha-HMX excited thermally and via electric fields at various frequencies. We focus on the role of insult type and strength on the energy increase for initial decomposition and onset of exothermic chemistry. We find both of these energies increase with the increasing rate of energy input and plateau as the processes become athermal for high loading rates. We also find that the energy increase required for exothermic reactions and, to a lesser extent, that for initial chemical reactions depend on the insult type. Decomposition can be induced with relatively weak insults if the appropriate modes are targeted but increasing anharmonicities during heating lead to fast energy transfer and equilibration between modes that limit the effect of loading type. PMID- 24400689 TI - Introduction: Perampanel--new mode of action and new option for patients with epilepsy. AB - With perampanel the first-in-class selective alpha-amino-3-hydroxy-5-methyl-4 isoxazolprepionic acid (AMPA) receptor antagonist has been finally approved for add-on treatment in patients with focal-onset seizures. This suggests additional therapeutic potential in hitherto difficult-to-treat epilepsies. PMID- 24400688 TI - Basal values, intra-day and inter-day variations in tear film osmolarity and tear fluorescein clearance. AB - PURPOSE: The aim of this study was to determine the normal inter-day and intra day variations in tear film osmolarity and the tear fluorescein clearance test (T FCT) in healthy subjects. METHODS: Tear samples from 24 young, healthy adults were collected from 11:00 AM to 1:00 PM (midday) and 5:00 PM to 7:00 PM (evening) on three non-consecutive days. Tear osmolarity measurement and the T-FCT were performed to assess the basal values and inter-day and intra-day variations of the test results. A freezing point depression osmometer was used to analyze the tear osmolarity, and the T-FCT was performed using a fluorophotometer. RESULTS: The mean osmolarity value was 270 +/- 4.4 mOsm/l and the mean T-FCT result was 2.97 +/- 0.17 fluorescence arbitrary units. The inter-day or intra-day tear osmolarity values did not differ significantly. The T-FCT results varied significantly during the day, with significantly (p = 0.0004) higher results in the evening; no significant differences were found in the inter-day analysis. CONCLUSIONS: Tear osmolarity was unaffected by intra-day variations; however, the T-FCT showed an inter-day variation, which indicated that the time of day when the test is performed must be considered when it is used to evaluate the diagnosis of dry eye disease, disease progression or therapeutic effectiveness. PMID- 24400690 TI - Medical management of refractory epilepsy--practical treatment with novel antiepileptic drugs. AB - The ultimate treatment goal in epilepsy therapy is always freedom from seizures with as few treatment adverse effects as possible. If seizures persist with the first monotherapy, alternative monotherapy with another antiepileptic drug (AED) should be considered. Continuing seizures should lead to a reevaluation of differential diagnosis and adherence. Epilepsy surgery as an alternative therapy may be suitable in selected cases. If the diagnosis of epilepsy is established and epilepsy surgery is not appropriate, AED treatment should be optimized. Evidence for how to proceed is lacking. Concepts such as rational polytherapy have been advocated but remain speculative concerning better efficacy based on the use of AEDs with differing modes of action. A variety of new AEDs including rufinamide, lacosamide, vigabatrin, perampanel, and retigabine have been recently introduced in the United States. They are briefly characterized in this update review. PMID- 24400691 TI - Efficacy of perampanel: a review of pooled data. AB - Perampanel (PER) has been tested in three randomized placebo-controlled prospective phase III trials as an adjunctive antiepileptic drug (AED) in adult and adolescent patients age 12 years and older who had ongoing focal epileptic seizures despite receiving one to three AEDs. Patients were randomized to once daily placebo or maintenance dosages of 2, 4, or 8 mg of PER daily in one trial or to dosages of 8 and 12 mg of PER in the other two studies. Baseline and double blind titration periods comprised 6 weeks each before a 12-week maintenance phase. Primary endpoints were median change in partial seizure frequency (baseline vs. double-blind phase), and the percentage of patients achieving >50% reduction in seizure frequency (so-called responders, baseline vs. maintenance). All patients had the opportunity to enter an open follow-up study that allowed a titration of PER of up to 12 mg. Pooled data of all three studies included 1,478 patients. There was a statistically significant median change in seizure frequency and responder rates with PER dosages of 4, 8, and 12 mg (p < 0.01, each dose vs. placebo). Both the results of each trial and the pooled data are reported in this review. For the open follow-up study, 1,218 patients were recruited. Ninety-one percent finally reached maintenance dosages of 10 or 12 mg. After 1 year, both median seizure reduction and responder rates reached almost 50%. PMID- 24400692 TI - Adverse effects and safety profile of perampanel: a review of pooled data. AB - Quality of life is directly related to the number and severity of adverse effects, and a successful antiepileptic medication must demonstrate a good balance between efficacy and tolerability. Perampanel is a newly licensed antiepileptic medication for the adjunctive treatment of patients (age 12 and older) with partial epilepsy with or without secondary generalization. Safety endpoints in the three phase III trials (304, 305, and 306) included treatment emergent adverse events (TEAEs), vital signs, clinical laboratory parameters, and electrocardiography studies (ECGs). The most common adverse drug reactions in patients receiving perampanel were dizziness, somnolence, fatigue, irritability, nausea, and falls. Of particular concern to patients are cognitive and psychiatric side effects. Overall, depression and aggression were reported more frequently in patients taking perampanel, particularly at higher doses, than in patients taking placebo. TEAEs necessitated the withdrawal of perampanel in 99 patients (9.5%) and placebo in 21 patients (4.8%). Typically this was due to dizziness, convulsion, and somnolence. There were no clinically important changes or treatment group differences in vital signs, ECG measures, or biochemical or hematologic parameters. Weight increase of greater than 7% was seen in 14.6% of perampanel-treated patients versus 7.1% of placebo-treated patients. Overall, perampanel appears to be associated with a relatively low incidence of serious adverse effects, particularly at low doses, and the majority of TEAEs were mild or moderate in intensity. The incidence of predictable side effects, such as somnolence and dizziness, is seen more frequently at higher doses. Of importance is the greater rate of psychiatric side effects in patients treated with perampanel, principally, irritability and aggression, than with placebo. However, the rate of serious psychiatric TEAEs was low. PMID- 24400693 TI - First clinical experiences with perampanel--the Kork experience in 74 patients. AB - Perampanel (PER) has been approved for adjunctive treatment of partial-onset seizures in patients age 12 years and older. In Germany, PER was licensed and marketed in September of 2012. At our tertiary referral epilepsy center, a couple of difficult-to-treat patients were awaiting this introduction of PER; therefore, we were able to initiate treatment in many patients within a short period of time. For this report we collected and analyzed the data of the first patients who had been started on add-on PER between September and December of 2012, so that we were able to evaluate at least 6 months of treatment when we made this analysis. At cutoff in June of 2013, 74 patients could be analyzed. Mean age was 38.4 years (range 15-71 years). PER doses ranged from 4 to 14 mg (mean 8.8 mg). All patients took PER once daily at bedtime. Seventy-one patients had focal epileptic seizures; the remaining four patients had Lennox-Gastaut syndrome. Considering the last 3 months of observation compared with baseline, 34 patients (46%) were responders with a reduction of seizure frequency of at least 50%. Ten patients of these (14% of all) were seizure-free. Adverse events were reported in 40 patients (54%). Leading side effects were somnolence (n = 31, 42%) and dizziness (n = 13, 18%), followed by ataxia, irritability, falls, cognitive slowing, and depression in single cases. Six-month retention rate was 70%. Our first clinical experiences with add-on PER in a highly selected group of difficult-to-treat epilepsies are promising. PMID- 24400694 TI - Long-term follow-up of pure linear ablation for persistent atrial fibrillation without circumferential pulmonary vein isolation. AB - BACKGROUND: The long-term outcome of radiofrequency catheter ablation in persistent atrial fibrillation (AF) patients remains controversial due to different procedural strategies. This study aimed to present the clinical outcome of a pure linear ablation approach without circumferential pulmonary vein isolation (CPVI) over an extended (>5 years) follow-up period. METHODS: From January 2005 to December 2009, 120 consecutive patients (94 men; age, 53.6 +/- 10.3 years) with drug-refractory persistent AF that underwent pure linear ablation using AF termination as the desired procedural endpoint were enrolled. RESULTS: In the primary procedure, sinus rhythm was restored by ablation in 75 (62.5%) patients, and the remaining 45 patients in whom AF could not be terminated by ablation received electrical cardioversion. During a median follow up period of 5.1 (range 3.2-7.5) years, sinus rhythm was maintained in 48 (40.0%) patients without any antiarrhythmic drugs after a single procedure. There was a higher long-term success in the patients in whom AF was terminated by ablation than in those requiring cardioversion (49.3 vs. 24.4%; P = 0.007). CONCLUSION: Linear catheter ablation without CPVI is effective for persistent AF. Patients with AF terminated by ablation were associated with a better long-term outcome than those requiring cardioversion. PMID- 24400696 TI - Interface thermodynamic state-induced high-performance memristors. AB - A new class of memristors based on long-range-ordered CeO2 nanocubes with a controlled degree of self-assembly is presented, in which the regularity and range of the nanocubes can be greatly improved with a highly concentrated dispersed surfactant. The magnitudes of the hydrophobicity and surface energy components as functions of surfactant concentration were also investigated. The self-assembled nanostructure was found to demonstrate excellent degradation in device threshold voltage with excellent uniformity in resistive switching parameters, particularly a set voltage distribution of ~ 0.2 V over 30 successive cycles and a fast response time for writing (0.2 MUs) and erasing (1 MUs) operations, thus offering great potential for nonvolatile memory applications with high performance at low cost. PMID- 24400695 TI - IL-1alpha reversibly inhibits skeletal muscle ryanodine receptor. a novel mechanism for critical illness myopathy? AB - Critical illness myopathies in patients with sepsis or sustained mechanical ventilation prolong intensive care treatment and threaten both patients and health budgets; no specific therapy is available. Underlying pathophysiological mechanisms are still patchy. We characterized IL-1alpha action on muscle performance in "skinned" muscle fibers using force transducers and confocal Ca(2+) fluorescence microscopy for force/Ca(2+) transients and Ca(2+) sparks. Association of IL-1alpha with sarcoplasmic reticulum (SR) release channel, ryanodine receptor (RyR) 1, was investigated with coimmunoprecipitation and confocal immunofluorescence colocalization. Membrane integrity was studied in single, intact fibers challenged with IL-1alpha. IL-1alpha reversibly stabilized Mg(2+) inhibition of Ca(2+) release. Low Mg(2+)-induced force and Ca(2+) transients were reversibly abolished by IL-1alpha. At normal Mg(2+), IL-1alpha reversibly increased caffeine-induced force and Ca(2+) transients. IL-1alpha reduced SR Ca(2+) leak via RyR1, as judged by (1) increased SR Ca(2+) retention, (2) increased IL-1alpha force transients being reproduced by 25 MUM tetracaine, and (3) reduced Ca(2+) spark frequencies by IL-1alpha or tetracaine. Coimmunoprecipitation confirmed RyR1/IL-1 association. RyR1/IL-1 immunofluorescence patterns perfectly colocalized. Long-term, 8-hour IL-1alpha challenge of intact muscle fibers compromised membrane integrity in approximately 50% of fibers, and confirmed intracellular IL-1alpha deposition. IL-1alpha exerts a novel, specific, and reversible interaction mechanism with the skeletal muscle RyR1 macromolecular release complex without the need to act via its membrane IL-1 receptor, as IL-1R membrane expression levels were not detectable in Western blots or immunostaining of single fibers. We present a potential explanation of how the inflammatory mediator, IL-1alpha, may contribute to muscle weakness in critical illness. PMID- 24400697 TI - Watching sport on television, physical activity, and risk of obesity in older adults. AB - BACKGROUND: Television (TV) viewing has been associated with obesity although the effects of specific TV content on health and other behaviours remains unknown. We examined the association between watching sport on TV, physical activity levels, and risk of obesity. METHODS: We studied 6,733 (aged 64.9 +/- 9.2 yrs) men and women from the English Longitudinal Study of Ageing, a prospective study of community dwelling older adults. Data were collected on self reported TV time and content, and physical activity. Nurses measured height and weight for the calculation of body mass index. RESULTS: On average, participants reported viewing TV for 5.3 +/- 4.1 hours per day and 30.3% of the sample watched sport on TV at least twice a week. There was no association between watching sport and physical activity levels. Participants that watched sports every day were at higher risk of obesity [odds ratio = 1.39, 95% CI, 1.15, 1.68) after adjustment for age, sex, smoking, alcohol, physical activity, total TV time, disability, and self-rated health. CONCLUSIONS: Watching elite athletes may have no role in the promotion of physical activity in older adults, which has implications for staging large sporting events with physical activity legacy promises. PMID- 24400698 TI - Typology of public outreach for biodiversity conservation projects in Spain. AB - Conservation education and outreach programs are a key approach to promote public understanding of the importance of biodiversity conservation. We reviewed 85 biodiversity conservation projects supported by the Spanish Ministry of Environment's Biodiversity Foundation. Through content analysis and descriptive statistics, we examined how the projects carried out communication, education, and public awareness and participation (CEPA) actions. We also used multivariate statistical analysis to develop a typology of 4 classes of biodiversity conservation projects on the basis of CEPA implementation. The classifications were delineated by purpose of CEPA, level of integration of CEPA actions, type of CEPA goals, main CEPA stakeholders, and aim of conservation. Our results confirm the existence of 2 key positions: CEPA has intrinsic value (i.e., they supposed the implementation of any CEPA action indirectly supported conservation) and CEPA is an instrument for achieving conservation goals. We also found that most CEPA actions addressed general audiences and school children, ignored minority groups and women, and did not include evaluation. The characteristics of the 4 types of projects and their frequency of implementation in the sample reflect the need for better integration of different types of actions (communication, education, and participation) and improved fostering of participation of multiple stakeholders in developing policy and implementing management strategies. PMID- 24400699 TI - Effects of artemisinin antimalarials on Cytochrome P450 enzymes in vitro using recombinant enzymes and human liver microsomes: potential implications for combination therapies. AB - 1. Cytochrome P450 enzyme system is the most important contributor to oxidative metabolism of drugs. Modification, and more specifically inhibition, of this system is an important determinant of several drug-drug interactions (DDIs). 2. Effects of the antimalarial agent artemisinin and its structural analogues, artemether, artesunate and dihydroartemisinin, on seven of the major human liver CYP isoforms (CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4) were evaluated using recombinant enzymes (fluorometric assay) and human liver microsomes (LC-MS/MS analysis). Inhibitory potency (IC50) and mechanisms of inhibition were evaluated using nonlinear regression analysis. In vitro-in vivo extrapolation using the [I]/Ki ratio was applied to predict the risk of DDI in vivo. 3. All compounds tested inhibited the enzymatic activity of CYPs, mostly through a mixed type of inhibition, with CYP1A2, 2B6, 2C19 and 3A4 being affected. A high risk of interaction in vivo was predicted if artemisinin is coadministrated with CYP1A2 or 2C19 substrates. 4. With respect to CYP1A2 inhibition in vivo by artemisinin compounds, our findings are in line with previously published data. However, reported risks of interaction may be overpredicted and should be interpreted with caution. PMID- 24400700 TI - Nonuniform sampling and maximum entropy reconstruction in multidimensional NMR. AB - NMR spectroscopy is one of the most powerful and versatile analytic tools available to chemists. The discrete Fourier transform (DFT) played a seminal role in the development of modern NMR, including the multidimensional methods that are essential for characterizing complex biomolecules. However, it suffers from well known limitations: chiefly the difficulty in obtaining high-resolution spectral estimates from short data records. Because the time required to perform an experiment is proportional to the number of data samples, this problem imposes a sampling burden for multidimensional NMR experiments. At high magnetic field, where spectral dispersion is greatest, the problem becomes particularly acute. Consequently multidimensional NMR experiments that rely on the DFT must either sacrifice resolution in order to be completed in reasonable time or use inordinate amounts of time to achieve the potential resolution afforded by high field magnets. Maximum entropy (MaxEnt) reconstruction is a non-Fourier method of spectrum analysis that can provide high-resolution spectral estimates from short data records. It can also be used with nonuniformly sampled data sets. Since resolution is substantially determined by the largest evolution time sampled, nonuniform sampling enables high resolution while avoiding the need to uniformly sample at large numbers of evolution times. The Nyquist sampling theorem does not apply to nonuniformly sampled data, and artifacts that occur with the use of nonuniform sampling can be viewed as frequency-aliased signals. Strategies for suppressing nonuniform sampling artifacts include the careful design of the sampling scheme and special methods for computing the spectrum. Researchers now routinely report that they can complete an N-dimensional NMR experiment 3(N-1) times faster (a 3D experiment in one ninth of the time). As a result, high resolution three- and four-dimensional experiments that were prohibitively time consuming are now practical. Conversely, tailored sampling in the indirect dimensions has led to improved sensitivity. Further advances in nonuniform sampling strategies could enable further reductions in sampling requirements for high resolution NMR spectra, and the combination of these strategies with robust non-Fourier methods of spectrum analysis (such as MaxEnt) represent a profound change in the way researchers conduct multidimensional experiments. The potential benefits will enable more advanced applications of multidimensional NMR spectroscopy to study biological macromolecules, metabolomics, natural products, dynamic systems, and other areas where resolution, sensitivity, or experiment time are limiting. Just as the development of multidimensional NMR methods presaged multidimensional methods in other areas of spectroscopy, we anticipate that nonuniform sampling approaches will find applications in other forms of spectroscopy. PMID- 24400702 TI - Taking stock: Australian responses to alcohol and other drugs in the longer term. PMID- 24400701 TI - Stepped care for depression is easy to recommend, but harder to implement: results of an explorative study within primary care in the Netherlands. AB - BACKGROUND: Depression is a common mental disorder with a high burden of disease which is mainly treated in primary care. It is unclear to what extent stepped care principles are applied in routine primary care. The first aim of this explorative study was to examine the gap between routine primary depression care and optimal care, as formulated in the depression guidelines. The second aim was to explore the facilitators and barriers that affect the provision of optimal care. METHODS: Optimal care was operationalised by indicators covering the entire continuum of depression care: from prevention to chronic depression. Routine care was investigated by interviewing general practitioners (GPs) individually and together with other mental health care providers about the depression care they delivered collaboratively. Qualitative analysis of transcripts was performed using thematic coding. Additionally, the GPs completed a self-report questionnaire. RESULTS: Six GPs and 22 other (mostly primary) mental health care providers participated. The GPs and their primary care colleagues embraced a general stepped care approach. They offered psycho-education and counselling to mildly depressed patients. When the treatment effects were not satisfactory or patients were more severely depressed, the GPs offered, or referred to, psychotherapy or pharmacotherapy. Patients with a complex and severe depressive disorder were directly referred to specialised mental health care. However, GPs relied on their clinical judgment and rarely used instruments to assess and monitor the severity of depressive symptoms. Structured, evidence based interventions such as self-management and e-health were rarely offered to patients with depressive symptoms. Specific psychological interventions for relapse prevention or for chronically depressed patients were not available. A wide range of influencing factors for the provision of optimal depression care were put forward. Close collaboration with other mental health care professionals was considered an important factor for improvement by nearly all GPs. CONCLUSIONS: The management of depression in primary care seems in line with stepped care principles, although it can be improved by applying more elements of a stepped care approach. Collaboration between GPs and mental health care providers in primary care and secondary care should be enhanced. PMID- 24400703 TI - Public participation in local alcohol regulation: Findings from a survey of New Zealand communities. AB - INTRODUCTION AND AIMS: In many high-income countries, the responsibility for alcohol regulation is being devolved from central to local governments. Although seeking public input is typically required by law, there remains little empirical evidence on whether and how the public is involved. We investigated public participation in local liquor licensing and related regulation in New Zealand. DESIGN AND METHODS: In 2007, we randomly sampled 2337 residents from the national electoral roll in seven communities and invited them to complete a postal questionnaire assessing their level of general community engagement, whether they had taken action on alcohol issues, and barriers to participation they perceived or encountered. RESULTS: A total of 1372 individuals responded (59% response). Fifty-two percent were current members of community organisations, and 40% had ever taken action on a local issue. Respondents considered alcohol to be a major problem locally, but only 4% had been involved in action to address a problem, whereas 18% had considered taking action. In their communities, 12% and 24%, respectively, felt they could influence the number or location of alcohol outlets. There was little variation across communities. DISCUSSION AND CONCLUSION: Despite high levels of general community engagement and alcohol being widely regarded as a local problem, few community members reported acting on alcohol issues, and their self-efficacy to effect change was low. PMID- 24400704 TI - Steroid users and the unique challenge they pose to needle and syringe program workers. AB - INTRODUCTION AND AIMS: Needle and syringe programs (NSP), which provide sterile injecting equipment, are a cornerstone of Australia's drug harm reduction strategy and assist in reducing the spread of blood-borne virus infections, such as HIV and hepatitis C, among people who inject drugs. Some reports suggest that steroid users are an increasing proportion of clientele at NSPs. In this research, we investigate the experience of NSP workers who come into contact with people who use steroids and other performance- and image-enhancing drugs (PIED). DESIGN AND METHOD: Thirteen NSP workers were recruited using purposive sampling strategies. Participants were interviewed using a semi-structured interview guide. Interviews were recorded, transcribed and coded for themes. RESULTS: There are three key findings of this study. Firstly, NSP workers do not feel well informed about the substances that PIED users are injecting. Secondly, they were unsure what equipment PIED users required. Thirdly, PIED users were perceived to differ from other client groups, and these differences impacted upon the level of rapport staff could build with this group. DISCUSSION AND CONCLUSION: PIED users pose unique challenges for NSP workers compared with other NSP client groups. The PIEDs used and the way in which they are used are substantially different compared with other NSP clients, and there appears to be a lack of knowledge within the workforce about these substances. This study highlights the need to engage in workforce training, but also the need to more effectively engage with PIED users in relation to effective harm reduction strategies. PMID- 24400706 TI - Maternal depressive symptoms are associated with low fearfulness in preschoolers. AB - The purpose of this study is to examine whether maternal depressive symptoms predict low positive emotionality and high temperamental fearfulness in preschool children. Maternal depressive symptoms were assessed prenatally and at 2, 6, and 36 months postnatally. Positive emotionality and temperamental fearfulness were assessed using laboratory observations in a large cohort of typically developing Dutch preschoolers (N = 799; 404 boys) at age 36 months (M = 37.53, SD = 1.50). Children exposed to elevated levels of maternal depressive symptoms in the first 3 years of life behaved less fearfully at age 3 years in a novel context that primarily elicited a startle response (B = -0.08, SE = 0.03, p = .01). The severity rather than timing of or change in maternal depressive symptoms accounted for the observed effect. In the present sample, maternal depressive symptoms were not associated with positive emotionality in the offspring (p > .05). Findings suggest a relation between maternal depressive symptoms and decreased offspring fearfulness in a low-risk community sample of young children. PMID- 24400708 TI - Development and validation of a French Canadian version of the Falls Behavioral (FaB) Scale. AB - PURPOSE: To develop a French Canadian version of the Falls Behavioral (FaB) Scale and examine its psychometric properties. METHODS: The FaB was adapted in French Canadian (FaB-FC) and validated according to standard guidelines for cross cultural adaptation of questionnaires. The internal consistency and construct validity of the FaB-FC were studied among 64 community-dwelling adults aged 60 and over. The concurrent validity and test-retest reliability of the FaB-FC were respectively examined among subsamples including 31 bilingual and 33 unilingual participants. RESULTS: The FaB-FC showed good concurrent validity with the original FaB (ICC2 = 0.94; 0.87-0.97), as well as good test-retest reliability (ICC2 = 0.94; 0.88-0.97). The FaB-FC also demonstrated high internal consistency (alpha = 0.91). Moreover, analyses showed significant associations of the FaB-FC scores with fear of falling and balance confidence scores, attesting to its construct validity. CONCLUSION: This study provides evidence that the FaB-FC has sound psychometric properties. Since falls are associated with multiple risk factors, including behavioral factors, the FaB-FC is undoubtedly a relevant assessment tool for clinicians and researchers working toward fall prevention among French-speaking community-dwelling seniors. IMPLICATIONS FOR REHABILITATION: Fall-related behaviors should be addressed in the assessment of community-dwelling seniors' fall risks. Like the original FaB, the French Canadian version of the tool (FaB-FC) is valid and reliable for assessing fall related behaviors. The FaB-FC is a relevant complementary assessment tool for identifying seniors at risk for falls. The FaB-FC could also be useful in guiding fall prevention interventions and measuring the impact of these interventions on seniors' behaviors. PMID- 24400707 TI - Pilot test and validation of the peak day method of prospective determination of ovulation against a handheld urine hormone monitor. AB - BACKGROUND: Transient exposures may influence fertility and early embryonic development. To assess the time of conception in vivo and conduct concurrent biomonitoring, ovulation must be identified prospectively. We report on the development and validation of a simple, prospective method, the Peak Day method, to determine likely day of ovulation based upon daily observations of cervical fluid. METHODS: We recruited 98 women to learn the Peak Day method from a brochure, 26 of whom concurrently used the method with blinded daily urine hormone monitoring (estrone glucuronide and luteinizing hormone). All women were instructed to complete an exposure questionnaire immediately upon identifying ovulation. Briefly, the exposure questionnaire captured time-varying and transient exposures such as medication use, water consumption, and amount of sleep. We assessed timely completion of the exposure questionnaire, agreement of women's estimated day of ovulation (EDO) and the EDO by expert review, and agreement between the EDO by expert review and by blinded urine monitoring. RESULTS: Of 147 cycles evaluated, women selected an EDO in 130 (88%) and subsequently completed the periovulatory exposure questionnaire in 122 (94%) cycles. Of the 26 cycles evaluated with blinded hormonal monitoring, the Peak Day "best quality" algorithm, based upon cervical fluid, identified ovulation +/- 3 days of the urine monitor in 24 cycles (92%). CONCLUSIONS: With simple written instructions, women can identify an estimated day of ovulation and perform periovulatory exposure assessment. The Peak Day method is highly cost-effective and could be applied by researchers to target periconceptional or very early developmental stage exposure assessment. PMID- 24400709 TI - Experiences of participation in rhythm and movement therapy after stroke. AB - PURPOSE: The aim of this study was to investigate how persons with stroke experience participation in rhythm and music therapy. METHODS: To gain knowledge of the qualitatively different ways persons with stroke experience participation in Ronnie Gardiner Rhythm and Music (RGRM) therapy, a phenomenographic approach was chosen. Interviews with 17 persons with stroke were done. Selection criteria were set to capture the variations in how the phenomenon appeared to the informants. RESULTS: Two qualitatively different ways of experiencing the RGRM therapy were identified: (A) challenge leading to connection with the body and (B) being able. A feeling of being connected to the body was achieved as a result of the challenging tasks. By gaining a feeling of body awareness joy, energy and desire to do things increased. Learning new skills was promoted by having to be concentrated during therapy sessions and a sense of being able to carry out difficult tasks was achieved. CONCLUSIONS: Participation in RGRM seems to have helped the persons come to terms with their changed bodies, leading to feelings of being connected with their bodies. A feeling of change in competence occurred when an ability to carry out the tasks was simultaneously achieved. IMPLICATIONS FOR REHABILITATION: Stroke may cause considerable functional limitations with needs of rehabilitation services as a consequence. Participation in rhythm and movement activities may help persons who have had a stroke come to terms with their "new" bodies. The rhythm and movement activities were considered demanding and helped return to a meaningful life. PMID- 24400710 TI - Decision support framework for developing regional energy strategies. AB - In an effort to reduce "carbon pollution" as well as prepare the U.S. for the impacts of climate change, President Obama's 2013 Climate Action Plan calls for changes to be made to the nation's energy system. In addition to focusing on alternative portfolios of different fuels and power-generation technologies, researchers and advisory panels have urged that changes to the nation's energy system be based on a decision-making framework that incorporates stakeholders and accounts for real-world resource, supply, and demand constraints. To date, research and development on such a framework have proven elusive. The research reported here describes the development and test of a potential decision support framework that combines elements from structured decision-making (SDM) with portfolio analysis, methods that have been used independently to elicit preferences in complex decision contexts. This hybrid framework aimed to (1) provide necessary background information to users regarding the development of coupled climate-energy strategies; (2) account for users' values and objectives; (3) allow for the construction of bespoke energy portfolios bounded by real-world supply and demand constraints; and (4) provide a more rigorous basis for addressing trade-offs. Results show that this framework was user-friendly, led to significant increases in users' knowledge about energy systems and, importantly, led to more internally consistent decisions. For these reasons, this framework may serve as a suitable template for supporting decisions about energy transitions in the United States and abroad. PMID- 24400714 TI - Remarkable scan rate dependence for a highly constrained dinuclear iron(II) spin crossover complex with a wide thermal hysteresis loop. AB - The abrupt [HS-HS] <-> localized [HS-LS] spin crossovers of a new triazole-based diiron(II) complex result in a record-equaling thermal hysteresis loop width for a dinuclear complex (DeltaT = 22 K by SQUID magnetometer in "settle" mode) and show a remarkable scan rate dependence of only the cooling branch, as revealed by detailed magnetic, DSC, and Mossbauer studies. PMID- 24400715 TI - Determination of nanoparticle surface coatings and nanoparticle purity using microscale thermogravimetric analysis. AB - The use of nanoparticles in some applications (i.e., nanomedical, nanofiltration, or nanoelectronic) requires small samples with well-known purities and composition. In addition, when nanoparticles are introduced into complex environments (e.g., biological fluids), the particles may become coated with matter, such as proteins or lipid layers. Many of today's analytical techniques are not able to address small-scale samples of nanoparticles to determine purity and the presence of surface coatings. Through the use of an elevated-temperature quartz crystal microbalance (QCM) method we call microscale thermogravimetric analysis, or MU-TGA, the nanoparticle purity, as well as the presence of any surface coatings of nanomaterials, can be measured. Microscale thermogravimetric analysis is used to determine the presence and amount of surface-bound ligand coverage on gold nanoparticles and confirm the presence of a poly(ethylene glycol) coating on SiO2 nanoparticles. Results are compared to traditional analytical techniques to demonstrate reproducibility and validity of MU-TGA for determining the presence of nanoparticle surface coatings. Carbon nanotube samples are also analyzed and compared to conventional TGA. The results demonstrate MU-TGA is a valid method for quantitative determination of the coatings on nanoparticles, and in some cases, can provide purity and compositional data of the nanoparticles themselves. PMID- 24400716 TI - Vertically aligned peptide nanostructures using plasma-enhanced chemical vapor deposition. AB - In this study, we utilize plasma-enhanced chemical vapor deposition (PECVD) for the deposition of nanostructures composed of diphenylalanine. PECVD is a solvent free approach and allows sublimation of the peptide to form dense, uniform arrays of peptide nanostructures on a variety of substrates. The PECVD deposited d diphenylalanine nanostructures have a range of chemical and physical properties depending on the specific discharge parameters used during the deposition process. PMID- 24400717 TI - Gain-of-function KCNH2 mutations in patients with Brugada syndrome. AB - BACKGROUND: Brugada syndrome (BrS) is an inherited disease characterized by right precordial ST segment elevation on electrocardiograms (ECGs) that predisposes patients to sudden cardiac death as a result of polymorphic ventricular tachyarrhythmia or ventricular fibrillation (VF). In BrS patients, except for SCN5A, mutations in other responsible genes are poorly elucidated. METHODS AND RESULTS: We identified 4 KCNH2 mutations, T152I, R164C, W927G, and R1135H, in 236 consecutive probands with BrS or Brugada-like ECG. Three of these mutation carriers showed QTc intervals shorter than 360 milliseconds and 1 experienced VF. We performed patch-clamp analyses on I(Kr) reconstituted with the KCNH2 mutations in Chinese hamster ovary cells and compared the phenotypes of the patients with different genotypes. Three mutations, R164C, W927G, and R1135H, increased I(Kr) densities. Three mutations, T152I, R164C, and W927G, caused a negative shift in voltage-dependent activation curves. Only the R1135H mutant channel prolonged the deactivation time constants. We also identified 20 SCN5A and 5 CACNA1C mutation carriers in our cohort. Comparison of probands' phenotypes with 3 different genotypes revealed that KCNH2 mutation carriers showed shorter QTc intervals and SCN5A mutation carriers had longer QRS durations. CONCLUSIONS: All KCNH2 mutations that we identified in probands with BrS exerted gain-of-function effects on I(Kr) channels, which may partially explain the ECG findings in our patients. PMID- 24400718 TI - Halogen bond and free internal rotation: the microwave spectrum of CF3Cl-dimethyl ether. AB - The rotational spectra of two isotopologues of the molecular complex CF3Cl dimethyl ether have been measured with pulsed jet Fourier transform microwave spectroscopy. The rotational spectrum encodes information on the global minimum configuration, stabilized by a Cl...O halogen bond, and on the almost free rotation of the -CF3 group. PMID- 24400719 TI - Stereo-acuity in patients implanted with multifocal intraocular lenses: is the choice of stereotest relevant? AB - PURPOSE: A randomized and double-blinded study design was implemented to assess the stereo-acuity in patients symmetrically implanted with four types of multifocal intraocular lenses (MIOLs), compared to a monofocal lens (control group). In addition, the influence of the type of test employed for the evaluation of stereo-acuity was explored. MATERIALS AND METHODS: Six months after cataract intervention, stereo-acuity was measured with the Titmus and TNO stereotests in 143 patients implanted with one of the following MIOL lens types: hybrid spherical SN60D3, hybrid aspheric SN6AD1, diffractive aspheric ZMA00 and refractive spherical NXG1. A control group implanted with the monofocal aspheric ZA9003 (in which stereo-acuity was measured with a near addition) was also included in the study. RESULTS: Statistically significant better stereo-acuity was found in the monofocal group with both stereotests (except for the SN60D3 group with the Titmus test) (all p < 0.001). No significant differences in stereo acuity between MIOLs were found using the Titmus test. However, with the TNO, patients implanted with hybrid diffractive MIOLs exhibited statistically significant worse stereo-acuity than those with the refractive design (SN60D3, p < 0.001; SN6AD1, p = 0.006). CONCLUSIONS: Patients implanted with MIOLs have worse stereo-acuity than those implanted with monofocal IOLs due to the decrease in retinal image contrast originating in the simultaneous presence of two images. A wavelength-based stereotest such as the TNO induces large differences in image contrast between fellow eyes implanted with diffractive-based MIOLs, which may result in an underestimation of the real stereo-acuity of the patient. PMID- 24400720 TI - (Pro)renin receptor and V-ATPase: from Drosophila to humans. AB - A decade ago, the (P)RR [(pro)renin receptor] was discovered and depicted as a potential activator of the tissue renin-angiotensin system. For this reason, the role of the (P)RR in cardiovascular diseases and diabetes has been particularly studied. However, the discovery of embryonic lethality after (P)RR gene deletion in mouse and zebrafish paved the way for additional roles of (P)RR in cell homoeostasis. Indeed, the (P)RR has been shown to associate with vacuolar H+ ATPase, hence its other name ATP6ap2. Developmental studies in Xenopus and Drosophila have revealed an essential role of this association to promote the canonical and non-canonical Wnt signalling pathways, whereas studies with tissue specific gene deletion have pointed out a role in autophagy. The present review aims to summarize recent findings on the cellular functions of (P)RR emerging from various mutated and transgenic animal models. PMID- 24400721 TI - The renin-angiotensin-aldosterone system in pre-eclampsia: the delicate balance between good and bad. AB - Pregnancy demands major changes of the cardiovascular system, and this involves, among others, activation of the RAAS (renin-angiotensin-aldosterone system), allowing an aldosterone-dependent increase in volume. Remarkably, a relative resistance to the pressor response of AngII (angiotensin II) develops simultaneously to prevent the increase in blood pressure that would normally accompany RAAS activation. The increase in volume, the degree of RAAS activation and the diminished pressor response to AngII are less pronounced in pre eclampsia. However, animal models displaying excessive RAAS activation also result in a pre-eclampsia-like syndrome, and the aldosterone/renin ratio is elevated in pre-eclampsia compared with a normal pregnancy. New insights into the pathogenesis of pre-eclampsia have revealed a major role for VEGF (vascular endothelial growth factor), VEGF-inactivating sFlt-1 (soluble fms-like tyrosine kinase-1) and AT1 (angiotensin II type 1) receptor autoantibodies. The last mentioned activate AT(1) receptors, thereby potentially suppressing circulating renin and aldosterone. VEGF, both directly and indirectly (by increasing capillary density), affects adrenal aldosterone synthesis. The present review summarizes all of the recent findings regarding RAAS regulation in pre-eclampsia compared with normal pregnancy, concluding that factors such as sFlt-1 and AT(1) receptor autoantibodies disturb the delicate balance that normally results in a volume increase and a diminished vasoconstrictor response to AngII in pregnant women. It is possible that there are non-parallel changes in the circulating and renal RAAS in pre-eclampsia, which are potentially reflected by the urinary levels of renin. PMID- 24400722 TI - Osteonecrosis of the jaw in a Crohn's disease patient following a course of Bisphosphonate and Adalimumab therapy: a case report. AB - BACKGROUND: Bisphosphonates have a widespread indication for osteoporosis and are also applied in cancer patients with skeletal-related conditions. Bisphosphonate associated osteonecrosis of the jaw (BRONJ) is a feared side effect which is hard to treat and often affects patient's quality of life in an extensive manner. Adalimumab (Humira(r)), a fully human recombinant antibody specific for tumor necrosis factor- alpha, is approved for treatment in patients with Inflammatory Bowel Disease like ulcerative colitis or Crohn's disease. CASE PRESENTATION: In March 2013, a 36-year-old female presented with right-sided perimandibular swelling, recurrent facial pain and exposed necrotic bone after previous extraction of tooth 47. She had the medical history of Crohn's disease for more than one decade with chronic active enterocolitis, fistula disease as well as previous oral manifestation and was currently treated with Adalimumab since September 2008. Due to steroid-induced osteoporosis, diagnosed in 2004, she received oral Bisphosphonates (Risedronate) from 2004 until 2007 followed by two infusions of Zoledronic acid in 2008 and 2009. CONCLUSION: This patient with a medical history of Crohn's disease and gastrointestinal remission under Adalimumab therapy presented with osteonecrosis of the jaw after suspended oral and intravenous Bisphosphonate therapy implicating that the biologic therapy with an anti-TNF-alpha antibody might promote the manifestation of osteonecrosis and compromise oral healing capacity. PMID- 24400723 TI - Future directions in the design, development, and investigation of technology as a service delivery vehicle. AB - Treatment outcome research with children and adolescents has progressed to such an extent that numerous handbooks have been devoted to reviewing and summarizing the evidence base. Ensuring that consumers of these advancements in state-of-the field interventions have the opportunity to access, engage in, and benefit from this evidence base, however, has been wrought with challenge. As such, much discussion exists about innovative strategies for overcoming the gap between research and practice; yet no other potential solution that has received more attention in both the popular and academic press than technology. The promise of technology is not surprising given the fast-paced evolution in development and, in turn, a seemingly endless range of possibilities for novel service delivery platforms. Yet this is precisely the most formidable challenge threatening to upset the very promise of this potential solution: The rate of emerging technologies is far outpacing the field's capacity to demonstrate the conceptual or empirical benefits of such an approach. Accordingly, this article aims to provide a series of recommendations that better situate empirical enquiry at the core of a collaborative development, testing, and deployment process that must define this line of work if the promise of mental health technologies is going to be a reality for front-line clinicians and the clients they serve. PMID- 24400724 TI - Surgical treatment of an invasive thymoma extending into the superior vena cava and right atrium. AB - Although invasive thymoma commonly infiltrates neighbouring mediastinal structures, its extension into the superior vena cava (SVC) and consequent SVC occlusion are rare. In such cases, the urgent removal of the thymoma and radical resection of the infiltrated SVC representreasonable options, since induction therapy is time-consuming and useless for symptom resolution. A case of invasive thymoma extending into the SVC and right atrium (RA) with SVC syndrome is reported. The patient underwent a combined resection of the invasive tumor and SVC under cardiopulmonary bypass (CPB), and the SVC and bilateral brachiocephalic vein (BCV) were reconstructed with an autologous pericardial 'Y' conduit. After 40 months of follow-up, the patient showed a patent graft and no tumor recurrence. PMID- 24400725 TI - Spatio-temporal analysis on enterovirus cases through integrated surveillance in Taiwan. AB - BACKGROUND: Severe epidemics of enterovirus have occurred frequently in Malaysia, Singapore, Taiwan, Cambodia, and China, involving cases of pulmonary edema, hemorrhage and encephalitis, and an effective vaccine has not been available. The specific aim of this study was to understand the epidemiological characteristics of mild and severe enterovirus cases through integrated surveillance data. METHODS: All enterovirus cases in Taiwan over almost ten years from three main databases, including national notifiable diseases surveillance, sentinel physician surveillance and laboratory surveillance programs from July 1, 1999 to December 31, 2008 were analyzed. The Pearson's correlation coefficient was applied for measuring the consistency of the trends in the cases between different surveillance systems. Cross correlation analysis in a time series model was applied for examining the capability to predict severe enterovirus infections. Poisson temporal, spatial and space-time scan statistics were used for identifying the most likely clusters of severe enterovirus outbreaks. The directional distribution method with two standard deviations of ellipse was applied to measure the size and the movement of the epidemic. RESULTS: The secular trend showed that the number of severe EV cases peaked in 2008, and the number of mild EV cases was significantly correlated with that of severe ones occurring in the same week [r = 0.553, p < 0.01]. These severe EV cases showed significantly higher association with the weekly positive isolation rates of EV 71 than the mild cases [severe: 0.498, p < 0.01 vs. mild: 0.278, p < 0.01]. In a time series model, the increase of mild EV cases was the significant predictor for the occurrence of severe EV cases. The directional distribution showed that both the mild and severe EV cases spread extensively during the peak. Before the detected spatio-temporal clusters in June 2008, the mild cases had begun to rise since May 2008, and the outbreak spread from south to north. CONCLUSIONS: Local public health professionals can monitor the temporal and spatial trends plus spatio-temporal clusters and isolation rate of EV-71 in mild and severe EV cases in a community when virus transmission is high, to provide early warning signals and to prevent subsequent severe epidemics. PMID- 24400726 TI - Optimism and challenge for science-based conservation of migratory species in and out of U.S. National Parks. AB - Public agencies sometimes seek outside guidance when capacity to achieve their mission is limited. Through a cooperative agreement and collaborations with the U.S. National Park Service (NPS), we developed recommendations for a conservation program for migratory species. Although NPS manages ~ 36 million hectares of land and water in 401 units, there is no centralized program to conserve wild animals reliant on NPS units that also migrate hundreds to thousands of kilometers beyond parks. Migrations are imperiled by habitat destruction, unsustainable harvest, climate change, and other impediments. A successful program to counter these challenges requires public support, national and international outreach, and flourishing migrant populations. We recommended two initial steps. First, in the short term, launch or build on a suite of projects for high-profile migratory species that can serve as proof to demonstrate the centrality of NPS units to conservation at different scales. Second, over the longer term, build new capacity to conserve migratory species. Capacity building will entail increasing the limited knowledge among park staff about how and where species or populations migrate, conditions that enable migration, and identifying species' needs and resolving them both within and beyond parks. Building capacity will also require ensuring that park superintendents and staff at all levels support conservation beyond statutory borders. Until additional diverse stakeholders and a broader American public realize what can be lost and do more to protect it and engage more with land management agencies to implement actions that facilitate conservation, long distance migrations are increasingly likely to become phenomena of the past. PMID- 24400727 TI - Parenting styles and parents' perspectives on how their own emotions affect the functioning of children with autism spectrum disorders. AB - The grounded theory method was used to analyze the parenting styles used by caregivers to rear children with autism spectrum disorders (ASD) and to investigate parents' experiences regarding how to help their child overcome the symptoms. Thirty-two parents from 28 families of children with ASD in mainland China were interviewed. Analysis of interview transcripts revealed four patterns of parenting styles which varied in affiliation to the roles of caretaker and coach. Based on their experience, a sizable group of parents perceived that their own emotions influence the child's emotions and his/her symptoms. The results suggest the value of developing intervention programs on emotion regulation and positive parenting for the parents of children with ASD. PMID- 24400729 TI - Radionuclide imaging of drug delivery for patient selection in targeted therapy. AB - INTRODUCTION: During the last decade, numerous antibodies and tyrosine kinase inhibitors have been developed for cancer treatment. However, only a limited number of these agents have been shown to significantly improve survival of patients. Therefore, it is of crucial importance to identify the subset of patients who benefit from targeted therapy. Biomarkers can play an important role in selecting the right drug for the right patient. AREAS COVERED: In this review, the potential role of molecular imaging of drug delivery for patient selection in targeted therapy will be discussed. The advantages and limitations of molecular imaging will be compared to those of conventional biomarkers. Moreover, we will address the factors that affect imaging of drug delivery, such as target expression, type of drug, in vivo accessibility of the receptor (e.g., vascular density, vascular permeability, interstitial pressure), enhanced permeability and retention (EPR) effect, receptor internalization, tracer protein dose and timing of imaging. EXPERT OPINION: Molecular imaging of drug delivery clearly has potential for patient selection for targeted therapy. The main advantage of this technique is that not only can antigen expression be measured noninvasively but also target accessibility is taken into account. However, up to now, most of these studies have been performed in preclinical models. Therefore, future research should focus on bringing promising tracers to the clinic, preferable in an early stage of drug development in order to test their potential role as a biomarker. PMID- 24400730 TI - Properties, characteristics and applications of microbubbles for sonothrombolysis. AB - INTRODUCTION: Ultrasound enhancement of thrombolysis (sonothrombolysis) is further potentiated by administration of acoustically active microbubbles, which may be developed into powerful adjuvant therapies for thrombolytic treatment of occlusive conditions such as ischaemic stroke. AREAS COVERED: The role of microbubbles in sonothrombolysis is evaluated based on published in vitro and in vivo evidence and a critical review of clinical trials to date. Microbubble, ultrasound and drug parameters compiled from a broad search of the existing literature are tabulated. Mechanisms of microbubble-enhanced sonothrombolysis are discussed, with particular focus on acoustic cavitation and thermal effects. A number of challenges to widespread clinical adoption are identified. Key factors for future optimisation of treatment and microbubble design are proposed. EXPERT OPINION: Microbubble enhancement of thrombolysis is supported by a broad range of in vitro and in vivo evidence that demonstrates improved lysis compared to conventional drug treatment or ultrasound without microbubbles. Clinically, this is shown by accelerated recanalisation of occluded arteries; however, further research is needed to ensure patient safety. Before such techniques can enter widespread clinical practice, an improved understanding of the role of microbubbles in sonothrombolysis is required, in addition to demonstration of significant improvement over existing treatments and the development of reliable real-time monitoring protocols. PMID- 24400731 TI - 5-hydroxymethylcytosine-mediated DNA demethylation in stem cells and development. AB - The pursuit of DNA demethylation has a colorful history, but it was not until 2009 that the stars of this story, the Ten-eleven-translocation (Tet) family of proteins, were really identified. Tet proteins convert 5-methylcytosine to 5 hydroxymethylcytosine (5hmC), which can be further oxidized to 5-formylcytosine and 5-cyboxycytosine by Tet proteins to achieve DNA demethylation. Recent studies have revealed that 5hmC-mediated DNA demethylation can play essential roles in diverse biological processes, including development and diseases. Here, we review recent discoveries in 5hmC-mediated DNA demethylation in the context of stem cells and development. PMID- 24400732 TI - Polybrominated diphenyl ethers and alternative flame retardants in air and precipitation samples from the northern Lake Victoria region, East Africa. AB - High volume air and precipitation samples were collected close to the shore of Lake Victoria at Entebbe, Uganda, between October 2008 and July 2010 inclusive. Polybrominated diphenyl ethers (PBDEs) and alternative flame retardants (AFRs) were analyzed by GC-MS. BDEs 47, 99, and 209 were the predominant PBDEs with mean concentrations (in air) of 9.84, 4.38, 8.27 pg m(-3) and mean fluxes in precipitation of 3.40, 6.23, and 7.82 ng m(-2) sample(-1), respectively. 1,2 bis(2,4,6-tribromophenoxy)ethane (BTBPE), and hexabromocyclododecane (HBCDD), anti- and syn-Dechlorane plus were detected at levels comparable with those of PBDEs. Both PBDEs and AFRs in air generally increased from 2008 to 2010. Elevated PBDE concentrations in air were associated with slow moving low altitude air masses from the region immediately adjacent to the lake, while low concentrations were mostly associated with fast moving westerly and southwesterly air masses. Analysis of the octa- and nona-BDE profiles suggested photolysis and pyrolytic debromination of BDE-209 in the air samples. The highly halogenated and most abundant PBDEs and AFRs in air also predominated in precipitation samples. This is the first study to report flame retardants in high volume air samples and precipitation in Equatorial Africa. PMID- 24400733 TI - Are minority status children's cross-ethnic friendships beneficial in a multiethnic context? AB - Past research has demonstrated the negative impact of perceived ethnic discrimination (PED) on psychological well-being among children. Given research demonstrating the benefits of cross-ethnic friendship for children's intergroup attitudes, we examined whether cross-ethnic friendships would attenuate the effects of PED on well-being and resilience within a multi-ethnic context. Two hundred and forty-seven South Asian British children (M = 11 years) recruited from 37 classrooms completed measures of perceived cross-ethnic friendship quantity and quality, PED, psychological well-being, and resilience. Friendship quality, but not quantity, had direct positive associations with psychological well-being and resilience. A higher quantity of cross-ethnic friendships moderated the negative effects of PED on both outcomes. Results suggest that cross-ethnic friendships are beneficial for South Asian British children by functioning as a protective factor from the negative effects of discrimination within a multi-ethnic context. PMID- 24400735 TI - Impact of drying on solid state modifications and drug distribution in ibuprofen loaded calcium stearate pellets. AB - Drying is a common pharmaceutical process, whose potential to alter the final drug properties-even at relatively low temperatures-is often neglected. The present study addresses the impact of drying at 20 and 50 degrees C on wet extruded calcium stearate (CaSt) pellets. Drying at 20 degrees C caused the majority of ibuprofen to accumulate at the pellet surface due to a strong convective flow from the pellet's center to the surface. In contrast, pellets dried at 50 degrees C still contained ibuprofen in the pellet's interior due to the higher drying rate and the associated film breakage during drying. Moreover, the higher drying temperature caused CaSt to form a second lamellar phase and ibuprofen to convert (partly) into its amorphous state. Overall, the drying process affected the solid state and the spatial ibuprofen distribution within the pellet. Knowledge of these effects can aid in tailoring advanced multipellet formulations. PMID- 24400734 TI - Attitudes and barriers towards participation in an acupuncture trial among breast cancer patients: a survey study. AB - BACKGROUND: As breast cancer patients increasingly use complementary and alternative medicine (CAM), clinical trials are needed to guide appropriate clinical use. We sought to identify socio-demographic, clinical and psychological factors related to willingness to participate (WTP) and to determine barriers to participation in an acupuncture clinical trial among breast cancer patients. METHODS: We conducted a cross-sectional survey study among post-menopausal women with stage I-III breast cancer on aromatase inhibitors at an urban academic cancer center. RESULTS: Of the 300 participants (92% response rate), 148 (49.8%) reported WTP in an acupuncture clinical trial. Higher education (p = 0.001), increased acupuncture expectancy (p < 0.001), and previous radiation therapy (p = 0.004) were significantly associated with WTP. Travel difficulty (p = 0.002), concern with experimentation (p = 0.013), and lack of interest in acupuncture (p < 0.001) were significant barriers to WTP. Barriers differed significantly by socio-demographic factors with white people more likely to endorse travel difficulty (p = 0.018) and non-white people more likely to report concern with experimentation (p = 0.024). Older patients and those with lower education were more likely to report concern with experimentation and lack of interest in acupuncture (p < 0.05). CONCLUSIONS: Although nearly half of the respondents reported WTP, significant barriers to participation exist and differ among subgroups. Research addressing these barriers is needed to ensure effective accrual and improve the representation of individuals from diverse backgrounds. PMID- 24400736 TI - Treatment with oral beta-blockers during pregnancy complicated by maternal heart disease increases the risk of fetal growth restriction. AB - OBJECTIVE: To investigate the effect on fetal growth of treatment with oral beta blockers during pregnancy in women with congenital or acquired heart disease. DESIGN: Historical matched cohort study. SETTING: Centre for Pregnant Women with Heart Disease, Copenhagen University Hospital, Denmark. POPULATION: A cohort of 175 women with heart disease, grouped according to beta-blocker treatment, and a cohort of 627 women from the overall population matched on seven birthweight determining factors. METHODS: Differences between groups were tested by simple descriptive statistics and assessed using standard hypothesis tests. Associations were estimated by correlational analysis and multivariable regression. MAIN OUTCOME MEASURE: Proportion of infants born small for gestational age (SGA). RESULTS: More of the infants exposed to beta-blockers were SGA compared with non exposed infants (29.4 versus 15.3%; P < 0.05). After adjustment for birthweight determining factors, beta-blocker treatment and maternal body mass index (BMI) were the only factors independently associated with SGA (the relative difference in expected birthweight was -8.6%; 95% CI -13.3 to -3.9%; P = 0.0004). After adjustment for BMI, beta-blocker treatment was associated with an increased risk of SGA (OR 2.65; 95% CI 1.15-6.10; P = 0.02). In a subgroup with isolated tachyarrhythmias, SGA infants were more frequent in the beta-blocker exposed group compared with the non-exposed group (31 versus 10%; P < 0.005). Beta blocker treatment was the only independent predictor of SGA, adjusting for several factors influencing fetal growth (the relative difference in expected birthweight was -12.2%; 95% CI -19.9 to -3.9%; P = 0.001). CONCLUSIONS: In a historical cohort of pregnancies complicated by maternal heart disease, treatment with beta-blockers was found to be independently associated with an increased risk of delivering an SGA infant. PMID- 24400738 TI - Thin layer coulometry based on ion-exchanger membranes for heparin detection in undiluted human blood. AB - We explore here for the first time a potentially calibration-free methodology for the detection of protamine (and, by titration, heparin) in undiluted human blood in the therapeutic concentration range from 20 to 120 mg L(-1). The use of a thin layer sample (5.8 MUL) confined between a tubular protamine selective membrane (inner diameter, 600 MUm) and a Ag/AgCl wire (diameter 400 MUm) achieves an exhaustive depletion from the sample. Coulometry detection was chosen for the interrogation of the thin layer, employing a double pulse technique with 120 s for each pulse. Protamine calibration curves were recorded at physiological concentrations and in undiluted human blood. A linear relationship was obtained in both cases, but a diminished sensitivity was observed in contact with blood, which is explained with a partial passivation of the inner Ag/AgCl element. Heparin-protamine titrations were performed in undiluted human blood samples, mimicking the final application with patients undergoing critical care. The observed values correlate satisfactorily with those of an alternative technique, so-called flash-chronopotentiometry on planar membranes. PMID- 24400739 TI - Computational identification of miRNAs, their targets and functions in three spined stickleback (Gasterosteus aculeatus). AB - An intriguing question in biology is how the evolution of gene regulation is shaped by natural selection in natural populations. Among the many known regulatory mechanisms, regulation of gene expression by microRNAs (miRNAs) is of critical importance. However, our understanding of their evolution in natural populations is limited. Studying the role of miRNAs in three-spined stickleback, an important natural model for speciation research, may provide new insights into adaptive polymorphisms. However, lack of annotation of miRNA genes in its genome is a bottleneck. To fill this research gap, we used the genome of three-spined stickleback to predict miRNAs and their targets. We predicted 1486 mature miRNAs using the homology-based miRNA prediction approach. We then performed functional annotation and enrichment analysis of these targets, which identified over represented motifs. Further, a database resource (GAmiRdb) has been developed for dynamically searching miRNAs and their targets exclusively in three-spined stickleback. Finally, the database was used in two case studies focusing on freshwater adaptation in natural populations. In the first study, we found 44 genomic regions overlapping with predicted miRNA targets. In the second study, we identified two SNPs altering the MRE seed site of sperm-specific glyceraldehyde-3 phosphate gene. These findings highlight the importance of the GAmiRdb knowledge base in understanding adaptive evolution. PMID- 24400740 TI - abFASP-MS: affinity-based filter-aided sample preparation mass spectrometry for quantitative analysis of chemically labeled protein complexes. AB - Affinity purification coupled to 1-D gel-free liquid chromatography mass spectrometry (LC-MS) is a well-established and widespread approach for the analyses of noncovalently interacting protein complexes. In this study, two proteins conjugated to a streptavidin-binding peptide and hemagglutinin double tag were expressed in the respective Flp-In HEK293 cell lines: green fluorescent protein (SH-GFP) and TANK binding kinase 1 (SH-TBK1_MOUSE). Fluorescent anti-HA immunoblots revealed that the expression level of SH-GFP was ~50% lower than that of SH-TBK1_MOUSE. Subsequently, the input material was normalized to obtain a similar quantity of purified SH-tagged proteins. Optimization of the release of protein complexes from the anti-HA-agarose with different eluting agents was then assessed. With respect to the total number of protein groups identified in the purified complexes, elution with 2% SDS surpassed both 100 mM glycine and 100 mM formic acid. Relative quantitation of the purified protein complexes using TMT 6 plex reagents confirmed the higher efficiency of the 2% SDS elution followed by filter-aided sample preparation (FASP). The data presented in this study provide a new application of FASP to quantitative MS analysis of affinity-purified protein complexes. We have termed the approach abFASP-MS, or affinity-based filter-aided sample preparation mass spectrometry. PMID- 24400741 TI - Origin and ablation of the adenosine triphosphate induced atrial fibrillation after circumferential pulmonary vein isolation: effects on procedural success rate. AB - INTRODUCTION: Adenosine triphosphate (ATP) has been used to provoke dormant pulmonary vein (PV) conduction after circumferential PV isolation (CPVI). However, there have been no systematic studies examining the incidence and the mechanism of ATP-induced atrial fibrillation (AF) following CPVI in paroxysmal AF. In this study, we explore the mechanism of ATP-induced AF and assess the feasibility of eliminating this response by additional radiofrequency (RF) ablation. METHODS AND RESULTS: A total of 300 consecutive patients with paroxysmal AF underwent CPVI. After all PVs were isolated, intravenous ATP (40 mg) was administered during an intravenous isoproterenol (ISP) infusion (5 MUg/min). AF was reproducibly induced by ATP in 39 patients. Non-PV foci were confirmed and located in 29 of these patients at the onset of AF, including 27 foci in the superior vena cava (SVC), 1 focus in the crista terminalis, and 1 focus near the antrum of the PV. In all these cases, ATP-induced AF was eliminated after the non-PV foci were successfully ablated. For the other 10 patients, the foci triggering AF could not be confirmed or located due to the transient effect of ATP, thus no further ablation was performed. After a mean follow-up period of 18.7 +/- 6.4 (8-24) months, the success rate in the ATP induced AF group was not significantly different compared with the conventional treatment group who did not exhibit ATP-induced AF (76.9% vs 67.3%; P = 0.25). But in the subgroup of which the ATP-induced AF could be eliminated by additional RF ablation, the success rate was significantly higher than the non-ATP inducible group (86.2% vs 67.3%; P = 0.04). CONCLUSIONS: A large proportion of the ATP induced AF post CPVI were initiated by rapid firing in the SVC. Eliminating this response by additional ablation may have an influence on clinical results of paroxysmal AF ablation. PMID- 24400742 TI - New fragmentation pathways in K-THF collisions as studied by electron-transfer experiments: negative ion formation. AB - Time-of-flight (TOF) negative ion mass spectra have been obtained in collisions of 20-100 eV neutral potassium atoms with tetrahydrofuran (C4H8O), an analogue for the sugar unit in DNA/RNA. Major enhancements in O(-) and C2H3O(-) production were observed compared with earlier dissociative electron attachment (DEA) experiments. In further contrast with DEA, no evidence was observed for dehydrogenated parent anions, and three new fragment anions were detected: CH(-), C2(-), and C2H(-). These contrasting results for potassium impact and DEA highlight significant differences in the reaction pathways initiated by the two electron delivery processes. PMID- 24400743 TI - Sexual behaviour, sexually transmitted infections and attitudes to chlamydia testing among a unique national sample of young Australians: baseline data from a randomised controlled trial. AB - BACKGROUND: Chlamydia infection is the most common notifiable sexually transmitted infection (STI) in Australia and mostly affects young people (15 - 25 years). This paper presents baseline data from a randomised controlled trial that aimed to increase chlamydia testing among sexually active young people. The objectives were to identify associations between sexual behaviour, substance use and STI history and explore attitudes to chlamydia testing. METHODS: This study was conducted in cyberspace. Study recruitment, allocation, delivery of interventions and baseline and follow up data collection all took place online. Participants were 16 - 25 years old and resided in Australia. Substance use correlates of sexual activity; predictors of history of STIs; barriers to and facilitators of chlamydia testing were analysed. RESULTS: Of 856 participants (79.1% female), 704 had experienced penetrative intercourse. Sexually active participants were more likely to smoke regularly or daily, to drink alcohol, or to have binge drunk or used marijuana or other illicit substances recently. Risk factors for having a history of any STI were 3 or more sexual partners ever, 6 or more partners in the past 12 months, condom non-use and being 20 years or older. Almost all sexually active participants said that they would have a chlamydia test if their doctor recommended it. CONCLUSIONS: Sexually active young people are at risk of STIs and may engage in substance use risk behaviours. Where one health risk behaviour is identified, it is important to seek information about others. Chlamydia testing can be facilitated by doctors and nurses recommending it. Primary care providers have a useful role in chlamydia control. TRIAL REGISTRATION: Australian and New Zealand Trials Registry ACTRN12607000582459. PMID- 24400745 TI - Vital dyes in ophthalmology: a chemical perspective. AB - Vital dyes have advanced diagnosis and surgical technique in various specialties, including oncology, gastroenterology and ophthalmology. Intra-operative and diagnostic dyes are finding uses in all areas of ophthalmology, including cornea, cataract, retina, glaucoma, orbit and conjunctiva. We provide a summary of current knowledge of the chemical concepts of vital dyes in ophthalmology. We review the properties of dyes, techniques of application, indications and complications in ocular surgery. Vital dyes represent an expanding area of research, and novel dyes deserve further investigation. PMID- 24400744 TI - Accuracy of 16/18G core needle biopsy for ultrasound-visible breast lesions. AB - BACKGROUND: To assess the accuracy of ultrasound-guided 16G or 18G core needle biopsy (CNB) for ultrasound-visible breast lesions, and to analyze the effects of lesion features. METHODS: Between July 2005 and July 2012, 4,453 ultrasound detected breast lesions underwent ultrasound-guided CNB and were retrospectively reviewed. Surgical excision was performed for 955 lesions (566 with 16G CNB and 389 with 18G CNB) which constitute the basis of the study. Histological findings were compared between the ultrasound-guided CNB and the surgical excision to determine sensitivity, false-negative rate, agreement rate, and underestimation rate, according to different lesion features. RESULTS: Final pathological results were malignant in 84.1% (invasive carcinoma, ductal carcinoma in situ, lymphoma, and metastases), high-risk in 8.4% (atypical lesions, papillary lesions, and phyllodes tumors), and benign in 7.5%. False-negative rates were 1.4% for 16G and 18G CNB. Agreement rates between histological findings of CNB and surgery were 92.4% for 16G and 92.8% for 18G CNB. Overall underestimate rates (high-risk CNB becoming malignant on surgery and ductal carcinoma in situ becoming invasive carcinoma) were 47.4% for 16G and 48.9% for 18G CNB. Agreements were better for mass lesions (16G: 92.7%; 18G: 93.7%) than for non-mass lesions (16G, 85.7%; 18G, 78.3%) (P <0.01). For mass lesions with a diameter <=10 mm, the agreement rates (16G, 83.3%; 18G, 86.7%) were lower (P <0.01). CONCLUSIONS: Ultrasound-guided 16G and 18G CNB are accurate for evaluating ultrasound-visible breast mass lesions with a diameter >10 mm. PMID- 24400746 TI - Achieving both giant d(33) and high T(c) in patassium-sodium niobate ternary system. AB - Both giant d33 and high TC have been obtained in a lead-free piezoelectric ternary system (0.995 - x)K0.48Na0.52NbO3-0.005BiScO3 xBi0.5(Na0.7K0.2Li0.1)0.5ZrO3. Thanks to the rhombohedral-tetragonal phase coexistence and the enhanced dielectric and ferroelectric properties, the ceramic with a composition of x = 0.04 shows a giant d33 of ~366 pC/N together with TC of ~335 degrees C, thereby paving the way for achieving both high d33 and high TC in KNN-based materials. In addition, such a ceramic has a good thermal stability of d33 (e.g., d33 > 319 pC/N, T <= 300 degrees C) and an enhanced stability of ferroelectric properties against temperature. The domain-wall energy barrier of ~0.15 eV is derived from the temperature dependence of the back-switching polarization. PMID- 24400737 TI - Heme enzyme structure and function. PMID- 24400747 TI - Effect of trilostane and mitotane on aldosterone secretory reserve in dogs with pituitary-dependent hyperadrenocorticism. AB - BACKGROUND: Maximal aldosterone secretion in healthy dogs occurs 30 minutes postadrenocorticotropin (ACTH; 5 MUg/kg IV) stimulation. The effect of trilostane and mitotane on aldosterone at that time is unknown. OBJECTIVES: To assess the effect of trilostane and mitotane in dogs with pituitary-dependent hyperadrenocorticism on aldosterone secretory reserve. To determine if aldosterone concentration correlates with electrolyte concentrations. ANIMALS: Serum collected from 79 client-owned dogs and 33 stored samples. METHODS: Client owned dogs had ACTH stimulation tests with cortisol concentrations measured at 0 and 60 minutes and aldosterone concentrations measured at 0, 30, and 60 minutes. Stored samples had aldosterone concentrations measured at 0 and 60 minutes. Ten historical clinically healthy controls were included. All had basal sodium and potassium concentrations measured. RESULTS: The aldosterone concentrations in the mitotane- and trilostane-treated dogs at 30 and 60 minutes post-ACTH were significantly lower than in clinically healthy dogs; no significant difference was detected in aldosterone concentration between 30 and 60 minutes in treated dogs. However, a significantly higher percentage of dogs had decreased aldosterone secretory reserve detected at 30 minutes than at 60 minutes. At 30 minutes, decreased secretory reserve was detected in 49% and 78% of trilostane- and mitotane-treated dogs, respectively. No correlation was detected between aldosterone and serum electrolyte concentrations. CONCLUSIONS AND CLINICAL IMPORTANCE: Decreased aldosterone secretory reserve is common in trilostane- and mitotane-treated dogs; it cannot be predicted by measurement of serum electrolyte concentrations. Aldosterone concentration at 30 minutes post-ACTH stimulation identifies more dogs with decreased aldosterone secretory reserve than conventional testing at 60 minutes. PMID- 24400749 TI - Aplastic anaemia. PMID- 24400748 TI - A usability study of a mobile health application for rural Ghanaian midwives. AB - INTRODUCTION: Midwives in rural Ghana work at the frontline of the health care system, where they have access to essential data about the patient population. However, current methods of data capture, primarily pen and paper, make the data neither accessible nor usable for monitoring patient care or program evaluation. Electronic health (eHealth) systems present a potential mechanism for enhancing the roles of midwives by providing tools for collecting, exchanging, and viewing patient data as well as offering midwives the possibility for receiving information and decision support. Introducing such technology in low-resource settings has been challenging because of low levels of user acceptance, software design that does not match the end-user environment, and/or unforeseen challenges such as irregular power availability. These challenges are often attributable to a lack of understanding by the software developers of the end users' needs and work environment. METHODS: A mobile health (mHealth) application known as mClinic was designed to support midwife access to the Millennium Village-Global Network, an eHealth delivery platform that captures data for managing patient care as well as program evaluation and monitoring, decision making, and management. We conducted a descriptive usability study composed of 3 phases to evaluate an mClinic prototype: 1) hybrid lab-live software evaluation of mClinic to identify usability issues; 2) completion of a usability questionnaire; and 3) interviews that included low-fidelity prototyping of new functionality proposed by midwives. RESULTS: The heuristic evaluation identified usability problems related to 4 of 8 usability categories. Analysis of usability questionnaire data indicated that the midwives perceived mClinic as useful but were more neutral about the ease of use. Analysis of midwives' reactions to low-fidelity prototypes during the interview process supported the applicability of mClinic to midwives' work and identified the need for additional functionality. DISCUSSION: User acceptance is essential for the success of any mHealth implementation. Usability testing identified mClinic development flaws and needed software enhancements. PMID- 24400750 TI - From the editorial office. PMID- 24400751 TI - Headache associate editors declaration of conflicts of interest. PMID- 24400754 TI - Should butalbital ever be given, much less to a pregnant woman? PMID- 24400755 TI - Daily triptan use for intractable migraine. PMID- 24400756 TI - Long-acting triptans and weather-related migraines. PMID- 24400757 TI - Headache associated with telaprevir treatment. PMID- 24400758 TI - Burning mouth syndrome response to high-dose vitamin C. PMID- 24400759 TI - Roadblock to the only FDA-approved treatment for chronic migraine. PMID- 24400760 TI - Classification challenge in migrainous infarction. PMID- 24400761 TI - Vagus nerve stimulation for refractory cluster headaches. PMID- 24400762 TI - The efficacy of transdermal sumatriptan is too low for general use - a response. PMID- 24400763 TI - Craniomandibular neurovascular dysfunction syndrome and headache. PMID- 24400764 TI - Headache and sleep: also assess circadian rhythm sleep disorders. PMID- 24400765 TI - Headache and sleep: also assess circadian rhythm sleep disorders: a response. PMID- 24400767 TI - Clinical trials update. 2013: year in review. AB - This section of Headache annually reviews the status of recently completed and ongoing major clinical trials involving common headache disorders. The review will focus on multicenter trials of new therapies, as well as novel formulations of previously approved therapeutics. Table 1 summarizes the major therapeutic headache trials that are ongoing at the present time, according to data obtained from both the "ClinicalTrials.Gov" website and from corporate press releases and presentations. PMID- 24400769 TI - The multitarget drug approach in migraine treatment: the new challenge to conquer. AB - Migraine is a complex neurovascular disorder where a complex and interrelated neuronal spinal, supraspinal and central mechanisms are involved. Although we have greatly advanced in the knowledge of the main pathways involved in this disorder, the current drugs used are not effective in all patients, suggesting that the key mechanism related to headache relief remains elusive. In this context, the multi-target drug approach or network pharmacology emerges as a new step in the development of innovative migraine pharmacotherapy. The design, discovery, and development of new drugs that reach several (instead of unique) specific targets (functional selectivity) involved in the migraine pathophysiology is essential to progress in the migraine treatment and open a new field of study about the main pathways and targets that could synergistically improve the migraine management. PMID- 24400770 TI - Medication overuse headache. PMID- 24400771 TI - Energy analysis reveals the negative effect of delays in passive movement mirror therapy. AB - Wavelet transform energy analyses of the mean and standard error of the electromyogram (EMG) and electroencephalogram (EEG) of eight subjects were investigated in passive movement mirror therapies with no delay (in-phase) and with delay (out-of-phase) situations in two frequency bands of 7.81-15.62 and 15.62-31.25 Hz. It was found that the energy levels of EEG at electrode C4 in the in-phase situation were lower than those in out-of-phase situations, while the energy levels of flexor and extensor forearm muscle groups were larger. With two exceptions, this pattern could be seen in all other subjects. The difference between the in-phase (D0) and out-of-phase situations (D025 and D05) for the frequency range of 15.62-31.25 Hz was found to be significant at a significance level of 0.05 (paired t-test analysis). The respective elevation and decline of EEG and EGM with regard to the increase of the delay may indicate the necessity for synchronization of passive movement and mirror therapy. PMID- 24400772 TI - Digital image analysis of endoscopic ultrasonography is helpful in diagnosing gastric mesenchymal tumors. AB - BACKGROUND: Endoscopic ultrasonography (EUS) is a valuable imaging tool for evaluating subepithelial lesions in the stomach. However, there are few studies on differentiation between gastrointestinal stromal tumors (GISTs) and benign mesenchymal tumors, such as leiomyoma or schwannoma, with the use of EUS. In addition, there are limitations in the analysis of the characteristic features of such tumors due to poor interobserver agreement as a result of subjective interpretation of EUS images. Therefore, the aim of this study was to evaluate the role of digital image analysis in distinguishing the features of GISTs from those of benign mesenchymal tumors on EUS. METHODS: We enrolled 65 patients with histopathologically proven gastric GIST, leiomyoma or schwannoma on surgically resected specimens who underwent EUS examination at our endoscopic unit from January 2007 to September 2010. After standardization of the EUS images, brightness values including the mean (Tmean), indicative of echogenicity, and the standard deviation (TSD), indicative of heterogeneity, in the tumors were analyzed. RESULTS: The Tmean and TSD were significantly higher in GIST than in leiomyoma and schwannoma (p < 0.001). However, there was no significant difference in the Tmean or TSD between benign and malignant GISTs. The sensitivity and specificity were almost optimized for differentiating GIST from leiomyoma or schwannoma when the critical values of Tmean and TSD were 65 and 75, respectively. The presence of at least 1 of these 2 findings in a given tumor resulted in a sensitivity of 94%, specificity of 80%, positive predictive value of 94%, negative predictive value of 80%, and accuracy of 90.8% for predicting GIST. CONCLUSIONS: Digital image analysis provides objective information on EUS images; thus, it can be useful in diagnosing gastric mesenchymal tumors. PMID- 24400773 TI - Worldwide HLA-E nucleotide and haplotype variability reveals a conserved gene for coding and 3' untranslated regions. AB - The human leukocyte antigen-E (HLA-E) locus is a human major histocompatibility complex (MHC) gene associated with immune-modulation and suppression of the immune response by the interaction with specific natural killer (NK) and T cell receptors (TCRs). It is considered one of the most conserved genes of the human MHC; however, this low nucleotide variability seems to be a consequence of the scarce number of studies focusing on this subject. In this manuscript we assessed the nucleotide variability at the HLA-E coding and 3' untranslated regions (3'UTRs) in Brazil and in the populations from the 1000Genomes Consortium. Twenty eight variable sites arranged into 33 haplotypes were detected and most of these haplotypes (98.2%) are encoding one of the two HLA-E molecules found worldwide, E*01:01 and E*01:03. Moreover, three worldwide spread haplotypes, associated with the coding alleles E*01:01:01, E*01:03:01 and E*01:03:02, account for 85% of all HLA-E haplotypes, suggesting that they arose early before human speciation. In addition, the low nucleotide diversity found for the HLA-E coding and 3'UTR in worldwide populations suggests that the HLA-E gene is in fact a conserved gene, which might be a consequence of its key role in the modulation of the immune system. PMID- 24400774 TI - Emerging drugs for acromegaly. AB - INTRODUCTION: Acromegaly is a rare disease that severely impacts patients' health all the while, being a slowly progressing illness. In the past decades, advancements in treatment modalities, especially development of new drugs, as well as focused guidelines has improved management of acromegaly. Still, many patients are considered not sufficiently treated and there remains an ongoing need for further development. AREAS COVERED: This article reviews new medical treatments currently under clinical investigation (such as pasireotide, oral octreotide and somatoprim) and under experimental development (such as octreotide implants, CAM2029 and ATL-1103). EXPERT OPINION: As it seems unlikely that one single agent may achieve cure in 100% of cases, there is an urgent need for new agents that help patients where current medication fails. Imperatively, this means we have to improve our understanding of the underlying pathogenetic and molecular mechanisms. PMID- 24400775 TI - Speech-language pathologists' contribution to the assessment of decision-making capacity in aphasia: a survey of common practices. AB - Speech-language pathologists' scope of practice is currently unclear in relation to their contribution to the multi-disciplinary assessment of decision-making capacity for clients with aphasia and related neurogenic communication disorders. The primary aim of the current research study was to investigate the common practices of speech-language pathologists involved in assessments of decision making capacity. The study was completed through the use of an online survey. There were 51 of 59 respondents who indicated involvement in evaluations of decision-making. Involvement in this kind of assessment was most commonly reported by speech-language pathologists working in inpatient acute and rehabilitation settings. Respondents reported using a variety of formal and informal assessment methods in their contributions to capacity assessment. Discussion with multidisciplinary team members was reported to have the greatest influence on their recommendations. Speech-language pathologists reported that they were dissatisfied with current protocols for capacity assessments in their workplace and indicated they would benefit from further education and training in this area. The findings of this study are discussed in light of their implications for speech-language pathology practice. PMID- 24400776 TI - What is your diagnosis? Upper eyelid swelling in a dog. PMID- 24400778 TI - Managing stress and anxiety through qigong exercise in healthy adults: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: An increasing number of studies have documented the effectiveness of qigong exercise in helping people reduce psychological stress and anxiety, but there is a scarcity of systematic reviews evaluating evidence from randomized controlled trials (RCTs) conducted among healthy subjects. METHODS: Thirteen databases were searched for RCTs from their inception through June 2013. Effects of qigong exercise were pooled across trials. Standardized mean differences (SMDs) were calculated for the pooled effects. Heterogeneity was assessed using the I2 test. The risk of bias was assessed using the Cochrane criteria. RESULTS: Seven RCTs met the inclusion criteria. Two RCTs suggested that qigong exercise immediately relieved anxiety among healthy adults, compared to lecture attendance and structured movements only. Four RCTs suggested qigong exercise relieved anxiety (pooled SMD = -0.75; 95% CI, -1.11 to -0.40), and three RCTs suggested that qigong exercise reduced stress (pooled SMD = -0.88; 95% CI, -1.22 to -0.55) among healthy subjects following one to three months of qigong practice, compared to wait-list controls. CONCLUSIONS: The available evidence suggests that qigong exercise reduces stress and anxiety in healthy adults. However, given the limited number of RCTs and their methodological flaws, further rigorously designed RCTs are needed. PMID- 24400777 TI - Discovery of ABT-267, a pan-genotypic inhibitor of HCV NS5A. AB - We describe here N-phenylpyrrolidine-based inhibitors of HCV NS5A with excellent potency, metabolic stability, and pharmacokinetics. Compounds with 2S,5S stereochemistry at the pyrrolidine ring provided improved genotype 1 (GT1) potency compared to the 2R,5R analogues. Furthermore, the attachment of substituents at the 4-position of the central N-phenyl group resulted in compounds with improved potency. Substitution with tert-butyl, as in compound 38 (ABT-267), provided compounds with low-picomolar EC50 values and superior pharmacokinetics. It was discovered that compound 38 was a pan-genotypic HCV inhibitor, with an EC50 range of 1.7-19.3 pM against GT1a, -1b, -2a, -2b, -3a, 4a, and -5a and 366 pM against GT6a. Compound 38 decreased HCV RNA up to 3.10 log10 IU/mL during 3-day monotherapy in treatment-naive HCV GT1-infected subjects and is currently in phase 3 clinical trials in combination with an NS3 protease inhibitor with ritonavir (r) (ABT-450/r) and an NS5B non-nucleoside polymerase inhibitor (ABT-333), with and without ribavirin. PMID- 24400779 TI - D-alpha-tocopheryl polyethylene glycol 1000 succinate: a view from FTICR MS and tandem MS. AB - D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) is an important polymeric excipient frequently used in drug formulation. However, differing compositions of the TPGS samples between batches are believed to result in variable performance of the formulated product. Herein, a high performance method using Fourier-transform ion cyclotron resonance (FTICR) mass spectrometry (MS) and tandem mass spectrometry (MS/MS) to analyze the composition of TPGS samples and the structure of TPGS was established. Aided by high mass accuracy and high resolution, the full MS overview of TPGS is able to provide composition information, and diagnostic fragments from collisionally activated dissociation (CAD) and electron capture dissociation (ECD) MS/MS can be used for the identification of the TPGS structure. ECD and CAD show different preferences in bond cleavage, and an interesting cross-ring cleavage was generated by CAD. Fragmentation information from ECD/ECD MS(3) is useful for providing confidence in the results. The influence of different ionization agents (Na(+), Li(+), and Ag(+)) on fragmentation of TPGS was investigated with the silver adduct providing different fragments. In addition to the methodology study, the MS and MS/MS results from four batches of TPGS samples from two manufacturers were compared. This method can be utilized for the composition and structure study of many other polymeric compounds. FTICR MS/MS demonstrated its promising role as a structural characterization tool complementary to traditional spectroscopy techniques. PMID- 24400780 TI - A dual role for integrin-linked kinase and beta1-integrin in modulating cardiac aging. AB - Cardiac performance decreases with age, which is a major risk factor for cardiovascular disease and mortality in the aging human population, but the molecular mechanisms underlying cardiac aging are still poorly understood. Investigating the role of integrin-linked kinase (ilk) and beta1-integrin (myospheroid, mys) in Drosophila, which colocalize near cardiomyocyte contacts and Z-bands, we find that reduced ilk or mys function prevents the typical changes of cardiac aging seen in wildtype, such as arrhythmias. In particular, the characteristic increase in cardiac arrhythmias with age is prevented in ilk and mys heterozygous flies with nearly identical genetic background, and they live longer, in line with previous findings in Caenorhabditis elegans for ilk and in Drosophila for mys. Consistent with these findings, we observed elevated beta1 integrin protein levels in old compared with young wild-type flies, and cardiac specific overexpression of mys in young flies causes aging-like heart dysfunction. Moreover, moderate cardiac-specific knockdown of integrin-linked kinase (ILK)/integrin pathway-associated genes also prevented the decline in cardiac performance with age. In contrast, strong cardiac knockdown of ilk or ILK associated genes can severely compromise cardiac integrity, including cardiomyocyte adhesion and overall heart function. These data suggest that ilk/mys function is necessary for establishing and maintaining normal heart structure and function, and appropriate fine-tuning of this pathway can retard the age-dependent decline in cardiac performance and extend lifespan. Thus, ILK/integrin-associated signaling emerges as an important and conserved genetic mechanism in longevity, and as a new means to improve age-dependent cardiac performance, in addition to its vital role in maintaining cardiac integrity. PMID- 24400782 TI - Electron transfer from humic substances to biogenic and abiogenic Fe(III) oxyhydroxide minerals. AB - Microbial humic substance (HS) reduction and subsequent abiotic electron transfer from reduced HS to poorly soluble Fe(III) (oxyhydr)oxides, a process named electron shuttling, significantly increases microbial Fe(III) mineral reduction rates. However, the importance of electron shuttling in nature and notably the electron transfer from HS to biogenic Fe(III) (oxyhydr)oxides have thus far not been determined. In this study, we have quantified the rate and extent of electron transfer from reduced and nonreduced Pahokee Peat humic acids (PPHA) and fresh soil organic matter (SOM) extracts to both synthetic and environmentally relevant biogenic Fe(III) (oxyhydr)oxides. We found that biogenic Fe(III) minerals were reduced faster and to an equal or higher degree than their abiogenic counterparts. Differences were attributed to differences in crystallinity and the association of bacterial biomass with biogenic minerals. Compared to purified PPHA, SOM extract transferred fewer electrons per milligram of carbon and electron transfer was observed only to poorly crystalline ferrihydrite but not to more crystalline goethite. This indicates a difference in redox potential distribution of the redox-active functional groups in extracted SOM relative to the purified PPHA. Our results suggest that HS electron shuttling can also contribute to iron redox processes in environments where biogenic Fe(III) minerals are present. PMID- 24400781 TI - Metalloradical approach to 2H-chromenes. AB - Cobalt(III)-carbene radicals, generated through metalloradical activation of salicyl N-tosylhydrazones by cobalt(II) complexes of porphyrins, readily undergo radical addition to terminal alkynes to produce salicyl-vinyl radical intermediates. Subsequent hydrogen atom transfer (HAT) from the hydroxy group of the salicyl moiety to the vinyl radical leads to the formation of 2H-chromenes. The Co(II)-catalyzed process can tolerate various substitution patterns and produces the corresponding 2H-chromene products in good isolated yields. EPR spectroscopy and radical-trapping experiments with TEMPO are in agreement with the proposed radical mechanism. DFT calculations reveal the formation of the salicyl-vinyl radical intermediate by a metalloradical-mediated process. Unexpectedly, subsequent HAT from the hydroxy moiety to the vinyl radical leads to formation of an o-quinone methide intermediate, which dissociates spontaneously from the cobalt center and easily undergoes an endocyclic, sigmatropic ring-closing reaction to form the final 2H-chromene product. PMID- 24400783 TI - Functional pi-gelators and their applications. PMID- 24400784 TI - Late organized left atrial thrombus on a left atrial appendage closure device. PMID- 24400785 TI - A study of the dietary intake of Cypriot children and adolescents aged 6-18 years and the association of mother's educational status and children's weight status on adherence to nutritional recommendations. AB - BACKGROUND: A balanced diet is fundamental for healthy growth and development of children. The aim of this study was to document and evaluate the dietary intake of Cypriot children aged 6-18 years (y) against recommendations, and to determine whether maternal education and children's weight status are associated with adherence to recommendations. METHODS: The dietary intake of a random sample of 1414 Cypriot children was assessed using a 3-day food diary. Adherence to recommendations was estimated and the association of their mother's education and their own weight status on adherence were explored. RESULTS: A large percentage of children consumed less than the minimum of 45% energy (en) of carbohydrate (18.4%-66.5% in different age groups) and exceeded the recommended intakes of total fat (42.4%-83.8%), saturated fatty acids (90.4%-97.1%) and protein (65.2% 82.7%), while almost all (94.7%-100%) failed to meet the recommended fibre intake. Additionally, a large proportion of children (27.0%-59.0%) consumed >300 mg/day cholesterol and exceeded the upper limit of sodium (47.5%-78.5%). In children aged 9.0-13.9y, there was a high prevalence of inadequacy for magnesium (85.0%-89.9%), in girls aged 14.0-18.9y, of Vitamin A (25.3%), Vitamin B6 (21.0%) and iron (25.3%) and in boys of the same group, of Vitamin A (35.8%). Children whose mother was more educated were more likely to consume >15%en from protein, Odds Ratio (OR) 1.85 (95% CI:1.13-3.03) for mothers with tertiary education and exceed the consumption of 300 mg/day cholesterol (OR 2.13 (95% CI:1.29-3.50) and OR 1.84 (95% CI:1.09-3.09) for mothers with secondary and tertiary education respectively). Children whose mothers were more educated, were less likely to have Vitamin B1 (p<0.05) and Vitamin B6 intakes below the EAR (p < 0.05 for secondary school and p < 0.001 for College/University) and iron intake below the AI (p < 0.001). Overweight/obese children were more likely to consume >15%en protein (OR 1.85 (95% CI:1.26-2.71) and have a < Adequate Intake of calcium (OR 1.85 (95% CI:1.11-3.06)). CONCLUSION: Cypriot children consume a low quality diet. Maternal education and children's own weight status are associated with children's adherence to recommendations. Public health policies need to be evaluated to improve dietary quality and reduce disease burden. PMID- 24400786 TI - Antifibrotic effect of pirfenidone on human pterygium fibroblasts. AB - OBJECTIVE: The effects of pirfenidone were investigated on cultured human pterygium fibroblasts (HPFs). METHODS: HPFs were obtained from pterygium surgery and subjected to primary culture. After treatment with 0.5, 1.0 or 1.5 mg/mL pirfenidone, MTT and cell migration assays were performed, and procollagen secretion and TGF-beta expression were measured by Western blotting and immunofluorescence analysis. RESULTS: Pirfenidone had a significant inhibitory effect on HPF proliferation, migration and collagen synthesis. There were no differences between the cells treated with 0.5, 1.0 and 1.5 mg/mL pirfenidone and the controls in the MTT assay. After 48 h of treatment with 1.0 or 1.5 mg/mL pirfenidone, TGF-beta expression was significantly decreased. CONCLUSIONS: These findings demonstrate that pirfenidone inhibits the proliferation, migration and procollagen secretion of HPFs at nontoxic concentrations by decreasing TGF-beta expression. Thus, pirfenidone may be considered as a safe adjuvant for pterygium surgery to prevent recurrence. PMID- 24400787 TI - Performance of individual vs. group sampling for inferring dispersal under isolation-by-distance. AB - Models of isolation-by-distance formalize the effects of genetic drift and gene flow in a spatial context where gene dispersal is spatially limited. These models have been used to show that, at an appropriate spatial scale, dispersal parameters can be inferred from the regression of genetic differentiation against geographic distance between sampling locations. This approach is compelling because it is relatively simple and robust and has rather low sampling requirements. In continuous populations, dispersal can be inferred from isolation by-distance patterns using either individuals or groups as sampling units. Intrigued by empirical findings where individual samples seemed to provide more power, we used simulations to compare the performances of the two methods in a range of situations with different dispersal distributions. We found that sampling individuals provide more power in a range of dispersal conditions that is narrow but fits many realistic situations. These situations were characterized not only by the general steepness of isolation-by-distance but also by the intrinsic shape of the dispersal kernel. The performances of the two approaches are otherwise similar, suggesting that the choice of a sampling unit is globally less important than other settings such as a study's spatial scale. PMID- 24400788 TI - Beyond equivalence of care in prison pharmacy. AB - Prison healthcare has undergone a significant transformation over recent times. The main aim of these changes was to ensure prisoners received the same level of care as patients in the community. Prisons are a unique environment to provide healthcare within. Both the environment and the patient group provide a challenge to healthcare delivery. One of the biggest challenges currently being faced by healthcare providers is the misuse and abuse of prescription medication. It seems that the changes that have been made in prison healthcare, to ensure that prisoners receive the same level of care as patients in the community over recent times, have led to an increase in this problem. Prison pharmacy is ideally placed to help reduce the misuse and abuse of prescription medication. This can be achieved by using the skills and knowledge of the pharmacy department to ensure appropriate prescribing of medication liable to misuse and abuse. PMID- 24400789 TI - Intrapartum management associated with obesity in nulliparous women. AB - INTRODUCTION: The objective of this systematic review was to determine the current state of knowledge about intrapartum management associated with obesity in healthy nulliparous women. Nulliparous obese women are at higher risk for unplanned cesarean birth when compared with their normal-weight counterparts, and much of this increased risk is associated with labor management differences. There is a need to better understand the differences in intrapartum management of nulliparous women who are obese. METHODS: The PubMed, CINAHL, EBSCO, Google Scholar, and MEDLINE databases were searched in August 2012, with identified studies then assessed for applicability and quality. Eight studies were retained for the review. RESULTS: Intrapartum interventions used significantly more often for healthy, obese nulliparous women when compared with normal-weight women were induction of labor, augmentation of labor, and cesarean birth. It is unclear if assisted vaginal birth occurs more frequently among obese women. Epidural anesthesia, artificial rupture of membranes prior to 6 cm of cervical dilation, and early hospital admission were shown in separate studies to be used more often in obese women. Intrapartum interventions were used more frequently in obese women in a dose-dependent manner by body mass index. DISCUSSION: Future studies examining the intrapartum management of obese nulliparous women are needed with: 1) samples defined by standardized obesity classifications; 2) further analysis of diverse intrapartum interventions; and 3) prospective, randomized designs to allow for causality conclusions linking intrapartum intervention use to an obese woman's risk for cesarean birth. Implications for clinical practice from this systematic review are that healthy, nulliparous obese women are exposed to common intrapartum interventions more often than normal-weight women. In the absence of evidence on the use of appropriate use of intrapartum interventions in this population, health care providers should carefully monitor management choices when working with healthy, nulliparous obese women. PMID- 24400790 TI - Recovery times after sugammadex: is the data flawed? PMID- 24400791 TI - Breast cancer and sexuality: the impacts of breast cancer treatment on the sex lives of women in Brazil. AB - This paper presents findings from a qualitative study of the impact on women's sexual lives after diagnosis and treatment for breast cancer in Ribeirao Preto, Sao Paulo. The study involved 36 women, 15 of whom were interviewed and the remainder of whom participated in focus and body-image group discussions. Data collection was undertaken between 2008 and 2010. Findings focus on women's experience of breast cancer as a life-threatening condition and document reappraisals of their lives in general, seeking to situate these women's sexual lives within the context of wider ideals about femininity and sexual cultures in Brazil. Women expressed anxiety concerning the effects of treatment for breast cancer, particularly concerns about body image. We draw together implications of the prior findings for the sexual scripts played out in women's sexual relationships and lives. Three main sexual scripts - 'traditional gender roles', 'ageing' and 'egalitarian pleasure-oriented' - are identified and discussed in relation to both the life-changing impact of diagnosis of cancer and wider changes in gender dimensions of Brazilian sexual culture. PMID- 24400792 TI - Multivariate analysis of prognostic factors in patients with pulmonary actinomycosis. AB - BACKGROUND: There have been few studies of pulmonary actinomycosis, which is an uncommon anaerobic infection. Consequently, the optimal therapeutic regimen, appropriate duration of treatment, long-term prognosis, and factors predicting prognosis are not well established. METHODS: We retrospectively reviewed the medical records of histopathologically confirmed cases of pulmonary actinomycosis seen between November 2003 and December 2012. RESULTS: The study included 68 patients with a mean age of 58.4 +/- 11.6 years. Of the 68, initial surgery was performed in 15 patients (22.1%), while the remaining 53 (77.9%) received antibiotic therapy initially. In the initial antibiotic group, 45/53 (84.9%) were cured without relapse (median antibiotic duration 5.3 months). 5/53 (9.4%) patients were refractory medically (median antibiotic duration 9.7 months), and 3/53 (5.7%) experienced a recurrence (median time to relapse 35.3 months). In the initial surgery group, 14/15 (93.3%) were cured and treatment failure occurred in one (6.7%). In the multivariate analysis, the absence of an antibiotic response at 1 month was the only independent factor associated with a poor treatment outcome, with an adjusted odds ratio of 49.2 (95% CI, 3.34-724.30). There was no significant difference in treatment outcome based on the size of the parenchymal lesion, comorbidities, whether intravenous antibiotics were used, antibiotic therapy duration, or whether the initial treatment was surgical. CONCLUSIONS: Antibiotic treatment with or without surgery was effective for treatment of pulmonary actinomycosis. Nevertheless, treatment failure or recurrence occurred in a considerable proportion of patients, especially those resistant to the initial antibiotic treatment. PMID- 24400794 TI - The role of pro-resolution lipid mediators in infectious disease. AB - Inflammation is an essential host defence against infection, but can be damaging when excessive. Resolution of inflammation is an active process, and the pro resolution effects of lipoxins, resolvins and protectins have received significant interest. Here, we review emerging data on the role of these lipid mediators in infectious disease. Lipoxins influence host control of Mycobacterium tuberculosis, Toxoplasma gondii, Trypanosoma cruzi and Plasmodium berghei cerebral malaria in mice. Their effects are protective in toxoplasmosis, T. cruzi infection and cerebral malaria but detrimental in tuberculosis; related to the balance between pathogen-control and excessive immune response. Topical lipoxin abrogates the tissue damage seen in a rabbit model of Porphyromonas gingivalis periodontitis. The increased virulence of H5N1 influenza A virus in mice correlates with reduced expression of SOCS2, required to mediate the effects of lipoxin. Mice unable to synthesize lipoxin suffer increased lung pathology during respiratory syncytial virus infection. Protectin suppresses influenza A virus replication in vitro and increases survival in a mouse model of severe influenza infection. Resolvins were investigated in a number of animal models of systemic bacterial infection, and were found to enhance phagocytic clearance of bacteria, reduce inflammation severity, promote neutrophil apoptosis, modulate neutrophil chemotaxis and importantly, reduce mortality. Interestingly, resolvin also enhances the antibacterial effect of ciprofloxacin and vancomycin. Topical resolvin application reduces the severity of herpes simplex virus ocular infection in mice. If the effects of these mediators translate from pre-clinical studies into successful clinical trials, they represent promising new strategies in managing infectious disease. PMID- 24400795 TI - Probiotic antigens stimulate hepatic natural killer T cells. AB - Increasing evidence suggests that gut flora play an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Our previous studies show that hepatic natural killer T (NKT) cells play a significant role in the pathogenesis of NAFLD. In this study, we explore the mechanism by which modification of gut flora leads to the alteration of hepatic NKT cells and improvement of steatosis. Mice were fed a high-fat (HF) diet to induce NAFLD. Some of them also received different doses of mixed-strain probiotics (VSL#3); single-strain probiotic (Bifidobacterium infantis) or antibiotics. Animal weight, glucose tolerance, liver steatosis and hepatic NKT cells were assessed. Lipid extracts from probiotics were tested for their ability to activate NKT cells. Toll-like receptor 4 (TLR4) knockout mice were also evaluated for their responses to HF diet. High-dose VSL#3 was more effective than low-dose VSL#3 and B. infantis for the improvement of hepatic NKT cell depletion and steatosis. The lipids extracted from VSL#3 stimulated NKT cells both in vivo and in vitro. In contrast, lipids from B. infantis decreased alpha-GalCer-mediated NKT cell activation in vitro, but were able to stimulate NKT cells. TLR4 knockout mice have a similar response to HF-diet-induced NKT cell depletion and obesity. These results suggest that alterations in the gut flora have profound effects on hepatic NKT cells and steatosis, which are both strain-specific and dose dependent, but not through TLR4 signalling. Furthermore, these data suggest that probiotics may contain bacterial glycolipid antigens that directly modulate the effector functions of hepatic NKT cells. PMID- 24400797 TI - ABM: worldwide rather than international. PMID- 24400796 TI - Exosomal proteins in the aqueous humor as novel biomarkers in patients with neovascular age-related macular degeneration. AB - Age-related macular degeneration (AMD) describes the progressive degeneration of the retinal pigment epithelium (RPE), retina, and choriocapillaris and is the leading cause of blindness in people over 50. The molecular mechanisms underlying this multifactorial disease remain largely unknown. To uncover novel secretory biomarkers related to the pathogenesis of AMD, we adopted an integrated approach to compare the proteins identified in the conditioned medium (CM) of cultured RPE cells and the exosomes derived from CM and from the aqueous humor (AH) of AMD patients by LC-ESI-MS/MS. Finally, LC-MRM was performed on the AH from patients and controls, which revealed that cathepsin D, cytokeratin 8, and four other proteins increased in the AH of AMD patients. The present study has identified potential biomarkers and therapeutic targets for AMD treatment, such as proteins related to the autophagy-lysosomal pathway and epithelial-mesenchymal transition, and demonstrated a novel and effective approach to identifying AMD-associated proteins that might be secreted by RPE in vivo in the form of exosomes. The proteomics-based characterization of this multifactorial disease could help to match a particular marker to particular target-based therapy in AMD patients with various phenotypes. PMID- 24400798 TI - Restricting kidney transplant wait-listing for obese patients: let's stop defending the indefensible. AB - The allocation of limited medical resources represents an ethical dilemma that continues to generate lively debates. While the allocation of allografts to wait listed patients is done in a transparent manner, with its rules open to public debate and prone to continuous improvement, the practice of wait-listing is not centrally regulated, and its rules are often less scrutinized. Denial of kidney transplant wait-listing to obese individuals has been a common practice by most transplant centers. On the face of it, this practice is justified by commonly accepted ethical standards, yet there is now mounting evidence that these justifications do not withstand closer scrutiny. A candid and open debate in the Nephrology and Transplant community is needed to examine the true motivations that underlie the practice of denying wait-listing to obese individuals, and to find a solution that is truly in the best interest of our patients. PMID- 24400799 TI - Should dialysate calcium be individualized? AB - The growing interest in a personalized choice of dialysate calcium concentration faces some important unsolved questions. First, the desired aims to be achieved should be clarified, as different d-Ca concentrations might differentially impact dialysis calcium balance and serum calcium concentration. A second point to be addressed is how to achieve the desired goals; the kinetics of calcium during dialysis treatment are complex. This is not an easy task and probably only an automatic device able to read serum calcium concentration in real-time and adjust d-Ca to it might supply an effective method for individualizing d-Ca. Finally, it is not even clear whether individualizing d-Ca is worth doing; cost-effectiveness studies might give some further insights into this intricate issue. PMID- 24400800 TI - Oral iron for patients receiving dialysis: what is the evidence? AB - This review aims to summarize the available evidence of the effectiveness of oral iron in patients receiving dialysis. Four small randomized controlled trials (105 evaluated patients) compared oral iron supplements with placebo or no treatment; hemoglobin and ferritin levels did not differ significantly between groups at the end of the studies, while transferrin saturation levels fell in the placebo group in two studies. One trial (46 evaluated patients), comparing different ferrous iron preparations, found that hemoglobin levels and iron indices were maintained, but not increased. Another trial (54 evaluated patients) compared heme iron polypeptide with ferrous sulfate; hemoglobin and transferrin saturation levels remained stable with both agents, but ferritin levels fell with heme iron polypeptide, but not ferrous sulfate. Two observational studies found that iron supplements can maintain hemoglobin and iron indices. Oral iron supplements were poorly tolerated. These sparse data suggest that oral iron is of little or no benefit in raising hemoglobin and iron indices in patients receiving dialysis. Further data are required to determine if oral iron can maintain adequate iron indices following iron replenishment using intravenous iron supplements. PMID- 24400801 TI - What are the causes of the ill effects of chronic hemodialysis? Is routine hemodialysis enough to improve patient well being? PMID- 24400802 TI - Vitamin K antagonists: beyond bleeding. AB - Warfarin is the most widely used oral anticoagulant in clinical use today. Indications range from prosthetic valve replacement to recurrent thromboembolic events due to antiphospholipid syndrome. In hemodialysis (HD) patients, warfarin use is even more frequent than in the nonrenal population due to increased cardiovascular comorbidities. The use of warfarin in dialysis patients with atrial fibrillation requires particular caution because side effects may outweigh the assumed benefit of reduced stroke rates. Besides increased bleeding risk, coumarins exert side effects which are not in the focus of clinical routine, yet they deserve special consideration in dialysis patients and should influence the decision of whether or not to prescribe vitamin K antagonists in cases lacking clear guidelines. Issues to be taken into consideration in HD patients are the induction or acceleration of cardiovascular calcifications, a 10-fold increased risk of calciphylaxis and problems related to maintaining a target INR range. New anticoagulants like direct thrombin inhibitors are promising but have not yet been approved for ESRD patients. Here, we summarize the nontraditional side effects of coumarins and give recommendations about the use of vitamin K antagonists in ESRD patients. PMID- 24400803 TI - Catheter-related infection and septicemia: impact of seasonality and modifiable practices from the DOPPS. AB - Hemodialysis (HD) catheter-related infection (CRI) and septicemia contribute to adverse outcomes. The impact of seasonality and prophylactic dialysis practices during high-risk periods remain unexplored. This multicenter study analyzed DOPPS data from 12,122 HD patients (from 442 facilities) to determine the association between seasonally related climatic variables and CRI and septicemia. Climatic variables were determined by linkage to National Climatic Data Center of National Oceanic and Atmospheric Administration data. Catheter care protocols were examined to determine if they could mitigate infection risk during high-risk seasons. Survival models were used to estimate the adjusted hazard ratio (AHR) of septicemia by season and by facility catheter dressing protocol. The overall catheter-related septicemia rate was 0.47 per 1000 catheter days. It varied by season, with an AHR for summer of 1.46 (95% CI: 1.19-1.80) compared with winter. Septicemia was associated with temperature (AHR = 1.07; 95% CI: 1.02-1.13; p < 0.001). Dressing protocols using chlorhexidine (AHR of septicemia = 0.55; 95% CI: 0.39-0.78) were associated with fewest episodes of CRI or septicemia. Higher catheter-related septicemia in summer may be due to seasonal conditions (e.g., heat, perspiration) that facilitate bacterial growth and compromise protective measures. Extra vigilance and use of chlorhexidine-based dressing protocols may provide prophylaxis against CRI and septicemia. PMID- 24400807 TI - Enantioselective component selection in multicomponent supramolecular gels. AB - We investigate a two-component acid-amine gelation system in which chirality plays a vital role. A carboxylic acid based on a second generation l-lysine dendron interacts with chiral amines and subsequently assembles into supramolecular gel fibers. The chirality of the amine controls the assembly of the resulting diastereomeric complexes, even if this chirality is relatively "poor quality". Importantly, the selective incorporation of one enantiomer of an amine over the other into the gel network has been demonstrated, with the R amine that forms complexes which assemble into the most stable gel being primarily selected for incorporation. Thermodynamic control has been proven by forming a gel exclusively with an S amine, allowing the R enantiomer to diffuse through the gel network, and displacing it from the "solidlike" fibers, demonstrating that these gels adapt and evolve in response to chemical stimuli to which they are exposed. Excess amine, which remains unincorporated within the solidlike gel fiber network, can diffuse out and be reacted with an isocyanate, allowing us to quantify the enantioselectivity of component selection but also demonstrating how gels can act as selective reservoirs of potential reagents, releasing them on demand to undergo further reactions; hence, component-selective gel assembly can be coupled with controlled reactivity. PMID- 24400806 TI - Novel class of benzoic acid ester derivatives as potent PDE4 inhibitors for inhaled administration in the treatment of respiratory diseases. AB - The first steps in the selection process of a new anti-inflammatory drug for the inhaled treatment of asthma and chronic obstructive pulmonary disease are herein described. A series of novel ester derivatives of 1-(3-(cyclopropylmethoxy)-4 (difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl) ethanol have been synthesized and evaluated for inhibitory activity toward cAMP-specific phosphodiesterase-4 (PDE4). In particular, esters of variously substituted benzoic acids were extensively explored, and structural modification of the alcoholic and benzoic moieties were performed to maximize the inhibitory potency. Several compounds with high activity in cell-free and cell-based assays were obtained. Through the evaluation of opportune in vitro ADME properties, a potential candidate suitable for inhaled administration in respiratory diseases was identified and tested in an in vivo model of pulmonary inflammation, proving its efficacy. PMID- 24400808 TI - Chemical deposition of Cu(2)O nanocrystals with precise morphology control. AB - Copper(I) oxide nanoparticles (NPs) are emerging as a technologically important material, with applications ranging from antibacterial and fungicidal agents to photocatalysis. It is well established that the activity of Cu2O NPs is dependent on their crystalline morphology. Here we describe direct preparation of Cu2O nanocrystals (NCs) on various substrates by chemical deposition (CD), without the need of additives, achieving precise control over the NC morphology. The substrates are preactivated by gold seeding and treated with deposition solutions comprising copper sulfate, formaldehyde, NaOH, and citrate as a complexant. Production of NC deposits ranging from complete cubes to complete octahedra is demonstrated, as well as a full set of intermediate morphologies, i.e., truncated octahedra, cuboctahedra, and truncated cubes. The NC morphology is defined by the NaOH and complexant concentrations in the deposition solution, attributed to competitive adsorption of citrate and hydroxide anions on the Cu2O {100} and {111} crystal faces and selective stabilization of these faces. A sequential deposition scheme, i.e., Cu2O deposition on pregrown Cu2O NCs of a different morphology, is also presented. The full range of morphologies can be produced by controlling the deposition times in the two solutions, promoting the cubic and octahedral crystal habits. Growth rates in the ?100? and ?111? directions for the two solutions are estimated. The Cu2O NCs are characterized by SEM, TEM, GI-XRD, and UV-vis spectroscopy. It is concluded that CD furnishes a simple, effective, generally applicable, and scalable route to the synthesis of morphologically controlled Cu2O NCs on a variety of conductive and nonconductive surfaces. PMID- 24400810 TI - Horizontal Denture: A Prosthodontic Alternative for Severe Maxillary Atrophy. PMID- 24400811 TI - Innovations in nutrition education and global health: the Bangalore Boston nutrition collaborative. AB - BACKGROUND: India has a wide range of nutrition and health problems which require professionals with appropriate skills, knowledge and trans-disciplinary collaborative abilities to influence policy making at the national and global level. METHODS: The Bangalore Boston Nutrition Collaborative (BBNC) was established as collaboration between St. John's Research Institute (SJRI), Harvard School of Public Health and Tufts University, with a focus on nutrition research and training. The goals of the BBNC were to conduct an interdisciplinary course, develop web-based courses and identify promising Indian students and junior faculty for graduate training in Boston. RESULTS: From 2010, an annual two week short course in nutrition research methods was conducted on the SJRI campus taught by international faculty from Indian and US universities. More than 100 students applied yearly for approximately 30 positions. The course had didactic lectures in the morning and practical hands-on sessions in the afternoon. Student rating of the course was excellent and consistent across the years. The ratings on the design and conduct of the course significantly improved (p <0.001) from 2010 to 2012. Through open-ended questions, students reported the main strengths of the course to be the excellent faculty and practical "hands-on" sessions. A web based learning system TYRO, was developed, which can be used for distance learning. Four faculty members/graduate students from SJRI have visited Boston for collaborative research efforts. CONCLUSION: The BBNC has become a well established capacity building and research training program for young professionals in nutrition and global health. Efforts are ongoing to secure long term funding to sustain and expand this collaboration to deliver high quality nutrition and global health education enabled by information and communication technologies. PMID- 24400812 TI - Diagnosis and surgical treatment of multiple endocrine neoplasia type 2A. AB - BACKGROUND: This study aims to introduce the diagnosis and surgical treatment of the rare disease multiple endocrine neoplasia type 2A (MEN 2A). METHODS: Thirteen cases of MEN 2A were diagnosed as medullary thyroid carcinoma (MTC) and pheochromocytoma by biochemical tests and imaging examination. They were treated by bilateral adrenal tumor excision or laparoscopic surgery. RESULTS: Nine patients were treated by bilateral adrenal tumor excision and the remaining four were treated by laparoscopic surgery for pheochromocytoma. Ten patients were treated by total thyroidectomy and bilateral lymph nodes dissection and the remaining three were treated by unilateral thyroidectomy for MTC. Up to now, three patients have died of MTC distant metastasis. CONCLUSIONS: We confirmed that MEN 2A can be diagnosed by biochemical tests and imaging examination when genetic testing is not available. Surgical excision is the predominant way to treat MEN 2A; pheochromocytoma should be excised at first when pheochromocytoma and MTC occur simultaneously. PMID- 24400813 TI - Autopilot: an online data acquisition control system for the enhanced high throughput characterization of intact proteins. AB - The ability to study organisms by direct analysis of their proteomes without digestion via mass spectrometry has benefited greatly from recent advances in separation techniques, instrumentation, and bioinformatics. However, improvements to data acquisition logic have lagged in comparison. Past workflows for Top Down Proteomics (TDPs) have focused on high throughput at the expense of maximal protein coverage and characterization. This mode of data acquisition has led to enormous overlap in the identification of highly abundant proteins in subsequent LC-MS injections. Furthermore, a wealth of data is left underutilized by analyzing each newly targeted species as unique, rather than as part of a collection of fragmentation events on a distinct proteoform. Here, we present a major advance in software for acquisition of TDP data that incorporates a fully automated workflow able to detect intact masses, guide fragmentation to achieve maximal identification and characterization of intact protein species, and perform database search online to yield real-time protein identifications. On Pseudomonas aeruginosa, the software combines fragmentation events of the same precursor with previously obtained fragments to achieve improved characterization of the target form by an average of 42 orders of magnitude in confidence. When HCD fragmentation optimization was applied to intact proteins ions, there was an 18.5 order of magnitude gain in confidence. These improved metrics set the stage for increased proteome coverage and characterization of higher order organisms in the future for sharply improved control over MS instruments in a project- and lab wide context. PMID- 24400809 TI - DNA dynamics and single-molecule biology. PMID- 24400814 TI - Bispectral index analysis during cardiac arrest and cardiopulmonary resuscitation in a propofol-anesthetized calf. AB - OBJECTIVE: To describe bispectral index (BIS) findings and compare them with cardiovascular and respiratory trends during cardiac arrest and successful CPR in a propofol-anesthetized calf. CASE SUMMARY: A 3-month-old calf was anesthetized as part of a research project. A thromboxane analog drug (U46619) was administered IV to induce pulmonary hypertension. Within 10 minutes following U46619 administration, cardiac activity deteriorated, leading to asystole. At this point, BIS and suppression rate were 0 and 100, respectively. Anesthetic drug delivery was discontinued and external chest compressions were initiated. During CPR, end-tidal CO2 concentration decreased and BIS increased, but no spontaneous cardiac activity was noted, thus IV epinephrine was administered. Return of spontaneous circulation was achieved and systemic arterial hypertension developed, while BIS briefly decreased and then increased during the following 2 minutes. The calf's cardiopulmonary variables returned to physiological ranges within 10 minutes after the return of spontaneous circulation and remained stable. UNIQUE INFORMATION PROVIDED: This is the first report in which BIS is documented together with standard monitoring techniques during cardiopulmonary arrest and resuscitation in a calf. BIS varied with cardiovascular performance, and may be indicative of cerebral blood flow in this context. Further research may be warranted to define the role of BIS for monitoring cerebral activity during CPR. PMID- 24400815 TI - Osteopontin and galectin-3 predict the risk of ventricular tachycardia and fibrillation in heart failure patients with implantable defibrillators. AB - BACKGROUND: Myocardial extracellular matrix remodelling provides electrical heterogeneity entailing ventricular tachycardia/fibrillation (VT/VF) in heart failure (HF) patients. Osteopontin (OPN) and Galectin-3 (Gal-3) are fibrosis markers and may reflect the extension of the arrhythmogenic substrate. We assessed whether plasma OPN and Gal-3 predict the risk of sustained VT/VF in a cohort of HF patients with implantable cardioverter-defibrillator (ICD). METHODS: A total of 75 HF patients underwent pre-ICD implantation clinical evaluation and assessment of plasma OPN and Gal-3. The primary endpoint was the time to the occurrence of the first sustained VT/VF. Hazard ratios (HR) were derived from Cox proportional-hazards analysis. RESULTS: Patients with coronary artery disease (CAD) had higher plasma OPN (79.8 +/- 44.0 ng/mL vs. 66.0 +/- 31.8 ng/mL; P = 0.04). Both Gal-3 (r = -0.38; P = 0.01) and OPN (r = -0.27; p = 0.01) were negatively related to estimated glomerular filtration rate. After 29 +/- 17 months, 20 patients (27%) reached the primary endpoint. Patients with VT/VF had higher plasma OPN and Gal-3 (97.4 +/- 51.7 ng/mL vs. 65.9 +/- 31.3 ng/mL; P = 0.002 and 19.7 +/- 8.5 ng/mL vs. 16.2 +/- 6.2 ng/mL; P = 0.05). In univariate analysis, OPN (log-OPN, HR: 32.4; 95%CI: 3.9-264.7; P = 0.001) and Gal-3 (HR: 1.05; 95%CI: 1.00-1.11; P = 0.04) predicted sustained VT/VF. In multivariable analysis, both OPN (HR: 41.4; 95%CI: 3.8-441.9; P = 0.002) and Gal-3 (HR: 1.06; 95%CI: 1.00-1.12; P = 0.03) retained their prognostic power after correction for age, sex, history of MI, EF, NYHA class, eGFR, use of ACE-I, and amiodarone. CONCLUSIONS: Plasma OPN and Gal-3 predict sustained VT/VF in HF patients at high risk for SCD. Larger prospective studies should outline the role of these biomarkers in predicting SCD on top of conventional risk stratification. PMID- 24400816 TI - Beyond BMI: The "Metabolically healthy obese" phenotype & its association with clinical/subclinical cardiovascular disease and all-cause mortality -- a systematic review. AB - BACKGROUND: A subgroup has emerged within the obese that do not display the typical metabolic disorders associated with obesity and are hypothesized to have lower risk of complications. The purpose of this review was to analyze the literature which has examined the burden of cardiovascular disease (CVD) and all cause mortality in the metabolically healthy obese (MHO) population. METHODS: Pubmed, Cochrane Library, and Web of Science were searched from their inception until December 2012. Studies were included which clearly defined the MHO group (using either insulin sensitivity and/or components of metabolic syndrome AND obesity) and its association with either all cause mortality, CVD mortality, incident CVD, and/or subclinical CVD. RESULTS: A total of 20 studies were identified; 15 cohort and 5 cross-sectional. Eight studies used the NCEP Adult Treatment Panel III definition of metabolic syndrome to define "metabolically healthy", while another nine used insulin resistance. Seven studies assessed all cause mortality, seven assessed CVD mortality, and nine assessed incident CVD. MHO was found to be significantly associated with all-cause mortality in two studies (30%), CVD mortality in one study (14%), and incident CVD in three studies (33%). Of the six studies which examined subclinical disease, four (67%) showed significantly higher mean common carotid artery intima media thickness (CCA-IMT), coronary artery calcium (CAC), or other subclinical CVD markers in the MHO as compared to their MHNW counterparts. CONCLUSIONS: MHO is an important, emerging phenotype with a CVD risk between healthy, normal weight and unhealthy, obese individuals. Successful work towards a universally accepted definition of MHO would improve (and simplify) future studies and aid inter-study comparisons. Usefulness of a definition inclusive of insulin sensitivity and stricter criteria for metabolic syndrome components as well as the potential addition of markers of fatty liver and inflammation should be explored. Clinicians should be hesitant to reassure patients that the metabolically benign phenotype is safe, as increased risk cardiovascular disease and death have been shown. PMID- 24400819 TI - 'He is proud of my courage to ask him to be circumcised': experiences of female partners of male circumcision clients in Iringa region, Tanzania. AB - Male circumcision programmes in Tanzania seek to increase demand among older, married clients who are more likely to have steady female sexual partners. Understanding women's roles throughout their partners' circumcision and any resultant changes in relationship dynamics are important considerations as efforts are made to scale up male circumcision. We conducted interviews with 32 wives of male circumcision clients from November 2011 to February 2012 in Iringa, Tanzania. Transcripts were digitally recorded, transcribed and translated into English and codes were developed based on emerging themes. Women were instrumental in convincing their husbands to be circumcised, but early resumption of sexual activity was common and a minority of women reported their husbands' emotional abuse or risk compensation following circumcision. These findings suggest that married women play a key role in their husbands' decisions to be circumcised, but women's needs for information and education are not being met and gender inequalities further decrease women's abilities to reduce their risk of HIV in this context. Strategies to more meaningfully engage women in male circumcision programmes are needed. PMID- 24400818 TI - One hundred years of progress in nurse-midwifery: with women, then and now. PMID- 24400817 TI - Ultra-deep Illumina sequencing accurately identifies MHC class IIb alleles and provides evidence for copy number variation in the guppy (Poecilia reticulata). AB - We address the bioinformatic issue of accurately separating amplified genes of the major histocompatibility complex (MHC) from artefacts generated during high throughput sequencing workflows. We fit observed ultra-deep sequencing depths (hundreds to thousands of sequences per amplicon) of allelic variants to expectations from genetic models of copy number variation (CNV). We provide a simple, accurate and repeatable method for genotyping multigene families, evaluating our method via analyses of 209 b of MHC class IIb exon 2 in guppies (Poecilia reticulata). Genotype repeatability for resequenced individuals (N = 49) was high (100%) within the same sequencing run. However, repeatability dropped to 83.7% between independent runs, either because of lower mean amplicon sequencing depth in the initial run or random PCR effects. This highlights the importance of fully independent replicates. Significant improvements in genotyping accuracy were made by greatly reducing type I genotyping error (i.e. accepting an artefact as a true allele), which may occur when using low-depth allele validation thresholds used by previous methods. Only a small amount (4.9%) of type II error (i.e. rejecting a genuine allele as an artefact) was detected through fully independent sequencing runs. We observed 1-6 alleles per individual, and evidence of sharing of alleles across loci. Variation in the total number of MHC class II loci among individuals, both among and within populations was also observed, and some genotypes appeared to be partially hemizygous; total allelic dosage added up to an odd number of allelic copies. Collectively, observations provide evidence of MHC CNV and its complex basis in natural populations. PMID- 24400820 TI - Statistical significance of normalized global alignment. AB - The comparison of homologous proteins from different species is a first step toward a function assignment and a reconstruction of the species evolution. Though local alignment is mostly used for this purpose, global alignment is important for constructing multiple alignments or phylogenetic trees. However, statistical significance of global alignments is not completely clear, lacking a specific statistical model to describe alignments or depending on computationally expensive methods like Z-score. Recently we presented a normalized global alignment, defined as the best compromise between global alignment cost and length, and showed that this new technique led to better classification results than Z-score at a much lower computational cost. However, it is necessary to analyze the statistical significance of the normalized global alignment in order to be considered a completely functional algorithm for protein alignment. Experiments with unrelated proteins extracted from the SCOP ASTRAL database showed that normalized global alignment scores can be fitted to a log-normal distribution. This fact, obtained without any theoretical support, can be used to derive statistical significance of normalized global alignments. Results are summarized in a table with fitted parameters for different scoring schemes. PMID- 24400821 TI - How long shall we record electroencephalography? AB - BACKGROUND: The duration of electroencephalography (EEG) recordings varies widely among laboratories. Although several recommendations had been published, there are no previous studies directly addressing this. AIMS OF THE STUDY: To assess the effect of the recording duration on detection of EEG abnormalities in a tertiary referral centre for epilepsy. METHODS: We have reviewed 1005 EEG recordings and determined the shortest recording duration necessary to identify interictal EEG abnormalities. RESULTS: Standard, awake recordings shorter than 20 min yielded a significantly lower incidence of abnormal findings as compared to longer recordings. Although there was an increase in the diagnostic yield from 30 to 180 min recording duration, this failed to reach the level of significance. For sleep recordings, there was no significant increase in the diagnostic yield beyond 30 min. CONCLUSIONS: Our results provide evidence for recommending at least 20 min recording duration for standard awake EEGs and 30 min for sleep EEG recordings. As data were derived from patients referred to our epilepsy centre, the results are only valid for epilepsy-related indications. PMID- 24400822 TI - Intensified specimen collection to improve tuberculosis diagnosis in children from Rural South Africa, an observational study. AB - BACKGROUND: In drug-resistant TB settings, specimen collection is critical for drug-susceptibility testing (DST). This observational study included multiple specimen types collected from pediatric TB suspects with the aim to determine diagnostic yield and inform clinical practice in children with drug-resistant and drug-susceptible TB. METHODS: From 03/2009-07/2010, TB suspects aged >=6 months and <=12 years were recruited among outpatient and inpatient settings. Subjects were new TB suspects or had persistent symptoms despite >=2 months of TB treatment. The protocol included collection of a single blood and urine specimen, a single sputum induction and, if inpatients and <5 years of age, collection of 3 gastric aspirates (GA). Samples were cultured on solid and/or liquid media. DST was by 1% proportion method. RESULTS: Among 118 children with possible, probable or confirmed TB, the mean age was 4.9 years [SD 3.2] and 64 (62%) of those tested were HIV-positive. Eight (7%) subjects were culture-positive from at least one specimen; yield did not differ by HIV status or TB treatment history. Among those with positive cultures, 7/8 (88%) were from induced sputum, 5/6 (83%) from GA, 3/8 (38%) from blood, and 3/7 (43%) from urine. In subjects with both induced sputum and GA collection, sputum provided one additional case compared to GA. Multidrug resistant (MDR)-TB was detected by urine culture alone in one child >5 years old. Pan-resistant extensively drug resistant (XDR)-TB was identified by cultures from all sites in one subject. CONCLUSIONS: TB was cultured from HIV positive and -negative children, and allowed for identification of MDR and XDR-TB cases. Urine and induced sputum each provided an additional TB diagnosis and, when compared to GA, may be considered a less invasive, same-day method of specimen collection for childhood TB suspects. This study illustrates the continued challenges and limitations of available strategies for pediatric TB diagnostics. PMID- 24400823 TI - Does host plant richness explain diversity of ectomycorrhizal fungi? Re evaluation of Gao et al. (2013) data sets reveals sampling effects. AB - The generally positive relationship between biodiversity of groups of directly or indirectly interacting organisms is one of the most important ecological concepts (Gaston, 2000 Nature, 405, 220-227; Scherber C, Eisenhauer N, Weisser WW et al., 2010 Nature, 468, 553-556). In a recent issue of Molecular Ecology, Gao C, Shi N N, Liu Y-X et al. (2013: 22, 3403-3414) reported that the richness of plants and ectomycorrhizal fungi is positively correlated both at local and at global scales. Here, we challenge these findings by re-analysis of data and ascribe the reported results to sampling effect and poor data compilation. PMID- 24400824 TI - Pain and analgesic use after robot-assisted radical prostatectomy. AB - PURPOSE: While robot-assisted radical prostatectomy (RARP) is associated with shortened convalescence and decreased blood loss over open prostatectomy, little objective data is available regarding postoperative pain/discomfort and use of analgesic medications after RARP. We sought to examine these parameters in a contemporary cohort. PATIENTS AND METHODS: From 2011 to 2013, patients undergoing RARP were prospectively enrolled in a study to examine various pain parameters and carefully monitor opiate and other analgesic medication use while the patient recovered in the hospital. After discharge, the patients were asked to fill out a daily questionnaire regarding their pain parameters and self-report opiate usage. All questionnaires were based on the Wong-Baker FACES pain rating scale (0-10). Opiate dosages were converted to the approximate oral morphine sulfate equivalent dose (MSE). RESULTS: A total of 60 patients, mean age 61 years, were enrolled in the study, underwent RARP, and completed follow-up questionnaires. None had a history of chronic narcotic use. Intraoperative opiate use was 94.1 mg MSE. There were 73.3% who received immediate postoperative ketorolac. After RARP, the main source of pain/discomfort was abdominal/incisional, followed by urethral catheter related, penile, and bladder spasm-related discomfort. Abdominal pain was generally moderate for most patients and decreased significantly after about 4 days. Penile and urethral catheter-related discomfort was mild throughout the study period. Opiate analgesic medication use quickly decreased as the subjective pain scores improved. CONCLUSIONS: After RARP, most patients experience mild/moderate abdominal discomfort, which improves steadily over several days. There is also a quick decline in the average opiate pain medication use that corresponds to the subjective improvement in pain symptoms. This information is useful for clinicians counseling patients on the pain associated with RARP and can serve as a reference to compare the convalescence associated with the other options for treatment of patients with localized prostate cancer. PMID- 24400825 TI - Exploring the relationship between technology use, hearing help-seeking, and hearing aid outcomes in older adults. AB - OBJECTIVE: The objective of this study was to explore technology use and its relationship to help-seeking for hearing impairment (HI) and success with hearing aids among older adults. Previous research had suggested a link between higher levels of technology use and hearing aid success. DESIGN: General technology use was evaluated using a purposefully developed 25-item questionnaire. Twelve items related to everyday technology use (e.g. DVD player) and 13 related to advanced technology use (e.g. Bluetooth). STUDY SAMPLE: Four groups of older adults with HI participated in the study: (1) non-consulters (n=49), (2) consulters (n=62), (3) unsuccessful hearing aid owners (n=61), and (4) successful hearing aid owners (n=79). RESULTS: Preliminary analyses revealed a main effect in the use of everyday and advanced technology across the four participant groups. However, it was found that age and living arrangements accounted for most of the variance in reported everyday technology use (p=.030; p=.029, respectively) and age and gender accounted for the variance in reported advanced technology use (p<.001; p=.040, respectively). For everyday technology, an increase in age and living alone were associated with decreased technology use and for advanced technology use, age and female gender were associated with decreased technology use. CONCLUSIONS: Although we hypothesized that technology use would be less amongst non-consulters and unsuccessful hearing aid owners, our findings did not support this prediction. Technology use did not vary by group membership once the covariates of age, gender, and living arrangements were accounted for. PMID- 24400826 TI - A 21-locus autosomal SNP multiplex and its application in forensic science. AB - To develop a cost-effective technique for single-nucleotide polymorphism (SNP) genotyping and improve the efficiency to analyze degraded DNA, we have established a novel multiplex system including 21-locus autosomal SNPs and amelogenin locus, which was based on allele-specific amplification (ASA) and universal reporter primers (URP). The target amplicons for each of the 21 SNPs arranged from 63 base pair (bp) to 192 bp. The system was tested in 539 samples from three ethnic groups (Han, Mongolian, and Zhuang population) in China, and the total power of discrimination (TPD) and cumulative probability of exclusion (CPE) were more than 0.99999999 and 0.98, respectively. The system was further validated with forensic samples and full profiles could be achieved from degraded DNA and 63 case-type samples. In summary, the multiplex system offers an effective technique for individual identification of forensic samples and is much more efficient in the analysis of degraded DNA compared with standard STR typing. PMID- 24400827 TI - Effects of CBRN decontaminants in common use by first responders on the recovery of latent fingerprints--assessment of the loss of ridge detail on glass. AB - Following a CBRN incident, first responders use decontamination procedures to reduce the risk of exposure. The effect of decontamination on forensic trace material has, however, not been fully examined. This study sought to evaluate the effect of five different physical or chemical decontamination materials on the recovery of latent fingerprints. Fingerprints were deposited on glass slides, decontaminated, and assessed on the presence of ridge detail. The results demonstrate that decontamination affects the quality of latent fingerprints substantially. On at least 61% of the fingerprints, a reduced amount of ridge detail was observed upon decontamination. Furthermore, development with cyanoacrylate appeared not to succeed anymore. Instead, the ability of vacuum metal deposition to successfully develop decontaminated fingerprints is demonstrated. The results from this study may contribute to an increased forensic awareness regarding decontamination and emphasize the necessity for further research into new item decontamination procedures or new forensic initiatives prior to decontamination. PMID- 24400828 TI - Optimized development of sebaceous fingermarks on nonporous substrates with conformal columnar thin films. AB - A form of physical vapor deposition, called the conformal-evaporated-film-by rotation (CEFR) method, was optimized for the conformal deposition of columnar thin films (CTFs) on sebaceous fingermarks. Relying on the surface topology of the fingermark, the CTF development technique is different from traditional development techniques. After the optimization of the development conditions, the CTF development technique was found to be superior to traditional development methods on several nonporous substrates: the smooth side of Scotch((r)) Multitask, Gorilla((r)) , and Scotch((r)) Duct tapes; clear and black soft plastics; stained and sealed walnut and cherry woods; partial bloody fingermarks on stainless steel; and discharged cartridge casings. It was equally as good as other development techniques on other substrates, but worse on a few. The optimization study is expected to assist in designing a mobile CEFR apparatus capable of on-scene development of fingermarks. PMID- 24400829 TI - Using spatial, temporal and evidence-status data to improve ballistic imaging performance. AB - Firearms identification imaging systems help solve crimes by comparing newly acquired images of cartridge casings or bullets to a database of images obtained from past crime scenes. We formulate an optimization problem that bases its matching decisions not only on the similarity between pairs of images, but also on the time and spatial location of each new acquisition and each database entry. The objective is to maximize the detection probability subject to a constraint on the false positive rate. We use data on all cartridge casings matches detected in Israel during 2006-2008 to estimate most of the model parameters. We estimate matching accuracy from two different studies and predict that the optimal use of extraneous information would increase the detection probability from 0.931 to 0.987 and from 0.707 to 0.844, respectively. These improvements are achieved by favoring pairs of images that are closer together in space and time. PMID- 24400830 TI - Identifying diagonal cutter marks on thin wires using 3D imaging. AB - We present work on matching 2-mm-thick wires using optical 3D imaging methods. Marks on such small surfaces are difficult to match using a comparison microscope as this 2D imaging method does not provide height data about the sample surface. Moreover, these 2D microscopy images may be affected by illumination. Hence, the reference and investigated sample should be present at the same time. We employed scanning white light interferometry and confocal microscopy to provide quantitative 3D profiles for reliable comparison of samples that are unavailable for simultaneous analysis. We show that 3D profiling offers a solution by allowing illumination-independent sample comparison. We correctly identified 74 of 80 profiles using consecutive matching striae (CMS) criteria, and we were able to match samples based on profiles measured using different 3D imaging devices. The results suggest that the used methods allow matching cutter marks on thin wires, which has been difficult previously. PMID- 24400831 TI - Commentary on: Pressman MR, Caudill DS. Alcohol-induced blackout as a criminal defense or mitigating factor: an evidence-based review and admissibility as scientific evidence. J Forensic Sci 2013;58(4):932-40. PMID- 24400832 TI - Secretome analysis of human mesenchymal stem cells undergoing chondrogenic differentiation. AB - Human mesenchymal stem cells (hMSCs) can be triggered to differentiate toward chondrocytes and thus harbor great therapeutic potential for the repair of cartilage defects in osteoarthritis (OA) and other articular diseases. However, the molecular mechanisms underlying the chondrogenesis process are still in part unknown. In this work, we followed a double-stable isotope labeling by amino acids in cell culture (SILAC) strategy to evaluate the quantitative modulation of the secretome of stem cells isolated from bone marrow (hBMSCs) during the first steps of their chondrogenic differentiation. Analysis by LC-ESI-MS/MS led to the identification of 221 proteins with a reported extracellular localization. Most of them were characteristic of cartilage extracellular matrix, and 34 showed statistically significant quantitative alterations during chondrogenesis. These include, among others, cartilage markers such as Proteoglycan 4 or COMP, anticatabolic markers (TIMP1), reported markers of cartilage development (Versican), and a suggested marker of chondrogenesis, CRAC1. Altogether, our work demonstrates the usefulness of secretome analysis for understanding the mechanisms responsible for cartilage matrix formation, and it reports a panel of extracellular markers potentially useful for the evaluation of tissue development in cell therapy- or tissue engineering-based approaches for cartilage repair. PMID- 24400833 TI - Controlled Epstein-Barr virus reactivation after allogeneic transplantation is associated with improved survival. AB - Epstein-Barr virus reactivation (EBV-R) frequently occurs in patients having allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the impact of controlled EBV-R on survival of 190 patients (114M/76F, median age: 51 yr, range 18-69), having HSCT for hematological malignancies (105 acute leukemias and myelodysplasias, 71 lymphoproliferative disorders, 14 others). Overall survival (OS) and progression-free survival (PFS) were compared between patients with and without EBV-R. Of 138, patients had reduced-intensity conditioning regimen. Various stem cell sources (141 PB, 33 umbilical cord blood and 16 bone marrow) were used. Patients with EBV-R had longer PFS and OS than those without EBV-R: PFS at 2 yr 69% vs. 51% and at 5 yr 47% vs. 38% (P < 0.04); OS at 2 yr 76% vs. 64% and at 5 yr 63% vs. 47%) (P < 0.001). The use of rituximab had no impact on OS and PFS, but it reduced the intensity of GVHD, despite the fact that TRM was not significantly different between the two groups of patients. So, rituximab may have an additional effect to other factors on PFS and OS. In multivariate analysis, antithymocyte globulin administration was not a significant factor for PFS (P = 0.68) and for OS (P = 0.81). Circulating NK cells were significantly increased by 22% (P = 0.03) in EBV-R patients with no differences for other parameters. Controlled EBV-R in the setting of HSCT is associated with better OS and PFS, with a significant increase in circulating NK cells. PMID- 24400834 TI - Anti-hepatitis C virus dinorditerpenes from the roots of Flueggea virosa. AB - Along with four known terpenoids (1-4), eight new dinorditerpenes (5-12) were isolated and identified from the roots of Flueggea virosa. The absolute configurations of 4-6 were determined by the Mosher's method, and that of 5 was confirmed by single-crystal X-ray diffraction analysis. Using the hepatitis C virus cell culture infection system, compounds 1, 3, 11, and 12 exhibited significant anti-HCV activity with EC50 values of 5.6, 5.0, 7.5, and 6.6 MUM, respectively. Compounds 11 and 12 were nontoxic toward the tested Huh7.5 cell lines. PMID- 24400835 TI - Leaf surface wax is a source of plant methane formation under UV radiation and in the presence of oxygen. AB - The terrestrial vegetation is a source of UV radiation-induced aerobic methane (CH4 ) release to the atmosphere. Hitherto pectin, a plant structural component, has been considered as the most likely precursor for this CH4 release. However, most of the leaf pectin is situated below the surface wax layer, and UV transmittance of the cuticle differs among plant species. In some species, the cuticle effectively absorbs and/or reflects UV radiation. Thus, pectin may not necessarily contribute substantially to the UV radiation-induced CH4 emission measured at surface level in all species. Here, we investigated the potential of the leaf surface wax itself as a source of UV radiation-induced leaf aerobic CH4 formation. Isolated leaf surface wax emitted CH4 at substantial rates in response to UV radiation. This discovery has implications for how the phenomenon should be scaled to global levels. In relation to this, we demonstrated that the UV radiation-induced CH4 emission is independent of leaf area index above unity. Further, we observed that the presence of O2 in the atmosphere was necessary for achieving the highest rates of CH4 emission. Methane formation from leaf surface wax is supposedly a two-step process initiated by a photolytic rearrangement reaction of the major component followed by an alpha-cleavage of the generated ketone. PMID- 24400836 TI - Probing the N-terminal beta-sheet conversion in the crystal structure of the human prion protein bound to a nanobody. AB - Prions are fatal neurodegenerative transmissible agents causing several incurable illnesses in humans and animals. Prion diseases are caused by the structural conversion of the cellular prion protein, PrP(C), into its misfolded oligomeric form, known as prion or PrP(Sc). The canonical human PrP(C) (HuPrP) fold features an unstructured N-terminal part (residues 23-124) and a well-defined C-terminal globular domain (residues 125-231). Compelling evidence indicates that an evolutionary N-terminal conserved motif AGAAAAGA (residues 113-120) plays an important role in the conversion to PrP(Sc). The intrinsic flexibility of the N terminal has hampered efforts to obtain detailed atomic information on the structural features of this palindromic region. In this study, we crystallized the full-length HuPrP in complex with a nanobody (Nb484) that inhibits prion propagation. In the complex, the prion protein is unstructured from residue 23 to 116. The palindromic motif adopts a stable and fully extended configuration to form a three-stranded antiparallel beta-sheet with the beta1 and beta2 strands, demonstrating that the full-length HuPrP(C) can adopt a more elaborate beta0 beta1-alpha1-beta2-alpha2-alpha3 structural organization than the canonical beta1 alpha1-beta2-alpha2-alpha3 prion-like fold. From this structure, it appears that the palindromic motif mediates beta-enrichment in the PrP(C) monomer as one of the early events in the conversion of PrP(C) into PrP(Sc). PMID- 24400837 TI - Knowledge of the patient as decision-making power: staff members' perceptions of interprofessional collaboration in challenging situations in psychiatric inpatient care. AB - Challenging situations in psychiatric inpatient settings call for interprofessional collaboration, but the roles and responsibilities held by members of different professions is unclear. The aim of this study was to describe staff members' perceptions of interprofessional collaboration in the context of challenging situations in psychiatric inpatient care. Prior to the study taking place, ethical approval was granted. Focus group interviews were conducted with 26 physicians, ward managers, psychiatric nurses, and nursing assistants. These interviews were then transcribed and analysed using qualitative content analysis. Results described participants' perceptions of shared responsibilities, profession-specific responsibilities and professional approaches. In this, recognising knowledge of the patient as decision-making power was understood to be a recurring theme. This is a delimited qualitative study that reflects the specific working conditions of the participants at the time the study was conducted. The findings suggest that nursing assistants are the most influential professionals due to their closeness to and first-hand knowledge of patients. The results also point to the possibility of other professionals gaining influence by getting closer to patients and utilising their professional knowledge, thus contributing to a more person-centred care. PMID- 24400838 TI - Does clinical teacher training always improve teaching effectiveness as opposed to no teacher training? A randomized controlled study. AB - BACKGROUND: Teacher training may improve teaching effectiveness, but it might also have paradoxical effects. Research on expertise development suggests that the integration of new strategies may result in a temporary deterioration of performance until higher levels of competence are reached. In this study, the impact of a clinical teacher training on teaching effectiveness was assessed in an intensive course in emergency medicine. As primary study outcome students' practical skills at the end of their course were chosen. METHODS: The authors matched 18 clinical teachers according to clinical experience and teaching experience and then randomly assigned them to a two-day-teacher training, or no training. After 14 days, both groups taught within a 12-hour intensive course in emergency medicine for undergraduate students. The course followed a clearly defined curriculum. After the course students were assessed by structured clinical examination (SCE) and MCQ. The teaching quality was rated by students using a questionnaire. RESULTS: Data for 96 students with trained teachers, and 97 students with untrained teachers were included. Students taught by untrained teachers performed better in the SCE domains 'alarm call' (p < 0.01) and 'ventilation' (p = 0.01), while the domains 'chest compressions' and 'use of automated defibrillator' did not differ. MCQ scores revealed no statistical difference. Overall, teaching quality was rated significantly better by students of untrained teachers (p = 0.05). CONCLUSIONS: At the end of a structured intensive course in emergency medicine, students of trained clinical teachers performed worse in 2 of 4 practical SCE domains compared to students of untrained teachers. In addition, subjective evaluations of teaching quality were worse in the group of trained teachers. Difficulties in integrating new strategies in their teaching styles might be a possible explanation. PMID- 24400839 TI - Di-MU-oxo dimetal core of Mn(IV) and Ti(IV) as a linker between two chiral salen complexes leading to the stereoselective formation of different M- and P-helical structures. AB - Because of restricted rotational freedom along the metal-metal axis, a di-MU-oxo dimetal core could be an excellent building block to create dinuclear compounds with well-defined stereochemistry, but their stereoselective synthesis remains a challenge. We herein report the formation of di-MU-oxo dimanganese(IV) complexes with tetradentate salen ligands bearing different degrees of steric bulk, in order to study stereochemical aspects of the dimerization reaction that potentially generates multiple stereoisomers. X-ray crystallography shows that the di-MU-oxo dimanganese(IV) complex with salen, where salen is (R,R)-N,N' bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine, adopts a unique structure in which two salen complexes are arranged in an M-helical fashion. According to the solution study using (1)H, (2)H NMR, and circular dichroism spectroscopies, the dimerization reaction is highly diastereoselective in the presence of the tert-butyl group at the 3/3' position as a determinant steric factor. In contrast, the di-MU-oxo dititanium(IV) complex with the same salen ligand was previously reported to afford an opposite P-helical dimer. The present DFT study clarifies that a less-covalent Ti-O bonding causes a distortion of the di-MU-oxo dititanium(IV) core structure, generating a completely different framework for interligand interaction. The present study provides a solid basis to understand the stereochemistry for the formation of the di-MU-oxo dimetal core. PMID- 24400840 TI - Heat generated during seating of dental implant fixtures. AB - Frictional heat can be generated during seating of dental implants into a drill prepared osteotomy. This in vitro study tested the heat generated by implant seating in dense bovine mandible ramus. A thermocouple was placed approximately 0.5 mm from the rim of the osteotomy during seating of each dental implant. Four diameters of implants were tested. The average temperature increases were 0.075 degrees C for the 5.7-mm-diameter implant, 0.97 degrees C for the 4.7-mm-diameter implant, 1.4 degrees C for the 3.7-mm-diameter implant, and 8.6 degrees C for the 2.5-mm-diameter implant. The results showed that heat was indeed generated and a small temperature rise occurred, apparently by the friction of the implant surface against the fresh-cut bone surface. Bone is a poor thermal conductor. The titanium of the implant and the steel of the handpiece are much better heat conductors. Titanium may be 70 times more heat conductive than bone. The larger diameter and displacement implant may act as a heat sink to draw away any heat produced from the friction of seating the implant at the bone-implant interface. The peak temperature duration was momentary, and not measured, but this was approximately less than 1 second. Except for the 2.5-mm-diameter implants, the temperature rises and durations were found to be below those previously deemed to be detrimental, so no clinically significant osseous damage would be expected during dental implant fixture seating of standard and large-diameter-sized implants. A 2.5-mm implant may generate detrimental heat during seating in nonvital bone, but this may be clinically insignificant in vital bone. The surface area and thermal conductivity are important factors in removing generated heat transfer at the bone-implant interface. The F value as determined by analysis of variance was 69.22, and the P value was less than .0001, demonstrating significant differences between the groups considered as a whole. PMID- 24400841 TI - Non-invasive imaging of carotid arterial restenosis using 3T cardiovascular magnetic resonance. AB - BACKGROUND: Restenosis of the carotid artery is common following carotid endarterectomy, but analysis of lesion composition has mostly been based on histological study of explanted restenotic lesions. This study investigated the ability of 3T cardiovascular magnetic resonance (CMR) to determine the components of recurrent carotid artery disease and examined whether these differed from primary atherosclerotic plaque. METHODS: 50 patients underwent 3T CMR of both carotid arteries using a standard multicontrast protocol: time-of-flight (TOF), T1-weighted (T1W), T2-weighted (T2W), and PD-weighted (PDW) Turbo-Spin-Echo (TSE) sequences. 25 patients had previously undergone carotid endarterectomy (mean time since surgery 1580 days, range 45-6560 days), and 25 with primary asymptomatic atherosclerotic plaques served as controls. Two experienced reviewers analysed the multicontrast CMR images according to the presence or absence of major plaque features and assigned an overall classification type. RESULTS: In patients with recurrent carotid disease following endarterectomy, the mean degree of restenosis was 51% (range 30-90%). Three distinct types of restenosis were identified: 5 patients (20%) showed CMR characteristics of fibro-atheromatous tissue, 11 patients (44%) had plaque features consistent with possible myointimal (fibromuscular) hyperplasia, and 6 patients (24%) had recurrent plaque suggestive of further lipid accumulation. Three patients (12%) showed evidence of post surgical dissection of the carotid intima. Compared to primary atherosclerotic plaques, restenotic plaques were more likely to contain fibro-atheromatous tissue (p = 0.05) and smooth muscle (p < 0.01), and less likely to contain lipid (p < 0.01). Composition did not differ significantly between patients with early and late restenosis. CONCLUSIONS: As defined by CMR, restenotic lesions of the carotid artery fall into three distinct types and differ in composition from primary atherosclerotic plaques. If validated by subsequent histological studies, these findings could suggest a role for CMR in detecting high-risk (i.e. lipid rich) restenotic lesions. PMID- 24400842 TI - Factors predicting failure of AV "fistula first" policy in the elderly. AB - An arteriovenous fistula (AVF) is the preferential hemodialysis (HD) access. The goal of this study was to identify factors associated with pre-dialysis AVF failure in an elderly HD population. We used United States Renal Data System + Medicare claims data to identify patients >= 67 years old who had an AVF as their initial vascular access placed pre-dialysis. Failure of the AVF to be used for initial HD, was used as the outcome. Logistic regression model was used to identify factors associated with AVF failure. The study cohort consisted of 20,360 subjects (76.2 +/- 6.02 year old, 58.5% men). Forty-eight percent of patients initiated dialysis using an AVF, while 52% used a catheter or an AVG. The following variables found to be associated with AVF failure when an AVF was created at least 4 months pre-HD initiation: older age (odds ratio [OR] 1.01; 95% confidence interval [CI] 1.00-1.02), female gender (OR 1.69; 95% CI 1.55-1.83), black race (OR 1.41; 95% CI 1.26-1.58), history of diabetes (OR 1.22; 95% CI 1.06 1.39), cardiac failure (OR 1.26; 95% CI 1.15-1.37), and shorter duration of pre end-stage renal disease (ESRD) nephrology care (OR for a nephrology care of less than 6 months prior to ESRD of 1.22 compared with a pre-ESRD nephrology follow up of more than 12 months; 95% CI 1.07-1.38). OR for AVF failure for the entire cohort showed similar findings. In an elderly HD population, there is an association of older age, female gender, black race, diabetes, cardiac failure and shorter pre-ESRD nephrology care with predialysis AVF failure. PMID- 24400843 TI - Effect of oxidation of dietary proteins with performic acid on true ileal amino acid digestibility as determined in the growing rat. AB - The study examined the impact of oxidation with performic acid on the true ileal amino acid digestibility (TIAAD) of seven dietary protein sources. TIAAD of both the unoxidized and oxidized protein sources was determined in the growing rat and compared. After oxidation, TIAAD was 30 and 58% higher across amino acids (P < 0.001) for the more poorly digestible protein sources, zein and blood meal respectively, 6-16% lower (P < 0.05) for the more highly digestible protein sources (casein, soy protein isolate, and beef muscle protein), and generally unchanged (<2% difference) for the more moderately digested protein sources (lactalbumin and gelatin). Overall, the change in TIAAD after oxidation was negatively correlated (P < 0.001, r = -0.90) with the TIAAD prior to oxidation, most likely as a result of the balance between two processes, protein denaturation resulting in increased digestion and indigestible limit peptide formation resulting in decreased digestion. PMID- 24400845 TI - Entropy contribution toward micelle-driven deintercalation of drug-DNA complex. AB - Micelle-assisted "deintercalation" of intercalated drug/mutagen molecules from DNA is a well-established phenomenon; however, the driving energy cost for such a process is still not properly understood. In the present contribution, we have estimated the various energetic parameters for the SDS micelle-assisted deintercalation of a model DNA intercalator phenosafranine (PSF) using isothermal titration calorimetry (ITC) measurement. Both steady-state and picosecond resolved fluorescence measurements provide strong evidence for the relocation of PSF molecules from the DNA interior to the micellar interface at an SDS concentration above cmc. The overall deintercalation process has been found to be enthalpy-wise forbidden (endothermic); however, it is strongly favored by a high positive entropy change, which can be correlated with the change in the associated hydration structure at the macromolecular interface. PMID- 24400844 TI - Selenium induces a multi-targeted cell death process in addition to ROS formation. AB - Selenium compounds inhibit neoplastic growth. Redox active selenium compounds are evolving as promising chemotherapeutic agents through tumour selectivity and multi-target response, which are of great benefit in preventing development of drug resistance. Generation of reactive oxygen species is implicated in selenium mediated cytotoxic effects on cancer cells. Recent findings indicate that activation of diverse intracellular signalling leading to cell death depends on the chemical form of selenium applied and/or cell line investigated. In the present study, we aimed at deciphering different modes of cell death in a single cell line (HeLa) upon treatment with three redox active selenium compounds (selenite, selenodiglutathione and seleno-DL-cystine). Both selenite and selenodiglutathione exhibited equipotent toxicity (IC50 5 MUM) in these cells with striking differences in toxicity mechanisms. Morphological and molecular alterations provided evidence of necroptosis-like cell death in selenite treatment, whereas selenodiglutathione induced apoptosis-like cell death. We demonstrate that selenodiglutathione efficiently glutathionylated free protein thiols, which might explain the early differences in cytotoxic effects induced by selenite and selenodiglutathione. In contrast, seleno-DL-cystine treatment at an IC50 concentration of 100 MUM induced morphologically two distinct different types of cell death, one with apoptosis-like phenotype, while the other was reminiscent of paraptosis-like cell death, characterized by induction of unfolded protein response, ER-stress and occurrence of large cytoplasmic vacuoles. Collectively, the current results underline the diverse cytotoxic effects and variable potential of redox active selenium compounds on the survival of HeLa cells and thereby substantiate the potential of chemical species-specific usage of selenium in the treatment of cancers. PMID- 24400846 TI - Study Protocol--Alcohol Management Plans (AMPs) in remote indigenous communities in Queensland: their impacts on injury, violence, health and social indicators and their cost-effectiveness. AB - BACKGROUND: In 2002/03 the Queensland Government responded to high rates of alcohol-related harm in discrete Indigenous communities by implementing alcohol management plans (AMPs), designed to include supply and harm reduction and treatment measures. Tighter alcohol supply and carriage restrictions followed in 2008 following indications of reductions in violence and injury. Despite the plans being in place for over a decade, no comprehensive independent review has assessed to what level the designed aims were achieved and what effect the plans have had on Indigenous community residents and service providers. This study will describe the long-term impacts on important health, economic and social outcomes of Queensland's AMPs. METHODS/DESIGN: The project has two main studies, 1) outcome evaluation using de-identified epidemiological data on injury, violence and other health and social indicators for across Queensland, including de identified databases compiled from relevant routinely-available administrative data sets, and 2) a process evaluation to map the nature, timing and content of intervention components targeting alcohol. Process evaluation will also be used to assess the fidelity with which the designed intervention components have been implemented, their uptake and community responses to them and their perceived impacts on alcohol supply and consumption, injury, violence and community health. Interviews and focus groups with Indigenous residents and service providers will be used. The study will be conducted in all 24 of Queensland's Indigenous communities affected by alcohol management plans. DISCUSSION: This evaluation will report on the impacts of the original aims for AMPs, what impact they have had on Indigenous residents and service providers. A central outcome will be the establishment of relevant databases describing the parameters of the changes seen. This will permit comprehensive and rigorous surveillance systems to be put in place and provided to communities empowering them with the best credible evidence to judge future policy and program requirements for themselves. The project will inform impending alcohol policy and program adjustments in Queensland and other Australian jurisdictions.The project has been approved by the James Cook University Human Research Ethics Committee (approval number H4967 & H5241). PMID- 24400847 TI - AchievemenT of target resting HEart rate on beta-blockers in patients with stable angiNA and hypertension (ATHENA) in routine clinical practice in Russia. AB - OBJECTIVES: The primary objective of this study was to establish the proportion of patients with stable angina and arterial hypertension on beta-blocker (BB) treatment reaching target resting heart rates (RHR) of 55-60 beats per min in clinical cardiology and general practice in Russia. Secondary objectives included the association between achievement of target RHR and mean BB doses, Seattle Angina Questionnaire (SAQ) scores and achievement of target blood pressure (BP) levels (systolic/diastolic BP <140/90 mmHg). RESEARCH DESIGN AND METHODS: ATHENA (AchievemenT of target resting HEart rate on beta-blockers in patients with stable angiNA and hypertension) was a non-interventional, cross-sectional, observational study conducted in 20 sites in Russia (NCT01321242). The study population comprised patients aged >=18 years with stable angina (class I-III) and primary hypertension, on BB treatment for >=2 months prior to enrollment. RESULTS: Of 399 study participants, 62 (15.5%; 95% confidence interval [CI]: 0.121 to 0.195) achieved target RHR. Clinical characteristics associated with significant differences between subgroups achieving and not achieving target RHR were systolic BP (131.1 vs 138.2 mmHg, P = 0.006), diastolic BP (78.6 vs 83.5 mmHg, P < 0.001) and frequency of nitroglycerin administration (1.5% vs 3.0%, P = 0.045). Most patients were taking bisoprolol (48.9%) and metoprolol (36.1%), with mean daily doses of 5.5 mg and 73.7 mg, respectively. Median SAQ scores were: 52.8 physical limitation, 50.0 angina stability, 60.0 angina frequency, 75.0 treatment satisfaction, 50.0 disease perception (quality of life) and 59.6 total score, with no significant differences between subgroups. Patients achieving target RHR were significantly more likely also to achieve target BP, compared with patients not achieving target RHR (72.6% vs 53.4%; P = 0.005; odds ratio: 2.309; 95% CI: 1.270 to 4.197). CONCLUSION: In a Russian population with stable angina and hypertension on BB treatment, RHR control was suboptimal. ClinicalTrials.gov identifier: NCT01321242. PMID- 24400848 TI - Epidemiology of extrapulmonary tuberculosis in Brazil: a hierarchical model. AB - BACKGROUND: Although extrapulmonary tuberculosis (EPTB) is less frequent than Pulmonary Tuberculosis (PTB) and is a secondary target for national TB control programs, its significance has increased worldwide during the HIV epidemic. The objective of this study was to examine the epidemiology of EPTB in Brazil between 2007 and 2011. METHODS: Cross-sectional study involving all cases of TB reported to the Brazilian Notifiable Diseases Surveillance System (Sistema de Informacoes de Agravo de Notificacao - SINAN) in Brazil between 2007 and 2011. Sociodemographic and clinical characteristics of patients with exclusively PTB and exclusively EPTB were compared. Following analysis with Pearson's chi-square test, variables with p < 0.05 were included in a hierarchical regression model. Variables with p < 0.05 in the corresponding level were kept in the model. RESULTS: A total of 427,548 cases of TB were included. Of these, 356,342 cases (83.35%; 95% confidence interval (CI) 83.23% - 83.45%) were PTB, 57,217 (13.37%; 95% CI 13.28% - 13.48%) were EPTB, 13,989 (3.27%; 95% CI 3.21% - 3.32%) were concurrent pulmonary and extrapulmonary TB. Patients with EPTB were mainly white (16.7%), and most (29.1%) patients had five to eight years of education. Among comorbidities, HIV infection was prominent (OR 2.15; 95% CI 2.09 - 2.21), although the proportion of cases awaiting test results or untested was high (39%). Ethanol use (OR 0.45; 95% CI 0.43 - 0.46), diabetes mellitus (OR 0.54; 95% CI 0.51 - 0.57) and mental illness (OR 0.88; 95% CI 0.82 - 0.95) were associated with PTB. CONCLUSIONS: Thirteen percent of patients diagnosed with TB in Brazil have only EPTB. More effective diagnostic strategies and control measures are needed to reduce the number of cases of extrapulmonary TB in Brazil. PMID- 24400850 TI - 1910s' brains revisited. Cortical complexity in early 20th century patients with intellectual disability or with dementia praecox. AB - OBJECTIVE: The idea of cortical surface anomalies in subjects with intellectual disability (mental retardation) and schizophrenia can be traced back to early 20th century qualitative observations. Since it is unknown whether modern quantitative measures of cortical complexity and folding would retrieve those early empirical observations, we measured fractal dimension and sulcal span index in photographs of human brains taken in the 1910's. METHOD: Brain photographs were compared between 36 patients with mental retardation and 21 patients with dementia praecox for the fractal dimension and sulcal span index. Also, a mental retardation subgroup with no-or-non-understandable speech (n = 12) was compared with a subgroup with comprehensible speech (n = 23). RESULTS: Mental retardation group had a lower whole-brain fractal dimension than dementia praecox, and a higher sulcal span index in left posterior cortex. The mental retardation subgroup with comprehensible speech had a lower fractal dimension in left hemisphere than the subgroup with no-or-non-understandable speech and a lower sulcal index in left posterior cortex. CONCLUSION: Measures of cortical complexity and folding suggest differences between mental retardation and dementia praecox, and regional variations according to language abilities in mental retardation. The findings provide a unique picture of cortical surface changes in their original untreated form, one century ago. PMID- 24400851 TI - Virus epidemics can lead to a population-wide spread of intragenomic parasites in a previously parasite-free asexual population. AB - Sexual reproduction is problematic to explain due to its costs, most notably the twofold cost of sex. Yet, sex has been suggested to be favourable in the presence of proliferating intragenomic parasites given that sexual recombination provides a mechanism to confine the accumulation of deleterious mutations. Kraaijeveld et al. compared recently the accumulation of transposons in sexually and asexually reproducing lines of the same species, the parasitoid wasp Leptopilina clavipes. They discovered that within asexually reproducing wasps, the number of gypsy-like retrotransposons was increased fourfold, whereas other retrotransposons were not. Interestingly, gypsy-like retrotransposons are closely related to retroviruses. Endogenous retroviruses are retroviruses that have integrated to the germ line cells and are inherited thereafter vertically. They can also replicate within the genome similarly to retrotransposons as well as form virus particles and infect previously uninfected cells. This highlights the possibility that endogenous retroviruses could play a role in the evolution of sexual reproduction. Here, we show with an individual-based computational model that a virus epidemic within a previously parasite-free asexual population may establish a new intragenomic parasite to the population. Moreover and in contrast to other transposons, the possibility of endogenous viruses to maintain a virus epidemic and simultaneously provide resistance to individuals carrying active endogenous viruses selects for the presence of active intragenomic parasites in the population despite their deleterious effects. Our results suggest that the viral nature of certain intragenomic parasites should be taken into account when sex and its benefits are being considered. PMID- 24400854 TI - Single-molecule femtochemistry: molecular imaging at the space-time limit. AB - Through a combination of light and electron probes, it may be possible to record single-molecule dynamics with simultaneous sub-Angstrom spatial and femtosecond temporal resolution. Single-molecule femtochemistry is becoming a realistic prospect through a melding of laser spectroscopy and electron microscopy techniques. The paper by Lee et al. in this issue of ACS Nano takes a significant step toward chemical imaging at the space-time limit of chemical processes. By imaging electroluminescence spectra of single porphyrin molecules with submolecular resolution, the authors extract the implicit femtosecond dynamics of the coupled electron orbital-molecular skeletal motion triggered by a reduction oxidation scattering process. PMID- 24400855 TI - Primary obstructive megaureter: the role of high pressure balloon dilation. AB - BACKGROUND AND PURPOSE: There is a growing interest in minimally invasive treatment of primary obstructive megaureter (POM) in children. The absence of long-term follow-up data, however, makes it difficult to establish the indication for an endoscopic approach. The aim of our study is to determine the long-term efficacy of endourologic high-pressure balloon dilation of the vesicoureteral junction (VUJ) in children with POM that necessitates surgical treatment. METHODS: We retrospectively reviewed the clinical records from children with POM who were treated with endourologic high-pressure balloon dilation of the VUJ from March 2003 to April 2010. To determine the long-term, a cohort study was conducted in November 2011. Endourologic dilation of the VUJ was performed with a semicompliant high-pressure balloon (2.7 FG) with a minimum balloon size of 3 mm, followed by placement of a Double-J stent. RESULTS: We have treated 29 (32 renal units, left [n=16], right [n=10] and bilateral [n=3]) children with a diagnosis of POM within this period. The median age at the time of the endourologic treatment was 4.04 months (range 1.6-39 months). In three cases, an open ureteral reimplantation was needed, in two cases because of intraoperative technical failure and postoperative Double-J stent migration in one patient. The 26 children (29 renal units) who had a successful endourologic dilation of the VUJ were followed with ultrasonography and MAG-3-Lasix (furosemide) studies that showed a progressive improvement of both the ureterohydronephrosis and drainage in the first 18 months in 20 patients (23 renal units) (69%). In two patients who were treated with a 3 mm balloon, a further dilation was needed, with an excellent outcome. The cohort study (at a median follow-up of 47 months) showed that in all patients who had a good outcome at the 18-month follow-up after endourologic balloon dilation remained asymptomatic with resolution of ureterohydronephrosis on the US and good drainage on the renogram, in the children with some persistent hydronephrosis. CONCLUSIONS: Our study shows that children with POM who were treated with high-pressure ballon dilation of the VUJ who have satisfactory appearance at 18 months maintain these results over time. PMID- 24400856 TI - Chronotype-dependent circadian rhythmicity of driving safety. AB - Among the factors associated with driving safety, sleep-related variables constitute a leading cause of road accidents. Circadian fluctuations of driver's somnolence has been previously linked to road safety. However, the role of chronotype in this relationship has been poorly investigated. Thus, the aim of the present work was to address whether driving performance is influenced by circadian patterns, in turn modulated by the driver's chronotype and the time of day (i.e. synchrony effect). We assessed 47 healthy young adults with specific chronotypes in several simulated driving sessions, both in the morning and in the evening. We collected driving performance data, along with self-reported levels of activation prior to each driving session and other sleep-related variables. Participants drove less safely when testing times took place outside their optimal time of day, as determined by their chronotype and confirmed by self reported levels of activation. These differences were more pronounced in the morning, when morning types shown a better driving performance. Our results suggest that chronotype plays an important role as a modulator of the relationship between the time of day and driving safety. Therefore, it is necessary to acknowledge this variable in theoretical models of driving behavior, and for the improvement of occupational accidents prevention programs. PMID- 24400857 TI - The yurt: a mobile home of nomadic populations dwelling in the Mongolian steppe is still used both as a sun clock and a calendar. AB - The yurt is the traditional home of the nomadic Turkmen, the Kyrgyz, the Kazakhs, the Uzbeks, the Kalmyks, the Buryats and the Mongolians. As the impact of the western modern world, in terms of technological and behavioural changes, is slower than anywhere else, the use of the yurt is widespread in the Mongolian steppes, where nomadic life has been maintaining its traditional behaviour for at least 800 years. The Mongolian yurt entrance faces south and combines spatial and functional properties. An open circular hole named the "toon" can be found at the centre of the roof. On sunny days, a ray of sunshine revolves around its inner wall. Depending on the season, the light first appears between 5:40 am and 7:40 am and moves around the different inner walls (khana). The sundial enables the nomads to schedule their daily activities such as the herd milking and its processing, the drying of dung for fuel, the prayers and performing fighting games. The angle of the sun's light coming through the toon and lighting a space on the floor by the yurt entrance can vary according to the time of the year. Such clues are used to guess what time it is and which month it is, and thus help the Mongolians decide whether or not to start travelling from summer to winter pastures. The Mongolians pay special attention to the transhumances, seasonal movements based on a specific time, in order to prevent harming the livestock during the harsh Mongolian winter, and to choose the right time to move the yurt. They also pay attention not to offend the spirits of the wind, the earth and the sky. Regarded as the warrant of their ancestors' cultural traditions, nomadic people remain faithful to their heritage and respect their surrounding environment. Thus, the yurt has remained their reference to time in the heart of the Mongolian steppes. PMID- 24400858 TI - Polyandric acid A, a clerodane diterpenoid from the Australian medicinal plant Dodonaea polyandra, attenuates pro-inflammatory cytokine secretion in vitro and in vivo. AB - Dodonaea polyandra is a medicinal plant used traditionally by the Kuuku I'yu (Northern Kaanju) indigenous people of Cape York Peninsula, Australia. The most potent of the diterpenoids previously identified from this plant, polyandric acid A (1), has been examined for inhibition of pro-inflammatory cytokine production and other inflammatory mediators using well-established acute and chronic mouse ear edema models and in vitro cellular models. Topical application of 1 significantly inhibited interleukin-1beta production in mouse ear tissue in an acute model. In a chronic skin inflammation model, a marked reduction in ear thickness, associated with significant reduction in myeloperoxidase accumulation, was observed. Treatment of primary neonatal human keratinocytes with 1 followed by activation with phorbol ester/ionomycin showed a significant reduction in IL-6 secretion. The present study provides evidence that the anti-inflammatory properties of 1 are due to inhibition of pro-inflammatory cytokines associated with skin inflammation and may be useful in applications for skin inflammatory conditions including psoriasis and dermatitis. PMID- 24400859 TI - Effect of genotype on pulmonary hypertension risk in patients with thalassemia. AB - INTRODUCTION: Pulmonary hypertension is one of the major complications in patients with non-transfusion-dependent thalassemia (NTDT). Patients with NTDT have distinct genetic subgroups. Therefore, the effects of different genotype groups on pulmonary hypertension risk in patients with NTDT were assessed. METHODS: A cross-sectional study was conducted in patients with NTDT aged >= 10 yr old at Srinagarind University Hospital and Udonthani Hospital, Thailand. Pulmonary hypertension risk was defined as peak tricuspid regurgitation velocity > 2.9 m/s by trans-thoracic echocardiography. Clinical characteristics and laboratory data that literature has indicated as risk factors for pulmonary hypertension were collected. The effect of genotype group on pulmonary hypertension risk was evaluated by using multivariate logistic regression analysis. RESULTS: Of 219 patients, pulmonary hypertension risk was found in 24 patients (10.96%). All patients were categorized into two groups according to genetic data that included: (i) beta-thalassemia (139, 63.5%), (ii) alpha thalassemia and combined alpha and beta-thalassemia (80, 36.5%). Genotype groups were statistically and significantly associated with pulmonary hypertension risk based on the adjusted odds ratios after adjustment for other factors. Patients with beta-thalassemia had a statistically significant higher risk for pulmonary hypertension risk (odds ratio = 9.47, P = 0.036) compared to patients with alpha thalassemia and patients with combined alpha and beta-thalassemia. CONCLUSION: The genotype group is an independent risk factor for pulmonary hypertension in patients with NTDT. Echocardiography should be routinely recommended for all patients with beta-thalassemia. Routine screening in patients with alpha thalassemia and combined alpha and beta-thalassemia, however, may not be necessary or should focus on the older population. PMID- 24400860 TI - Sex differences in the ability to recognise non-verbal displays of emotion: a meta-analysis. AB - The present study aimed to quantify the magnitude of sex differences in humans' ability to accurately recognise non-verbal emotional displays. Studies of relevance were those that required explicit labelling of discrete emotions presented in the visual and/or auditory modality. A final set of 551 effect sizes from 215 samples was included in a multilevel meta-analysis. The results showed a small overall advantage in favour of females on emotion recognition tasks (d=0.19). However, the magnitude of that sex difference was moderated by several factors, namely specific emotion, emotion type (negative, positive), sex of the actor, sensory modality (visual, audio, audio-visual) and age of the participants. Method of presentation (computer, slides, print, etc.), type of measurement (response time, accuracy) and year of publication did not significantly contribute to variance in effect sizes. These findings are discussed in the context of social and biological explanations of sex differences in emotion recognition. PMID- 24400861 TI - Comparison of the sensitivity of the UKCAT and A Levels to sociodemographic characteristics: a national study. AB - BACKGROUND: The UK Clinical Aptitude Test (UKCAT) was introduced to facilitate widening participation in medical and dental education in the UK by providing universities with a continuous variable to aid selection; one that might be less sensitive to the sociodemographic background of candidates compared to traditional measures of educational attainment. Initial research suggested that males, candidates from more advantaged socioeconomic backgrounds and those who attended independent or grammar schools performed better on the test. The introduction of the A* grade at A level permits more detailed analysis of the relationship between UKCAT scores, secondary educational attainment and sociodemographic variables. Thus, our aim was to further assess whether the UKCAT is likely to add incremental value over A level (predicted or actual) attainment in the selection process. METHODS: Data relating to UKCAT and A level performance from 8,180 candidates applying to medicine in 2009 who had complete information relating to six key sociodemographic variables were analysed. A series of regression analyses were conducted in order to evaluate the ability of sociodemographic status to predict performance on two outcome measures: A level 'best of three' tariff score; and the UKCAT scores. RESULTS: In this sample A level attainment was independently and positively predicted by four sociodemographic variables (independent/grammar schooling, White ethnicity, age and professional social class background). These variables also independently and positively predicted UKCAT scores. There was a suggestion that UKCAT scores were less sensitive to educational background compared to A level attainment. In contrast to A level attainment, UKCAT score was independently and positively predicted by having English as a first language and male sex. CONCLUSIONS: Our findings are consistent with a previous report; most of the sociodemographic factors that predict A level attainment also predict UKCAT performance. However, compared to A levels, males and those speaking English as a first language perform better on UKCAT. Our findings suggest that UKCAT scores may be more influenced by sex and less sensitive to school type compared to A levels. These factors must be considered by institutions utilising the UKCAT as a component of the medical and dental school selection process. PMID- 24400862 TI - Gastrointestinal involvement in granulomatosis with polyangiitis and microscopic polyangiitis: histological features and outcome. AB - AIM: Gastrointestinal (GI) involvement in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) is rare. METHOD: Medical charts of seven patients with GPA and MPA and GI involvement were reviewed regarding clinical presentation, outcome, diagnostic tools and therapy. Second, the cellular composition of the inflammatory infiltrate associated with the vascular lesions in histological samples (ileum, colon, rectum, duodenum) were investigated to identify possible treatment targets. Immunohistochemistry was done with antibodies against CD20, CD3 and CD34. Samples from a healthy control group (n = 15) were used for comparison. RESULTS: Mean age at onset of the first symptoms of vasculitis was 48 +/- 21.3 years. At time of diagnosis GI symptoms were present in five out of seven patients (71%) and occurred during relapse of the vasculitis in two patients (29%). All patients had abdominal pain, four of seven (57%) had an acute kidney injury and three patients required renal replacement therapy. At the time of diagnosis five of seven patients (71%) required surgery and mean Birmingham Vasculitis Activity Score (BVAS) on admission was high (26.3 +/- 7.7). Regarding outcome, one patient died due to gastrointestinal bleeding. Histological analysis showed significantly higher expression of CD3 in this patient compared to the control group (P = 0.02). Analysis of expression of CD20 and CD34 showed no statistically significant differences between patients with GPA and MPA with GI involvement compared to the control group. CONCLUSIONS: GI involvement in GPA and MPA is rare. Therapy directed at T cells might be an alternative treatment option. PMID- 24400863 TI - Two coexisting tank bromeliads host distinct algal communities on a tropical inselberg. AB - The tank bromeliads Aechmea aquilega (Salisb.) and Catopsis berteroniana (Schultes f.) coexist on a sun-exposed Neotropical inselberg in French Guiana, where they permit conspicuous freshwater pools to form that differ in size, complexity and detritus content. We sampled the algal communities (both eukaryotic and cyanobacterial taxa, including colourless forms) inhabiting either A. aquilega (n = 31) or C. berteroniana (n = 30) and examined differences in community composition and biomass patterns in relation to several biotic and abiotic variables. Chlorella sp. and Bumilleriopsis sp. were the most common taxa and dominated the algal biomass in A. aquilega and C. berteroniana, respectively. Using a redundancy analysis, we found that water volume, habitat complexity and the density of phagotrophic protozoa and collector-gatherer invertebrates were the main factors explaining the distribution of the algal taxa among the samples. Hierarchical clustering procedures based on abundance and presence/absence data clearly segregated the samples according to bromeliad species, revealing that the algal communities in the smaller bromeliad species were not a subset of the communities found in the larger bromeliad species. We conclude that, even though two coexisting tank bromeliad populations create adjacent aquatic habitats, each population hosts a distinct algal community. Hence, bromeliad diversity is thought to promote the local diversity of freshwater algae in the Neotropics. PMID- 24400864 TI - Influence of photoinduced electron transfer on lanthanide-based coordination polymer luminescence: a comparison between two pseudoisoreticular molecular networks. AB - The luminescent properties of two families of heteronuclear lanthanide-containing coordination polymers are compared. These families have general chemical formulas [Ln2-2xLn'2x(ip)3(H2O)9.6H2O]infinity and [Ln2 2xLn'2x(aip)2(H2O)10.(aip).4H2O]infinity where H2ip and H2aip stand for isophthalic acid and 5-amino-isophthalic acid, respectively, and where Ln and Ln' are one of the lanthanide ions between Sm(3+) and Dy(3+). Heteronuclear compounds that belong to each family are isostructural to the already reported homonuclear compounds [Gd2(ip)3(H2O)9.6H2O]infinity and [Eu2(aip)2(H2O)10.(aip).4H2O]infinity, respectively. These two crystal structures are very similar. However, despite similar chemical formulas, similar crystal structures, and similar hydration rates, these two families of compounds present very different luminescent properties that have thus been deeply investigated. This study demonstrates that these different optical behaviors can be attributed to the presence of a PET (photoinduced electron transfer) mechanism that is only present in the amino-isophthalate-containing coordination polymers. PMID- 24400865 TI - Feasibility of asymmetric stretch assessment in the ascending aortic wall with DENSE cardiovascular magnetic resonance. AB - BACKGROUND: Vessel diameter is the principal imaging parameter assessed clinically for aortic disease, but adverse events can occur at normal diameters. Aortic stiffness has been studied as an additional imaging-based risk factor, and has been shown to be an independent predictor of cardiovascular morbidity and all cause mortality. Reports suggest that some aortic pathology is asymmetric around the vessel circumference, a feature which would not be identified with current imaging approaches. We propose that this asymmetry may be revealed using Displacement Encoding with Stimulated Echoes (DENSE). The objective of this study is to investigate the feasibility of assessing asymmetric stretch in healthy and diseased ascending aortas using DENSE. METHODS: Aortic wall displacement was assessed with DENSE cardiovascular magnetic resonance (CMR) in 5 volunteers and 15 consecutive patients. Analysis was performed in a cross-sectional plane through the ascending aorta at the pulmonary artery. Displacement data was used to determine the wall stretch between the expanded and resting states of the aorta, in four quadrants around the aortic circumference. RESULTS: Analysis of variance (ANOVA) did not only show significant differences in stretch between groups of volunteers (p<0.001), but also significant differences in stretch along the circumference of the aorta (p<0.001), indicating an asymmetric stretch pattern. Furthermore, there is a significant difference in the asymmetry between volunteers and different groups of patients (p<0.01). CONCLUSIONS: Evaluation of asymmetric stretch is feasible in the ascending aorta with DENSE CMR. Clear differences in stretch are seen between patients and volunteers, with asymmetric patterns demonstrated around the aortic circumference. PMID- 24400866 TI - Clinicopathologic characteristics and prognosis of glycogen-rich clear cell carcinoma of the breast. AB - Glycogen-rich clear cell carcinoma (GRCC) of the breast is a rare type of breast carcinoma. Knowledge about the characteristics of this type is fragmentary, and the prognosis is on debate. In this study, we aimed to summarize the clinical, pathologic, and biologic characteristics of GRCC of the breast and analyze the survival. We reviewed the cases of breast cancer in our hospital between January 1999 and December 2009 and identified 28 patients as GRCC of the breast. The routine hematoxylin-eosin staining, periodic acid-Schiff (PAS) staining, and diastase PAS staining were performed on the tumor tissues. The expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2), Ki67 and P53 were evaluated by immunohistochemistry. Tumors with a HER-2 score of 2+ were confirmed by fluorescent in situ hybridization test. Each GRCC case, who had complete follow-up data, was compared with four cases of usual invasive ductal carcinomas as controls in the same database and matched with age, year of diagnosis, tumor size, nodal status, and immunophenotype. The chi-squared test and the Fisher's exact test were used to compare the characteristics of GRCC cases and controls. The univariate analysis was used to study the prognosis, and Kaplan-Meier method was used to compare the survival of two groups. The clinicopathologic and imaging features were analyzed in the GRCC cases. Tumor sizes ranged from 0.8 to 7.5 cm (mean, 3.2 cm). Thirteen cases (46.4%) had positive lymph nodes. The positivity of ER and PR was 61.5% (16 of 26). HER-2 was positive for three cases (12%). The positivity of Ki67 and P53 were 87.5% and 45.8%, respectively. Twenty-four cases were followed up from 19 to 158 months. The prognosis of GRCC of the breast was significantly related with the number of positive lymph nodes (p < 0.001), and patients with more than 10 positive lymph nodes were at high risk of recurrence or metastasis. There was no significant difference in overall survival (p = 0.547), and disease-free survival (p = 0.900) between GRCC of the breast and the usual invasive ductal carcinomas. GRCC of the breast may not have a worse survival. PMID- 24400867 TI - Challenges in hypertension: the haiti experience. PMID- 24400869 TI - Oxidation of cysteinesulfinic acid by hexachloroiridate(IV). AB - We report the results of an experimental study of the oxidation of cysteinesulfinic acid (CysSO2H) by [IrCl6](2-) in aqueous media at 25 degrees C in order to gain insight into the mechanisms of oxidation of alkylsulfinic acids by simple one-electron oxidants. When the reaction is performed with exclusion of O2 between pH 3 and 5, it is complete in several seconds. The products are [IrCl6](3-) and CysSO3H. Kinetic data obtained by stopped-flow UV-vis methods with [CysSO2H] ? [Ir(IV)]0 reveal the rate law to be -d[Ir(IV)]/dt = k[Ir(IV)](2)[CysSO2H]/[Ir(III)] with a negligible pH dependence. The value of k is (6.8 +/- 0.12) * 10(3) M(-1) s(-1) at MU = 0.1 M (NaClO4). A mechanism is inferred in which the first step is a rapid and reversible electron-transfer equilibrium between Ir(IV) and CysSO2(-) to form Ir(III) and CysSO2(*). The second step is the rate-limiting inner-sphere oxidation of CysSO2(*) by Ir(IV). Production of CysSO3H is proposed to occur through hydrolysis of an Ir(III)-bound sulfonyl chloride that is the immediate product of the inner-sphere second step. PMID- 24400868 TI - Arecoline-induced myofibroblast transdifferentiation from human buccal mucosal fibroblasts is mediated by ZEB1. AB - Oral submucous fibrosis (OSF) is considered as a pre-cancerous condition of the oral mucosa and is highly associated with habitual areca quid chewing. Arecoline is the major alkaloid in areca quid and is thought to be involved in the pathogenesis of OSF. Our previous studies have demonstrated that arecoline could induce epithelial-mesenchymal transition (EMT)-related factors in primary human buccal mucosal fibroblasts (BMFs). Therefore, we investigated the expression of zinc finger E-box binding homeobox 1 (ZEB1), which is a well-known transcriptional factor in EMT, in OSF tissues and its role in arecoline-induced myofibroblast transdifferentiation from BMFs. The expression of ZEB1, as well as the myofibroblast marker alpha-smooth muscle actin (alpha-SMA), was significantly increased in OSF tissues, respectively. With immunofluorescence analysis, arecoline induced the formation of alpha-SMA-positive stress fibres in BMFs expressing nuclear ZEB1. Arecoline also induced collagen contraction of BMFs in vitro. By chromatin immunoprecipitation, the binding of ZEB1 to the alpha-SMA promoter in BMFs was increased by arecoline. The promoter activity of alpha-SMA in BMFs was also induced by arecoline, while knockdown of ZEB1 abolished arecoline-induced alpha-SMA promoter activity and collagen contraction of BMFs. Long-term exposure of BMFs to arecoline induced the expression of fibrogenic genes and ZEB1. Silencing of ZEB1 in fibrotic BMFs from an OSF patient also suppressed the expression of alpha-SMA and myofibroblast activity. Inhibition of insulin-like growth factor receptor-1 could suppress arecoline-induced ZEB1 activation in BMFs. Our data suggest that ZEB1 may participate in the pathogenesis of areca quid-associated OSF by activating the alpha-SMA promoter and inducing myofibroblast transdifferentiation from BMFs. PMID- 24400870 TI - A longitudinal study of the impact of chronic psychological stress on health related quality of life and clinical biomarkers: protocol for the Australian Healthy Aging of Women Study. AB - BACKGROUND: Despite advancements in our understanding of the importance of stress reduction in achieving good health, we still only have limited insight into the impact of stress on cellular function. Recent studies have suggested that exposure to prolonged psychological stress may alter an individual's physiological responses, and contribute to morbidity and mortality. This paper presents an overview of the study protocol we are using to examine the impact of life stressors on lifestyle factors, health-related quality of life and novel and established biomarkers of stress in midlife and older Australian women.The primary aim of this study is to explore the links between chronic psychological stress on both subjective and objective health markers in midlife and older Australian women. The study examines the extent to which exposure frightening, upsetting or stressful events such as natural disasters, illness or death of a relative, miscarriage and relationship conflict is correlated with a variety of objective and subjective health markers. METHODS/DESIGN: This study is embedded within the longitudinal Healthy Aging of Women's study which has collected data from midlife and older Australian women at 5 yearly intervals since 2001, and uses the Allostastic model of women's health by Groer and colleagues in 2010. The current study expands the focus of the HOW study and will assess the impact of life stressors on quality of life and clinical biomarkers in midlife and older Australian women to explain the impact of chronic psychological stress in women. DISCUSSION: The proposed study hypothesizes that women are at increased risk of exposure to multiple or repeated stressors, some being unique to women, and the frequency and chronicity of stressors increases women's risk of adverse health outcomes. This study aims to further our understanding of the relationships between stressful life experiences, perceived quality of life, stress biomarkers, chronic illness, and health status in women. PMID- 24400871 TI - Apigenin in combination with Akt inhibition significantly enhances thyrotropin stimulated radioiodide accumulation in thyroid cells. AB - BACKGROUND: Selectively increased radioiodine accumulation in thyroid cells by thyrotropin (TSH) allows targeted treatment of thyroid cancer. However, the extent of TSH-stimulated radioiodine accumulation in some thyroid tumors is not sufficient to confer therapeutic efficacy. Hence, it is of clinical importance to identify novel strategies to selectively further enhance TSH-stimulated thyroidal radioiodine accumulation. METHODS: PCCl3 rat thyroid cells, PCCl3 cells overexpressing BRAF(V600E), or primary cultured tumor cells from a thyroid cancer mouse model, under TSH stimulation were treated with various reagents for 24 hours. Cells were then subjected to radioactive iodide uptake, kinetics, efflux assays, and protein extraction followed by Western blotting against selected antibodies. RESULTS: We previously reported that Akt inhibition increased radioiodine accumulation in thyroid cells under chronic TSH stimulation. Here, we identified Apigenin, a plant-derived flavonoid, as a reagent to further enhance the iodide influx rate increased by Akt inhibition in thyroid cells under acute TSH stimulation. Akt inhibition is permissive for Apigenin's action, as Apigenin alone had little effect. This action of Apigenin requires p38 MAPK activity but not PKC-delta. The increase in radioiodide accumulation by Apigenin with Akt inhibition was also observed in thyroid cells expressing BRAF(V600E) and in primary cultured thyroid tumor cells from TRbeta(PV/PV) mice. CONCLUSION: Taken together, Apigenin may serve as a dietary supplement in combination with Akt inhibitors to enhance therapeutic efficacy of radioiodine for thyroid cancer. PMID- 24400872 TI - Monoclonal antibodies raised against 167-180 aa sequence of human carbonic anhydrase XII inhibit its enzymatic activity. AB - Abstract Human carbonic anhydrase XII (CA XII) is a single-pass transmembrane protein with an extracellular catalytic domain. This enzyme is being recognized as a potential biomarker for different tumours. The current study was aimed to generate monoclonal antibodies (MAbs) neutralizing the enzymatic activity of CA XII. Bioinformatics analysis of CA XII structure revealed surface-exposed sequences located in a proximity of its catalytic centre. Two MAbs against the selected antigenic peptide spanning 167-180 aa sequence of CA XII were generated. The MAbs were reactive with recombinant catalytic domain of CA XII expressed either in E. coli or mammalian cells. Inhibitory activity of the MAbs was demonstrated by a stopped flow CO2 hydration assay. The study provides new data on the surface-exposed linear CA XII epitope that may serve as a target for inhibitory antibodies with a potential immunotherapeutic application. PMID- 24400873 TI - Parametric likelihood inference for interval censored competing risks data. AB - Parametric estimation of the cumulative incidence function (CIF) is considered for competing risks data subject to interval censoring. Existing parametric models of the CIF for right censored competing risks data are adapted to the general case of interval censoring. Maximum likelihood estimators for the CIF are considered under the assumed models, extending earlier work on nonparametric estimation. A simple naive likelihood estimator is also considered that utilizes only part of the observed data. The naive estimator enables separate estimation of models for each cause, unlike full maximum likelihood in which all models are fit simultaneously. The naive likelihood is shown to be valid under mixed case interval censoring, but not under an independent inspection process model, in contrast with full maximum likelihood which is valid under both interval censoring models. In simulations, the naive estimator is shown to perform well and yield comparable efficiency to the full likelihood estimator in some settings. The methods are applied to data from a large, recent randomized clinical trial for the prevention of mother-to-child transmission of HIV. PMID- 24400874 TI - Sex differences in activation of the hypothalamic-pituitary-adrenal axis by methamphetamine. AB - Dysregulation of hypothalamic-pituitary-adrenal (HPA) axis activation is associated with changes in addiction-related behaviors. In this study, we tested whether sex differences in the acute effects of methamphetamine (MA) exposure involve differential activation of the HPA axis. Male and female mice were injected with MA (1 mg/kg) or saline for comparison of plasma corticosterone and analysis of the immediate early gene c-Fos in brain. There was a prolonged elevation in corticosterone levels in female compared to male mice. C-Fos was elevated in both sexes following MA in HPA axis-associated regions, including the hypothalamic paraventricular nucleus (PVN), central amygdala, cingulate, and CA3 hippocampal region. MA increased the number of c-Fos and c-Fos/glucocorticoid receptor (GR) dual-labeled cells to a greater extent in males than females in the cingulate and CA3 regions. MA also increased the number of c-fos/vasopressin dual labeled cells in the PVN as well as the number and percentage of c-Fos/GR dual labeled cells in the PVN and central amygdala, although no sex differences in dual labeling were found in these regions. Thus, sex differences in MA-induced plasma corticosterone levels and activation of distinct brain regions and proteins involved in HPA axis regulation may contribute to sex differences in acute effects of MA on the brain. Methamphetamine induces a prolonged plasma corticosterone response in females compared to males. This may be mediated by increased neural activation, involving a greater activation of glucocorticoid receptor-positive cells, in males in the CA3 and cingulate brain regions, which are involved in negative feedback functions. These findings indicate a sex difference in the neural regulation of methamphetamine-induced plasma corticosterone release. PMID- 24400875 TI - Controlled, parametric, individualized, 2D and 3D imaging measurements of aerosol deposition in the respiratory tract of healthy human volunteers: in vivo data analysis. AB - BACKGROUND: To provide a validation dataset for aerosol deposition modeling, a clinical trial was performed in which the inhalation parameters and the inhaled aerosol were controlled or characterized. METHODS: Eleven, healthy, never smokers, male participants completed the study. Each participant performed two inhalations of (99m)Tc-labeled aerosol from a vibrating mesh nebulizer, which differed by a single controlled parameter (aerosol particle size: "small" or "large"; inhalation: "deep" or "shallow"; carrier gas: air or a helium-oxygen mix). The deposition measurements were made by planar imaging, and single photon emission computed tomography-computed tomography (SPECT-CT). RESULTS: The difference between the mean activity measured by two-dimensional imaging and that delivered from the nebulizer was 2.7%, which was not statistically significant. The total activity deposited was significantly lower in the left lung than in the right lung (p<0.0001) with a mean ratio (left/right) of 0.87+/-0.1 standard deviation (SD). However, when normalized to lung air volume, the left lung deposition was significantly higher (p=0.0085) with a mean ratio of 1.08+/-0.12 SD. A comparison of the three-dimensional central-to-peripheral (nC/P3D) ratio showed that it was significantly higher for the left lung (p<0.0001) with a mean ratio (left/right) of 1.36+/-0.20 SD. The effect of particle size was statistically significant on the nC/P3D ratio (p=0.0014), extrathoracic deposition (p=0.0037), and 24-hr clearance (p<0.0001), contrary to the inhalation parameters, which showed no effect. CONCLUSIONS: This article presents the results of an analysis of the in vivo deposition data, obtained in a clinical study designed to provide data for model validation. This study has demonstrated the value of SPECT imaging over planar, the influence of particle size on regional distribution within the lung, and differences in deposition between the left and right lungs. PMID- 24400876 TI - Anatase titania nanorods as an intercalation anode material for rechargeable sodium batteries. AB - For the first time, we report the electrochemical activity of anatase TiO2 nanorods in a Na cell. The anatase TiO2 nanorods were synthesized by a hydrothermal method, and their surfaces were coated by carbon to improve the electric conductivity through carbonization of pitch at 700 degrees C for 2 h in Ar flow. The resulting structure does not change before and after the carbon coating, as confirmed by X-ray diffraction (XRD). Transmission electron microscopic images confirm the presence of a carbon coating on the anatase TiO2 nanorods. In cell tests, anodes of bare and carbon-coated anatase TiO2 nanorods exhibit stable cycling performance and attain a capacity of about 172 and 193 mAh g(-1) on the first charge, respectively, in the voltage range of 3-0 V. With the help of the conductive carbon layers, the carbon-coated anatase TiO2 delivers more capacity at high rates, 104 mAh g(-1) at the 10 C-rate (3.3 A g(-1)), 82 mAh g(-1) at the 30 C-rate (10 A g(-1)), and 53 mAh g(-1) at the 100 C-rate (33 A g( 1)). By contrast, the anode of bare anatase TiO2 nanorods delivers only about 38 mAh g(-1) at the 10 C-rate (3.3 A g(-1)). The excellent cyclability and high-rate capability are the result of a Na(+) insertion and extraction reaction into the host structure coupled with Ti(4+/3+) redox reaction, as revealed by X-ray absorption spectroscopy. PMID- 24400877 TI - Acquisition and excretion of Bartonella quintana by the cat flea, Ctenocephalides felis felis. AB - Bartonella quintana is transmitted by the infected faeces of body lice. Recently, this bacterium was detected in cat fleas (Ctenocephalides felis) and in two humans with chronic adenopathy whose only risk factor was contact with cat fleas. In this study, a total of 960 C. felis were divided into 12 groups (2 control groups and 10 infected groups) each containing 80 fleas. The fleas were fed B. quintana-inoculated human blood at different dilutions (~3.6 * 10(4) - 8.4 * 10(9) bacteria) for 4 days via an artificial membrane. Subsequently, all flea groups were fed uninfected blood until day 13 postinfection (dpi). On day 3 pi, B. quintana was detected with two specific genes by quantitative PCR in 60-100% of randomly chosen fleas per dilution: 52% (26/50) in the infected fleas in Trial 1 and 90% (45/50) of the fleas in Trial 2. B. quintana was also identified by molecular and culture assays in flea faeces. The average number of B. quintana as determined by qPCR decreased until the 11th dpi and was absent in both trials at the 13th dpi. Bacteria were localized only in the flea gastrointestinal gut by specific immunohistochemistry. Our results indicate that cat fleas can acquire B. quintana by feeding and release viable organisms into their faeces. Therefore, fleas may play a role as vectors of trench fever or other clinical manifestations that are caused by B. quintana. However, the biological role of C. felis in the transmission of B. quintana under natural conditions is yet to be defined. PMID- 24400878 TI - An overview of platelet indices and methods for evaluating platelet function in thrombocytopenic patients. AB - Thrombocytopenia is associated with bleeding risk. However, in thrombocytopenic patients, platelet count does not correlate with bleeding risk and other factors are thus likely to contribute to this risk. This review presents currently available platelet-related markers available on automated haematology analysers and commonly used methods for testing platelet function. The test principles, advantages and disadvantages of each test are described. We also evaluate the current literature regarding the clinical utility of the test for prediction of bleeding in thrombocytopenia in haematological and oncological diseases. We find that several platelet-related markers are available, but information about the clinical utility in thrombocytopenia is limited. Studies support that mean platelet volume (MPV) can aid diagnosing the cause of thrombocytopenia and low MPV may be associated with bleeding in thrombocytopenia. Flow cytometry, platelet aggregometry and platelet secretion tests are used to diagnose specific platelet function defects. The flow cytometric activation marker P-selectin and surface coverage by the Cone-and-Plate[let] analyser predict bleeding in selected thrombocytopenic populations. To fully uncover the clinical utility of platelet related tests, information about the prevalence of platelet function defects in thrombocytopenic conditions is required. Finally, knowledge of the performance in thrombocytopenic samples from patients is essential. PMID- 24400879 TI - Differences in serum SP-D levels between German and Japanese subjects are associated with SFTPD gene polymorphisms. AB - BACKGROUND: Surfactant protein A (SP-A) and SP-D are clinically established in Japan as serum biomarkers for diagnosing interstitial lung diseases (ILDs). Serum SP-D levels are affected by genetic variants. We conducted the present study to examine whether serum SP-A and/or SP-D levels in healthy subjects (HS) and patients with ILDs differ between populations with different genetic backgrounds. METHODS: German subjects (n = 303; 138 patients with idiopathic interstitial pneumonias [IIPs] and 165 HS) and Japanese subjects (n = 369; 94 patients with IIPs and 275 HS) were enrolled. Serum SP-A and SP-D levels were measured using an enzyme-linked immunosorbent assay, and four single-nucleotide polymorphisms (SNPs) in the SFTPD gene were genotyped using genomic DNA extracted from blood samples. RESULTS: In both the German and Japanese cohorts, serum SP-A and SP-D levels were significantly higher in patients with IIPs than in HS. There were no significant differences in SP-A levels between the German and Japanese cohorts; however, we found that serum SP-D levels were significantly higher in the German cohort, both in patients with IIPs and in HS (p < 0.001 and p = 0.005, respectively). Furthermore, the genotype distributions of the four SNPs in the SFTPD gene (rs721917, rs1998374, rs2243639, and rs3088308) were significantly different between German and Japanese cohorts (p < 0.001, p < 0.001, p = 0.022, and p < 0.001, respectively), and univariate linear regression analyses revealed that the genotypes of rs721917, rs1998374, and rs2243639 significantly correlated with serum SP-D levels (p < 0.001, p < 0.001, and p = 0.011, respectively). Furthermore, multivariate analyses revealed that the genotypes of these three SNPs correlated independently with serum SP-D levels (p < 0.001, p = 0.001, and p = 0.038, respectively), whereas ethnicity did not significantly correlate with serum SP-D levels. CONCLUSIONS: In patients with IIPs and HS, serum SP-D, but not SP-A, levels were significantly higher in the German than in the Japanese cohort, in part, because of the different frequencies of SFTPD gene polymorphisms. PMID- 24400880 TI - Type I collagen accelerates the spreading of lens epithelial cells through the expression and activation of matrix metalloproteinases. AB - PURPOSE: Matrix metalloproteinases (MMPs) are involved in posterior capsule opacification (PCO), but the mechanisms that promote MMP expression are yet to be determined. In this study, we investigated whether type I collagen, which is only detected in aged or cataractous lens capsules, affects the expression and activation of MMPs in primary-cultured chicken lens epithelial cells (LECs). MATERIALS AND METHODS: Chicken LECs were isolated from chicken embryos and cultured in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum (FBS) on type I collagen-coated dishes. The activity of secreted MMPs was examined using gelatin zymography, and cell spreading was determined as the average area of randomly distributed cells. For some experiments, LECs were cultured in the presence of the broad-spectrum MMP inhibitor, GM6001. LECs cultured on uncoated dishes were used as controls. To examine the involvement of MMP in cell migration, a wound-healing assay was performed in the presence of the MMP inhibitor. RESULTS: Chicken LECs constitutively express the pro-form of MMP 2. When LECs were cultured on type I collagen-coated dishes, they expressed the active form of MMP-2 and the pro-form of MMP-9. This expression and activation by type I collagen was also observed in the human LEC line SRA-01/04, but not the human Muller glial cell line, MIO-M1. Type I collagen enhanced cell spreading, which was suppressed by the MMP inhibitor. Type I collagen also accelerated alpha smooth muscle actin expression. In addition, LEC migration was inhibited by the MMP inhibitor in a dose-dependent manner in the wound-healing assay. CONCLUSION: Type I collagen promotes the expression and activation of MMPs in a LEC-specific manner. These results suggest that type I collagen may play a role in PCO development. PMID- 24400881 TI - Utility of initial prehospital end-tidal carbon dioxide measurements to predict poor outcomes in adult asthmatic patients. AB - STUDY OBJECTIVE: To determine if an initial (before treatment) prehospital end tidal carbon dioxide (EtCO2) measurement in adult, non-chronic obstructive pulmonary disease (COPD), asthmatic patients predicts patient outcomes. METHODS: This is a retrospective chart review of EtCO2 assessment data in a convenience sample of adult, asthmatic patients transported via advanced life support (ALS) units to a large, urban, academic hospital. Initial EtCO2 measurements were obtained routinely on all respiratory distress patients in the field, and emergency department physicians were unaware of the results. Data were analyzed using descriptive statistics, including percentages, means, and 95% confidence intervals (CI). RESULTS: We reviewed data for prehospital initial EtCO2 measurements on 299 unique asthma patients (repeat visits by same patient were not included). Mean (SD) age was 43.1 years (12.5) and 142 (47.5%) were male. The mean EtCO2 measurement was 38.8 mmHg (SD +/- 9.5; CI: 37.7-39.9; range: 14-82). Examination of initial EtCO2 measurements by deciles revealed that extreme values, in the lowest (14-28 mmHg) and highest (50-82 mmHg) deciles, experienced more markers of poor outcome than less extreme measurements. Patients were thus dichotomized by extreme (n = 59) or nonextreme (n = 240) EtCO2 measurements. More extreme patients were ultimately intubated (30.5 vs. 5.8%; p < 0.001; positive predictive value (ppv) = 30.5% ), and/or admitted to the intensive care unit (ICU) (28.8 vs. 6.7%; p <0.001; ppv = 28.8%), and/or died (5.1 vs. 0%; p = 0.007 [Fisher's exact test]; ppv = 5.1%), than nonextreme patients, respectively. CONCLUSION: Extreme (both low and high) prehospital initial EtCO2 measurements may be associated with markers of poor patient outcomes. Future work will prospectively determine whether the addition of this information improves early recognition of severe asthma episodes beyond clinical assessment. PMID- 24400882 TI - Synthesis and biological evaluation of new bisphosphonate-dextran conjugates targeting breast primary tumor. AB - Bisphosphonates (BPs) have interesting antitumor effects as well in vitro as in vivo, despite their poor bioavailability in the organism after oral ingestion. To overcome this problem and reduce drug doses and secondary effects, we report the chemical synthesis of new bioconjugates. They were built with a nitrogen containing BP as the drug covalently coupled to the carboxymethyldextran. This polysaccharide was used as a carrier, in order to increase BP lifetime in bloodstream and to target tumor cells which have a strong affinity with dextran. The efficiency of our vectorization system was biologically proved in vitro and in vivo on mammalian carcinoma models in mice. PMID- 24400883 TI - The assessment of a structured online formative assessment program: a randomised controlled trial. AB - BACKGROUND: Online formative assessment continues to be an important area of research and methods which actively engage the learner and provide useful learning outcomes are of particular interest. This study reports on the outcomes of a two year study of medical students using formative assessment tools. METHOD: The study was conducted over two consecutive years using two different strategies for engaging students. The Year 1 strategy involved voluntary use of the formative assessment tool by 129 students. In Year 2, a second cohort of 130 students was encouraged to complete the formative assessment by incorporating summative assessment elements into it. Outcomes from pre and post testing students around the formative assessment intervention were used as measures of learning. To compare improvement scores between the two years a two-way Analysis of Variance (ANOVA) model was fitted to the data. RESULTS: The ANOVA model showed that there was a significant difference in improvement scores between students in the two years (mean improvement percentage 19% vs. 38.5%, p < 0.0001). Students were more likely to complete formative assessment items if they had a summative component. In Year 2, the time spent using the formative assessment tool had no impact on student improvement, nor did the number of assessment items completed. CONCLUSION: The online medium is a valuable learning resource, capable of providing timely formative feedback and stimulating student-centered learning. However the production of quality content is a time-consuming task and careful consideration must be given to the strategies employed to ensure its efficacy. Course designers should consider the potential positive impact summative components to formative assessment may have on student engagement and outcomes. PMID- 24400884 TI - Hypertension in Haiti: the challenge of best possible practice. AB - On the fourth anniversary, it is impossible to discuss hypertension in Haiti without acknowledging the almost incalculable negative impact of the January 12, 2010 earthquake. It was catastrophic not only in terms of death and physical injury, but also the widespread destruction of a tenuous infrastructure and public health system. Yet, paradoxically, this virtual blank slate could be an opportunity to develop an innovative pragmatic approach to the equally devastating problem of hypertension as the most common contributing cause of death in Haiti. Rising Phoenix-like literally from the ashes and rubble, there are lessons to be learned from the Haiti experience, as a potential model for the management of hypertension in the community in low resource venues in the Caribbean and beyond. Haiti has very poor comparative outcomes, and specific challenges related to high prevalence stroke, renal failure, and heart failure as negative prognostic consequences of undiagnosed and uncontrolled hypertension. There are severe public health challenges related to salt education, as well as societal challenges related to negative social determinants of health and disease, and the structural violence of overwhelming poverty. Pragmatism is necessary as we attempt to combine the tenets of evidence based medicine with reality based medicine restrictions imposed by low resource. It is through the generation of Best Possible Practice (BPP) models of care that colleagues can develop systems of mutual knowledge sharing, service, and support. This approach extends to screening and diagnosis, where there is no electricity for semi- or automatic manometric devices and requisite need to train in manual/ auscultatory technique, to education and curricula built specifically around a flexible hypertension community management guideline as the accepted standard to aspire to. A successful approach requires solid guiding principles, including a commitment to best attainable quality and value(s). It also requires standing together as a community of dedicated medical professionals. PMID- 24400885 TI - Association between 318C/T polymorphism of the CTLA-4 gene and systemic lupus erythematosus in Iranian patients. AB - BACKGROUND: Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is an important negative regulator of T-cell response. It is a functional candidate gene connected with susceptibility to systemic lupus erythematosus (SLE). We analyzed the role of -318C/T polymorphism in the promoter region of the CTLA-4 gene in Iranian patients suffering from SLE. METHODS: A total of 180 SLE patients and 304 healthy ethnically matched controls were enrolled in the study. DNA was extracted from blood samples according to the standard procedure. Polymerase chain reaction restriction fragments length polymorphism (PCR-RFLP) was used to analyze the genotype and allele frequencies of these polymorphisms. RESULTS: The CC genotype was observed in 170 (94.5%) of the SLE patients, which was significantly different compared to the controls (251 [82.4%]; P = 0.0001, OR = 3.51 95%CI = 1.77-7.53). T allele was significantly more common in the controls (9.2%) compared to SLE patients 2.8% (P = 0.0001, OR = 0.26, 95%CI = 0.13-0.53). There was no significant correlation between different genotypes and age, gender or family history of SLE in the studied population. CONCLUSION: It can be concluded that -318C/T polymorphism of CTLA-4 gene might play a significant role in the development of SLE in the Iranian patients. PMID- 24400886 TI - Electrochemistry, chemical reactivity, and time-resolved infrared spectroscopy of donor-acceptor systems [(Q(x))Pt(pap(y))] (Q = substituted o-quinone or o iminoquinone; pap = phenylazopyridine). AB - The donor-acceptor complex [((O,N)Q(2-))Pt(pap(0))] (1; pap = phenylazopyridine, (O,N)Q(0) = 4,6-di-tert-butyl-N-phenyl-o-iminobenzoquinone), which displays strong pi-bonding interactions and shows strong absorption in the near-IR region, has been investigated with respect to its redox-induced reactivity and electrochemical and excited-state properties. The one-electron-oxidized product [((O,N)Q(*-))Pt(pap(0))](BF4) ([1]BF4) was chemically isolated. Single-crystal X ray diffraction studies establish the iminosemiquinone form of (O,N)Q in [1](+). Simulation of the cyclic voltammograms of 1 recorded in the presence of PPh3 elucidates the mechanism and delivers relevant thermodynamic and kinetic parameters for the redox-induced reaction with PPh3. The thermodynamically stable product of this reaction, complex [((O,N)Q(*-)) Pt(PPh3)2](PF6) ([2]PF6), was isolated and characterized by X-ray crystallography, electrochemistry, and electron paramagnetic resonance spectroscopy. Picosecond time-resolved infrared spectroscopic studies on complex 1b (one of the positional isomers of 1) and its analogue [((O,O)Q(2-))Pt(pap(0))] (3; (O,O)Q = 3,5-di-tert-butyl-o-benzoquinone) provided insight into the excited-state dynamics and revealed that the nature of the lowest excited state in the amidophenolate complex 1b is primarily diimine ligand-based, while it is predominantly an interligand charge-transfer state in the case of 3. Density functional theory calculations on [1](n+) provided further insight into the nature of the frontier orbitals of various redox forms and vibrational mode assignments. We discuss the mechanistic details of the newly established redox-induced reactivity of 1 with electron donors and propose a mechanism for this process. PMID- 24400887 TI - Bacteria associated with yellow lupine grown on a metal-contaminated soil: in vitro screening and in vivo evaluation for their potential to enhance Cd phytoextraction. AB - In order to stimulate selection for plant-associated bacteria with the potential to improve Cd phytoextraction, yellow lupine plants were grown on a metal contaminated field soil. It was hypothesised that growing these plants on this contaminated soil, which is a source of bacteria possessing different traits to cope with Cd, could enhance colonisation of lupine with potential plant associated bacteria that could then be inoculated in Cd-exposed plants to reduce Cd phytotoxicity and enhance Cd uptake. All cultivable bacteria from rhizosphere, root and stem were isolated and genotypically and phenotypically characterised. Many of the rhizobacteria and root endophytes produce siderophores, organic acids, indole-3-acetic acid (IAA) and aminocyclopropane-1-carboxylate (ACC) deaminase, as well as being resistant to Cd and Zn. Most of the stem endophytes could produce organic acids (73.8%) and IAA (74.3%), however, only a minor fraction (up to 0.7%) were Cd or Zn resistant or could produce siderophores or ACC deaminase. A siderophore- and ACC deaminase-producing, highly Cd-resistant Rhizobium sp. from the rhizosphere, a siderophore-, organic acid-, IAA- and ACC deaminase-producing highly Cd-resistant Pseudomonas sp. colonising the roots, a highly Cd- and Zn-resistant organic acid and IAA-producing Clavibacter sp. present in the stem, and a consortium composed of these three strains were inoculated into non-exposed and Cd-exposed yellow lupine plants. Although all selected strains possessed promising in vitro characteristics to improve Cd phytoextraction, inoculation of none of the strains (i) reduced Cd phytotoxicity nor (ii) strongly affected plant Cd uptake. This work highlights that in vitro characterisation of bacteria is not sufficient to predict the in vivo behaviour of bacteria in interaction with their host plants. PMID- 24400888 TI - Enhanced resistive switching phenomena using low-positive-voltage format and self compliance IrOx/GdOx/W cross-point memories. AB - Enhanced resistive switching phenomena of IrOx/GdOx/W cross-point memory devices have been observed as compared to the via-hole devices. The as-deposited Gd2O3 films with a thickness of approximately 15 nm show polycrystalline that is observed using high-resolution transmission electron microscope. Via-hole memory device shows bipolar resistive switching phenomena with a large formation voltage of -6.4 V and high operation current of >1 mA, while the cross-point memory device shows also bipolar resistive switching with low-voltage format of +2 V and self-compliance operation current of <300 MUA. Switching mechanism is based on the formation and rupture of conducting filament at the IrOx/GdOx interface, owing to oxygen ion migration. The oxygen-rich GdOx layer formation at the IrOx/GdOx interface will also help control the resistive switching characteristics. This cross-point memory device has also Repeatable 100 DC switching cycles, narrow distribution of LRS/HRS, excellent pulse endurance of >10,000 in every cycle, and good data retention of >104 s. This memory device has great potential for future nanoscale high-density non-volatile memory applications. PMID- 24400889 TI - Osteosarcoma of the breast. PMID- 24400891 TI - Rosmarinic acid extract for antioxidant, antiallergic, and alpha-glucosidase inhibitory activities, isolated by supramolecular technique and solvent extraction from Perilla leaves. AB - Rosmarinic acid extract with potent biological activities was successfully isolated by supramolecular technique and solvent extraction from Perilla leaves. By the supramolecular complex which was formed from flavocommelin and Perilla leaf extract as initial materials, the supernatant containing rosmarinic acid was isolated. Rosmarinic acid extract (62.9 +/- 4.5% purity) was partly purified by partitioning ethyl acetate and water. Rosmarinic acid extract exhibited high total phenolic content of 433.9 +/- 58.6 MUg/mg of gallic acid equivalent, effective DPPH radical scavenging activity (SC50 of 5.5 +/- 0.2 MUg/mL), antiallergic activity (IC50 of 52.9 +/- 6.7 MUg/mL), and alpha-glucosidase inhibitory activity (IC50 of 0.23 +/- 0.01 mg/mL). Rosmarinic acid extract shows high potential for diabetes mellitus and allergy treatments by inhibiting alpha glucosidase activity and measuring beta-hexosaminidase, related to life-style disease. PMID- 24400892 TI - Differentiation of postpartum Graves' thyrotoxicosis from postpartum destructive thyrotoxicosis using antithyrotropin receptor antibodies and thyroid blood flow. AB - BACKGROUND: Postpartum thyroid dysfunction occurs in approximately 5-10% of women in the general population within one year of delivery. Differentiation of postpartum Graves' thyrotoxicosis (PPGr) from postpartum destructive thyrotoxicosis (PPDT) is essential because of the difference in treatment measures between the two. However, it is sometimes difficult because radioactive iodine uptake is contraindicated when patients are lactating. We examined the usefulness of determining the time of onset postpartum and measurement of antithyrotropin (anti-TSH) receptor antibodies and thyroid blood flow. METHODS: Forty-two patients with newly developed thyrotoxicosis after delivery were examined: 18 had Graves' disease and 24 had destructive thyrotoxicosis. Serum free thyroxine (fT4), free triiodothyronine (fT3), and TSH were measured by chemiluminescent immunoassays. Anti-TSH receptor antibodies (TRAb), antithyroglobulin antibodies (TgAb), and antithyroid peroxidase antibodies (TPOAb) were measured by the Elecsys electrochemiluminescence immunoassay. Thyroid volume and blood flow (TBF) were measured quantitatively by color flow Doppler ultrasonography. RESULTS: Onset of thyrotoxicosis was distributed from 2 to 12 months postpartum. Twelve (85.7%) of 14 patients who developed thyrotoxicosis at three months or earlier after delivery had PPDT. On the other hand, all 11 patients who developed thyrotoxicosis at 6.5 months or later had PPGr. All patients with PPGr had positive TRAb (14.9+/-14.9 IU/L, mean+/-standard deviation (SD)) and all patients with PPDT had negative TRAb (0.1+/-0.3 IU/L, p<0.0001). Fifteen (83.3%) of 18 PPGr patients had high TBF of more than 4.0% (8.9+/-4.4), and all PPDT patients had low TBF of <4.0% (1.6+/-1.0, p<0.0001). The fT3/fT4 ratio was higher in PPGr (64.0+/-23.9) than in PPDT (38.9+/-13.1, p<0.0002), but absolute values overlapped between the two. CONCLUSION: Early onset of thyrotoxicosis postpartum was associated mainly with PPDT, and a late onset was suggestive of PPGr. Positive TRAb and high TBF >4.0% are indicators of postpartum onset of Graves' disease. PMID- 24400890 TI - The functional role of microRNAs in alcoholic liver injury. AB - The function of microRNAs (miRNAs) during alcoholic liver disease (ALD) has recently become of great interest in biological research. Studies have shown that ALD associated miRNAs play a crucial role in the regulation of liver-inflammatory agents such as tumour necrosis factor-alpha (TNF-alpha), one of the key inflammatory agents responsible for liver fibrosis (liver scarring) and the critical contributor of alcoholic liver disease. Lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria, is responsible for TNF alpha release by Kupffer cells. miRNAs are the critical mediators of LPS signalling in Kupffer cells, hepatocytes and hepatic stellate cells. Certain miRNAs, in particular miR-155 and miR-21, show a positive correlation in up regulation of LPS signalling when they are exposed to ethanol. ALD is related to enhanced gut permeability that allows the levels of LPS to increase, leads to increased secretion of TNF-alpha by the Kupffer cells and subsequently promotes alcoholic liver injury through specific miRNAs. Meanwhile, two of the most frequently dysregulated miRNAs in steatohepatitis, miR-122 and miR-34a are the critical mediators in ethanol/LPS activated survival signalling during ALD. In this review, we summarize recent findings regarding the experimental and clinical aspects of functions of specific microRNAs, focusing mainly on inflammation and cell survival after ethanol/LPS treatment, and advances on the role of circulating miRNAs in human alcoholic disorders. PMID- 24400893 TI - Electrolyte effect on lamellar domain morphology in a nonionic surfactant solution below the Krafft temperature. AB - In our previous papers, we have studied the lamellar domain morphology in aqueous solutions of nonionic surfactants C16E6 and C16E7 below the Krafft temperature. In this study, electrolyte effects on lamellar domain morphology have been investigated by means of DSC, confocal microscope, small/wide-angle X-ray scattering (SAXS/WAXS). It has been found that vesicles in C16E7 solution are transformed to network structures by adding chaotropic ion Cl(-), F(-) and CH3COO(-), whereas the network structures in C16E6 solution are gradually changed to the vesicles with increasing kosmotropic ion SCN(-) concentration. Especially, we focused on the SCN(-) ion effects on the C16E6 system, and found that the characteristic morphology of cylinder-like domains were formed in a certain specific concentration range. In the SAXS observation in nm scale, we have also found that the repeat distance of lamellar structures in the C16E6/NaSCN solution is anomalously swollen when adding 1.2-2 mol/kg NaSCN, where the cylinder-like domains are formed. We have concluded that the cylindrical vesicles could be explained by the osmotic pressure difference due to the addition of NaSCN. PMID- 24400895 TI - Clinical practice guidelines come to a turning point. PMID- 24400896 TI - Unravelling potassium nutrition in ectomycorrhizal associations. PMID- 24400897 TI - Why is a raven like a writing desk? Origins of the sunflower that is neither an artichoke nor from Jerusalem. PMID- 24400899 TI - A MYB coiled-coil transcription factor interacts with NSP2 and is involved in nodulation in Lotus japonicus. AB - Transcription factor complex formation is a central step in regulating gene expression. In this report, a novel MYB coiled-coil transcription factor referred to as IPN2, for Interacting Protein of NSP2, is described. The interaction between IPN2 and NSP2 was examined by protein pull-down assays and bimolecular fluorescence complementation (BiFC). Subcellular localization of proteins, gene expression and gene function were assessed in transgenic hairy roots expressing tagged recombinant proteins, promoter-reporter and RNA interference (RNAi) constructs, respectively. The GRAS domain of NSP2 and the coiled-coil domain of IPN2 were found to be responsible for the interaction between the two proteins. IPN2 had strong transcription activation activity, bound directly to the NIN gene promoter, and was localized to the nuclei of Lotus japonicus root cells. The expression of IPN2 was elevated during nodule development, coinciding with increased NSP2 gene expression during nodule organogenesis. RNAi-mediated knockdown expression of IPN2 did not affect arbuscular mycorrhizal development, but had deleterious effects on rhizobial infection and nodule formation in L. japonicus. These results demonstrate an important role of IPN2 in nodule organogenesis and place a new MYB transcription factor in the Nod signaling pathway. PMID- 24400898 TI - DELLA activity is required for successful pollen development in the Columbia ecotype of Arabidopsis. AB - Excessive gibberellin (GA) signalling, mediated through the DELLA proteins, has a negative impact on plant fertility. Loss of DELLA activity in the monocot rice (Oryza sativa) causes complete male sterility, but not in the dicot model Arabidopsis (Arabidopsis thaliana) ecotype Landsberg erecta (Ler), in which DELLA function has been studied most extensively, leading to the assumption that DELLA activity is not essential for Arabidopsis pollen development. A novel DELLA fertility phenotype was identified in the Columbia (Col-0) ecotype that necessitates re-evaluation of the general conclusions drawn from Ler. Fertility phenotypes were compared between the Col-0 and Ler ecotypes under conditions of chemical and genetic GA overdose, including mutants in both ecotypes lacking the DELLA paralogues REPRESSOR OF ga1-3 (RGA) and GA INSENSITIVE (GAI). Ler displays a less severe fertility phenotype than Col-0 under GA treatment. Col-0 rga gai mutants, in contrast with the equivalent Ler phenotype, were entirely male sterile, caused by post-meiotic defects in pollen development, which were rescued by the reintroduction of DELLA into either the tapetum or developing pollen. We conclude that DELLA activity is essential for Arabidopsis pollen development. Differences between the fertility responses of Col-0 and Ler might be caused by differences in downstream signalling pathways or altered DELLA expression. PMID- 24400900 TI - Stem girdling affects the quantity of CO2 transported in xylem as well as CO2 efflux from soil. AB - There is recent clear evidence that an important fraction of root-respired CO2 is transported upward in the transpiration stream in tree stems rather than fluxing to the soil. In this study, we aimed to quantify the contribution of root respired CO2 to both soil CO2 efflux and xylem CO2 transport by manipulating the autotrophic component of belowground respiration. We compared soil CO2 efflux and the flux of root-respired CO2 transported in the transpiration stream in girdled and nongirdled 9-yr-old oak trees (Quercus robur) to assess the impact of a change in the autotrophic component of belowground respiration on both CO2 fluxes. Stem girdling decreased xylem CO2 concentration, indicating that belowground respiration contributes to the aboveground transport of internal CO2 . Girdling also decreased soil CO2 efflux. These results confirmed that root respiration contributes to xylem CO2 transport and that failure to account for this flux results in inaccurate estimates of belowground respiration when efflux based methods are used. This research adds to the growing body of evidence that efflux-based measurements of belowground respiration underestimate autotrophic contributions. PMID- 24400901 TI - Increasing atmospheric CO2 overrides the historical legacy of multiple stable biome states in Africa. AB - The dominant vegetation over much of the global land surface is not predetermined by contemporary climate, but also influenced by past environmental conditions. This confounds attempts to predict current and future biome distributions, because even a perfect model would project multiple possible biomes without knowledge of the historical vegetation state. Here we compare the distribution of tree- and grass-dominated biomes across Africa simulated using a dynamic global vegetation model (DGVM). We explicitly evaluate where and under what conditions multiple stable biome states are possible for current and projected future climates. Our simulation results show that multiple stable biomes states are possible for vast areas of tropical and subtropical Africa under current conditions. Widespread loss of the potential for multiple stable biomes states is projected in the 21st Century, driven by increasing atmospheric CO2 . Many sites where currently both tree-dominated and grass-dominated biomes are possible become deterministically tree-dominated. Regions with multiple stable biome states are widespread and require consideration when attempting to predict future vegetation changes. Testing for behaviour characteristic of systems with multiple stable equilibria, such as hysteresis and dependence on historical conditions, and the resulting uncertainty in simulated vegetation, will lead to improved projections of global change impacts. PMID- 24400902 TI - Chemical similarity between historical and novel host plants promotes range and host expansion of the mountain pine beetle in a naive host ecosystem. AB - Host plant secondary chemistry can have cascading impacts on host and range expansion of herbivorous insect populations. We investigated the role of host secondary compounds on pheromone production by the mountain pine beetle (Dendroctonus ponderosae) (MPB) and beetle attraction in response to a historical (lodgepole pine, Pinus contorta var. latifolia) and a novel (jack pine, Pinus banksiana) hosts, as pheromones regulate the host colonization process. Beetles emit the same pheromones from both hosts, but more trans-verbenol, the primary aggregation pheromone, was emitted by female beetles on the novel host. The phloem of the novel host contains more alpha-pinene, a secondary compound that is the precursor for trans-verbenol production in beetle, than the historical host. Beetle-induced emission of 3-carene, another secondary compound found in both hosts, was also higher from the novel host. Field tests showed that the addition of 3-carene to the pheromone mixture mimicking the aggregation pheromones produced from the two host species increased beetle capture. We conclude that chemical similarity between historical and novel hosts has facilitated host expansion of MPB in jack pine forests through the exploitation of common host secondary compounds for pheromone production and aggregation on the hosts. Furthermore, broods emerging from the novel host were larger in terms of body size. PMID- 24400903 TI - Evolution of a symbiotic receptor through gene duplications in the legume rhizobium mutualism. AB - The symbiosis between legumes and nitrogen-fixing rhizobia co-opted pre-existing endomycorrhizal features. In particular, both symbionts release lipo chitooligosaccharides (LCOs) that are recognized by LysM-type receptor kinases. We investigated the evolutionary history of rhizobial LCO receptor genes MtLYK3 LjNFR1 to gain insight into the evolutionary origin of the rhizobial symbiosis. We performed a phylogenetic analysis integrating gene copies from nonlegumes and legumes, including the non-nodulating, phylogenetically basal legume Cercis chinensis. Signatures of differentiation between copies were investigated through patterns of molecular evolution. We show that two rounds of duplication preceded the evolution of the rhizobial symbiosis in legumes. Molecular evolution patterns indicate that the resulting three paralogous gene copies experienced different selective constraints. In particular, one copy maintained the ancestral function, and another specialized into perception of rhizobial LCOs. It has been suggested that legume LCO receptors evolved from a putative ancestral defense-related chitin receptor through the acquisition of two kinase motifs. However, the phylogenetic analysis shows that these domains are actually ancestral, suggesting that this scenario is unlikely. Our study underlines the evolutionary significance of gene duplication and subsequent neofunctionalization in MtLYK3 LjNFR1 genes. We hypothesize that their ancestor was more likely a mycorrhizal LCO receptor, than a defense-related receptor kinase. PMID- 24400904 TI - The LOSS OF APOMEIOSIS (LOA) locus in Hieracium praealtum can function independently of the associated large-scale repetitive chromosomal structure. AB - Apomixis or asexual seed formation in Hieracium praealtum (Asteraceae) is controlled by two independent dominant loci. One of these, the LOSS OF APOMEIOSIS (LOA) locus, controls apomixis initiation, mitotic embryo sac formation (apospory) and suppression of the sexual pathway. The LOA locus is found near the end of a hemizygous chromosome surrounded by extensive repeats extending along the chromosome arm. Similar apomixis-carrying chromosome structures have been found in some apomictic grasses, suggesting that the extensive repetitive sequences may be functionally relevant to apomixis. Fluorescence in situ hybridization (FISH) was used to examine chromosomes of apomeiosis deletion mutants and rare recombinants in the critical LOA region arising from a cross between sexual Hieracium pilosella and apomictic H. praealtum. The combined analyses of aposporous and nonaposporous recombinant progeny and chromosomal karyotypes were used to determine that the functional LOA locus can be genetically separated from the very extensive repeat regions found on the LOA carrying chromosome. The large-scale repetitive sequences associated with the LOA locus in H. praealtum are not essential for apospory or suppression of sexual megasporogenesis (female meiosis). PMID- 24400905 TI - The widespread crucifer species Cardamine flexuosa is an allotetraploid with a conserved subgenomic structure. AB - The origin of Cardamine flexuosa (Wavy Bittercress) has been a conundrum for more than six decades. Here we identify its parental species, analyse its genome structure in comparison to parental genomes and describe intergenomic structural variations in C. flexuosa. Genomic in situ hybridization (GISH) and comparative chromosome painting (CCP) uncovered the parental genomes and the chromosome composition of C. flexuosa and its presumed diploid progenitors. Cardamine flexuosa is an allotetraploid (2n = 4x = 32), originating from two diploid species, Cardamine amara and Cardamine hirsuta (2n = 2x = 16). The two parental species display almost perfectly conserved chromosomal collinearity for seven out of the eight chromosomes. A 13 Mb pericentric inversion distinguishes chromosome CA1 from CH1. A comparative cytomolecular map was established for C. flexuosa by CCP/GISH. Whereas conserved chromosome collinearity between the C. amara and C. hirsuta subgenomes might have promoted intergenomic rearrangements through homeologous recombination, only one reciprocal translocation between two homeologues has occurred since the origin of C. flexuosa. The genome of C. flexuosa demonstrates that allopolyploids can maintain remarkably stable subgenomes over 10(4) -10(5) yr throughout a wide distribution range. By contrast, the rRNA genes underwent genome-specific elimination towards a diploid like number of loci. PMID- 24400908 TI - Conversion of oxazolidinediones to isoindoloisoquinolinones via intramolecular Friedel-Crafts reaction. AB - Treatment of oxazolidinediones with TiCl4 in CH2Cl2 resulted in conversion to isoindoloisoquinolinones via intramolecular Friedel-Crafts reaction with extrusion of CO2 in the transformation. The alkaloid nuevamine has been synthesized under these conditions in a regiospecific manner. PMID- 24400907 TI - Prevalence and factors associated with low bone mineral density in Saudi women: a community based survey. AB - BACKGROUND: Low bone mineral density (BMD) is a public health issue in Saudi Arabia. This study measured the prevalence and factors associated with low BMD in Saudi women in Riyadh, Saudi Arabia. METHODS: A cross sectional study using two stage cluster sampling technique was conducted in Riyadh, 2009. Thirty clusters, each comprising of 300 houses were randomly chosen and from each cluster 38-40 households were selected to identify 1150 women of >40 years. Women were invited to primary health care center for filling of self-administered questionnaire (n = 1069) comprising of sociodemographic, health, diet and physical activity variables. 1008 women underwent screening for low BMD using the quantitative ultrasound technique. 535 (53%) women with positive screening test were referred to King Khalid Hospital for Dual X-ray Energy absorptiometry (DXA). RESULTS: 362 women underwent DXA and 212 (39.6%) were screened low BMD either at lumbar spine or femur neck. Mean age of women was 55.26(+/-8.84) years. Multivariate logistic analysis found; being aged 61 to 70 years (OR 2.75, 95% CI: 1.32-1.48), no literacy (OR 2.97, 95% CI:1.44 - 6.12) or primary education (OR 4.12, 95% CI:2.05 8.29), history of fractures (OR 2.20, 95% CI:1.03- 4.69) and not drinking laban(diluted yogurt) (OR 2.81, 95% CI:1.47- 5.37) significantly associated with low BMD. CONCLUSIONS: Women with low level of education, who do not drink laban and had history of fractures were at high risk of low BMD. PMID- 24400909 TI - An organocatalytic Michael-Michael cascade for the enantioselective construction of spirocyclopentane bioxindoles: control of four contiguous stereocenters. AB - An organocatalytic Michael-Michael cascade for the enantioselective construction of spirocyclopentane bioxindoles was developed in moderate to good yield with good diastereoselectivities and excellent enantioselectivities. The straightforward process, catalyzed by a bifunctional chiral squaramide catalyst, serves as a powerful tool for the enantioselective construction of potentially biological bioxindoles with four contiguous chiral centers, of which two are spiro all-carbon quaternary centers on a single cyclopentane ring. PMID- 24400910 TI - The 'drug policy ratchet': why do sanctions for new psychoactive drugs typically only go up? AB - It has been much more common for drugs to be subjected to tighter rather than looser control as drugs and evidence about their effects have has emerged. We argue that there is in place a drug policy ratchet which subjects new psychoactive substances (NPS) to increasing control through the continuation of historical patterns that involve the attribution to emerging drugs of guilt by three different kinds of association: guilt by deviant association; guilt by lunatic association; and guilt by molecular association. We use our contemporary ethnographic experience of drug policy-making to show how these processes continue to be applied to policy on NPS, alongside selective, narrative use of evidence and the 'silent silencing' by absorption of the concept of evidence based policy. We show that the drug policy ratchet cannot be justified as an example of the precautionary principle in action, as this principle is itself not rationally justified. We conclude that recognition of the drug policy ratchet and its mechanisms may help researchers and policy-makers to improve regulation of NPS. PMID- 24400911 TI - Clinical significance and detection of microRNA-21 in serum of patients with diffuse large B-cell lymphoma in Chinese population. AB - BACKGROUND: Expression patterns of microRNAs in serum are involved in potentially non-invasive biomarkers for various diseases. The purpose of this study is to examine the expression of miR-21 in serum of patients with diffuse large B-cell lymphoma (DLBCL) and to validate the significance of miR-21 in early diagnosis, genotyping, treatment options as well as its prognosis estimates of Chinese DLBCL. METHODS: miR-21 expression was detected by fluorescent quantity polymerase chain reaction (qPCR) in 9 DLBCL cell lines (OCI-Ly1, OCI-Ly3, OCI-Ly4, OCI-Ly7, OCI-Ly8, OCI-Ly10, OCI-Ly18, OCI-Ly19, and HBL), as well as in tumor tissue and serum samples from patients with DLBCL (germinal center B-cell-like (GCB) DLBCL 32; activated B-cell-like (ABC) DLBCL 30) and 50 healthy subjects. RESULTS: Expression of miR-21 was increased in DLBCL cell lines. Compared with the miR-21 expression of GCB subgroup (OCI-Ly1, OCI-Ly4, OCI-Ly7, OCI-Ly8, OCI-Ly18, OCI Ly19), ABC subgroup (OCI-Ly3, OCI-Ly10, and HBL) has higher expression (t = 11.18, P < 0.01). Circulating miR-21 level in sera from patients with DLBCLwas associated with matched tumor tissue (r(2) = 0.931, P < 0.0001). Consistent with the in vitro, miR-21 expression levels in serum of patients with DLBCL [21.38(10.26-45.21)] were higher than those in serum of control cases [1.87(1.05 3.97); U = 168, P = 0.000]. Moreover, miR-21 expression levels in serum of patients with subgroup ABC [28.68(14.92~98.44)] were higher than that of patients with subgroup GCB [18.3(7.32~33.46); U = 336, P = 0.043]. miR-21 expression in serum of DLBCL with stage I and II were higher than those in stage III and IV (U = 62, P = 0.013 in GCB type; U = 53, P = 0.014 in ABC type). Compared with relapse-free survival in patients with DLBCL, high expression of miR-21 was associated with well prognosis (U = 259, P = 0.035). CONCLUSION: miR-21 expressed in the serum of patients with DLBCL from Chinese was associated with clinical stage, molecular subgroup, and prognosis estimates. miR-21 may be served as a biomarker in early diagnosis, genotyping, treatment options, and prognosis estimating of Chinese DLBCL. PMID- 24400912 TI - Set-valued dynamic treatment regimes for competing outcomes. AB - Dynamic treatment regimes (DTRs) operationalize the clinical decision process as a sequence of functions, one for each clinical decision, where each function maps up-to-date patient information to a single recommended treatment. Current methods for estimating optimal DTRs, for example Q-learning, require the specification of a single outcome by which the "goodness" of competing dynamic treatment regimes is measured. However, this is an over-simplification of the goal of clinical decision making, which aims to balance several potentially competing outcomes, for example, symptom relief and side-effect burden. When there are competing outcomes and patients do not know or cannot communicate their preferences, formation of a single composite outcome that correctly balances the competing outcomes is not possible. This problem also occurs when patient preferences evolve over time. We propose a method for constructing DTRs that accommodates competing outcomes by recommending sets of treatments at each decision point. Formally, we construct a sequence of set-valued functions that take as input up to-date patient information and give as output a recommended subset of the possible treatments. For a given patient history, the recommended set of treatments contains all treatments that produce non-inferior outcome vectors. Constructing these set-valued functions requires solving a non-trivial enumeration problem. We offer an exact enumeration algorithm by recasting the problem as a linear mixed integer program. The proposed methods are illustrated using data from the CATIE schizophrenia study. PMID- 24400906 TI - Should I stay or should I go: biogeographic and evolutionary history of a polyploid complex (Chrysanthemum indicum complex) in response to Pleistocene climate change in China. AB - Quaternary climatic oscillations greatly influenced the distribution and pattern of biodiversity in the Northern Hemisphere. Here we examine how such oscillations in South East Asia may have affected the demographic and evolutionary history of a polyploid plant complex associated with semi-dry habitats. We analyzed plastid and nuclear ribosomal DNA (rDNA) internal transcribed spacer (ITS) sequence variation within the Chrysanthemum indicum complex (Asteraceae), which comprises diploid and polyploid plants distributed throughout China. In total, 368 individuals from 47 populations across the geographical range of the complex were analyzed. We show that the relatively widespread tetraploid form of C. indicum expanded its range southward in the Pleistocene, possibly during the most recent or previous glacial period when conditions became drier and forests retreated in southern China. In marked contrast, diploid and other polyploid members of the complex failed to expand their ranges at these times or have since undergone range contractions in contrast to tetraploid C. indicum. We conclude that hybridization and gene flow between taxa occurred frequently during the evolutionary history of the complex, causing considerable sharing of chlorotypes and ITS types. Nevertheless, taxa within ploidy levels could be largely distinguished according to chlorotype and/or ITS type. PMID- 24400913 TI - Acute exposure of rabbit eyes to artificial light in vivo: effect on corneal and third eyelid conjunctival histology and the gene expression of PAFR. AB - PURPOSE: To study the effect of acute exposure of rabbit eyes to artificial sunlight in vivo, on the integrity of corneal and conjunctival tissue as well as on the gene expression of the receptor for platelet activating factor (PAFR). METHODS: New Zealand albino rabbits were immobilized opposite a 300 W Osram Ultra Vitalux(r) light bulb with an emission radiation spectrum similar to that of normal sunlight at noon, and exposed to ultraviolet B radiation in the range of the reported threshold for corneal damage. Corneal and third eyelid tissue samples were removed from exposed eyes at 2, 6 and 24 h following the end of the exposure to the bulb light and were subsequently processed for histochemical staining and RNA extraction. The gene expression of PAFR was detected with real time reverse transcription polymerase chain reaction. RESULTS: Some epithelial shedding was detected in the corneal tissue as a result of acute exposure to artificial sunlight. In the eyelid conjunctiva, a marked accumulation of eosinophils was noticed, as early as 2 h post-exposure, apparently directed toward the upper part of the epithelial layer. This effect appears to subside by hour 24. No statistically significant changes in gene expression were detected in the corneal tissue, whereas in the third eyelid, PAFR gene expression was significantly induced, most prominently at t = 2 and 6 h post-exposure. CONCLUSION: Acute exposure of rabbit eyes to artificial sunlight induced a marked infiltration of eosinophils into the epithelial layer of the conjunctiva but no gross alterations in the cornea or the third eyelid. The gene expression of PAFR was upregulated, as an effect of light exposure, in the third eyelid but not in the cornea. PMID- 24400914 TI - Detection of microcirculatory impairment by transcutaneous oxymetry monitoring during hemodialysis: an observational study. AB - BACKGROUND: Little is known about the effects of intermittent hemodialysis on microcirculatory perfusion. The aim of this study is to assess the effects of hemodialysis on microvascular perfusion using transcutaneous oxymetry (TCPO2). METHODS: In this observational study, hourly TCPO2 measurements were performed during hemodialysis sessions. Ankle brachial index (ABI) was carried out to classify patients according their vascular condition. RESULTS: 50 patients (mean age 70 +/- 8 years old) were enrolled. Mean TCPO2 decreased significantly on average 23.9% between start and finish of hemodialysis. Severe ischemia (TCPO2 < 30 mmHg) and critical ischemia (TCPO2 < 10 mmHg) occurred during dialysis in 47.1% and 15.5% respectively. Critical ischemia occurred only in limbs with ABI < 0.9 (8.3%) or > 1.3 (28%). Patients with critical ischemia experienced a significantly larger decline in mean blood pressure (32.4 +/- 26.1 mmHg vs 12.7 +/- 10.7 mmHg; P = 0.007) and a more pronounced ultrafiltration (45.55 +/- 16.9 ml/kg vs 35.17 +/- 18.2 ml/kg; P = 0.04) compared to patients without ischemia. Clinical outcomes (death or vascular procedures) were five times more frequent in patients who had developed critical ischemia (55.7% vs 10.1% P = 0.01). The elevated age of patients, the low basal value of TCPO2, and the occurrence of critical ischemia were more frequently associated with clinical outcome (P = 0.03, P = 0.048, P = 0.01 respectively). CONCLUSIONS: This study demonstrates that hemodialysis induces microcirculatory injury, dependent on blood pressure reduction, peripheral vascular state and ultrafiltration. The occurrence of critical ischemia is associated to pejorative patient outcome and therefore, TCPO2 seems to be useful to avoid potential distal tissue damage during hemodialysis. PMID- 24400916 TI - Quantitative chemistry and the discrete geometry of conformal atom-thin crystals. AB - When flat or on a firm mechanical substrate, the atomic composition and atomistic structure of two-dimensional crystals dictate their chemical, electronic, optical, and mechanical properties. These properties change when the two dimensional and ideal crystal structure evolves into arbitrary shapes, providing a direct and dramatic link among geometry and material properties due to the larger structural flexibility when compared to bulk three-dimensional materials. We describe methods to understand the local geometrical information of two dimensional conformal crystals quantitatively and directly from atomic positions, even in the presence of atomistic defects. We then discuss direct relations among the discrete geometry and chemically relevant quantities--mean bond lengths, hybridization angles, and sigma-pi hybridization. These concepts are illustrated for carbon-based materials and ionic crystals. The pyramidalization angle turns out to be linearly proportional to the mean curvature for relevant crystalline configurations. Discrete geometry provides direct quantitative information on the potential chemistry of conformal two-dimensional crystals. PMID- 24400915 TI - A comparison of ketamine and morphine analgesia in prehospital trauma care: a cluster randomized clinical trial in rural Quang Tri province, Vietnam. AB - BACKGROUND: The use of opioid analgesics in prehospital trauma care has been reported to have negative side effects on the airway and circulation. Several studies of urban trauma management have recommend ketamine as a safe and efficient analgesic. To date, however, no controlled trials of prehospital opioid analgesics versus ketamine in rural trauma management have been published. OBJECTIVE: This study aimed to compare the analgesic effects and side effects of ketamine and morphine in a prehospital, low-resource setting. METHODS: The study was conducted with a prospective, cluster-randomized design. The Quang Tri province of Vietnam was divided into two sectors that alternated monthly between ketamine and morphine treatments. A total of 169 trauma patients were treated outside hospital settings with ketamine, while 139 patients were treated with morphine. RESULTS: The treatment effects were measured by comparing the Visual Analogue Scale (VAS) ratings in the field to those upon on admission. The analgesic effects were positive and similar for the two drugs. The rate of vomiting was significantly lower in the ketamine group (5%) than in the morphine group (19%, 95% CI for difference 8-22%). The rate of hallucinations and agitation was higher in ketamine-treated patients (11%) than in the morphine treated patients (1.5%, 95% CI for difference 4-16%). In this study, patients with head trauma (n = 57) showed no adverse effects on consciousness level after being treated with ketamine. CONCLUSION: Ketamine had an analgesic effect similar to morphine and carried a lower risk of airway problems. The risk of hallucinations and agitation was increased in the ketamine group. These findings are of medical significance, particularly in rough and low-resource scenarios. PMID- 24400917 TI - [(18)F]Fluoromethyl-PBR28 as a potential radiotracer for TSPO: preclinical comparison with [(11)C]PBR28 in a rat model of neuroinflammation. AB - To develop radiotracer for the translocator protein 18 kDa (TSPO) in vivo, N-(2 [(18)F]fluoromethoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([(18)F]1, [(18)F]fluoromethyl-PBR28) was prepared by incorporating of fluorine-18 into triazolium triflate-PBR28 precursor (7). The radiochemical yield of [(18)F]1 after HPLC purification was 35.8 +/- 3.2% (n = 11, decay corrected). Radiotracer [(18)F]1 was found to be chemically stable when incubated in human serum for 4 h at 37 degrees C. Both aryloxyanilide analogs (1 and 2) behaved similarly in terms of lipophilicity and in vitro affinity for TSPO. Here, both radiotracers were directly compared in the same inflammatory rat to determine whether either radiotracer provides more promising in vivo TSPO binding. Uptake of [(18)F]1 in the inflammatory lesion was comparable to that of [(11)C]PBR28, and [(18)F]1 rapidly approached the highest target-to-background ratio at early imaging time (35 min postinjection versus 85 min postinjection for [(11)C]PBR28). These results suggest that [(18)F]1 is a promising radiotracer for imaging acute neuroinflammation in rat. In addition, our use of a triazolium triflate precursor for [(18)F]fluoromethyl ether group provides the convenient application for radiofluorination of radiotracer containing a methoxy group. PMID- 24400918 TI - Phase behavior of medium and high internal phase water-in-oil emulsions stabilized solely by hydrophobized bacterial cellulose nanofibrils. AB - Water-in-oil emulsions stabilized solely by bacterial cellulose nanofibers (BCNs), which were hydrophobized by esterification with organic acids of various chain lengths (acetic acid, C2-; hexanoic acid, C6-; dodecanoic acid, C12-), were produced and characterized. When using freeze-dried C6-BCN and C12-BCN, only a maximum water volume fraction (phiw) of 60% could be stabilized, while no emulsion was obtained for C2-BCN. However, the maximum phiw increased to 71%, 81%, and 77% for C2-BCN, C6-BCN, and C12-BCN, respectively, 150 h after the initial emulsification, thereby creating high internal phase water-in-toluene emulsions. The observed time-dependent behavior of these emulsions is consistent with the disentanglement and dispersion of freeze-dried modified BCN bundles into individual nanofibers with time. These emulsions exhibited catastrophic phase separation when phiw was increased, as opposed to catastrophic phase inversion observed for other Pickering emulsions. PMID- 24400919 TI - A 3D-printed high power nuclear spin polarizer. AB - Three-dimensional printing with high-temperature plastic is used to enable spin exchange optical pumping (SEOP) and hyperpolarization of xenon-129 gas. The use of 3D printed structures increases the simplicity of integration of the following key components with a variable temperature SEOP probe: (i) in situ NMR circuit operating at 84 kHz (Larmor frequencies of (129)Xe and (1)H nuclear spins), (ii) <0.3 nm narrowed 200 W laser source, (iii) in situ high-resolution near-IR spectroscopy, (iv) thermoelectric temperature control, (v) retroreflection optics, and (vi) optomechanical alignment system. The rapid prototyping endowed by 3D printing dramatically reduces production time and expenses while allowing reproducibility and integration of "off-the-shelf" components and enables the concept of printing on demand. The utility of this SEOP setup is demonstrated here to obtain near-unity (129)Xe polarization values in a 0.5 L optical pumping cell, including ~74 +/- 7% at 1000 Torr xenon partial pressure, a record value at such high Xe density. Values for the (129)Xe polarization exponential build-up rate [(3.63 +/- 0.15) * 10(-2) min(-1)] and in-cell (129)Xe spin-lattice relaxation time (T1 = 2.19 +/- 0.06 h) for 1000 Torr Xe were in excellent agreement with the ratio of the gas-phase polarizations for (129)Xe and Rb (PRb ~ 96%). Hyperpolarization-enhanced (129)Xe gas imaging was demonstrated with a spherical phantom following automated gas transfer from the polarizer. Taken together, these results support the development of a wide range of chemical, biochemical, material science, and biomedical applications. PMID- 24400920 TI - Randomized double-blind study of the effect of dexamethasone and methylprednisolone pulse in the control of rheumatoid arthritis flare-up: a preliminary study. AB - AIM: The objective of this study was to compare the efficacy and safety of dexamethasone and methylprednisolone for pulse therapy of rheumatoid arthritis flare-up. METHODS: This randomized double-blind controlled study was performed in the Emam Reza Educational Hospital of Tabriz University of Medical Sciences, Tabriz, Iran. Thirty rheumatoid arthritis patients who had severely active disease were recruited to the dexamethasone and methylprednisolone pulse groups. Disease activity of all the patients was measured by the Disease Activity Score in 28 joints (DAS28) at baseline, and days 4 and 30. RESULTS: The differences in the DAS28 at days 4 and 30, and the number of patients whose DAS28 obtained less than 3.2 and 2.6 in the dexamethasone and methylprednisolone groups were non significant. There was not any significant difference between the adverse effects of the treatments in the two groups. CONCLUSIONS: The results of the study suggest that dexamethasone pulse therapy is a safe and effective treatment for severe rheumatoid arthritis flare-up. PMID- 24400921 TI - Assessing analgesic use in patients with advanced cancer: development of a new scale--the Analgesic Quantification Algorithm. AB - OBJECTIVE: Many patients with advanced cancer frequently use analgesic medications for their pain. Systematically assessing and quantifying changes in analgesic use remains challenging in the clinical trials setting. Currently, there is no sensitive scale for categorizing the intensity of analgesic medications to understand the reasons for changes in patient-reported pain. We assessed whether the Analgesic Quantification Algorithm (AQA) is more sensitive than the World Health Organization Analgesic Treatment Ladder (WHO-AL) for quantifying analgesic medication use among patients with advanced cancer. METHODS: An expanded equianalgesic potency conversion table was developed to establish oral morphine equivalents for use in the AQA. Categories of opioid use were selected to increase sensitivity within the higher dose range of opioids and to better capture increases in analgesic dose intensity. The resulting 8-point AQA scale corresponds to no analgesic use, non-opioid analgesics, weak opioids only, <=75 mg, >75-150 mg, >150-300 mg, >300-600 mg, and >600 mg oral morphine equivalents per day. Baseline and 6-month analgesic data from a clinical trial of cancer patients were compared for each instrument. RESULTS: At both time points, the 4-point WHO-AL demonstrated a ceiling effect with a clustering of patients in the strong opioid category, whereas the AQA resulted in a distribution of scores throughout the eight categories, including the five strong opioid categories. CONCLUSIONS: The AQA represents a more sensitive measure of analgesic use than the WHO-AL, and may better determine whether changes in pain assessments in clinical trials are due to the intervention or changes in analgesic use. PMID- 24400923 TI - Morphological versus genetic diversity of Viola reichenbachiana and V. riviniana (sect. Viola, Violaceae) from soils differing in heavy metal content. AB - Morphological characters, AFLP markers and flow cytometry were used to investigate the morphological and genetic variability and differentiation of Viola reichenbachiana and V. riviniana in non-metallicolous (NM) and metallicolous (M) populations. The aims were to clarify the taxonomic status of plants occurring in ore-bearing areas, to determine any relationship in V. reichenbachiana and V. riviniana from sites not polluted with heavy metals, and to examine the genetic variability and differentiation of M and NM populations of both species. Multivariate analyses based on morphological characters showed significant differences between V. reichenbachiana and V. riviniana from non polluted sites, high levels of intra- and inter-population variability, and the occurrence of inter-specific hybrids. Plants from M populations showed hybrid characters but also fell within the range of V. riviniana or V. reichenbachiana. There were no significant differences in relative genome size between plants from polluted areas and V. riviniana from NM populations. Bayesian analysis of population genetic structure based on AFLP markers distinguished two main groups: V. reichenbachiana and V. riviniana together with the M populations. That analysis also revealed the occurrence of populations of inter-specific hybrids from non-polluted areas. Further Bayesian analysis of V. riviniana including NM and M populations separated all the studied M populations from NM populations. We conclude that plants forming the M populations are well adapted to a metal polluted environment, and could be considered as stabilised introgressive forms resulting from unidirectional (asymmetric) introgression toward V. riviniana. PMID- 24400922 TI - Managing the changing burden of cancer in Asia. AB - Asia accounts for 60% of the world population and half the global burden of cancer. The incidence of cancer cases is estimated to increase from 6.1 million in 2008 to 10.6 million in 2030, due to ageing and growing populations, lifestyle and socioeconomic changes. Striking variations in ethnicity, sociocultural practices, human development index, habits and dietary patterns are reflected in the burden and pattern of cancer in different regions. The existing and emerging cancer patterns and burden in different regions of Asia call for political recognition of cancer as an important public health problem and for balanced investments in public and professional awareness. Prevention as well as early detection of cancers leads to both better health outcomes and considerable savings in treatment costs. Cancer health services are still evolving, and require substantial investment to ensure equitable access to cancer care for all sections of the population. In this review, we discuss the changing burden of cancer in Asia, along with appropriate management strategies. Strategies should promote healthy ageing via healthy lifestyles, tobacco and alcohol control measures, hepatitis B virus (HBV) and human papillomavirus (HPV) vaccination, cancer screening services, and vertical investments in strengthening cancer healthcare infrastructure to improve equitable access to services. PMID- 24400924 TI - The Quebec BCG Vaccination Registry (1956-1992): assessing data quality and linkage with administrative health databases. AB - BACKGROUND: Vaccination registries have undoubtedly proven useful for estimating vaccination coverage as well as examining vaccine safety and effectiveness. However, their use for population health research is often limited. The Bacillus Calmette-Guerin (BCG) Vaccination Registry for the Canadian province of Quebec comprises some 4 million vaccination records (1926-1992). This registry represents a unique opportunity to study potential associations between BCG vaccination and various health outcomes. So far, such studies have been hampered by the absence of a computerized version of the registry. We determined the completeness and accuracy of the recently computerized BCG Vaccination Registry, as well as examined its linkability with demographic and administrative medical databases. METHODS: Two systematically selected verification samples, each representing ~0.1% of the registry, were used to ascertain accuracy and completeness of the electronic BCG Vaccination Registry. Agreement between the paper [listings (n = 4,987 records) and vaccination certificates (n = 4,709 records)] and electronic formats was determined along several nominal and BCG related variables. Linkage feasibility with the Birth Registry (probabilistic approach) and provincial Healthcare Registration File (deterministic approach) was examined using nominal identifiers for a random sample of 3,500 individuals born from 1961 to 1974 and BCG vaccinated between 1970 and 1974. RESULTS: Exact agreement was observed for 99.6% and 81.5% of records upon comparing, respectively, the paper listings and vaccination certificates to their corresponding computerized records. The proportion of successful linkage was 77% with the Birth Registry, 70% with the Healthcare Registration File, 57% with both, and varied by birth year. CONCLUSIONS: Computerization of this Registry yielded excellent results. The registry was complete and accurate, and linkage with administrative databases was highly feasible. This study represents the first step towards assembling large scale population-based epidemiological studies which will enable filling important knowledge gaps on the potential health effects of early life non-specific stimulation of the immune function, as resulting from BCG vaccination. PMID- 24400926 TI - Ultrasensitive resonance scattering (RS) spectral detection for trace tetracycline in milk using aptamer-coated nanogold (ACNG) as a catalyst. AB - This paper reports an ultrasensitive resonance scattering (RS) method to detect tetracycline (TET) in milk based on the competition of aptamers between nanogold and TET, aggregation of naked nanogold, nanocatalytic Fehling reaction, and RS signals of catalytic product Cu2O cubic. The detection principle was confirmed by the nanoparticle size analyzer (NANOS), scanning electron microscopy (SEM), and X ray diffraction (XRD). The variations of RS intensity had good linear correlation with TET concentrations, and the limit of detection was calculated as 11.6 nM. The proposed method was successfully applied for analysis of TET in milk, with total recoveries ranging from 105 to 109%. PMID- 24400927 TI - Giant recurrent phyllodes tumors of the breast: treatment dilemmas and literature review. PMID- 24400925 TI - Molecular, genetic and stem cell-mediated therapeutic strategies for spinal muscular atrophy (SMA). AB - Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease. It is the first genetic cause of infant mortality. It is caused by mutations in the survival motor neuron 1 (SMN1) gene, leading to the reduction of SMN protein. The most striking component is the loss of alpha motor neurons in the ventral horn of the spinal cord, resulting in progressive paralysis and eventually premature death. There is no current treatment other than supportive care, although the past decade has seen a striking advancement in understanding of both SMA genetics and molecular mechanisms. A variety of disease modifying interventions are rapidly bridging the translational gap from the laboratory to clinical trials. In this review, we would like to outline the most interesting therapeutic strategies that are currently developing, which are represented by molecular, gene and stem cell-mediated approaches for the treatment of SMA. PMID- 24400929 TI - Polystyrenes with hydrophilic end groups: synthesis, characterization, and effects on the self-assembly of breath figure arrays. AB - We report the synthesis and characterization of a series of hydroxyl-end functionalized polystyrenes (PS-OH) and the formation of patterned porous films. The polymers were synthesized by chain end reaction of polystyrene having a bromide end group (PS-Br) with hydramines including ethanolamine, diethanol amine, 2-amino-1,3-propanediol, and 2-(2-aminoethoxy) ethanol. The polymers were characterized by gel permeation chromatography (GPC), nuclear magnetic resonance (NMR), matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS), and differential scanning calorimetry (DSC). It was found that the end groups can influence the glass transition temperature (T(g)) of the polystyrenes. The polymers with different end groups were then used to prepare honeycomb-patterned porous films by the breath figure method. Results reveal that the subtle chain-end modification leads to a dramatic change in the morphology of the films. Honeycomb films with large area ordered structure can be easily prepared from PS-OH. Effects of the end groups as well as blending PS-OH with PS-Br on the surface pore diameter, pore center distance, and the hierarchical structure were studied in detail. As supported by the results of polymer hydrophilicity, in situ observation of the film formation process, as well as the chain mobility, the film structure is supposed to be mainly determined by the precipitation of polystyrene at the solution/water droplet interface and the interfacial activity enhanced by the end groups. PMID- 24400928 TI - Complexes possessing rare "tertiary" sulfonamide nitrogen-to-metal bonds of normal length: fac-[Re(CO)3(N(SO2R)dien)]PF6 complexes with hydrophilic sulfonamide ligands. AB - Tertiary sulfonamide nitrogen-to-metal bonds of normal length are very rare. We recently discovered such a bond in one class of fac-[Re(CO)3(N(SO2R)(CH2Z)2)](n) complexes (Z = 2-pyridyl) with N(SO2R)dpa ligands derived from di-(2 picolyl)amine (N(H)dpa). fac-[M(CO)3(N(SO2R)(CH2Z)2)](n) agents (M = (186/188)Re, (99m)Tc) could find use as radiopharmaceutical bioconjugates when R is a targeting moiety. However, the planar, electron-withdrawing 2-pyridyl groups of N(SO2R)dpa destabilize the ligand to base and create relatively rigid chelate rings, raising the possibility that the rare M-N(sulfonamide) bond is an artifact of a restricted geometry. Also, the hydrophobic 2-pyridyl groups could cause undesirable accumulation in the liver, limiting future use in radiopharmaceuticals. Our goal is to identify a robust, hydrophilic, and flexible N(CH2Z)2 chelate framework. New C2-symmetric ligands, N(SO2R)(CH2Z)2 with (Z = CH2NH2; R = Me, dmb, or tol), were prepared by treating N(H)dien(Boc)2, a protected diethylenetriamine (N(H)dien) derivative, with methanesulfonyl chloride (MeSO2Cl), 3,5-dimethylbenzenesulfonyl chloride (dmbSO2Cl), and 4 methylbenzenesulfonyl chloride (tolSO2Cl). Treatment of fac-[Re(CO)3(H2O)3](+) with these ligands, designated as N(SO2R)dien, afforded new fac [Re(CO)3(N(SO2R)dien)]PF6 complexes. Comparing the fac-[Re(CO)3(N(SO2Me)dien)]PF6 and fac-[Re(CO)3(N(SO2Me)dpa)]PF6 complexes, we find that the Re(I) N(sulfonamide) bonds are normal in length and statistically identical and that the methyl (13)C NMR signal has an unusually upfield shift compared to that in the free ligand. We attribute this unusual upfield shift to the fact that the sulfonamide N undergoes an sp(2)-to-sp(3) rehybridization upon coordination to Re(I) in both complexes. Thus, the sulfonamide N of N(SO2R)dien ligands is a good donor, even though the chelate rings are conformationally flexible. Addition of the strongly basic and potentially monodentate ligand, 4-dimethylaminopyridine, did not affect the fac-[Re(CO)3(N(SO2tol)dien)]PF6 complex, even after several weeks. This complex is also stable to heat in aqueous solution. These results indicate that N(SO2R)dien ligands form fac-[Re(CO)3(N(SO2R)dien)]PF6 complexes sufficiently robust to be utilized for radiopharmaceutical development. PMID- 24400930 TI - Emerging techniques employed in aptamer-based diagnostic tests. AB - Since aptamers were reported in 1990, research into the applications of aptamers, particularly diagnostic applications, has been growing. Aptamers can act as recognition elements instead of antibodies. In this regard, aptamers have unique characteristics because they are composed of nucleic acids. Intra- and intermolecular interactions of nucleic acids can be easily tailored following straightforward hybridization rules. Nucleic acids can be enzymatically replicated and their sequences can be determined using high-throughput methods. Using these properties, ligand-induced structural change-based aptamer sensors for homogeneous assays, polymerase- and/or nuclease-combined aptamer sensors for ultrasensitive assays, and microarray/next-generation sequencing-based aptamer sensors for multiplexed assays have been developed. This article reviews these unique aptamer sensors, demonstrating their great potential for diagnostic applications. PMID- 24400931 TI - Characterization of phosphatidylethanol blood concentrations for screening alcohol consumption in early pregnancy. AB - OBJECTIVE: Phosphatidylethanol (PEth) is formed endogenously by the direct action of ethanol, and has a half-life long enough to make it a reliable biomarker of alcohol exposure in early pregnancy. In this study, we aimed to characterize PEth blood concentrations to differentiate different levels of alcohol exposure in pregnant women. METHODS: The study consisted of 305 consecutive pregnant women who had been referred to our hospital for antenatal care. Of them, 117 self reported alcohol ingestion in the first trimester of pregnancy and 188 were abstainers. Total PEth concentration in whole blood was quantified by liquid chromatography-mass spectrometry (LC-MS/MS). Alcohol ingestion was classified according to the United States National Institute on Alcohol Abuse and Alcoholism into light drinkers: <= 3 drinks/week, moderate drinkers: 3-7 drinks/week, and heavier drinkers: > 7 drinks/week (a standard drink = 14 g of ethanol). RESULTS: Participants had quantifiable PEth blood levels 3-4 weeks after the last drink. There were 4.8% abstainers who had positive PEth concentrations; all of them reported a positive history of alcohol consumption before conception. PEth blood concentrations were significantly correlated to drinks per occasion (r = 0.44; P < 0.001) and days drinking per week (r = 0.34; P < 0.001). However, almost 74% of participants with <= 3 drinks/week of alcohol, and 46% with 3-7 drinks/week, had PEth blood concentrations below the lower limit of quantification (LLOQ). The area under the curve (AUC) generated by a receiver operation characteristic curve (ROC) analysis increased as the cutoff value of PEth blood concentration increased. However, the cutoff values were below or close to the LLOQ. CONCLUSIONS: Our study presents a formal characterization of PEth blood concentrations for screening alcohol ingestion in first-trimester pregnant women. However, caution is recommended for overrepresenting either negative or positive results. PMID- 24400932 TI - Serum biochemical markers of central nerve system damage in children with acute elemental mercury intoxication. AB - OBJECTIVE: Acute mercury intoxication among children can occur through unintentional exposure, and neurotoxicity is one of the main findings in acute exposures. In this study, we aimed to study the central nerve system markers, namely neuron-specific enolase (NSE), S100B, and glutamate receptor (GRIA 1) levels and discuss the mechanisms of central nerve system damage and whether these parameters could be used as markers of acute elemental mercury intoxication neurotoxicity. MATERIALS AND METHODS: This is a case-control study which includes 169 children with acute elemental mercury intoxication, who were exposed to mercury in the school laboratory from a broken jar, and 45 sex- and age-matched controls without mercury exposure. Patient group were divided into three subgroups according to the neurological examination performed during the admission. Neuropathy Group included the children with neurological symptoms including peripheral neuropathy and decreased muscle strength (n = 39) (with or without dilated pupils). Dilated Pupil Group included the children who had mid dilated/dilated pupils (n = 52). Asymptomatic Exposure Group included the children who did not have any neurological symptoms (n = 78). Serum NSE, S100B, GRIA 1, blood, and urine mercury levels were determined. RESULTS: NSE, S100B, GRIA 1, and blood mercury levels were significantly higher in exposed group than the nonexposed subjects (Median values NSE 22.4 ng/mL, 17.2 ng/mL; S100B 0.09 ng/mL, 0.08 ng/mL; GRIA 1 70.6 pg/mL, 54.1 pg/mL, and blood mercury 15.2 MUg/L, 0.23 MUg/L for exposed and nonexposed groups, respectively). GRIA 1 levels found to differ between exposed and nonexposed groups and it has also been found to be increased in the subgroups with positive neurological findings compared to that in neurological finding negative groups. S100B levels were found to be increased in exposed and having neurological symptom groups. There was not a significant difference between exposed-not having neurological symptom patients and control group. NSE levels were found to be higher in all subgroups when compared to those in controls, however there was not a significant difference between the subgroups. CONCLUSION: Serum NSE, GRIA 1, and S100B were increased with mercury exposure. GRIA 1 and S100B levels were observed to have the power to discriminate neurological symptom positive and negative groups. The increase in S100B levels are thought to be protecting the neurons and preventing further NSE elevations. PMID- 24400933 TI - Hemodialysis clearance of glyphosate following a life-threatening ingestion of glyphosate-surfactant herbicide. AB - CONTEXT: Ingestion of glyphosate-surfactant herbicides (GlySH) can result in acute kidney injury, electrolyte abnormalities, acidosis, cardiovascular collapse, and death. In severe toxicity, the use of hemodialysis is reported, but largely unsupported by kinetic analysis. We report the dialysis clearance of glyphosate following a suicidal ingestion of a glyphosate-containing herbicide. CASE DETAILS: A 62-year-old man was brought to the emergency department (ED) 8.5 h after drinking a bottle of commercial herbicide containing a 41% solution of glyphosate isopropylamine, in polyoxyethyleneamine (POEA) surfactant and water. He was bradycardic and obtunded with respiratory depression necessitating intubation and mechanical ventilation. Initial laboratory results were significant for the following: pH, 7.11; PCO2, 64 mmHg; PO2, 48 mmHg; potassium, 7.8 mEq/L; Cr 3.3, mg/dL; bicarbonate, 22 mEq/L; anion gap, 18 mEq/L; and lactate, 7.5 mmol/L. Acidosis and hyperkalemia persisted despite ventilation and fluid resuscitation. The patient underwent hemodialysis 16 h post ingestion, after which he demonstrated resolution of acidosis and hyperkalemia, and improvement in clinical status. Serum glyphosate concentrations were drawn prior to, during, and after hemodialysis. The extraction ratio and hemodialysis clearance were calculated to be 91.8% and 97.5 mL/min, respectively. DISCUSSION: We demonstrate the successful clearance of glyphosate using hemodialysis, with corresponding clinical improvement in a patient with several poor prognostic factors (advanced age, large volume ingested, and impaired consciousness). The effects of hemodialysis on the surfactant compound are unknown. Hemodialysis can be considered when severe acidosis and acute kidney injury complicate ingestion of glyphosate-containing products. PMID- 24400935 TI - Carbenic nitrile imines: properties and reactivity. AB - Structures and properties of nitrile imines were investigated computationally at B3LYP and CCSD(T) levels. Whereas NBO analysis at the B3LYP DFT level invariably predicts a propargylic electronic structure, CCSD(T) calculations permit a clear distinction between propargylic, allenic, and carbenic structures. Nitrile imines with strong IR absorptions above ca. 2150 cm(-1) have propargylic structures with a CN triple bond (RCNNSiMe3 and R2BCNNBR2), and those with IR absorptions below ca. 2150 cm(-1) are allenic (HCNNH, PhCNNH, and HCNNPh). Nitrile imines lacking significant cumulenic IR absorptions at 1900-2200 cm(-1) are carbenic (R-(C:)-N?N R'). Electronegative but lone pair-donating groups NR2, OR, and F stabilize the carbenic form of nitrile imines in the same way they stabilize "normal" singlet carbenes, including N-heterocyclic carbenes. NBO analyses at the CCSD(T) level confirm the classification into propargylic, allenic, and carbenic reactivity types. Carbenic nitrile imines are predicted to form azoketenes 21 with CO, to form [2+2] and [2+4] cycloadducts and borane adducts, and to cyclize to 1H diazirenes of the type 24 in mildly exothermic reactions with activation energies in the range 29-38 kcal/mol. Such reactions will be readily accessible photochemically and thermally, e.g., under the conditions of matrix photolysis and flash vacuum thermolysis. PMID- 24400934 TI - Evaluation of pain and function after two home exercise programs in a clinical trial on women with chronic neck pain - with special emphasises on completers and responders. AB - BACKGROUND: Different types of exercises can help manage chronic neck pain. Supervised exercise interventions are widely used, but these protocols require substantial resources. The aim of this trial, which focused on adherence, was to evaluate two home exercise interventions. METHODS: This parallel group randomized controlled trial included 57 women randomly allocated into two groups - a strength training group (STRENGTH, 34 subjects) and a stretching group (STRETCH, 23 subjects). The interventions focused on the neck and shoulder muscles and lasted for 12 months. The STRENGTH group performed weight training and ended each session with stretching exercises. These stretching exercises constituted the entirety of the STRETCH group's training session. Both groups were instructed to exercise three times per week. All the participants kept an exercise diary. In addition, all participants were offered support via phone and e-mail. The primary outcomes were pain intensity and function. The trial included a four- to six month and a twelve-month follow-up. A completer in this study exercised at least 1,5 times per week during eight unbroken weeks. A responder in this study reported clinically significant improvements on pain and function. The statistical analyses used the Mann Whitney U-test, Wilcoxon signed-rank test, and X2 test. RESULTS: At four- to six-months, the numbers of completers were 19 in the STRENGTH group and 17 in the STRETCH group. At twelve months, the corresponding numbers were 11 (STRENGTH) and 10 (STRETCH). At four- to six months, the proportions of subjects reporting clinically important changes (STRENGTH and STRETCH) were for neck pain: 47% and 41%, shoulder pain: 47% and 47%, function: 37% and 29%. At twelve months, the corresponding numbers were for neck pain: 45% and 40%, shoulder pain: 55% and 50%, function: 55% and 20%. CONCLUSIONS: No differences in the two primary outcomes between the two interventions were found, a finding that may be due to the insufficient statistical power of the study. Both interventions based on home exercises improved the two primary outcomes, but the adherences were relatively low. Future studies should investigate ways to improve adherence to home exercise treatments. TRIAL REGISTRATION: ClinicalTrials.gov Id: NCT01876680. PMID- 24400936 TI - Adventures in rural and remote health services innovation: the role of researcher as collaborator. PMID- 24400937 TI - Motivational intervention to enhance post-detoxification 12-Step group affiliation: a randomized controlled trial. AB - AIMS: To compare a motivational intervention (MI) focused on increasing involvement in 12-Step groups (TSGs; e.g. Alcoholics Anonymous) versus brief advice (BA) to attend TSGs. DESIGN: Patients were assigned randomly to either the MI or BA condition, and followed-up at 6 months after discharge. SETTING AND PARTICIPANTS: One hundred and forty substance use disorder (SUD) patients undergoing in-patient detoxification (detox) in Norway. MEASUREMENTS: The primary outcome was TSG affiliation measured with the Alcoholics Anonymous Affiliation Scale (AAAS), which combines meeting attendance and TSG involvement. Substance use and problem severity were also measured. FINDINGS: At 6 months after treatment, compared with the BA group, the MI group had higher TSG affiliation [0.91 point higher AAAS score; 95% confidence interval (CI) = 0.04 to 1.78; P = 0.041]. The MI group reported 3.5 fewer days of alcohol use (2.1 versus 5.6 days; 95% CI = -6.5 to -0.6; P = 0.020) and 4.0 fewer days of drug use (3.8 versus 7.8 days; 95% CI = -7.5 to -0.4; P = 0.028); however, abstinence rates and severity scores did not differ between conditions. Analyses controlling for duration of in patient treatment did not alter the results. CONCLUSIONS: A motivational intervention in an in-patient detox ward was more successful than brief advice in terms of patient engagement in 12-Step groups and reduced substance use at 6 months after discharge. There is a potential benefit of adding a maintenance focused element to standard detox. PMID- 24400938 TI - Adaptation of lettuce mosaic virus to Catharanthus roseus involves mutations in the central domain of the VPg. AB - An isolate of Lettuce mosaic virus (LMV, a Potyvirus) infecting Madagascar periwinckle (Catharanthus roseus) was identified and characterized by Illumina deep sequencing. LMV-Cr has no close affinities to previously sequenced LMV isolates and represents a novel, divergent LMV clade. Inoculation experiments with other representative LMV isolates showed that they are unable to infect C. roseus, which was not known to be a host for LMV. However, three C. roseus variants of one of these isolates, LMV-AF199, could be selected and partially or completely sequenced. These variants are characterized by the accumulation of mutations affecting the C-terminal part of the cylindrical inclusion (CI) helicase and the central part of the VPg. In particular, a serine to proline mutation at amino acid 143 of the VPg was observed in all three independently selected variants and is also present in the LMV-Cr isolate, making it a prime candidate as a host-range determinant. Other mutations at VPg positions 65 and 144 could also contribute to the ability to infect C. roseus. Inoculation experiments involving a recombinant LMV expressing a permissive lettuce eukaryotic translation initiation factor 4E (eIF4E) suggest that eIF4E does not contribute to the interaction of most LMV isolates with C. roseus. PMID- 24400939 TI - A soybean acyl carrier protein, GmACP, is important for root nodule symbiosis. AB - Legumes (members of family Fabaceae) establish a symbiotic relationship with nitrogen-fixing soil bacteria (rhizobia) to overcome nitrogen source limitation. Single root hair epidermal cells serve as the entry point for bacteria to infect the host root, leading to development of a new organ, the nodule, which the bacteria colonize. In the present study, the putative role of a soybean acyl carrier protein (ACP), GmACP (Glyma18g47950), was examined in nodulation. ACP represent an essential cofactor protein in fatty acid biosynthesis. Phylogenetic analysis of plant ACP protein sequences showed that GmACP was classified in a legume-specific clade. Quantitative reverse-transcription polymerase chain reaction analysis demonstrated that GmACP was expressed in all soybean tissues but showed higher transcript accumulation in nodule tissue. RNA interference mediated gene silencing of GmACP resulted in a significant reduction in nodule numbers on soybean transgenic roots. Fluorescent protein-labeled GmACP was localized to plastids in planta, the site of de novo fatty acid biosynthesis in plants. Analysis of the fatty acid content of root tissue silenced for GmACP expression, as determined by gas chromatography-mass spectrometry, showed an approximately 22% reduction, specifically in palmitic and stearic acid. Taken together, our data provide evidence that GmACP plays an important role in nodulation. PMID- 24400940 TI - Cost-effectiveness of rituximab as maintenance treatment for relapsed follicular lymphoma: results of a population-based study. AB - OBJECTIVES: On the basis of two population-based registries, our study aims to calculate the real-world cost-effectiveness of rituximab maintenance compared with observation in relapsed or refractory follicular lymphoma patients who responded to second-line chemotherapy. METHODS: Data were obtained from the EORTC20981 trial, the Netherlands Cancer Registry and two population-based registries. A Markov model was developed to calculate cost per life year gained (LYG) and quality-adjusted life years (QALYs) for three scenarios. RESULTS: Our real-world patients were (62 years) 6 to 7 years older and had higher complete response rates to second-line chemotherapy than the trial population. Differences between the real-world rituximab and observation group were observed for second line chemotherapy and disease progression. Groups were more balanced after using propensity matching. Relying entirely on updated trial results (scenario1) in combination with local cost data resulted in ratios of ?11,259 per LYG and ?12,655 per QALY. For scenario2, consisting of trial efficacy and matched real world costs, ratios of ?21,202 per LYG and ?23,821 per QALY were calculated. Using real-world matched evidence (scenario3) for both effectiveness and costs showed ratios of ?10,591 per LYG and ?11,245 per QALY. CONCLUSION: Although differences in real-world and trial population were found, using real-world data as well as results from long-term trial follow-up showed favourable ICERs for rituximab maintenance. Nevertheless, results showed that caution is required with data synthesis, interpretation and generalisability of results. As different scenarios provide answers to different questions, we recommend healthcare decision-makers to recognise the importance of calculating several cost effectiveness scenarios. PMID- 24400941 TI - A semiparametric approach to simultaneous covariance estimation for bivariate sparse longitudinal data. AB - Estimation of the covariance structure for irregular sparse longitudinal data has been studied by many authors in recent years but typically using fully parametric specifications. In addition, when data are collected from several groups over time, it is known that assuming the same or completely different covariance matrices over groups can lead to loss of efficiency and/or bias. Nonparametric approaches have been proposed for estimating the covariance matrix for regular univariate longitudinal data by sharing information across the groups under study. For the irregular case, with longitudinal measurements that are bivariate or multivariate, modeling becomes more difficult. In this article, to model bivariate sparse longitudinal data from several groups, we propose a flexible covariance structure via a novel matrix stick-breaking process for the residual covariance structure and a Dirichlet process mixture of normals for the random effects. Simulation studies are performed to investigate the effectiveness of the proposed approach over more traditional approaches. We also analyze a subset of Framingham Heart Study data to examine how the blood pressure trajectories and covariance structures differ for the patients from different BMI groups (high, medium, and low) at baseline. PMID- 24400942 TI - Haemolytic uremic syndrome following fire ant bites. AB - BACKGROUND: Haemolytic-uremic syndrome (HUS) is a severe, life-threatening disease with symptoms such as haemolytic anaemia, renal failure, and a low platelet count. Possible aetiology includes bacterial infections, medication, post-hematopoietic cell transplantation, pregnancy, autoimmune disease, and acquired immunodeficiency syndrome. CASE PRESENTATION: We report the case of a 21 year-old healthy man who developed acute renal failure caused by HUS. Typical symptoms of HUS combined with severe uraemia developed following a large local reaction after suspected Solenopsis invicta (fire ant) bites. He was successfully treated with plasma exchange and achieved complete recovery of renal function. CONCLUSION: This is the first case illustrating a serious systemic reaction of HUS to fire ant bites, and highlights this severe complication in patients who sustain fire ant bites. PMID- 24400943 TI - Epithelial wound healing on keratin film, amniotic membrane and polystyrene in vitro. AB - PURPOSE: Corneal epithelial wound healing is a major issue in ocular surface (OS) reconstruction. Aim of this study was to evaluate parameters of epithelial wound healing in vitro on transparent keratin films (KFs) derived from human hair in comparison with amniotic membrane (AM) and polystyrene. MATERIALS AND METHODS: The human corneal epithelial cell line (HCE-T) was expanded on KF, AM and commercially available 24-well polystyrene cell culture plates in vitro to compare cell proliferation, migration and attachment by 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide, scratch-wound healing and adhesion assay. Cells cultured on KF and AM at an air-liquid interface for 14 d were stained with hematoxylin and eosin for histology. RESULTS: The highest proliferation of HCE-T cells was observed on polystyrene at all time points (p < 0.05). At a seeding density of 5 * 10(3) cells/well, no difference in proliferation was found between AM and KF after 24 h and 72 h (p = 0.582 and p = 0.066), while higher proliferation was observed on AM compared to KF after 48 h (p = 0.005). At a seeding density of 1 * 10(4) cells/well, no difference was found between AM and KF after 24 h (p = 0.252), while higher proliferation was observed on AM compared to KF after 48 h and 72 h (p = 0.001 and p = 0.003). The significantly fastest cell migration was observed on polystyrene at all time points (p < 0.01). Cell migration was significantly higher on KF compared to AM at 48 h (p < 0.05). After 30 min, there were significantly more cells attached to AM compared to polystyrene and KF (p = 0.032 and p = 0.001). No significant difference in cell attachment was observed between KF and polystyrene (p = 0.147). Histology demonstrated that HCE-T cells cultured on KF and AM at an air-liquid interface for 14 d form a multilayered epithelium similar to normal human corneal epithelium. CONCLUSION: Transparent KFs derived from human hair support proliferation, migration, adhesion and differentiation of HCE-T cells in vitro. Therefore, it could be a promising alternative to AM for OS reconstruction. PMID- 24400944 TI - Probability of a shockable presenting rhythm as a function of EMS response time. AB - INTRODUCTION: Survival from cardiac arrest is associated with having a shockable presenting rhythm (VF/pulseless VT) upon EMS arrival. A concern is that several studies have reported a decline in the incidence of VF/PVT over the past few decades. One plausible explanation is that contemporary cardiovascular therapies, such as increased use of statin and beta blocker drugs, may shorten the duration of VF/PVT after arrest. As a result, EMS response time would become an increasingly important factor in the likelihood of a shockable presenting rhythm, and consequently, cardiac arrest survival. OBJECTIVE: To develop a model describing the likelihood of shockable presenting rhythm as a function of EMS response time. METHODS: We conducted a retrospective observational study of cardiac arrest using the North Carolina Prehospital Care Reporting System (PreMIS). Inclusionary criteria consisted of adult patients suffering nontraumatic cardiac arrests witnessed by a layperson between January 1 and June 30, 2012. Patients defibrillated prior to EMS arrival were excluded. Chi-square and t-tests were used to analyze the relationship between shockable presenting rhythm and patient age, gender, and race; response time measured as elapsed minutes between 9-1-1 call receipt and scene arrival; and bystander CPR. Logistic regression was used to calculate the adjusted odds ratio (OR) of shockable presenting rhythm as a function of response time while controlling for statistically significant covariates. RESULTS: A total of 599 patients met inclusion criteria. Overall, VF/PVT was observed in 159 patients (26.5%). VF/PVT was less likely with increasing EMS response time (OR 0.92, 95% CI = 0.87-0.97, p < 0.01) and age (OR 0.98, 95% CI = 0.97-0.99, p < 0.01), while males (OR 1.98, 95% CI = 1.29-3.03, p < 0.01) and Caucasians (OR 1.86, 95% CI = 1.17-2.95, p < 0.01) were more likely to have shockable presenting rhythm. Bystander CPR was not associated with shockable presenting rhythm, although EMS response time was longer among patients with bystander CPR compared to those without (9.83 vs. 8.83 minutes, p < 0.01). CONCLUSIONS: We found that for every one minute of added ambulance response time, the odds of shockable presenting rhythm declined by 8%. This information could prove useful for EMS managers tasked with developing EMS system response strategies for cardiac arrest management. PMID- 24400945 TI - Graphene networks anchored with sn@graphene as lithium ion battery anode. AB - A facile and scalable in situ chemical vapor deposition (CVD) technique using metal precursors as a catalyst and a three-dimensional (3D) self-assembly of NaCl particles as a template is developed for one-step fabrication of 3D porous graphene networks anchored with Sn nanoparticles (5-30 nm) encapsulated with graphene shells of about 1 nm (Sn@G-PGNWs) as a superior lithium ion battery anode. In the constructed architecture, the CVD-synthesized graphene shells with excellent elasticity can effectively not only avoid the direct exposure of encapsulated Sn to the electrolyte and preserve the structural and interfacial stabilization of Sn nanoparticles but also suppress the aggregation of Sn nanoparticles and buffer the volume expansion, while the interconnected 3D porous graphene networks with high electrical conductivity, large surface area, and high mechanical flexibility tightly pin the core-shell structure of Sn@G and thus lead to remarkably enhanced electrical conductivity and structural integrity of the overall electrode. As a consequence, this 3D hybrid anode exhibits very high rate performance (1022 mAh/g at 0.2 C, 865 mAh/g at 0.5 C, 780 mAh/g at 1 C, 652 mAh/g at 2 C, 459 mAh/g at 5 C, and 270 mAh/g at 10 C, 1 C = 1 A/g) and extremely long cycling stability even at high rates (a high capacity of 682 mAh/g is achieved at 2 A/g and is maintained approximately 96.3% after 1000 cycles). As far as we know, this is the best rate capacity and longest cycle life ever reported for a Sn-based lithium ion battery anode. PMID- 24400946 TI - Obesity, sex and pubertal status affect appetite hormone responses to a mixed glucose and whey protein drink in adolescents. AB - BACKGROUND AND OBJECTIVES: Little information is available on how food intake regulatory hormones may be altered during pubertal development and across the weight spectrum in adolescents. Therefore, the effect of obesity, sex and pubertal status on subjective appetite and appetite hormones in response to a mixed glucose and whey protein drink was determined in 8-18 year old adolescents. PATIENTS AND METHODS: A cross-sectional cohort study was conducted at the Hospital for Sick Children, Toronto. After a 12 h fast, normal weight (n = 5 female, 4 male) and obese (n = 5 female, 4 male) adolescents (Experiment 1), and pre-early pubertal (n = 10) and mid-late pubertal (n = 10) obese male adolescents (Experiment 2) consumed a 250 ml glucose (30 g) and whey protein (30 g) beverage. Insulin, PYY, ghrelin and subjective appetite were measured over 120 min. RESULTS: Obese adolescents (Experiment 1) have higher insulin, PYY and lower ghrelin (P < 0.006) than normal weight controls, with a more pronounced effect in males (P < 0.037). Puberty (Experiment 2) did not affect insulin (P = 0.305), but the change in PYY in response to the drink was greater (P = 0.032) and ghrelin was lower (P = 0.026) in mid-late pubertal than pre-early pubertal obese males. Average appetite 60 min post-drink was higher in obese and mid-late pubertal adolescents, but not related to hormone changes. CONCLUSIONS: Obesity, sex and pubertal status affect macronutrient-stimulated appetite hormone secretion and these factors may alter food intake in obese children during pubertal development. PMID- 24400947 TI - Psoriatic arthritis screening tools: study design and methodological challenges. PMID- 24400948 TI - Determination of the triple helical chain conformation of beta-glucan by facile and reliable triple-detector size exclusion chromatography. AB - Triple helical polysaccharides (t-polysaccharides) are easily gelated in water, resulting in difficult fractionation, leading to the complex and time-consuming chain conformational characterization. Moreover, the fractionation is not always successful due to the coexistence of individual chains and aggregates. In this work, we developed a facile and reliable method to rapidly and accurately characterize the chain conformation of t-polysaccharide without fractionation needed in traditional conformation characterization. A triple helical beta-1,3 glucan (t-beta-1,3-glucan), extracted from the fruiting bodies of Lentinus edodes, was identified to consist of a beta-1,3-glucan with two beta-1,6-D glucopyranoside branchings for every five beta-1,3-glucopyranoside linear linkages by one- and two-dimensional NMR and GC-MS analysis. The chain conformations of the t-beta-glucan in aqueous solution and in DMSO were successfully characterized by a combination of size exclusion chromatography (SEC), multiangle static light scattering, a differential refractometer, and a capillary viscosity detector (triple-detector SEC). The results revealed that the predominate species of the t-beta-glucan in a 0.15 M NaCl aqueous solution existed as a triple helical conformation with high chain stiffness, and a few aggregates (4%) coexisted here. The Mark-Houwink and ?S(2)?(1/2) versus M(w) equations of individual triple helical chains and aggregates were obtained simultaneously, and the results confirmed again the coexistence of two kinds of chain conformations. The fractal dimension indicated that the aggregate in the aqueous solution was a kind of reversible microgel with a 3D network structure. Furthermore, the chain morphology of the t-beta-glucan in aqueous solution was observed directly by transmission electron microscopy and atomic force microscopy to support the worm-like chain for the individuals and 3D network for the aggregates. The triple-detector SEC technology was facile and reliable for the system with two fractions of different chain conformation, and the test time required was only 1/30 of what the traditional method needed. PMID- 24400949 TI - The genetic diversity and spatial genetic structure of the Corso-Sardinian endemic Ferula arrigonii Bocchieri (Apiaceae). AB - Corsica and Sardinia represent major hotspots of plant diversity in the Mediterranean area and are priority regions for conservation due to their high number of endemic plant species. However, information supporting human decision making on the conservation of these species is still scarce, especially at the genetic level. In this work, the first assessment is reported of the species-wide spatial genetic structure and diversity of Ferula arrigonii Bocchieri, a Corso Sardinian endemic located in a few coastal sites and on small islands. Nine populations covering the entire natural range of the species were investigated by means of AFLP (amplified fragment length polymorphism) markers. Results indicate that this species is characterised by high levels of genetic polymorphism (92% polymorphic fragments) and of genetic diversity (H(w) = 0.317) and by relatively low differentiation among populations (F(st) = 0.057). PCoA, Bayesian analysis and neighbour-joining clustering were also employed to investigate the genetic structure of this species. Three genetically distinct groups were detected, although with considerable overlap between populations. PMID- 24400950 TI - The craving experience questionnaire: a brief, theory-based measure of consummatory desire and craving. AB - BACKGROUND AND AIMS: Research into craving is hampered by lack of theoretical specification and a plethora of substance-specific measures. This study aimed to develop a generic measure of craving based on elaborated intrusion (EI) theory. Confirmatory factor analysis (CFA) examined whether a generic measure replicated the three-factor structure of the Alcohol Craving Experience (ACE) scale over different consummatory targets and time-frames. DESIGN: Twelve studies were pooled for CFA. Targets included alcohol, cigarettes, chocolate and food. Focal periods varied from the present moment to the previous week. Separate analyses were conducted for strength and frequency forms. SETTING: Nine studies included university students, with single studies drawn from an internet survey, a community sample of smokers and alcohol-dependent out-patients. PARTICIPANTS: A heterogeneous sample of 1230 participants. MEASUREMENTS: Adaptations of the ACE questionnaire. FINDINGS: Both craving strength [comparative fit indices (CFI = 0.974; root mean square error of approximation (RMSEA) = 0.039, 95% confidence interval (CI) = 0.035-0.044] and frequency (CFI = 0.971, RMSEA = 0.049, 95% CI = 0.044-0.055) gave an acceptable three-factor solution across desired targets that mapped onto the structure of the original ACE (intensity, imagery, intrusiveness), after removing an item, re-allocating another and taking intercorrelated error terms into account. Similar structures were obtained across time-frames and targets. Preliminary validity data on the resulting 10-item Craving Experience Questionnaire (CEQ) for cigarettes and alcohol were strong. CONCLUSIONS: The Craving Experience Questionnaire (CEQ) is a brief, conceptually grounded and psychometrically sound measure of desires. It demonstrates a consistent factor structure across a range of consummatory targets in both laboratory and clinical contexts. PMID- 24400951 TI - Is group A thawed plasma suitable as the first option for emergency release transfusion? (CME). AB - BACKGROUND: Group AB plasma, which lacks anti-A and anti-B isohemagglutinins, is issued for emergency transfusion when a patient's ABO group is unknown, but the relative scarcity of group AB blood donors limits its availability. We sought to establish a thawed plasma inventory to improve the rapid availability of plasma in the emergency release setting but were concerned about potential wastage of group AB plasma. STUDY DESIGN AND METHODS: Recognizing that plasma-incompatible apheresis platelets are routinely transfused and only rarely result in hemolytic reactions if the donor is blood group O, and considering that group A plasma would be compatible with approximately 85% of our patient population, we instituted an emergency release policy whereby thawed group A plasma is issued to all patients of unknown blood group or if compatible plasma is not available. ABO compatible plasma is then issued, if needed, once the patient's blood group is determined. We prospectively assessed the outcomes of all patients who received incompatible plasma under our policy. RESULTS: During the first 5 years under this policy, 385 emergency release requests for plasma were received by our blood bank. Among them, 23 group B or AB patients met criteria for receiving a median of 2 units of incompatible group A plasma. No hemolytic transfusion reactions or other adverse events related to transfusion were seen in any of these 23 patients. CONCLUSION: We propose that group A plasma may be an acceptable alternative to AB plasma as the first option in the emergency release setting. PMID- 24400952 TI - Evaluation of subfoveal choroidal thickness in pregnant women using enhanced depth imaging optical coherence tomography. AB - PURPOSE: To evaluate the subfoveal choroidal thickness (SFCT) measured by enhanced depth imaging optical coherence tomography (EDI-OCT) in pregnant women. METHODS: In this prospective and cross-sectional study, 100 pregnant women and 100 age-matched nonpregnant women were enrolled. The SFCT was measured by EDI OCT. The refractive error, intraocular pressure (IOP), axial length (AL), central corneal thickness (CCT), systolic and diastolic blood pressure, and ocular perfusion pressure (OPP) were also measured. Pregnancy-related factors including gestational age, maternal weight gain, and fetal weight were noted. RESULTS: Mean SFCT was 371.1 +/- 61.8 um in the study group and 337.2 +/- 62.4 um in the control group (p < 0.001). No significant correlation was found between SFCT and spherical refraction, IOP, AL, CCT, OPP, gestational age, maternal weight gain, or fetal weight. CONCLUSION: Our results suggest that subfoveal choroidal thickness increases in pregnant women compared with age-matched nonpregnant women. PMID- 24400954 TI - Aggregation of negatively charged colloidal particles in the presence of multivalent cations. AB - The aggregation and charging behavior of sulfate and carboxyl latex particles in the presence of different multivalent salts was studied. Time-resolved light scattering and electrophoresis are the main experimental techniques used. In particular, the influence of the type of counterion is investigated. The main conclusion is that the valence of the counterion is highly relevant in determining the aggregation behavior, whereas its chemical nature is rather unimportant. Multivalent ions of higher valence destabilize the suspensions more effectively, in particular, by shifting the critical coagulation concentration (CCC) to lower values. This behavior reflects the classical Schulze-Hardy rule. Comparison with literature data reveals that the presently investigated systems behave similarly to the ones described earlier, but the observed dependence on valence is weaker than in some other systems. Moreover, we observe a slowdown of the aggregation at high electrolyte concentrations. This slowdown can be explained by the greater viscosity of the electrolyte solutions under these conditions. PMID- 24400953 TI - Pharmacokinetics of oral vs. intravenous dexamethasone in patients hospitalized with community-acquired pneumonia. AB - AIM: The use of corticosteroids as adjunctive therapy might be effective in patients with community-acquired pneumonia (CAP). Oral administration of dexamethasone is a practical and safer alternative to the intravenous route. Since patients hospitalized with pneumonia might have delayed gastric emptying, this study explored systemic exposure in terms of area under the concentration time curve (AUC) of oral dexamethasone in patients hospitalized with CAP. METHODS: In this randomized, open label study, 30 patients admitted with CAP were randomized to receive either 4 mg intravenous or 6 mg oral dexamethasone for 4 consecutive days. Serial blood samples were obtained before and after drug administration. RESULTS: Median AUC to infinity was 626 MUg l(-1) h (IQR 401 1161) for the intravenous group and 774 MUg l(-1) h (IQR 618-1146) for the oral group. The AUC ratio of 6 mg oral and 4 mg intravenous dexamethasone was 1.22 (95% confidence interval (CI) 0.81, 1.82), which represents a bioavailability of 81% (95% CI 54, 121) after correction for differences in dexamethasone dose. CONCLUSIONS: Bioavailability of oral dexamethasone in patients hospitalized with pneumonia is sufficient. This makes oral dexamethasone an appropriate alternative for intravenous administration in these patients. PMID- 24400955 TI - From hydrated Ni3(OH)2(C8H4O4)2(H2O)4 to anhydrous Ni2(OH)2(C8H4O4): impact of structural transformations on magnetic properties. AB - Dehydration of the hybrid compound [Ni3(OH)2(tp)2(H2O)4] (1) upon heating led to the sequential removal of coordinated water molecules to give [Ni3(OH)2(tp)2(H2O)2] (2) at T1 = 433 K and thereafter anhydrous [Ni2(OH)2(tp)] (3) at T2 = 483 K. These two successive structural transformations were thoroughly characterized by powder X-ray diffraction assisted by density functional theory calculations. The crystal structures of the two new compounds 2 and 3 were determined. It was shown that at T1 (433 K) the infinite nickel oxide chains built of the repeating structural unit [Ni3(MU3-OH)2](4+) in 1 collapse and lead to infinite porous layers, forming compound 2. The second transformation at T2 (483 K) gave the expected anhydrous compound 3, which is isostructural with Co2(OH)2(tp). These irreversible transitions directly affect the magnetic behavior of each phase. Hence, 1 was found to be antiferromagnetic at TN = 4.11 K, with metamagnetic behavior with a threshold field Hc of ca. 0.6 T. Compound 2 exhibits canted antiferromagnetism below TN = 3.19 K, and 3 is ferromagnetic below TC = 4.5 K. PMID- 24400956 TI - Evaluation of the medium-term outcomes and impact of the Rowan Nicks Scholarship Programme. AB - BACKGROUND: Rowan Nicks was a cardiothoracic surgeon in Sydney. He endowed the Rowan Nicks Scholarship Programme of the Royal Australasian College of Surgeons, which was initiated in 1991 to provide opportunities for clinicians from developing countries so that they return to their countries as leaders and teachers. This paper's objective was to evaluate the outcomes and impact of the scholarship on individuals and their communities. METHODS: A survey was undertaken of 34 eligible scholars of whom 29 participated. It was directed at whether objectives were achieved in technical skills, patient management and in competency in research and leadership. RESULTS: Ninety-eight per cent of scholars returned to work in their home country. Twenty-eight of 29 were working in their chosen specialty and had returned to their former positions. The clinical/operative skills obtained were regarded as useful by 86%, and 22/29 (76%) scholars reported they had gained worthwhile leadership and administrative skills. Improved clinical outcomes for patients were achieved as evidenced by reduced mortality and less disability. There was also a positive impact on health systems. The best documented of these were improved trauma management, development of paediatric surgery in rural Bangladesh, a new cardiac unit in Myanmar, organ transplantation and better injury outcomes in Papua New Guinea. CONCLUSION: The programme has resulted in potential and actual leaders returning to their home countries where they positively impacted on health and surgical services. This has resulted in a reduced burden of surgical disease in the scholars' countries as measured by less death, disability and deformity. PMID- 24400958 TI - Bimolecular photoinduced electron transfer beyond the diffusion limit: the Rehm Weller experiment revisited with femtosecond time resolution. AB - To access the intrinsic, diffusion free, rate constant of bimolecular photoinduced electron transfer reactions, fluorescence quenching experiments have been performed with 14 donor/acceptor pairs, covering a driving-force range going from 0.6 to 2.4 eV, using steady-state and femtosecond time-resolved emission, and applying a diffusion-reaction model that accounts for the static and transient stages of the quenching for the analysis. The intrinsic electron transfer rate constants are up to 2 orders of magnitude larger than the diffusion rate constant in acetonitrile. Above ~1.5 eV, a slight decrease of the rate constant is observed, pointing to a much weaker Marcus inverted region than those reported for other types of electron transfer reactions, such as charge recombination. Despite this, the driving force dependence can be rationalized in terms of Marcus theory. PMID- 24400957 TI - Factors associated with chronic musculoskeletal pain in patients with chronic kidney disease. AB - BACKGROUND: Chronic musculoskeletal (MS) pain is common in patients with chronic kidney disease (CKD) undergoing haemodialysis. However, epidemiological data for chronic MS pain and factors associated with chronic MS pain in patients with early- or late-stage CKD who are not undergoing dialysis are limited. METHOD: A cross-sectional study to evaluate the prevalence of chronic MS pain and factors associated with chronic MS pain in patients with early- and late-stage CKD who were not undergoing dialysis, was conducted. In addition, the distribution of pain severity among patients with different stages of CKD was evaluated. RESULTS: Of the 456 CKD patients studied, 53.3% (n = 243/456) had chronic MS pain. Chronic MS pain was independently and significantly associated with hyperuricemia as co morbidity, as well as with the calcium * phosphate product levels. In CKD patients with hyperuricemia, chronic MS pain showed a negative, independent significant association with diabetes mellitus as a co-morbidity (odds ratio: 0.413, p = 0.020). However, in the CKD patients without hyperuricemia as a co morbidity, chronic MS pain showed an independent significant association with the calcium * phosphate product levels (odds ratio: 1.093, p = 0.027). Furthermore, stage-5 CKD patients seemed to experience more severe chronic MS pain than patients with other stages of CKD. CONCLUSION: Chronic MS pain is common in CKD patients. Chronic MS pain was independently and significantly associated with hyperuricemia as co-morbidity, and with the calcium * phosphate product levels in early- and late-stage CKD patients who were not on dialysis. PMID- 24400959 TI - Inter-hemispheric recruitment as a function of task complexity, age and cognitive reserve. AB - In a behavioral divided visual field study, we investigated the efficiency of inter-hemispheric cooperation according to (1) task computational complexity (physical-identity versus name-identity letter matching), (2) age (younger versus older adults) and (3) educational attainment, used as a proxy for cognitive reserve. Overall, the results indicated a shift from within- to across-hemisphere processing advantage with increasing task complexity, suggesting that bilateral engagement leads to enhanced performance under high-demand conditions. This pattern was influenced by age, with older adults showing no within-hemisphere advantage in the simpler task and a greater across-hemisphere advantage in the more complex one, consistent with an age-compensatory view of inter-hemispheric recruitment. Moreover, for older adults, more years of education was associated with a weaker across-hemisphere advantage. Thus, we propose that cognitive reserve may account for bilateral engagement efficiency. Finally, the groups differed in terms of laterality effects, with only younger adults demonstrating a left visual field advantage in the name-identity task, lending some support to the right hemi-aging hypothesis. PMID- 24400960 TI - Photoswitching in two-component surface-mounted metal-organic frameworks: optically triggered release from a molecular container. AB - The remote control of surface properties is one of the key challenges in interfacial systems chemistry. Here, we report the realization of a SURMOF (surface-mounted metal-organic framework)-based hybrid system in which a crucial component can be switched by light. The realization of this two-component system is made possible by installing vertical compositional gradients via liquid-phase epitaxy. After loading the porous coating with guest molecules, its release is initiated by illumination with visible light and monitored by a quartz crystal microbalance. PMID- 24400961 TI - A rare cause of arm and shoulder pain in an eight-year-old girl: Pancoast's syndrome secondary to lobar pneumonia. PMID- 24400962 TI - Paroxysmal Nocturnal Hemoglobinuria is rare cause for thrombosis of the intra abdominal veins in the ethnic Indian population - results from FLAER-based flowcytometry screening. AB - BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) may present as cytopenia, hemolysis, or thrombosis at unusual sites including splanchnic vessels. Thrombosis of the portal veins and hepatic veins are associated with thrombophilic risk factors: deficiencies of protein C, protein S, and antithrombin, positivity for antiphospholipid antibodies, and factor V Leiden mutation. There is limited information regarding PNH presenting primarily as a thrombotic event. We prospectively screened 142 consecutive patients with intrabdominal thrombosis and 106 controls with fluorescently labeled inactive toxin aerolysin (FLAER)-based flowcytometry to assess the frequency of PNH as a thrombophilic risk factor in patients with intra-abdominal thrombosis. METHODS: Granulocytes of patients and controls were screened with CD 24 and FLAER and monocytes with CD 14 and FLAER. Dual negativity of >1% events in both lineages was interpreted as a positive PNH clone. Screening for thrombophilia risk factors was carried out. RESULTS: Two (1.4%) cases had large PNH clones. RBC also demonstrated the PNH defect. Thrombophilia risk factors were as follows: deficiency of protein S, protein C, and antithrombin in 13.4%, 4.9%, and 2.1%, respectively, and positivity for anti-beta-2 glycoprotein 1, anticardiolipin antibodies, and lupus anticoagulant in 9.2%, 1.4%, and 0.7%, respectively. Factor V Leiden mutation was seen in 1.4% patients. CONCLUSION: PNH was uncommon in patients with intra-abdominal thrombosis in the ethnic Indian population. Despite low positivity, screening by flowcytometry for PNH is of value in this group of patients because it provides an opportunity to rapidly establish the diagnosis of this treatable disorder, which might otherwise be missed if the initial presentation is only thrombotic. PMID- 24400963 TI - Examination of the use of complementary and alternative medicine in Central Appalachia, USA. AB - INTRODUCTION: A growing number of people in the USA and worldwide use complementary and alternative medicine (CAM). CAM usage has been reported to differ by region. Little is known about the usage of CAM, especially among the Appalachian region population. The aim of this study is to evaluate the usage of CAM among adults in Central Appalachia. METHODS: A 23-question survey was distributed to 250 participants seeking free medical care at remote area medical events held in Wise County, Virginia in July 2012 and in Buchanan County, Virginia in October 2012. The questions on the survey addressed various aspects concerning CAM: forms of treatment used, frequency of use, main reasons for using CAM, and where they obtained their CAM therapies. The survey also collected demographic characteristics of the respondents. Subjects were asked to complete a two-page survey while waiting for service. RESULTS: A total of 192 (76.8%) responses were useful and complete. About 56% of the CAM users were female and 55% had an annual gross income of less than $20,000. About 49% had used CAM therapies in the past, of which 58% used CAM therapies at least once a month. Respondents used CAM because it worked well (n=52; 27%), had less side effects (n=45; 23%), and was affordable (n=43; 22%). CAM therapies were used mainly to address back pain (n=23; 15.6%), general health and wellbeing (n=22; 14.9%), depression and anxiety (n=11; 7.5%), and general pain (n=11; 7.5%), among others. Having a primary care provider, current level of education, and gross annual income were significantly associated with CAM use (p<0.001). Most respondents (n=94; 85%) were comfortable telling their doctor or other medical personnel about their use of CAM therapies. CONCLUSION: The prevalence of CAM usage among people in the Central Appalachia region was high, and higher than the national average. Most respondents were comfortable sharing their CAM usage information with their healthcare providers. More research is needed to further understand the factors underpinning CAM usage by the Central Appalachia population. PMID- 24400964 TI - Determinants of financial performance of home-visit nursing agencies in Japan. AB - BACKGROUND: Japan has the highest aging population in the world and promotion of home health services is an urgent policy issue. As home-visit nursing plays a major role in home health services, the Japanese government began promotion of this activity in 1994. However, the scale of home-visit nursing agencies has remained small (the average numbers of nursing staff and other staff were 4.2 and 1.7, respectively, in 2011) and financial performance (profitability) is a concern in such small agencies. Additionally, the factors related to profitability in home-visit nursing agencies in Japan have not been examined multilaterally and in detail. Therefore, the purpose of the study was to examine the determinants of financial performance of home-visit nursing agencies. METHODS: We performed a nationwide survey of 2,912 randomly selected home-visit nursing agencies in Japan. Multinomial logistic regression was used to clarify the determinants of profitability of the agency (profitable, stable or unprofitable) based on variables related to management of the agency (operating structure, management by a nurse manager, employment, patient utilization, quality control, regional cooperation, and financial condition). RESULTS: Among the selected home-visit nursing agencies, responses suitable for analysis were obtained from 1,340 (effective response rate, 46.0%). Multinomial logistic regression analysis showed that both profitability and unprofitability were related to multiple variables in management of the agency when compared to agencies with stable financial performance. These variables included the number of nursing staff/rehabilitation staff/patients, being owned by a hospital, the number of cooperative hospitals, home-death rate among terminal patients, controlling staff objectives by nurse managers, and income going to compensation. CONCLUSIONS: The results suggest that many variables in management of a home visit nursing agency, including the operating structure of the agency, regional cooperation, staff employment, patient utilization, and quality control of care, have an influence in both profitable and unprofitable agencies. These findings indicate the importance of consideration of management issues in achieving stable financial performance in home-visit nursing agencies in Japan. The findings may also be useful in other countries with growing aging populations. PMID- 24400965 TI - Comparison of success rates between two video laryngoscope systems used in a prehospital clinical trial. AB - OBJECTIVES: The primary aims of this study were to compare paramedic success rates and complications of two different video laryngoscopes in a prehospital clinical study. METHODS: This study was a multi-agency, prospective, non randomized, cross over clinical trial involving paramedics from four different EMS agencies. Following completion of training sessions, six Storz CMACTM video laryngoscopes and six King VisionTM (KV) video laryngoscopes were divided between agencies and placed into service for 6 months. Paramedics were instructed to use the video laryngoscope for all patients estimated to be >= 18 years old who required advanced airway management per standard operating procedure. After 6 months, the devices were crossed over for the final 6 months of the study period. Data collection was completed using a telephone data collection system with a member of the research team (available 24/7). First attempt success, overall success, and success by attempt, were compared between treatment groups using exact logistic regression adjusted for call type and user experience. RESULTS: Over a 12-month period, 107 patients (66 CMAC, 41 KV) were treated with a study device. The CMAC had a significantly higher likelihood of first attempt success (OR = 1.85; 95% CI 0.74, 4.62; p = 0.188), overall success (OR = 7.37; 95% CI 1.73, 11.1; p = 0.002), and success by attempt (OR = 3.38; 95% CI 1.67, 6.8; p = 0.007) compared to KV. Providers reverted to direct laryngoscopy in 80% (27/34) of the video laryngoscope failure cases, with the remaining patients having their airways successfully managed with a supraglottic airway in 3 cases and bag-valve mask in 4 cases. The provider-reported complications were similar and none were statistically different between treatment groups. Complication rates were not statistically different between devices. CONCLUSION: The CMAC had a higher likelihood of successful intubation compared to the King Vision. Complication rates were not statistically different between groups. Video laryngoscope placement success rates were not higher than our historical direct laryngoscopy success rates. PMID- 24400966 TI - Novel alleles of Lan- in Japanese populations. PMID- 24400967 TI - The effects of a breastfeeding self-efficacy intervention on short-term breastfeeding outcomes among primiparous mothers in Wuhan, China. AB - AIMS: To evaluate the effects of a breastfeeding intervention on primiparous mothers' breastfeeding self-efficacy, breastfeeding duration and exclusivity at 4 and 8 weeks postpartum. BACKGROUND: Few studies have examined the effects of breastfeeding self-efficacy on improved breastfeeding outcomes among primiparous mothers in China. DESIGN: An experimental pre-test and posttest, two-group design was used in the study. METHODS: A total of 74 participants were recruited to the study from a tertiary hospital in central China, from June-October 2012. An individualized, standardized nursing intervention based on the Self-Efficacy Theory was delivered to enhance mothers' breastfeeding self-efficacy, breastfeeding duration and exclusivity at 4 and 8 weeks postpartum. Participants were randomly assigned to an intervention or referent group. Participants in the intervention group received three individualized, self-efficacy-enhancing sessions. Participants in the referent group received standard care. RESULTS: Participants in the intervention group showed significantly greater increases in breastfeeding self-efficacy, exclusivity and duration than participants in the control group at 4 and 8 weeks postpartum (except for duration at 4 weeks). High baseline breastfeeding self-efficacy predicted higher breastfeeding self-efficacy later and more exclusive breast-feeding. CONCLUSION: The findings in this study suggest that intervention aimed at increasing self-efficacy has a significant impact on maternal breastfeeding self-efficacy and short-term breastfeeding outcomes. PMID- 24400968 TI - Eculizumab prevents recurrent antiphospholipid antibody syndrome and enables successful renal transplantation. AB - Renal transplantation in patients with antiphospholipid antibodies has historically proven challenging due to increased risk for thrombosis and allograft failure. This is especially true for patients with antiphospholipid antibody syndrome (APS) and its rare subtype, the catastrophic antiphospholipid antibody syndrome (CAPS). Since a critical mechanism of thrombosis in APS/CAPS is one mediated by complement activation, we hypothesized that preemptive treatment with the terminal complement inhibitor, eculizumab, would reduce the extent of vascular injury and thrombosis, enabling renal transplantation for patients in whom it would otherwise be contraindicated. Three patients with APS, two with a history of CAPS, were treated with continuous systemic anticoagulation together with eculizumab prior to and following live donor renal transplantation. Two patients were also sensitized to human leukocyte antigens (HLA) and required plasmapheresis for reduction of donor-specific antibodies. After follow-up ranging from 4 months to 4 years, all patients have functioning renal allografts. No systemic thrombotic events or early graft losses were observed. While the appropriate duration of treatment remains to be determined, this case series suggests that complement inhibitors such as eculizumab may prove to be effective in preventing the recurrence of APS after renal transplantation. PMID- 24400969 TI - Molecular cloning and function characterization of a new macrophage-activating protein from Tremella fuciformis. AB - Silver ear mushroom ( Tremella fuciformis ) is an edible fungus with health benefits. In this study, we purified a new T. fuciformis protein (TFP) and demonstrated its ability to activate primary murine macrophages. The isolation procedure involved ammonium sulfate fractionation and ion exchange chromatography. TFP naturally formed a 24 kDa homodimeric protein and did not contain glycan residues. The TFP gene was cloned using the rapid amplification of cDNA ends method, and the cDNA sequence of TFP was composed of 408 nucleotides with a 336 nucleotide open reading frame encoding a 112 amino acid protein. TFP was capable of stimulating TNF-alpha, IL-1beta, IL-1ra, and IL-12 production in addition to CD86/MHC class II expression, mRNA expression of M1-type chemokines, and nuclear NF-kappaB accumulation in murine peritoneal macrophage cells. Furthermore, TFP failed to stimulate TLR4-neutralized and TLR4-knockout macrophages, suggesting that TLR4 is a required receptor for TFP signaling on macrophages. Taken together, these results indicate that TFP may be an important bioactive compound from T. fuciformis that induces M1-polarized activation through a TLR4-dependent NF-kappaB signaling pathway. PMID- 24400971 TI - Revised French guidelines for the diagnosis and management of migraine in adults and children. PMID- 24400970 TI - Association of social and cognitive impairment and biomarkers in autism spectrum disorders. AB - OBJECTIVES: The neurological basis for autism is still not fully understood, and the role of the interaction between neuro-inflammation and neurotransmission impairment needs to be clearer. This study aims to test the possible association between impaired levels of gamma aminobutyric acid (GABA), serotonin, dopamine, oxytocin, and interferon-gamma-induced protein-16 (IFI16) and the severity of social and cognitive dysfunctions in individuals with autism spectrum disorders. MATERIALS AND METHODS: GABA, serotonin, dopamine, oxytocin, and IFI16 as biochemical parameters related to neurochemistry and inflammation were determined in the plasma of 52 Saudi autistic male patients, categorized as mild-moderate and severe as indicated by their Childhood Autism Rating Scale (CARS) or social responsiveness scale (SRS), and compared to 30 age- and gender-matched control samples. RESULTS: The data indicated that Saudi patients with autism have remarkably impaired plasma levels of the measured parameters compared to age and gender-matched controls. While serotonin in platelet-free plasma and dopamine did not correlated with the severity in social and cognitive dysfunction, GABA, oxytocin, and IFI16 were remarkably associated with the severity of both tested scores (SRS and CARS). CONCLUSIONS: The relationship between the selected parameters confirms the role of impaired neurochemistry and neuro-inflammation in the etiology of autism spectrum disorders and the possibility of using GABA, oxytocin, and IFI16 as markers of autism severity. Receiver operating characteristic analysis together with predictiveness diagrams proved that the measured parameters could be used as predictive biomarkers of clinical symptoms and provide significant guidance for future therapeutic strategy to re-establish physiological homeostasis. PMID- 24400972 TI - Does methamphetamine use increase violent behaviour? Evidence from a prospective longitudinal study. AB - AIMS: To determine whether violent behaviour increases during periods of methamphetamine use and whether this is due to methamphetamine-induced psychotic symptoms. DESIGN: A fixed-effects (within-subject) analysis of four non contiguous 1-month observation periods from a longitudinal prospective cohort study. SETTING: Sydney and Brisbane, Australia. PARTICIPANTS: A total of 278 participants aged 16 years or older who met DSM-IV criteria for methamphetamine dependence on entry to the study but who did not meet DSM-IV criteria for life time schizophrenia or mania. MEASUREMENTS: Violent behaviour was defined as severe hostility in the past month on the Brief Psychiatric Rating Scale (BPRS) (corresponding to assault/damage to property). Days of methamphetamine and other substance use in the past month were assessed using the Opiate Treatment Index. Positive psychotic symptoms in the past month were identified using the BPRS. FINDINGS: There was a dose-related increase in violent behaviour when an individual was using methamphetamine compared with when they were not after adjusting for other substance use and socio-demographics [cf. no use in the past month: 1-15 days of use odds ratio (OR) = 2.8, 95% confidence interval (CI) =1.6 4.9; 16+ days of use OR = 9.5, 95% CI = 4.8-19.1]. The odds of violent behaviour were further increased by psychotic symptoms (OR = 2.0, 95% CI = 1.1-3.6), which accounted for 22-30% of violent behaviour related to methamphetamine use. Heavy alcohol consumption also increased the risk of violent behaviour (OR = 3.1, 95% CI = 1.4-7.0) and accounted for 12-18% of the violence risk related to methamphetamine use. CONCLUSIONS: There is a dose-related increase in violent behaviour during periods of methamphetamine use that is largely independent of the violence risk associated with psychotic symptoms. PMID- 24400973 TI - Improving breast cancer knowledge: the use of a computerized breast cancer education tool during a clinical consultation with a breast specialist. PMID- 24400974 TI - New metal phthalocyanines/metal simple hydroxide multilayers: experimental evidence of dipolar field-driven magnetic behavior. AB - A series of new hybrid multilayers has been synthesized by insertion-grafting of transition metal (Cu(II), Co(II), Ni(II), and Zn(II)) tetrasulfonato phthalocyanines between layers of Cu(II) and Co(II) simple hydroxides. The structural and spectroscopic investigations confirm the formation of new layered hybrid materials in which the phthalocyanines act as pillars between the inorganic layers. The magnetic investigations show that all copper hydroxide based compounds behave similarly, presenting an overall antiferromagnetic behavior with no ordering down to 1.8 K. On the contrary, the cobalt hydroxide based compounds present a ferrimagnetic ordering around 6 K, regardless of the nature of the metal phthalocyanine between the inorganic layers. The latter observation points to strictly dipolar interactions between the inorganic layers. The amplitude of the dipolar field has been evaluated from X-band and Q-band EPR spectroscopy investigation (Bdipolar ~ 30 mT). PMID- 24400975 TI - Products and mechanism of the reactions of OH radicals and Cl atoms with methyl methacrylate (CH2?C(CH3)C(O)OCH3) in the presence of NOx. AB - The OH radical and Cl atom initiated photodegradation of methyl methacrylate has been investigated in a 1080 L quartz-glass environmental chamber at 298 +/- 2 K and atmospheric pressure of synthetic air using in situ FTIR spectroscopy to monitor the reactants and products. The major products observed in the OH reaction were methyl pyruvate (92 +/- 16%) together with formaldehyde (87 +/- 12%) as a coproduct from the C1-C2 bond cleavage channel of the intermediate 1,2 hydroxyalkoxy radical, formed by the addition of OH to the terminal carbon of the double bond which is designated C1. For the Cl atom reaction, the products identified were chloroacetone (41 +/- 6%) together with its coproduct formaldehyde (35 +/- 5%) and methyl pyruvate (24 +/- 4%) together with its coproduct formylchloride (25 +/- 4%). The results show that the fate of the intermediate 1,2-chloroalkoxy radical involves not only cleavage of the C1-C2 bond but also quite substantial cleavage of the C2-C3 bond. The present results are compared with previous studies of acrylates, showing different branching ratios for the OH and Cl addition reactions in the presence of NOx. Atmospheric implications are discussed. PMID- 24400976 TI - Rationale and design of the INNOVATE Trial: an international cooperative study on surgical versus conservative treatment for odontoid fractures in the elderly. AB - BACKGROUND: Fractures of the odontoid process of the axis are the most common fractures of the geriatric cervical spine. As the population ages, their incidence is expected to increase progressively, as is the number of very old patients (>80 years) with an odontoid fracture. No consensus exists on the optimal treatment (surgical or conservative) and the most relevant outcome parameter (osseous union, fracture stability or clinical outcome). The aim of the INNOVATE (INterNational study on Odontoid frActure Treatment in the Elderly) Trial is to prospectively assess fracture healing and clinical outcome after surgical and conservative treatment for odontoid fractures in the elderly patient, with a specific focus on the very old patient. METHODS/DESIGN: The trial is an observational study in which eleven centres in five European countries are involved. All patients admitted to one of these centres who meet the selection criteria (>=55 years, acute (2 * 10(6) CD34+ cells/kg) in 82.3% of patients within a median 2 (1-6) apheresis days. Patients had stem cells collected between days +8 and +15, with a median +12 day. Median total CD34+ cells/kg collected was 5.95 * 10(6) (0.1-36.8). Seventy-one percent of patients yielded >2 * 10(6) CD34+ cells/kg in <=2 d of apheresis and were defined as good mobilizers. While median CD34+ cells/kg collected for good mobilizers was 7.6 * 10(6) , it was 2.6 * 10(6) for poor mobilizers (P < 0.001). This regimen was safe with a low rate of febrile neutropenia (7.6%) and acceptable rates of RBC (40.5%) and platelet transfusions (22.8%). Hematopoietic recovery after auto-SCT was achieved on expected time. Therapy-related myelodysplastic syndrome/acute myeloid leukemia occurred in only one patient (1.3%) with in a median follow-up of 16 months after chemomobilization. We conclude that HD etoposide and G-CSF chemomobilization appear to result in effective, tolerable, and safe stem cell collection in the majority of heavily pretreated lymphoma patients. PMID- 24400989 TI - Mono-, few-, and multiple layers of copper antimony sulfide (CuSbS2): a ternary layered sulfide. AB - Layered materials with controlled thickness down to monolayer are being intensively investigated for unraveling and harnessing their dimension-dependent properties. Copper antimony sulfide (CuSbS2) is a ternary layered semiconductor material that has been considered as an absorber material in thin film solar cells due to its optimal band gap (~1.5 eV) with high absorption coefficient of over >10(4) cm(-1). We have for the first time developed solution-based approaches for the synthesis of mono-, few-, and multiple layers of CuSbS2. These include a colloidal bottom-up approach for the synthesis of CuSbS2 nanoplates with thicknesses from six layers to several layers, and a hybrid bottom-up-top down approach for the formation of CuSbS2 mesobelts. The latter can be exfoliated by Li-ion intercalation and sonication to obtain layers down to monolayer thickness. Time-dependent TEM studies provide important insights into the growth mechanism of mesobelts. At the initial stage the nanoplates grow laterally to form nanosheets as the primary structure, followed by their folding and attachment through homoepitaxy to form prolate-like secondary structures. Eventually, these prolate-like structures form mesocrystals by oriented attachment crystal growth. The changes in optical properties with layer thickness down to monolayers have been studied. In order to understand the thickness dependent optical and electrical properties, we have calculated the electronic structures of mono- and multiple layers (bulk) of CuSbS2 using the hybrid functional method (HSE 06). We find that the monolayers exhibit noticeably different properties from the multilayered or the bulk system, with a markedly increased band gap that is, however, compromised by the presence of localized surface states. These localized states are predominantly composed of energetically favorable Sb pz states, which break off from the rest of the Sb p states that would otherwise be at the top of the gap. The developed solution based synthesis approaches are versatile and can likely be extended to other complex layered sulfides. PMID- 24400990 TI - Strong oxidation resistance of atomically thin boron nitride nanosheets. AB - Investigation of oxidation resistance of two-dimensional (2D) materials is critical for many of their applications because 2D materials could have higher oxidation kinetics than their bulk counterparts due to predominant surface atoms and structural distortions. In this study, the oxidation behavior of high-quality boron nitride (BN) nanosheets of 1-4 layers thick has been examined by heating in air. Atomic force microscopy and Raman spectroscopy analyses reveal that monolayer BN nanosheets can sustain up to 850 degrees C, and the starting temperature of oxygen doping/oxidation of BN nanosheets only slightly increases with the increase of nanosheet layer and depends on heating conditions. Elongated etch lines are found on the oxidized monolayer BN nanosheets, suggesting that the BN nanosheets are first cut along the chemisorbed oxygen chains and then the oxidative etching grows perpendicularly to these cut lines. The stronger oxidation resistance of BN nanosheets makes them more preferable for high temperature applications than graphene. PMID- 24400991 TI - High serum C1q-binding adiponectin levels in male patients with acute coronary syndrome. AB - BACKGROUND: The complement system is part of the immune system in acute coronary syndrome (ACS). Adiponectin has anti-atherogenic and anti-inflammatory properties. Adiponectin and C1q form a protein complex in blood, and serum C1q binding adiponectin (C1q-APN) can be measured. We investigated the comparative evaluation of serum C1q-APN levels in males with ACS, stable angina pectoris (SAP) versus controls. METHODS: The study subjects were 138 Japanese patients who underwent diagnostic coronary angiography. Blood total adiponectin (Total-APN), C1q-APN and C1q were measured by enzyme-linked immunosorbent assays. Patients were divided into three groups according to the clinical condition: ACS (n = 78), SAP (n = 41) or normal coronary (NC, n = 19) groups. RESULTS: Serum C1q levels were significantly higher in the ACS group (54.9+/-1.2 MUg/mL) than in the NC group (48.0+/-2.5 MUg/mL). Although serum Total-APN levels were significantly lower in the SAP and ACS groups, compared with the NC group (7.0+/-0.5, 7.2+/ 0.3, 10.6+/-2.0 MUg/mL, respectively), serum C1q-APN levels were significantly higher in the ACS group than in the NC and SAP groups (112.1+/-4.1, 66.3+/-4.4, 65.7+/-2.9 units/mL, respectively). CONCLUSIONS: Patients with ACS had higher serum C1q-APN levels. TRIAL REGISTRATION: UMIN000002997. PMID- 24400992 TI - Genetic and environmental contributions to the associations between intraindividual variability in reaction time and cognitive function. AB - Intraindividual variability (IIV) in reaction time has been related to cognitive decline, but questions remain about the nature of this relationship. Mean and range in movement and decision time for simple reaction time were available from 241 individuals aged 51-86 years at the fifth testing wave of the Swedish Adoption/Twin Study of Aging. Cognitive performance on four factors was also available: verbal, spatial, memory, and speed. Analyses indicated that range in reaction time could be used as an indicator of IIV. Heritability estimates were 35% for mean reaction and 20% for range in reaction. Multivariate analysis indicated that the genetic variance on the memory, speed, and spatial factors is shared with genetic variance for mean or range in reaction time. IIV shares significant genetic variance with fluid ability in late adulthood, over and above and genetic variance shared with mean reaction time. PMID- 24400993 TI - Preoperative plasma club (clara) cell secretory protein levels are associated with primary graft dysfunction after lung transplantation. AB - Inherent recipient factors, including pretransplant diagnosis, obesity and elevated pulmonary pressures, are established primary graft dysfunction (PGD) risks. We evaluated the relationship between preoperative lung injury biomarkers and PGD to gain further mechanistic insight in recipients. We performed a prospective cohort study of recipients in the Lung Transplant Outcomes Group enrolled between 2002 and 2010. Our primary outcome was Grade 3 PGD on Day 2 or 3. We measured preoperative plasma levels of five biomarkers (CC-16, sRAGE, ICAM 1, IL-8 and Protein C) that were previously associated with PGD when measured at the postoperative time point. We used multivariable logistic regression to adjust for potential confounders. Of 714 subjects, 130 (18%) developed PGD. Median CC-16 levels were elevated in subjects with PGD (10.1 vs. 6.0, p<0.001). CC-16 was associated with PGD in nonidiopathic pulmonary fibrosis (non-IPF) subjects (OR for highest quartile of CC-16: 2.87, 95% CI: 1.37, 6.00, p=0.005) but not in subjects with IPF (OR 1.38, 95% CI: 0.43, 4.45, p=0.59). After adjustment, preoperative CC-16 levels remained associated with PGD (OR: 3.03, 95% CI: 1.26, 7.30, p=0.013) in non-IPF subjects. Our study suggests the importance of preexisting airway epithelial injury in PGD. Markers of airway epithelial injury may be helpful in pretransplant risk stratification in specific recipients. PMID- 24400994 TI - Prevalence and interventional outcomes of patients with resolution of ST-segment elevation between prehospital and in-hospital ECG. AB - OBJECTIVE: To determine the prevalence and significance of ST-segment elevation resolution between prehospital and first hospital ECG. METHODS: We examined consecutive prehospital ECGs transmitted to a single medical command center in southwestern Pennsylvania between January 1, 2009 and December 31, 2011. We included ECG cases with ST-segment elevation myocardial infarction (STEMI) and excluded cases with incomplete prehospital and/or hospital data. Our primary outcome was ST-segment resolution (STR), defined by cases no longer meeting STEMI criteria on the first in-hospital ECG. Primary variables of interest included prehospital vital signs and treatment, cardiac catheterization findings, and time intervals for diagnostics and treatment. Analysis included t-tests for continuous variables and chi-squared analysis for categorical variables. RESULTS: We reviewed 24,197 prehospital ECGs and identified 293 cases of prehospital STEMI. Complete hospital and prehospital records were available for 83 cases (28%). Analyzed cohort was an average 62 years old and the majority were male (67%), with a primary complaint of chest pain (93%). STR occurred in 18 cases (22%, CI 14-32%). There were no differences between STR and non-STR cases in prehospital vital signs or treatments. 95% of patients underwent cardiac catheterization with a mean door-to-needle time of 57 minutes (interquartile range 43-71). Comparing STR and non-STR cases, significant lesions (>=50%) were found in 94 and 97% of patients (p = 0.6), and subtotal or total lesions (>=95%) were found in 63 and 85% (p = 0.1), respectively. CONCLUSIONS: We found that ST-segment resolution occurred prior to catheterization in 1 of 5 patients with prehospital STEMI, emphasizing the necessity of prehospital ECG in risk stratification of patients with suspected coronary disease. Coronary lesions and intervention rates did not differ between STR and non-STR, suggesting that catheterization is warranted even when STEMI criteria are no longer met in-hospital. PMID- 24400996 TI - Outbreak of pathogenic Escherichia coli in an outdoor-housed non-human primate colony. AB - BACKGROUND: Pathogenic Escherichia coli has been identified as an etiologic agent in humans causing acute diarrhea or even death but has been rarely reported in non-human primates (NHP). An outbreak of diarrhea occurred in an outdoor-housed NHP colony over a period of 2 months with an attack rate of 29%. METHODS: Bacterial culture and PCR were performed on the fecal specimens to identify enteroinvasive E. coli (EIEC) and Enterohemorrhagic E. coli (EHEC) in the NHPs. RESULTS: By random sampling of 10% of fecal samples of diarrheal cases, four cases of EIEC in rhesus macaques and two cases of EHEC in cynomolgus macaques were confirmed. CONCLUSION: This is the first time EIEC and EHEC have been reported in NHPs associated with diarrhea. The primary source of infection could not be determined. PMID- 24400995 TI - Modulation of gut-specific mechanisms by chronic delta(9)-tetrahydrocannabinol administration in male rhesus macaques infected with simian immunodeficiency virus: a systems biology analysis. AB - Our studies have demonstrated that chronic Delta(9)-tetrahydrocannabinol (THC) administration results in a generalized attenuation of viral load and tissue inflammation in simian immunodeficiency virus (SIV)-infected male rhesus macaques. Gut-associated lymphoid tissue is an important site for HIV replication and inflammation that can impact disease progression. We used a systems approach to examine the duodenal immune environment in 4- to 6-year-old male rhesus monkeys inoculated intravenously with SIVMAC251 after 17 months of chronic THC administration (0.18-0.32 mg/kg, intramuscularly, twice daily). Duodenal tissue samples excised from chronic THC- (N=4) and vehicle (VEH)-treated (N=4) subjects at ~5 months postinoculation showed lower viral load, increased duodenal integrin beta 7(+)(beta7) CD4(+) and CD8(+) central memory T cells, and a significant preferential increase in Th2 cytokine expression. Gene array analysis identified six genes that were differentially expressed in intestinal samples of the THC/SIV animals when compared to those differentially expressed between VEH/SIV and uninfected controls. These genes were identified as having significant participation in (1) apoptosis, (2) cell survival, proliferation, and morphogenesis, and (3) energy and substrate metabolic processes. Additional analysis comparing the duodenal gene expression in THC/SIV vs. VEH/SIV animals identified 93 differentially expressed genes that participate in processes involved in muscle contraction, protein folding, cytoskeleton remodeling, cell adhesion, and cell signaling. Immunohistochemical staining showed attenuated apoptosis in epithelial crypt cells of THC/SIV subjects. Our results indicate that chronic THC administration modulated duodenal T cell populations, favored a pro-Th2 cytokine balance, and decreased intestinal apoptosis. These findings reveal novel mechanisms that may potentially contribute to cannabinoid-mediated disease modulation. PMID- 24400997 TI - Feedback control of TET system with variable coupling coefficients for a novel artificial anal sphincter. AB - For treating severe faecal incontinence, the authors developed an intelligent artificial anal sphincter system (AASS) equipped with a feedback sensor that utilized a transcutaneous energy transfer system (TETS). To deliver the correct amount of power (i.e. to match the load demand under variable coupling conditions caused by changes in positioning between the coils due to fitting and changes in posture), a regulating method to stabilize output voltage with a closed loop variable-frequency controller was developed in this paper. The method via which the voltage gain characteristics of a voltage-fed series-tuned TETS were derived is also described. The theoretical analysis was verified by the results of the experiment. A numerical analysis method was used as a control rule with respect to the relationship between operating frequency and output voltage. To validate the feedback control rules, a prototype of the TET charging system was constructed, and its performance was validated with the coupling variation between 0.12-0.42. The results show that the output voltage of the secondary side can be maintained at a constant 7 V across the whole coupling coefficient range, with a switching frequency regulation range of 271.4-320.5 kHz, and the proposed controller has reached a maximal end-to-end power efficiency of 67.5% at 1 W. PMID- 24400998 TI - Acute effects of green tea extract intake on exogenous and endogenous metabolites in human plasma. AB - The acute effects of green tea extract (GTE) on plasma metabolites in vivo are largely unknown. In this parallel, double-blind study, the transient changes in total and free concentrations of catechins were measured in plasma from healthy males following the consumption of a single GTE dose (559.2 mg total catechins, 120.4 mg caffeine). Furthermore, the acute effects on endogenous metabolites were assessed 2 h after GTE intake using four-phase metabolite profiling. The ratios of the catechin concentrations in plasma to those in the GTE followed the order ECG/CG > EC > GCG > EGCG > EGC > C > GC. The gallated catechins EGCG, CG/ECG, GC, and GCG were also present in their free form. Sixteen out of 163 mostly endogenous metabolites were affected by acute GTE ingestion, when compared to placebo. These included caffeine, salicylate, hippurate, taurine, 3,4 dihydroxyphenylethylene-glycol, serotonin, some cholesterylesters, fatty acids, triglycerides, and sphingosines. Our results on the exogenous metabolites largely confirm previous studies, while our findings on the endogenous metabolites are novel and may suggest specific biological targets. PMID- 24400999 TI - Diagnosis, prevalence estimation and burden measurement in population surveys of headache: presenting the HARDSHIP questionnaire. AB - The global burden of headache is very large, but knowledge of it is far from complete and needs still to be gathered. Published population-based studies have used variable methodology, which has influenced findings and made comparisons difficult. The Global Campaign against Headache is undertaking initiatives to improve and standardize methods in use for cross-sectional studies. One requirement is for a survey instrument with proven cross-cultural validity. This report describes the development of such an instrument. Two of the authors developed the initial version, which was used with adaptations in population based studies in China, Ethiopia, India, Nepal, Pakistan, Russia, Saudi Arabia, Zambia and 10 countries in the European Union. The resultant evolution of this instrument was reviewed by an expert consensus group drawn from all world regions. The final output was the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire, designed for application by trained lay interviewers. HARDSHIP is a modular instrument incorporating demographic enquiry, diagnostic questions based on ICHD-3 beta criteria, and enquiries into each of the following as components of headache attributed burden: symptom burden; health-care utilization; disability and productive time losses; impact on education, career and earnings; perception of control; interictal burden; overall individual burden; effects on relationships and family dynamics; effects on others, including household partner and children; quality of life; wellbeing; obesity as a comorbidity. HARDSHIP already has demonstrated validity and acceptability in multiple languages and cultures. Modules may be included or not, and others (e.g., on additional comorbidities) added, according to the purpose of the study and resources (especially time) available. PMID- 24401000 TI - In-silico models of stem cell and developmental systems. AB - Understanding how developmental systems evolve over time is a key question in stem cell and developmental biology research. However, due to hurdles of existing experimental techniques, our understanding of these systems as a whole remains partial and coarse. In recent years, we have been constructing in-silico models that synthesize experimental knowledge using software engineering tools. Our approach integrates known isolated mechanisms with simplified assumptions where the knowledge is limited. This has proven to be a powerful, yet underutilized, tool to analyze the developmental process. The models provide a means to study development in-silico by altering the model's specifications, and thereby predict unforeseen phenomena to guide future experimental trials. To date, three organs from diverse evolutionary organisms have been modeled: the mouse pancreas, the C. elegans gonad, and partial rodent brain development. Analysis and execution of the models recapitulated the development of the organs, anticipated known experimental results and gave rise to novel testable predictions. Some of these results had already been validated experimentally. In this paper, I review our efforts in realistic in-silico modeling of stem cell research and developmental biology and discuss achievements and challenges. I envision that in the future, in-silico models as presented in this paper would become a common and useful technique for research in developmental biology and related research fields, particularly regenerative medicine, tissue engineering and cancer therapeutics. PMID- 24401001 TI - Polybrominated diphenyl ethers in soils, sediments, and human hair in a plastic waste recycling area: a neglected heavily polluted area. AB - The release of pollutants during the recycling of contaminated plastics is a problem which has drawn worldwide attention; however, little information on the transfer of polybrominated diphenyl ethers (PBDEs) in these processes is available. We conducted a survey of PBDEs in soils, sediments, and human hair in a typical plastic waste recycling area in northern China. The total concentrations (ng/g) of 21 PBDEs were 1.25-5504 (average 600), 18.2-9889 (average 1619), and 1.50-861 (average 112) in soils, sediments, and hair, respectively. The PBDE concentrations were comparable to concentrations observed in e-waste recycling areas; however, the concentrations in soils and sediments were 1-3 orders of magnitude higher than in other areas, and the concentrations in hair were much higher than in other areas. This indicates that this area is highly polluted with PBDEs. BDE-209 was the dominant congener (representing 91.23%, 92.3%, and 91.5% of the total PBDEs observed in soils, sediments, and hair, respectively), indicating that the commercial deca-BDE product was dominant. The commercial penta- and octa-BDE products made small contributions to the total PBDE concentrations, unlike what has been found in some e-waste recycling areas. Our results show that crude plastic waste processing is a major contributor of PBDEs to the environment and humans, which should be of great concern. PMID- 24401002 TI - Breast carcinoma metastasis in retrosternal fat tissue. PMID- 24401003 TI - Self-assembly synthesis, structural features, and photophysical properties of dilanthanide complexes derived from a novel amide type ligand: energy transfer from Tb(III) to Eu(III) in a heterodinuclear derivative. AB - A novel amide type ligand benzyl-N,N-bis[(2'-furfurylaminoformyl)phenoxyl)ethyl] amine (L) has been designed and applied for the self-assembly generation of homodinuclear lanthanide coordination compounds [Ln2(MU2-L)2(NO3)6(EtOH)2] [Ln = Eu (1), Tb (2), and Gd (3)] and a heterodinuclear derivative [EuTb(MU2 L)2(NO3)6(EtOH)2] (4). All the complexes have been characterized by the X-ray single-crystal diffraction analyses. They are isostructural, crystallize in a monoclinic space group P21/c, and form [2 + 2] rectangular macrocycle structures. Compound 4 is the first example of a [2 + 2] rectangular macrocycle heterodinuclear EuTb complex assembled from an amide type ligand. In 4, the discrete 0D dimeric [EuTb(MU2-L)2(NO3)6(EtOH)2] units are extended, via the multiple N-H...O hydrogen bonds, into a 2D supramolecular network that has been topologically classified as a uninodal 4-connected underlying net with the sql [Shubnikov tetragonal plane net] topology. The triplet state ((3)pipi*) of L studied by the Gd(III) complex 3 demonstrated that the ligand beautifully populates Tb(III) emission (Phi = 52%), whereas the corresponding Eu(III) derivative 1 shows weak luminescence efficiency (Phi = 0.7%) because the triplet state of L has a poor match with (5)D1 energy level of Eu(III). Furthermore, the photoluminescent properties of heterodinuclear complex 4 have been compared with those of the analogous homodinuclear compounds. The quantum yield and lifetime measurements prove that energy transfer from Tb(III) to Eu(III) is being achieved, namely, that the Tb(III) center is also acting to sensitize the Eu(III) and enhancing Eu(III) emission in 4. PMID- 24401004 TI - Levels of saliva cotinine in electronic cigarette users. AB - AIMS: To assess saliva cotinine levels in experienced users of e-cigarettes ('vapers'). DESIGN, SETTING AND PARTICIPANTS: An internet survey in 2011 and 2012, with collection of saliva vials by mail. Participants were 71 users of e cigarettes enrolled mainly on websites and online forums dedicated to e cigarettes. MEASUREMENTS: Use of e-cigarettes, tobacco and nicotine medications. Collection of saliva by mail and analysis of cotinine by liquid chromatography mass spectrometry. FINDINGS: Most participants (89%) were former smokers, most (92%) were using e-cigarettes daily, had been using e-cigarettes for 12 months on average and puffed a median of 150 times per day on their e-cigarettes [mean = 220 puffs/day, 95% confidence interval (CI) = 169-271]. The median concentration of nicotine in refill liquids was 16 mg/ml (mean = 16.4, 95% CI = 14.5-18.3). In the 62 e-cigarette users who, in the past 5 days, had not used any tobacco or nicotine medications, the median cotinine level was 353 ng/ml (mean = 374, 95% CI = 318-429), the correlation between cotinine and nicotine concentration in e liquids was r = 0.33 (P = 0.013), and the correlation between cotinine and the number of cigarettes smoked per day before quitting smoking was r = 0.48 (P < 0.001). CONCLUSIONS: At least some experienced users of electronic cigarettes appear to be able to gain as much nicotine from those products as do cigarette smokers. PMID- 24401006 TI - A replication competent HSV-1(McKrae) with a mutation in the amino-terminus of glycoprotein K (gK) is unable to infect mouse trigeminal ganglia after cornea infection. AB - PURPOSE: To determine the role of the amino terminus of herpes simplex virus-1 (HSV-1) glycoprotein K (gK) in corneal infection, neuroinvasion, and establishment of virus latency in trigeminal ganglia of mice. METHODS: The recombinant virus HSV-1 (McKDeltagK31-68) was constructed by engineering gK genes encoding gK lacking 38 amino acids immediately after the gK signal sequence. A rescued virus was also produced. Mouse eyes were scarified and infected with 10(5) plaque forming units (PFU) in each eye. Clinical signs of ocular disease were monitored daily. Thirty days postinfection trigeminal ganglia were collected and processed for quantitative PCR (qPCR) analysis of viral DNA and recovery of infectious virions by cell culture of ganglionic tissues. RESULTS: Deletion of the amino terminus of gK encoded by the McKDeltagK31-68 mutant virus did not substantially affect its replication kinetics on African green monkey kidney cells (Vero), while it reduced cell-to-cell spread. McK viral infection of scarified mouse corneas with 10(5) PFU produced severe ocular disease. In contrast, McKDeltagK31-68 viral infection with 10(5) PFU produced no significant ocular disease symptoms. All ganglia from mice infected with the McK virus produced high numbers of infectious virions upon explant culture in Vero cells, in agreement with qPCR results detecting high number of HSV-1 viral DNA in ganglionic tissues. In contrast, qPCR failed to detect any viral genomes in McKDeltagK31-68 ganglia, while two of the ten ganglia revealed the presence of low numbers of infectious virions upon explant culture in Vero cells. CONCLUSIONS: The results show that the amino terminus of gK is essential for neuroinvasiveness and acute herpes keratitis in the mouse eye model. It is likely that gK is involved in efficient infection of axonal termini, since mouse eye scarification provided a direct access to the high density of neuronal axons innervating mouse corneas. PMID- 24401005 TI - Age-dependent ferritin elevations and HFE C282Y mutation as risk factors for symptomatic knee osteoarthritis in males: a longitudinal cohort study. AB - BACKGROUND: Age, gender and genetic predisposition are major intrinsic risk factors for osteoarthritis (OA). Iron increases are associated with age and gene mutation. In the present study, we examined whether serum ferritin, an indicator of total body iron stores, correlates with clinical features in patients with OA, and whether the hemochromatosis Fe (HFE) gene mutation plays a role. METHODS: In a 2-year longitudinal observational study, 127 patients with knee OA and 20 healthy individuals (controls) were enrolled. All patients underwent standardized weight-bearing fixed-flexion posteroanterior knee radiographs. Peripheral blood samples were analyzed for serum ferritin, and genotyped for HFE using allelic discrimination methods. RESULTS: Higher levels of serum ferritin were found in patients older than 56 years (P =0.0186) and males (P =0.0006), with a trend toward higher ferritin in patients with OA. HFE gene mutation carriers were more prevalent among patients with OA than among healthy controls. When stratified further by gender, we found that male patients with OA had higher levels of serum ferritin than male control subjects [odds ratio = 4.18 (limits of 95% confidence interval: 0.86-27.69, P = 0.048)]. Analyses of radiographic data indicated that higher ferritin was associated with narrower joint space width at baseline (P = 0.032) in male patients. Additionally, among men, risk prediction of radiographic severity [Kellgren-Lawrence (KL) grade >2)] in the higher ferritin group was almost five times that of the lower ferritin group (odds ratio = 4.74, P = 0.023). CONCLUSION: Our data suggest that increased ferritin levels are associated with symptomatic knee OA in males. This finding needs to be validated in a larger cohort of patients. PMID- 24401007 TI - Experimental warming drives a seasonal shift in the timing of host-parasite dynamics with consequences for disease risk. AB - Multi-species experiments are critical for identifying the mechanisms through which climate change influences population dynamics and community interactions within ecological systems, including infectious diseases. Using a host-parasite system involving freshwater snails, amphibians and trematode parasites, we conducted a year-long, outdoor experiment to evaluate how warming affected net parasite production, the timing of infection and the resultant pathology. Warming of 3 degrees C caused snail intermediate hosts to release parasites 9 months earlier and increased infected snail mortality by fourfold, leading to decreased overlap between amphibians and parasites. As a result, warming halved amphibian infection loads and reduced pathology by 67%, despite comparable total parasite production across temperature treatments. These results demonstrate that climate disease theory should be expanded to account for predicted changes in host and parasite phenology, which may often be more important than changes in total parasite output for predicting climate-driven changes in disease risk. PMID- 24401008 TI - Glycemic variability is higher in type 1 diabetes patients with microvascular complications irrespective of glycemic control. AB - BACKGROUND: Increased glycemic variability (GV) may be associated with diabetes complications. Our study assessed the relationship between microvascular complications (MVCs) and GV calculated from continuous glucose monitoring (CGM) data in type 1 diabetes patients. SUBJECTS AND METHODS: Thirty-two patients with type 1 diabetes (16 with and 16 without MVC) participated in this cross-sectional study. Vibration perception threshold (VPT), microalbuminuria, and fundoscopy were used to detect MVC. CGM data were recorded for 2 weeks and analyzed using proprietary software. Total SD (SDT), coefficient of variation (CV), and mean amplitude of glycemic excursions (MAGE) were compared. RESULTS: Patients with any MVC had significantly higher GV, calculated from CGM, than patients without MVC (SDT, 4.1 +/- 0.6 vs. 3.4 +/- 0.8 mmol/L [P = 0.010]; CV, 0.43 +/- 0.06 vs. 0.38 +/- 0.08 [P = 0.032]; MAGE, 6.9 +/- 1.2 vs. 5.9 +/- 1.2 mmol/L [P = 0.014]) but comparable glycated hemoglobin (HbA1c) (70 +/- 9 vs. 69 +/- 10 mmol/mol [8.6 +/- 0.8% vs. 8.5 +/- 0.9%], difference not significant). No significant difference in GV was found between the two groups when using only self-monitored blood glucose (SMBG) data. A positive association was found between VPT and SDT in all patients (r = 0.51, P = 0.0026). CONCLUSIONS: Patients with type 1 diabetes and any MVC had significantly higher GV calculated from CGM, but not from SMBG, than patients with comparable glycemic control but without complications. This supports the hypothesis that increased GV might be associated with MVC in type 1 diabetes and that HbA1c may not describe diabetes control completely. PMID- 24401009 TI - Ultrathin TiO2(B) nanorods with superior lithium-ion storage performance. AB - The peculiar architecture of a novel class of anisotropic TiO2(B) nanocrystals, which were synthesized by an surfactant-assisted nonaqueous sol-gel route, was profitably exploited to fabricate highly efficient mesoporous electrodes for Li storage. These electrodes are composed of a continuous spongy network of interconnected nanoscale units with a rod-shaped profile that terminates into one or two bulgelike or branch-shaped apexes spanning areas of about 5 * 10 nm(2). This architecture transcribes into a superior cycling performance (a charge capacitance of 222 mAh g(-1) was achieved by a carbon-free TiO2(B)-nanorods-based electrode vs 110 mAh g(-1) exhibited by a comparable TiO2-anatase electrode) and good chemical stability (more than 90% of the initial capacity remains after 100 charging/discharging cycles). Their outstanding lithiation/delithiation capabilities were also exploited to fabricate electrochromic devices that revealed an excellent coloration efficiency (130 cm(2) C(-1) at 800 nm) upon the application of 1.5 V as well as an extremely fast electrochromic switching (coloration time ~5 s). PMID- 24401010 TI - Effects of prochloraz on DNA damage, lipid peroxidation and antioxidant system in vitro. AB - Prochloraz is a broad-spectrum contact imidazol fungicide used against several diseases in wheat, barley and oleaginous plants but also for treatment of flower production. Although prochloraz has endocrine disrupting and hepatocarcinogenic effects, there is lack of data on toxic effects of prochloraz. Therefore, we aimed to investigate the DNA damage effects of prochloraz in NRK-52E cells by using Ames and Comet assay. By using a standard alkaline Comet assay procedure, there was no DNA damage observed after 24 h prochloraz exposure. It also showed that prochloraz caused neither base-pair substitution nor frame shift mutations by using TA98, TA100 strains, respectively, with/without metabolic activation in Ames assay. Both Comet and Ames assays, the exposure concentrations were 12.5, 25, 50 and 100 uM. IC50 value of prochloraz was determined as 110.76 uM in NRK 52E cells by MTT cytotoxicity test. Also, we evaluated possible effects of prochloraz on lipid peroxidation, reduced glutathione (GSH), oxidized glutathione (GSSG) and antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione reductase (GSH-Rd) in NRK 52E cells at 1-50 uM concentrations. Prochloraz induced lipid peroxidation and altered glutathione contents and antioxidant enzyme activities in NRK-52E cells. Our results indicated that prochloraz showed no evidence of mutagenicity and DNA damage; however, some alterations were observed on lipid peroxidation and antioxidant systems in prochloraz treatment. PMID- 24401011 TI - Phase behavior and molecular packing of octadecyl phenols and their methyl ethers at the air/water interface. AB - Noncovalent molecular interactions, such as hydrogen bonding and van der Waals forces, play an important role in self-assembling to supramolecular structures. To study these forces, we chose monolayers at the air/water interface to limit the possible arrangements of the interacting molecules. Furthermore, monolayers provide useful tools to understand and study interactions between molecules in a controlled and fundamental way. The phase behavior and molecular packing of the phenols 1-(4-hydroxyphenyl)-octadecane (5a), 1-(3,4-dihydroxyphenyl)-octadecane (6), and 1-(2,3,4-trihydroxyphenyl)-octadecane (3) and their methyl ethers in monolayers at the air/water interface have been examined by pi/A isotherms, Brewster angle microscopy (BAM), grazing incidence X-ray diffraction (GIXD) measurements, and density functional theory (DFT) calculations. The phenols are synthesized by Friedel-Crafts acylation of methoxybenzenes, hydrogenation of the resulting aryl ketones, and cleavage of the aryl methyl ethers. In the pi/A isotherms and in BAM, the phenols show patches of the solid condensed phase at large molecular areas and the monolayers collapse at high pressures. Furthermore, the dimensions of the unit cell obtained by GIXD measurements are compatible with an arrangement of the phenyl rings that allows one aryl ring to interact with four adjacent phenyl rings in an edge-to-face arrangement, which leads to a significant binding energy. The experimental data are in good agreement with DFT calculations of 2D crystalline benzene and p-cresol arrangements. The enhanced monolayer stability of phenol 5a can be explained by hydrogen bonds of the hydroxyl group with water and van der Waals forces between the alkyl chains and aryl-aryl interactions. PMID- 24401013 TI - Resonant coherence in photosynthetic electronic energy transfer by site-dependent pigment-protein interactions. AB - We have numerically examined the effect of site-dependent reorganization on the dynamics of coherent electronic excitation energy transfer in a donor and acceptor pair of photosynthetic pigment-protein complex. Using the quasi adiabatic propagator path integral method (QUAPI), we have found that a specific proportionality between the site-energy mismatch epsilon and the site reorganization energy mismatch lambda simultaneously increases the length and robustness of the quantum coherence. This behavior is associated with a Rabi type resonance that is manifested in the amplitude and frequency in the coherent portion of the population dynamics. Impact of the resonance on robustness of the coherence under static disorder is also discussed. PMID- 24401012 TI - Infant motor development in rural Vietnam and intrauterine exposures to anaemia, iron deficiency and common mental disorders: a prospective community-based study. AB - BACKGROUND: Antenatal anaemia, iron deficiency and common mental disorders (CMD) are prevalent in low- and middle-income countries. The aim of this study was to examine the direct and indirect effects of antenatal exposures to these risks and infant motor development. METHODS: A cohort of women who were pregnant with a single foetus and between 12 and 20 weeks pregnant in 50 randomly-selected rural communes in Ha Nam province was recruited. Participants provided data twice during pregnancy (early and late gestation) and twice after giving birth (8 weeks and 6 months postpartum). The Edinburgh Postnatal Depression Scale was used at all four data collection waves to detect CMD (score >= 4). Maternal anaemia (Hb < 11 g/dL) and iron deficiency (ferritin < 15 ng/mL) were evaluated at early and late gestation. Infants' motor development was assessed by the Bayley of Infant and Toddler Development Motor Scales (BSID-M) at the age of six months. Direct and indirect effects of the exposures on the outcome were examined with Path analysis. RESULTS: In total, 497 of 523 (97%) eligible pregnant women were recruited and 418 mother-infant pairs provided complete data and were included in the analyses. The prevalence of anaemia was 21.5% in early pregnancy and 24.4% in late pregnancy. There was 4.1% iron deficiency at early pregnancy and 48.2% at late pregnancy. Clinically significant symptoms of CMD were apparent among 40% women in early pregnancy and 28% in late pregnancy. There were direct adverse effects on infant BSID-M scores at 6 months of age due to antenatal anaemia in late pregnancy (an estimated mean reduction of 2.61 points, 95% Confidence Interval, CI, 0.57 to 4.65) and CMD in early pregnancy (7.13 points, 95% CI 3.13 to 11.13). Iron deficiency and anaemia in early pregnancy were indirectly related to the outcome via anaemia during late pregnancy. CONCLUSIONS: Antenatal anaemia, iron deficiency, and CMD have a negative impact on subsequent infant motor development. These findings highlight the need to improve the quality of antenatal care when developing interventions for pregnant women that aim to optimise early childhood development in low- and middle-income countries. PMID- 24401014 TI - Monitoring biofouling communities could reduce impacts to mussel aquaculture by allowing synchronisation of husbandry techniques with peaks in settlement. AB - Fouling organisms in bivalve aquaculture cause significant economic losses for the industry. Managing biofouling is typically reactive, and involves time- and labour-intensive removal techniques. Mussel spat settlement and biofouling were documented over 20 months at three mussel farms within Port Phillip Bay (PPB), Australia to determine if knowledge of settlement patterns could assist farmers in avoiding biofouling. Mussel spat settlement was largely confined to a 2-month period at one farm. Of the problematic foulers, Ectopleura crocea settlement varied in space and time at all three farms, whilst Ciona intestinalis and Pomatoceros taeniata were present predominantly at one farm and exhibited more distinct settlement periods. Within PPB, complete avoidance of biofouling is impossible. However, diligent monitoring may help farmers avoid peaks in detrimental biofouling species and allow them to implement removal strategies such as manual cleaning, and postpone grading and re-socking practices, until after these peaks. PMID- 24401015 TI - Regiospecific solid-phase synthesis of branched oligoribonucleotides that mimic intronic lariat RNA intermediates. AB - We have developed new solid phase methods for the synthesis of branched RNAs that mimic intronic lariat RNA intermediates. These methods produce branched oligoribonucleotide sequences of arbitrary length, base composition, and regiochemistry at the branchpoint junction. The methods utilize branching monomers that allow for the growth of each branch regioselectively from any of the hydroxyl positions (5', 3', or 2') at the branch-point junction. The integrity and branchpoint connectivity of the synthetic products have been confirmed by HPLC and MS analysis, and cleavage of the 2',5' linkage by recombinant debranching enzyme. Nonhydrolyzable branched RNA analogues containing arabinose instead of ribose at the branchpoint junction were shown to inhibit debranching activity and, hence, represent "decoys" for sequestering RNA binding proteins thought to drive amyotrophic lateral sclerosis (ALS). PMID- 24401016 TI - Identification of three new nucleotide substitutions in the beta-globin gene: laboratoristic approach and impact on genetic counselling for beta-thalassaemia. AB - PURPOSE: Over the past two decades, a wide range of available methods for DNA analysis have allowed us to identify defects in globin genes associated with haemoglobin disorders and to correlate specific mutations with phenotypic expression. The purpose of this study was to evaluate the nature of three new nucleotide changes, mutation or single nucleotide polymorphism, found in the beta globin gene, to conduct an appropriate genetic counselling. PATIENTS AND METHODS: We report the molecular study performed in three probands and their families, sampling during the screening programme conducted at the Laboratory for Molecular Prenatal Diagnosis of Hemoglobinopathies at Villa Sofia-Cervello Hospital in Palermo, Italy. RESULTS: This work allowed us to report three new nucleotide substitutions of the beta-globin gene: a substitution of the nucleotide 16 in the CAP site area (HBB: c.-35 A>G), a substitution of the nucleotide 478 in the second intron (HBB: c.316-373) in association with beta-haemoglobin variant Hb G Copenhagen (HBB:c.142G>A) and a substitution of the nucleotide 1656 within the 3' UTR (HBB: c.*+182 G>A) in association with the 1393-bp deletion (NG_000007.3:g.70060_71452del1393). CONCLUSION: The present work emphasizes the importance of reporting the observed nucleotide changes to the Haemoglobin Variant Database, especially in the case of new or rare undefined mutations, to facilitate the determination of their phenotypic expression and the possible interactions with known molecular defects and to formulate an appropriate genetic counselling for couples at risk. PMID- 24401017 TI - Potential drug-drug and drug-condition interactions among fibromyalgia patients initiating pregabalin or duloxetine: prevalence and health care expenditure impact. AB - OBJECTIVE: To quantify the prevalence of potential drug-drug/drug-condition interactions (DDI/DCI) among fibromyalgia patients initiating pregabalin or duloxetine, and to determine the impact of potential DDI/DCI on health care expenditures. DESIGN: Retrospective cohort study. SETTING: U.S. clinical practice, as reflected within a large administrative claims database. SUBJECTS: Fibromyalgia patients newly initiating pregabalin or duloxetine between July 1, 2008 and October 1, 2010 (initiation date = index). OUTCOME MEASURES: Potential DDI measured using clinical software that identifies co-prescription of medications that potentially interact with pregabalin or duloxetine. Potential DCI, drawn from the contraindications and warnings and precautions sections of pregabalin and duloxetine prescribing information, measured using administrative claims-based algorithms. All-cause health care expenditures measured throughout a 6-month postindex period. Analyses included univariate, bivariate, and multivariable statistical approaches. RESULTS: Seven thousand seven hundred fifty one pregabalin and 7,785 duloxetine initiators were selected for study: mean age 49 years, 88% female. Only 1.4% of pregabalin initiators had >=1 potential pregabalin DCI; none had potential pregabalin DDI. In contrast, 67% of duloxetine initiators had potential duloxetine DDI/DCI, driven mostly by potential duloxetine DDI (62% of duloxetine initiators). Compared between pregabalin and duloxetine initiators, differences in the prevalence of potential DDI/DCI were statistically significant (P < 0.001). Multivariable analyses indicated that, among duloxetine initiators, those with potential duloxetine DDI/DCI had postinitiation health care expenditures that were $670 higher (P < 0.001) than those without potential duloxetine DDI/DCI. Among pregabalin initiators, potential pregabalin DDI/DCI were not associated with health care expenditures. CONCLUSIONS: Among fibromyalgia patients initiating pregabalin or duloxetine, potential duloxetine DDI could be highly prevalent. Among duloxetine initiators, potential duloxetine DDI/DCI were significantly associated with increased health care expenditures. PMID- 24401018 TI - Single-cell gene expression analysis reveals clonal architecture of blast-phase chronic myeloid leukaemia. PMID- 24401019 TI - Diabetes is a major risk factor for mortality after lung transplantation. AB - Survival following lung transplant (LTx) remains significantly lower than after other solid organ transplants. Diabetes mellitus (DM) is a mortality risk factor not comprehensively studied in LTx recipients. Notably, neither the relation of time of DM onset to survival nor the actual causes of DM-associated excess mortality have been described. We determined DM status, DM diagnosis date and all cause mortality in 386 consecutive adults who underwent LTx at our institution from January 1, 2001 to July 31, 2010. The relationship of DM to survival both as a categorical and time-dependent variable was studied. Fifty-three percent of patients had DM. Overall median survival was 5.2 (95% CI 3.8-6.6) years. At study end, 52% of patients had died, of whom 64% had DM. Estimated median survival was 10 years in patients without DM, 5.0 (3.3-6.8) years in patients with DM pre- and post-LTx and 4.3 (3.1-5.5) years in patients with new onset DM. As a time dependent covariate, DM was the strongest risk factor for mortality, hazard ratio 3.96 (2.85-5.51). Bronchiolitis obliterans syndrome was the main cause of death in all patients surviving >90 days, but its incidence was not increased in patients with DM. Further studies are warranted to determine whether improved glycemic control could improve outcomes in LTx recipients. PMID- 24401020 TI - Second-pandemic strain of Vibrio cholerae from the Philadelphia cholera outbreak of 1849. AB - In the 19th century, there were several major cholera pandemics in the Indian subcontinent, Europe, and North America. The causes of these outbreaks and the genomic strain identities remain a mystery. We used targeted high-throughput sequencing to reconstruct the Vibrio cholerae genome from the preserved intestine of a victim of the 1849 cholera outbreak in Philadelphia, part of the second cholera pandemic. This O1 biotype strain has 95 to 97% similarity with the classical O395 genome, differing by 203 single-nucleotide polymorphisms (SNPs), lacking three genomic islands, and probably having one or more tandem cholera toxin prophage (CTX) arrays, which potentially affected its virulence. This result highlights archived medical remains as a potential resource for investigations into the genomic origins of past pandemics. PMID- 24401021 TI - Tobacco 21--an idea whose time has come. PMID- 24401022 TI - Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. AB - BACKGROUND: The monoclonal anti-CD20 antibody rituximab, combined with chemotherapeutic agents, has been shown to prolong overall survival in physically fit patients with previously untreated chronic lymphocytic leukemia (CLL) but not in those with coexisting conditions. We investigated the benefit of the type 2, glycoengineered antibody obinutuzumab (also known as GA101) as compared with that of rituximab, each combined with chlorambucil, in patients with previously untreated CLL and coexisting conditions. METHODS: We randomly assigned 781 patients with previously untreated CLL and a score higher than 6 on the Cumulative Illness Rating Scale (CIRS) (range, 0 to 56, with higher scores indicating worse health status) or an estimated creatinine clearance of 30 to 69 ml per minute to receive chlorambucil, obinutuzumab plus chlorambucil, or rituximab plus chlorambucil. The primary end point was investigator-assessed progression-free survival. RESULTS: The patients had a median age of 73 years, creatinine clearance of 62 ml per minute, and CIRS score of 8 at baseline. Treatment with obinutuzumab-chlorambucil or rituximab-chlorambucil, as compared with chlorambucil monotherapy, increased response rates and prolonged progression free survival (median progression-free survival, 26.7 months with obinutuzumab chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio for progression or death, 0.18; 95% confidence interval [CI], 0.13 to 0.24; P<0.001; and 16.3 months with rituximab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio, 0.44; 95% CI, 0.34 to 0.57; P<0.001). Treatment with obinutuzumab-chlorambucil, as compared with chlorambucil alone, prolonged overall survival (hazard ratio for death, 0.41; 95% CI, 0.23 to 0.74; P=0.002). Treatment with obinutuzumab-chlorambucil, as compared with rituximab-chlorambucil, resulted in prolongation of progression-free survival (hazard ratio, 0.39; 95% CI, 0.31 to 0.49; P<0.001) and higher rates of complete response (20.7% vs. 7.0%) and molecular response. Infusion-related reactions and neutropenia were more common with obinutuzumab-chlorambucil than with rituximab-chlorambucil, but the risk of infection was not increased. CONCLUSIONS: Combining an anti-CD20 antibody with chemotherapy improved outcomes in patients with CLL and coexisting conditions. In this patient population, obinutuzumab was superior to rituximab when each was combined with chlorambucil. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT01010061.). PMID- 24401023 TI - EMS provider compliance with infection control recommendations is suboptimal. AB - INTRODUCTION: Standard precautions are disease transmission prevention strategies recommended by both the World Health Organization (WHO) and by the Centers for Disease Control and Prevention (CDC). Emergency medical services (EMS) personnel are expected to utilize standard precautions. METHODS: This was a prospective observational study of the use of standard precautions by EMS providers arriving at a large urban emergency department (ED). Research assistants (RAs) observed EMS crews throughout their arrival and delivery of patients and recorded data related to the use of gloves, hand hygiene, and equipment disinfection. RESULTS: A total of 423 EMS deliveries were observed, allowing for observation of 899 EMS providers. Only 512 (56.9%) EMS providers arrived wearing gloves. Hand washing was observed in 250 (27.8%) of providers. Reusable equipment disinfection was noted in only 31.6% of opportunities. The most commonly disinfected item was the stretcher (55%). CONCLUSION: EMS provider compliance with standard precautions and equipment disinfection recommendations is suboptimal. Strategies must be developed to improve EMS provider compliance with internationally recognized infection control guidelines. Key words: Emergency medical services, hand washing, hygiene, disinfection, disease prevention. PMID- 24401024 TI - A single vector-based strategy for marker-less gene replacement in Synechocystis sp. PCC 6803. AB - BACKGROUND: The cyanobacterium Synechocystis sp. PCC 6803 is widely used for research on photosynthesis and circadian rhythms, and also finds application in sustainable biotechnologies. Synechocystis is naturally transformable and undergoes homologous recombination, which enables the development of a variety of tools for genetic and genomic manipulations. To generate multiple gene deletions and/or replacements, marker-less manipulation methods based on counter-selection are generally employed. Currently available methods require two transformation steps with different DNA plasmids. RESULTS: In this study, we present a marker less gene deletion and replacement strategy in Synechocystis sp. PCC 6803 which needs only a single transformation step. The method utilizes an nptI-sacB double selection cassette and exploits the ability of the cyanobacterium to undergo two successive genomic recombination events via double and single crossing-over upon application of appropriate selective procedures. CONCLUSIONS: By reducing the number of cloning steps, this strategy will facilitate gene manipulation, gain-of function studies, and automated screening of mutants. PMID- 24401025 TI - Selective trans-membrane transport of alkali and alkaline earth cations through graphene oxide membranes based on cation-pi interactions. AB - Graphene and graphene oxide (G-O) have been demonstrated to be excellent filters for various gases and liquids, showing potential applications in areas such as molecular sieving and water desalination. In this paper, the selective trans membrane transport properties of alkali and alkaline earth cations through a membrane composed of stacked and overlapped G-O sheets ("G-O membrane") are investigated. The thermodynamics of the ion transport process reveal that the competition between the generated thermal motions and the interactions of cations with the G-O sheets results in the different penetration behaviors to temperature variations for the considered cations (K(+), Mg(2+), Ca(2+), and Ba(2+)). The interactions between the studied metal atoms and graphene are quantified by first principles calculations based on the plane-wave-basis-set density functional theory (DFT) approach. The mechanism of the selective ion trans-membrane transportation is discussed further and found to be consistent with the concept of cation-pi interactions involved in biological systems. The balance between cation-pi interactions of the cations considered with the sp(2) clusters of G-O membranes and the desolvation effect of the ions is responsible for the selectivity of G-O membranes toward the penetration of different ions. These results help us better understand the ion transport process through G-O membranes, from which the possibility of modeling the ion transport behavior of cellular membrane using G-O can be discussed further. The selectivity toward different ions also makes G-O membrane a promising candidate in areas of membrane separations. PMID- 24401026 TI - The continuum of HIV care in a Veterans' Affairs clinic. AB - The cascade of HIV care in the United States has become a focus for interventions aimed at improving the success of HIV treatment. The Atlanta VA Medical Center (AVAMC) Infectious Disease Clinic (IDC) is an urban clinic that provides care for over 1,400 people living with HIV (PLHIV) annually. Using data from the HIV Atlanta VA Cohort Study (HAVACS), we modeled the continuum of care in the AVAMC IDC and explored similarities and differences with national models. We conducted a cross-sectional analysis of 1,474 individuals receiving care in the AVAMC IDC. We estimated total PLHIV and defined several categories within the spectrum of HIV care. We then developed the continuum of care using two methodologies. The first required each stage to be a dependent subset of the immediate upstream stage. The second allowed each stage to be independent of upstream stages. Dependent stage categorization estimated that 95.3% of individuals were diagnosed with HIV, 89.8% of individuals were linked to care, 73.0% of individuals were retained in care, 65.9% of individuals were eligible for antiretroviral treatment (ART), 62.8% were prescribed ART, and 52.4% had a suppressed viral load (VL). Independent stage categorization estimated that 83.9% of individuals were prescribed ART and 61.5% had a suppressed VL. Our analyses showed that the AVAMC IDC estimates were significantly better than national estimates at every stage. This may reflect the benefits of a universal healthcare system. We propose the use of independent stages for the continuum as this more accurately represents healthcare utilization. PMID- 24401027 TI - Studies of aluminum reinsertion into borosilicate zeolites with intersecting channels of 10- and 12-ring channel systems. AB - The work here describes the kinetic analyses of aluminum replacement for boron in a suite of borosilicate molecular sieves. While the method has been described before as a means of converting synthesized borosilicates (with weak inherent acidity) to aluminosilicates (with much stronger acid strength) when there are large pores in the structure, here we carry out the transformation under less than optimal replacement concentrations, in order to better follow the kinetics. We examined several zeolite structures with boundary conditions of boron MEL where there are only 10-ring (or intermediate) pore structures and no Al is taken up, to multidimensional large pore zeolites, like boron beta, where Al substitution can occur everywhere. We also studied materials with both intermediate and large pores, SSZ-56, 57, 70, and 82. In the case of 57 up to 90% of the structure is made up of boron MEL. We observe that the pH drop is proportional to the Al reinsertion and is the same for all zeolites we studied. In one case, we compared a zeolite (SSZ-24) with boron and then no boron sites and found that Al does not go into defect sites. It was again confirmed (shown in earlier work) that Al will go into nest sites created by boron hydrolysis out of the substrate before Al treatment. Along those lines we also made two new observations: (1) the profile for Al uptake, as followed by pH drop, is the same kinetically, whether the boron is there or not; and (2) NMR showed that the boron is leaving the structure faster than Al can go back in (SSZ-33 study), even when we treat a material with boron in the lattice. PMID- 24401028 TI - Assessment of adolescents' communication on sexual and reproductive health matters with parents and associated factors among secondary and preparatory schools' students in Debremarkos town, North West Ethiopia. AB - BACKGROUND: Sexuality and reproductive health are among the most fundamental aspects of life. Poor parental involvement in preparing young people for safe sexual life and good reproductive health was part of the blame for the lack of skills on sexual decision making. Despite the growing needs, there is no adequate health service or counseling specifically suitable for this specific age group and research on the role of parents in this process has yielded inconsistent results. OBJECTIVE: The objective of the study is to assess adolescents' communication on sexual and reproductive health issues with parents and associated factors among secondary and preparatory schools students in Debremarkos town. METHODS: School based study was conducted among secondary and preparatory schools students in Debremarkos town, from April 8 to 21, 2012. Multistage sampling and self administered questionnaires were employed. RESULTS: The proportion of the students who had discussion on sexual & reproductive health issues with their parent was found to be 254 (36.9%). Mother who able to read and write (AOR = 2; 95% CI 1.3 to 3.1), adolescents accepting discussion of sexual & reproductive health issues (AOR = 2.5 95% CI 1.3 to 4.5), adolescents who ever got SRH information (AOR = 2; 95% CI 1.4 to 2.9), adolescents who ever had sexual intercourse (AOR = 1.7; 95% CI 1.1 to 2.6) were found to have significant positive associations, and being grade 12 students (AOR = 0.4; 95% CI 0.2 to 0.7) and having less than three family size (AOR = 0.5; 95% CI 0.2 to 0.9) showed significant negative associations. CONCLUSION AND RECOMMENDATION: Study unveils that parent -adolescent communications on sexual and reproductive health issues is low, only about one third of the students were communicating on SRH issues. Therefore; there is a need to equip and educate parents on different sexual & reproductive health issues. Comprehensive family life education should also be initiated for the students and parents. PMID- 24401030 TI - Effect of pectin methylesterase on carrot (Daucus carota) juice cloud stability. AB - To determine the effect of residual enzyme activity on carrot juice cloud, 0 to 1 U/g pectin methylesterase (PME) was added to pasteurized carrot juice. Cloud stability and particle diameters were measured to quantify juice cloud stability and clarification for 56 days of storage. All levels of PME addition resulted in clarification; higher amounts had a modest effect in causing more rapid clarification, due to a faster increase in particle size. The cloud initially exhibited a trimodal distribution of particle sizes. For enzyme-containing samples, particles in the smallest-sized mode initially aggregated to merge with the second peak over 5-10 days. This larger population then continued to aggregate more slowly over longer times. This observation of a more rapid destabilization process initially, followed by slower subsequent changes in the cloud, was also manifested in measurements of sedimentation extent and in turbidity tests. Optical microscopy showed that aggregation created elongated, fractal particle structures over time. PMID- 24401029 TI - Intraocular pressure homeostasis: maintaining balance in a high-pressure environment. AB - Although glaucoma is a relatively common blinding disease, most people do not develop glaucoma. A robust intraocular pressure (IOP) homeostatic mechanism keeps ocular pressures within relatively narrow acceptable bounds throughout most peoples' lives. The trabecular meshwork and/or Schlemm's canal inner wall cells respond to sustained IOP elevation and adjust the aqueous humor outflow resistance to restore IOP to acceptable levels. It appears that the cells sense IOP elevations as mechanical stretch or distortion of the actual outflow resistance and respond by initiating a complex extracellular matrix (ECM) turnover process that takes several days to complete. Although considerable information pertinent to this process is available, many aspects of the IOP homeostatic process remain to be elucidated. Components and mechanisms beyond ECM turnover could also be relevant to IOP homeostasis, but will not be addressed in detail here. Known aspects of the IOP homeostasis process as well as possible ways that it might function and impact glaucoma are discussed. PMID- 24401031 TI - Levels and distributions of hexachlorobutadiene and three chlorobenzenes in biosolids from wastewater treatment plants and in soils within and surrounding a chemical plant in China. AB - Although hexachlorobutadiene (HCBD) was recently proposed as a candidate persistent organic pollutant (POP) under the Stockholm Convention, information about its environmental levels and distributions is still very limited. In this work, HCBD was determined in the sewage sludge from 37 wastewater treatment plants (WWTPs) in 23 cities and 17 soils near a chemical plant in China. Three chlorobenzenes (CBs) (1,2,4-trichlorobenzene, 1,2,4,5-tetrachlorobenzene, and hexachlorobenzene) were simultaneously studied to help better understand the environmental behavior of HCBD. Concentrations of HCBD in sludge samples ranged from <0.03 to 74.3 ng/g dry weight (dw) with a median value of 0.30 ng/g dw, which was lower than those of the three CBs. Levels of HCBD were not correlated with capacity of the WWTPs and total organic carbon. For soils, high level of HCBD was found in the sample within the plant, with a rapid decreasing concentration trend with the increase of distance from the plant. It was suspected that releasing as a byproduct during manufacturing of chlorinated chemicals was the primary source of HCBD in the studied location. Further risk assessment indicated that the environmental risk of HCBD to soil organisms and the health risk to employees were very low through soil exposure within the plant. PMID- 24401032 TI - Sarcoidosis mimicking metastatic breast cancer in Korean woman with breast cancer. PMID- 24401035 TI - Azotobacter vinelandii siderophore can provide nitrogen to support the culture of the green algae Neochloris oleoabundans and Scenedesmus sp. BA032. AB - Microalgae are viewed as a potential future agricultural and biofuel feedstock and also provide an ideal biological means of carbon sequestration based on rapid growth rates and high biomass yields. Any potential improvement using high-yield microalgae to fix carbon will require additional fertilizer inputs to provide the necessary nitrogen required for protein and nucleotide biosynthesis. The free living diazotroph Azotobacter vinelandii can fix nitrogen under aerobic conditions in the presence of reduced carbon sources such as sucrose or glycerol and is also known to produce a variety of siderophores to scavenge different metals from the environment. In this study, we identified two strains of green algae, Neochloris oleoabundans and Scenedesmus sp. BA032, that are able to utilize the A. vinelandii siderophore azotobactin as a source of nitrogen to support growth. When grown in a co-culture, S. sp. BA032 and N. oleoabundans obtained the nitrogen required for growth through the association with A. vinelandii. These results, indicating a commensalistic relationship, provide a proof of concept for developing a mutualistic or symbiotic relationship between these two species using siderophores as a nitrogen shuttle and might further indicate an additional fate of siderophores in the environment. PMID- 24401033 TI - Comparative analysis of sodium coupled vitamin C transporter 2 in human osteoarthritis grade 1 and grade 3 tissues. AB - BACKGROUND: Nutrient levels are known to influence the development of osteoarthritis (OA), presumably by modulating levels of matrix biosynthesis and degradation. These processes may be affected by ascorbic acid (AA), an antioxidant which acts as a cofactor for numerous biochemical reactions and is essential for post-translational modifications of collagen. In this study we examined the expression of SVCT2, the only known Sodium coupled vitamin C transporter isoform present in articular cartilage, in human articular cartilage explants derived from both normal and osteoarthritis articular cartilage. METHODS: OA1 and OA3 human articular cartilage was carefully dissected and macroscopically graded for degeneration via the Collins scale. The tissue samples were histologically examined by Hematoxylin and Eosin and Safranin O and Fast Green staining. SVCT2 expression analysis was performed at mRNA level by quantitative real time PCR and at a protein level by immunohistochemistry. RESULTS: Our quantitative real time PCR showed marked variation in the expression of SVCT2 in human osteoarthritic articular cartilage. SVCT2 expression was significantly down-regulated (p = 0.0001) in the Collins grade 3 (OA3) compared to Collins grade 1 (OA1) tissue. Furthermore, slides stained with fluorescent antibodies to SVCT2 demonstrated greatly reduced fluorescence for the SVCT2 transporter on the chondrocyte plasma membrane in the osteoarthritic tissue samples. CONCLUSIONS: These findings demonstrate that the expression of SVCT2 transporter is significantly altered in human osteoarthritic tissues (OA3). The modulation of this transporter could therefore potentially influence the prevention, management and treatment of osteoarthritis. PMID- 24401034 TI - Age-related decline in cognitive control: the role of fluid intelligence and processing speed. AB - BACKGROUND: Research on cognitive control suggests an age-related decline in proactive control abilities whereas reactive control seems to remain intact. However, the reason of the differential age effect on cognitive control efficiency is still unclear. This study investigated the potential influence of fluid intelligence and processing speed on the selective age-related decline in proactive control. Eighty young and 80 healthy older adults were included in this study. The participants were submitted to a working memory recognition paradigm, assessing proactive and reactive cognitive control by manipulating the interference level across items. RESULTS: Repeated measures ANOVAs and hierarchical linear regressions indicated that the ability to appropriately use cognitive control processes during aging seems to be at least partially affected by the amount of available cognitive resources (assessed by fluid intelligence and processing speed abilities). CONCLUSIONS: This study highlights the potential role of cognitive resources on the selective age-related decline in proactive control, suggesting the importance of a more exhaustive approach considering the confounding variables during cognitive control assessment. PMID- 24401036 TI - The efficacy of co-treatment with suberoylanilide hydroxamic acid and mitomycin C on corneal scarring after therapeutic keratectomy: an animal study. AB - PURPOSE: This study was undertaken to evaluate the efficacy of co-treatment with suberoylanilide hydroxamic acid (SAHA) and mitomycin-C (MMC) on corneal fibrosis in an in-vivo model. MATERIALS AND METHODS: We examined the effect of co treatment with MMC and SAHA, a potent histone deacetylase inhibitor (HDACi), on the corneal fibrosis and haze produced in rats following photorefractive keratectomy (PRK). We further examined the toxicity of this co-treatment on human corneal epithelial (HCE) cells in-vitro. RESULTS: The combination of MMC and SAHA efficiently suppressed corneal fibrosis and haze following PRK. At the doses tested, SAHA had no inhibitory effect on human corneal epithelial cell viability, whereas MMC-treated cells showed increased apoptotic changes in Western blot testing and a fluorescence-activated cell sorting system. Co-treatment with SAHA and a low-dose of MMC minimized corneal haze after PRK and produced a significantly lower level of cytotoxic effects than treatment with MMC alone. CONCLUSIONS: Treatment with SAHA in combination with a low dose of MMC could be a novel and effective therapeutic strategy to suppress the proliferation of corneal myofibroblasts, thereby inhibiting corneal fibrosis or haze with minimal ocular surface toxicity. PMID- 24401037 TI - Close identity between alternatively folded state N2 of ubiquitin and the conformation of the protein bound to the ubiquitin-activating enzyme. AB - We present the nuclear Overhauser effect-based structure determination of the Q41N variant of ubiquitin at 2500 bar, where the alternatively folded N2 state is 97% populated. This allows us to characterize the structure of the "pure" N2 state of ubiquitin. The N2 state shows a substantial change in the orientation of strand beta5 compared to that of the normal folded N1 state, which matches the changes seen upon binding of ubiquitin to ubiquitin-activating enzyme E1. The recognition of E1 by ubiquitin is therefore best explained by conformational selection rather than induced-fit motion. PMID- 24401038 TI - Development of etoposide-loaded bovine serum albumin nanosuspensions for parenteral delivery. AB - Nanosuspensions emerge as a promising strategy for delivery of poorly water soluble drugs. Albumin is a versatile protein carrier for drug delivery and targeting. The purpose of this study was to develop a formulation of etoposide loaded bovine serum albumin (BSA) nanosuspensions, to study in vitro characterization, and to estimate the in vivo safety and tissue distribution of etoposide-loaded BSA nanosuspensions for parenteral delivery. Etoposide-loaded BSA nanosuspensions were prepared by high-pressure homogenization-solvent precipitation method. The particle size, zeta potential, drug entrapment efficiency, and drug loading of the lyophilized formulation were 182.3 nm, -22.18 mV, 86.44%, and 8.49% respectively. In vitro release files of the formulation presented sustained release properties. Preliminary safety study was conducted to evaluate the delivery system, and results indicated that myelosuppression effect of the etoposide-loaded BSA nanosuspensions group was significantly lower than the Injection(r) group. Furthermore, results of tissue distribution studies showed that the concentration and AUC of etoposide were increased significantly in lung, liver, spleen while reduced in heart, kidney compared with the etoposide injection(r) group after i.v. administration of etoposide-loaded BSA nanosuspensions. The formulation played a role in targeting delivery to lung, reduce toxicity, and side effects of etoposide. In conclusion, etoposide-loaded BSA nanosuspensions were promising for parenteral delivery of etoposide. PMID- 24401039 TI - SAR genotoxicity and tumorigenicity predictions for 2-MI and 4-MI using multiple SAR software. AB - CONTEXT: Caramel coloring chemicals, 2-methylimidazole (2-MI) and 4 methylimidazole (4-MI) have been used extensively in coloring soft drinks. The health effects of these chemicals have been concerned in the recent years. OBJECTIVE: In the present investigation, 2- and 4-MI were subjected to three commonly used structure-activity relationship (SAR) software to understand the utility of such software as a method of alternatives to animal testing in predicting potential genotoxicity and tumorigenicity. MATERIALS AND METHODS: Three SAR software: Osiris, ToxTree and DEREK, were used. Published procedures and/or manuals of respective software were utilized to generate data outputs and the data were evaluated in comparison with available toxicological data on 2- and 4-MI. RESULTS: The results show that these software predicted genotoxic activity in comparison with published genotoxicity for 2- and 4-MI. However, only one of three software used (Osiris) predicted imidazole ring in 4-MI to be tumorigenic; other software predicted them to be negative. DISCUSSION: Based on the weight of evidence of SAR results observed in this study and the genotoxicity and tumorigenicity reported using actual in vitro and in vivo animal testing in literature, it was concluded that the models used are useful for routine screening of chemicals; however, for better prediction, additional models may be employed. Software's ability to predict health effects depends on the type of structural alerts used as knowledgebase in developing such software. CONCLUSION: Three computational software used in this study predicted genotoxic activity of 2 and 4-MI, but did not predict tumorigenicity conclusively when compared to literature reported animal data. Additional mechanistic non-clinical studies may be conducted to better understand reported tumorigenicity. PMID- 24401040 TI - Templating fullerenes by domain boundaries of a nanoporous network. AB - We present a new templating approach that combines the templating properties of nanoporous networks with the dynamic properties and the lattice mismatch of domain boundaries. This templating approach allows for the inclusion of guests with different sizes without the need for a strict molecular design to tailor the nanoporous network. With this approach, nonperiodic patterns of functional molecules can be formed and studied. We show that domain boundaries in a trimesic acid network are preferred over pores within the network as adsorption sites for fullerenes by a factor of 100-200. Pristine fullerenes of different sizes and functionalized fullerenes were templated in this way. PMID- 24401041 TI - A randomized controlled trial to assess the clinical and cost effectiveness of a nurse-led Antenatal Asthma Management Service in South Australia (AAMS study). AB - BACKGROUND: Pregnancy presents a unique situation for the management of asthma as it can alter the course of asthma severity and its treatment, which in turn can affect pregnancy outcomes. Despite awareness of the substantial adverse effects associated with asthma during pregnancy, little has been done to improve its management and reduce associated perinatal morbidity and mortality. The aim of this randomized controlled trial is to evaluate the clinical and cost effectiveness of an Antenatal Asthma Management Service. METHODS/DESIGN: DESIGN: Multicentre, randomized controlled trial. INCLUSION CRITERIA: Women with physician diagnosed asthma, which is not currently in remission, who are less than 20 weeks gestation with a singleton pregnancy and do not have a chronic medical condition.Trial entry and randomization: Eligible women with asthma, stratified by treatment site, disease severity and parity, will be randomized into either the 'Standard Care Group' or the 'Intervention Group'.Study groups: Both groups will be followed prospectively throughout pregnancy. Women in the 'Standard Care Group' will receive routine obstetric care reflecting current clinical practice in Australian hospitals. Women in the 'Intervention Group' will receive additional care through the nurse-led Antenatal Asthma Management Service, based in the antenatal outpatient clinic. Women will receive asthma education with a full assessment of their asthma at 18, 24, 30 and 36 weeks gestation. Each antenatal visit will include a 60 min session where asthma management skills are assessed including: medication adherence and knowledge, inhaler device technique, recognition of asthma deterioration and possession of a written asthma action plan. Furthermore, subjects will receive education about asthma control and management skills including trigger avoidance and smoking cessation counseling when appropriate.Primary study outcome: Asthma exacerbations during pregnancy. SAMPLE SIZE: A sample size of 378 women will be sufficient to show an absolute reduction in asthma exacerbations during pregnancy of 20% (alpha 0.05 two-tailed, 90% power, 5% loss to follow-up). DISCUSSION: The integration of an asthma education program within the antenatal clinic setting has the significant potential to improve the participation of pregnant women in the self management of their asthma, reduce asthma exacerbations and improve perinatal health outcomes. TRIAL REGISTRATION: ACTRN12613000244707. PMID- 24401042 TI - Layer-by-layer modification of cation exchange membranes controls ion selectivity and water splitting. AB - The present study investigates the possibility of inducing monovalent ion permselectivity on standard cation exchange membranes, by the layer-by-layer (LbL) assembly of poly(ethyleneimine) (PEI)/poly(styrenesulfonate) (PSS) polyelectrolyte multilayers. Coating of the (PEI/PSS)N LbL multilayers on the CMX membrane caused only moderate variation of the ohmic resistance of the membrane systems. Nonetheless, the polyelectrolyte multilayers had a substantial influence on the monovalent ion permselectivity of the membranes. Permselectivity comparable to that of a commercial monovalent-ion-permselective membrane was obtained with only six bilayers of polyelectrolytes, yet with significantly lower energy consumption per mole of Na(+) ions transported through the membranes. The monovalent ion permselectivity stems from an increased Donnan exclusion for divalent ions and hydrophobization of the surface of the membranes concomitant to their modification. Double-layer capacitance obtained from impedance measurements shows a qualitative indication of the divalent ion repulsion of the membranes. At overlimiting current densities, water dissociation occurred at membranes with PEI terminated layers and increased with the number of layers, while it was nearly absent for the PSS-terminated layers. Hence, LbL layers allow switching on and turning off water splitting at the surface of ion exchange membranes. PMID- 24401043 TI - Thermodynamic, dynamic and solvational properties of PDEdelta binding to farnesylated cystein: a model study for uncovering the molecular mechanism of PDEdelta interaction with prenylated proteins. AB - The protein PDEdelta is an important solubilizing factor for several prenylated proteins including the Ras subfamily members. The binding occurs mainly through the farnesyl anchor of Ras proteins, which is recognized by a hydrophobic pocket of PDEdelta. In this study, we carried out a detailed study of the thermodynamic and solvational properties of PDEdelta binding to farnesyl-cystein, which serves as a model for PDEdelta association to prenylated proteins. Using various biophysical approaches in conjunction with theoretical considerations, we show here that binding of the largely hydrophobic ligand surprisingly has enthalpy driven signature, and the entropy change is largely controlled by the fine balance between the hydrational and conformational terms. Moreover, binding of PDEdelta to farnesyl-cystein is accompanied by an increase in thermal stability, the release of about 150 water molecules from the interacting species, a decrease in solvent accessible surface area, and a marked decrease of the volume fluctuations and hence dynamics of the protein. Altogether, our results shed more light on the molecular mechanism of PDEdelta interaction with prenylated Ras proteins, which is also prerequisite for an optimization of the structure-based molecular design of drugs against Ras related diseases and for understanding the multitude of biological functions of PDEdelta. PMID- 24401045 TI - Comparison of the performance of the Cepheid Xpert HemosIL Factor II and Factor V and the ViennaLab FV-PTH-MTHFR StripAssay kits for molecular thrombophilia profiling. AB - AIMS: To compare the performance of two assays used for the detection of mutations/polymorphisms in the Factor V, Factor II, and methylenetetrahydrofolate reductase genes among patients referred for the management of a thrombotic event. MATERIALS AND METHODS: We tested 40 different patient samples using two assays, the ViennaLab FV-PTH-MTHFR StripAssay and the Cepheid Xpert HemosIL. RESULTS: The two assays were 100% concordant in their produced results with no samples failing the testing procedures in both. CONCLUSION: This is the first report to evaluate the performance of the ViennaLab FV-PTH-MTHFR StripAssay and the Cepheid Xpert HemosIL. Both assays can be introduced to the operation of molecular diagnostic laboratories to cover the referrals from different disciplines, especially in tertiary care centers with emergency departments. PMID- 24401044 TI - The risk for persistent adult alcohol and nicotine dependence: the role of childhood maltreatment. AB - BACKGROUND AND AIMS: Alcohol and nicotine dependence are associated with considerable morbidity and mortality, especially when cases are persistent. The risk for alcohol and nicotine dependence is increased by childhood maltreatment. However, the influence of childhood maltreatment on dependence course is unknown, and is evaluated in the current study. DESIGN: Physical, sexual and emotional abuse, and physical and emotional neglect, were evaluated as predictors of persistent alcohol and nicotine dependence over 3 years of follow-up, with and without control for other childhood adversities. SETTING: National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). PARTICIPANTS: NESARC participants completing baseline and follow-up who met criteria at baseline for past-year alcohol dependence (n = 1172) and nicotine dependence (n = 4017). MEASUREMENTS: Alcohol Use Disorder and Associated Disabilities Interview Schedule (AUDADIS) measures of alcohol/nicotine dependence, childhood maltreatment and other adverse childhood experiences (e.g. parental divorce). FINDINGS: Controlling for demographics only, physical, sexual and emotional abuse and physical neglect predicted 3-year persistence of alcohol dependence [adjusted odds ratio (AOR) = 1.50-2.99; 95% CI = 1.04-4.68] and nicotine dependence (AOR = 1.37-1.74; 95% CI = 1.13-2.11). With other childhood adversities also controlled, maltreatment types remained predictive for alcohol persistence (AOR = 1.53-3.02; 95% CI = 1.07-4.71) and nicotine persistence (AOR = 1.35-1.72; 95% CI = 1.11 2.09). Further, a greater number of maltreatment types incrementally influenced persistence risk (AOR = 1.19-1.36; 95% CI = 1.11-1.56). CONCLUSIONS: A history of childhood maltreatment predicts persistent adult alcohol and nicotine dependence. This association, robust to control for other childhood adversities, suggests that maltreatment (rather than a generally difficult childhood) affects the course of dependence. PMID- 24401047 TI - Medicaid policy on sterilization--anachronistic or still relevant? PMID- 24401046 TI - Medication errors in prehospital management of simulated pediatric anaphylaxis. AB - BACKGROUND: Systematic evaluation of the performances of prehospital providers during actual pediatric anaphylaxis cases has never been reported. Epinephrine medication errors in pediatric resuscitation are common, but the root causes of these errors are not fully understood. OBJECTIVE: The primary objective of this study was to identify underlying causes of prehospital medication errors that were observed during a simulated pediatric anaphylaxis reaction. METHODS: Two- and 4-person emergency medical services crews from eight geographically diverse agencies participated in a 20-minute simulation of a 5-year old child with progressive respiratory distress and hypotension from an anaphylactic reaction. Crews used their own equipment and drugs. A checklist-based scoring protocol was developed to help identify errors. A trained facilitator conducted a structured debriefing, supplemented by playback of video recordings, immediately after the simulated event to elicit underlying causes of errors. Errors were analyzed with mixed quantitative and qualitative methods. RESULTS: One hundred forty-two subjects participated in 62 simulation sessions. Ninety-five percent of crews (59/62) gave epinephrine, but 27 of those crews (46%) delivered the correct dose of epinephrine in an appropriate concentration and route. Twelve crews (20%) gave a dose that was >=5 times the correct dose; 8 crews (14%) bolused epinephrine intravenously. Among the 55 crews who gave diphenhydramine, 4 delivered the protocol-based dose. Three crews provided an intravenous steroid, and 1 used the protocol-based dose. Underlying causes of errors were categorized into eight themes: faulty reasoning, weight estimation errors, faulty recall of medication dosages, problematic references, calculation errors, dose estimation, communication errors, and medication delivery errors. CONCLUSION: Simulation, followed by a structured debriefing, identified multiple, underlying causes of medication errors in the prehospital management of pediatric anaphylactic reactions. Sequential and synergistic errors were observed with epinephrine delivery. PMID- 24401048 TI - Mom at bedside, appears calm. PMID- 24401050 TI - Mistargeting of peroxisomal EHHADH and inherited renal Fanconi's syndrome. AB - BACKGROUND: In renal Fanconi's syndrome, dysfunction in proximal tubular cells leads to renal losses of water, electrolytes, and low-molecular-weight nutrients. For most types of isolated Fanconi's syndrome, the genetic cause and underlying defect remain unknown. METHODS: We clinically and genetically characterized members of a five-generation black family with isolated autosomal dominant Fanconi's syndrome. We performed genomewide linkage analysis, gene sequencing, biochemical and cell-biologic investigations of renal proximal tubular cells, studies in knockout mice, and functional evaluations of mitochondria. Urine was studied with the use of proton nuclear magnetic resonance ((1)H-NMR) spectroscopy. RESULTS: We linked the phenotype of this family's Fanconi's syndrome to a single locus on chromosome 3q27, where a heterozygous missense mutation in EHHADH segregated with the disease. The p.E3K mutation created a new mitochondrial targeting motif in the N-terminal portion of EHHADH, an enzyme that is involved in peroxisomal oxidation of fatty acids and is expressed in the proximal tubule. Immunocytofluorescence studies showed mistargeting of the mutant EHHADH to mitochondria. Studies of proximal tubular cells revealed impaired mitochondrial oxidative phosphorylation and defects in the transport of fluids and a glucose analogue across the epithelium. (1)H-NMR spectroscopy showed elevated levels of mitochondrial metabolites in urine from affected family members. Ehhadh knockout mice showed no abnormalities in renal tubular cells, a finding that indicates a dominant negative nature of the mutation rather than haploinsufficiency. CONCLUSIONS: Mistargeting of peroxisomal EHHADH disrupts mitochondrial metabolism and leads to renal Fanconi's syndrome; this indicates a central role of mitochondria in proximal tubular function. The dominant negative effect of the mistargeted protein adds to the spectrum of monogenic mechanisms of Fanconi's syndrome. (Funded by the European Commission Seventh Framework Programme and others.). PMID- 24401052 TI - ERCP for gallstone pancreatitis. PMID- 24401049 TI - A randomized trial of hyperglycemic control in pediatric intensive care. AB - BACKGROUND: Whether an insulin infusion should be used for tight control of hyperglycemia in critically ill children remains unclear. METHODS: We randomly assigned children (<=16 years of age) who were admitted to the pediatric intensive care unit (ICU) and were expected to require mechanical ventilation and vasoactive drugs for at least 12 hours to either tight glycemic control, with a target blood glucose range of 72 to 126 mg per deciliter (4.0 to 7.0 mmol per liter), or conventional glycemic control, with a target level below 216 mg per deciliter (12.0 mmol per liter). The primary outcome was the number of days alive and free from mechanical ventilation at 30 days after randomization. The main prespecified subgroup analysis compared children who had undergone cardiac surgery with those who had not. We also assessed costs of hospital and community health services. RESULTS: A total of 1369 patients at 13 centers in England underwent randomization: 694 to tight glycemic control and 675 to conventional glycemic control; 60% had undergone cardiac surgery. The mean between-group difference in the number of days alive and free from mechanical ventilation at 30 days was 0.36 days (95% confidence interval [CI], -0.42 to 1.14); the effects did not differ according to subgroup. Severe hypoglycemia (blood glucose, <36 mg per deciliter [2.0 mmol per liter]) occurred in a higher proportion of children in the tight-glycemic-control group than in the conventional-glycemic-control group (7.3% vs. 1.5%, P<0.001). Overall, the mean 12-month costs were lower in the tight-glycemic-control group than in the conventional-glycemic-control group. The mean 12-month costs were similar in the two groups in the cardiac-surgery subgroup, but in the subgroup that had not undergone cardiac surgery, the mean cost was significantly lower in the tight-glycemic-control group than in the conventional-glycemic-control group: -$13,120 (95% CI, -$24,682 to -$1,559). CONCLUSIONS: This multicenter, randomized trial showed that tight glycemic control in critically ill children had no significant effect on major clinical outcomes, although the incidence of hypoglycemia was higher with tight glucose control than with conventional glucose control. (Funded by the National Institute for Health Research, Health Technology Assessment Program, U.K. National Health Service; CHiP Current Controlled Trials number, ISRCTN61735247.). PMID- 24401053 TI - Images in clinical medicine. Emphysematous aortitis after endovascular graft. PMID- 24401054 TI - Case records of the Massachusetts General Hospital. Case 1-2014. A 32-year-old man with loss of vision and a rash. PMID- 24401051 TI - Upper-airway stimulation for obstructive sleep apnea. AB - BACKGROUND: Obstructive sleep apnea is associated with considerable health risks. Although continuous positive airway pressure (CPAP) can mitigate these risks, effectiveness can be reduced by inadequate adherence to treatment. We evaluated the clinical safety and effectiveness of upper-airway stimulation at 12 months for the treatment of moderate-to-severe obstructive sleep apnea. METHODS: Using a multicenter, prospective, single-group, cohort design, we surgically implanted an upper-airway stimulation device in patients with obstructive sleep apnea who had difficulty either accepting or adhering to CPAP therapy. The primary outcome measures were the apnea-hypopnea index (AHI; the number of apnea or hypopnea events per hour, with a score of >=15 indicating moderate-to-severe apnea) and the oxygen desaturation index (ODI; the number of times per hour of sleep that the blood oxygen level drops by >=4 percentage points from baseline). Secondary outcome measures were the Epworth Sleepiness Scale, the Functional Outcomes of Sleep Questionnaire (FOSQ), and the percentage of sleep time with the oxygen saturation less than 90%. Consecutive participants with a response were included in a randomized, controlled therapy-withdrawal trial. RESULTS: The study included 126 participants; 83% were men. The mean age was 54.5 years, and the mean body mass index (the weight in kilograms divided by the square of the height in meters) was 28.4. The median AHI score at 12 months decreased 68%, from 29.3 events per hour to 9.0 events per hour (P<0.001); the ODI score decreased 70%, from 25.4 events per hour to 7.4 events per hour (P<0.001). Secondary outcome measures showed a reduction in the effects of sleep apnea and improved quality of life. In the randomized phase, the mean AHI score did not differ significantly from the 12-month score in the nonrandomized phase among the 23 participants in the therapy-maintenance group (8.9 and 7.2 events per hour, respectively); the AHI score was significantly higher (indicating more severe apnea) among the 23 participants in the therapy-withdrawal group (25.8 vs. 7.6 events per hour, P<0.001). The ODI results followed a similar pattern. The rate of procedure related serious adverse events was less than 2%. CONCLUSIONS: In this uncontrolled cohort study, upper-airway stimulation led to significant improvements in objective and subjective measurements of the severity of obstructive sleep apnea. (Funded by Inspire Medical Systems; STAR ClinicalTrials.gov number, NCT01161420.). PMID- 24401055 TI - Tight glycemic control in children--is the target in sight? PMID- 24401056 TI - Hypoglossal-nerve stimulation for obstructive sleep apnea. PMID- 24401057 TI - Correcting mutations by RNA repair. PMID- 24401058 TI - Chronic critical illness. PMID- 24401059 TI - Door-to-balloon time and mortality. PMID- 24401060 TI - Door-to-balloon time and mortality. PMID- 24401061 TI - Door-to-balloon time and mortality. PMID- 24401062 TI - Door-to-balloon time and mortality. PMID- 24401063 TI - Door-to-balloon time and mortality. PMID- 24401064 TI - Door-to-balloon time and mortality. PMID- 24401065 TI - Door-to-balloon time and mortality. PMID- 24401066 TI - Diverse sources of C. difficile infection. PMID- 24401067 TI - Diverse sources of C. difficile infection. PMID- 24401068 TI - Diverse sources of C. difficile infection. PMID- 24401069 TI - Long-term cognitive impairment after critical illness. PMID- 24401070 TI - Long-term cognitive impairment after critical illness. PMID- 24401071 TI - Long-term cognitive impairment after critical illness. PMID- 24401072 TI - Meta-analysis and the Surgeon General's report on smoking and health. PMID- 24401073 TI - Pancreatic atrophy from sorafenib. PMID- 24401074 TI - Pancreatic atrophy from sorafenib. PMID- 24401075 TI - Images in clinical medicine. Digital frostbite. PMID- 24401077 TI - Excess body mass is associated with T cell differentiation indicative of immune ageing in children. AB - Obesity has been associated with accelerated biological ageing and immunosenescence. As the prevalence of childhood obesity is increasing, we wanted to determine if associations between obesity and immunosenescence would manifest in children. We studied 123 Mexican American adolescents aged 10-14 (mean 12.3 +/ 0.7) years, with body weights ranging from 30.1 to 115.2 kg (mean 52.5 +/- 14.5 kg). Blood samples were obtained to determine proportions of naive, central memory (CM), effector memory (EM), senescent and early, intermediate and highly differentiated subsets of CD4(+) and CD8(+) T cells. Overweight and obese children had significantly lowered proportions of early CD8(+) T cells (B = 11.55 and -5.51%, respectively) compared to healthy weight. Overweight children also had more EM (B = +7.53%), late (B = +8.90%) and senescent (B = +4.86%) CD8(+) T cells than healthy weight children, while obese children had more intermediate CD8(+) (B = +4.59%), EM CD8(+) (B = +5.49%), late CD4(+) (B = +2.01%) and senescent CD4(+) (B = +0.98%) T cells compared to healthy weight children. These findings withstood adjustment for potentially confounding variables, including age, gender and latent cytomegalovirus and Epstein-Barr virus infections. We conclude that excess body mass, even in adolescence, may accelerate immunosenescence and predispose children to increased risks of incurring immune-related health problems in adulthood. PMID- 24401078 TI - Degree of knowledge of health care professionals about pain management and use of opioids in pediatrics. AB - OBJECTIVE: To evaluate the degree of knowledge about pain management and opioids use by professionals working at three pediatric units. DESIGN: This is a cross sectional study. SETTING: This study was carried out at three pediatric units (pediatrics, intensive care unit, and oncology) of Hospital de Clinicas de Porto Alegre, which is a university hospital located in southern Brazil. SUBJECT: The subjects of this study include physicians, pharmacists, physiotherapists, nurses, nursing technicians, and nursing assistants. METHODS: Cross-sectional study carried out in a university hospital in southern Brazil. A self-applicable semi structured questionnaire was handed out to 182 professionals from December 2011 to March 2012. RESULTS: The response rate was 67% (122); the average percentage of correct answers was 63.2 +/- 1.4%. The most frequent errors were: an opioid must not be used if the cause of pain is unknown (47%; 54/115); patients often develop respiratory depression (42.3%; 22/52); and confusion about symptoms of withdrawal, tolerance, and dependency syndromes (81.9%; 95/116). Only 8.8% (10/114) reported the use of pain scales to identify pain in children. The most often cited hindrance to control pain was the difficulty to measure and spot pain in pediatric patients. Finally, 50.8% (62/122) of them did not have any previous training in pain management. CONCLUSIONS: Problems in the processes of pain identification, measurement, and treatment have been found. Results suggest that there is a need for both an investment in continuing education of professionals and the development of protocols to optimize the analgesic therapy, thus preventing increased child suffering. PMID- 24401076 TI - Diagnosis and management of antibody-mediated rejection: current status and novel approaches. AB - Advances in multimodal immunotherapy have significantly reduced acute rejection rates and substantially improved 1-year graft survival following renal transplantation. However, long-term (10-year) survival rates have stagnated over the past decade. Recent studies indicate that antibody-mediated rejection (ABMR) is among the most important barriers to improving long-term outcomes. Improved understanding of the roles of acute and chronic ABMR has evolved in recent years following major progress in the technical ability to detect and quantify recipient anti-HLA antibody production. Additionally, new knowledge of the immunobiology of B cells and plasma cells that pertains to allograft rejection and tolerance has emerged. Still, questions regarding the classification of ABMR, the precision of diagnostic approaches, and the efficacy of various strategies for managing affected patients abound. This review article provides an overview of current thinking and research surrounding the pathophysiology and diagnosis of ABMR, ABMR-related outcomes, ABMR prevention and treatment, as well as possible future directions in treatment. PMID- 24401079 TI - Targeting a G-protein-coupled receptor overexpressed in endocrine tumors by magnetic nanoparticles to induce cell death. AB - Nanotherapy using targeted magnetic nanoparticles grafted with peptidic ligands of receptors overexpressed in cancers is a promising therapeutic strategy. However, nanoconjugation of peptides can dramatically affect their properties with respect to receptor recognition, mechanism of internalization, intracellular trafficking, and fate. Furthermore, investigations are needed to better understand the mechanism whereby application of an alternating magnetic field to cells containing targeted nanoparticles induces cell death. Here, we designed a nanoplatform (termed MG-IONP-DY647) composed of an iron oxide nanocrystal decorated with a ligand of a G-protein coupled receptor, the cholecystokinin-2 receptor (CCK2R) that is overexpressed in several malignant cancers. MG-IONP DY647 did not stimulate inflammasome of Raw 264.7 macrophages. They recognized cells expressing CCK2R with a high specificity, subsequently internalized via a mechanism involving recruitment of beta-arrestins, clathrin-coated pits, and dynamin and were directed to lysosomes. Binding and internalization of MG-IONP DY647 were dependent on the density of the ligand at the nanoparticle surface and were slowed down relative to free ligand. Trafficking of CCK2R internalized with the nanoparticles was slightly modified relative to CCK2R internalized in response to free ligand. Application of an alternating magnetic field to cells containing MG-IONP-DY647 induced apoptosis and cell death through a lysosomal death pathway, demonstrating that cell death is triggered even though nanoparticles of low thermal power are internalized in minute amounts by the cells. Together with pioneer findings using iron oxide nanoparticles targeting tumoral cells expressing epidermal growth factor receptor, these data represent a solid basis for future studies aiming at establishing the proof-of-concept of nanotherapy of cancers using ligand-grafted magnetic nanoparticles specifically internalized via cell surface receptors. PMID- 24401080 TI - Regulation of red fluorescent light emission in a cryptic marine fish. AB - INTRODUCTION: Animal colouration is a trade-off between being seen by intended, intra- or inter-specific receivers while not being seen by the unintended. Many fishes solve this problem by adaptive colouration. Here, we investigate whether this also holds for fluorescent pigments. In those aquatic environments in which the ambient light is dominated by bluish light, red fluorescence can generate high-contrast signals. The marine, cryptic fish Tripterygion delaisi inhabits such environments and has a bright red-fluorescent iris that can be rapidly up- and down-regulated. Here, we described the physiological and cellular mechanism of this phenomenon using a neurostimulation treatment with KCl and histology. RESULTS: KCl-treatment revealed that eye fluorescence regulation is achieved through dispersal and aggregation of black-pigmented melanosomes within melanophores. Histology showed that globular, fluorescent iridophores on the anterior side of the iris are grouped and each group is encased by finger-like extensions of a single posterior melanophore. Together they form a so-called chromatophore unit. By dispersal and aggregation of melanosomes into and out of the peripheral membranous extensions of the melanophore, the fluorescent iridophores are covered or revealed on the anterior (outside) of the iris. CONCLUSION: T. delaisi possesses a well-developed mechanism to control the fluorescent emission from its eyes, which may be advantageous given its cryptic lifestyle. This is the first time chromatophore units are found to control fluorescent emission in marine teleost fishes. We expect other fluorescent fish species to use similar mechanisms in the iris or elsewhere in the body. In contrast to a previously described mechanism based on dendritic fluorescent chromatophores, chromatophore units control fluorescent emission through the cooperation between two chromatophore types: an emitting and an occluding type. The discovery of a second mechanism for fluorescence modulation strengthens our view that fluorescence is a relevant and adaptive component of fish colouration. PMID- 24401082 TI - Indirubin 3'-monoxime, from a Chinese traditional herbal formula, suppresses viremia in humanized mice infected with multidrug-resistant HIV. PMID- 24401081 TI - Carbon source dependent promoters in yeasts. AB - Budding yeasts are important expression hosts for the production of recombinant proteins.The choice of the right promoter is a crucial point for efficient gene expression, as most regulations take place at the transcriptional level. A wide and constantly increasing range of inducible, derepressed and constitutive promoters have been applied for gene expression in yeasts in the past; their different behaviours were a reflection of the different needs of individual processes.Within this review we summarize the majority of the large available set of carbon source dependent promoters for protein expression in yeasts, either induced or derepressed by the particular carbon source provided. We examined the most common derepressed promoters for Saccharomyces cerevisiae and other yeasts, and described carbon source inducible promoters and promoters induced by non sugar carbon sources. A special focus is given to promoters that are activated as soon as glucose is depleted, since such promoters can be very effective and offer an uncomplicated and scalable cultivation procedure. PMID- 24401084 TI - Assessment of an interprofessional online curriculum for palliative care communication training. AB - BACKGROUND: Curricular changes to palliative care communication training are needed in order to accommodate a variety of learners, especially in lieu of the projected national shortage of hospice and palliative medicine physicians and nurses. OBJECTIVE: This study assessed the utility of a palliative care communication curriculum offered through an online platform and also examined health care professionals' clinical communication experiences related to palliative care topics. DESIGN: Four of the seven modules of the COMFORT communication curriculum were made available online, and participant assessments and knowledge skills were measured. SETTING: Modules were completed and assessed by 177 participants, including 105 nurses, 25 physicians, and a category of 'other' disciplines totaling 47. MEASUREMENTS: Premodule surveys consisted of closed-ended items developed by the interdisciplinary research team. Postcurriculum evaluation and knowledge quizzes were used to assess program effectiveness. RESULTS: Among all participants, end-of-life care and recurrence of disease were considered the most challenging communication contexts and discussion about treatment options the least challenging. Mean responses to postcurriculum evaluation for all modules across nurse and physician participants was greater than 4 on a scale of 1 to 5. CONCLUSIONS: This study identifies the COMFORT communication curriculum as an effective online curricular tool to teach multiple disciplines specific palliative care communication. PMID- 24401083 TI - Baulamycins A and B, broad-spectrum antibiotics identified as inhibitors of siderophore biosynthesis in Staphylococcus aureus and Bacillus anthracis. AB - Siderophores are high-affinity iron chelators produced by microorganisms and frequently contribute to the virulence of human pathogens. Targeted inhibition of the biosynthesis of siderophores staphyloferrin B of Staphylococcus aureus and petrobactin of Bacillus anthracis hold considerable potential as a single or combined treatment for methicillin-resistant S. aureus (MRSA) and anthrax infection, respectively. The biosynthetic pathways for both siderophores involve a nonribosomal peptide synthetase independent siderophore (NIS) synthetase, including SbnE in staphyloferrin B and AsbA in petrobactin. In this study, we developed a biochemical assay specific for NIS synthetases to screen for inhibitors of SbnE and AsbA against a library of marine microbial-derived natural product extracts (NPEs). Analysis of the NPE derived from Streptomyces tempisquensis led to the isolation of the novel antibiotics baulamycins A (BmcA, 6) and B (BmcB, 7). BmcA and BmcB displayed in vitro activity with IC50 values of 4.8 MUM and 19 MUM against SbnE and 180 MUM and 200 MUM against AsbA, respectively. Kinetic analysis showed that the compounds function as reversible competitive enzyme inhibitors. Liquid culture studies with S. aureus , B. anthracis , E. coli , and several other bacterial pathogens demonstrated the capacity of these natural products to penetrate bacterial barriers and inhibit growth of both Gram-positive and Gram-negative species. These studies provide proof-of-concept that natural product inhibitors targeting siderophore virulence factors can provide access to novel broad-spectrum antibiotics, which may serve as important leads for the development of potent anti-infective agents. PMID- 24401085 TI - The laparoscopic hiatoplasty with antireflux surgery is a safe and effective procedure to repair giant hiatal hernia. AB - BACKGROUND: Although minimally invasive repair of giant hiatal hernias is a very surgical challenge which requires advanced laparoscopic learning curve, several reports showed that is a safe and effective procedure, with lower morbidity than open approach. In the present study we show the outcomes of 13 patients who underwent a laparoscopic repair of giant hiatal hernia. METHODS: A total of 13 patients underwent laparoscopic posterior hiatoplasty and Nissen fundoplication. Follow-up evaluation was done clinically at intervals of 3, 6 and 12 months after surgery using the Gastro-oesophageal Reflux Health-Related Quality of Life scale, a barium swallow study, an upper gastrointestinal endoscopy, an oesophageal manometry, a combined ambulatory 24-h multichannel impedance pH and bilirubin monitoring. Anatomic recurrence was defined as any evidence of gastric herniation above the diaphragmatic edge. RESULTS: There were no intraoperative complications and no conversions to open technique. Symptomatic GORD-HQL outcomes demonstrated a statistical significant decrease of mean value equal to 3.2 compare to 37.4 of preoperative assessment (p < 0.0001). Combined 24-h multichannel impedance pH and bilirubin monitoring after 12 months did not show any evidence of pathological acid or non acid reflux. CONCLUSION: All patients were satisfied of procedure and no hernia recurrence was recorded in the study group, treated respecting several crucial surgical principles, e.g., complete sac excision, appropriate crural closure, also with direct hiatal defect where possible, and routine use of antireflux procedure. PMID- 24401086 TI - Metmyoglobin reduction by polyphenols and mechanism of the conversion of metmyoglobin to oxymyoglobin by quercetin. AB - The effect of antioxidant polyphenols and related phenolic compounds from plants on the reduction of metmyoglobin (MetMb) was investigated. Potent activity in the reduction of MetMb to oxymyoglobin (MbO2), a bright red protein in meat, was observed for three flavonols, kaempferol, myricetin, and quercetin, at 300 MUmol/L against 60 MUmol/L MetMb. Sinapic acid, catechin, nordihydroguaiaretic acid, taxifolin, morin, and ferulic acid promoted reduction at 600 MUmol/L. A mechanism for the reduction by one of the active flavonols, quercetin, was proposed on the basis of analytical results for redox reaction products derived from quercetin. This suggested the importance of a high propensity toward reduction of the flavonol structure and rapid convertibility of the quinone form to the phenol form for the MbO2 reduction and the maintenance of the level of MbO2 produced. PMID- 24401087 TI - Integrity of the LXXLL motif in Stat6 is required for the inhibition of breast cancer cell growth and enhancement of differentiation in the context of progesterone. AB - BACKGROUND: Progesterone is essential for the proliferation and differentiation of mammary gland epithelium. Studies of breast cancer cells have demonstrated a biphasic progesterone response consisting of an initial proliferative burst followed by sustained growth arrest. However, the transcriptional factors acting with the progesterone receptor (PR) to mediate the effects of progesterone on mammary cell growth and differentiation remain to be determined. Recently, it was demonstrated that signal transducer and activator of transcription 6 (Stat6) is a cell growth suppressor. Similar to progesterone-bound PR, Stat6 acts by inducing the expression of the G1 cyclin-dependent kinase inhibitors p21 and p27. The possible interaction between Stat6 and progesterone pathways in mammary cells was therefore investigated in the present study. METHODS: ChIP and luciferase were assayed to determine whether Stat6 induces p21 and p27 expression by recruitment at the proximal Sp1-binding sites of the gene promoters. Immunoprecipitation and Western blotting were performed to investigate the interaction between Stat6 and PR-B. The cellular DNA content and cell cycle distribution in breast cancer cells were analyzed by FACS. RESULTS: We found that Stat6 interacts with progesterone activated PR in T47D cells. Stat6 synergizes with progesterone-bound PR to transactivate the p21 and p27 gene promoters at the proximal Sp1-binding sites. Moreover, Stat6 overexpression and knockdown, respectively, increased or prevented the induction of p21 and p27 gene expression by progesterone. Stat6 knockdown also abolished the inhibitory effects of progesterone on pRB phosphorylation, G1/S cell cycle progression, and cell proliferation. In addition, knockdown of Stat6 expression prevented the induction of breast cell differentiation markers, previously identified as progesterone target genes. Finally, Stat6 gene expression levels increased following progesterone treatment, indicating a positive auto-regulatory loop between PR and Stat6. CONCLUSIONS: Taken together, these data identify Stat6 as a coactivator of PR mediating the growth-inhibitory and differentiation effects of progesterone on breast cancer cells. PMID- 24401088 TI - Truncated monocyte chemoattractant protein-1 can alleviate cardiac injury in mice with viral myocarditis via infiltration of mononuclear cells. AB - BALB/c mice inoculated intraperitoneally with coxsackievirus group B type 3 (CVB3) were allocated to five groups; namely, a viral myocarditis group infected with CVB3 alone (control group), an antibody intervention group that received intracardiac anti-MCP-1, an antibody intervention control group that received goat IgG, a tMCP-1 intervention group that received plasmid pVMt expressing tMCP 1, and a tMCP-1 intervention control group that received plasmid pVAX1. There was also a normal control group. The ratio of murine heart weight to body weight, pathological score of myocardial tissue, serum creatine kinase-MB titers and CVB3 loading of myocardial tissue were assessed. The cardiac lesions in mice that received 20, 40 or 60 ug pVMt (P < 0.05) were less severe than those in control mice with untreated viral myocarditis. In addition, fewer mononuclear cells had infiltrated the myocardium of mice who received 40 or 60 ug pVMt intramyocardially (P < 0.01), whereas there was no difference in mononuclear cell infiltration between mice with viral myocarditis and those that received 20 ug pVMt (P > 0.05). There was also no difference between mice that received anti-MCP 1 antibody and those that received 40 ug pVMt in ratio of HW/BW, serum CK-MB titers and pathological score (P > 0.05). This study showed that tMCP-1 can alleviate cardiac lesions and cardiac injury in mice with viral myocarditis via infiltration of mononuclear cells. Thus, tMCP-1 may be an alternative to anti-MCP 1 antibody treatment of viral myocarditis. Further research is required. PMID- 24401089 TI - Postprandial effects of long-term niacin/laropiprant use on glucose and lipid metabolism and on cardiovascular risk in patients with polycystic ovary syndrome. AB - AIM: This study investigated the effect of long-term niacin/laropiprant therapy on CV risk and IR in obese women with PCOS. METHODS: In this double-blind randomized placebo-controlled trial, 13 and 12 PCOS women completed a 12 week course of niacin/laropiprant or placebo, respectively. Fasted subjects had an endothelial function test (EndoPat2000) and then consumed a mixed meal with blood sampled postprandially for 6 h before and after intervention. RESULTS: By 12 weeks, niacin/laropiprant lowered low-density lipoprotein cholesterol (LDL-c) (13%) and increased HDL-c (17%). Despite a reduction in fasting triglycerides (21%), the drug had no effect on their postprandial rise (2.69 +/- 1.44 vs. 2.49 +/- 1.14 mmol/l, p = 0.72). However, following the mixed meal, plasma glucose area under the response curve increased from 13.1 +/- 2.9 to 14.0 +/- 2.8 mmol/l, p = 0.05, as a consequence of both increased insulin resistance [HOMA-IR: 2.2 (1.2, 4.2) vs. 3.8(1.3, 5.5), p = 0.02] and a reduced acute insulin response to glucose [424 (211, 975) vs. 257(122, 418) pmol/mmol, p = 0.04]. Niacin/laropiprant did not improve RHI (1.97 +/- 0.40 vs. 2.05 +/- 0.58, p = 0.33) or hsCRP. CONCLUSIONS: In PCOS, niacin/laropiprant had a significant negative impact on postprandial glucose and no improvement in postprandial hypertriglyceridaemia, with at least the former mediated through increased IR and reduced beta-cell function. This data may help explain why the improvement in fasting lipids has not translated into improved CV risk markers in PCOS. PMID- 24401090 TI - Preparation of gold/silver/titania trilayered nanorods and their photocatalytic activities. AB - Gold/silver/titania trilayered nanorods have been prepared by the successive deposition of silver and titania layers on gold nanorod cores, and their photocatalytic activities were investigated under visible-light illumination (lambda > 420 nm). The photocatalytic activity of the trilayered nanorods in the oxidation of 2-propanol depends on both the Au/Ag composition and the thickness of the TiO2 shell. It increases with increasing Ag content up to [Au]/[Ag] = 1:5 (molar ratio) and then decreases with further increasing Ag content. The photocatalytic activity also increases with increasing TiO2 shell thickness up to 10 nm and then decreases with further increases in the shell thickness. These effects were explained by electron-transfer and energy-transfer mechanisms. PMID- 24401091 TI - Sequences in the terminal protein and reverse transcriptase domains of the hepatitis B virus polymerase contribute to RNA binding and encapsidation. AB - Hepatitis B virus (HBV) antiviral therapy is plagued by limited efficacy and resistance to most nucleos(t)ide analog drugs. We have proposed that the complex RNA binding mechanism of the HBV reverse transcriptase (P) may be a novel target for antivirals. We previously found that RNA binds to the duck HBV (DHBV) P through interactions with the T3 and RT1 motifs in the viral terminal protein and reverse transcriptase domains, respectively. Here, we extended these studies to HBV P. HBV T3 and RT1 synthetic peptides bound RNA in a similar manner as did analogous DHBV peptides. The HBV T3 motif could partially substitute for DHBV T3 during RNA binding and DNA priming by DHBV P, whereas replacing RT1 supported substantial RNA binding but not priming. Substituting both the HBV T3 and RT1 motifs restored near wild-type levels of RNA binding but supported very little priming. Alanine-scanning mutations to the HBV T3 and RT1 motifs blocked HBV epsilon RNA binding in vitro and pgRNA encapsidation in cells. These data indicate that both the HBV T3 and RT1 motifs contain sequences essential for HBV epsilon RNA binding and encapsidation of the RNA pregenome, which is similar to their functions in DHBV. Small molecules that bind to T3 and/or RT1 would therefore inhibit encapsidation of the viral RNA and block genomic replication. Such drugs would target a novel viral function and would be good candidates for use in combination with the nucleoside analogs to improve efficacy of antiviral therapy. PMID- 24401092 TI - Bacillus subtilis class Ib ribonucleotide reductase: high activity and dynamic subunit interactions. AB - The class Ib ribonucleotide reductase (RNR) isolated from Bacillus subtilis was recently purified as a 1:1 ratio of NrdE (alpha) and NrdF (beta) subunits and determined to have a dimanganic-tyrosyl radical (Mn(III)2-Y.) cofactor. The activity of this RNR and the one reconstituted from recombinantly expressed NrdE and reconstituted Mn(III)2-Y. NrdF using dithiothreitol as the reductant, however, was low (160 nmol min(-1) mg(-1)). The apparent tight affinity between the two subunits, distinct from all class Ia RNRs, suggested that B. subtilis RNR might be the protein that yields to the elusive X-ray crystallographic characterization of an "active" RNR complex. We now report our efforts to optimize the activity of B. subtilis RNR by (1) isolation of NrdF with a homogeneous cofactor, and (2) identification and purification of the endogenous reductant(s). Goal one was achieved using anion exchange chromatography to separate apo-/mismetalated-NrdFs from Mn(III)2-Y. NrdF, yielding enzyme containing 4 Mn and 1 Y./beta2. Goal two was achieved by cloning, expressing, and purifying TrxA (thioredoxin), YosR (a glutaredoxin-like thioredoxin), and TrxB (thioredoxin reductase). The success of both goals increased the specific activity to ~1250 nmol min(-1) mg(-1) using a 1:1 mixture of NrdE:Mn(III)2-Y. NrdF and either TrxA or YosR and TrxB. The quaternary structures of NrdE, NrdF, and NrdE:NrdF (1:1) were characterized by size exclusion chromatography and analytical ultracentrifugation. At physiological concentrations (~1 MUM), NrdE is a monomer (alpha) and Mn(III)2-Y. NrdF is a dimer (beta2). A 1:1 mixture of NrdE:NrdF, however, is composed of a complex mixture of structures in contrast to expectations. PMID- 24401093 TI - Cytoprotective effect of lacritin on human corneal epithelial cells exposed to benzalkonium chloride in vitro. AB - PURPOSE: Benzalkonium chloride (BAK) is the most commonly found preservative in eye drops, and has been shown to cause ocular surface inflammation and toxicity. Lacritin is a human tear glycoprotein secreted from the lacrimal glands that has been found to be cytoprotective. This study was designed to determine if the presence of lacritin confers protection to a cultured human corneal epithelial (HCE) cell line, CRL-11515, and primary HCE cells after exposure to the ocular preservative agent BAK. MATERIALS AND METHODS: Recombinant human lacritin was cloned into intein fusion vectors, expressed in E. coli, and purified on chitin beads and DEAE Sepharose. Metabolic curves were established using the MTT assay after exposure of sub-confluent CRL-11515 cells to BAK or lacritin. Western blot analysis of lipidated LC3 (LC3-II) provided a measure of autophagy in CRL-11515 cells exposed to lacritin and/or BAK. RESULTS: BAK reduced CRL-11515 cellular metabolic activity in a time- and dose-dependent manner. BAK-induced cellular stress was evident by elevated autophagy that increased with rising concentrations of BAK compared to control (p < 0.05). Lacritin increased HCE cell proliferation at an optimal dose of 1 nM. Preconditioning HCE cells with 1 nM lacritin for 24 h prior to BAK exposure significantly dampened levels of LC3-II (p < 0.05) and promoted a significant increase in cellular metabolic activity (p < 0.01) compared to BAK alone. CONCLUSIONS: These results suggest lacritin protects cultured HCE cells stressed with BAK. Lacritin may have the potential to be used as a topical adjunctive therapy in eyes chronically exposed to BAK. PMID- 24401094 TI - Previous infection with Staphylococcus aureus strains attenuated experimental encephalomyelitis. AB - BACKGROUND: Bacterial superantigens are potent T cell activators that can activate T cells with specificity for antigens of the central nervous system (CNS). In this study, we compared the effect of two S. aureus strains on experimental autoimmune encephalomyelitis (EAE) development. C57BL/6 female mice were infected with S. aureus ATCC 51650, which produces toxic shock syndrome toxin 1 (TSST-1+) or S. aureus ATCC 43300, which does not produce toxins (TOX-). Three days later, the animals were subjected to EAE induction by immunization with myelin oligodendrocyte glycoprotein (MOG). The weight variation, disease incidence and clinical score were recorded daily. Cytokines and Foxp3+ regulatory T cells in the brain were evaluated during the acute disease phase. Cytokines and Foxp3+ regulatory T cells in the spleen and histopathological analysis of the CNS were assessed during the chronic stage. RESULTS: Previous infection with both strains similarly decreased the clinical score; however, only the TSST-1+ strain clearly diminished inflammation in the CNS. The infections also modulated cytokine production in the spleen and CNS. Reduced production of IL-5 and IL-10 was detected in MOG-stimulated spleen cultures in the TOX- and TSST-1+ infected groups, respectively. In S. aureus stimulated cultures, there was an increased production of IFN-gamma and IL-10 in both infected groups and an increased level of IL-5 in the TSST-1+ group. CNS infiltrating cell cultures from previously infected mice produced less IL-17 in response to MOG and more IFN-gamma in response to S. aureus stimulation. CONCLUSIONS: These results indicated that both strains attenuated clinical EAE manifestations, but only TSST-1 clearly decreased CNS inflammation. PMID- 24401095 TI - Formulation and evaluation of Cyclosporin A emulgel for ocular delivery. AB - Emulgels have been extensively covered as a promising drug delivery system for the administration of lipophilic drugs. This work was conducted to develop an emulgel formulation for Cyclosporin A (CsA) employing polycarbophil as the gelling agent for ocular delivery. The prepared emulgels were evaluated for their physical appearance, rheological behavior, drug release, stability, precorneal clearance and irritation. Results showed that CsA emulgel formulations prepared with polycarbophil exhibited acceptable physical properties and drug release, which remained consistent after storage for 3 months. A prolonged retention time was also observed on the ocular surface with improved ocular bioavailability and no irritation. Therefore, the polycarbophil-based emulgel could be exploited as a potential hydrophobic drug carrier for topical ocular drug delivery. PMID- 24401096 TI - Contaminant levels in Gulf of Mexico reef fish after the Deepwater Horizon oil spill as measured by a fishermen-led testing program. AB - The BP oil disaster posed a significant threat to the U.S. seafood industry. Invertebrates (shrimp, oyster, crab) and other nearshore species comprised the majority of postspill testing by federal and state agencies. Deeper water finfish were sampled less frequently, despite population ranges that overlapped with affected waters. We report on a voluntary testing program with Gulf of Mexico commercial fishermen to ensure the safety of their catch. Seven species of reef fish were tested for polycyclic aromatic hydrocarbons, several metals, and a constituent of Corexit 9500A and 9527A dispersants. Only two of 92 samples had detectable levels of benzo(a)pyrene-equivalents (a combined measure of carcinogenic potency across 7 different PAHs), which were still below federal safety thresholds. PAH ratios for these samples suggest pyrogenic (not petrogenic) contamination - indicating potential sources other than Deepwater Horizon. Metals were largely absent (cadmium, lead) or consistent with levels previously reported (mercury, arsenic). One notable exception was tilefish, which showed mercury concentrations lower than expected. We did not detect dispersant in any of our samples, indicating that it was not present in these species during the study period. Our findings suggest minimal risk to public health from these seafoods as a result of the disaster; however, the most contaminated areas were not sampled through this program. PMID- 24401097 TI - Free the Data. PMID- 24401098 TI - Steam stable mesoporous silica MCM-41 stabilized by trace amounts of Al. AB - Evaluation of low and ultralow Al content (Si/Al between 50 and 412) aluminosilicate Al-MCM-41 materials synthesized via three contrasting alumination routes, namely, direct mixed-gel synthesis, post-synthesis wet grafting, and post synthesis dry grafting, indicates that trace amounts of Al introduced via dry grafting can stabilize mesoporous silica MCM-41 to steaming at 900 degrees C for 4 h. It was found that trace amounts of Al (Si/Al > 400) introduced via so-called dry grafting of Al stabilize the virtually purely siliceous MCM-41 to steaming, whereas Al incorporated via other methods that involve aqueous media such as direct mixed gel synthesis or wet grafting of Al offer only limited protection at low Al content. It is particularly remarkable that a post-synthesis dry grafted Al-MCM-41 material possessing trace amounts of Al (i.e., Si/Al ratio of 412) and surface area and pore volume of 1112 m(2)/g and 1.20 cm(3)/g, respectively, retains 90% (998 m(2)/g) of the surface area and 85% (1.03 cm(3)/g) of the pore volume after exposure to steaming at 900 degrees C for 4 h. Under similar steam treatment conditions, the mesostructure of pure silica Si-MCM-41 is virtually destroyed and undergoes a 93% reduction in surface area (958 m(2)/g to 69 m(2)/g) and 88% decrease in pore volume (0.97 cm(3)/g to 0.12 cm(3)/g). The steam stable ultralow (i.e., trace) Al containing MCM-41 materials is found to be virtually similar to mesoporous pure silica Si-MCM-41 with hardly any detectable acidity. The improvement in steam stability arises from not only the presence of trace amounts of Al, but also from an apparent increase in the level of silica condensation that is specific to dry grafted alluminosilicate MCM-41 materials. The more highly condensed framework has fewer silanol groups and therefore is more resistant to hydrolysis under steaming conditions. PMID- 24401099 TI - Anti-tumor activity of grape juice concentrate in the rat tongue two-stage initiation-promotion protocol induced by 4-nitroquinoline 1-oxide. AB - The aim of this study was to evaluate the anti-tumor activity of grape juice concentrate following medium-term oral carcinogenesis assay induced by 4 nitroquinoline 1-oxide (4NQO). A total of 30 male Wistar rats were distributed into five groups, as follows (n = 6 per group): Group 1 - negative control group (non-treated group); Group 2 - received grape juice concentrate at 1% dose by gavage for eight consecutive weeks; Group 3 - received 4NQO for 8 weeks at 20 ppm dose in drinking water daily; Group 4 - received 4NQO at 20 ppm dose during 8 weeks in drinking water and treated with grape juice concentrate at 1% dose orally by gavage for first 4 weeks after 4-NQO administration; Group 5 - received 4NQO at 20 ppm dose for 8 weeks in drinking water and treated with grape juice concentrate at 1% dose orally by gavage between the 5th and 8th weeks daily. Histopathological analysis revealed a decrease in hyperplasic and dysplastic lesions in Group 4. Groups 4 and 5 showed decreased COX-2 and TNF-alpha and eNOS gene expression. Grape juice concentrate also increased SOD Cu/Zn and catalase expression. However, Ki-67 immunoexpression was reduced at the promotion step of oral carcinogenesis (G5). Taken together, our results demonstrate that grape juice concentrate modulates rat tongue carcinogenesis as a result of anti inflammatory activity, antioxidant activity and down-regulation of oral cells proliferation. PMID- 24401100 TI - A kinetic approach to the sequence-aggregation relationship in disease-related protein assembly. AB - It is generally accepted that oligomers of aggregating proteins play an important role in the onset of neurodegenerative diseases. While in silico aggregation studies of full length amyloidogenic proteins are computationally expensive, the assembly of short protein fragments derived from these proteins with similar aggregating properties has been extensively studied. In the present work, molecular dynamics simulations are performed to follow peptide aggregation on the microsecond time scale. By defining aggregation states, we identify transition networks, disconnectivity graphs, and first passage time distributions to describe the kinetics of the assembly process. This approach unravels differences in the aggregation into hexamers of two peptides with different primary structures. The first is GNNQQNY, a hydrophilic fragment from the prion protein Sup35, and the second is KLVFFAE, a fragment from amyloid-beta protein, with a hydrophobic core delimited by two charged amino acids. The assembly of GNNQQNY suggests a mechanism of monomer addition, with a bias toward parallel peptide pairs and a gradual increase in the amount of beta-strand content. For KLVFFAE, a mechanism involving dimers rather than monomers is revealed, involving a generally higher beta-strand content and a transition toward a larger number of antiparallel peptide pairs during the rearrangement of the hexamer. The differences observed for the aggregation of the two peptides suggests the existence of a sequence-aggregation relationship. PMID- 24401101 TI - Antiarthritic and chondroprotective activity of Lakshadi Guggul in novel alginate enclosed chitosan calcium phosphate nanocarriers. AB - AIM: This study aimed to evaluate the antiarthritic and chondroprotective potentials of Lakshadi Guggul (LG) and Cissus quadrangularis encapsulated in novel alginate-enclosed chitosan-calcium phosphate nanocarriers (NCs) both in vitro in primary human chondrocytes and in vivo in mice with collagen-induced arthritis. MATERIALS & METHODS: Chondrocytes exposed to IL-1beta and osteoarthritis chondrocytes grown in an ex vivo inflammation-based coculture were incubated with different concentrations of herbals, and cell modulatory activities were determined. For in vivo studies, herbals and their encapsulated nanoformulations were administered orally to DBA/1 mice with collagen-induced arthritis. RESULTS: C. quadrangularis and LG showed enhanced chondroprotective and proliferative activity in IL-1beta-exposed primary chondrocytes, with LG showing the highest therapeutic potency. LG increased viability, proliferative and mitogenic activity, and inhibited cell apoptosis and mitochondrial depolarization. In vivo studies with LG and alginate-enclosed chitosan-calcium phosphate LG NCs revealed cartilage regenerative activity in those administered with the nanoformulation. The NCs were nontoxic to mice, reduced joint swelling and paw volume, and inhibited gene expression of MMPs and cytokines. CONCLUSION: The promising results from this study reveal, for the first time, the novel polymeric NC encapsulating LG as a potential therapeutic for rheumatic diseases. PMID- 24401103 TI - Headache plus: trigeminal and autonomic features in a case of cervicogenic headache responsive to third occipital nerve radiofrequency ablation. AB - OBJECTIVE: To describe a case of cervicogenic headache with associated autonomic features and pain in a trigeminal distribution, all of which responded to third occipital nerve radiofrequency ablation. DESIGN: Single case report. SETTING: Massachusetts General Hospital Center for Pain Medicine. PATIENTS: A 38-year-old woman with history of migraines and motor vehicle accident. INTERVENTIONS: Right third occipital nerve diagnostic blocks and radiofrequency lesioning. OUTCOME MEASURES: Pain reduction; physical findings, including periorbital and mandibular facial swelling, tearing, conjunctival injection, and allodynia; and use of opioid and non-opioid pain medicines. RESULTS: The patient had complete relief of her pain and autonomic symptoms, and was able to stop all pain medications following a dedicated third occipital nerve lesioning. CONCLUSIONS: This case illustrates the diagnostic and therapeutic complexity of cervicogenic headache and the overlap with other headache types, including trigeminal autonomic cephalgias and migraine. It represents a unique proof of principle in that not only trigeminal nerve pain but also presumed neurogenic inflammation can be relieved by blockade of cervical nociceptive inputs. Further investigation into shared mechanisms of headache pathogenesis is warranted. PMID- 24401102 TI - Multiple distinct CHRNB3-CHRNA6 variants are genetic risk factors for nicotine dependence in African Americans and European Americans. AB - AIMS: Studies have shown association between common variants in the alpha6-beta3 nicotinic receptor subunit gene cluster and nicotine dependence in European ancestry populations. We investigate whether this generalizes to African Americans, whether the association is specific to nicotine dependence and whether this region contains additional genetic contributors to nicotine dependence. DESIGN: We examined consistency of association across studies and race between the alpha6beta3 nicotinic receptor subunit locus and nicotine, alcohol, marijuana and cocaine dependence in three independent studies. SETTING: United States of America. PARTICIPANTS: European Americans and African Americans from three case control studies of substance dependence. MEASUREMENTS: Subjects were evaluated using the Semi-Structured Assessment for the Genetics of Alcoholism. Nicotine dependence was determined using the Fagerstrom Test for Nicotine Dependence. FINDINGS: The single nucleotide polymorphism rs13273442 was associated significantly with nicotine dependence across all three studies in both ancestry groups [odds ratio (OR) = 0.75, P = 5.8 * 10(-4) European Americans; OR = 0.80, P = 0.05 African Americans]. No other substance dependence was associated consistently with this variant in either group. Another SNP in the region, rs4952, remains modestly associated with nicotine dependence in the combined data after conditioning on rs13273442. CONCLUSIONS: The common variant rs13273442 in the CHRNB3-CHNRA6 region is associated significantly with nicotine dependence in European Americans and African Americans across studies recruited for nicotine, alcohol and cocaine dependence. Although these data are modestly powered for other substances, our results provide no evidence that correlates of rs13273442 represent a general substance dependence liability. Additional variants probably account for some of the association of this region to nicotine dependence. PMID- 24401104 TI - Two hydroxypyruvate reductases encoded by OsHPR1 and OsHPR2 are involved in photorespiratory metabolism in rice. AB - Mutations in the photorespiration pathway display a lethal phenotype in atmospheric air, which can be fully recovered by elevated CO2 . An exception is that mutants of peroxisomal hydroxypyruvate reductase (HPR1) do not have this phenotype, indicating the presence of cytosolic bypass in the photorespiration pathway. In this study, we constructed overexpression of the OsHPR1 gene and RNA interference plants of OsHPR1 and OsHPR2 genes in rice (Oryza sativa L. cv. Zhonghua 11). Results from reverse transcription-polymerase chain reaction (RT PCR), Western blot, and enzyme assays showed that HPR1 activity changed significantly in corresponding transgenic lines without any effect on HPR2 activity, which is the same for HPR2. However, metabolite analysis and the serine glyoxylate aminotransferase (SGAT) activity assay showed that the metabolite flux of photorespiration was disturbed in RNAi lines of both HPR genes. Furthermore, HPR1 and HPR2 proteins were located to the peroxisome and cytosol, respectively, by transient expression experiment. Double mutant hpr1 * hpr2 was generated by crossing individual mutant of hpr1 and hpr2. The phenotypes of all transgenic lines were determined in ambient air and CO2 -elevated air. The phenotype typical of photorespiration mutants was observed only where activity of both HPR1 and HPR2 were downregulated in the same line. These findings demonstrate that two hydroxypyruvate reductases encoded by OsHPR1 and OsHPR2 are involved in photorespiratory metabolism in rice. PMID- 24401105 TI - The influence of paramedic and patient gender on the administration of analgesics in the out-of-hospital setting. AB - OBJECTIVE: To determine whether analgesic administration in the out-of-hospital setting is influenced by the gender of the patient or the gender of the paramedic. METHODS: This retrospective cohort study of patient care records included adult patients (age > 15 years) with moderate to severe pain (verbal numerical rating score 4-10) treated by paramedics between January 1, 2008 and December 31, 2009. Data extracted included patient pain severity score, analgesia provided by paramedics, and gender of the treating paramedic. Data was analyzed by descriptive statistics, chi(2) test, and logistic regression. The primary outcome measures were the effect of patient and paramedic gender on analgesic administration. RESULTS: The study population comprised 42,051 patients, median age of 57 years (38-75); 50.4% were female and 51% were administered an analgesic agent. For the outcome of receiving any analgesia, neither patient gender nor paramedic gender was predictive (p = NS). In a multivariate model for the outcome of receiving any analgesia, patient gender, paramedic gender, and the interaction between patient and paramedic gender were all nonsignificant (p = NS). For the outcome of receiving opioid analgesia (i.e., morphine or fentanyl), male patients were at greater odds of receiving an opioid (OR 1.52, 95% CI 1.29-1.79, p < 0.0001). Paramedic gender was not predictive of whether an opioid was given (p = NS). CONCLUSIONS: The gender of the paramedic did not appear to influence the odds of analgesic administration. Female patients were less likely to receive opioids. Paramedic gender does not explain this finding. PMID- 24401106 TI - Morphological stability and performance of polymer-fullerene solar cells under thermal stress: the impact of photoinduced PC60BM oligomerization. AB - We report a general light processing strategy for organic solar cells (OSC) that exploits the propensity of the fullerene derivative PC60BM to photo-oligomerize, which is capable of both stabilizing the polymer:PC60BM active layer morphology and enhancing the device stability under thermal annealing. The observations hold for blends of PC60BM with an array of benchmark donor polymer systems, including P3HT, DPP-TT-T, PTB7, and PCDTBT. The morphology and kinetics of the thermally induced PC60BM crystallization within the blend films are investigated as a function of substrate and temperature. PC60BM nucleation rates on SiOx substrates exhibit a pronounced peak profile with temperature, whose maximum is polymer and blend-composition dependent. Modest illumination (<10 mW/cm(2)) significantly suppresses nucleation, which is quantified as function of dose, but does not affect crystalline shape or growth, in the micrometer range. On PEDOT:PSS substrates, thermally induced PC60BM aggregation is observed on smaller (~ 100 nm) length scales, depending upon donor polymer, and also suppressed by light exposure. The concurrent thermal dissociation process of PC60BM oligomers in blend films is also investigated and the activation energy of the fullerene fullerene bond is estimated to be 0.96 +/- 0.04 eV. Following light processing, the thermal stability, and thus lifetime, of PCDTBT:PC60BM devices increases for annealing times up to 150 h. In contrast, PCDTBT:PC70BM OSCs are found to be largely light insensitive. The results are rationalized in terms of the suppression of PC60BM micro- and nanoscopic crystallization processes upon thermal annealing caused by photoinduced PC60BM oligomerization. PMID- 24401107 TI - Sex differences in HIV outcomes in the highly active antiretroviral therapy era: a systematic review. AB - To assess sex disparities in AIDS clinical and laboratory outcomes in the highly active antiretroviral therapy (HAART) era we conducted a systematic review of the published literature on mortality, disease progression, and laboratory outcomes among persons living with HIV and starting HAART. We performed systematic PubMed and targeted bibliographic searches of observational studies published between January, 1998, and November, 2013, that included persons starting HAART and reported analyses of mortality, progression to AIDS, or virologic or immunologic treatment outcomes by sex. Risk ratios (relative risks, odd ratios, and hazard ratios) and 95% confidence intervals were obtained. Sixty-five articles were included in this review. Thirty-nine studies were from North America and Europe and 26 were from Latin America, Asia, and Africa. Forty-four studies (68%) showed no statistically significant difference in risk of mortality, progression to AIDS, or virologic or immunologic treatment outcomes by sex. Decreased risk of death among females compared to males was observed in 24 of the 25 articles that included mortality analyses [pooled risk ratio 0.72 (95% confidence interval=0.69 0.75)], and decreased risk of death or AIDS was observed in 9 of the 13 articles that examined the composite outcome [pooled risk ratio=0.91 (0.84-0.98)]. There was no significant effect of sex on the risk of progression to AIDS [pooled risk ratio=1.15 (0.99-1.31)]. In this systematic review, females starting HAART appeared to have improved survival compared to males. However, this benefit was not associated with decreased progression to either AIDS or to differences in virologic or immunologic treatment outcomes. PMID- 24401108 TI - Serum miRNA expression profiles change in autoimmune vitiligo in mice. AB - It is widely believed that non-segmental vitiligo results from the autoimmune destruction of melanocytes. MicroRNAs (miRNAs), a class of small non-coding RNAs that negatively regulate gene expression, are involved in the immune cell development and function and regulate the development of autoimmune diseases. Recent studies demonstrate that functional miRNAs can be detected in the serum and serve as biomarkers of various diseases. In the present study, we used a mouse autoimmune vitiligo model, in which melanocyte autoreactive CD4+ T cells were adoptively transferred into Rag1(-/-) host mice. Serum miRNA expression was profiled in vitiligo developed mice and control mice using TaqMan RT-PCR arrays. We have found that the expressions of 20 serum miRNAs were changed in vitiligo mice compared to control mice. Three increased miRNAs, miR-146a, miR-191, and miR 342-3p, were further confirmed by a single TaqMan RT-PCR. Our findings suggest that miRNAs may be involved in vitiligo development and serum miRNAs could serve as serum biomarkers for vitiligo in mice. PMID- 24401112 TI - Potential utility of serum soluble LR11 as a diagnostic biomarker for intravascular large B-cell lymphoma. PMID- 24401111 TI - A mathematical model of seropositivity to malaria antigen, allowing seropositivity to be prolonged by exposure. AB - BACKGROUND: Malaria transmission intensity is traditionally estimated from entomological studies as the entomological inoculation rate (EIR), but this is labour intensive and also raises sampling issues due to the large variation from house to house. Incidence of malaria in the control group of a trial or in a cohort study can be used but is difficult to interpret and to compare between different places and between age groups because of differences in levels of acquired immunity. The reversible catalytic model has been developed to estimate malaria transmission intensity using age-stratified serological data. However, the limitation of this model is that it does not allow for persons to have their seropositivity boosted by exposure while they are already seropositive. The aim of this paper is to develop superinfection mathematical models that allow for antibody response to be boosted by exposure. METHOD: The superinfection models were fitted to age-stratified serological data using maximum likelihood method. RESULTS: The results showed that estimates of seroconversion rate were higher using the superinfection model than catalytic model. This difference was milder when the level of transmission was lower. This suggests that the catalytic model is underestimating the transmission intensity by up to 31%. The duration of seropositivity is shorter with superinfection model, but still seems too long. CONCLUSION: The model is important because it can produce more realistic estimates of the duration of seropositivity. This is analogous to Dietz model, which allowed for superinfection and produced more realistic estimates of the duration of infection as compared to the original Ross-MacDonald malaria model, which also ignores superinfection. PMID- 24401110 TI - A survey on robotic devices for upper limb rehabilitation. AB - The existing shortage of therapists and caregivers assisting physically disabled individuals at home is expected to increase and become serious problem in the near future. The patient population needing physical rehabilitation of the upper extremity is also constantly increasing. Robotic devices have the potential to address this problem as noted by the results of recent research studies. However, the availability of these devices in clinical settings is limited, leaving plenty of room for improvement. The purpose of this paper is to document a review of robotic devices for upper limb rehabilitation including those in developing phase in order to provide a comprehensive reference about existing solutions and facilitate the development of new and improved devices. In particular the following issues are discussed: application field, target group, type of assistance, mechanical design, control strategy and clinical evaluation. This paper also includes a comprehensive, tabulated comparison of technical solutions implemented in various systems. PMID- 24401113 TI - Controlling leakage currents: the role of the binding group and purity of the precursors for self-assembled monolayers in the performance of molecular diodes. AB - This paper describes that the performance of molecular diodes based on self assembled monolayers (SAMs) depends on the type of anchoring group and purity of the precursors of these SAMs. The SAMs were formed on ultrasmooth template stripped silver (Ag(TS)) surfaces, which served as the bottom-electrode, and a eutectic alloy of gallium-indium was used as the top-electrode. When these junctions incorporate SAMs of the form S(CH2)11Fc (= SC11Fc) derived from HSC11Fc, they are good molecular diodes and rectify currents with rectification ratios R (= |J(-1.0 V)|/|J(+1.0 V)|) of ~1.0 * 10(2). Replacing the thiol by disulfide or thioacetate functionalities in the precursor resulted in molecular diodes with values of R close to unity. Cyclic voltammetry and angle resolved X ray photoelectron spectroscopy indicated that the SAMs derived from the disulfide or thioacetate precursors have lower surface coverages and are more defective than SAMs derived from thiols. In the junctions these defective SAMs caused defects and increased the leakage currents. The purity of the thiol-precursor is also crucial: 3 or 5% of disulfide present in the thiol caused a 28 or 61% decrease in R, respectively, and >15% of disulfide lowered R to unity, while the yield in nonshorting junctions remained unchanged. Our results show that the type of binding group, and the puritiy of the thiols, are crucial parameters in the experimental design of molecular electronic devices to ensure optimal device performance by keeping leakage currents to a minimum. PMID- 24401109 TI - Microbial 'old friends', immunoregulation and socioeconomic status. AB - The immune system evolved to require input from at least three sources that we collectively term the 'old friends': (i) the commensal microbiotas transmitted by mothers and other family members; (ii) organisms from the natural environment that modulate and diversify the commensal microbiotas; and (iii) the 'old' infections that could persist in small isolated hunter-gatherer groups as relatively harmless subclinical infections or carrier states. These categories of organism had to be tolerated and co-evolved roles in the development and regulation of the immune system. By contrast, the 'crowd infections' (such as childhood virus infections) evolved later, when urbanization led to large communities. They did not evolve immunoregulatory roles because they either killed the host or induced solid immunity, and could not persist in hunter gatherer groups. Because the western lifestyle and medical practice deplete the 'old' infections (for example helminths), immunoregulatory disorders have increased, and the immune system has become more dependent upon microbiotas and the natural environment. However, urbanization maintains exposure to the crowd infections that lack immunoregulatory roles, while accelerating loss of exposure to the natural environment. This effect is most pronounced in individuals of low socioeconomic status (SES) who lack rural second homes and rural holidays. Interestingly, large epidemiological studies indicate that the health benefits of living close to green spaces are most pronounced for individuals of low SES. Here we discuss the immunoregulatory role of the natural environment, and how this may interact with, and modulate, the proinflammatory effects of psychosocial stressors in low SES individuals. PMID- 24401114 TI - The diversity of receptor recognition in cholesterol-dependent cytolysins. AB - Cholesterol-dependent cytolysins (CDCs) are bacterial pore-forming toxins secreted mainly by pathogenic Gram-positive bacteria. CDCs generally recognize and bind to membrane cholesterol to create pores and lyse target cells. However, in contrast to typical CDCs such as streptolysin O, several atypical CDCs have been reported. The first of these was intermedilysin, which is secreted by Streptococcus intermedius and has human cell-specificity, human CD59 (huCD59) being its receptor. In the study reported here, the diversity of receptor recognition among CDCs was investigated and multi-receptor recognition characteristics were identified within this toxin family. Streptococcus mitis derived human platelet aggregation factor (Sm-hPAF) secreted by S. mitis strain Nm-65 isolated from a patient with Kawasaki disease was previously shown to hemolyze erythrocytes in a species-dependent manner, its maximum activity being in human cells. In the present study, it was found that Sm-hPAF recognizes both membrane cholesterol and huCD59 as receptors for triggering pore-formation. Moreover, vaginolysin (VLY) of Gardnerella vaginalis showed similar characteristics to Sm-hPAF regarding receptor recognition. On the basis of the results presented here, the mode of receptor recognition of CDCs can be categorized into the following three groups: (i) Group I, comprising typical CDCs with high affinity to cholesterol and no or very little affinity to huCD59; (ii) Group II, including atypical CDCs such as ILY, with no or very little affinity to cholesterol and high affinity to huCD59; and (iii) Group III, which contains atypical CDCs such as Sm-hPAF and VLY with affinity to both cholesterol and huCD59. PMID- 24401115 TI - Inhibitory activity of carbonyl compounds on alcoholic fermentation by Saccharomyces cerevisiae. AB - Aldehydes and acids play important roles in the fermentation inhibition of biomass hydrolysates. A series of carbonyl compounds (vanillin, syringaldehyde, 4 hydroxybenzaldehyde, pyrogallol aldehyde, and o-phthalaldehyde) were used to examine the quantitative structure-inhibitory activity relationship of carbonyl compounds on alcoholic fermentation, based on the glucose consumption rate and the final ethanol yield. It was observed that pyrogallol aldehyde and o phthalaldehyde (5.0 mM) reduced the initial glucose consumption rate by 60 and 89%, respectively, and also decreased the final ethanol yield by 60 and 99%, respectively. Correlating the molecular descriptors to inhibition efficiency in yeast fermentation revealed a strong relationship between the energy of the lowest unoccupied molecular orbital (ELUMO) of aldehydes and their inhibitory efficiency in fermentation. On the other hand, vanillin, syringaldehyde, and 4 hydroxybenzaldehyde (5.0 mM) increased the final ethanol yields by 11, 4, and 1%, respectively. Addition of vanillin appeared to favor ethanol formation over glycerol formation and decreased the glycerol yield in yeast fermentation. Furthermore, alcohol dehydrogenase (ADH) activity dropped significantly from 3.85 to 2.72, 1.83, 0.46, and 0.11 U/mg at 6 h of fermentation at vanillin concentrations of 0, 2.5, 5.0, 10.0, and 25.0 mM correspondingly. In addition, fermentation inhibition by acetic acid and benzoic acid was pH-dependent. Addition of acetate, benzoate, and potassium chloride increased the glucose consumption rate, likely because the salts enhanced membrane permeability, thus increasing glucose consumption. PMID- 24401116 TI - Infusion phlebitis assessment measures: a systematic review. AB - RATIONALE, AIMS AND OBJECTIVES: Phlebitis is a common and painful complication of peripheral intravenous cannulation. The aim of this review was to identify the measures used in infusion phlebitis assessment and evaluate evidence regarding their reliability, validity, responsiveness and feasibility. METHOD: We conducted a systematic literature review of the Cochrane library, Ovid MEDLINE and EBSCO CINAHL until September 2013. All English-language studies (randomized controlled trials, prospective cohort and cross-sectional) that used an infusion phlebitis scale were retrieved and analysed to determine which symptoms were included in each scale and how these were measured. We evaluated studies that reported testing the psychometric properties of phlebitis assessment scales using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guidelines. RESULTS: Infusion phlebitis was the primary outcome measure in 233 studies. Fifty-three (23%) of these provided no actual definition of phlebitis. Of the 180 studies that reported measuring phlebitis incidence and/or severity, 101 (56%) used a scale and 79 (44%) used a definition alone. We identified 71 different phlebitis assessment scales. Three scales had undergone some psychometric analyses, but no scale had been rigorously tested. CONCLUSION: Many phlebitis scales exist, but none has been thoroughly validated for use in clinical practice. A lack of consensus on phlebitis measures has likely contributed to disparities in reported phlebitis incidence, precluding meaningful comparison of phlebitis rates. PMID- 24401117 TI - In vitro determinants of asbestos fiber toxicity: effect on the relative toxicity of Libby amphibole in primary human airway epithelial cells. AB - BACKGROUND: An abnormally high incidence of lung disease has been observed in the residents of Libby, Montana, which has been attributed to occupational and environmental exposure to fibrous amphiboles originating from a nearby contaminated vermiculite mine. The composition of Libby amphibole (LA) is complex and minimal toxicity data are available. In this study, we conduct a comparative particle toxicity analysis of LA compared with standard reference asbestiform amphibole samples. METHODS: Primary human airway epithelial cells (HAEC) were exposed to two different LA samples as well as standard amphibole reference samples. Analysis of the samples included a complete particle size distribution analysis, calculation of surface area by electron microscopy and by gas adsorption and quantification of surface-conjugated iron and hydroxyl radical production by the fibers. Interleukin-8 mRNA levels were quantified by qRT-PCR to measure relative pro-inflammatory response induced in HAEC in response to amphibole fiber exposure. The relative contribution of key physicochemical determinants on the observed pro-inflammatory response were also evaluated. RESULTS: The RTI amosite reference sample contained the longest fibers and demonstrated the greatest potency at increasing IL-8 transcript levels when evaluated on an equal mass basis. The two LA samples and the UICC amosite reference sample consisted of similar particle numbers per milligram as well as similar particle size distributions and induced comparable levels of IL-8 mRNA. A strong correlation was observed between the elongated particle (aspect ratio >=3:1) dose metrics of length and external surface area. Expression of the IL-8 data with respect to either of these metrics eliminated the differential response between the RTI amosite sample and the other samples that was observed when HAEC were exposed on an equal mass basis. CONCLUSIONS: On an equal mass basis, LA is as potent as the UICC amosite reference sample at inducing a pro-inflammatory response in HAEC but is less potent than the RTI amosite sample. The results of this study show that the particle length and particle surface area are highly correlated metrics that contribute significantly to the toxicological potential of these amphibole samples with respect to the inflammogenic response induced in airway epithelial cells. PMID- 24401118 TI - Old and new basal insulin formulations: understanding pharmacodynamics is still relevant in clinical practice. AB - Long-acting insulin analogues have been developed to mimic the physiology of basal insulin secretion more closely than human insulin formulations (Neutral Protamine Hagedorn, NPH). However, the clinical evidence in favour of analogues is still controversial. Although their major benefit as compared with NPH is a reduction in the hypoglycaemia risk, some cost/effectiveness analyses have not been favourable to analogues, largely because of their higher price. Nevertheless, these new formulations have conquered the insulin market. Human insulin represents currently no more than 20% of market share. Despite (in fact because of) the widespread use of insulin analogues it remains critical to analyse the pharmacodynamics (PD) of basal insulin formulations appropriately to interpret the results of clinical trials correctly. Importantly, these data may help physicians in tailoring insulin therapy to patients' individual needs and, additionally, when clinical evidence is not available, to optimize insulin treatment. For patients at low risk for/from hypoglycaemia, it might be acceptable and also cost-effective not to use long-acting insulin analogues as basal insulin replacement. Conversely, in patients with a higher degree of insulin deficiency and increased risk for hypoglycaemia, analogues are the best option due to their more physiological profile, as has been shown in PD and clinical studies. From this perspective optimizing basal insulin treatment, especially in type 2 diabetes patients who are less prone to hypoglycaemia, would be suitable making significant resources available for other relevant aspects of diabetes care. PMID- 24401119 TI - The elasticity of soap bubbles containing wormlike micelles. AB - Slow-motion imaging of the rupture of soap bubbles generally shows the edges of liquid films retracting at a constant speed (known as the Taylor-Culick velocity). Here we investigate soap bubbles formed from simple solutions of a cationic surfactant (cetyltrimethylammonium bromide - CTAB) and sodium salicylate. The interaction of salicylate ions with CTAB leads to the formation of wormlike micelles (WLM), which yield a viscoelastic behavior to the liquid film of the bubble. We demonstrate that these elastic bubbles collapse at a velocity up to 30 times higher than the Taylor-Culick limit, which has never been surpassed. This is because during the bubble inflation, the entangled WLM chains stretch, storing elastic energy. This extra energy is then released during the rupture of the bubble, yielding an additional driving force for film retraction (besides surface tension). This new mechanism for the bursting of elastic bubbles may have important implications to the breakup of viscoelastic sprays in industrial applications. PMID- 24401120 TI - Association between the hemodialysis adequacy and sexual dysfunction in chronic renal failure: a preliminary study. AB - BACKGROUND: The core question of the study was whether adequately achieved HD affected the sexual dysfunction in women on hemodialysis (HD) with chronic renal failure (CRF). METHODS: Thirty-seven female patients on HD, including 18 women with adequate HD and 19 women with non-adequate HD, and 36 healthy controls were included in this study. Demographic and clinical variables, including the sexual hormones estradiol and testosterone, were recorded. Sexual function was assessed according to the Female Sexual Function Index (FSFI) and results were compared between groups. Adequate HD was defined as an average urea clearance of over 1.3 (Kt/V) over three consecutive months. RESULTS: All domains of the FSFI questionnaire, with the exception of satisfaction, were higher in the control group than in the HD group. In comparing the adequate and non-adequate HD groups, there was no difference in any of the six domains of the FSDI questionnaire. Among the clinical variables, the number of menopausal women was higher in the HD group than in the control group (P = 0.023). Estradiol and testosterone levels were higher in the control group than in the HD group (P = 0.003, 0.027, respectively). The number of menopausal women and estradiol and testosterone levels showed no differences between the adequate and non-adequate HD groups. Correlation analysis between Kt/V and FSFI showed no significant relationship, but estrogen did show a significant relationship with FSFI (correlation coefficient = 0.399, P = 0.001). CONCLUSIONS: HD adequacy alone does not have a significant impact on sexual dysfunction. Other treatments options should be considered to treat sexual dysfunction in women with CRF. PMID- 24401121 TI - Correlation of foveal photoreceptor integrity with visual outcome in idiopathic epiretinal membrane. AB - PURPOSE: To evaluate the correlation of foveal photoreceptor integrity with visual outcome in patients undergoing idiopathic epiretinal membrane (ERM) surgery using spectral domain optical coherence tomography (SD-OCT). MATERIALS AND METHODS: Forty-three eyes of 43 patients were examined by SD-OCT before and at 1 and 6 months after vitrectomy for idiopathic ERM. Patients were divided into two groups based on the preoperative integrity of photoreceptor inner and outer segment junction (IS/OS) - Group I, intact IS/OS and Group D, disrupted IS/OS. Where present, disrupted length of IS/OS was measured, and the association between disrupted length of IS/OS and foveal thickness with best corrected visual acuity (BCVA) was evaluated. RESULTS: There were 27 eyes with an intact IS/OS (Group I) and 16 eyes with a disrupted IS/OS (Group D). Patients in Group I had significantly better postoperative BCVA and greater improvement than those in Group D at 6 months after surgery (p = 0.001 and p = 0.030, respectively). By 6 months after surgery, the disrupted length of IS/OS observed preoperatively in Group D had decreased significantly (p = 0.007). The disrupted length of IS/OS before and at 6 months after the surgery in Group D showed a positive correlation with BCVA (r = 0.632 and p = 0.009; r = 0.658 and p = 0.006, respectively). Foveal thickness did not correlate significantly with preoperative and postoperative BCVA. CONCLUSIONS: Preoperative disruption of foveal photoreceptors can be restored after ERM surgery. The preoperative integrity of foveal photoreceptors may be a clinically significant prognostic factor for visual recovery in patients with idiopathic ERM. PMID- 24401122 TI - Effect of disinfectant, water age, and pipe materials on bacterial and eukaryotic community structure in drinking water biofilm. AB - Availability of safe, pathogen-free drinking water is vital to public health; however, it is impossible to deliver sterile drinking water to consumers. Recent microbiome research is bringing new understanding to the true extent and diversity of microbes that inhabit water distribution systems. The purpose of this study was to determine how water chemistry in main distribution lines shape the microbiome in drinking water biofilms and to explore potential associations between opportunistic pathogens and indigenous drinking water microbes. Effects of disinfectant (chloramines, chlorine), water age (2.3 days, 5.7 days), and pipe material (cement, iron, PVC) were compared in parallel triplicate simulated water distribution systems. Pyrosequencing was employed to characterize bacteria and terminal restriction fragment polymorphism was used to profile both bacteria and eukaryotes inhabiting pipe biofilms. Disinfectant and water age were both observed to be strong factors in shaping bacterial and eukaryotic community structures. Pipe material only influenced the bacterial community structure (ANOSIM test, P < 0.05). Interactive effects of disinfectant, pipe material, and water age on both bacteria and eukaryotes were noted. Disinfectant concentration had the strongest effect on bacteria, while dissolved oxygen appeared to be a major driver for eukaryotes (BEST test). Several correlations of similarity metrics among populations of bacteria, eukaryotes, and opportunistic pathogens, as well as one significant association between mycobacterial and proteobacterial operational taxonomic units, provides insight into means by which manipulating the microbiome may lead to new avenues for limiting the growth of opportunistic pathogens (e.g., Legionella) or other nuisance organisms (e.g., nitrifiers). PMID- 24401123 TI - Prospecting for unannotated enzymes: discovery of a 3',5'-nucleotide bisphosphate phosphatase within the amidohydrolase superfamily. AB - In bacteria, 3',5'-adenosine bisphosphate (pAp) is generated from 3' phosphoadenosine 5'-phosphosulfate in the sulfate assimilation pathway, and from coenzyme A by the transfer of the phosphopantetheine group to the acyl-carrier protein. pAp is subsequently hydrolyzed to 5'-AMP and orthophosphate, and this reaction has been shown to be important for superoxide stress tolerance. Herein, we report the discovery of the first instance of an enzyme from the amidohydrolase superfamily that is capable of hydrolyzing pAp. Crystal structures of Cv1693 from Chromobacterium violaceum have been determined to a resolution of 1.9 A with AMP and orthophosphate bound in the active site. The enzyme has a trinuclear metal center in the active site with three Mn(2+) ions. This enzyme (Cv1693) belongs to the Cluster of Orthologous Groups cog0613 from the polymerase and histidinol phosphatase family of enzymes. The values of kcat and kcat/Km for the hydrolysis of pAp are 22 s(-1) and 1.4 * 10(6) M(-1) s(-1), respectively. The enzyme is promiscuous and is able to hydrolyze other 3',5'-bisphosphonucleotides (pGp, pCp, pUp, and pIp) and 2'-deoxynucleotides with comparable catalytic efficiency. The enzyme is capable of hydrolyzing short oligonucleotides (pdA)5, albeit at rates much lower than that of pAp. Enzymes from two other enzyme families have previously been found to hydrolyze pAp at physiologically significant rates. These enzymes include CysQ from Escherichia coli (cog1218) and YtqI/NrnA from Bacillus subtilis (cog0618). Identification of the functional homologues to the experimentally verified pAp phosphatases from cog0613, cog1218, and cog0618 suggests that there is relatively little overlap of enzymes with this function in sequenced bacterial genomes. PMID- 24401124 TI - Budesonide dry powder for inhalation: effects of leucine and mannitol on the efficiency of delivery. AB - OBJECTIVE: The aim of this study was to develop a budesonide dry powder for inhalation using l-leucine and l-leucine - sieved mannitol as a carrier. MATERIALS AND METHODS: Budesonide and l-leucine were co-spray dried at a mass ratio of 1:50 then blended with various mass ratios of sieved mannitol in the range of 20-80. A 2(3) factorial study was applied to investigate the effects of the spray drying variables; feed rate, aspirator setting and airflow rate on the powder characteristics. The prepared dry powders were characterized using fourier transform-infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and ultracentrifugation. Drug contents and aerosolization properties were evaluated using high performance liquid chromatography (HPLC) and the Andersen cascade impactor (ACI), respectively. RESULTS AND DISCUSSION: There was no interaction between budesonide and l-leucine after co-spraying. The budesonide dry powders had a mass median aerodynamic diameter (MMAD) in the range of 1.9-2.2 um at a flow rate of 60 L/min that was suitable for pulmonary delivery. Sieved mannitol as a coarse carrier decreased the interparticulate forces between fine particles of the co-spray dried budesonide-l-leucine and resulted in a high fine particle fraction (FPF) in the range of 64-68% while the co-spray dried powder of budesonide-l-leucine had an FPF of ~49%. CONCLUSIONS: Blending of the co-spray dried powder with sieved mannitol significantly improved the delivery efficiency of the micronized budesonide better than the co-spray dried with l-leucine alone. PMID- 24401125 TI - Hypothalamic expression of anorexigenic and orexigenic hormone receptors in obese females Neotomodon alstoni: effect of fasting. AB - Obesity is a world problem that requires a better understanding of its physiological and genetic basis, as well as the mechanisms by which the hypothalamus controls feeding behavior. The volcano mouse Neotomodon alstoni develops obesity in captivity when fed with regular chow diet, providing a novel model for the study of obesity. Females develop obesity more often than males; therefore, in this study, we analysed in females, in proestrous lean and obese, the differences in hypothalamus expression of receptors for leptin, ghrelin (growth hormone secretagogue receptor GHS-R), and VPAC, and correlates for plasma levels of total ghrelin. The main comparisons are between mice fed ad libitum and mice after 24 hours of fasting. Mice above 65 g body weight were considered obese, based on behavioral and physiological parameters such as food intake, plasma free fatty acids, and glucose tolerance. Hypothalamic tissue from obese and lean mice was analysed by western blot. Our results indicate that after ad libitum food access, obese mice show no significant differences in hypothalamic leptin receptors, but a significant increase of 60% in the GHS-R, and a nearly 62% decrease in VPAC2 was noted. After a 24-hour fast, plasma ghrelin increased nearly two fold in both lean and obese mice; increases of hypothalamic leptin receptors and GHS-R were also noted, while VPAC2 did not change significantly; levels of plasma free fatty acids were 50% less after fasting in obese than in lean animals. Our results indicate that in obese N. alstoni mice, the levels of orexigenic receptors in the hypothalamus correlate with overfeeding, and the fact that lean and obese females respond in different ways to a metabolic demand such as a 24-hour fast. PMID- 24401127 TI - Influence of solute charge and pyrrolidinium ionic liquid alkyl chain length on probe rotational reorientation dynamics. AB - In recent years, the effect of molecular charge on the rotational dynamics of probe solutes in room-temperature ionic liquids (RTILs) has been a subject of growing interest. For the purpose of extending our understanding of charged solute behavior within RTILs, we have studied the rotational dynamics of three illustrative xanthene fluorescent probes within a series of N-alkylpyrrolidinium bis(trifluoromethylsulfonyl)imide ([Cnmpyr][Tf2N]) RTILs with different n-alkyl chain lengths (n = 3, 4, 6, 8, or 10) using time-resolved fluorescence anisotropy decay. The rotational dynamics of the neutral probe rhodamine B (RhB) dye lies between the stick and slip boundary conditions due to the influence of specific hydrogen bonding interactions. The rotation of the negatively charged sulforhodamine 640 (SR640) is slower than that of its positively charged counterpart rhodamine 6G (R6G). An analysis based upon Stokes-Einstein-Debye hydrodynamics indicates that SR640 adheres to stick boundary conditions due to specific interactions, whereas the faster rotation of R6G is attributed to weaker electrostatic interactions. No significant dependence of the rotational dynamics on the solvent alkyl chain length was observed for any of the three dyes, suggesting that the specific interactions between dyes and RTILs are relatively independent of this solvent parameter. PMID- 24401128 TI - Tissue specific analysis reveals a differential organization and regulation of both ethylene biosynthesis and E8 during climacteric ripening of tomato. AB - BACKGROUND: Solanum lycopersicum or tomato is extensively studied with respect to the ethylene metabolism during climacteric ripening, focusing almost exclusively on fruit pericarp. In this work the ethylene biosynthesis pathway was examined in all major tomato fruit tissues: pericarp, septa, columella, placenta, locular gel and seeds. The tissue specific ethylene production rate was measured throughout fruit development, climacteric ripening and postharvest storage. All ethylene intermediate metabolites (1-aminocyclopropane-1-carboxylic acid (ACC), malonyl ACC (MACC) and S-adenosyl-L-methionine (SAM)) and enzyme activities (ACC-oxidase (ACO) and ACC-synthase (ACS)) were assessed. RESULTS: All tissues showed a similar climacteric pattern in ethylene productions, but with a different amplitude. Profound differences were found between tissue types at the metabolic and enzymatic level. The pericarp tissue produced the highest amount of ethylene, but showed only a low ACC content and limited ACS activity, while the locular gel accumulated a lot of ACC, MACC and SAM and showed only limited ACO and ACS activity. Central tissues (septa, columella and placenta) showed a strong accumulation of ACC and MACC. These differences indicate that the ethylene biosynthesis pathway is organized and regulated in a tissue specific way. The possible role of inter- and intra-tissue transport is discussed to explain these discrepancies. Furthermore, the antagonistic relation between ACO and E8, an ethylene biosynthesis inhibiting protein, was shown to be tissue specific and developmentally regulated. In addition, ethylene inhibition by E8 is not achieved by a direct interaction between ACO and E8, as previously suggested in literature. CONCLUSIONS: The Ethylene biosynthesis pathway and E8 show a tissue specific and developmental differentiation throughout tomato fruit development and ripening. PMID- 24401129 TI - Novel and emerging therapies for pulmonary hypertension. AB - The development of therapeutic concepts in pulmonary hypertension (PH) is intimately linked with the unraveling of pathogenetic sequelae. This perspective highlights advances in our understanding of the regulation of vasomotion and vascular remodeling that have led to "reverse-remodeling" and regenerative strategies as novel treatment concepts. Progress has been made in understanding redox-dependent signaling; inflammatory sequelae; and transcription factor, ion channel, and metabolic abnormalities, as well as growth factor-dependent hyperproliferation that underlies PH. We are, however, far from understanding the molecular pathways that differentially drive the various vascular phenotypes (intimal thickening, media hypertrophy, adventitial thickening, plexiform lesions, vascular pruning) in this disease. Antiproliferative strategies, transcription factor-based therapies, inflammation/immune cell-focused approaches, and epigenetic modulation-based therapies are all novel treatment concepts for PH. The proangiogenic potential of genetically engineered mesenchymal stem cells and endothelial progenitor cells has been explored as a regenerative strategy. The progress that has been made in identifying important cellular and molecular mechanisms and applying this knowledge to novel therapies is largely restricted to group 1 PH. However, understanding the molecular sequelae underlying PH in groups 2 through 5 PH is also urgently needed. PMID- 24401130 TI - The education of pain physicians. PMID- 24401131 TI - Integrated analysis of seaweed components during seasonal fluctuation by data mining across heterogeneous chemical measurements with network visualization. AB - Biological information is intricately intertwined with several factors. Therefore, comprehensive analytical methods such as integrated data analysis, combining several data measurements, are required. In this study, we describe a method of data preprocessing that can perform comprehensively integrated analysis based on a variety of multimeasurement of organic and inorganic chemical data from Sargassum fusiforme and explore the concealed biological information by statistical analyses with integrated data. Chemical components including polar and semipolar metabolites, minerals, major elemental and isotopic ratio, and thermal decompositional data were measured as environmentally responsive biological data in the seasonal variation. The obtained spectral data of complex chemical components were preprocessed to isolate pure peaks by removing noise and separating overlapping signals using the multivariate curve resolution alternating least-squares method before integrated analyses. By the input of these preprocessed multimeasurement chemical data, principal component analysis and self-organizing maps of integrated data showed changes in the chemical compositions during the mature stage and identified trends in seasonal variation. Correlation network analysis revealed multiple relationships between organic and inorganic components. Moreover, in terms of the relationship between metal group and metabolites, the results of structural equation modeling suggest that the structure of alginic acid changes during the growth of S. fusiforme, which affects its metal binding ability. This integrated analytical approach using a variety of chemical data can be developed for practical applications to obtain new biochemical knowledge including genetic and environmental information. PMID- 24401132 TI - Improvement of plant abiotic stress tolerance through modulation of the polyamine pathway. AB - Polyamines (mainly putrescine (Put), spermidine (Spd), and spermine (Spm)) have been widely found in a range of physiological processes and in almost all diverse environmental stresses. In various plant species, abiotic stresses modulated the accumulation of polyamines and related gene expression. Studies using loss-of function mutants and transgenic overexpression plants modulating polyamine metabolic pathways confirmed protective roles of polyamines during plant abiotic stress responses, and indicated the possibility to improve plant tolerance through genetic manipulation of the polyamine pathway. Additionally, putative mechanisms of polyamines involved in plant abiotic stress tolerance were thoroughly discussed and crosstalks among polyamine, abscisic acid, and nitric oxide in plant responses to abiotic stress were emphasized. Special attention was paid to the interaction between polyamine and reactive oxygen species, ion channels, amino acid and carbon metabolism, and other adaptive responses. Further studies are needed to elucidate the polyamine signaling pathway, especially polyamine-regulated downstream targets and the connections between polyamines and other stress responsive molecules. PMID- 24401133 TI - The G1057D polymorphism of insulin receptor substrate-2 associated with gestational diabetes mellitus. AB - OBJECTIVE: The Gly1057D polymorphism in the insulin receptor substrate-2 (IRS-2) gene has been reported to be associated with insulin resistance, obesity and type 2 diabetes; little is known about its possible association with gestational diabetes mellitus (GDM). To investigate this association we determined the distribution of its genotypes and frequency of alleles in GDM patients. MATERIALS AND METHODS: The study population consisted of 94 subjects; among them were 44 patients with GDM and 50 healthy controls without diabetes. Genomic DNA was extracted from the leukocyte by high pure polymerase chain reaction (PCR) template preparation kit. Genetic polymorphism of IRS-2 G1057D was detected by using PCR-based restriction fragment-length polymorphism (RFLP). RESULTS: For IRS 2 G1057D polymorphism, there was no significant difference in genotype distribution between GDM patients and controls. The risk for GDM was 2.97 times higher (95% CI: 0.89-9.93, p = 0.076) in the individuals with the IRS-2 DD genotype compared to the GG genotype. Also individuals with the IRS-2 D allele had a significantly higher risk of GDM compared with individuals with the IRS-2 G allele, with a relative risk of 1.86 (95% CI: 1.02-3.37, p = 0.042) for cases compared with population controls. CONCLUSION: These results suggest that IRS-2 1057D allele may be associated with GDM. PMID- 24401134 TI - Community consultation for prehospital research: experiences of study coordinators and principal investigators. AB - OBJECTIVE: To assess principal investigators' and study coordinators' views and experiences regarding community consultation in a multicenter trial of prehospital treatment for status epilepticus conducted under an exception from informed consent for research in emergency settings. METHODS: Principal investigators and study coordinators at all 17 hubs for the Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) were invited to complete a web-based survey regarding community consultation at their site for RAMPART. Major domains included 1) perceived goals of community consultation, 2) experiences with and views of community consultation methods used, 3) interactions with IRB regarding community consultation, and 4) general satisfaction and lessons learned. Descriptive statistics were tabulated for Likert scale data; relevant themes were reported for text-based data. RESULTS: Twenty-eight individuals (16 coordinators and 12 investigators) representing all 17 RAMPART hubs completed the survey. Respondents considered multiple community consultation goals to be important, with least support for the role of community consultation in altering study design. All sites used multiple methods (median = 5). The most widely used, and generally favored, method was attending previously scheduled meetings of existing groups. Respondents expressed frustration with low attendance and responsiveness at open public meetings. CONCLUSIONS: Coordinators and investigators in this trial viewed community consultation efforts as successful but reported real challenges generating public interest. Individuals with the condition under study were found to be more engaged and supportive of the trial. Respondents endorsed numerous potential goals of the community consultation process and often combined methods to achieve these goals. PMID- 24401135 TI - The influence of Hurricanes Katrina and Rita on the inflammatory cytokine response and protein expression in A549 cells exposed to PM2.5 collected in the Baton Rouge-Port Allen industrial corridor of Southeastern Louisiana in 2005. AB - Hurricanes Katrina and Rita hit the coast of Louisiana in 2005 and killed more than 2000 people. The two storms resulted in a significant spike in particulate matter (PM2.5) levels across the state of Louisiana. This report focuses on PM2.5 samples collected in 2005 from two monitoring sites in the neighboring cities of Baton Rouge and Port Allen, Louisiana. Inductively coupled plasma (ICP) revealed the presence of PM2.5-adsorbed representative and Fenton-active transition metals. Gas chromatography/mass spectrometry (GC-MS) analyses revealed the presence of 23 PAH compounds. Endotoxins were also detected. Metals and endotoxins were extracted with water. PAH were extracted with dichloromethane. In order to assess cytotoxicity, aqueous PM2.5 extracts were introduced to A549 Human Epithelial Lung Carcinoma Cells. Results indicated decreased cell viability in a dose-dependent manner, with an LC50 of 235 ug/ml and 250 ug/ml, respectively, for the two sites featured here. Endotoxins alone were not cytotoxic. The concentration of reactive oxygen species (ROS) and released LDH activity increased following exposure of A549 cells to aqueous PM2.5 extracts. Fluorescence microscopy revealed apoptotic and necrotic cell death mechanisms. ELISA revealed increased secretion of primary pro-inflammatory cytokines, IL-6, IL-8, and TNF-alpha. Global PCR gene expression revealed up-regulation of proteins associated with the cytokine storm; e.g. interleukins, chemokines, and TNF-alpha. Global antibody microarray was consistent with an inflammatory response, with up-regulation of cytokines involved in the down-field activation of the caspase cascade and kinase pathways. The up-regulation of metal-redox sensitive transcription factors, NF-kappabeta and AP-1, is consistent with a cell death mechanism initiated by Fenton-active transition metal redox catalysis. PMID- 24401136 TI - Effect of ellagic acid on some haematological, immunological and antioxidant parameters of rainbow trout (Oncorhynchus mykiss). AB - In this study, effect of ellagic acid on some haematological, immunological and antioxidant parameters in the blood and various tissues of rainbow trout (Oncorhynchus mykiss) were examined. Four groups of rainbow trout were fed experimental diets containing either no ellagic acid (control) or supplemented with ellagic acid at 50 mg/kg diet (EA-50), 100 mg/kg diet (EA-100) or 150 mg/kg diet (EA-150) for 21 days. Samples of the blood and tissue (liver, kidney and spleen) were collected at the end of the experiment and analysed for their haematological profile (the red blood cell count, the haemoglobin concentration and the haematocrit level), immune response (the white blood cell count, the oxidative radical production (NBT activity), the total plasma protein and total immunoglobulin level) and oxidant/antioxidant status (the malondialdehyde level, the superoxide dismutase, catalase and glutathione peroxidase activity as well as the reduced glutathione concentration). The findings of this study demonstrated that ellagic acid had a positive effect on the haematological parameters, the immune response and the antioxidant enzyme activities of the fish. PMID- 24401137 TI - Evaluation of enrichment method for the detection of Vibrio cholerae O1 using a rapid dipstick test in Bangladesh. AB - BACKGROUND: To evaluate the specificity of the Crystal VC dipstick test for detecting cholera. METHODS: We compared direct testing using the Crystal VC dipstick test and testing after enrichment for 6 h in alkaline peptone water (APW) to bacterial culture as the gold standard. Samples positive by dipstick but negative by culture were also tested using PCR. RESULTS: Stool was collected from 125 patients. The overall specificities of the direct testing and testing after 6 h enrichment in APW compared to bacterial culture were 91.8% and 98.4% (P = 0.125), respectively, and the sensitivities were 65.6% and 75.0% (P = 0.07), respectively. CONCLUSION: The increase in the sensitivity of the Crystal VC kit with the use of the 6-h enrichment step in APW compared to direct testing was marginally significant. The Crystal VC dipstick had a much higher specificity than previously reported (91-98%). Therefore, this method might be a promising screening tool for cholera outbreak surveillance in resource-limited settings where elimination of false-positive results is critical. PMID- 24401138 TI - Self-illuminating 64Cu-doped CdSe/ZnS nanocrystals for in vivo tumor imaging. AB - Construction of self-illuminating semiconducting nanocrystals, also called quantum dots (QDs), has attracted much attention recently due to their potential as highly sensitive optical probes for biological imaging applications. Here we prepared a self-illuminating QD system by doping positron-emitting radionuclide (64)Cu into CdSe/ZnS core/shell QDs via a cation-exchange reaction. The (64)Cu doped CdSe/ZnS QDs exhibit efficient Cerenkov resonance energy transfer (CRET). The signal of (64)Cu can accurately reflect the biodistribution of the QDs during circulation with no dissociation of (64)Cu from the nanoparticles. We also explored this system for in vivo tumor imaging. This nanoprobe showed high tumor targeting ability in a U87MG glioblastoma xenograft model (12.7% ID/g at 17 h time point) and feasibility for in vivo luminescence imaging of tumor in the absence of excitation light. The availability of these self-illuminating integrated QDs provides an accurate and convenient tool for in vivo tumor imaging and detection. PMID- 24401139 TI - Laparoscopic transabdominal preperitoneal repair of spigelian hernia-closure of the fascial defect is not necessary. AB - INTRODUCTION: Spigelian hernia (SH) is rare and is traditionally repaired using an open technique. There has been an increasing popularity of laparoscopic methods, with transabdominal preperitoneal (TAPP) repair being one of the popular techniques. Currently, most surgeons using the TAPP technique close the fascial defect prior to mesh placement. Here we report our experience with a TAPP repair that deliberately excludes approximation of the fascial defect. SUBJECTS AND METHODS: Prospective data were collected on consecutive patients undergoing elective SH repair under the care of a single surgeon between 2001 and 2012. Diagnosis was confirmed preoperatively using ultrasonography or computerized tomography. A laparoscopic TAPP repair was used without closing the defect. Following discharge all patients were followed up at 3 and 12 months. The clinical records were reviewed at the time this article was written. The technique, epidemiological characteristics, operative findings, hospital stay, morbidity, and follow-up are presented. RESULTS: Twenty-six patients (16 males) with a median age of 63 years were operated on. The follow-up period ranged between 6 months and 11 years (median, 4 years). Hernia defect size ranged from 2 to 10 cm. Mean operating time for unilateral defects was 45 minutes; that for bilateral defects was 70 minutes. Twenty-two patients were discharged on the same day. There were no postoperative complications or recurrences. CONCLUSIONS: Laparoscopic TAPP repair of SH without closing the defect is safe, effective, and durable. There is no additional benefit from routine closure of the fascial defect. On the contrary, there may be potential advantages in leaving the defect unopposed. PMID- 24401140 TI - Videoendoscopic single-port nipple-sparing mastectomy and immediate reconstruction. AB - PURPOSE: Single-incision videoendoscopic surgery has recently become popular as a result of the ongoing search for less invasive procedures. The aim of this study was to evaluate the safety and efficacy of endoscopic single-port nipple-sparing mastectomy, axillary lymphadenectomy, and immediate reconstruction in patients with breast cancer. PATIENTS AND METHODS: From May 14, 2012 through January 23, 2013, 10 patients underwent videoendoscopic single-port nipple-sparing mastectomy and axillary dissection via a single, limited incision and immediate prosthetic reconstruction. Patient charts were reviewed, and demographic data, operative time, complications and pathology results were analyzed. RESULTS: In all patients, videoendoscopic surgery was performed successfully. Of 10 patients, 7 were diagnosed as having invasive ductal carcinoma, 2 had a ductal carcinoma in situ, and 1 underwent bilateral prophylactic mastectomy. The weight of the resected gland was 300-650 g, with a mean of 420 g. There were no operative complications, and the mean operative time was 250 minutes (range, 160-330 minutes). One-stage reconstruction with implants was performed on 4 patients, whereas expanders were placed in the remaining 6. Surgical margins of all cases were pathologically negative, and there were no recurrences observed during the early follow-up period. CONCLUSIONS: Videoendoscopic single-port nipple-sparing mastectomy is technically feasible even in larger breasts, enabling immediate reconstruction with good cosmetic outcomes. However, further studies with larger clinical series and long-term follow-up are required to compare the safety and efficacy of the technique with those of the standard nipple-sparing mastectomy. PMID- 24401141 TI - Outcomes of robotic-assisted transhiatal esophagectomy for esophageal cancer after neoadjuvant chemoradiation. AB - BACKGROUND: We previously reported our experience performing robotic-assisted transhiatal esophagectomy (RATE) in patients with early-stage esophageal cancer who had had no preoperative treatment. The purpose of this report was to determine if RATE could be performed safely with good outcomes for esophageal cancer in a more recent series of patients, the majority of whom were treated with neoadjuvant chemoradiation. SUBJECTS AND METHODS: This was a retrospective review of patients with adenocarcinoma of the distal esophagus or gastroesophageal junction who underwent RATE between November 2006 and November 2012 at a single tertiary-care hospital. Main outcome measures included operative and oncologic parameters, morbidity, and mortality. RESULTS: In total, 23 patients underwent RATE, consisting of 20 men and 3 women with a median age of 64 years (range, 40-81 years). The majority of patients (19/23 [83%]) underwent neoadjuvant chemoradiation, although 1 patient had preoperative chemotherapy only, and 3 patients went straight to surgery. Median operative time was 231 minutes (range, 179-319 minutes), and median estimated blood loss was 100 mL (range, 25-400 mL). There were no conversions to open surgery. Complications included seven strictures, two anastomotic leaks, and two pericardial/pleural effusions requiring drainage. One patient required pyloroplasty 3 months after esophagectomy. One patient died from pulmonary failure 21 days after surgery (30 day mortality rate of 4%). The median length of stay was 9 days (range, 7-37 days). Seven of the 19 patients who underwent preoperative chemoradiation had a complete response on final pathology. The mean lymph node yield was 15 (range, 5 29), and surgical margins were negative for cancer in 21 cases. CONCLUSIONS: RATE can be performed safely with good oncologic outcomes following neoadjuvant chemoradiation in patients with esophageal cancer. This technique has become our choice of operation for most patients with esophageal cancer. PMID- 24401142 TI - Utilization of household food waste for the production of ethanol at high dry material content. AB - BACKGROUND: Environmental issues and shortage of fossil fuels have turned the public interest to the utilization of renewable, environmentally friendly fuels, such as ethanol. In order to minimize the competition between fuels and food production, researchers are focusing their efforts to the utilization of wastes and by-products as raw materials for the production of ethanol. household food wastes are being produced in great quantities in European Union and their handling can be a challenge. Moreover, their disposal can cause severe environmental issues (for example emission of greenhouse gasses). On the other hand, they contain significant amounts of sugars (both soluble and insoluble) and they can be used as raw material for the production of ethanol. RESULTS: Household food wastes were utilized as raw material for the production of ethanol at high dry material consistencies. A distinct liquefaction/saccharification step has been included to the process, which rapidly reduced the viscosity of the high solid content substrate, resulting in better mixing of the fermenting microorganism. This step had a positive effect in both ethanol production and productivity, leading to a significant increase in both values, which was up to 40.81% and 4.46 fold, respectively. Remaining solids (residue) after fermentation at 45% w/v dry material (which contained also the unhydrolyzed fraction of cellulose), were subjected to a hydrothermal pretreatment in order to be utilized as raw material for a subsequent ethanol fermentation. This led to an increase of 13.16% in the ethanol production levels achieving a final ethanol yield of 107.58 g/kg dry material. CONCLUSIONS: In conclusion, the ability of utilizing household food waste for the production of ethanol at elevated dry material content has been demonstrated. A separate liquefaction/saccharification process can increase both ethanol production and productivity. Finally, subsequent fermentation of the remaining solids could lead to an increase of the overall ethanol production yield. PMID- 24401143 TI - Strength training versus robot-assisted gait training after incomplete spinal cord injury: a randomized pilot study in patients depending on walking assistance. AB - BACKGROUND: Task-specific locomotor training has been promoted to improve walking related outcome after incomplete spinal cord injury (iSCI). However, there is also evidence that lower extremity strength training might lead to such improvements. The aim of this randomized cross-over pilot study was to compare changes in a broad spectrum of walking-related outcome measures and pain between robot-assisted gait training (RAGT) and strength training in patients with chronic iSCI, who depended on walking assistance. We hypothesized that task specific locomotor training would result in better improvements compared to strength training. METHODS: Nine participants with a chronic iSCI were randomized to group 1 or 2. Group 1 received 16 sessions of RAGT (45 min each) within 4 weeks followed by 16 sessions of strength training (45 min each) within 4 weeks. Group 2 received the same interventions in reversed order. Main outcome measures were the 10 m Walk Test (10MWT) at preferred and maximal speed. Furthermore, we assessed several measures such as walking speed under different conditions, balance, strength, and 2 questionnaires that evaluate risk of falling and pain. Data were collected at baseline, between interventions after 4 weeks, directly after the interventions and at follow-up 6 months after the interventions. Pain was assessed repeatedly throughout the study. RESULTS: There were no significant differences in changes in scores between the 2 interventions, except for maximal walking speed (10MWT), which improved significantly more after strength training than after RAGT. Pain reduced after both interventions. CONCLUSION: In patients with chronic iSCI dependent on walking assistance, RAGT was not more effective in improving walking-related outcome compared to lower extremity strength training. However, the low sample size limits generalizability and precision of data interpretation. TRIAL REGISTRATION: This study was registered at Clinicaltrials.gov (NCT01087918). PMID- 24401144 TI - Acid evoked thermal hyperalgesia involves peripheral P2Y1 receptor mediated TRPV1 phosphorylation in a rodent model of thrombus induced ischemic pain. AB - BACKGROUND: We previously developed a thrombus-induced ischemic pain (TIIP) animal model, which was characterized by chronic bilateral mechanical allodynia without thermal hyperalgesia (TH). On the other hand we had shown that intraplantar injection of acidic saline facilitated ATP-induced pain, which did result in the induction of TH in normal rats. Because acidic pH and increased ATP are closely associated with ischemic conditions, this study is designed to: (1) examine whether acidic saline injection into the hind paw causes the development of TH in TIIP, but not control, animals; and (2) determine which peripheral mechanisms are involved in the development of this TH. RESULTS: Repeated intraplantar injection of pH 4.0 saline, but not pH 5.5 and 7.0 saline, for 3 days following TIIP surgery resulted in the development of TH. After pH 4.0 saline injections, protein levels of hypoxia inducible factor-1alpha (HIF-1alpha) and carbonic anhydrase II (CA II) were elevated in the plantar muscle indicating that acidic stimulation intensified ischemic insults with decreased tissue acidity. At the same time point, there were no changes in the expression of TRPV1 in hind paw skin, whereas a significant increase in TRPV1 phosphorylation (pTRPV1) was shown in acidic saline (pH 4.0) injected TIIP (AS-TIIP) animals. Moreover, intraplantar injection of chelerythrine (a PKC inhibitor) and AMG9810 (a TRPV1 antagonist) effectively alleviated the established TH. In order to investigate which proton- or ATP-sensing receptors contributed to the development of TH, amiloride (an ASICs blocker), AMG9810, TNP-ATP (a P2Xs antagonist) or MRS2179 (a P2Y1 antagonist) were pre-injected before the pH 4.0 saline. Only MRS2179 significantly prevented the induction of TH, and the increased pTRPV1 ratio was also blocked in MRS2179 injected animals. CONCLUSION: Collectively these data show that maintenance of an acidic environment in the ischemic hind paw of TIIP rats results in the phosphorylation of TRPV1 receptors via a PKC dependent pathway, which leads to the development of TH mimicking what occurs in chronic ischemic patients with severe acidosis. More importantly, peripheral P2Y1 receptors play a pivotal role in this process, suggesting a novel peripheral mechanism underlying the development of TH in these patients. PMID- 24401145 TI - Unveiling the membrane-binding properties of N-terminal and C-terminal regions of G protein-coupled receptor kinase 5 by combined optical spectroscopies. AB - G protein-coupled receptor kinase 5 (GRK5) is thought to associate with membranes in part via N- and C-terminal segments that are typically disordered in available high-resolution crystal structures. Herein we investigate the interactions of these regions with model cell membrane using combined sum frequency generation (SFG) vibrational spectroscopy and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. It was found that both regions associate with POPC lipid bilayers but adopt different structures when doing so: GRK5 residues 2 31 (GRK5(2-31)) was in random coil whereas GRK5(546-565) was partially helical. When the subphase for the GRK5(2-31) peptide was changed to 40% TFE/60% 10 mM phosphate pH 7.4 buffer, a large change in the SFG amide I signal indicated that GRK5(2-31) became partially helical. By inspecting the membrane behavior of two different segments of GRK5(2-31), namely, GRK5(2-24) and GRK5(25-31), we found that residues 25-31 are responsible for membrane binding, whereas the helical character is imparted by residues 2-24. With SFG, we deduced that the orientation angle of the helical segment of GRK5(2-31) is 46 +/- 1 degrees relative to the surface normal in 40% TFE/60% 10 mM phosphate pH = 7.4 buffer but increases to 78 +/- 11 degrees with higher ionic strength. We also investigated the effect of PIP2 in the model membrane and concluded that the POPC:PIP2 (9:1) lipid bilayer did not change the behavior of either peptide compared to a pure POPC lipid bilayer. With ATR-FTIR, we also found that Ca(2+).calmodulin is able to extract both peptides from the POPC lipid bilayer, consistent with the role of this protein in disrupting GRK5 interactions with the plasma membrane in cells. PMID- 24401146 TI - Soluble gamma-secretase modulators selectively inhibit the production of the 42 amino acid amyloid beta peptide variant and augment the production of multiple carboxy-truncated amyloid beta species. AB - Alzheimer's disease (AD) is characterized pathologically by an abundance of extracellular neuritic plaques composed primarily of the 42-amino acid amyloid beta peptide variant (Abeta42). In the majority of familial AD (FAD) cases, e.g., those harboring mutations in presenilin 1 (PS1), there is a relative increase in the levels of Abeta42 compared to the levels of Abeta40. We previously reported the characterization of a series of aminothiazole-bridged aromates termed aryl aminothiazole gamma-secretase modulators or AGSMs [Kounnas, M. Z., et al. (2010) Neuron 67, 769-780] and showed their potential for use in the treatment of FAD [Wagner, S. L., et al. (2012) Arch. Neurol. 69, 1255-1258]. Here we describe a series of GSMs with physicochemical properties improved compared to those of AGSMs. Specific heterocycle replacements of the phenyl rings in AGSMs provided potent molecules with improved aqueous solubilities. A number of these soluble gamma-secretase modulators (SGSMs) potently lowered Abeta42 levels without inhibiting proteolysis of Notch or causing accumulation of amyloid precursor protein carboxy-terminal fragments, even at concentrations approximately 1000 fold greater than their IC50 values for reducing Abeta42 levels. The effects of one potent SGSM on Abeta peptide production were verified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, showing enhanced production of a number of carboxy-truncated Abeta species. This SGSM also inhibited Abeta42 peptide production in a highly purified reconstituted gamma secretase in vitro assay system and retained the ability to modulate gamma secretase-mediated proteolysis in a stably transfected cell culture model overexpressing a human PS1 mutation validating the potential for use in FAD. PMID- 24401147 TI - Tailoring of alginate-gelatin microspheres properties for oral Ciprofloxacin controlled release against Pseudomonas aeruginosa. AB - CONTEXT: Ciprofloxacin (Cip) is a broad spectrum antibiotic frequently used in the treatment of infectious diseases caused by Pseudomonas aeruginosa. Cip oral administration is commonly associated with poor drug biodisponibility, gastrointestinal tract irritation, and toxic undesirable side effects. OBJECTIVE: The aim of this work is to provide an oral biopolymeric system for controlled release of Cip. MATERIALS AND METHODS: Alginate-gelatin blend microspheres were crosslinked in the presence of 1,2-propylene glycol, calcium, and glutaraldehyde. Studies of Cip encapsulation and release were performed. Matrix characteristics were studied simultaneously by optical microscopy and Fourier transform infrared spectroscopy (FTIR) using synchrotron light, and by texturometric analysis. Microsphere surface topologies were observed by scanning electron microscopy (SEM), atomic force microscopy (AFM), and epifluorescence microscopy. RESULTS: Microspheres crosslinked with glutaraldehyde showed about 80% Cip encapsulation and less than 10% Cip release under simulated gastric conditions in 15 min, while a controlled release profile was observed at intestinal environment conditions. Antimicrobial activity against P. aeruginosa showed an increasing bacterial growth inhibition in time. Finally, bovine serum albumin (BSA) was used as model protein for binding of macromolecules onto active surface of microspheres, with a consequently modulation of Cip release. DISCUSSION AND CONCLUSIONS: The results are indicating that alginate/gelatin matrix crosslinked via Ca(2+) and glutaraldehyde can be tailored by decorating the microsphere surface with biological active molecules useful for targeting, making a potential tool to improve Cip oral administration for infection diseases. PMID- 24401148 TI - Preparation and characterization of poly (ethersulfone) nanofiltration membranes for amoxicillin removal from contaminated water. AB - Nowadays, antibiotics such as amoxicillin have been entered in water bodies. Nanofiltration has been proposed as an attractive technology for removal of antibiotics from aquatic environment instead of conventional wastewater treatment. In this paper, novel asymmetric flat sheet nanofiltration membranes were prepared via immersion precipitation technique and by using the poly(ethersulfone)/Brij(r)S100/Poly(vinylpirrolidone)/1-methyl-2-pyrolidone casting solutions. The effect of addition of Brij(r)S100 as a non-ionic surfactant additive as well as concentration of poly (ethersulfone) on morphology, wettability, pure water flux and rejection of amoxicillin were studied using the scanning electron microscopy, water contact angle apparatus and experimental set-up. The results indicated that the addition of Brij(r)S100 to the casting solutions resulted in the formation of membranes with higher hydrophilicity and relatively noticeable rejection of amoxicillin up to 99% in comparison with unmodified poly(ethersulfone) membrane. Contrary to amoxicillin rejection, pure water flux was decreased when higher poly(ethersulfone) concentration was employed. PMID- 24401149 TI - Nonnuclear nearly free electron conduction channels induced by doping charge in nanotube-molecular sheet composites. AB - Nearly free electron (NFE) states with density maxima in nonnuclear (NN) voids may have remarkable electron transport properties ranging from suppressed electron-phonon interaction to Wigner crystallization. Such NFE states, however, usually exist near the vacuum level, which makes them unsuitable for transport. Through first principles calculations on nanocomposites consisting of carbon nanotube (CNT) arrays sandwiched between boron nitride (BN) sheets, we describe a stratagem for stabilizing the NN-NFE states to below the Fermi level. By doping the CNTs with negative charge, we establish Coulomb barriers at CNTs walls that, together with the insulating BN sheets, define the transverse potentials of one dimensional (1D) transport channels, which support the NN-NFE states. PMID- 24401150 TI - Quantification of pulmonary inflammation after segmental allergen challenge using turbo-inversion recovery-magnitude magnetic resonance imaging. AB - RATIONALE: There is a need to develop novel noninvasive imaging biomarkers that help to evaluate antiinflammatory asthma treatments. OBJECTIVES: To investigate whether the extent of the segmental lung edema measured noninvasively using turbo inversion recovery-magnitude magnetic resonance imaging (TIRM MRI) corresponds to the severity of the regional allergic reaction determined by the percentage of eosinophils in bronchoalveolar lavage fluid (BAL) 24 hours after segmental allergen challenge in patients with asthma compared with normal control subjects. METHODS: Eleven volunteers with allergic asthma and five healthy volunteers underwent segmental challenges with different allergen doses by two bronchoscopies 24 hours apart. They had lung MRI at baseline and 6 and 24 hours after segmental challenge. MRI TIRM scores were correlated with the eosinophilic response at 24 hours. MEASUREMENTS AND MAIN RESULTS: In patients with asthma, there were significant differences of eosinophil percentages in BAL at 24 hours from segments given standard-dose, low-dose, or no allergen (saline) (P < 0.001). Correspondingly significant differences between the TIRM score in allergen standard-dose, low-dose, and saline-treated segments were observed at 24 hours post-challenge (P < 0.001). With increasing TIRM score at 24 hours the percent eosinophils per segment 24 hours post-challenge also increased accordingly (P < 0.001). There was interobserver agreement for TIRM score grading (kappa = 0.72 for 24-h time point). CONCLUSIONS: The MRI-based noninvasive TIRM score is a promising biomarker for the noninvasive detection of the inflammatory response after segmental allergen challenge in patients with asthma and may serve to monitor the therapeutic effectiveness of novel antiinflammatory drugs in future human trials. PMID- 24401151 TI - When pain memories are lost: a pilot study of semantic knowledge of pain in dementia. AB - OBJECTIVE: It has been documented that pain in people with dementia is often under-reported and poorly detected. The reasons for this are not clearly defined. This project aimed to explore semantic concepts of pain in people with dementia and whether this is associated with clinical pain report. DESIGN: Cohort study with nested cross-sectional analysis. SETTING: Acute general hospital medical wards for older people. SUBJECTS: People with dementia (N = 26) and control participants (N = 13). METHODS: Two subtests of semantic memory for pain: (1) Identifying painful situations from a standardized range of pictures; (2) Describing the concept of pain. Participants also indicated whether they were in pain or not, were observed for pain (PAINAD scale) and completed the Wong-Baker FACES scale to indicate pain severity. RESULTS: Compared with the control group, people with dementia were less able to identify painful situations and used fewer categories to define their concept of pain. In turn, the performance on these two measures was related to the reported presence and, albeit less strongly, to the reported severity of pain, indicating that a reduction in semantic memory for pain is associated with a decline in reported pain. CONCLUSIONS: This study is the first to show that semantic memory for pain is diminished in dementia patients. When using clinical pain tools, clinicians should consider these effects which may bias clinical pain ratings when they evaluate and manage pain in these patients. This might improve the recognition and management of pain in people with dementia. PMID- 24401152 TI - The expression and comparison of healthy and ptotic upper eyelid contours using a polynomial mathematical function. AB - PURPOSE: To derive a mathematical expression for the healthy upper eyelid (UE) contour and to use this expression to differentiate the normal UE curve from its abnormal configuration in the setting of blepharoptosis. METHODS: The study was designed as a cross-sectional study. Fifty healthy subjects (26M/24F) and 50 patients with blepharoptosis (28M/22F) with a margin-reflex distance (MRD1) of <=2.5 mm were recruited. A polynomial interpolation was used to approximate UE curve. The polynomial coefficients were calculated from digital eyelid images of all participants using a set of operator defined points along the UE curve. Coefficients up to the fourth-order polynomial, iris area covered by the UE, iris area covered by the lower eyelid and total iris area covered by both the upper and the lower eyelids were defined using the polynomial function and used in statistical comparisons. The t-test, Mann-Whitney U test and the Spearman's correlation test were used for statistical comparisons. RESULTS: The mathematical expression derived from the data of 50 healthy subjects aged 24.1 +/- 2.6 years was defined as y = 22.0915 + (-1.3213)x + 0.0318x(2 )+ (-0.0005x)(3). The fifth and the consecutive coefficients were <0.00001 in all cases and were not included in the polynomial function. None of the first fourth-order coefficients of the equation were found to be significantly different in male versus female subjects. In normal subjects, the percentage of the iris area covered by upper and lower lids was 6.46 +/- 5.17% and 0.66% +/- 1.62%, respectively. All coefficients and mean iris area covered by the UE were significantly different between healthy and ptotic eyelids. CONCLUSIONS: The healthy and abnormal eyelid contour can be defined and differentiated using a polynomial mathematical function. PMID- 24401153 TI - Genetic diversity of Plasmodium vivax population in Anhui province of China. AB - BACKGROUND: Although the numbers of malaria cases in China have been declining in recent years, outbreaks of Plasmodium vivax malaria were still being reported in rural areas south of the Yellow River. To better understand the transmission dynamics of P. vivax parasites in China, the extent of genetic diversity of P. vivax populations circulating in Bozhou of Anhui province of China were investigated using three polymorphic genetic markers: merozoite surface proteins 1 and 3alpha (pvmsp-1 and pvmsp-3alpha) and circumsporozoite protein (pvcsp). METHODS: Forty-five P. vivax clinical isolates from Bouzhou of Anhui province were collected from 2009 to 2010 and were analysed using PCR/RFLP or DNA sequencing. RESULTS: Seven and six distinct allelic variants were identified using PCR/RFLP analysis of pvmsp-3alpha with HhaI and AluI, respectively. DNA sequence analysis of pvmsp-1 (variable block 5) revealed that there were Sal-I and recombinant types but not Belem type, and seven distinct allelic variants in pvmsp-1 were detected, with recombinant subtype 2 (R2) being predominant (66.7%). All the isolates carried pvcsp with VK210 type but not VK247 or P. vivax-like types in the samples. Sequence analysis of pvcsp gene revealed 12 distinct allelic variants, with VK210-1 being predominant (41.5%). CONCLUSIONS: The present data indicate that there is some degree of genetic diversity among P. vivax populations in Anhui province of China. The genetic data obtained may assist in the surveillance of P. vivax infection in endemic areas or in tracking potential future disease outbreak. PMID- 24401154 TI - Sensitization of hepatocellular carcinoma cells to Apo2L/TRAIL by a novel Akt/NF kappaB signalling inhibitor. AB - Hepatocellular carcinoma (HCC) cells are intrinsically resistant to tumour necrosis factor-related apoptosis ligand (Apo2L/TRAIL), in part, due to the compensatory activation of nuclear factor-kappaB (NF-kappaB). To broaden the clinical utilization of Apo2L/TRAIL in HCC, OSU-A9, a potent indole-3-carbinol derived Akt/NF-kappaB signalling inhibitor was used to overcome the intrinsic resistance. The antitumour effects of OSU-A9, Apo2L/TRAIL and the therapeutic combination were assessed by MTT assay, caspase activation and PARP cleavage, and the synergistic interactions were determined by Calcusyn analysis. NF-kappaB reporter gene and RT-PCR were tested for the activation of NF-kappaB and the expression of death receptors (DR)4 and 5. OSU-A9 could sensitize HCC cells to Apo2L/TRAIL with high potency through down-regulation of Akt/NF-kappaB signalling. OSU-A9 dose-dependently reduced Akt phosphorylation and the expression and nuclear localization of RelA/p65, accompanied by parallel decreases in the expression of NF-kappaB target products, including Bcl-xL, Mcl 1, cIAP1, cIAP2 and survivin. Moreover, OSU-A9 increased DR5 expression through a reactive oxygen species (ROS)-dependent mechanism. Concertedly, these mechanisms underlie the synergistic interaction between OSU-A9 and Apo2L/TRAIL in mediating apoptotic death in HCC cells. The ability of OSU-A9 to accentuate Apo2L/TRAIL induced apoptosis by inactivating Akt/NF-kappaB signalling might foster a promising therapeutic strategy for HCC. PMID- 24401155 TI - Epidemiology of emergency medical service responses to older people who have fallen: a prospective cohort study. AB - OBJECTIVES: To describe the characteristics of older people who fall and call an emergency ambulance, and the operational and clinical impact of the ambulance responses they receive. METHODS: A prospective cohort study of people aged >=65 who had fallen and called for an ambulance was conducted between October 1, 2010 and June 30, 2011. Fall-related data were collected using a project-specific data collection tool. These data were then linked to routinely collected ambulance service clinical records and dispatch data, providing a sequential description of fall-related cases from time of ambulance dispatch through to the end of the prehospital episode of care. RESULTS: There were 1,610 cases eligible for analysis. The median response time was 15 minutes (IQR 10-24) and "long-lies" (>60 minutes on the ground) occurred in 13% of cases. Patients were predominantly female (61%) and community dwelling (82%). Forty-four percent had never previously called an ambulance for a fall, whereas 248 (15%) had called within the past month. The most common patient-reported reasons for falling were loss of balance (30%) and "simple trips" (25%). New injury and/or pain was documented for 1,172 (73%) of patients, and 656 (41%) presented with "abnormal" physiology; only 238 (15%) presented with no new injury/pain and normal physiology. The nontransport rate was 28%. CONCLUSION: In this population, ambulance services appear to provide timely responses to older people who have fallen, and "long lies" are relatively uncommon. More than one-quarter of patients were not transported to an emergency department, and repeat use of ambulance resources appears to be common. Opportunities exist to explore alternate pathways and models of care that maximize outcomes for nontransport patients as well as improving operational efficiency of the ambulance service. PMID- 24401157 TI - Molecular screening and predation evaluation of the key predators of Conopomorpha sinensis Bradley (Lepidoptera: Gracilariidae) in litchi orchards. AB - Conopomorpha sinensis Bradley (Lepidoptera: Gracilariidae) is one of the major fruit borer pests of litchi and longan in Southern China. Although chemical control is effective, alternative, biorational strategies are preferable, and should be developed. Predators play an important role in the biological control of agricultural pests, but an accurate method for the evaluation of predation in agriculture has not yet been developed. Here, we report a new, specific primer pair to amplify a C. sinensis cytochrome c oxidase subunit I (COI) sequence fragment that can be used to detect consumption of C. sinensis by its predators. C. sinensis DNA was found in several arthropods collected in the field, including the important C. sinensis predators M enochilus sexmaculata (Coccinellidae), Leucauge magnifica (Tetragnathidae), Propylea japonica (Coccinellidae), and Oxyopes sertatus (Oxyopidae). The detection rates of C. sinensis COI DNA in these predators were 39.3, 36.4, 27.3, and 27.2%, respectively. Laboratory consumption and hunting capacity analysis of M. sexmaculata and P. japonica adults indicated that they exhibit a Holling type II functional response on C. sinensis eggs under field temperatures. A polymerase chain reaction digestion analysis of M. sexmaculata and P. japonica adults after consumption of a single C. sinensis egg indicated that positive detection decreased with the extension of digestion time, and estimated prey DNA half-lives were 16.3 h in M. sexmaculata and 6.0 h in P. japonica. These data serve to characterize two major predators of C. sinensis with potential for biological control of C. sinensis in litchi orchards. PMID- 24401158 TI - A porphyrin-based molecular tweezer: guest-induced switching of forward and backward photoinduced energy transfer. AB - A bisindole-bridged-porphyrin tweezer (1), a pair of zinc porphyrins (PZn's) connected to bisindole bridge (BB) via the Cu(I)-mediated alkyne-azide click chemistry, exhibited unique switching in forward and backward photoinduced energy transfer by specific guest bindings. The addition of Cu(2+) caused a change in electronic absorption and fluorescence quenching of 1. MALDI-TOF-MS and FT-IR analyses indicated the formation of stable coordination complex between 1 and Cu(2+) (1-Cu(II)). Without Cu(2+) coordination, the excitation energy flows from BB to PZn's with significantly high energy transfer efficiency. In contrast, the direction of energy flow in 1 was completely reversed by the coordination of Cu(2+). The difference in fluorescence quantum yield between 1 and 1-Cu(II) indicates that more than 95% of excitation energy of PZn flows into Cu(II) coordinated BB. The energy transfer efficiency was further controlled by bidentate ligand coordination onto 1-Cu(II). When pyrophosphate ion was added to 1-Cu(II), the recovery of fluorescence emission from PZn was observed. The quantum mechanical calculations indicated that the Cu(II)-coordinated BB has square planar geometry, which can be distorted to form octahedral geometry due to the coordination of bidentate ligands. PMID- 24401159 TI - The early use of botulinum toxin in post-stroke spasticity: study protocol for a randomised controlled trial. AB - BACKGROUND: Patients surviving stroke but who have significant impairment of function in the affected arm are at more risk of developing pain, stiffness and contractures. The abnormal muscle activity, associated with post-stroke spasticity, is thought to be causally associated with the development of these complications. Treatment of spasticity is currently delayed until a patient develops signs of these complications. METHODS/DESIGN: This protocol is for a phase II study that aims to identify whether using OnabotulinumtoxinA (BoNT-A) in combination with physiotherapy early post stroke when initial abnormal muscle activity is neurophysiologically identified can prevent loss of range at joints and improve functional outcomes.The trial uses a screening phase to identify which people are appropriate to be included in a double blind randomised placebo controlled trial. All patients admitted to Sandwell and West Birmingham NHS Trust Hospitals with a diagnosis of stroke will be screened to identify functional activity in the arm. Those who have no function will be appropriate for further screening. Patients who are screened and have abnormal muscle activity identified on EMG will be given electrical stimulation to forearm extensors for 3 months and randomised to have either injections of BoNT-A or normal saline. The primary outcome measure is the action research arm test - a measure of arm function. Further measures include spasticity, stiffness, muscle strength and fatigue as well as measures of quality of life, participation and caregiver strain. TRIAL REGISTRATIONS: ISRCTN57435427, EudraCT2010-021257-39, NCT01882556. PMID- 24401160 TI - Phylogenetic distribution and evolutionary dynamics of the sex determination genes doublesex and transformer in insects. AB - Sex determination in insects is characterized by a gene cascade that is conserved at the bottom but contains diverse primary signals at the top. The bottom master switch gene doublesex is found in all insects. Its upstream regulator transformer is present in the orders Hymenoptera, Coleoptera and Diptera, but has thus far not been found in Lepidoptera and in the basal lineages of Diptera. transformer is presumed to be ancestral to the holometabolous insects based on its shared domains and conserved features of autoregulation and sex-specific splicing. We interpret that its absence in basal lineages of Diptera and its order-specific conserved domains indicate multiple independent losses or recruitments into the sex determination cascade. Duplications of transformer are found in derived families within the Hymenoptera, characterized by their complementary sex determination mechanism. As duplications are not found in any other insect order, they appear linked to the haplodiploid reproduction of the Hymenoptera. Further phylogenetic analyses combined with functional studies are needed to understand the evolutionary history of the transformer gene among insects. PMID- 24401161 TI - Biobutanol production in a Clostridium acetobutylicum biofilm reactor integrated with simultaneous product recovery by adsorption. AB - BACKGROUND: Clostridium acetobutylicum can propagate on fibrous matrices and form biofilms that have improved butanol tolerance and a high fermentation rate and can be repeatedly used. Previously, a novel macroporous resin, KA-I, was synthesized in our laboratory and was demonstrated to be a good adsorbent with high selectivity and capacity for butanol recovery from a model solution. Based on these results, we aimed to develop a process integrating a biofilm reactor with simultaneous product recovery using the KA-I resin to maximize the production efficiency of biobutanol. RESULTS: KA-I showed great affinity for butanol and butyrate and could selectively enhance acetoin production at the expense of acetone during the fermentation. The biofilm reactor exhibited high productivity with considerably low broth turbidity during repeated batch fermentations. By maintaining the butanol level above 6.5 g/L in the biofilm reactor, butyrate adsorption by the KA-I resin was effectively reduced. Co adsorption of acetone by the resin improved the fermentation performance. By redox modulation with methyl viologen (MV), the butanol-acetone ratio and the total product yield increased. An equivalent solvent titer of 96.5 to 130.7 g/L was achieved with a productivity of 1.0 to 1.5 g . L-1 . h-1. The solvent concentration and productivity increased by 4 to 6-fold and 3 to 5-fold, respectively, compared to traditional batch fermentation using planktonic culture. CONCLUSIONS: Compared to the conventional process, the integrated process dramatically improved the productivity and reduced the energy consumption as well as water usage in biobutanol production. While genetic engineering focuses on strain improvement to enhance butanol production, process development can fully exploit the productivity of a strain and maximize the production efficiency. PMID- 24401162 TI - Draft genomes of three Antarctic Psychrobacter strains producing antimicrobial compounds against Burkholderia cepacia complex, opportunistic human pathogens. AB - Herein we present the draft genomes of three Psychrobacter strains isolated from Antarctic sponges and able to inhibit the growth of bacteria belonging to the Burkholderia cepacia complex, responsible for infections of the respiratory system in patients affected by Cystic Fibrosis. The comparative analysis of the annotated genomes of these Psychrobacter strains highlighted their differences in terms of overall genomic content (e.g. shared gene sets) and allowed the identification of gene clusters hypothetically involved in the biosynthesis of antimicrobial compounds. PMID- 24401163 TI - Lung ultrasound in the critically ill. AB - Lung ultrasound is a basic application of critical ultrasound, defined as a loop associating urgent diagnoses with immediate therapeutic decisions. It requires the mastery of ten signs: the bat sign (pleural line), lung sliding (yielding seashore sign), the A-line (horizontal artifact), the quad sign, and sinusoid sign indicating pleural effusion, the fractal, and tissue-like sign indicating lung consolidation, the B-line, and lung rockets indicating interstitial syndrome, abolished lung sliding with the stratosphere sign suggesting pneumothorax, and the lung point indicating pneumothorax. Two more signs, the lung pulse and the dynamic air bronchogram, are used to distinguish atelectasis from pneumonia. All of these disorders were assessed using CT as the "gold standard" with sensitivity and specificity ranging from 90% to 100%, allowing ultrasound to be considered as a reasonable bedside "gold standard" in the critically ill. The BLUE-protocol is a fast protocol (<3 minutes), which allows diagnosis of acute respiratory failure. It includes a venous analysis done in appropriate cases. Pulmonary edema, pulmonary embolism, pneumonia, chronic obstructive pulmonary disease, asthma, and pneumothorax yield specific profiles. Pulmonary edema, e.g., yields anterior lung rockets associated with lung sliding, making the "B-profile." The FALLS-protocol adapts the BLUE-protocol to acute circulatory failure. It makes sequential search for obstructive, cardiogenic, hypovolemic, and distributive shock using simple real-time echocardiography (right ventricle dilatation, pericardial effusion), then lung ultrasound for assessing a direct parameter of clinical volemia: the apparition of B-lines, schematically, is considered as the endpoint for fluid therapy. Other aims of lung ultrasound are decreasing medical irradiation: the LUCIFLR program (most CTs in ARDS or trauma can be postponed), a use in traumatology, intensive care unit, neonates (the signs are the same than in adults), many disciplines (pulmonology, cardiology...), austere countries, and a help in any procedure (thoracentesis). A 1992, cost-effective gray-scale unit, without Doppler, and a microconvex probe are efficient. Lung ultrasound is a holistic discipline for many reasons (e.g., one probe, perfect for the lung, is able to scan the whole-body). Its integration can provide a new definition of priorities. The BLUE-protocol and FALLS-protocol allow simplification of expert echocardiography, a clear advantage when correct cardiac windows are missing. PMID- 24401164 TI - Blood markers of coagulation, fibrinolysis, endothelial dysfunction and inflammation in lacunar stroke versus non-lacunar stroke and non-stroke: systematic review and meta-analysis. AB - BACKGROUND: The cause of cerebral small vessel disease is not fully understood, yet it is important, accounting for about 25% of all strokes. It also increases the risk of having another stroke and contributes to about 40% of dementias. Various processes have been implicated, including microatheroma, endothelial dysfunction and inflammation. A previous review investigated endothelial dysfunction in lacunar stroke versus mostly non-stroke controls while another looked at markers of inflammation and endothelial damage in ischaemic stroke in general. We have focused on blood markers between clinically evident lacunar stroke and other subtypes of ischaemic stroke, thereby controlling for stroke in general. SUMMARY: We systematically assessed the literature for studies comparing blood markers of coagulation, fibrinolysis, endothelial dysfunction and inflammation in lacunar stroke versus non-stroke controls or other ischaemic stroke subtypes. We assessed the quality of included papers and meta-analysed results. We split the analysis on time of blood draw in relation to the stroke. We identified 1,468 full papers of which 42 were eligible for inclusion, including 4,816 ischaemic strokes, of which 2,196 were lacunar and 2,500 non stroke controls. Most studies subtyped stroke using TOAST. The definition of lacunar stroke varied between studies. Markers of coagulation/fibrinolysis (tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI), fibrinogen, D-dimer) were higher in lacunar stroke versus non-stroke although fibrinogen was no different to non-stroke in the acute phase. tPA and PAI were no different between lacunar and non-lacunar stroke. Fibrinogen and D-dimer were significantly lower in lacunar stroke compared to other ischaemic strokes, both acutely and chronically. Markers of endothelial dysfunction (homocysteine, von Willebrand Factor (vWF), E-selectin, P-selectin, intercellular adhesion molecule 1 (ICAM), vascular cellular adhesion molecule-1 (VCAM)) were higher or had insufficient or conflicting data (P-selectin, VCAM) in lacunar stroke versus non stroke. Compared to other ischaemic stroke subtypes, homocysteine did not differ in lacunar stroke while vWF was significantly lower in lacunar stroke acutely [atherothrombotic standardized mean difference, SMD, -0.34 (-0.61, -0.08); cardioembolic SMD -0.38 (-0.62, -0.14)], with insufficient data chronically. Markers of inflammation (C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6)) were higher in lacunar stroke versus non stroke, although there were no studies measuring TNF-alpha chronically and the sole study measuring IL-6 chronically showed no difference between lacunar stroke and non-stroke. Compared to other ischaemic stroke subtypes, there was no difference (CRP) or insufficient or conflicting data (TNF-alpha) to lacunar stroke. IL-6 was significantly lower [atherothrombotic SMD -0.37 (-0.63, -0.10); cardioembolic SMD -0.52 (-0.82, -0.22)] in lacunar stroke acutely, with insufficient data chronically. KEY MESSAGES: Lacunar stroke is an important stroke subtype. More studies comparing lacunar stroke to non-lacunar stroke specifically, rather than to non-stroke controls, are needed. Prospective studies with measurements taken well after the acute event are more likely to be helpful in determining pathogenesis. The available data in this review were limited and do not exclude the possibility that peripheral inflammatory processes including endothelial dysfunction are associated with lacunar stroke and cerebral small vessel disease. PMID- 24401165 TI - Corrosion casting of the subglottis following endotracheal tube intubation injury: a pilot study in Yorkshire piglets. AB - PURPOSE: Subglottic stenosis can result from endotracheal tube injury. The mechanism by which this occurs, however, is not well understood. The purpose of this study was to examine the role of angiogenesis, hypoxia and ischemia in subglottic mucosal injury following endotracheal intubation. METHODS: Six Yorkshire piglets were randomized to either a control group (N=3, ventilated through laryngeal mask airway for corrosion casting) or accelerated subglottic injury group through intubation and induced hypoxia as per a previously described model (N=3). The vasculature of all animals was injected with liquid methyl methacrylate. After polymerization, the surrounding tissue was corroded with potassium hydroxide. The subglottic region was evaluated using scanning electron microscopy looking for angiogenic and hypoxic or degenerative features and groups were compared using Mann-Whitney tests and Friedman's 2-way ANOVA. RESULTS: Animals in the accelerated subglottic injury group had less overall angiogenic features (P=.002) and more overall hypoxic/degenerative features (P=.000) compared with controls. Amongst angiogenic features, there was decreased budding (P=.000) and a trend toward decreased sprouting (P=.037) in the accelerated subglottic injury group with an increase in intussusception (P=.004), possibly representing early attempts at rapid revascularization. Amongst hypoxic/degenerative features, extravasation was the only feature that was significantly higher in the accelerated subglottic injury group (P=.000). CONCLUSIONS: Subglottic injury due to intubation and hypoxia may lead to decreased angiogenesis and increased blood vessel damage resulting in extravasation of fluid and a decreased propensity toward wound healing in this animal model. PMID- 24401166 TI - Diagnostic yield and safety of electromagnetic navigation bronchoscopy for lung nodules: a systematic review and meta-analysis. AB - BACKGROUND: Electromagnetic navigation bronchoscopy (ENB) is an emerging endoscopic technique for the diagnosis of peripheral lung lesions. A thorough analysis of ENB's yield and safety is required for comparison to other sampling modalities. OBJECTIVES: To describe ENB's yield and safety profile. METHODS: The MEDLINE and EMBASE databases were systematically searched for studies reporting ENB's yield for peripheral lung lesions. Two independent investigators extracted data and rated each study on a scale of methodological quality. Clearly defined performance outcomes were reconstructed and meta-analyzed. Subgroup analysis and meta-regression were used to identify possible sources of study heterogeneity. RESULTS: A total of 15 trials were included (1,033 lung nodules). A positive and definitive diagnosis was obtained after 64.9% of all ENB procedures (95% CI 59.2 70.3). Overall diagnostic accuracy was 73.9% (95% CI 68.0-79.2). Sensitivity to detect cancer was 71.1% (95% CI 64.6-76.8), with a negative predictive value of 52.1% (95% CI 43.5-60.6). Pneumothorax occurred in 3.1% of patients, requiring chest tube drainage in 1.6% of these cases. Original trials identified 6 variables associated with higher ENB yields: nodule location in the upper or middle lobes, nodule size, lower registration error, presence of a bronchus sign on CT imaging, combined use of an ultrasonic radial probe, and catheter suctioning as a sampling technique. Heterogeneity exploration revealed that studies using general anesthesia or rapid on-site cytological evaluation reported better yields. CONCLUSIONS: ENB is effective and particularly safe. Prospective studies are needed to clarify the role of several variables conditioning the yield of this technique. PMID- 24401167 TI - Creation and Delphi-method refinement of pediatric disaster triage simulations. AB - OBJECTIVE: There is a need for rigorously designed pediatric disaster triage (PDT) training simulations for paramedics. First, we sought to design three multiple patient incidents for EMS provider training simulations. Our second objective was to determine the appropriate interventions and triage level for each victim in each of the simulations and develop evaluation instruments for each simulation. The final objective was to ensure that each simulation and evaluation tool was free of bias toward any specific PDT strategy. METHODS: We created mixed-methods disaster simulation scenarios with pediatric victims: a school shooting, a school bus crash, and a multiple-victim house fire. Standardized patients, high-fidelity manikins, and low-fidelity manikins were used to portray the victims. Each simulation had similar acuity of injuries and 10 victims. Examples include children with special health-care needs, gunshot wounds, and smoke inhalation. Checklist-based evaluation tools and behaviorally anchored global assessments of function were created for each simulation. Eight physicians and paramedics from areas with differing PDT strategies were recruited as Subject Matter Experts (SMEs) for a modified Delphi iterative critique of the simulations and evaluation tools. The modified Delphi was managed with an online survey tool. The SMEs provided an expected triage category for each patient. The target for modified Delphi consensus was >=85%. Using Likert scales and free text, the SMEs assessed the validity of the simulations, including instances of bias toward a specific PDT strategy, clarity of learning objectives, and the correlation of the evaluation tools to the learning objectives and scenarios. RESULTS: After two rounds of the modified Delphi, consensus for expected triage level was >85% for 28 of 30 victims, with the remaining two achieving >85% consensus after three Delphi iterations. To achieve consensus, we amended 11 instances of bias toward a specific PDT strategy and corrected 10 instances of noncorrelation between evaluations and simulation. CONCLUSIONS: The modified Delphi process, used to derive novel PDT simulation and evaluation tools, yielded a high degree of consensus among the SMEs, and eliminated biases toward specific PDT strategies in the evaluations. The simulations and evaluation tools may now be tested for reliability and validity as part of a prehospital PDT curriculum. PMID- 24401169 TI - Nanoemulsion of eucalyptus oil and its larvicidal activity against Culex quinquefasciatus. AB - Filariasis is a mosquito-borne disease that causes lymphedema and the main vector is Culex quinquefasciatus. A simple measure was taken to eradicate the vector using nanoemulsion. Eucalyptus oil nanoemulsion was formulated in various ratios comprising of eucalyptus oil, tween 80 and water by ultrasonication. The stability of nanoemulsion was observed over a period of time and 1:2 ratios of eucalyptus oil (6%) and surfactant (12%) was found to be stable. The formulated eucalyptus oil nanoemulsion was characterized by transmission electron microscopy and dynamic light scattering. The nanoemulsion droplets were found to have a Z average diameter of 9.4 nm and were spherical in shape. The larvicidal activity of eucalyptus oil nanoemulsion and bulk emulsion was tested and compared. Our nanoemulsion showed higher activity when compared to bulk emulsion. The histopathology of larvae-treated and untreated nanoemulsion was analyzed. Furthermore, biochemical assays were carried out to examine the effect of nanoemulsion on biochemical characteristics of larvae. The treated larval homogenate showed decrease in total protein content and a significant reduction in the levels of acetylcholinesterase. The levels of acid and alkaline phosphatase also showed reduction as compared to control larval homogenate. PMID- 24401168 TI - Serial treatments of primed low-frequency rTMS in stroke: characteristics of responders vs. nonresponders. AB - PURPOSE: This study analyzed the characteristics of responders vs. nonresponders in people with stroke receiving a novel form of repetitive transcranial magnetic stimulation (rTMS) to improve hand function. METHODS: Twelve people with stroke received five treatments of 6-Hz primed low-frequency rTMS to the contralesional primary motor area. We compared demographic factors, clinical features, and the ipsilesional/contralesional volume ratio of selected brain regions in those who improved hand performance (N = 7) on the single-hand component of the Test Evaluant la performance des Membres superieurs des Personnes Agees (TEMPA) and those who showed no improvement (N = 5). RESULTS: Responders showed significantly greater baseline paretic hand function on the TEMPA, greater preservation volume of the ipsilesional posterior limb of the internal capsule (PLIC), and lower scores (i.e., less depression) on the Beck Depression Inventory than nonresponders. There were no differences in age, sex, stroke duration, paretic side, stroke hemisphere, baseline resting motor threshold for ipsilesional primary motor area (M1), NIH Stroke Scale, Upper Extremity Fugl-Meyer, Mini Mental State Examination, or preservation volume of M1, primary somatosensory area, premotor cortex, or supplementary motor area. CONCLUSION: Our results support that preserved PLIC volume is an important influential factor affecting responsiveness to rTMS. PMID- 24401170 TI - Prevalence and potential determinants of musculoskeletal disease symptoms among care workers in long-term care facilities in South Korea. AB - AIM: The purpose of this study was to investigate the degree and influencing factors of musculoskeletal disease symptoms among care workers in long-term care facilities in South Korea. METHODS: Participants in this cross-sectional study were 265 care workers in 15 long-term care facilities. Data were collected between 1 and 27 August 2011, using the Korea Occupational Safety and Health Agency (KOSHA) code H-30-2003 and analyzed using logistic regression with SPSS ver. 18.0. RESULTS: Of the care workers, 88.7% had pain in at least one of the six body parts. The highest prevalence of musculoskeletal disease symptoms was in the lower back and legs. Among the organizational factors, there were significant differences in neck pain by work shift and patient grade. Neck pain was more severe in the 8 h shift group than 12-24 h shift group. Care workers caring for patients who were classified in the first patient grade of long-term care insurance had 4.73 times more complaints of musculoskeletal symptoms in the neck, 9.54 times (95% confidence interval [CI] = 3.37-27.02) in the hand and wrist, 4.37 times (95% CI = 1.59-12.03) in the lower back, and 2.96 times (95% CI: 1.17 7.51) in the leg and foot. CONCLUSION: To prevent and manage musculoskeletal disease symptoms, activities and the intensity of work should be arranged systematically and planned, and the improvement of organizational factors such as appropriate assignment by patients' severity is considered. PMID- 24401171 TI - Phenotyping for patient safety: algorithm development for electronic health record based automated adverse event and medical error detection in neonatal intensive care. AB - BACKGROUND: Although electronic health records (EHRs) have the potential to provide a foundation for quality and safety algorithms, few studies have measured their impact on automated adverse event (AE) and medical error (ME) detection within the neonatal intensive care unit (NICU) environment. OBJECTIVE: This paper presents two phenotyping AE and ME detection algorithms (ie, IV infiltrations, narcotic medication oversedation and dosing errors) and describes manual annotation of airway management and medication/fluid AEs from NICU EHRs. METHODS: From 753 NICU patient EHRs from 2011, we developed two automatic AE/ME detection algorithms, and manually annotated 11 classes of AEs in 3263 clinical notes. Performance of the automatic AE/ME detection algorithms was compared to trigger tool and voluntary incident reporting results. AEs in clinical notes were double annotated and consensus achieved under neonatologist supervision. Sensitivity, positive predictive value (PPV), and specificity are reported. RESULTS: Twelve severe IV infiltrates were detected. The algorithm identified one more infiltrate than the trigger tool and eight more than incident reporting. One narcotic oversedation was detected demonstrating 100% agreement with the trigger tool. Additionally, 17 narcotic medication MEs were detected, an increase of 16 cases over voluntary incident reporting. CONCLUSIONS: Automated AE/ME detection algorithms provide higher sensitivity and PPV than currently used trigger tools or voluntary incident-reporting systems, including identification of potential dosing and frequency errors that current methods are unequipped to detect. PMID- 24401172 TI - Micropatterned multicolor dynamically adhesive substrates to control cell adhesion and multicellular organization. AB - We present a novel technique to examine cell-cell interactions and directed cell migration using micropatterned substrates of three distinct regions: an adhesive region, a nonadhesive region, and a dynamically adhesive region switched by addition of a soluble factor to the medium. Combining microcontact printing with avidin-biotin capture chemistry, we pattern nonadhesive regions of avidin that become adhesive through the capture of biotinylated fibronectin. Our strategy overcomes several limitations of current two-color dynamically adhesive substrates by incorporating a third, permanently nonadhesive region. Having three spatially and functionally distinct regions allows for the realization of more complex configurations of cellular cocultures as well as intricate interface geometries between two cell populations for diverse heterotypic cell-cell interaction studies. We can now achieve spatial control over the path and direction of migration in addition to temporal control of the onset of migration, enabling studies that better recapitulate coordinated multicellular migration and organization in vitro. We confirm that cellular behavior is unaltered on captured biotinylated fibronectin as compared to printed fibronectin by examining the cells' ability to spread, form adhesions, and migrate. We demonstrate the versatility of this approach in studies of migration and cellular cocultures, and further highlight its utility by probing Notch-Delta juxtacrine signaling at a patterned interface. PMID- 24401173 TI - Advance telephone calls ahead of reminder questionnaires increase response rate in non-responders compared to questionnaire reminders only: The RECORD phone trial. AB - BACKGROUND: Postal questionnaires are simple and economical for collecting outcome data for randomised controlled trials (RCTs) but are prone to non response. In the RECORD trial (a large pragmatic publicly funded RCT in UK) non responders were sent a reminder and another questionnaire at 1 year, of which 40% were returned. In subsequent years we investigated the effect of an advance telephone call to non-responders on responses rate to reminder questionnaires and the next questionnaire 4 months later. METHODS: Non-responders to annual questionnaires were randomised to receive a telephone call from the trial office ahead of the reminder questionnaire in addition to the usual reminder schedule (n=390) or to a control group that received the usual reminder schedule only (n=363). The primary outcome was response to the reminder questionnaire within 21 days; secondary outcomes were response to a questionnaire 4 months later; completeness of quality of life instruments; and the number of participants declining further follow-up. Results are presented as odds ratios from a logistic regression intention-to-treat (ITT) analysis and then percentage difference and 95% confidence intervals (CI) for both ITT and average treatment effect on the treated (ATT) analyses. RESULTS: The proportions that responded were 67.8% (265/390) in the intervention group compared to 62.5% (227/363) in the control group. The ITT estimate was a 5.4% increase (95% CI -1.4 to 12.2). Four months later percentages responding were 51.8% (202) and 42.7% (155). The ITT estimate was a 9.1% increase (95% CI 2.0 to 16.2). In the intervention group 12.3% (48/390) of participants were not telephoned because questionnaires were returned before the scheduled telephone call. ATT estimates adjusting for this were 6.2% (95% CI -1.6 to 14.0) and 10.4% (95% CI 2.2 to 18.5), respectively. CONCLUSIONS: The telephone call resulted in a slight increase in response to the reminder questionnaire, however at 4 months later the proportion in the telephoned group responding was greater. This study suggests that pre-notification telephone calls may only be worthwhile if further questionnaires are to be sent out soon after reminder questionnaires. TRIAL REGISTRATION: Current Clinical Trials ISRCTN51647438. PMID- 24401174 TI - [Unrecognized juvenile dermatomyositis complicated by calcinosis universalis: a case report from Cameroon]. AB - Juvenile dermatomyositis is a rare autoimmune disease that causes inflammation of the skin and muscles. Calcinosis may complicate its course, especially when the diagnosis is late or the corticosteroid therapy inadequate. In those cases, significant joint disability may occur. Few cases are reported in sub-Saharan Africa, probably because it is rarely recognized in these areas. We report the first Cameroonian case, occurring in a 9-year-old girl. Although she sought treatment early in the disease course, the dermatomyositis was diagnosed quite late, after the onset of calcinosis universalis and severe disability. Early diagnosis of the disease and effective treatment are essential to prevent calcinosis universalis from complicating this disease in children. PMID- 24401176 TI - Alcohol and Public Health. Under the influence. PMID- 24401177 TI - Pretreatment with laccase and a phenolic mediator degrades lignin and enhances saccharification of Eucalyptus feedstock. AB - BACKGROUND: Biofuel production from lignocellulosic material is hampered by biomass recalcitrance towards enzymatic hydrolysis due to the compact architecture of the plant cell wall and the presence of lignin. The purpose of this work is to study the ability of an industrially available laccase-mediator system to modify and remove lignin during pretreatment of wood (Eucalyptus globulus) feedstock, thus improving saccharification, and to analyze the chemical modifications produced in the whole material and especially in the recalcitrant lignin moiety. RESULTS: Up to 50% lignin removal from ground eucalypt wood was attained by pretreatment with recombinant Myceliophthora thermophila laccase and methyl syringate as mediator, followed by alkaline peroxide extraction in a multistage sequence. The lignin removal directly correlated with increases (approximately 40%) in glucose and xylose yields after enzymatic hydrolysis. The pretreatment using laccase alone (without mediator) removed up to 20% of lignin from eucalypt wood. Pyrolysis-gas chromatography/mass spectrometry of the pretreated wood revealed modifications of the lignin polymer, as shown by lignin markers with shortened side chains and increased syringyl-to-guaiacyl ratio. Additional information on the chemical modifications produced was obtained by two dimensional nuclear magnetic resonance of the whole wood swollen in dimethylsulfoxide-d6. The spectra obtained revealed the removal of guaiacyl and syringyl lignin units, although with a preferential removal of the former, and the lower number of aliphatic side-chains per phenylpropane unit (involved in main beta-O-4' and beta-beta' inter-unit linkages), in agreement with the pyrolysis-gas chromatography/mass spectrometry results, without a substantial change in the wood polysaccharide signals. However, the most noticeable modification observed in the spectra was the formation of Calpha-oxidized syringyl lignin units during the enzymatic treatment. Further insight into the modifications of lignin structure, affecting other inter-unit linkages and oxidized structures, was attained by nuclear magnetic resonance of the lignins isolated from the eucalypt feedstock after the enzymatic pretreatments. CONCLUSIONS: This work shows the potential of an oxidative enzymatic pretreatment to delignify and improve cellulase saccharification of a hardwood feedstock (eucalypt wood) when applied directly on the ground lignocellulosic material, and reveals the main chemical changes in the pretreated material, and its recalcitrant lignin moiety, behind the above results. PMID- 24401178 TI - A forerunner of qualitative health research: Risueno's report against the use of statistics. AB - In this article we discuss and examine the report presented to the Academie Royale de Medicine of Paris by the Spanish doctor Benigno Risueno de Amador in 1836, in which he argued against the calculation of probabilities in the health sciences. In his report, Risueno opposed the proposals put forward by Pierre Louis, precursor of the application of statistics in the health sciences. The report was a pioneering document that rejected the use of statistics in clinical practice and medical research. At the same time, however, it could well be considered a seminal document of a certain kind of qualitative research methodology in the health sciences. PMID- 24401179 TI - Sex determination mechanisms in the Calliphoridae (blow flies). AB - The Calliphoridae or blow flies are a family of insects that occupy diverse habitats and perform important ecological roles, particularly the decomposition of animal remains. Some Calliphoridae species are also important in the forensic sciences, in agriculture (e.g. as livestock pests) and in medicine (e.g. maggot therapy). Calliphoridae provide striking examples in support of the hypothesis that sex determination regulatory gene hierarchies evolve in the reverse order, with the gene at the top being the most recently added. Unlike the model fly Drosophila melanogaster, where sex is determined by the number of X chromosomes, in the Australian sheep blow fly (Lucilia cuprina) sex is determined by a Y linked male-determining gene (M). A different regulatory system appears to operate in the hairy maggot blow fly (Chrysomya rufifacies) where the maternal genotype determines sex. It is hypothesized that females heterozygous for a dominant female-determining factor (F/f) produce only female offspring and homozygous f/f females produce only sons. The bottom of the regulatory hierarchy appears to be the same in D. melanogaster and L. cuprina, with sex-specific splicing of doublesex transcripts being controlled by the female-specific Transformer (TRA) protein. We discuss a model that has been proposed for how tra transcripts are sex-specifically spliced in calliphorids, which is very different from D. melanogaster. PMID- 24401180 TI - epsilon-Caprolactone in micro-chambered ceramic beads--a new carrier for gentamicin. AB - PURPOSE: The purpose of this preliminary and descriptive study was to evaluate a biodegradable drug delivery system in combination with an innovative ceramic implant. METHODS: The delivery of gentamicin of standardized samples was measured in the laboratory using ultra-high-performance liquid chromatography. Biocompatibility and biodegradation of the materials was investigated in an animal experiment in sheep up to 14 months. As carrier epsilon-caprolactone, 1:1 mixed with gentamicin, intruded into micro-chambered beta-tricalcium-phosphate beads (MCB(r)) was studied. RESULTS AND DISCUSSION: Gentamicin was released in calculable concentrations during the first 30 days. The release from epsilon caprolactone was higher than that from polymethylmethacrylate and more predictable. The caprolactone carrier was reabsorbed by osteoclasts. PMID- 24401181 TI - Radiation dosimetry of florbetapir F 18. AB - BACKGROUND: Florbetapir is one of several 18F-labeled amyloid plaque imaging tracers for positron emission tomography (PET). As the bio-distribution and radiation dose of PET tracers in human research are important for estimating the relative risks and benefits, a study was conducted to obtain this information on florbetapir. METHODS: Nine cognitively normal subjects (six females and three males, age 58 +/- 10 years, weight 81 +/- 17 kg) received an intravenous bolus injection of 395 +/- 27.9 MBq of florbetapir, and whole-body emission scans were performed over approximately 6 h. Computed tomography scans were acquired for attenuation correction. Volumes of interest (VOIs) for source organs including the brain, liver, lung, heart wall, and vertebrae were defined on the PET images. The VOIs of the gallbladder, urinary bladder, and large and small intestines were also defined. Using reference man organ volumes (ICRP 30), total activity was calculated per organ for each time point. The resultant time-activity curves (TACs) were fitted with constrained exponentials. Kinetic data were entered into OLINDA/EXM software to calculate dose estimates; the dynamic urinary bladder and ICRP 30 GI tract models were employed. The effective dose (ED) for each subject was estimated from the acquired data using the adult model. RESULTS: The mean ED determined for nine healthy volunteers was 18.60 +/- 4.26 MUSv/MBq or 6.88 mSv for a 370-MBq dose. The organs that received the highest radiation absorbed doses were the gallbladder, upper large intestine, small intestine, liver, and urinary bladder at 143.0 +/- 80.20, 74.50 +/- 34.20, 65.50 +/- 29.60, 64.40 +/- 22.10, and 27.10 +/- 11.70 MUSv/MBq, respectively. CONCLUSIONS: The ED for florbetapir has been calculated for nine healthy volunteers. At a dose of 370 MBq florbetapir, the total average ED is approximately 6.88 mSv. PMID- 24401182 TI - Tests for two trees using likelihood methods. AB - This article considers two similar likelihood-based test statistics for comparing two fixed trees, the Kishino-Hasegawa (KH) test statistic and the likelihood ratio (LR) statistic, as well as a number of different methods for determining thresholds to declare a significant result. An explanation is given for why the KH test, which uses the KH test statistic and normal theory thresholds, need not give correct type I error probabilities under the appropriate null hypothesis. Simulations show that the KH test tends to give much smaller type I error probabilities than expected. The article presents a computationally efficient normal-theory parametric bootstrap method for determining better KH test statistic thresholds. For the LR statistic, existing mixture of chi-squares results for determining thresholds are extended to cases in which a tree with two or three zero edge-lengths exhibits the two trees being compared. The resulting chi-bar test and use of the KH test statistic with normal bootstrap are shown through simulation to give good performance but are more difficult to implement than the KH test. Two conservative approaches are presented which require only log likelihoods and simple chi-square thresholds. While they did not perform as well as chi-bar and normal bootstrap methods in the simulations considered, they gave better performance than the KH test and have just as simple an implementation. As a by-product of parametric bootstrap considerations, an adjustment to the Swofford-Olsen-Waddell-Hillis (SOWH) test is proposed. PMID- 24401183 TI - Molecular predictors of locoregional and distant metastases in oropharyngeal squamous cell carcinoma. AB - BACKGROUND: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing due to fundamental changes in oncogenesis related to effects of the human papilomavirus (HPV). Virally-mediated tumours behave and respond to treatment differently than their classic, carcinogenically-mediated counterparts despite similar stage and grade of disease. This difference in behaviour has lead to investigation of etiologies of OPSCC at the molecular level. OBJECTIVE: This study was designed to identify biomarker profiles predictive of locoregional and distant metastases and recurrence in OPSCC. METHODS: Cross-sectional study of a prospectively-collected oropharyngeal tumour database was undertaken. All patients with OPSCC presenting to the University of Alberta Hospital from 2002 2009 were included in the study. Data collection from the Alberta Cancer Registry, including demographics, nodal status, distant metastases, treatment, recurrence, and survival, was undertaken. Tissue micro-arrays (TMAs) were constructed for each tumour specimen using triplicate cores (0.6mm) of formalin fixed, paraffin-embedded (FFPE) pre-treatment tumour tissue. TMAs were processed using immunohistochemistry for p16, EGFR, Ki67, p53, and Bcl-XL. Positivity for each biomarker was determined using quantified AQUAnalysis (r) scores on histoplots. Multivariate statistics were utilized to assess the relationship between each biomarker and locoregional and distant metastases, as well as recurrence-free survival (RFS). RESULTS: High expression of p16 (p=0.000) and Bcl XL (p=0.039) independently demonstrated a significant association with nodal disease at presentation. Kaplan-Meier analysis demonstrated improved RFS in patients with high p16 and decreased RFS in patients with high p53 expression. Cox regression analysis supported p16 as an independent prognosticator for improved RFS. p53 demonstrated an association with recurrence, but when compared to p16 status, nodal status, and staging, was not an independent predictor of recurrence. CONCLUSIONS: Biomarker profiling using p16, Bcl-xL, and p53 may be useful in prognostication and treatment planning in patients with OPSCC. PMID- 24401184 TI - Evidence-based prehospital management of severe traumatic brain injury: a comparative analysis of current clinical practice guidelines. AB - OBJECTIVE: This study appraised the completeness and level of evidence behind prehospital recommendations in clinical practice guidelines (CPGs) for management of severe traumatic brain injury (TBI). Differences and similarities in key recommendations for prehospital emergency care were assessed between current CPGs. METHODS: A systematic search identified current evidence-based CPGs for the management of severe TBI. The identified CPGs were screened for prehospital recommendations. Finally, an evaluation of the completeness and level of evidence for each of the identified recommendations was carried out. A review of the literature identified additional evidence. Designs of the retrieved publications were considered and classified according to the GRADE levels of evidence. RESULTS: This study identified 12 current CPGs for the management of patients after traumatic brain injury. Of these, twenty-one prehospital recommendations were selected. Only a few CPGs made recommendations on temperature management and ventilation patterns. Statements on prehospital transport and advanced airway management were common to all of the guidelines. Statements on initial treatment demonstrated the greatest variability. The literature review identified several relevant publications not included in the CPGs even after we controlled for the indicated time-intervals of their literature search. In addition, evidence from more recent trials published outside the search-interval of the clinical practice guidelines was found. CONCLUSIONS: The use of current guidelines on traumatic brain injury will not always facilitate decisions about best or most appropriate practice for prehospital practitioners. The amount of recommended prehospital interventions varied considerably, and there was large content variation in prehospital recommendations in these guidelines. Not all evidence was taken into account and not all CPGs were up-to-date. PMID- 24401185 TI - On the importance of unconditional rewards for blood donations. PMID- 24401186 TI - Increased soluble ST2 predicts long-term mortality in patients with stable coronary artery disease: results from the Ludwigshafen risk and cardiovascular health study. AB - BACKGROUND: Soluble suppression of tumorigenicity 2 (sST2) has emerged as a strong prognostic biomarker in patients with heart failure and myocardial infarction. The aim of this study was to evaluate the long-term prognostic value of sST2 in patients with stable coronary artery disease (CAD). METHODS: sST2 plasma concentrations were measured in 1345 patients with stable CAD referred for coronary angiography at a single tertiary care center. The primary endpoint was all-cause mortality. RESULTS: During a median follow-up time of 9.8 years, 477 (36%) patients died. The median sST2 plasma concentration at baseline was significantly higher among decedents than survivors (21.4 vs 18.5 ng/mL; P < 0.001). In multivariate Cox proportional hazards regression analysis, sST2 was an independent predictor of all-cause mortality (risk ratio 1.16 per 1-SD increase in log-transformed values; 95% CI 1.05-1.29; P = 0.004). In the same multivariate analysis, amino-terminal pro-B-type natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin T (hs-cTnT) were also independent predictors, whereas galectin-3 was not. Patients with sST2 in the highest quartile (>24.6 ng/mL) displayed a 2-fold increased risk of death in univariate analysis, which was attenuated but remained significant in a fully adjusted model (risk ratio 1.39; 95% CI 1.10-1.76; P = 0.006). Further analysis showed that the prognostic impact of sST2 was additive to NT-proBNP and hs-cTnT. Using a multibiomarker approach combining these 3 complementary makers, we demonstrated that patients with all 3 biomarkers in the highest quartiles had the poorest outcome. CONCLUSIONS: In this cohort of patients with stable CAD, increased sST2 was an independent predictor of long-term all-cause mortality and provided complementary prognostic information to hs-cTnT and NT-proBNP. PMID- 24401187 TI - Knowledge, group-based medical mistrust, future expectations, and perceived disadvantages of medical genetic testing: perspectives of Black African immigrants/refugees. AB - BACKGROUND: Reasons for low participation of ethnic minorities in genetic studies are multifactorial and often poorly understood. Based on published literature, participation in genetic testing is low among Black African immigrants/refugees although they are purported to bear disproportionate disease burden. Thus, research involving Black African immigrant/refugee populations that examine their perspectives on participating in genetic studies is needed. OBJECTIVES: This report examines and describes the knowledge of medical genetics, group-based medical mistrust, and future expectations of genetic research and the influence of these measures on the perceived disadvantages of genetic testing among Black African immigrants/refugees. METHODS: Using a cross-sectional survey design, a nonprobability sample (n = 212) of Black African immigrants/refugees was administered a questionnaire. Participants ranged in age from 18 to 61 years (mean = 38.91, SD = 9.78). The questionnaire consisted of 5 instruments: (a) sociodemographic characteristics, (b) Knowledge of Medical Genetics scale, (c) Group-Based Medical Mistrust Scale, (d) Future Expectations/Anticipated Consequences of Genetics Research scale, and (e) Perceived Disadvantages of Genetic Testing scale. RESULTS: Participants were concerned that genetic research may result in scientists 'playing God,' interfering with the natural order of life. In multivariate analyses, the perceived disadvantages of genetic testing increased as medical mistrust and anticipated negative impacts of genetic testing increased. Increase in genetic knowledge contributed to a decrease in perceived disadvantages. CONCLUSIONS: Our findings suggest that recruitment of Black African immigrants/refugees in genetic studies should address potential low knowledge of genetics, concerns about medical mistrust, the expectations/anticipated consequences of genetic research, and the perceived disadvantages of genetic testing. PMID- 24401188 TI - Cryptic diversity in host-associated populations of Tetra pinnatifidae (Acari: Eriophyoidea): what do morphometric, mitochondrial and nuclear data reveal and conceal? AB - Traditional morphology-based taxonomy of eriophyoid mites (Acari: Eriophyoidea) has been challenged by molecular-based technologies in the detection of cryptic species. However, the implications of such cryptic diversity appear to differ when methods based on different types of data are used. Here, samples of a host associated eriophyoid mite species, Tetra pinnatifidae, collected from different host plants and localities are evaluated. The congruence of results based on morphometric (32 characters), mitochondrial (16S), and nuclear (28S) data were evaluated and showed a host-associated cryptic diversity dividing this morphospecies into several groups/clades that were morphometrically indistinguishable. In comparison, the 16S data confirmed cryptic speciation and intra-clade host-associated diversity, while 28S did not. In contrast, 28S data revealed potential gene flow between host-associated populations. High mitochondrial divergence, as well as low nuclear and morphological divergence indicated very recent stage of cryptic diversity of this eriophyoid mite. PMID- 24401189 TI - Relationships between vascular endothelial growth factor levels and temperament and character inventory traits in healthy Japanese subjects. AB - BACKGROUND AND AIM: Personality traits and vascular endothelial growth factor (VEGF) levels are both independently correlated with major depressive disorder and depressive mood. However, no studies have reported associations between personality traits and VEGF levels. Thus, we hypothesized that there is a correlation between the results of the Temperament and Character Inventory (TCI) and VEGF levels. METHODS: We investigated 179 healthy participants who completed the TCI. We collected a serum sample from each subject and measured each participant's VEGF level by an enzyme-linked immunosorbent assay (ELISA). Simple and multiple regression analyses were performed to examine the correlations between the scores on the seven TCI dimensions and several other factors, including gender, age and VEGF level. RESULTS: A total of 150 subjects completed the examination. Among the dimensions of the TCI, the harm avoidance (HA) scores were negatively correlated with VEGF levels, but there were no significant correlations between the scores for any other dimensions and VEGF levels. The HA score was significantly correlated with sex, age and VEGF level, and single and multiple regression analyses yielded the same results. CONCLUSION: VEGF may be associated with certain personality factors. This study is the first to demonstrate a direct association between VEGF levels and a dimension of the TCI in healthy subjects. PMID- 24401190 TI - Primary carcinoid tumor of the skin: a literature review. AB - Primary carcinoid tumor of the skin (PCTS) is an uncommon indolent neoplasm, with 10 cases described in the literature. The tumors affect patients in the sixth to ninth decades of life (mean = 66.3 years) with an equal gender distribution and predilection for the head and trunk. They present as slowly enlarging nodules of variable duration, ranging from 1 to 60 years (mean = 11.4 years). PCTS is characterized by architectural, cytomorphologic, ultrastructural, and immunohistochemical features typical of a low-grade neoplasm with neuroendocrine differentiation. PCTS typically follows a benign clinical course and therefore has to be distinguished from cutaneous metastases of visceral carcinoid tumors, which herald dissemination of malignancy and poor prognosis. While the distinction from other histologically similar entities can be achieved by histopathological examination, PCTS can be distinguished from a visceral metastasis only by a judicious clinicopathologic correlation. Herein we describe the clinical presentation, histological appearance, and management of these tumors. PMID- 24401191 TI - Papillary thyroid microcarcinoma: how to diagnose and manage this epidemic? AB - The incidence of papillary thyroid microcarcinoma (PTmC) has been increasing everywhere due to the improvement of imaging and morphological diagnoses and probably also due to environmental alterations. Despite this, the mortality caused by thyroid cancer has not increased, reflecting the low clinical aggressiveness of most papillary thyroid carcinomas (PTCs) and the quality of the available treatment. The criteria used to classify PTmC remain questionable, making the clinical risk evaluation of these lesions very difficult. There is no solid basis for establishing the most appropriate tumor size (currently <10 mm) to distinguish PTmC from PTC. Moreover, PTmCs encompass all sorts of PTC histotypes, thus turning the whole group of PTmC genetically and biologically heterogeneous. In this review, we address the 2 most interesting issues from a practical standpoint: Are there any specific morphological or molecular features distinguishing PTmC from PTC? Is it possible to predict the clinical behavior of PTmC in fine needle aspiration biopsy and in surgical specimens, using morphological and/or molecular markers? PMID- 24401192 TI - The hyaline vascular type of Castleman's disease of the ovary: a case report. AB - Castleman's disease in the pelvic cavity is rare. We present a 72-year-old woman with hyaline vascular type of Castleman's disease of the right ovary. Right ovarian enlargement was detected in the medical examination. Computed tomography revealed a solid mass, measured 2.5 cm in size, in the right ovary. A bilateral salpingo-oophorectomy was performed. Morphologically, lymphoid follicles with regressed germinal centers (GCs) were surrounded by a broad mantle zone composed of concentric rings of small lymphocytes, and the hyalinized blood vessels with plump endothelial cells penetrated radially into GCs. Proliferation of follicular dendritic cells, which were positive for CD21 and epidermal growth factor receptor, were detected in GCs and mantle zone. No other lesions were found. To the best of our knowledge, this is the first case of hyaline vascular type of Castleman's disease of ovarian primary. PMID- 24401193 TI - Molecular modelling of HLA-B*35:132. AB - Here we describe the molecular modelling of the new variant HLA-B*35:132. This allele shows one mismatch with B*35:01:01:01 in exon 3 at position 575 where a T is substituted by a C, which implies an amino acidic change from Leucine to Proline. This seems not to alter the molecular structure and not to compromise the HLA complex and T-cell receptor interaction. PMID- 24401194 TI - Feasibility study of veterinary antibiotic consumption in Germany--comparison of ADDs and UDDs by animal production type, antimicrobial class and indication. AB - BACKGROUND: Within a feasibility study the use of antibiotics in pigs and cattle was determined in 24 veterinary practices in Lower Saxony and on 66 farms in North Rhine-Westphalia in Germany. Focus was laid on the comparison of the Used Daily Doses (UDD) (dose per animal and day prescribed by the veterinarians) with the Defined Animal Daily Doses (ADD) (dose per animal and day calculated by means of recommended dosages and estimated live weights). RESULTS: For piglets and calves most of the UDD (50% and 46% of nUDD, respectively) were above the ADD (i.e. UDD/ADD-ratio above 1.25). Regarding sows, fattening pigs, dairy and beef cattle, most of the UDDs (49% to 65% of nUDD) were lower than the respective ADD (i.e. UDD/ADD-ratio below 0.8). In pigs, the UDDs of beta-lactams, fluoroquinolones and cephalosporins, and in cattle, those of macrolides and beta lactams were often below the ADDs. Tetracyclines were frequently used above the recommended dose.Enteric diseases were more often treated below the recommended dose than respiratory diseases, possibly due to overestimation of the live weight (diarrhea in young animals, respiratory diseases in elder animals) and consequently overestimation of the recommended dose. CONCLUSION: Comparisons between UDD and ADD can be used to observe differences between antimicrobials and trends in the usage of antibiotics. But individual treatment comparisons of UDD and ADD must be interpreted carefully, because they may be due to lower live weights than estimated. Correlating such data with data on the occurrence of resistant bacteria in future may help to improve resistance prevention and control. PMID- 24401195 TI - Extra-genital endometriosis. AB - BACKGROUND: Even if endometriosis is usually an exclusively gynecological issue, atypical locations fall within the interest of general surgery. The aim of our retrospective study focuses on the need for surgeons to face this rare condition, in order to avoid unnecessary or inadequate treatment. METHODS: We retrospectively analyzed clinical presentations, previous endometriosis diagnosis and surgical acts on a group of 60 patients, whose mean age was 38.2 years old, with extra-genital endometriosis. RESULTS: Among the 60 cases of extra-genital endometriosis collected, bowel foci, 37 cases - 61,7% - were the most frequent; then we collected 13 (21.7%) skin, 7 (11.7%) urinary tract and 3 (5%) whole pelvis localizations. It's important to underline the finding of 2 aggressive malignant transformations. CONCLUSIONS: Extra-genital endometriosis should be considered as a cause of otherwise inexplicable abdominal pain in young women. Since imaging techniques lack in specificity, we propose explorative laparoscopy as a powerful diagnostic means. Moreover laparoscopy can be turned into a therapeutic act, also limiting the adherences issue, which is associated with this illness and would worsen with open surgery. Extra-genital endometriosis should be treated also to avoid rare, but possible, risk of cancerization. PMID- 24401198 TI - Evaluation of physiological parameters before and after respiratory physiotherapy in newborns with acute viral bronchiolitis. AB - BACKGROUND: Acute viral bronchiolitis is a respiratory disease with high morbidity that affects newborn in the first two years of life. Its treatment with physiotherapy has been highlighted as an important tool, however, there is no consensus regarding its effects on patients improvement. We aimed to evaluate the physiological parameters before and after the procedure respiratory therapy in newborn with acute viral bronchiolitis. METHOD: This was a cross sectional observational study in 30 newborns with acute viral bronchiolitis and indicated for physiotherapy care in a hospitalized Urgency and Emergency Unit. It was collected the clinical data of newborn through evaluation form, and we measured heart rate (HR), oxygen saturation (SpO2) and respiratory rate (RR). We measured the variables before physiotherapy treatment, 3, 6 and 9 minutes after the physiotherapy treatment. RESULTS: There has been no change in HR, however, we observed a decrease in RR at 6 and 9 min compared to 3 min and increase in SpO2 at 3, 6 and 9 min compared to before physiotherapy. CONCLUSION: Respiratory physiotherapy may be an effective therapy for the treatment of newborn with Acute Viral Bronchitis. PMID- 24401199 TI - Practical applications of insects' sexual development for pest control. AB - Elucidation of the sex differentiation pathway in insects offers an opportunity to understand key aspects of evolutionary developmental biology. In addition, it provides the understanding necessary to manipulate insects in order to develop new synthetic genetics-based tools for the control of pest insects. Considerable progress has been made in this, especially in improvements to the sterile insect technique (SIT). Large scale sex separation is considered highly desirable or essential for most SIT targets. This separation can be provided by genetic methods based on sex-specific gene expression. Investigation of sex determination by many groups has provided molecular components and methods for this. Though the primary sex determination signal varies considerably, key regulatory genes and mechanisms remain surprisingly similar. In most cases studied so far, a primary signal is transmitted to a basal gene at the bottom of the hierarchy (dsx) through an alternative splicing cascade; dsx is itself differentially spliced in males and females. A sex-specific alternative splicing system therefore offers an attractive route to achieve female-specific expression. Experience has shown that alternative splicing modules can be developed with cross-species function; modularity and standardisation and re-use of parts are key principles of synthetic biology. Both female-killing and sex reversal (XX females to phenotypic males) can in principle also be used as efficient alternatives to sterilisation in SIT-like methods. Sexual maturity is yet another area where understanding of sexual development may be applied to insect control programmes. Further detailed understanding of this crucial aspect of insect biology will undoubtedly continue to underpin innovative practical applications. PMID- 24401200 TI - Reply: Comment on 'Recombinant LH supplementation to a standard GnRH antagonist protocol in women of 35 years or older undergoing IVF/ICSI: a randomized controlled multicentre study'. PMID- 24401201 TI - Comment on 'Recombinant LH supplementation to a standard GnRH antagonist protocol in women of 35 years old or older undergoing IVF/ICSI: a randomized controlled multicentre study'. PMID- 24401202 TI - Reply: poor ovarian responders: to meta-analyse or not, that is the question. PMID- 24401203 TI - Poor ovarian responders: to meta-analyse or not, that is the question. PMID- 24401204 TI - Search and insights into novel genetic alterations leading to classical and atypical Werner syndrome. AB - Segmental progeroid syndromes are a group of disorders with multiple features resembling accelerated aging. Adult-onset Werner syndrome (WS) and childhood onset Hutchinson-Gilford progeria syndrome are the best known examples. The discovery of genes responsible for such syndromes has facilitated our understanding of the basic mechanisms of aging as well as the pathogenesis of other common, age-related diseases. Our International Registry of Werner Syndrome accesses progeroid pedigrees from all over the world, including those for whom we have ruled out a mutation at the WRN locus. Cases without WRN mutations are operationally categorized as 'atypical WS' (AWS). In 2003, we identified LMNA mutations among a subset of AWS cases using a candidate gene approach. As of 2013, the Registry has 142 WS patients with WRN mutations, 11 AWS patients with LMNA mutations, and 49 AWS patients that have neither WRN nor LMNA mutations. Efforts are underway to identify the responsible genes for AWS with unknown genetic causes. While WS and AWS are rare disorders, the causative genes have been shown to have much wider implications for cancer, cardiovascular disease and the biology of aging. Remarkably, centenarian studies revealed WRN and LMNA polymorphic variants among those who have escaped various geriatric disorders. PMID- 24401205 TI - Protection induced by a glycoprotein E-deleted bovine herpesvirus type 1 marker strain used either as an inactivated or live attenuated vaccine in cattle. AB - BACKGROUND: Bovine herpesvirus type 1 (BoHV-1) is the causative agent of respiratory and genital tract infections; causing a high economic loss in all continents. Use of marker vaccines in IBR eradication programs is widely accepted since it allows for protection of the animals against the disease while adding the possibility of differentiating vaccinated from infected animals.The aim of the present study was the development and evaluation of safety and efficacy of a glycoprotein E-deleted (gE-) BoHV-1 marker vaccine strain (BoHV-1DeltagEbetagal) generated by homologous recombination, replacing the viral gE gene with the beta galactosidase (betagal) gene. RESULTS: In vitro growth kinetics of the BoHV 1DeltagEbetagal virus was similar to BoHV-1 LA. The immune response triggered by the new recombinant strain in cattle was characterized both as live attenuated vaccine (LAV) and as an inactivated vaccine. BoHV-1DeltagEbetagal was highly immunogenic in both formulations, inducing specific humoral and cellular immune responses. Antibody titers found in animals vaccinated with the inactivated vaccine based on BoHV-1DeltagEbetagal was similar to the titers found for the control vaccine (BoHV-1 LA). In the same way, titers of inactivated vaccine groups were significantly higher than any of the LAV immunized groups, independently of the inoculation route (p < 0.001). Levels of IFN-gamma were significantly higher (p < 0.001) in those animals that received the LAV compared to those that received the inactivated vaccine. BoHV-1DeltagEbetagal exhibited an evident attenuation when administered as a LAV; no virus was detected in nasal secretions of vaccinated or sentinel animals during the post-vaccination period. BoHV-1DeltagEbetagal, when used in either formulation, elicited an efficient immune response that protected animals against challenge with virulent wild-type BoHV-1. Also, the deletion of the gE gene served as an immunological marker to differentiate vaccinated animals from infected animals. All animals vaccinated with the BoHV-1DeltagE betagal strain were protected against disease after challenge and shed significantly less virus than control calves, regardless of the route and formulation they were inoculated. CONCLUSIONS: Based on its attenuation, immunogenicity and protective effect after challenge, BoHV 1DeltagEbetagal virus is an efficient and safe vaccine candidate when used either as inactivated or as live attenuated forms. PMID- 24401206 TI - Tertiary structure prediction and identification of druggable pocket in the cancer biomarker - Osteopontin-c. AB - BACKGROUND: Osteopontin (Eta, secreted sialoprotein 1, opn) is secreted from different cell types including cancer cells. Three splice variant forms namely osteopontin-a, osteopontin-b and osteopontin-c have been identified. The main astonishing feature is that osteopontin-c is found to be elevated in almost all types of cancer cells. This was the vital point to consider it for sequence analysis and structure predictions which provide ample chances for prognostic, therapeutic and preventive cancer research. METHODS: Osteopontin-c gene sequence was determined from Breast Cancer sample and was translated to protein sequence. It was then analyzed using various software and web tools for binding pockets, docking and druggability analysis. Due to the lack of homological templates, tertiary structure was predicted using ab-initio method server - I-TASSER and was evaluated after refinement using web tools. Refined structure was compared with known bone sialoprotein electron microscopic structure and docked with CD44 for binding analysis and binding pockets were identified for drug designing. RESULTS: Signal sequence of about sixteen amino acid residues was identified using signal sequence prediction servers. Due to the absence of known structures of similar proteins, three dimensional structure of osteopontin-c was predicted using I TASSER server. The predicted structure was refined with the help of SUMMA server and was validated using SAVES server. Molecular dynamic analysis was carried out using GROMACS software. The final model was built and was used for docking with CD44. Druggable pockets were identified using pocket energies. CONCLUSIONS: The tertiary structure of osteopontin-c was predicted successfully using the ab initio method and the predictions showed that osteopontin-c is of fibrous nature comparable to firbronectin. Docking studies showed the significant similarities of QSAET motif in the interaction of CD44 and osteopontins between the normal and splice variant forms of osteopontins and binding pockets analyses revealed several pockets which paved the way to the identification of a druggable pocket. PMID- 24401207 TI - Changes in adipokine levels in autism spectrum disorders. AB - BACKGROUND AND OBJECTIVE: The etiopathogenesis of autism spectrum disorders (ASD) is largely unknown, but it seems to involve dysfunction in several biological systems. Among many possible biological pathways, the immune system has emerged as potentially involved. Recent studies have shown association between cytokines (molecules that mediate immune cell interaction) and ASD. Adipokines are cytokines secreted mainly by adipose tissue and may have systemic effects. The main objective of this study was to compare the plasma levels of three adipokines between patients with ASD and healthy controls. Another aim was to correlate the levels of these adipokines and the severity of autistic symptoms as measured by the Social Responsiveness Scale (SRS). METHODS: We collected plasma from 30 patients and 19 controls and measured the levels of adiponectin, leptin and resistin using a commercially available kit. We also used the SRS as a tool to assess the severity of autistic symptoms. RESULTS: We found decreased levels of resistin, increased levels of leptin and unaltered levels of adiponectin in plasma from ASD subjects in comparison with controls. There was also a negative correlation between the levels of adiponectin and the severity of symptoms as assessed by the SRS. CONCLUSION: There are significant changes in the plasma levels of adipokines from patients with ASDs. They suggest the occurrence of systemic changes in ASD and may be hallmarks of the disease. PMID- 24401208 TI - In vitro interaction between SURFACEN(r) and surfactant protein A against Leishmania amazonensis. AB - Leishmaniasis is caused by a parasite of the Leishmania genus, affecting more than 12 million people in 98 countries. The control of leishmaniasis remains a serious problem. There are currently no vaccines for leishmaniasis. The drugs available are toxic, expensive and frequently ineffective. The in vitro activity of SURFACEN(r) and SP-A against Leishmania amazonensis was evaluated. The combination of both products resulted in a synergic pharmacology effect, demonstrated by a fractional inhibitory concentration index <0.5. A more effective combination was a SURFACEN/SP-A ratio of 4:1, using a method of fixed ratio. The therapeutic effect of SURFACEN and SP-A as antileishmanial compounds was demonstrated, with a potentiation of activity when they were incubated in conjunction. Our results propose an exploration of these products in order to design new formulations against the Leishmania parasite. PMID- 24401209 TI - Survival and neurologic outcome after out-of-hospital cardiac arrest: results one year after regionalization of post-cardiac arrest care in a large metropolitan area. AB - BACKGROUND: Post-resuscitation care of cardiac arrest patients at specialized centers may improve outcome after out-of-hospital cardiac arrest (OOHCA). This study describes experience with regionalized care of resuscitated patients. METHODS: Los Angeles (LA) County established regionalized cardiac care in 2006. Since 2010, protocols mandate transport of nontraumatic OOHCA patients with field return of spontaneous circulation (ROSC) to a STEMI Receiving Center (SRC) with a hypothermia protocol. All SRC report outcomes to a registry maintained by the LA County Emergency Medical Services (EMS) Agency. We report the first year's data. The primary outcome was survival with good neurologic outcome, defined by a Cerebral Performance Category (CPC) score of 1 or 2. RESULTS: The SRC treated 927 patients from April 2011 through March 2012 with median age 67; 38% were female. There were 342 patients (37%) who survived to hospital discharge. CPC scores were unknown in 47 patients. Of the 880 patients with known CPC scores, 197 (22%) survived to hospital discharge with a CPC score of 1 or 2. The initial rhythm was VF/VT in 311 (34%) patients, of whom 275 (88%) were witnessed. For patients with an initial shockable rhythm, 183 (59%) survived to hospital discharge and 120 (41%) had survival with good neurologic outcome. Excluding patients who were alert or died in the ED, 165 (71%) patients with shockable rhythms received therapeutic hypothermia (TH), of whom 67 (42%) had survival with good neurologic outcome. Overall, 387 patients (42%) received TH. In the TH group, the adjusted OR for CPC 1 or 2 was 2.0 (95%CI 1.2-3.5, p = 0.01), compared with no TH. In contrast, the proportion of survival with good neurologic outcome in the City of LA in 2001 for all witnessed arrests (irrespective of field ROSC) with a shockable rhythm was 6%. CONCLUSION: We found higher rates of neurologically intact survival from OOHCA in our system after regionalization of post resuscitation care as compared to historical data. PMID- 24401210 TI - LXR agonism improves TNF-alpha-induced endothelial dysfunction in the absence of its cholesterol-modulating effects. AB - Stimulation of the liver X receptor (LXR) is associated with anti-inflammatory and vascular-protective effects under hyperlipemic conditions. We examined whether LXR stimulation influences TNF-alpha-induced endothelial dysfunction under normolipemic conditions. Endothelium-dependent vasorelaxation of aortic rings was determined in an organ water bath. Human umbilical vein endothelial cells (HUVEC) were exposed to TNF-alpha (10 ng/ml) in the presence or absence of 5 MUM of the LXR agonist T0901317 or GW3965 and changes in TNF-alpha-induced endothelial cell apoptosis, inflammation, oxidative stress, and NO metabolism were analyzed. T0901317 improved TNF-alpha-impaired endothelium-dependent relaxation of aortic rings in response to acetylcholine. T0901317 decreased the TNF-alpha-induced apoptosis and inflammation as indicated by a decrease in caspase 3/7 activity, VCAM-1 mRNA expression and subsequent mononuclear cell adhesion. Furthermore, T0901317 reduced the expression of the oxidative stress markers: AT1R, NOX4, and p22phox and normalized the TNF-alpha-induced NOX activity to basal levels. In line with the reduced AT1R expression, T0901317 impaired the Ang II responsiveness. T0901317 influenced NO metabolism as indicated by a decrease in TNF-alpha-upregulated arginase activity, a reversal of TNF-alpha-induced downregulation of argininosuccinate synthase mRNA expression and eNOS expression to basal levels and a raise in NO production. Furthermore, T0901317 decreased the TNF-alpha-induced superoxide and nitrotyrosine production, but did not upregulate the TNF-alpha-downregulated eNOS dimer/monomer ratio. Silencing of LXRbeta, but not of LXRalpha, abrogated the anti-apoptotic effects of T0901317. We conclude that LXR agonism improves TNF-alpha-impaired endothelial function via its anti-apoptotic, anti-inflammatory, and anti-oxidative properties and its capacity to restore TNF-alpha-impaired NO bioavailability independent of its cholesterol-modulating effects. PMID- 24401211 TI - Omega-3 PUFAs improved endothelial function and arterial stiffness with a parallel antiinflammatory effect in adults with metabolic syndrome. AB - OBJECTIVES: Metabolic syndrome (MetS) is associated with adverse cardiovascular events, and impaired vascular function. In this study we evaluated the effects of omega-3 polyunsaturated fatty acids (PUFAs) supplementation on vascular function, inflammatory and fibrinolytic process in subjects with MetS. METHODS: We studied the effect of a 12 weeks oral treatment with 2 g/day of omega-3 PUFAs in 29 (15 male) subjects (mean age 44 +/- 12 years) with MetS on three occasions (day0: baseline, day 28 and day 84). The study was carried out on two separate arms (PUFAs and placebo), according to a randomized, placebo-controlled, double-blind, cross-over design. The diagnosis of MetS was based on the guidelines of Adult Treatment Panel III definition. Endothelial function was evaluated by flow mediated dilation (FMD) of the brachial artery. Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness. Serum levels of interleukin-6(IL-6) and plasminogen activator inhibitor-1(PAI-1) were measured by ELISA. RESULTS: Treatment with PUFAs resulted in a significant improvement from day 0 to 28 and 84 in FMD and PWV (p < 0.001 for all). Nevertheless, treatment with placebo resulted in no significant changes in FMD (p = 0.63) and PWV (p = 0.17). Moreover, PUFAs treatment, compared to placebo, decreased IL-6 levels (p = 0.03) and increased PAI-1 levels (p = 0.03). Finally, treatment with PUFAs resulted in a significant decrease in fasting triglyceride levels from day 0 to 28 and 84 (p < 0.001) and in serum total cholesterol levels (p < 0.001). CONCLUSIONS: In subjects with MetS, treatment with omega-3 PUFAs improved endothelial function and arterial stiffness with a parallel antiinflammatory effect. PMID- 24401212 TI - Hydroxytyrosol suppresses MMP-9 and COX-2 activity and expression in activated human monocytes via PKCalpha and PKCbeta1 inhibition. AB - OBJECTIVE: Hydroxytyrosol (HT), the major olive oil antioxidant polyphenol in cardioprotective Mediterranean diets, is endowed with anti-inflammatory and anti atherosclerotic activity. The production of cyclooxygenase (COX)-2-dependent inflammatory eicosanoids and the functionally linked release of matrix metalloproteinase (MMP)-9 by macrophages likely contribute to plaque instability leading to acute coronary events. Objective of the study was to examine the HT effects on inflammatory markers in human activated monocytes, including MMP-9 and COX-2 activity and expression and explore HT underlying mechanisms. METHODS AND RESULTS: Human peripheral blood mononuclear cells (PBMC) and U937 monocytes were treated with 1-10 MUmol/L HT before activation with phorbol myristate acetate (PMA). HT blunted monocyte matrix invasive potential and reduced MMP-9 release and expression at zymography, ELISA and RT-PCR, with an IC50 = 10 MUmol/L ( P< 0.05), without affecting tissue inhibitor of metalloproteinase (TIMP)-1. Moreover, HT inhibited prostaglandin (PG)E2 production and COX-2 expression, without affecting COX-1. These effects were mediated by inhibition of transcription factor nuclear factor (NF)-kappaB and protein kinase C (PKC)alpha and PKCbeta1 activation. CONCLUSION: HT, at nutritionally relevant concentrations, reduces MMP-9 and COX-2 induction in activated human monocytes via PKCalpha and PKCbeta1 inhibition, thus featuring novel anti-inflammatory properties. Overall, such results contribute to explaining the vascular protective effects by olive oil polyphenols in Mediterranean diets. PMID- 24401213 TI - A polymorphism at IGF1 locus is associated with carotid intima media thickness and endothelium-dependent vasodilatation. AB - OBJECTIVE: Whether IGF-1 has a protective or a detrimental role in vascular homeostasis remains unsettled. There is evidence that the C/T polymorphism rs35767 near the promoter region of the IGF1 gene located in chromosome 12 is associated with plasma IGF-1 levels. We investigated the effects of this polymorphism on circulating IGF-1 levels, carotid intima media thickness (cIMT) and endothelial-dependent vasodilation. METHODS: Two samples of adult nondiabetic Whites were studied. Sample 1 comprised 1124 individuals in whom cIMT was measured by ultrasonography. Sample 2 included 162 drug-naive hypertensive individuals in whom endothelium-dependent and endothelium-independent vasodilation were assessed by intra-arterial infusion of acetylcholine (ACh), and sodium nitroprusside (SNP), respectively. IGF-1 was determined by chemiluminescent immunoassay. rs35767 polymorphism was screened using a TaqMan allelic discrimination assay. RESULTS: In sample 1, IGF-1 levels were higher in subjects carrying the T allele compared with CC carriers (178 +/- 78 vs. 166 +/- 60 ng/mL, respectively; P = 0.007 adjusted for age, gender, and BMI). cIMT was lower in subjects carrying the T allele compared with CC carriers (0.71 +/- 0.20 vs. 0.76 +/- 0.22 mm, respectively; P < 0.0001 adjusted for age, gender, and BMI). In sample 2, maximally ACh-stimulated forearm blood flow was higher in subjects carrying the T allele compared with CC carriers (343 +/- 191 vs. 281 +/- 125%, respectively; P = 0.02 adjusted for age, gender, and BMI). CONCLUSION: Subjects carrying the T allele exhibited significantly higher levels of circulating IGF-1, lower values of cIMT, and higher endothelium-dependent vasodilatation compared with CC carriers. These findings support the idea that IGF-1 plays a role in the pathogenesis of atherosclerosis. PMID- 24401214 TI - Intensive lipid lowering therapy with titrated rosuvastatin yields greater atherosclerotic aortic plaque regression: Serial magnetic resonance imaging observations from RAPID study. AB - OBJECTIVE: Although previous randomized clinical trials established a basis for lipid guidelines worldwide, they employed fixed doses of statins throughout trials (fire-and-forget approach). In the real clinical setting, however, statin doses are titrated to achieve target low-density lipoprotein cholesterol (LDL-C) levels (treat-to-target approach). The major objective was to investigate whether intensive lipid-lowering therapy using the treat-to-target approach yielded greater regression of aortic plaques. METHODS: We therefore performed a prospective, randomized trial comparing the effects of standard (achieve LDL-C levels recommended by the Japanese guidelines) and intensive (achieve 30% lower LDL-C levels than standard) rosuvastatin therapy for 1 year in 60 hypercholesterolemic patients with a primary endpoint of aortic atherosclerotic plaques evaluated by non-invasive magnetic resonance imaging (MRI). RESULTS: Average doses were 2.9 +/- 3.1 and 6.5 +/- 5.1 mg/day for standard (n = 29) and intensive therapy group (n = 31), respectively. Although both therapies significantly reduced LDL-C and high-sensitivity C-reactive protein (hsCRP) levels, LDL-C reduction was significantly greater in the intensive group (-46 vs. -34%). MRI study showed that thoracic aortic plaques were significantly regressed in both groups, with greater regression of thoracic plaque in the intensive group (-9.1 vs. -3.2%, p = 0.01). Multivariate analyses revealed that thoracic plaque regression was significantly correlated with hsCRP reduction, but not with changes in serum lipids, endothelial function, or doses of rosuvastatin. CONCLUSION: Intensive statin therapy with titration targeting lower LDL-C levels resulted in greater thoracic aortic plaque regression compared to standard therapy, which was correlated with hsCRP reduction, suggesting that intensive statin therapy could provide better clinical outcomes. PMID- 24401215 TI - Curcumin modulation of high fat diet-induced atherosclerosis and steatohepatosis in LDL receptor deficient mice. AB - OBJECTIVE: Consuming curcumin may benefit health by modulating lipid metabolism and suppressing atherogenesis. Fatty acid binding proteins (FABP-4/aP2) and CD36 expression are key factors in lipid accumulation in macrophages and foam cell formation in atherogenesis. Our earlier observations suggest that curcumin's suppression of atherogenesis might be mediated through changes in aP2 and CD36 expression in macrophages. Thus, this study aimed to further elucidate the impact of increasing doses of curcumin on modulation of these molecular mediators on high fat diet-induced atherogenesis, inflammation, and steatohepatosis in Ldlr(-/ ) mice. METHODS: Ldlr(-/-) mice were fed low fat (LF) or high fat (HF) diet supplemented with curcumin (500 HF + LC; 1000 HF + MC; 1500 HF + HC mg/kg diet) for 16 wks. Fecal samples were analyzed for total lipid content. Lipids accumulation in THP-1 cells and expression of aP2, CD36 and lipid accumulation in peritoneal macrophages were measured. Fatty streak lesions and expression of IL-6 and MCP-1 in descending aortas were quantified. Aortic root was stained for fatty and fibrotic deposits and for the expression of aP2 and VCAM-1. Total free fatty acids, insulin, glucose, triglycerides, and cholesterol as well as several inflammatory cytokines were measured in plasma. The liver's total lipids, cholesterol, triglycerides, and HDL content were measured, and the presence of fat droplets, peri-portal fibrosis and glycogen was examined histologically. RESULTS: Curcumin dose-dependently reduced uptake of oxLDL in THP-1 cells. Curcumin also reduced body weight gain and body fat without affecting fat distribution. During early intervention, curcumin decreased fecal fat, but at later stages, it increased fat excretion. Curcumin at medium doses of 500-1000 mg/kg diet was effective at reducing fatty streak formation and suppressing aortic expression of IL-6 in the descending aorta and blood levels of several inflammatory cytokines, but at a higher dose (HF + HC, 1500 mg/kg diet), it had adverse effects on some of these parameters. This U-shape like trend was also present when aortic root sections were examined histologically. However, at a high dose, curcumin suppressed development of steatohepatosis, reduced fibrotic tissue, and preserved glycogen levels in liver. CONCLUSION: Curcumin through a series of complex mechanisms, alleviated the adverse effects of high fat diet on weight gain, fatty liver development, dyslipidemia, expression of inflammatory cytokines and atherosclerosis in Ldlr(-/-) mouse model of human atherosclerosis. One of the mechanisms by which low dose curcumin modulates atherogenesis is through suppression of aP2 and CD36 expression in macrophages, which are the key players in atherogenesis. Overall, these effects of curcumin are dose-dependent; specifically, a medium dose of curcumin in HF diet appears to be more effective than a higher dose of curcumin. PMID- 24401216 TI - Reduced CD14 expression on classical monocytes and vascular endothelial adhesion markers independently associate with carotid artery intima media thickness in chronically HIV-1 infected adults on virologically suppressive anti-retroviral therapy. AB - HIV infection causes systemic immune inflammation, and increases the risk for cardiovascular (CVD) disease even among those on virologically suppressive anti retroviral treatment (ART). We performed a biostatistical analysis and screen of candidate cellular and plasma biomarkers for association with carotid artery intima-media thickness (CIMT), independent of traditional CVD risk factors such as age, gender, systolic blood pressure (SBP), lipid levels, smoking and diabetes. We conducted a multi-stage analysis based on a cross-sectional study of CVD risk in HIV-infected subjects age >45 years on ART for >6 months. The goal of this analysis was to identify candidate cellular and plasma biomarkers of CIMT in HIV-1 infected adults. We further sought to determine if these candidate biomarkers were independent of traditional CVD risk factors previously identified in HIV negative adults. High-resolution B-mode ultrasound images of the right common carotid common artery (CCA) were obtained. Plasma soluble inflammatory mediators, cytokines and chemokines were detected. Monocytes were defined by CD14/CD16 expression, and CD8+ T-cell activation by CD38/HLA-DR expression. Subjects were a median of 49.5 years old, 87% male, had a CIMT of 0.73 mm, FRS of 6%, a median viral load of 48 copies/mL, and CD4+ T cell count of 479 cells/MUL. Soluble VCAM-1, and expansion of CD14dimCD16- monocytes each associated with higher CIMT independently of age and SBP. These factors are distinct components of a shared atherogenic process; 1) vascular endothelial molecular expression and 2) vascular monocytes that enter into the vascular endothelium and promote atherosclerotic plaque. PMID- 24401217 TI - Airflow limitation in smokers is associated with arterial stiffness: the Nagahama Study. AB - BACKGROUND: Pathophysiological mechanisms of associations between airflow limitation (AL) and arterial stiffness remain unclear. One factor that might affect both AL and arterial stiffness is habitual smoking. The aim of this study is to investigate a possible interaction of smoking on the association between AL and arterial stiffness. METHODS: Study subjects consisted of 8790 apparently healthy community residents. Airflow limitation was defined as a ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity of less than 70%. Brachial-to-ankle pulse wave velocity (baPWV) was used as an index of arterial stiffness. Smoking habit was investigated using a structured questionnaire. RESULTS: Subjects with AL had significantly higher baPWV (AL 1381 +/- 334, control 1261 +/- 227 cm/s, p < 0.001). In a separate analysis by smoking habit, advanced arterial stiffness in AL was observed only in smokers (non-smokers: AL 1300 +/- 220, control 1260 +/- 218; smokers: AL 1436 +/- 384, control 1264 +/- 243 cm/s). Other clinical features of subjects with AL were older age; increased plasma hsCRP levels; and a high prevalence of male sex, hypertension, and smoking experience. Multiple linear regression analysis adjusted for these covariates identified the smoking * AL interaction as an independent determinant of baPWV (beta = 0.066, p < 0.001). Conversely, baPWV was an independent determinant of AL in current and past smokers, but not in never smokers. CONCLUSIONS: AL arising from cigarette smoking, but not AL in non-smokers, was associated with arterial stiffness in a general population independently of established risk factors. Measurement of subclinical arterial change in smokers may be useful in identifying persons at risk for AL. PMID- 24401218 TI - HDL-C, triglycerides and carotid IMT: a meta-analysis of 21,000 patients with automated edge detection IMT measurement. AB - OBJECTIVE: Common carotid artery (CCA) intima-media thickness (IMT), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL C), but not triglyceride levels, are markers of future cardiovascular events. The relationship between these three factors is, however, unclear. METHODS: We included six large observational studies that used the same harmonized, B-mode ultrasound protocol, the same software for IMT measurement by automatic edge detection on CCA in a plaque-free region, following the Mannheim consensus, and certification of all sonographers. Using the best view of the CCA, the sonographer had to confirm that the quality index was >= 0.5 on a measurement performed on 10-mm length. We used individual data meta-analysis to estimate the cross-sectional associations of lipids with CCA-IMT. RESULTS: Overall, 21,587 patients with complete information on lipids and CCA-IMT were available. Age- and sex-adjusted CCA-IMT differed by -7.8 MUm (95% CI -9.1 to -6.5 MUm, P < 0.001) per 1 SD higher HDL-C level. After further adjustment for other atherosclerosis risk factors, the relationship was attenuated, but remained significant (regression coefficient, -3.7 MUm; P < 0.001). This was found regardless of LDL-C levels (P for heterogeneity = 0.70). After adjustment for age and sex, triglycerides were positively associated with CCA-IMT, overall and in each LDL-C subgroup, but not after further adjustments for other risk factors. CONCLUSIONS: Relationships between HDL-C and triglyceride levels and CCA-IMT were consistent with that previously observed with clinical events by the Emergency Risk Collaboration group, including at low LDL-C levels. This reinforces the need to verify whether raising HDL-C levels decreases both CCA-IMT and future clinical events. PMID- 24401219 TI - Subclinical cardiovascular disease in plaque psoriasis: association or causal link? AB - BACKGROUND: Psoriasis patients have a high prevalence of cardiovascular events and are thought to have a relative risk increase of 25% as compared to the general population. However, a causal relationship between psoriasis and cardiovascular disease has not been established. We sought to perform a systematic review of existing data regarding the presence of endothelial dysfunction and subclinical atherosclerosis in patients with plaque psoriasis. METHODS: A systematic literature search was performed, using Medline database and Ovid SP for relevant literature up to November 2012. Twelve studies met inclusion criteria from an initial search result of 529 articles. RESULTS: Among the twelve studies meeting inclusion criteria, two (17%) reported increased mean coronary artery calcification (CAC) in psoriatic patients. Six studies (50%) showed carotid intima-media thickness [CIMT] increase in psoriasis. Five studies (42%) examined flow mediated dilation [FMD], of which three showed decreased FMD in psoriasis patients. One study (8%) each demonstrated a decreased coronary flow reserve and increased arterial stiffness as assessed by pulse wave velocity. CONCLUSIONS: Patients with psoriasis have an increased burden of subclinical atherosclerosis and endothelial dysfunction. Patients with greater severity and/or disease duration should be targeted for primary screening for cardiovascular disease risk reduction. PMID- 24401220 TI - Erythrocyte membrane n-3 fatty acid levels and carotid atherosclerosis in Chinese men and women. AB - OBJECTIVE: Prospective studies have supported the beneficial effects of n-3 fatty acid consumption on cardiac deaths, but limited data focused on atherosclerosis. We investigated the associations between n-3 fatty acids in erythrocytes and atherosclerosis in middle-aged and older Chinese. METHODS: 847 subjects (285 men and 562 women), aged 40-65 years, from Guangzhou, China were included in this community-based cross-sectional study between December 2005 and January 2008. The levels of alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in erythrocytes were measured by gas chromatography. Carotid ultrasound examination was conducted to obtain intima-media thickness of the common carotid artery and the carotid bifurcation. Dietary data and other covariates were collected using interviewer-administered questionnaires. RESULTS: After adjustment for age, sex, and other confounders, negative dose-response associations between the contents of individual n-3 polyunsaturated fatty acids in the erythrocyte membrane and the prevalence of carotid artery wall thickening and plaque were observed. A comparison in the highest and lowest tertiles gave odds ratios (95% confidence interval) for thickening in the walls of the common carotid artery of 0.58 (0. 34-0.97; P-trend = 0. 037) for DHA, and 0.39 (0.23 0.67; P-trend < 0.001) for ALA. However, EPA was not significantly associated with carotid atherosclerosis. Similar results were found for thickening at the carotid bifurcation and the occurrence of carotid artery plaque. CONCLUSIONS: Higher levels of DHA and ALA in the erythrocyte membrane were significantly associated with a lower burden of subclinical atherosclerosis. PMID- 24401222 TI - An association between central aortic pressure and subclinical organ damage of the heart among a general Japanese cohort: Circulatory Risk in Communities Study (CIRCS). AB - BACKGROUND: This study aimed to investigate associations between central aortic pressure (CAP) and subclinical organ damage of the heart amongst the general population. METHODS: We conducted a cross-sectional study in a community-based population, consisting of 3002 men and women aged between 40 and 79 years. The CAP was measured using the HEM-9000AI device, an automated tonometer. Electrocardiograms (ECG) were read according to the Minnesota Code. Subclinical organ damage in the heart was defined as measurable left high amplitude R waves (LHAR), major and minor ST-T abnormalities, and left ventricular hypertrophy (LVH). RESULTS: Age- and sex-adjusted prevalence of LHAR, major and minor ST-T abnormalities, and LVH was higher for subjects in the highest tertile of CAP levels than those in the lowest tertile. After further adjustments for other cardiovascular risk factors, these associations did not change substantially. The multivariable odds ratios (ORs) (95% CI) of LHAR, major and minor ST-T abnormalities, and LVH for the highest tertile of CAP levels compared to the lowest tertile were 2.7(1.9-3.9), 1.8(1.1-2.9), 1.7(1.3-2.3) and 3.2(1.3-8.1), respectively. The positive associations with LHAR and minor ST-T abnormalities were observed primarily among non-hypertensive subjects. The respective corresponding ORs were 2.8(1.7-4.6) and 1.7(1.2-2.4) for non-hypertensive subjects, and 1.7(0.9-3.3) and 1.1(0.7-1.8) for hypertensive subjects. CONCLUSION: CAP levels were associated with subclinical organ damage of the heart independent of cardiovascular risk factors, and these associations were primarily seen in non-hypertensive subjects. PMID- 24401223 TI - Cardiovascular risk, lipidemic phenotype and steatosis. A comparative analysis of cirrhotic and non-cirrhotic liver disease due to varying etiology. AB - BACKGROUND: Liver regulates lipid metabolism in health and disease states. Nevertheless, the entity of cardiovascular risk (CVR) resulting from dysregulation of lipid metabolism secondary to liver disease is poorly characterized. AIM AND METHODS: To review, based on a PubMed literature search, the features and the determinants of serum lipid phenotype and its correlation with hepatic steatosis, insulin resistance (IR) and CVR across the wide spectrum of the most common chronic liver diseases due to different etiologies. RESULTS: Alcoholic liver disease (ALD) is associated with steatosis, IR and a typical lipid profile. The relationship between alcohol intake, incident type 2 diabetes (T2D) and CVR describes a J-shaped curve. Non-alcoholic fatty liver disease (NAFLD), and probably nonalcoholic steatohepatitis (NASH) in particular, is associated with IR, atherogenic dyslipidemia and increased CVR independent of traditional risk factors. Moreover, NASH-cirrhosis and T2D contribute to increasing CVR in liver transplant recipients. HBV infection is generally free from IR, steatosis and CVR. HCV-associated dysmetabolic syndrome, featuring steatosis, hypocholesterolemia and IR, appears to be associated with substantially increased CVR. Hyperlipidemia is an almost universal finding in primary biliary cirrhosis, a condition typically spared from steatosis and associated with neither subclinical atherosclerosis nor excess CVR. Finally, little is known on CVR in patients with hepatocellular carcinoma. CONCLUSIONS: CVR is increased in ALD, NAFLD and chronic HCV infection, all conditions featuring IR and steatosis. Therefore, irrespective of serum lipid phenotype, hepatic steatosis and IR may be major shared determinants in amplifying CVR in common liver disease due to varying etiology. PMID- 24401221 TI - Efficacy, safety and effect on biomarkers related to cholesterol and lipoprotein metabolism of rosuvastatin 10 or 20 mg plus ezetimibe 10 mg vs. simvastatin 40 or 80 mg plus ezetimibe 10 mg in high-risk patients: Results of the GRAVITY randomized study. AB - OBJECTIVES: Combination therapy may help high-risk patients achieve low-density lipoprotein cholesterol (LDL-C) goals. Impact of rosuvastatin 10 or 20 mg plus ezetimibe 10 mg (RSV10/EZE10 and RSV20/EZE10) has not been fully characterized previously. GRAVITY (NCT00525824) compared efficacy, safety and effect on biomarkers of RSV10/EZE10 and RSV20/EZE10 vs. simvastatin 40 mg and 80 mg plus EZE10 (SIM40/EZE10 and SIM80/EZE10) in patients with coronary heart disease (CHD) or CHD risk equivalent. METHODS: Adult patients (n = 833) were randomized to RSV10/EZE10, RSV20/EZE10, SIM40/EZE10 or SIM80/EZE10. Following a 6-week dietary lead-in, patients received 6 weeks' statin monotherapy followed by same statin dose plus ezetimibe for 6 more weeks. Primary endpoint was LDL-C change from baseline to 12 weeks. RESULTS: Significantly greater (p < 0.05) reductions in LDL C and other atherogenic lipids were observed with RSV20/EZE10 vs. SIM40/EZE10 and SIM80/EZE10 and with RSV10/EZE10 vs. SIM40/EZE10. A significantly greater proportion of patients achieved LDL-C goals of <100 mg/dl and <70 mg/dl with RSV20/EZE10 vs. SIM40/EZE10 and SIM80/EZE10 and with RSV10/EZE10 vs. SIM40/EZE10. LDL-C was reduced ~10-14% further with combination therapy vs. monotherapy. Statin monotherapy reduced cholesterol and bile acid synthesis biomarkers, ezetimibe reduced beta-sitosterol (sterol absorption marker), and combination therapy achieved additive reductions in lipoprotein-associated phospholipase A2 mass and activity, free cholesterol and 7-ketocholesterol. Safety profiles of rosuvastatin/ezetimibe and simvastatin/ezetimibe combinations were comparable. CONCLUSION: Co-administration of rosuvastatin 10 or 20 mg plus ezetimibe achieved significant improvements in lipid profiles in high-risk patients vs. simvastatin 40 or 80 mg plus ezetimibe. PMID- 24401224 TI - CER-001, a HDL-mimetic, stimulates the reverse lipid transport and atherosclerosis regression in high cholesterol diet-fed LDL-receptor deficient mice. AB - OBJECTIVE: CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and phospholipids that was designed to mimic the beneficial properties of nascent pre-beta HDL. In this study, we have evaluated the capacity of CER-001 to perform reverse lipid transport in single dose studies as well as to regress atherosclerosis in LDLr(-/-) mice after short-term multiple-dose infusions. APPROACH AND RESULTS: CER-001 induced cholesterol efflux from macrophages and exhibited anti-inflammatory response similar to natural HDL. Studies with HUVEC demonstrated CER-001 at a concentration of 500 MUg/mL completely suppressed the secretion of cytokines IL-6, IL-8, GM-CSF and MCP-1. Following infusion of CER-001 (10mg/kg) in C57Bl/6J mice, we observed a transient increase in the mobilization of unesterified cholesterol in HDL particles containing recombinant human apoA-I. Finally we show that cholesterol elimination was stimulated in CER-001 treated animals as demonstrated by the increased cholesterol concentration in liver and feces. In a familial hypercholesterolemia mouse model (LDL-receptor deficient mice), the infusion of CER-001 caused 17% and 32% reductions in plaque size, 17% and 23% reductions in lipid content after 5 and 10 doses given every 2 days, respectively. Also, there was an 80% reduction in macrophage content in the plaque following 5 doses, and decreased VCAM-1 expression by 16% and 22% in the plaque following 5 and 10 intravenous doses of CER-001, respectively. CONCLUSION: These data demonstrate that CER-001 rapidly enhances reverse lipid transport in the mouse, reducing vascular inflammation and promoting regression of diet-induced atherosclerosis in LDLr(-/-) mice upon a short-term multiple dose treatment. PMID- 24401225 TI - Response to antiplatelet therapy and platelet reactivity to thrombin receptor activating peptide-6 in cardiovascular interventions: Differences between peripheral and coronary angioplasty. AB - BACKGROUND: The long-term prognosis of patients with peripheral arterial disease (PAD) is significantly worse than the prognosis of coronary artery disease (CAD) patients. Detrimental platelet activation could contribute to the increased rate of adverse cardiovascular events in PAD. We therefore investigated whether response to antiplatelet therapy and thrombin inducible platelet activation differ between patients with best medical therapy undergoing angioplasty and stenting for symptomatic PAD (n = 166) or CAD (n = 104). METHODS: Adenosine diphosphate (ADP), arachidonic acid (AA) and thrombin receptor activating peptide (TRAP)-6 inducible platelet reactivity was measured by multiple electrode aggregometry (MEA). Platelet surface expression of P-selectin and activated glycoprotein IIb/IIIa (GPIIb/IIIa) in response to ADP, AA, and TRAP-6, and the formation of monocyte-platelet aggregates (MPA) in response to ADP and TRAP-6 were assessed by flow cytometry. RESULTS: Patients with PAD had significantly higher platelet reactivity in response to ADP and AA by MEA compared to CAD patients. Likewise, the expression of P-selectin and GPIIb/IIIa following stimulation with ADP and AA, and MPA formation in response to ADP were significantly higher in PAD patients than in CAD patients. In response to TRAP-6, patients with PAD showed a significantly increased platelet aggregation by MEA, higher expression of activated GPIIb/IIIa, and more pronounced formation of MPA than CAD patients. CONCLUSION: Following angioplasty and stenting, PAD patients exhibit a significantly diminished response to dual antiplatelet therapy and an increased susceptibility to TRAP-6 inducible platelet activation compared to CAD patients. PMID- 24401226 TI - Effect of fructose on postprandial triglycerides: a systematic review and meta analysis of controlled feeding trials. AB - BACKGROUND: In the absence of consistent clinical evidence, concerns have been raised that fructose raises postprandial triglycerides. PURPOSE: A systematic review and meta-analysis was conducted to assess the effect of fructose on postprandial triglycerides. DATA SOURCES: Relevant studies were identified from MEDLINE, EMBASE, and Cochrane databases (through September 3, 2013). DATA SELECTION: Relevant clinical trials of >= 7-days were included in the analysis. DATA EXTRACTION: Two independent reviewers extracted relevant data with disagreements reconciled by consensus. The Heyland Methodological Quality Score (MQS) assessed study quality. Data were pooled by the generic inverse variance method using random effects models and expressed as standardized mean differences (SMD) with 95% confidence intervals (CI). Heterogeneity was assessed (Cochran Q statistic) and quantified (I(2) statistic). DATA SYNTHESIS: Eligibility criteria were met by 14 isocaloric trials (n = 290), in which fructose was exchanged isocalorically for other carbohydrate in the diet, and two hypercaloric trials (n = 33), in which fructose supplemented the background diet with excess energy from high-dose fructose compared with the background diet alone (without the excess energy). There was no significant effect in the isocaloric trials (SMD: 0.14 [95% CI: -0.02, 0.30]) with evidence of considerable heterogeneity explained by a single trial. Hypercaloric trials, however, showed a significant postprandial triglyceride raising-effect of fructose (SMD: 0.65 [95% CI: 0.30, 1.01]). LIMITATIONS: Most of the available trials were small, short, and of poor quality. Interpretation of the isocaloric trials is complicated by the large influence of a single trial. CONCLUSIONS: Pooled analyses show that fructose in isocaloric exchange for other carbohydrate does not increase postprandial triglycerides, although an effect cannot be excluded under all conditions. Fructose providing excess energy does increase postprandial triglycerides. Larger, longer, and higher-quality trials are needed. PROTOCOL REGISTRATION: ClinicalTrials.gov identifier, NCT01363791. PMID- 24401227 TI - Relationship of lipid oxidation with subclinical atherosclerosis and 10-year coronary events in general population. AB - OBJECTIVES: To assess 1) the association of lipid oxidation biomarkers with 10 year coronary artery disease (CAD) events and subclinical atherosclerosis, and 2) the reclassification capacity of these biomarkers over Framingham-derived CAD risk functions, in a general population. METHODS: Within the framework of the REGICOR study, 4782 individuals aged between 25 and 74 years were recruited in a population-based cohort study. Follow-up of the 4042 who met the eligibility criteria was carried out. Plasma, circulating oxidized low-density lipoprotein (oxLDL) and oxLDL antibodies (OLAB) were measured in a random sample of 2793 participants. End-points included fatal and non-fatal acute myocardial infarction (AMI) and angina. Carotid intima-media thickness (IMT) in the highest quintile and ankle-brachial index <0.9 were considered indicators of subclinical atherosclerosis. RESULTS: Mean age was 50.0 (13.4) years, and 52.4% were women. There were 103 CAD events (34 myocardial infarction, 43 angina, 26 coronary deaths), and 306 subclinical atherosclerosis cases. Oxidized LDL was independently associated with higher incidence of CAD events (HR = 1.70; 95% Confidence Interval: 1.02-2.84), but not with subclinical atherosclerosis. The net classification index of the Framingham-derived CAD risk function was significantly improved when ox-LDL was included (NRI = 14.67% [4.90; 24.45], P = 0.003). No associations were found between OLAB and clinical or subclinical events. The reference values for oxLDL and OLAB are also provided (percentiles). CONCLUSIONS: OxLDL was independently associated with 10-year CAD events but not subclinical atherosclerosis in a general population, and improved the reclassification capacity of Framingham-derived CAD risk functions. PMID- 24401228 TI - Simvastatin treatment upregulates intestinal lipid secretion pathways in a rodent model of the metabolic syndrome. AB - OBJECTIVE: Statins are widely used for the treatment of hyperlipidemia to reduce cardiovascular disease (CVD) risk. Intriguingly, recent reports suggest that whilst statins are effective in reducing hepatic cholesterol synthesis, they in turn may up-regulate intestinal cholesterol absorption. The direct effects and/or mechanisms of this phenomenon remain largely unknown. The aim of this study was to investigate the potential for statins to increase intestinal lipid absorption and/or secretion in a rodent model of the metabolic syndrome (MetS). METHODS AND RESULTS: Mets JCR:LA-cp rats received a 1% cholesterol diet containing Simvastatin (0.01% w/w), for 8 weeks. Fasting and postprandial plasma biochemical profile was assessed using enzymatic assays and a modified apoB48 (chylomicron; CM) western blotting protocol. Statin treatment reduced fasting plasma TG (-49%), cholesterol (-24%) and postprandial plasma apoB48 (-58%). The intestinal secretion of lipids into mesenteric lymph was assessed using lymph fistulae procedures. Interestingly, MetS rats treated with statin secreted greater cholesterol (1.9-fold) and TG (1.5-fold) per apoB48 particle, into mesenteric lymph. This was shown to be as a result of simvastatin-induced increase in intestinal cholesterol absorption (31.5%). Experiments using in vivo inhibition of lipoprotein lipase (LPL; poloxamer-407) demonstrated statin treatment reduced hepatic cholesterol secretion (-49%), but significantly increased hepatic (73%) TG secretion in MetS rats. Statin treatment also increased the expression of genes involved in lipid synthesis (Hmgcr, Srebp1, Fas, Acc; 33-67%) and reduced those involved in efflux (Abca1, Abcg8; -36 to 73%) in enterocytes and liver of MetS rats versus untreated control. CONCLUSIONS: In a rodent model of MetS, statin treatment adversely up-regulates intestinal lipid secretion as a result of increased intestinal cholesterol absorption, and increases the intestinal expression of genes involved in lipid synthesis; effects which may confound clinical benefits to remnant dyslipidemia. PMID- 24401229 TI - Inverse correlation between coronary and retinal blood flows in patients with normal coronary arteries and slow coronary blood flow. AB - BACKGROUND: The "Slow Coronary Flow" (SCF) phenomenon in the presence of angiographically normal coronaries is attributed to microvascular and endothelial dysfunction. The microcirculation can be non-invasively assessed by measuring retinal blood flow velocity. The aim of the present study was to evaluate the efficacy of the "Retinal Functional Imager" (RFI) device as a noninvasive method of diagnosing patients with slow coronary flow. METHODS: Coronary blood flow velocity assessed by corrected TIMI Frame Count and retinal arterioles blood flow assessed by RFI were measured in 28 consecutive patients with normal coronary arteries. The patients were divided into 2 groups: a slow coronary flow (SCF) and a normal coronary flow (NCF) groups. RESULTS: Inverse correlation was found between retinal and coronary blood flows so that higher retinal arterial flow velocity was observed in the SCF group (3.8 +/- 1.1 mm/s vs. 2.9 +/- 0.61 mm/s, respectively, p = 0.022). RFI provided 73% sensitivity and 77% specificity for diagnosing SCF using ROC analysis. Additionally, patients with SCF had higher values of serum LDL cholesterol (104.7 +/- 18.93 mg/dl vs. 81.55 +/- 14.62 mg/dl in NCF, p = 0.005), Glucose (96.9 +/- 23.0 mg/dl vs. 83.55 +/- 9.7 mg/dl in NCF, p = 0.024), and lower percentage of statin consumption (40.0% vs. 76.9% in NCF, p = 0.049). CONCLUSIONS: Slow coronary blood flow can be non-invasively diagnosed with Retinal Functional Imager. Patients with normal coronary arteries and slow coronary blood flow have high retinal arteriolar blood flow. Early non-invasive diagnosis of SCF might help detect individuals who are at higher risk to develop coronary atherosclerosis, and to provide them with early preventive measures. PMID- 24401230 TI - Reshape of the arterial wall as a slow reacting vascular structure? PMID- 24401231 TI - Metformin and liraglutide ameliorate high glucose-induced oxidative stress via inhibition of PKC-NAD(P)H oxidase pathway in human aortic endothelial cells. AB - OBJECTIVE: Metformin and glucagon like peptide-1 (GLP-1) prevent diabetic cardiovascular complications and atherosclerosis. However, the direct effects on hyperglycemia-induced oxidative stress in endothelial cells are not fully understood. Thus, we aimed to evaluate the effects of metformin and a GLP-1 analog, liraglutide on high glucose-induced oxidative stress. METHODS: Production of reactive oxygen species (ROS), activation of protein kinase C (PKC) and NAD(P)H oxidase, and changes in signaling molecules in response to high glucose exposure were evaluated in human aortic endothelial cells with and without treatment of metformin and liraglutide, alone or in combination. PKC-NAD(P)H oxidase pathway was assessed by translocation of GFP-fused PKCbeta2 isoform and GFP-fused p47phox, a regulatory subunit of NAD(P)H oxidase, in addition to endogenous PKC phosphorylation and NAD(P)H oxidase activity. RESULTS: High glucose-induced ROS overproduction was blunted by metformin or liraglutide treatment, with a further decrease by a combination of these drugs. Exposure to high glucose caused PKCbeta2 translocation and a time-dependent phosphorylation of endogenous PKC but failed to induce its translocation and phosphorylation in the cells treated with metformin and liraglutide. Furthermore, both drugs inhibited p47phox translocation and NAD(P)H oxidase activation, and prevented the high glucose-induced changes in intracellulalr diacylglycerol (DAG) level and phosphorylation of AMP-activated protein kinase (AMPK). A combination of these drugs further enhanced all of these effects. CONCLUSIONS: Metformin and liraglutide ameliorate high glucose-induced oxidative stress by inhibiting PKC NAD(P)H oxidase pathway. A combination of these two drugs provides augmented protective effects, suggesting the clinical usefulness in prevention of diabetic vascular complications. PMID- 24401232 TI - HDL anti-oxidant function associates with LDL level in young adults. AB - OBJECTIVES: The primary objective was to evaluate predictors of HDL anti-oxidant function in young adults. BACKGROUND: High-density lipoprotein (HDL) cholesterol is considered a protective factor for cardiovascular disease (CVD). However, increased levels are not always associated with decreased cardiovascular risk. A better understanding of the importance of HDL functionality and how it affects CVD risk is needed. METHODS: Fifty non-Hispanic white subjects from the Testing Responses on Youth (TROY) study were randomly selected to investigate whether differences in HDL anti-oxidant function are associated with traditional cardiovascular risk factors, including carotid intima media thickness (CIMT), arterial stiffness and other inflammatory/metabolic parameters. HDL anti-oxidant capacity was evaluated by assessing its ability to inhibit low-density lipoprotein (LDL) cholesterol oxidation by air using a DCF-based fluorescent assay and expressed as a HDL oxidant index (HOI). The associations between HOI and other variables were assessed using both linear and logistic regression. RESULTS: Eleven subjects (25%) had an HOI >= 1, indicating a pro-oxidant HDL. Age, LDL, high sensitivity C-reactive protein (hsCRP), and paraoxonase activity (PON1), but not HDL, were all associated with HOI level in univariate linear regression models. In multivariate models that mutually adjusted for these variables, LDL remained the strongest predictor of HOI (0.13 increase in HOI per 1 SD increase in LDL, 95% CI 0.04, 0.22). Atherogenic index of plasma, pulse pressure, homocysteine, glucose, insulin, CIMT and measurements of arterial stiffness were not associated with HOI in this population. CONCLUSIONS: These results suggest LDL, hsCRP and DBP might predict HDL anti-oxidant function at an early age. PMID- 24401233 TI - MicroRNA-133a regulates insulin-like growth factor-1 receptor expression and vascular smooth muscle cell proliferation in murine atherosclerosis. AB - OBJECTIVE: MicroRNA-133a (miR-133a) and insulin-like growth factor-1 (IGF-1) are two different molecules known to regulate cardiovascular cell proliferation. This study tested whether miR-133a affects expression of IGF-1 receptor (IGF-1R) and proliferation of IGF-1-stimulated vascular smooth muscle cells (VSMC) in a murine model of atherosclerosis. METHODS AND RESULTS: Expression of IGF-1R was analyzed by immuno-fluorescence and immuno-blotting, and miR-133a by qRT-PCR in the aortas of wild-type C57BL/6J (WT) and apolipoprotein-E deficient (ApoE(-/-)) mice. Compared to those in WT aortas, the IGF-1R and miR-133a levels were lower in ApoE(-/-) aortas. ApoE(-/-) VSMC grew slower than WT cells in the cultures with IGF-1-containing medium. MiR-133a-specific inhibitor decreased miR-133a, IGF-1R expression, IGF-1-stimulated VSMC growth in lipoprotein deficient media. By contrast, miR-133a precursor increased IGF-1R levels and promoted IGF-1-induced VSMC proliferation. In the luciferase-IGF-1R 3'UTR reporter system, the reporter luciferase activity was not inhibited in VSMC with miR-133a overexpression. IGF 1R mRNA half-life in ApoE(-/-) VSMC was shorter than that in WT VSMC. MiR-133a inhibitor reduced but precursor increased the mRNA half-life, although the effects appeared less striking in ApoE(-/-) VSMC than in WT cells. CONCLUSION: MiR-133a serves as a stimulatory factor for IGF-1R expression through prolonging IGF-1R mRNA half-life. In atherosclerosis induced by ApoE deficiency, reduced miR 133a expression is associated with lower IGF-1R levels and suppressive VSMC growth. Administration of miR-133a precursor may potentiate IGF-1-stimulated VSMC survival and growth. PMID- 24401234 TI - APOE polymorphism and carotid atherosclerosis in Korean population: the Dong-gu Study and the Namwon Study. AB - OBJECTIVE: We evaluated the association between APOE polymorphism and carotid atherosclerosis in two large independent cohorts from South Korea. METHODS: The datasets were from the Dong-gu Study (N = 9056) and the Namwon Study (N = 10,158). Carotid ultrasonography was performed to measure carotid intima-media thickness (IMT) and the presence of carotid plaques. The APOE polymorphism was determined by PCR-RFLP. We performed combined and separate analyses for the two datasets. RESULTS: In the combined analysis, individuals with E2E2 or E2E3 genotype had a lower common carotid IMT compared with individuals with E3E3 genotype (0.684 mm vs. 0.736 mm, p = 0.007; 0.718 mm vs. 0.736 mm, p < 0.001, respectively). This association was very slightly attenuated but remained statistically significant after adjustment for blood lipids (0.690 mm vs. 0.736 mm, p = 0.033; 0.725 mm vs. 0.736 mm, p = 0.005, respectively). Compared with individuals with E3E3 genotype, individuals with E2E3 genotype had lower risk for carotid plaque (odds ratio (OR) = 0.83, 95% confidence interval (CI) = 0.75 0.93), while individuals with E3E4 genotype had a higher risk for carotid plaque (OR = 1.09, 95% CI = 1.00-1.20). After adjustment for blood lipids, ORs of E2E3 genotype for carotid plaque was slightly attenuated but remained significant (OR = 0.87 95% CI = 0.78-0.97), while OR of E3E4 genotype were slightly attenuated and not significant (OR = 1.08, 95% CI, 0.99-1.18). CONCLUSIONS: We found that APOE polymorphism is associated with carotid atherosclerosis and this association was partly mediated through blood lipid. Our results suggest that APOE polymorphism may influence atherosclerosis through non-lipid pathways. PMID- 24401235 TI - Peripheral microvascular dysfunction predicts residual risk in coronary artery disease patients on statin therapy. AB - OBJECTIVE: Although lowering of low-density lipoprotein cholesterol (LDL-C) by statins is essential in treatment of coronary artery disease (CAD) patients, there is considerable residual risk of secondary coronary artery events (CAE). We examined whether microvascular dysfunction (MiD), measured by peripheral artery tonometry (PAT), can predict prognosis of CAD patients previously treated with statins. METHODS: We measured log-transformed reactive hyperemia index (L_RHI) in 213 CAD patients who had already achieved LDL-C <100 by statin therapy. Patients were followed-up for secondary CAE for a median of 2.7 years. Patients were divided into two groups: L_RHI >= 0.54 (n = 99) and L_RHI < 0.54 (n = 114). RESULTS: During follow-up, CAE occurred in 4 (4.0%) patients in the L_RHI >= 0.54 group and 18 (15.8%) patients in the L_RHI < 0.54 group (P = 0.006). Cox regression analysis indicated that L_RHI was an independent predictor for CAE even after adjustment by Framingham traditional risk factors (FRF; age, T-C/HDL-C ratio, systolic blood pressure, diabetes, current smoker, and gender) and estimated glomerular filtration rate (eGFR) for secondary CAE (HR 0.79, 95% CI: 0.66-0.95). ROC analysis for CAE prediction showed that the AUC for models including FRF only, FRF + eGFR, and FRF + eGFR + L_RHI were 0.60, 0.71, and 0.77, respectively. Moreover, adding eGFR to FRF only (0.63, P = 0.003) and adding L_RHI to the FRF + eGFR model were associated with significant improvement of net reclassification improvement (0.79, P = 0.007). CONCLUSION: MiD measured by non invasive PAT adds incremental predictive ability to traditional risk factors for prognosis of CAD patients successfully treated with statins. PMID- 24401237 TI - Is Toll-like receptor responsiveness a marker and predictor of coronary artery disease? PMID- 24401236 TI - Validation of the association between a branched chain amino acid metabolite profile and extremes of coronary artery disease in patients referred for cardiac catheterization. AB - OBJECTIVE: To validate independent associations between branched-chain amino acids (BCAA) and other metabolites with coronary artery disease (CAD). METHODS: We conducted mass-spectrometry-based profiling of 63 metabolites in fasting plasma from 1983 sequential patients undergoing cardiac catheterization. Significant CAD was defined as CADindex >= 32 (at least one vessel with >= 95% stenosis; N = 995) and no CAD as CADindex <= 23 and no previous cardiac events (N = 610). Individuals (N = 378) with CAD severity between these extremes were excluded. Principal components analysis (PCA) reduced large numbers of correlated metabolites into uncorrelated factors. Association between metabolite factors and significant CAD vs. no CAD was tested using logistic regression; and between metabolite factors and severity of CAD was tested using linear regression. RESULTS: Of twelve PCA-derived metabolite factors, two were associated with CAD in multivariable models: factor 10, composed of BCAA (adjusted odds ratio, OR, 1.20; 95% CI 1.05-1.35, p = 0.005) and factor 7, composed of short-chain acylcarnitines, which include byproducts of BCAA metabolism (adjusted OR 1.30; 95% CI 1.14-1.48, p = 0.001). After adjustment for glycated albumin (marker of insulin resistance [IR]) both factors 7 (p = 0.0001) and 10 (p = 0.004) remained associated with CAD. Severity of CAD as a continuous variable (including patients with non-obstructive disease) was associated with metabolite factors 2, 3, 6, 7, 8 and 9; only factors 7 and 10 were associated in multivariable models. CONCLUSIONS: We validated the independent association of metabolites involved in BCAA metabolism with CAD extremes. These metabolites may be reporting on novel mechanisms of CAD pathogenesis that are independent of IR and diabetes. PMID- 24401238 TI - Associations of matrix metalloproteinase-9 and monocyte chemoattractant protein-1 concentrations with carotid atherosclerosis, based on measurements of plaque and intima-media thickness. AB - PURPOSE: To examine associations of matrix metalloproteinase-9 (MMP-9) and monocyte chemoattractant protein-1 (MCP-1) concentrations with the severity of carotid atherosclerosis, based on measurements of carotid plaque and intima-media thickness (IMT). METHODS: This cross-sectional study included 116 stroke-free participants (45.7% males, 54.3% females; mean age, 64.73 +/- 14.53 years). Serum MMP-9 and MCP-1 concentrations were measured, and plaque morphology, including total plaque score (PS), plaque stability, and IMT, was assessed ultrasonographically. Participants were grouped according to total PS (0, 1-2, >= 3), plaque stability (no plaque, stable, unstable) and IMT tertiles (<0.8 mm, 0.8 1 mm, >1 mm). Multinomial logistic regression models were used to assess the associations of MMP-9 and MCP-1 concentrations with plaque and IMT values after adjusting for vascular risk factors. RESULTS: MMP-9 quartiles (vs. quartile 1) were significantly associated with a greater prevalence of plaque instability [Q2: odds ratio (OR) = 5.13, 95% confidence interval (CI) = 1.01-24.9, p = 0.042; Q3: OR = 15.5, 95% CI = 3.1-78.1, p = 0.001; Q4: OR = 13.2, 95% CI = 2.7-64.97, p = 0.001] and high total PS (Q3: OR = 10.02, 95% CI = 1.5-65.33, p = 0.016; Q4: OR = 21.5, 95% CI = 3.5-132.1, p = 0.001). MCP-1 concentration was significantly associated with IMT (OR = 22.94, 95% CI = 2.14-245.66, p = 0.01). CONCLUSIONS: Elevated serum MMP-9 concentration was independently associated with high total carotid artery PS, plaque instability, and large IMT value. MCP-1 concentration was independently associated with IMT, but not with plaque morphology. PMID- 24401239 TI - Pomegranate extract (POMx) decreases the atherogenicity of serum and of human monocyte-derived macrophages (HMDM) in simvastatin-treated hypercholesterolemic patients: a double-blinded, placebo-controlled, randomized, prospective pilot study. AB - OBJECTIVE: To analyze pomegranate extract (POMx) effects on serum and on human HMDM atherogenicity in simvastatin - treated hypercholesterolemic patients. METHODS AND RESULTS: Patients were randomly assigned to receive either simvastatin (20 mg/day) + vegan placebo pill (n = 11), or simvastatin (20 mg/day) + POMx pill (1g/day, n = 12). Fasting blood samples were collected at baseline and after 1 and 2 months of therapy. HMDM were collected from 3 patients in each group at baseline and after 2 months of therapy, as well as from 3 healthy subjects. After 2 months of therapy, serum LDL-cholesterol levels significantly decreased, by 23%, in the simvastatin + placebo group, and by 26% in the simvastatin + POMx group. Simvastatin + POMx therapy increased serum thiols concentration by 6%. Patients' HMDM reactive oxygen species (ROS) levels were significantly increased, by 69%, vs. healthy subjects HMDM. After 2 months of therapy, HMDM ROS levels decreased by 18% in the simvastatin + placebo group, whereas in the simvastatin + POMx group it decreased by up to 30%. A novel finding was the triglycerides levels in the patients' HMDM at baseline which were significantly higher, by 71%, vs. healthy subjects HMDM. The simvastatin + POMx, but not the simvastatin + placebo therapy, significantly reduced macrophage triglycerides content by 48%, vs. baseline levels. In addition, whereas the simvastatin + placebo therapy significantly decreased the patients' HMDM cholesterol biosynthesis rate by 33%, the simvastatin + POMx therapy further decreased it, by 44%. CONCLUSION: The addition of POMx to simvastatin therapy in hypercholesterolemic patients improved oxidative stress and lipid status in the patient's serum and in their HMDM. These anti-atherogenic effects could reduce the risk for atherosclerosis development. PMID- 24401240 TI - Postprandial effects of a high salt meal on serum sodium, arterial stiffness, markers of nitric oxide production and markers of endothelial function. AB - AIM: The aim of the study was to determine if a high salt meal containing 65 mmol Na causes a rise in sodium concentrations and a reduction in plasma nitrate/nitrite concentrations (an index of nitric oxide production). Secondary aims were to determine the effects of a high salt meal on augmentation index (AIx) a measure of arterial stiffness and markers of endothelial function. METHODS AND RESULTS: In a randomised cross-over study 16 healthy normotensive adults consumed a low sodium soup containing 5 mmol Na and a high sodium soup containing 65 mmol Na. Sodium, plasma nitrate/nitrite, endothelin-1 (ET-1), C reactive protein (CRP), vasopressin (AVP) and atrial natriuretic peptide (ANP) concentrations before and every 30 min after the soup for 2 h. Blood pressure (BP) and AI were also measured at these time points. There were significant increases in serum sodium, osmolality and chloride in response to the high sodium meal. However plasma nitrate/nitrite concentrations were not different between meals (meal p = 0.812; time p = 0.45; meal * time interaction p = 0.50). Plasma ANP, AVP and ET-1 were not different between meals. AI was significantly increased following the high sodium meal (p = 0.02) but there was no effect on BP. CONCLUSIONS: A meal containing 65 mmol Na increases serum sodium and arterial stiffness but does not alter postprandial nitrate/nitrite concentration in healthy normotensive individuals. Further research is needed to explore the mechanism by which salt affects vascular function in the postprandial period. This trial was registered with the Australian and New Zealand Clinical Trials Registry Unique Identifier: ACTRN12611000583943http://www.anzctr.org.au/trial_view.aspx?ID=343019. PMID- 24401241 TI - Reversal of atherosclerosis with apolipoprotein A1: back to basics. PMID- 24401242 TI - The J-curve relationship between diastolic pressure and coronary collateral circulation in patients with single chronic total occlusion. AB - BACKGROUND: In our previous study, we had shown that high diastolic blood pressure (DBP) was positively related to well-developed coronary collateral circulation (CCC). This study sought to find out the more precise relationship between DBP and CCC. METHODS AND RESULTS: To investigate this, we conducted a study of 671 patients with single chronic total occlusion of coronary artery. The DBP of the patients was divided into six groups: <= 65 mmHg, >65-<= 75 mmHg, >75 <= 85 mmHg, >85-<= 95 mmHg, >95-<= 105 mmHg, >105 mmHg). The extent of CCC was graded as poorly-developed or well-developed collaterals according to Rentrop classification. There was a J-curve relationship between the level of DBP and the incidence of poorly-developed collaterals. CONCLUSION: The relationship between DBP and CCC is similar to the J-curve relationship between DBP and cardiovascular risk. The influence of DBP on the development of CCC may be one of the pathophysiologic mechanisms of the J-curve phenomenon relating DBP to cardiovascular risk. PMID- 24401243 TI - Continuation of statin therapy and a decreased risk of atrial fibrillation/flutter in patients with and without chronic kidney disease. AB - BACKGROUND: To contain cost, Taiwan's previous National Health Insurance Reimbursement Policy requested that physicians discontinue their patients' statin therapy once the serum cholesterol had reached appropriate levels. This allowed us to evaluate the association between statin continuation and the occurrence of atrial fibrillation/flutter and whether it was modified by chronic kidney disease (CKD) status. METHODS: Patients who initiated statin therapy between January 1, 2001 and December 31, 2009 were identified from a random sample of one million subjects in the Taiwan National Health Insurance Research Database. The outcome was atrial fibrillation/flutter. A proportional hazard regression model with time varying statin use was applied to estimate the hazard ratios (HR) and 95% confidence intervals (CIs) for atrial fibrillation/flutter according to current statin use versus treatment discontinuation, adjusted for baseline disease risk scores and time-varying covariates. RESULTS: A total of 6767 CKD and 63,678 non CKD patients initiating statin therapy were included and followed for an average of 4.0 years. A total of 1118 participants experienced new-onset atrial fibrillation/flutter. The incidence of atrial fibrillation/flutter was approximately 2 fold higher in the CKD patients. Continuation of statin therapy was associated with a 22% (adjusted hazard ratio 0.78; 95% CI: 0.65-0.93) and 57% (adjusted HR 0.43; 95% CI: 0.27-0.68) decrease in atrial fibrillation/flutter hazard as compared with discontinuation in non-CKD and CKD patients, respectively. CONCLUSIONS: Continuation of statin therapy was associated with a decreased risk of atrial fibrillation/flutter among CKD and non-CKD patients. However, further randomized studies are still needed to assess the association. PMID- 24401244 TI - Using plasma matrix metalloproteinase-9 and monocyte chemoattractant protein-1 to predict future cardiovascular events in subjects with carotid atherosclerosis. PMID- 24401245 TI - Association between anthropometric measures of obesity and subclinical atherosclerosis in Bangladesh. AB - BACKGROUND: Anthropometric measures such as waist-hip-ratio (WHR), waist-height ratio (WHtR), waist circumference, Mid-upper arm circumference (MUAC), and upper thigh circumference, have been linked to the risk of cardiovascular disease (CVD). However, their relationships with subclinical atherosclerosis are unclear. Studies in normal-weight populations, especially in Asian countries where leanness is prevalent, are lacking. METHODS: We conducted a cross-sectional study to assess the associations of WHR, WHtR, waist circumference, hip circumference, body mass index (BMI), MUAC and upper thigh circumference with carotid intima media thickness (cIMT) among 562 middle-aged participants free of CVD in rural Bangladesh. RESULTS: After adjusting for age and sex, WHR and waist circumference but not BMI showed a positive significant association with cIMT. In multivariate analysis, each standard deviation (SD) increase of WHR (0.08) or WHtR (0.07) was associated with an 8.96 MUm (95% CI, 1.12-16.81) or 11.45 MUm (95%CI, 0.86-22.04) difference in cIMT, respectively, after controlling for age, sex, BMI, smoking status, education level, and systolic blood pressure (SBP). The associations of WHR and WHtR with cIMT were independent of the influence of other anthropometric measures. The associations of other anthropometric measures and cIMT were not apparent. CONCLUSIONS: In our relatively lean, healthy Asian population, WHR and WHtR appear to be better predictors of early atherosclerosis than other common surrogates of adiposity. PMID- 24401246 TI - Plasma autoantibodies against apolipoprotein B-100 peptide 210 in subclinical atherosclerosis. AB - OBJECTIVE: Experimental studies have suggested that autoimmunity is involved in atherosclerosis and provided evidence that both protective and pro-atherogenic immune responses exist. This concept has received support from small clinical studies implicating autoantibodies directed against apolipoprotein B-100 (apoB 100) in human atherosclerosis. We examined circulating autoantibodies directed against native and malondialdehyde (MDA)-modified epitope p210 of apoB-100 (IgG p210nat and IgM-p210MDA) in relation to early atherosclerosis in a large, European longitudinal cohort study of healthy high-risk individuals. APPROACH AND RESULTS: IgG-p210nat and IgM-p210MDA were quantified in baseline plasma samples of 3430 participants in the IMPROVE study and related to composite and segment specific measures of severity and rate of progression of carotid intima-media thickness (cIMT) determined at baseline and after 30 months. IgM-p210MDA autoantibody levels were independently related to several cIMT measures both in the common carotid artery and in the carotid bulb, including measures of cIMT progression, higher levels being associated with lower cIMT or slower cIMT progression. Consistent inverse relationships were also found between plasma levels of IgG-p210nat and baseline composite measures of cIMT. These associations disappeared when adjusting for established and emerging risk factors, and there were no associations with rate of cIMT progression besides in certain secondary stratified analyses. CONCLUSIONS: The present study provides further evidence of involvement of autoantibodies against native and MDA-modified apoB-100 peptide 210 in cardiovascular disease in humans and demonstrates that these associations are present already at a subclinical stage of the disease. PMID- 24401247 TI - Serum calcium and phosphate concentrations and intracranial atherosclerosis. AB - OBJECTIVE: Serum calcium and phosphate concentrations are independent risk factors for stroke and positively associated with extracranial carotid atherosclerosis. We evaluated whether higher serum calcium and phosphate concentrations would be associated with intracranial atherosclerosis in a stroke free Korean population. METHODS: We retrospectively analyzed the records of 361 stroke-free subjects who consecutively visited a general health promotion center. Included subjects had serum calcium, phosphate, and albumin drawn and underwent brain magnetic resonance angiography. The basilar, middle cerebral, intracranial internal carotid, and intracranial vertebral arteries were evaluated. Serum calcium concentration was corrected for serum albumin concentration. RESULTS: Mean +/- SD values were 52 +/- 10 years for age, 2.35 +/- 0.09 mmol/l for uncorrected serum calcium concentration, 2.24 +/- 0.08 mmol/l for corrected serum calcium concentration, and 1.19 +/- 0.18 mmol/l for serum phosphate concentration. Seventy-four subjects (21%) had intracranial atherosclerosis. Subjects in the upper three quartiles of corrected serum calcium concentration had a significantly greater risk for intracranial atherosclerosis compared with the lowest quartile with the odds ratios of 3.50 (95% confidence interval 1.50 8.15), 3.11 (95% confidence interval 1.26-7.69), and 3.77 (95% confidence interval 1.58-9.03), respectively. However, serum phosphate and uncorrected serum calcium concentrations were not associated with intracranial atherosclerosis. CONCLUSION: Corrected serum calcium concentrations are positively associated with the presence of intracranial atherosclerosis. PMID- 24401248 TI - Editor in Chief's report for Atherosclerosis for 2013. PMID- 24401250 TI - Time to turn the page. PMID- 24401249 TI - From the Emeritus Founding Editors. PMID- 24401251 TI - The 6th World Congress of Paediatric Cardiology and Cardiac Surgery, Cape Town 2013. PMID- 24401252 TI - The Seventh World Congress of Pediatric Cardiology and Cardiac Surgery, Istanbul, Turkey, June 19-24, 2017: "Bridge together". AB - The Seventh World Congress of Pediatric Cardiology and Cardiac Surgery will held in Istanbul, the only city in the world that is located on two continents, June 19-24, 2017. This World Congress promises academic excellence in a culturally stimulating environment. All those interested in the care of patients with pediatric and congenital cardiac disease should attend this meeting, which represents "The Olympics of our Profession". PMID- 24401253 TI - Magnetic resonance imaging-guided surgical design: can we optimise the Fontan operation? AB - The Fontan procedure, although an imperfect solution for children born with a single functional ventricle, is the only reconstruction at present short of transplantation. The haemodynamics associated with the total cavopulmonary connection, the modern approach to Fontan, are severely altered from the normal biventricular circulation and may contribute to the long-term complications that are frequently noted. Through recent technological advances, spear-headed by advances in medical imaging, it is now possible to virtually model these surgical procedures and evaluate the patient-specific haemodynamics as part of the pre operative planning process. This is a novel paradigm with the potential to revolutionise the approach to Fontan surgery, help to optimise the haemodynamic results, and improve patient outcomes. This review provides a brief overview of these methods, presents preliminary results of their clinical usage, and offers insights into its potential future directions. PMID- 24401254 TI - Exercise capacity in the Fontan circulation. AB - The Fontan operation can create a stable circulation from childhood through early adulthood. However, the absence of a sub-pulmonary pumping chamber leads to a physiology in which exercise capacity is limited and decreases with age starting in adolescence. The limitation in exercise capacity is more pronounced at peak levels of exercise, but is still present during more modest levels of activity. The underlying causes of exercise impairment relate to both central cardiovascular factors (oxygen delivery) and peripheral factors (oxygen extraction). Interventions to improve cardiac preload and to improve lean muscle mass may help to improve exercise capacity and, perhaps, will alter the "natural history" of the progressive decline. PMID- 24401255 TI - End-organ consequences of the Fontan operation: liver fibrosis, protein-losing enteropathy and plastic bronchitis. AB - The Fontan operation, although part of a life-saving surgical strategy, manifests a variety of end-organ complications and unique morbidities that are being recognised with increasing frequency as patients survive into their second and third decades of life and beyond. Liver fibrosis, protein-losing enteropathy and plastic bronchitis are consequences of a complex physiology involving circulatory insufficiency, inflammation and lymphatic derangement. These conditions are manifest in a chronic, indolent state. Management strategies are emerging, which shed some light on the origins of these complications. A better characterisation of the end-organ consequences of the Fontan circulation is necessary, which can then allow for development of specific methods for treatment. Ideally, the goal is to establish systematic strategies that might reduce or eliminate the development of these potentially life-threatening challenges. PMID- 24401256 TI - Heart transplant after the Fontan operation. AB - Although the Fontan operation may provide a durable circulation for some patients with functionally univentricular hearts for several decades, circulatory failure becomes more common over time. Medical and/or surgical interventions can improve the circulation for some period of time; however, many patients will experience end-stage circulatory failure. Heart transplantation may be considered in these patients. This review will cover the indications and evaluation for heart transplantation, management of patients while waiting for heart transplantation and the current outcomes of transplantation in this population. PMID- 24401257 TI - Surgical revisions and mechanical support of the failing Fontan. AB - Despite its many anatomic modifications, Fontan failure remains prevalent in adult patients living with single-ventricle physiology. Although the Fontan operation has created a generation of survivors of complex single-ventricle disease, recognition of the limitation of this circulation is increasing. Most commonly, survivors suffer from ventricular dysfunction, protein-losing enteropathy, plastic bronchitis and arrhythmias. Although several medical therapies exist to palliate these long-term complications, surgical treatments are becoming increasingly useful, including the introduction of mechanical devices and cardiac transplantation. Currently, there are a variety of options available for mechanical support of the failing Fontan. Further developments in mechanical support technology will be required to tailor-make specific devices for this unique population. Owing to the fact that availability of donor hearts for transplantation is limited, mechanical support will play an increasingly important role in the management of complications of the Fontan circulation. PMID- 24401258 TI - The birth of a new era: the introduction of the systemic-to-pulmonary artery shunt for the treatment of cyanotic congenital heart disease. AB - Cardiac surgery was revolutionized on November 29, 1944, when Eileen Saxon underwent the first systemic-to-pulmonary artery shunt at Johns Hopkins University in Baltimore, Maryland, United States of America. The systemic-to pulmonary artery shunt was initially developed in the laboratory and then applied to patients through the unique collaboration of Vivien Thomas, Alfred Blalock, and Helen B. Taussig. This innovation was the first operation to successfully treat cyanotic cardiac disease. The history of the first operation to successfully treat cyanotic heart disease is an extraordinary history of courage, innovation, and scientific breakthrough. Just as striking is perhaps the ability of the protagonists of this story to overcome seemingly insurmountable barriers of racial and gender discrimination and revolutionize medicine. PMID- 24401259 TI - Tetralogy of Fallot: nosological, morphological, and morphogenetic considerations. AB - It is timely, in the 125th anniversary of the initial description by Fallot of the hearts most frequently seen in patients presenting with "la maladie bleu", that we revisit his descriptions, and discuss his findings in the light of ongoing controversies. Fallot described three hearts in his initial publication, and pointed to the same tetralogy of morphological features that we recognise today, namely, an interventricular communication, biventricular connection of the aorta, subpulmonary stenosis, and right ventricular hypertrophy. In one of the hearts, he noted that the aorta arose exclusively from the right ventricle. In other words, one of his initial cases exhibited double-outlet right ventricle. When we now compare findings in hearts with the features of the tetralogy, we can observe significant variations in the nature of the borders of the plane of deficient ventricular septation when viewed from the aspect of the right ventricle. We also find that this plane, usually described as the ventricular septal defect, is not the same as the geometric plane separating the cavities of the right and left ventricles. This means that the latter plane, the interventricular communication, is not necessarily the same as the ventricular septal defect. We are now able to provide further insights into these features by examining hearts prepared from developing mice. Additional molecular investigations will be required, however, to uncover the mechanisms responsible for producing the morphological changes underscoring tetralogy of Fallot. PMID- 24401260 TI - Tetralogy of Fallot: epidemiology meets real-world management: lessons from the Baltimore-Washington Infant Study. AB - Decades ago, mass-scale epidemiologic studies were undertaken to accurately describe the prevalence of congenital heart disease and associated malformations, and to identify inheritance patterns, teratogenic influence and aetiologic underpinnings. Despite phenomenal breakthroughs in molecular diagnosis of congenital heart disease, original population-based studies for detailed knowledge of prevalence, associated malformations, and appropriate patient and family counselling remain invaluable to the armamentarium and knowledge base of paediatric cardiologists. No modern-era studies have supplanted the importance of the Baltimore-Washington Infant Study undertaken from 1981 to 1989. In this article, we reprise the findings of the Baltimore-Washington Infant Study in tetralogy of Fallot, as well as to review current molecular diagnosis. PMID- 24401261 TI - The essential echocardiographic features of tetralogy of Fallot. AB - This presentation will demonstrate the essential features of tetralogy of Fallot in the infant and child before surgery, as well as some noteworthy features in the foetus. The four features, namely, subpulmonary stenosis, ventricular septal defect, aortic override, and right ventricular hypertrophy, can all be easily demonstrated by echocardiography. In addition, morphology of the pulmonary valve and the main and branch pulmonary arteries can be seen. The position of the coronary arteries and the major variants of proximal coronary anatomy can be defined. The arch anatomy and the presence of associated major aortopulmonary collateral arteries can be defined. All these features can be demonstrated in the foetus as well, after the first trimester, and the presence of major aortopulmonary collateral arteries can be seen more clearly because the lungs, being fluid filled, aid in ultrasound and do not provide the barrier that the air filled lung presents after birth. PMID- 24401262 TI - The role of cardiac catheterisation in patients with tetralogy of Fallot. AB - Cardiac catheterisation plays an important role in the management of patients with tetralogy of Fallot. There are a number of palliative transcatheter interventions that can be performed in the neonatal period to allow for improved oxygen saturations and interval growth of the pulmonary arteries until corrective surgery is performed. Most patients develop branch pulmonary artery stenosis, right ventricular outflow tract obstruction, pulmonary insufficiency, or significant residual left-to-right shunts during long-term follow-up after corrective surgery. Transcatheter interventions can be performed to treat many of these issues, often eliminating or delaying the need for subsequent surgery. The indications for cardiac catheterisation and the specifics for various interventional procedures for patients with tetralogy of Fallot are reviewed in this manuscript. PMID- 24401263 TI - Management of arrhythmias in patients with a tetralogy of Fallot. AB - Although arrhythmias are commonly found in patients with all different types of congenital heart disease, perhaps no patient is at higher risk of late development of arrhythmias that may result in sudden death than in the patient following tetralogy of Fallot repair. Despite major improvement in the surgical repair of this disease, a significant percentage of these patients continue to remain at risk for the late development of arrhythmias, and a small percentage will develop life-threatening arrhythmias and sudden death. Which patients remain at highest risk is still not clearly delineated. Diligent arrhythmia surveillance and aggressive treatment strategies are necessary to minimise this risk. This article highlights important strategies to manage arrhythmia development and prevention in this patient population. PMID- 24401264 TI - The importance of small for gestational age in the risk assessment of infants with critical congenital heart disease. AB - BACKGROUND: Infants with critical congenital heart disease who require cardiothoracic surgical intervention may have significant post-operative mortality and morbidity. Infants who are small for gestational age <10th percentile with foetal growth restriction may have end-organ dysfunction that may predispose them to increased morbidity or mortality. METHODS: A single institution retrospective review was performed in 230 infants with congenital heart disease who had cardiothoracic surgical intervention <60 days of age. Pre-, peri-, and post-operative morbidity and mortality markers were collected along with demographics and anthropometric measurements. RESULTS: There were 230 infants, 57 (23.3%) small for gestational age and 173 (70.6%) appropriate for gestational age. No significant difference was noted in pre-operative markers - gestational age, age at surgery, corrected gestational age, Society for Thoracic Surgeons and European Association for Cardiothoracic Surgery mortality score; or post-operative factors - length of stay, ventilation days, arrhythmias, need for extracorporeal membrane oxygenation, vocal cord dysfunction, hearing loss; or end organ dysfunction - gastro-intestinal, renal, central nervous system, or genetic. Small for gestational age infants were more likely to have failed vision tests (p = 0.006). Small for gestational age infants were more likely to have increased 30 day (p = 0.005) and discharge mortality (p = 0.035). Small for gestational age infants with normal birth weight (>2500 g) were also at increased risk of 30-day mortality compared with appropriate for gestational age infants (p = 0.045). CONCLUSIONS: Small for gestational age infants with congenital heart disease who undergo cardiothoracic surgery <60 days of age have increased risk of mortality and failed vision screening. Assessment of foetal growth restriction as part of routine pre-operative screening may be beneficial. PMID- 24401265 TI - Modern surgical management of patients with tetralogy of Fallot. AB - Tetralogy of Fallot is the most common cyanotic heart defect seen in children beyond infancy. There is considerable variation in surgical management today ranging from differences in timing of complete repair versus initial use of a shunt for palliation, and methods for right ventricular outflow tract reconstruction. This article will examine some of the current surgical management techniques for patients with Tetralogy of Fallot. PMID- 24401266 TI - Transcatheter pulmonary valve insertion, expanded use and future directions. AB - Transcatheter pulmonary valve replacement with the Melody(r) valve is an accepted alternative to surgical replacement of the pulmonary valve for some patients and therefore a complementary strategy in the long-term management of several groups of patients with congenital heart disease. It allows at least extending the time between sternotomies and possibly improving late outcomes. With a combined surgical and percutaneous approach, late morbidity for some of these patients will likely be diminished. This manuscript will review the current expanded applications for this technology, demonstrate several examples of its use and discuss future directions for this evolving equipment. PMID- 24401267 TI - Surgical pulmonary valve insertion. AB - Pulmonary valve replacement is being performed with increasing frequency in patients with various congenital heart diseases. Chronic pulmonary regurgitation after repair of tetralogy of Fallot is a typical situation that requires pulmonary valve replacement. Chronic pulmonary regurgitation after repair of tetralogy of Fallot can lead to right ventricular dilatation, biventricular dysfunction, heart failure symptoms, arrhythmias, and sudden death. Although pulmonary valve replacement can lead to improvement in functional class and a substantial decrease or normalisation of right ventricular volumes, the optimal timing of pulmonary valve replacement in patients with chronic pulmonary regurgitation is still unknown. There are several options for surgical pulmonary valve replacement. However, no ideal pulmonary valve substitute exists currently and most of the surgically implanted pulmonary valves will eventually require re replacement. This article will review options and timing of surgical pulmonary valve insertion in patients with chronic pulmonary regurgitation after repair of tetralogy of Fallot. PMID- 24401268 TI - Management of adults with Tetralogy of Fallot. AB - Tetralogy of Fallot is the most common form of cyanotic congenital cardiac disease. Patients with previously repaired tetralogy of Fallot are the most common patients seen in the Program for Adults with Congenital Heart Disease at The Johns Hopkins All Children's Heart Institute. Guidelines for the management of these patients are available from multiple sources including The American College of Cardiology (ACC) and The American Heart Association (AHA), The Canadian Cardiovascular Society, and The European Society of Cardiology (ESC). These guidelines describe multiple components related to the care for these patients including strategies for medical follow-up, the management of arrhythmias and electrophysiological diseases, and the treatment of chronic pulmonary insufficiency and stenosis. Several new strategies are available for replacement of the pulmonary valve including transcatheter replacement of the pulmonary valve and replacement of the pulmonary valve with a self-manufactured bicuspid polytetrafluoroethylene pulmonary valve. PMID- 24401269 TI - Surgical management of tetralogy of Fallot: where are we now and what is yet to come. PMID- 24401270 TI - Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia. AB - T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer that is frequently associated with activating mutations in NOTCH1 and dysregulation of MYC. Here, we performed 2 complementary screens to identify FDA-approved drugs and drug-like small molecules with activity against T-ALL. We developed a zebrafish system to screen small molecules for toxic activity toward MYC overexpressing thymocytes and used a human T-ALL cell line to screen for small molecules that synergize with Notch inhibitors. We identified the antipsychotic drug perphenazine in both screens due to its ability to induce apoptosis in fish, mouse, and human T-ALL cells. Using ligand-affinity chromatography coupled with mass spectrometry, we identified protein phosphatase 2A (PP2A) as a perphenazine target. T-ALL cell lines treated with perphenazine exhibited rapid dephosphorylation of multiple PP2A substrates and subsequent apoptosis. Moreover, shRNA knockdown of specific PP2A subunits attenuated perphenazine activity, indicating that PP2A mediates the drug's antileukemic activity. Finally, human T ALLs treated with perphenazine exhibited suppressed cell growth and dephosphorylation of PP2A targets in vitro and in vivo. Our findings provide a mechanistic explanation for the recurring identification of phenothiazines as a class of drugs with anticancer effects. Furthermore, these data suggest that pharmacologic PP2A activation in T-ALL and other cancers driven by hyperphosphorylated PP2A substrates has therapeutic potential. PMID- 24401271 TI - Interplay between FGF21 and insulin action in the liver regulates metabolism. AB - The hormone FGF21 regulates carbohydrate and lipid homeostasis as well as body weight, and increasing FGF21 improves metabolic abnormalities associated with obesity and diabetes. FGF21 is thought to act on its target tissues, including liver and adipose tissue, to improve insulin sensitivity and reduce adiposity. Here, we used mice with selective hepatic inactivation of the IR (LIRKO) to determine whether insulin sensitization in liver mediates FGF21 metabolic actions. Remarkably, hyperglycemia was completely normalized following FGF21 treatment in LIRKO mice, even though FGF21 did not reduce gluconeogenesis in these animals. Improvements in blood sugar were due in part to increased glucose uptake in brown fat, browning of white fat, and overall increased energy expenditure. These effects were preserved even after removal of the main interscapular brown fat pad. In contrast to its retained effects on reducing glucose levels, the effects of FGF21 on reducing circulating cholesterol and hepatic triglycerides and regulating the expression of key genes involved in cholesterol and lipid metabolism in liver were disrupted in LIRKO mice. Thus, FGF21 corrects hyperglycemia in diabetic mice independently of insulin action in the liver by increasing energy metabolism via activation of brown fat and browning of white fat, but intact liver insulin action is required for FGF21 to control hepatic lipid metabolism. PMID- 24401272 TI - Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis. AB - TGF-beta is essential for vascular development; however, excess TGF-beta signaling promotes thoracic aortic aneurysm and dissection in multiple disorders, including Marfan syndrome. Since the pathology of TGF-beta overactivity manifests primarily within the arterial media, it is widely assumed that suppression of TGF beta signaling in vascular smooth muscle cells will ameliorate aortic disease. We tested this hypothesis by conditional inactivation of Tgfbr2, which encodes the TGF-beta type II receptor, in smooth muscle cells of postweanling mice. Surprisingly, the thoracic aorta rapidly thickened, dilated, and dissected in these animals. Tgfbr2 disruption predictably decreased canonical Smad signaling, but unexpectedly increased MAPK signaling. Type II receptor-independent effects of TGF-beta and pathological responses by nonrecombined smooth muscle cells were excluded by serologic neutralization. Aortic disease was caused by a perturbed contractile apparatus in medial cells and growth factor production by adventitial cells, both of which resulted in maladaptive paracrine interactions between the vessel wall compartments. Treatment with rapamycin restored a quiescent smooth muscle phenotype and prevented dissection. Tgfbr2 disruption in smooth muscle cells also accelerated aneurysm growth in a murine model of Marfan syndrome. Our data indicate that basal TGF-beta signaling in smooth muscle promotes postnatal aortic wall homeostasis and impedes disease progression. PMID- 24401273 TI - Disruption of vascular Ca2+-activated chloride currents lowers blood pressure. AB - High blood pressure is the leading risk factor for death worldwide. One of the hallmarks is a rise of peripheral vascular resistance, which largely depends on arteriole tone. Ca2+-activated chloride currents (CaCCs) in vascular smooth muscle cells (VSMCs) are candidates for increasing vascular contractility. We analyzed the vascular tree and identified substantial CaCCs in VSMCs of the aorta and carotid arteries. CaCCs were small or absent in VSMCs of medium-sized vessels such as mesenteric arteries and larger retinal arterioles. In small vessels of the retina, brain, and skeletal muscle, where contractile intermediate cells or pericytes gradually replace VSMCs, CaCCs were particularly large. Targeted disruption of the calcium-activated chloride channel TMEM16A, also known as ANO1, in VSMCs, intermediate cells, and pericytes eliminated CaCCs in all vessels studied. Mice lacking vascular TMEM16A had lower systemic blood pressure and a decreased hypertensive response following vasoconstrictor treatment. There was no difference in contractility of medium-sized mesenteric arteries; however, responsiveness of the aorta and small retinal arterioles to the vasoconstriction inducing drug U46619 was reduced. TMEM16A also was required for peripheral blood vessel contractility, as the response to U46619 was attenuated in isolated perfused hind limbs from mutant mice. Out data suggest that TMEM16A plays a general role in arteriolar and capillary blood flow and is a promising target for the treatment of hypertension. PMID- 24401274 TI - Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction. AB - Interaction of the chemokine CXCL12 with its receptor CXCR4 promotes neuronal function and survival during embryonic development and throughout adulthood. Previous studies indicated that MU-opioid agonists specifically elevate neuronal levels of the protein ferritin heavy chain (FHC), which negatively regulates CXCR4 signaling and affects the neuroprotective function of the CXCL12/CXCR4 axis. Here, we determined that CXCL12/CXCR4 activity increased dendritic spine density, and also examined FHC expression and CXCR4 status in opiate abusers and patients with HIV-associated neurocognitive disorders (HAND), which is typically exacerbated by illicit drug use. Drug abusers and HIV patients with HAND had increased levels of FHC, which correlated with reduced CXCR4 activation, within cortical neurons. We confirmed these findings in a nonhuman primate model of SIV infection with morphine administration. Transfection of a CXCR4-expressing human cell line with an iron-deficient FHC mutant confirmed that increased FHC expression deregulated CXCR4 signaling and that this function of FHC was independent of iron binding. Furthermore, examination of morphine-treated rodents and isolated neurons expressing FHC shRNA revealed that FHC contributed to morphine-induced dendritic spine loss. Together, these data implicate FHC dependent deregulation of CXCL12/CXCR4 as a contributing factor to cognitive dysfunction in neuroAIDS. PMID- 24401275 TI - MNK1 pathway activity maintains protein synthesis in rapalog-treated gliomas. AB - High levels of mammalian target of rapamycin complex 1 (mTORC1) activity in malignant gliomas promote tumor progression, suggesting that targeting mTORC1 has potential as a therapeutic strategy. Remarkably, clinical trials in patients with glioma revealed that rapamycin analogs (rapalogs) have limited efficacy, indicating activation of resistance mechanisms. Targeted depletion of MAPK interacting Ser/Thr kinase 1 (MNK1) sensitizes glioma cells to the mTORC1 inhibitor rapamycin through an indistinct mechanism. Here, we analyzed how MNK1 and mTORC1 signaling pathways regulate the assembly of translation initiation complexes, using the cap analog m7GTP to enrich for initiation complexes in glioma cells followed by mass spectrometry-based quantitative proteomics. Association of eukaryotic translation initiation factor 4E (eIF4E) with eIF4E binding protein 1 (4EBP1) was regulated by the mTORC1 pathway, whereas pharmacological blocking of MNK activity by CGP57380 or MNK1 knockdown, along with mTORC1 inhibition by RAD001, increased 4EBP1 binding to eIF4E. Furthermore, combined MNK1 and mTORC1 inhibition profoundly inhibited 4EBP1 phosphorylation at Ser65, protein synthesis and proliferation in glioma cells, and reduced tumor growth in an orthotopic glioblastoma (GBM) mouse model. Immunohistochemical analysis of GBM samples revealed increased 4EBP1 phosphorylation. Taken together, our data indicate that rapalog-activated MNK1 signaling promotes glioma growth through regulation of 4EBP1 and indicate a molecular cross-talk between the mTORC1 and MNK1 pathways that has potential to be exploited therapeutically. PMID- 24401276 TI - Prenatal retinoid deficiency leads to airway hyperresponsiveness in adult mice. AB - There is increasing evidence that vitamin A deficiency in utero correlates with abnormal airway smooth muscle (SM) function in postnatal life. The bioactive vitamin A metabolite retinoic acid (RA) is essential for formation of the lung primordium; however, little is known about the impact of early fetal RA deficiency on postnatal lung structure and function. Here, we provide evidence that during murine lung development, endogenous RA has a key role in restricting the airway SM differentiation program during airway formation. Using murine models of pharmacological, genetic, and dietary vitamin A/RA deficiency, we found that disruption of RA signaling during embryonic development consistently resulted in an altered airway SM phenotype with markedly increased expression of SM markers. The aberrant phenotype persisted postnatally regardless of the adult vitamin A status and manifested as structural changes in the bronchial SM and hyperresponsiveness of the airway without evidence of inflammation. Our data reveal a role for endogenous RA signaling in restricting SM differentiation and preventing precocious and excessive SM differentiation when airways are forming. PMID- 24401277 TI - Human IgG Fc domain engineering enhances antitoxin neutralizing antibody activity. AB - The effector activity of antibodies is dependent on engagement with Fcgamma receptors (FcgammaRs) and activation of the associated intracellular signaling pathways. Preclinical evaluation of therapeutic humanized or chimeric mAbs to study the interactions of their Fc regions with FcgammaRs is hampered by substantial structural and functional FcgammaR diversity among species. In this report, we used mice expressing only human FcgammaRs to evaluate the contribution of FcgammaR-mediated pathways to the neutralizing activity of an anti-anthrax toxin chimeric mAb. We observed that the protective activity of this mAb was highly dependent upon FcgammaR engagement, with minimal protection against anthrax toxin observed in FcgammaR-deficient mice following mAb administration. We generated anti-anthrax toxin mAbs with specific Fc domain variants with selectively enhanced affinity for particular human FcgammaRs and assessed their activity in FcgammaR-humanized mice. We determined that Fc domain variants that were capable of selectively engaging activating FcgammaRs substantially enhanced the in vitro and in vivo activity of anthrax toxin-neutralizing antibodies. These findings indicate that the application of Fc domain engineering is a feasible strategy to enhance toxin-neutralizing activity and suggest that engineered antitoxin antibodies will have improved therapeutic efficacy. PMID- 24401278 TI - Gaze properties of women judging the attractiveness of masculine and feminine male faces. AB - Most studies of female facial masculinity preference have relied upon self reported preference, with participants selecting or rating the attractiveness of faces that differ in masculinity. However, researchers have not established a consensus as to whether women's general preference is for male faces that are masculine or feminine, and several studies have indicated that women prefer neither. We investigated women's preferences for male facial masculinity using standard two-alternative forced choice (2AFC) preference trials, paired with eye tracking measures, to determine whether conscious and non-conscious measures of preference yield similar results. We found that women expressed a preference for, gazed longer at, and fixated more frequently on feminized male faces. We also found effects of relationship status, relationship context (whether faced are judged for attractiveness as a long- or short-term partner), and hormonal contraceptive use. These results support previous findings that women express a preference for feminized over masculinized male faces, demonstrate that non conscious measures of preference for this trait echo consciously expressed preferences, and suggest that certain aspects of the preference decision-making process may be better captured by eye tracking than by 2AFC preference trials. PMID- 24401279 TI - Frank intrabiliary rupture in liver hydatidosis located in the hilar plate: a surgical challenge. AB - BACKGROUND: Frank intrabiliary rupture (FIR) is a severe complication that occurs in around 30% of patients with liver hydatidosis. When FIR is present, the contents of the cyst may pass into the common bile duct and cause a variety of complications. If the FIR is located in the hilar confluence, surgical repair is a challenge. Currently there are no data regarding its optimum treatment. MATERIAL AND METHODS: Between May 2007 and December 2012, we treated 59 patients with liver hydatidosis. Four patients, all women, with a mean age of 51.7 years, had hydatid cysts located between segments IVb and V and FIR affecting the hilar plate. In 3 cases, the initial clinical condition was obstructive jaundice. The fourth patient presented recurrence after having undergone two operations as a child. RESULTS: In each patient a major hepatectomy was performed with hilar plate reconstruction (3 left and 1 right). Morbidity included mild biliary fistula (1 patient) and abdominal collection resolved by percutaneous drainage (1 patient). There was no mortality. During follow-up (47 months), no recurrences of the disease or biliary strictures were recorded. CONCLUSIONS: FIR is a severe complication of liver hydatidosis. When it is located in the hilar confluence, liver resection may be the best surgical option for definitive resolution of the problem. PMID- 24401280 TI - Modifications to the PUFA index: are they justified at this stage? PMID- 24401281 TI - Identification of prognostic relevant chromosomal abnormalities in chronic lymphocytic leukemia using microarray-based genomic profiling. AB - BACKGROUND: Characteristic genomic abnormalities in patients with B cell chronic lymphocytic leukemia (CLL) have been shown to provide important prognostic information. Fluorescence in situ hybridization (FISH) and multiplex ligation dependent probe amplification (MLPA), currently used in clinical diagnostics of CLL, are targeted tests aimed at specific genomic loci. Microarray-based genomic profiling is a new high-resolution tool that enables genome-wide analyses. The aim of this study was to compare two recently launched genomic microarray platforms, i.e., the CytoScan HD Array (Affymetrix) and the HumanOmniExpress Array (Illumina), with FISH and MLPA to ascertain whether these latter tests can be replaced by either one of the microarray platforms in a clinical diagnostic setting. RESULT: Microarray-based genomic profiling and FISH were performed in all 28 CLL patients. For an unbiased comparison of the performance of both microarray platforms 9 patients were evaluated on both platforms, resulting in the identification of exactly identical genomic aberrations. To evaluate the detection limit of the microarray platforms we included 7 patients in which the genomic abnormalities were present in a relatively low percentage of the cells (range 5-28%) as previously determined by FISH. We found that both microarray platforms allowed the detection of copy number abnormalities present in as few as 16% of the cells. In addition, we found that microarray-based genomic profiling allowed the identification of genomic abnormalities that could not be detected by FISH and/or MLPA, including a focal TP53 loss and copy neutral losses of heterozygosity of chromosome 17p. CONCLUSION: From our results we conclude that although the microarray platforms exhibit a somewhat lower limit of detection compared to FISH, they still allow the detection of copy number abnormalities present in as few as 16% of the cells. By applying similar interpretation criteria, the results obtained from both platforms were comparable. In addition, we conclude that both microarray platforms allow the identification of additional potential prognostic relevant abnormalities such as focal TP53 deletions and copy neutral losses of heterozygosity of chromosome 17p, which would have remained undetected by FISH or MLPA. The prognostic relevance of these novel genomic alterations requires further evaluation in prospective clinical trials. PMID- 24401282 TI - Accuracy of verbal self-reported blood glucose in teenagers with type I diabetes at diabetes ski camp. AB - BACKGROUND: While there have been considerable advances in diabetes management, self-monitoring of blood glucose remains vital. A number of studies, predominantly in adults, have confirmed that logbook entries are prone to a number of common errors. To date, no studies in either adults or children have looked at the accuracy of verbally reported self-monitored blood glucose levels (SMBG). Our aim was to determine the accuracy of verbally reported SMBG levels in adolescents at a diabetes camp. METHODS: Dual Data (verbally reported and meter downloaded values) were obtained as part of camp safety monitoring from 20 adolescents (aged 13-18 years) attending a 3 day diabetes winter camp. Blood glucose values were classified as: accurate, absent/phantom, or modified - verbally reported value > / < meter downloaded value. No participant had prior awareness of the planned meter data download at camp conclusion. RESULTS: Discrepancies between verbally reported and meter downloaded values were observed in 14/20 (70%) participants and in 53/394 (13.5%) instances of testing. Absent/Phantom readings were the most common error at 30/394 (7.6%). Errors relating to hypoglycaemia were seen in 8/47 (17%) hypoglycaemia-related incidents of testing. No relationship with HbA1c was found between those with reporting errors and those without (p > 0.05). CONCLUSION: While 70% of adolescents had errors, the overall error rate at 13.5% is lower than that previously reported for logbook studies. While this rate is lower than expected, misreporting remains a concern, particularly in the context of diabetes camp and exercise induced hypoglycaemia. PMID- 24401283 TI - Dermatological complications after bariatric surgery: report of two cases and review of the literature. AB - Bariatric surgery aims at weight reduction of severely obese patients. The Roux en-Y technique is one of the most common bariatric procedures and is occasionally accompanied by nutrient insufficiencies and metabolic changes. According to the literature, skin architecture and immunity change after bariatric surgery and may lead to inflammation and increased susceptibility to pathogens. Additionally, vitamin and mineral deficiencies frequently develop in these patients and affect the skin's defense mechanisms, possibly contributing to dermatological complications. Knowledge and recognition of skin changes after bariatric surgery make an important asset for the dermatologist and help in the proper treatment of these patients. We report 2 cases of infectious skin lesions where vitamin and trace element deficiencies have possibly contributed to their persistence and resistance to traditional treatments. PMID- 24401284 TI - Under the influence: 1. False dawn for minimum unit pricing. PMID- 24401285 TI - Genome expression analysis by suppression subtractive hybridization identified overexpression of Humanin, a target gene in gastric cancer chemoresistance. AB - BACKGROUND: In cancer cells, apoptosis is an important mechanism that influences the outcome of chemotherapy and the development of chemoresistance. To find the genes involved in chemoresistance and the development of gastric cancer, we used the suppression subtractive hybridization method to identify the genes that are overexpressed in gastric cancer tissues compared to normal gastric tissues. RESULTS: In the suppression subtractive hybridization library we constructed, the most highly overexpressed genes were humanin isoforms. Humanin is a recently identified endogenous peptide that has anti-apoptotic activity and has been selected for further study due to its potential role in the chemoresistance of gastric cancer. Upregulation of humanin isoforms was also observed in clinical samples by using quantitative real-time PCR. Among the studied isoforms, humanin isoform 3, with an expression level of 4.166 +/- 1.44 fold, was the most overexpressed isoform in GC. CONCLUSIONS: The overexpression of humanin in gastric cancer suggests a role for chemoresistance and provides new insight into the biology of gastric cancer. We propose that humanin isoforms are novel targets for combating chemoresistance in gastric cancer. PMID- 24401286 TI - Prenylation defects in inherited retinal diseases. AB - Many proteins depend on post-translational prenylation for a correct subcellular localisation and membrane anchoring. This involves the covalent attachment of farnesyl or geranylgeranyl residues to cysteines residing in consensus motifs at the C-terminal parts of proteins. Retinal photoreceptor cells are highly compartmentalised and membranous structures, and therefore it can be expected that the proper function of many retinal proteins depends on prenylation, which has been proven for several proteins that are absent or defective in different inherited retinal diseases (IRDs). These include proteins involved in the phototransduction cascade, such as GRK1, the phosphodiesterase 6 subunits and the transducin gamma subunit, or proteins involved in transport processes, such as RAB28 and retinitis pigmentosa GTPase regulator (RPGR). In addition, there is another class of general prenylation defects due to mutations in proteins such as AIPL1, PDE6D and rab escort protein-1 (REP-1), which can act as chaperones for subsets of prenylated retinal proteins that are associated with IRDs. REP-1 also is a key accessory protein of geranylgeranyltransferase II, an enzyme involved in the geranylgeranylation of almost all members of a large family of Rab GTPases. Finally, mutations in the mevalonate kinase (MVK) gene, which were known to be principally associated with mevalonic aciduria, were recently associated with non syndromic retinitis pigmentosa. We hypothesise that MVK deficiency results in a depletion of prenyl moieties that affects the prenylation of many proteins synthesised specifically in the retina, including Rabs. In this review, we discuss the entire spectrum of prenylation defects underlying progressive degeneration of photoreceptors, the retinal pigment epithelium and the choroid. PMID- 24401288 TI - Engaging pediatric intensive care unit (PICU) clinical staff to lead practice improvement: the PICU participatory action research project (PICU-PAR). AB - BACKGROUND: Despite considerable efforts, engaging staff to lead quality improvement activities in practice settings is a persistent challenge. At British Columbia Children's Hospital (BCCH), the pediatric intensive care unit (PICU) undertook a new phase of quality improvement actions based on the Community of Practice (CoP) model with Participatory Action Research (PAR). This approach aims to mobilize the PICU 'community' as a whole with a focus on practice; namely, to create a 'community of practice' to support reflection, learning, and innovation in everyday work. METHODOLOGY: An iterative two-stage PAR process using mixed methods has been developed among the PICU CoP to describe the environment (stage 1) and implement specific interventions (stage 2). Stage 1 is ethnographic description of the unit's care practice. Surveys, interviews, focus groups, and direct observations describe the clinical staff's experiences and perspectives around bedside care and quality endeavors in the PICU. Contrasts and comparisons across participants, time and activities help understanding the PICU culture and experience. Stage 2 is a succession of PAR spirals, using results from phase 1 to set up specific interventions aimed at building the staff's capability to conduct QI projects while acquiring appropriate technical skills and leadership capacity (primary outcome). Team communication, information, and interaction will be enhanced through a knowledge exchange (KE) and a wireless network of iPADs. RELEVANCE: Lack of leadership at the staff level in order to improve daily practice is a recognized challenge that faces many hospitals. We believe that the PAR approach within a highly motivated CoP is a sound method to create the social dynamic and cultural context within which clinical teams can grow, reflect, innovate and feel proud to better serve patients. PMID- 24401289 TI - Neurotensin receptor 1 gene polymorphisms are associated with personality traits in healthy Chinese individuals. AB - AIMS: Neurotensin receptor 1 (NTR1) is a neurotensin (NT) receptor subtype with a high affinity for NT. NT and NTR1 signaling are involved in modulating the dopamine system. Individual variations in the dopamine system have been demonstrated to determine certain dimensions of personality, but no studies have thus far investigated the involvement of the NTR1 in the biological determination of personality. We therefore examined this link in a Chinese Han population. METHODS: We genotyped 3 single nucleotide polymorphisms (SNPs) (rs6090453C/G, rs6011914C/G, and rs2427422A/G) of the NTR1 gene and collected the data about the personality traits of novelty seeking (NS), harm avoidance (HA), and reward dependence (RD), as well as their subscales (measured by the Tridimensional Personality Questionnaire), in 575 healthy Chinese Han subjects. Then we examined the association between the 3 NTR1 gene polymorphisms and each personality trait. RESULTS: There were significant differences in the HA2, HA3 and RD1 scores between rs6090453C/G genotypes (F = 3.425, 5.651, 4.054, p = 0.033, 0.004, 0.018, respectively), in the HA2 and total RD scores between rs6011914C/G genotypes (F = 4.080, 3.712, p = 0.017, 0.025, respectively), and in the total RD (chi(2) = 7.301, p = 0.026) and RD3 (F = 4.119, p = 0.017) scores between the rs2427422A/G genotypes. There were significant male-specific differences in the RD1 scores between the rs6090453C/G genotypes (F = 3.334, p = 0.037), in the total HA (F = 3.043, p = 0.049), HA2 (F = 4.472, p = 0.012) and RD3 (chi(2) = 6.997, p = 0.030) scores between the rs6011914C/G genotypes, and in the HA2 (F = 3.177, p = 0.043), total RD (chi(2) = 7.032, p = 0.030), and RD3 (F = 4.563, p = 0.011) scores between the rs2427422A/G genotypes. We also demonstrated a significant female specific difference in the total RD scores between the rs6011914C/G genotypes (F = 3.677, p = 0.026). There was no significant difference in the total NS and subscale scores between the genotypes of all 3 SNPs (all p > 0.05). CONCLUSIONS: The variations in the NTR1 gene were involved in the biological mechanisms of HA and RD personality traits; however, the effect is influenced by gender. PMID- 24401290 TI - Public health implications of contamination of Franc CFA (XAF) circulating in Buea (Cameroon) with drug resistant pathogens. AB - BACKGROUND: Studies in different parts of the world have implicated money as a vehicle for transmission of pathogens. Such information which is necessary to facilitate infection control strategies is lacking in many sub-Saharan countries including Cameroon. This study analyzed the Franc de la Communaute Financiere d'Afrique (Franc CFA), the currency used in Cameroon and other countries in the Central African sub-region, as a potential vehicle for transmission of pathogenic bacteria and fungi, particularly drug-resistant strains, to generate findings which could create awareness on currency contamination and serve as a guide when formulating health policies on currency. METHODS: Two hundred and thirteen currency samples representing various denominations of notes and coins randomly collected from diverse sources in Buea, Cameroon were analyzed for bacteria and fungi. The sensitivity of bacterial isolates to antibiotics was tested using the disc diffusion method. The relationship between contamination and physical state, source or denomination of currency was assessed using the chi2 test. All statistics were discussed at 0.05 significance level. RESULTS: Two hundred (93.9%) samples were contaminated with notes (96.6%) showing higher contamination than coins (88.2%). Uncirculated (mint) samples showed no contamination. There was a significant difference (P<0.05) in contamination with respect to currency denomination, physical state and source. All samples from butchers and patients/personnel in hospitals were contaminated. Lower denominations showed significantly higher (P = 0.008) levels of contamination than higher denominations. Dirty currency was more contaminated than clean currency. Nine bacterial species were isolated. Coagulase-negative Staphylococcus (CoNS) (54.9%) and Staphylococcus aureus (20.1%) predominated. Among the fungi detected, Aspergillus sp (17.3%) and Penicillium sp (15.9%) showed higher frequency of occurrence. Bacteria were susceptible (100%) to ceftriaxone, gentamicin, norfloxacin and ofloxacin. Susceptibility to amoxicillin, penicillin, ampicillin, vancomycin and cotrimoxazole was low. Staphylococci were resistant (100%) to vancomycin, penicillin G, and amoxicillin. CoNS in addition showed resistance (100%) to cotrimoxazole. CONCLUSIONS: The CFA franc circulating in Buea could serve as a vehicle for transmission of drug resistant pathogenic or potential organisms and contamination could be due to currency usage and handling as mint notes were not contaminated. Hygiene practices during or after handling currency is greatly encouraged to prevent infection. PMID- 24401291 TI - Oral intake of specific bioactive collagen peptides reduces skin wrinkles and increases dermal matrix synthesis. AB - Dietary consumption of food supplements has been found to modulate skin functions and can therefore be useful in the treatment of skin aging. However, there is only a limited number of clinical studies supporting these claims. In this double blind, placebo-controlled study, the effectiveness of the specific bioactive collagen peptide (BCP) VERISOL(r) on eye wrinkle formation and stimulation of procollagen I, elastin and fibrillin biosynthesis in the skin was assessed. A hundred and fourteen women aged 45-65 years were randomized to receive 2.5 g of BCP or placebo, once daily for 8 weeks, with 57 subjects being allocated to each treatment group. Skin wrinkles were objectively measured in all subjects, before starting the treatment, after 4 and 8 weeks as well as 4 weeks after the last intake (4-week regression phase). A subgroup was established for suction blister biopsies analyzing procollagen I, elastin and fibrillin at the beginning of the treatment and after 8 weeks of intake. The ingestion of the specific BCP used in this study promoted a statistically significant reduction of eye wrinkle volume (p < 0.05) in comparison to the placebo group after 4 and 8 weeks (20%) of intake. Moreover a positive long-lasting effect was observed 4 weeks after the last BCP administration (p < 0.05). Additionally, after 8 weeks of intake a statistically significantly higher content of procollagen type I (65%) and elastin (18%) in the BCP-treated volunteers compared to the placebo-treated patients was detected. For fibrillin, a 6% increase could be determined after BCP treatment compared to the placebo, but this effect failed to reach the level of statistical significance. In conclusion, our findings demonstrate that the oral intake of specific bioactive collagen peptides (Verisol(r)) reduced skin wrinkles and had positive effects on dermal matrix synthesis. PMID- 24401292 TI - A critical evaluation of the UK SunSmart campaign and its relevance to Black and minority ethnic communities. AB - Skin cancer is the most common cancer in the United Kingdom and is rising to epidemic proportions. While the majority of skin cancers are treatable, malignant melanoma kills over 2,000 people in the United Kingdom each year, with all skin cancers killing a total of more than 2,500 people annually. SunSmart, the United Kingdom's major skin cancer public health initiative, was implemented to raise awareness about sun exposure and to promote sun safety behaviours. However, it has failed to curb the incidence and mortality rates. Furthermore, while Australia has the highest skin cancer incidence rates globally, the mortality rates are lower than those in the United Kingdom. There has also been a growing amount of evidence demonstrating ethnic disparities in skin cancer survival rates. Even though incidence rates of skin cancer among Black and minority ethnic (BME) groups are significantly lower, it is often diagnosed late, resulting in higher mortality rates. This, coupled with climate change and the proportion of BME groups expected to rise in the United Kingdom from 8% to 20% by 2051, raises public health concerns. This article aims to critically analyse the UK SunSmart campaign's success in addressing skin cancer in the population and in particular its relevance to BME communities. It also compares this approach with the Australian campaign. This article demonstrates that Australia's campaign has been more successful than the United Kingdom's due to their more comprehensive application of health promotion and public health principles. PMID- 24401294 TI - Cardiopulmonary bypass during pregnancy--fetal demise: an enigma. PMID- 24401293 TI - Coercion and polio eradication efforts in Moradabad. AB - We introduce the problem of vaccine coercion as reported in Moradabad, India. We offer commentary and critical analysis on ethical complexities at the intersection of global public health and regional political strife and relate them to broader vaccine goals. We draw upon a historical example from malaria vaccine efforts, focusing specifically on ethical and health justice issues expressed through the use of coercion in vaccine administration. We suggest how coercion is indicative of failed leadership in public health and consider community-based collaborations as models for cultivating local investment and trust in vaccination campaigns and for success in global public health initiatives. PMID- 24401287 TI - Proceedings from the Third National Institutes of Health International Congress on Advances in Uterine Leiomyoma Research: comprehensive review, conference summary and future recommendations. AB - BACKGROUND Uterine fibroids are the most common gynecologic tumors in women of reproductive age yet the etiology and pathogenesis of these lesions remain poorly understood. Age, African ancestry, nulliparity and obesity have been identified as predisposing factors for uterine fibroids. Symptomatic tumors can cause excessive uterine bleeding, bladder dysfunction and pelvic pain, as well as associated reproductive disorders such as infertility, miscarriage and other adverse pregnancy outcomes. Currently, there are limited noninvasive therapies for fibroids and no early intervention or prevention strategies are readily available. This review summarizes the advances in basic, applied and translational uterine fibroid research, in addition to current and proposed approaches to clinical management as presented at the 'Advances in Uterine Leiomyoma Research: 3rd NIH International Congress'. Congress recommendations and a review of the fibroid literature are also reported. METHODS This review is a report of meeting proceedings, the resulting recommendations and a literature review of the subject. RESULTS The research data presented highlights the complexity of uterine fibroids and the convergence of ethnicity, race, genetics, epigenetics and environmental factors, including lifestyle and possible socioeconomic parameters on disease manifestation. The data presented suggest it is likely that the majority of women with uterine fibroids will have normal pregnancy outcomes; however, additional research is warranted. As an alternative to surgery, an effective long-term medical treatment for uterine fibroids should reduce heavy uterine bleeding and fibroid/uterine volume without excessive side effects. This goal has not been achieved and current treatments reduce symptoms only temporarily; however, a multi-disciplined approach to understanding the molecular origins and pathogenesis of uterine fibroids, as presented in this report, makes our quest for identifying novel targets for noninvasive, possibly nonsystemic and effective long-term treatment very promising. CONCLUSIONS The Congress facilitated the exchange of scientific information among members of the uterine leiomyoma research and health-care communities. While advances in research have deepened our knowledge of the pathobiology of fibroids, their etiology still remains incompletely understood. Further needs exist for determination of risk factors and initiation of preventive measures for fibroids, in addition to continued development of new medical and minimally invasive options for treatment. PMID- 24401295 TI - Correlation of cardiac output and sevoflurane required to maintain anesthetic depth targeted with entropy index. AB - AIMS AND OBJECTIVES: We investigated the correlation of reduced cardiac output on required sevoflurane to maintain targeted anesthesia depth. MATERIALS AND METHODS: 36 patients undergoing coronary artery bypass grafting with cardiopulmonary bypass were prospectively included in the study. Inspired sevoflurane concentration was adjusted to ensure state entropy index < 40. Analgesia was provided by either boluses of fentanyl 200 MUg or continuous infusion of fentanyl 5 MUg/kg/h; the total dose of fentanyl administered in the patients was not different (fentanyl boluses 6.5 +/- 0.3 MUg/kg/h vs. fentanyl infusion 5 MUg/kg/h). Cardiac-index (CI), end tidal sevoflurane (ETsev) and entropy index were measured simultaneously at 1-5 min after sternotomy, during internal mammary artery harvesting and during pericardiotomy. 108 sets of variables (entropy index, ETsev, CI) were recorded from 36 subjects at three time points; 13 sets were excluded due to technical drawbacks in measurements. 95 data sets were eligible for analysis. Sixty-five data sets measured in patients with target state entropy index were analyzed to establish the relationship between CI and ETsev. RESULTS: We did not find a linear correlation between ETsev and CI in patients with target entropy index (correlation coefficient = 0.18, P = 0.14). The ETsev necessary to maintain the target level of anesthesia was lower in patients with CI <= 2.2 l/min/m2 (1.15% +/- 0.28%) than patients with CI > 2.2 l/min/m2 (1.37% +/- 0.31%), P = 0.01. CONCLUSION: Relationship between CI and ETsev required for maintaining target level of anesthesia is non-linear. Patients with CI <= 2.2 l/min/m2 need lower levels of the ETsev for maintenance of the target anesthesia at an entropy index < 40. PMID- 24401296 TI - The effects of different ventilator modes on cerebral tissue oxygen saturation in patients with bidirectional superior cavopulmonary connection. AB - AIMS AND OBJECTIVES: We used near-infrared spectroscopy to document changes in cerebral tissue oxygen saturation (SctO2) in response to ventilation mode alterations after bidirectional Glenn (BDG; superior cavopulmonary connection) procedure. We also determined whether spontaneous ventilation have a beneficial effect on hemodynamic status, lactate and SctO2 when compared with other ventilation modes. MATERIALS AND METHODS: 20 consecutive patients undergoing BDG were included. We measured SctO 2 during three ventilator modes (intermittent positive-pressure ventilation [IPPV]; synchronized intermittent mandatory ventilation [SIMV]; and continuous positive airway pressure + pressure support ventilation [CPAP + PSV]). We, also, measured mean airway pressure (AWP), arterial blood gases, lactate and systolic arterial pressures (SAP). RESULTS: There was no change in SctO2 in IPPV and SIMV modes; the SctO2 measured during CPAP + PSV and after extubation increased significantly (60.5 +/- 11, 61 +/- 10, 65 +/- 10, 66 +/- 11 respectively) (P < 0.05). The differences in the SAP measured during IPPV and SIMV modes was insignificant; the SAP increased significantly during CPAP + PSV mode and after extubation compared with IPPV and SIMV (109 +/- 11, 110 +/- 12, 95 +/- 17, 99 +/- 13 mmHg, respectively) (P < 0.05). Mean AWP did not change during IPPV and SIMV modes, mean AWP decreased significantly during CPAP + PSV mode (14 +/- 4, 14 +/- 3, 10 +/- 1 mmHg, respectively) (P < 0.01). CONCLUSIONS: The SctO2 was higher during CPAP + PSV ventilation and after extubation compared to IPPV and SIMV modes of ventilation. The mean AWP was lower during CPAP + PSV ventilation compared to IPPV and SIMV modes of ventilation. PMID- 24401297 TI - Anesthesia management for MitraClip device implantation. AB - AIMS AND OBJECTIVES: Percutaneous MitraClip implantation has been demonstrated as an alternative procedure in high-risk patients with symptomatic severe mitral regurgitation (MR) who are not suitable (or) denied mitral valve repair/replacement due to excessive co morbidity. The MitraClip implantation was performed under general anesthesia and with 3-dimensional transesophageal echocardiography (TEE) and fluoroscopic guidance. MATERIALS AND METHODS: Peri operative patient data were extracted from the electronic and paper medical records of 21 patients who underwent MitraClip implantations. RESULTS: Four MitraClip implantation were performed in the catheterization laboratory; remaining 17 were performed in the hybrid operating theatre. In 2 patients, procedure was aborted, in one due to migration of the Chiari network into the left atrium and in second one, the leaflets and chords of the mitral valve torn during clipping resulting in consideration for open surgery. In the remaining 19 patients, MitraClip was implanted and the patients showed acute reduction of severe MR to mild-moderate MR. All the patients had invasive blood pressure monitoring and the initial six patients had central venous catheterization prior to the procedure. Intravenous heparin was administered after the guiding catheter was introduced through the inter-atrial septum and activated clotting time was maintained beyond 250 s throughout the procedure. Protamine was administered at the end of the procedure. All the patients were monitored in the intensive care unit after the procedure. CONCLUSIONS: Percutaneous MitraClip implantation is a feasible alternative in high-risk patients with symptomatic severe MR. Anesthesia management requirements are similar to open surgical mitral valve repair or replacement. TEE plays a vital role during the MitraClip implantation. PMID- 24401298 TI - Multimodal neuromonitoring in pediatric cardiac anesthesia. AB - Despite significant improvements in overall outcome, neurological injury remains a feared complication following pediatric congenital heart surgery (CHS). Only if adverse events are detected early enough, can effective actions be initiated preventing potentially serious injury. The multifactorial etiology of neurological injury in CHS patients makes it unlikely that one single monitoring modality will be effective in capturing all possible threats. Improving current and developing new technologies and combining them according to the concept of multimodal monitoring may allow for early detection and possible intervention with the goal to further improve neurological outcome in children undergoing CHS. PMID- 24401299 TI - Cardiopulmonary bypass in pregnancy. AB - Cardiac surgery carried out on cardiopulmonary bypass (CPB) in a pregnant woman is associated with poor neonatal outcomes although maternal outcomes are similar to cardiac surgery in non-pregnant women. Most adverse maternal and fetal outcomes from cardiac surgery during pregnancy are attributed to effects of CPB. The CPB is associated with utero-placental hypoperfusion due to a number of factors, which may translate into low fetal cardiac output, hypoxia and even death. Better maternal and fetal outcomes may be achieved by early pre-operative optimization of maternal cardiovascular status, use of perioperative fetal monitoring, optimization of CPB, delivery of a viable fetus before the operation and scheduling cardiac surgery on an elective basis during the second trimester. PMID- 24401300 TI - Unicommissural unicuspid aortic valve. PMID- 24401301 TI - Real and pseudo clot in left atrial appendage. PMID- 24401302 TI - Transesophageal echocardiographic image of partial aortic disruption. PMID- 24401303 TI - Cardiac surgery during pregnancy: continuous fetal monitoring using umbilical artery Doppler flow velocity indices. AB - The fetal death rate associated with cardiac surgery with cardiopulmonary bypass (CPB) is as high as 9.5-29%. We report continuous monitoring of fetal heart rate and umbilical artery flow-velocity waveforms by transvaginal ultrasonography and their analyses in relation to events of the CPB in two cases in second trimester of pregnancy undergoing mitral valve replacement. Our findings suggest that the transition of circulation from corporeal to extracorporeal is the most important event during surgery; the associated decrease in mean arterial pressure (MAP) at this stage potentially has deleterious effects on the fetus, which get aggravated with the use of vasopressors. We suggest careful management of CPB at this stage, which include partial controlled CPB at initiation and gradual transition to full CPB; this strategy maintains high MAP and avoids the use of vasopressors. Maternal and fetal monitoring can timely recognize the potential problems and provide window for the required treatment. PMID- 24401304 TI - Emergency mitral valve replacement for acute severe mitral regurgitation following balloon mitral valvotomy: pathophysiology of hemodynamic collapse and peri-operative management issues. AB - Severe mitral regurgitation (MR) following balloon mitral valvotomy (BMV) needing emergent mitral valve replacement is a rare complication. The unrelieved mitral stenosis is compounded by severe MR leading to acute rise in pulmonary hypertension and right ventricular afterload, decreased coronary perfusion, ischemia and right ventricular failure. Associated septal shift and falling left ventricular preload leads to a vicious cycle of myocardial ischemia and hemodynamic collapse and needs to be addressed emergently before the onset of end organ damage. In this report, we describe the pathophysiology of hemodynamic collapse and peri-operative management issues in a case of mitral valve replacement for acute severe MR following BMV. PMID- 24401305 TI - Stroke associated with left atrial mass: association of cerebral aneurysm with left atrial myxoma! AB - Association of LA myxoma with cerebral aneurysm is rare. We describe a patient who had LA mass and cerebral aneurysm and developed stroke. The patient underwent clipping of the cerebral aneurysm. We discuss the pathology of the association and the anesthetic management. PMID- 24401306 TI - Management of high-risk reentry sternotomy in an infant for repair of a giant pseudoaneurysm of the right ventricular outflow tract. AB - Improved survival from congenital heart disease has led to an increasing need for complex reoperation by reentrant sternotomy. Peripheral cannulation and initiation of cardiopulmonary bypass prior to sternotomy to avoid the risk of cardiac injury and massive hemorrhage is an option in adults and larger children, but femoral vessel size precludes this strategy in infants. We describe the management of a high-risk reentry sternotomy in an infant for repair of a giant pseudoaneurysm after prior homograft repair of tetralogy of Fallot, using surgical dissection for suprasternal cannulation of the innominate artery and subxyphoid cannulation of the inferior vena cava. PMID- 24401307 TI - Management of a case of left tracheal sleeve pneumonectomy under cardiopulmonary bypass: anesthesia perspectives. AB - The lung tumors with carinal involvement are frequently managed with tracheal sleeve pneumonectomy and tracheobronchial anastomosis without use of cardiopulmonary bypass (CPB). Various modes of ventilation have been described during tracheal resection and anastomosis. Use of CPB during this period allows the procedure to be conducted in a more controlled way. We performed tracheal sleeve pneumonectomy for adenoid cystic carcinoma of left lung involving carina. The surgery was performed in two stages. In the first stage, left pneumonectomy was performed and in the second stage after 48 h, tracheobronchial resection and anastomosis was performed under CPB. Second stage was delayed to avoid excessive bleeding (due to heparinization) from the extensive vascular raw area left after pneumonectomy. Meticulous peri-operative planning and optimal post-operative care helped in successful management of a complex case, which is associated with high morbidity and mortality. PMID- 24401308 TI - Localized pericardial tamponade: does it always need exploration? AB - A 48-year-old female patient underwent coronary artery bypass surgery. One-hour after surgery, the patient developed hemodynamic instability. Transthoracic echocardiography (TTE) was inconclusive. Transesophageal echocardiography (TEE) was performed and it revealed localised collection around right atrium. In spite of the evidence of localized tamponade, wait and watch policy was employed rather than re-exploring the patient emergently. The patient recovered uneventfully. If hemodynamics remain stable and there is no fall in hematocrit and no increase in effusion on TEE/TTE examination, then localized tamponade can be managed conservatively without reexploring the patient. PMID- 24401309 TI - In response to "Anaphylaxis during intravenous administration of amiodarone": is amiodarone the best choice for management of atrial fibrillation? PMID- 24401310 TI - In response to "Posterior mediastinal mass: do we need to worry much?". PMID- 24401311 TI - Unexplained desaturation following a Glenn shunt. PMID- 24401312 TI - Accidental cannulation of aberrant radial artery. PMID- 24401313 TI - Preanesthesia assessment clinic for cardiac surgery by cardiac anesthesiologist: a practice statement. PMID- 24401314 TI - Occurence of internet addiction in a general population sample: a latent class analysis. AB - BACKGROUND: Prevalence studies of Internet addiction in the general population are rare. In addition, a lack of approved criteria hampers estimation of its occurrence. AIMS: This study conducted a latent class analysis (LCA) in a large general population sample to estimate prevalence. METHODS: A telephone survey was conducted based on a random digit dialling procedure including landline telephone (n=14,022) and cell phone numbers (n=1,001) in participants aged 14-64. The Compulsive Internet Use Scale (CIUS) served as the basis for a LCA used to look for subgroups representing participants with Internet addiction or at-risk use. CIUS was given to participants reporting to use the Internet for private purposes at least 1 h on a typical weekday or at least 1 h on a day at the weekend (n=8,130). RESULTS: A 6-class model showed best model fit and included two groups likely to represent Internet addiction and at-risk Internet use. Both groups showed less social participation and the Internet addiction group less general trust in other people. Proportions of probable Internet addiction were 1.0% (CI 0.9-1.2) among the entire sample, 2.4% (CI 1.9-3.1) in the age group 14-24, and 4.0% (CI 2.7-5.7) in the age group 14-16. No difference in estimated proportions between males and females was found. Unemployment (OR 3.13; CI 1.74-5.65) and migration background (OR 3.04; CI 2.12-4.36) were related to Internet addiction. CONCLUSIONS: This LCA-based study differentiated groups likely to have Internet addiction and at-risk use in the general population and provides characteristics to further define this rather new disorder. PMID- 24401315 TI - White matter changes in patients with Parkinson's disease carrying small CGG expansion FMR1 alleles: a pilot study. AB - BACKGROUND/AIMS: Alleles of the FMR1 gene containing small expansions of the CGG trinucleotide repeat comprise premutation and grey-zone alleles. Premutation alleles may cause late-onset Fragile X-associated tremor/ataxia syndrome attributed to the neurotoxic effect of elevated FMR1 transcripts. Our earlier data suggested that both grey-zone and low-end premutation alleles might also play a significant role in the acquisition of the parkinsonian phenotype due to mitochondrial dysfunction caused by elevated FMR1 mRNA toxicity. These data were obtained through clinical and molecular comparisons between carriers of grey zone/low-end premutation alleles and group-matched non-carrier controls from patients with idiopathic Parkinson's disease (iPD). We aimed to explore the relationship between grey-zone alleles, parkinsonism and white matter changes. METHODS: This study compared the extent and severity of white matter hyperintensity (WMH) on magnetic resonance imaging, using a semi-quantitative method, between 11 grey-zone/low-end premutation carriers and 20 non-carrier controls with iPD from our earlier study. Relationships between WMH scores, and cognitive and motor test scores were assessed for carriers and non-carriers. RESULTS: Supratentorial WMH scores, and tremor and ataxia motor scores were significantly higher in carriers compared with disease controls. Moreover, some associations between cognitive decline and WMH scores were specific for each respective carrier status category. CONCLUSIONS: The results support our earlier claim that grey-zone alleles contribute to the severity of parkinsonism and white matter changes. PMID- 24401316 TI - Translating gerontology into practice. PMID- 24401317 TI - Estrogen treatment predisposes to severe and persistent vaginal candidiasis in diabetic mice. AB - BACKGROUND: Increased levels of estrogen and diabetes mellitus separately predispose to vaginal candidiasis (VC). However, the compounding effect of estrogen on the severity and persistence of VC in diabetic females is not clear. METHODS: To address this issue, a diabetic mouse model with estrogen-maintained VC was developed and evaluated for vaginal fungal burden (VFB) and immune competence at different time points throughout the study period. RESULTS: Blood glucose levels in estrogen-treated diabetic mice were consistently lower than that in untreated counterparts. Estrogen-treated C. albicans-infected non diabetic mice experienced persistent episodes of VC as compared with naive controls (P < 0.01). However, severity and persistence of VC in estrogen-treated C. albicans-infected diabetic mice was significantly greater than that in non diabetic counterparts (P < 0.05). Mortality rates among estrogen-treated C. albicans-infected diabetic mice were significantly higher (P < 0.05) than that in non-diabetic counterparts. Statistically significant (P < 0.05) and persistent suppression of the delayed hypersensitivity response (DTH) was evident in estrogen-treated C. albicans-infected diabetic and non-diabetic mice as compared with controls. Levels of expression of the inhibitory molecule CD152 on vaginal and splenic T cells isolated from estrogen-treated C. albicans infected mice was significantly higher than that in naive untreated controls (P < 0.01). CONCLUSIONS: These findings suggest that estrogen treatment in diabetic females may protect against the progression of DM on the one hand and predispose to severe and persistent VC on the other. The later outcome could be related to the immunosuppressed status of the host. PMID- 24401318 TI - microRNAs miR-27a and miR-27b directly regulate liver dihydropyrimidine dehydrogenase expression through two conserved binding sites. AB - Dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) is the rate-limiting enzyme in the uracil catabolic pathway and has a pivotal role in the pharmacokinetics of the commonly prescribed anticancer drug 5-fluorouracil (5 FU). Deficiency of DPD, whether due to inadequate expression or deleterious variants in DPYD, has been linked to severe toxic responses to 5-FU. Little is known about the mechanisms governing DPD expression in the liver. In this report, we show increased accumulation of RNA-induced silencing complex (RISC) proteins on DPYD mRNA in cells overexpressing the highly homologous microRNAs (miRNA) miR 27a and miR-27b. These miRNAs were shown to repress DPD expression through two conserved recognition sites in DPYD. The IC50 of 5-FU for HCT116 cells overexpressing miR-27a or miR-27b was 4.4 MUmol/L (both), significantly lower than that for cells expressing a nontargeting (scramble) control miRNA (14.3 MUmol/L; P = 3.3 * 10(-5) and P = 1.5 * 10(-7), respectively). Mouse liver DPD enzyme activity was inversely correlated with expression levels of miR-27a (R(2) = 0.49; P = 0.0012) and miR-27b (R(2) = 0.29; P = 0.022). A common variant in the hairpin loop region of hsa-mir-27a (rs895819) was also shown to be associated with elevated expression of the miR-27a in a panel of cell lines (P = 0.029) and in a transgenic overexpression model (P = 0.0011). Furthermore, rs895819 was associated with reduced DPD enzyme activity (P = 0.028) in a cohort of 40 healthy volunteers. Taken together, these results suggest that miR-27a and miR-27b expression may be pharmacologically relevant modulators of DPD enzyme function in the liver. Furthermore, our data suggest that rs895819 may be a potential risk allele for 5-FU sensitivity. PMID- 24401319 TI - TPCA-1 is a direct dual inhibitor of STAT3 and NF-kappaB and regresses mutant EGFR-associated human non-small cell lung cancers. AB - Epidermal growth factor receptor (EGFR) is a clinical therapeutic target to treat a subset of non-small cell lung cancer (NSCLC) harboring EGFR mutants. However, some patients with a similar kind of EGFR mutation show intrinsic resistance to tyrosine kinase inhibitors (TKI). It indicates that other key molecules are involved in the survival of these cancer cells. We showed here that 2 [(aminocarbonyl)amino]-5 -(4-fluorophenyl)-3- thiophenecarboxamide (TPCA-1), a previously reported inhibitor of IkappaB kinases (IKK), blocked STAT3 recruitment to upstream kinases by docking into SH2 domain of STAT3 and attenuated STAT3 activity induced by cytokines and cytoplasmic tyrosine kinases. TPCA-1 is an effective inhibitor of STAT3 phosphorylation, DNA binding, and transactivation in vivo. It selectively repressed proliferation of NSCLC cells with constitutive STAT3 activation. In addition, using pharmacologic and genetic approaches, we found that both NF-kappaB and STAT3 could regulate the transcripts of interleukin (IL)-6 and COX-2 in NSCLC harboring EGFR mutations. Moreover, gefitinib treatment only did not efficiently suppress NF-kappaB and STAT3 activity. In contrast, we found that treatment with TKIs increased phosho-STAT3 level in target cells. Inhibiting EGFR, STAT3, and NF-kappaB by combination of TKIs with TPCA-1 showed increased sensitivity and enhanced apoptosis induced by gefitinib. Collectively, in this work, we identified TPCA-1 as a direct dual inhibitor for both IKKs and STAT3, whereas treatment targeting EGFR only could not sufficiently repress NF kappaB and STAT3 pathways for lung cancers harboring mutant EGFR. Therefore, synergistic treatment of TPCA-1 with TKIs has potential to be a more effective strategy for cancers. PMID- 24401320 TI - Cost-effectiveness of respiratory syncytial virus prophylaxis in premature infants less than 32 weeks gestational age in Turkey: author's reply. PMID- 24401321 TI - Changes in health behaviors and their associations with depressive symptoms among Israelis aged 50+. AB - OBJECTIVE: To examine the longitudinal association between changes in health behaviors and depression and determine the mediating effect of health characteristics on this association. METHOD: Based on the first and second waves of the Survey of Health, Aging and Retirement in Europe (SHARE)-Israel, depressive symptoms of 1,524 Israelis aged 50 or older were analyzed using logistic regression. RESULTS: Changes in physical activity and body weight are associated with depressive symptoms after adjusting for confounders. However, after adding measures of health, the respective correlations of weight gain and commenced physical activity with depression disappear, and the correlation between continued activity and depression is reduced. DISCUSSION: Changes in health behaviors are related to mental health in late life, but their effect is mediated by physical and functional health. Future interventions should nevertheless target older individuals who stop physical activity and those who remain inactive to lessen the risk of depression. PMID- 24401322 TI - Trends in the utilization and outcomes of Medicare patients hospitalized for hip fracture, 2000-2008. AB - OBJECTIVE: This study examines temporal trends in hip fracture related utilization and outcomes among elderly fee-for-service Medicare beneficiaries. METHOD: The study uses claims data for a 5% sample of Medicare beneficiaries with an incident hip fracture hospitalization between 2000 and 2008. We present annual mean patient characteristics, health services utilization, and outcomes and use ordinary least squares regressions to examine adjusted trends in utilization and outcomes after controlling for changes in patient characteristics. RESULTS: We observe a statistically significant temporal decline in inpatient acute days and a statistically significant increase in inpatient post-acute days following hip fractures. In models that control for patient characteristics, we observe statistically significant declines in 1-year hip fracture readmission and mortality rates. Rates of nursing home residence 1-year following fracture were unchanged and remain high. DISCUSSION: Hip fractures remain highly debilitating events and pose significant challenges for the financing of public health insurance programs. PMID- 24401323 TI - Clinical outcome of hypofractionated breath-hold image-guided SABR of primary lung tumors and lung metastases. AB - BACKGROUND: Stereotactic Ablative RadioTherapy (SABR) of lung tumors/metastases has been shown to be an effective treatment modality with low toxicity. Outcome and toxicity were retrospectively evaluated in a unique single-institution cohort treated with intensity-modulated image-guided breath-hold SABR (igSABR) without external immobilization. The dose-response relationship is analyzed based on Biologically Equivalent Dose (BED). PATIENTS AND METHODS: 50 lesions in 43 patients with primary NSCLC (n = 27) or lung-metastases of various primaries (n = 16) were consecutively treated with igSABR with Active-Breathing-Coordinator (ABC(r)) and repeat-breath-hold cone-beam-CT. After an initial dose-finding/ escalation period, 5 x 12 Gy for peripheral lesions and single doses of 5 Gy to varying dose levels for central lesions were applied. Overall-survival (OS), progression-free-survival (PFS), progression pattern, local control (LC) and toxicity were analyzed. RESULTS: The median BED2 was 83 Gy. 12 lesions were treated with a BED2 of <80 Gy, and 38 lesions with a BED2 of >80 Gy. Median follow-up was 15 months. Actuarial 1- and 2-year OS were 67% and 43%; respectively. Cause of death was non-disease-related in 27%. Actuarial 1- and 2 year PFS was 42% and 28%. Progression site was predominantly distant. Actuarial 1 and 2 year LC was 90% and 85%. LC showed a trend for a correlation to BED2 (p = 0.1167). Pneumonitis requiring conservative treatment occurred in 23%. CONCLUSION: Intensity-modulated breath-hold igSABR results in high LC-rates and low toxicity in this unfavorable patient cohort with inoperable lung tumors or metastases. A BED2 of <80 Gy was associated with reduced local control. PMID- 24401324 TI - Inadvertent intravenous administration of maternal breast milk in a six-week-old infant: a case report and review of the literature. AB - BACKGROUND: Accidental intravenous administration of an enteral feeding can be fatal or cause complications such as sepsis, acute respiratory and circulatory failure, acute renal failure, hepatic insufficiency, coagulation disorders and severe permanent neurological sequelae. These "wrong route" errors are possible due to compatible connections between enteral feeding systems and intravascular infusion catheters. CASE PRESENTATION: We report a six-week-old male infant who received a 5 ml intravenous infusion of breast milk. Within five minutes of administration the child developed tachycardia and tachypnea, accompanied by a sudden decrease in oxygen saturation on pulse oximetry to 69%. The infant received supplemental oxygen via nasal cannula and was transferred to the pediatric intensive care unit. Broad-spectrum antibiotics were administered for 48 hours. Vital signs returned to normal within a few hours. Neurological follow up through 3 years did not reveal any neurodevelopmental abnormalities. CONCLUSION: Development of specific enteral feeding connections, which are incompatible with intravascular catheter connections, is needed urgently to prevent a misconnection with potential morbidity or mortality of children. PMID- 24401325 TI - Kruppel-like factor 5 promotes lung tumorigenesis through upregulation of Sox4. AB - BACKGROUND: Kruppel-like factor 5 (KLF5), a member of zinc finger class of DNA binding transcriptional regulators, has attracted attention because of its important regulatory activities linked to diverse functions such as cell growth, proliferation, differentiation, apoptosis and tumorigenesis in a number of systems. However, its biological functions in the initiation and progression of lung tumorigenesis remain largely unexplored. METHODS: Quantitative realtime PCR and Western Blot were used to detect the expression of KLF5 in lung cancer tissues and cell lines. Retro-viruses were used to generate KLF5 stable expression lung cancer cell line. Small interfering RNA was used to silence the expression of KLF5 and Sox4. BrdU assay was used to determine the proliferation of cells. Luciferase and Chromatin immunoprecipitation assays were used to detect the regulation of Sox4 by KLF5. RESULTS: KLF5 was up-regulated in lung cancer tissues and cell lines. Overexpression of KLF5 promotes while knockdown of its expression inhibits cell proliferation in two cell lines derived from lung carcinoma. At the molecular level, our results revealed that KLF5 positively regulates Sox4 expression through a transcriptional mechanism. Sox4 deficiency blocked the proliferative roles of KLF5 in lung cancer cells. CONCLUSION: our data identified the KLF5/Sox4 regulatory signaling play an important role in lung tumorigenesis, which might represent novel therapeutic targets to manage lung carcinoma. PMID- 24401326 TI - Diazepam binding inhibitor and dehydroepiandrosterone sulphate plasma levels in borderline personality disorder adolescents. AB - BACKGROUND: Borderline personality disorder (BPD) patients display a complex and heterogeneous clinical phenotype that plausibly implies variable underlying pathogenic mechanisms. A dysregulation of peripheral benzodiazepine receptors has previously been shown in BPD peripheral tissues, implying possible alterations of its ligand, the diazepam binding inhibitor (DBI) or of the downstream products of its activation, i.e. neuroactive steroids. METHODS: The aim of this work consisted in assessing, by ELISA, fasting plasma levels of DBI and dehydroepiandrosterone sulphate (DHEA-S), including cortisol and the cortisol-to DHEA-S molar ratio (CDR), in 17 BPD adolescents versus 13 healthy controls, testing the possibility that clinical scales related to depressive or anxious traits (CDI, STAI-Y) or to disease severity (BPDCL) might be associated with a selective dysregulation of these parameters. RESULTS: DBI plasma levels were unchanged, while DHEA-S ones were significantly increased (approx. 70%) and the CDR decreased in BPD patients. No meaningful correlations with clinical variables emerged. CONCLUSION: Our results indicate that a dysfunction of the neurosteroid system might be operative in BPD in spite of unchanged DBI plasma levels and that DHEA-S might represent a generalized trait marker for the altered stress response that is associated with this disorder. PMID- 24401327 TI - Confirmed field hybridization of native and introduced Phragmites australis (Poaceae) in North America. AB - PREMISE OF THE STUDY: Intraspecific hybridization between native and introduced lineages of a species can increase invasiveness and may lead to the decline of native lineages. The introduction of Eurasian Phragmites australis has caused profound changes to wetland habitats across North America, yet evidence for hybridization between native and introduced Phragmites australis in North America is lacking and has puzzled researchers for over a decade. Here we present the first confirmed field hybridization event between the two lineages. METHODS: Hybrid plants were initially recognized during field surveys by their intermediate morphology and distinct herbivore community. We verified hybrid status using chloroplast DNA haplotypes and microsatellite markers. KEY RESULTS: Confirmed hybrid stems were restricted to one site and displayed morphological characteristics of both native and introduced P. australis. Based on their microsatellite profiles, all samples likely represent a single clone of a first generation hybrid. Sequencing of cpDNA indicates that the maternal parent is from the introduced lineage. CONCLUSIONS: Identification of hybrid P. australis in the field is complex and requires multiple characters. All suspected hybrids should be verified using genetic techniques. Preventing the spread of introduced genes and genotypes through North America will require recognition and rapid management response to hybrid plants. PMID- 24401328 TI - Molecular phylogenetics supports widespread cryptic species in moonworts (Botrychium s.s., Ophioglossaceae). AB - PREMISE OF THE STUDY: Previous phylogenetic studies of moonworts (Botrychium sensu stricto (s.s.)) included few taxa from outside of North America. This low geographical representation limited interpretations of relationships of this group rich in cryptic species. With 18 out of 30 species in the genus being polyploid, understanding their evolutionary history remains a major challenge. METHODS: A new molecular phylogeny was reconstructed using Maximum Likelihood (ML) and Bayesian Inference (BI) analyses based on multiple accessions of the most wide-ranging Arctic taxa of Botrychium in North America and Europe using three noncoding plastid DNA regions (psbA-trnH(GUG), trnL(UAA)-trnF(GAA) intergenic spacer, and rpL16 intron). KEY RESULTS: The new phylogeny confirms the identity of several recently described species and proposed new taxa. Nine subclades are newly identified within the two major clades in Botrychium s.s.: Lanceolatum and Lunaria. Chloroplast DNA was variable enough to separate morphologically cryptic species in the Lunaria clade. On the contrary, much less variation is seen within the morphologically variable Lanceolatum clade despite sampling over the same broad geographic range. The chloroplast region psbA trnH(GUG) is identified as an efficient DNA barcode for the identification of cryptic taxa in Botrychium s.s. CONCLUSIONS: The combined increase in species representation, samples from throughout the geographic range of each species, and sequencing of multiple plastid DNA regions supports morphologically cryptic species in Botrychium s.s. PMID- 24401329 TI - Sudden hearing loss subsequent to diarrhea: what is the missing link? AB - Sudden sensorineural hearing loss (SSNHL) is a debilitating condition with an incidence of nearly 20 per 100,000 in populations. Metronidazole-induced ototoxicity is an extremely rare etiology of SSNHL. In this report, we describe a young female with bilateral SSNHL due to oral use of metronidazole. A 23 years old female presented to the emergency department with acute bilateral hearing loss. We found out that her hearing loss had started 4 days after initiation of metronidazole which was administered for treatment of diarrhea. This case report shows that physicians should be aware of the uncommon side effects while prescribing metronidazole to patients in order to manage the possible adverse events on time. PMID- 24401330 TI - Cutaneous application of leukotriene B4 as an in vivo model of psoriasis-like skin inflammation: an immunohistological study. AB - BACKGROUND: Research has revealed new insights into the pathogenesis of psoriasis, leading to new therapeutic options. So far the order of changes in the pathogenesis of psoriasis is unclear. The responses to cutaneous leukotriene B4 (LTB4) application have been studied in the past as an in vivo model for inflammation. The aim of the present study is to find out the order of changes of key steps in inflammation, which all have been shown to be involved in mature psoriatic lesions. OBJECTIVE: To study the dynamics of the consecutive stages of inflammation in challenged skin as a reflection of a psoriasis-like inflammatory response. METHODS: We examined the dynamics of epidermal growth control and the key representatives of the innate and acquired immune system during the first 72 h after challenging the skin by LTB4 application. RESULTS: Interleukin 17 positive (IL-17+) cells dominate the acute phase of inflammation, whereas T-Bet+ cells seem to increase gradually during the entire observation period. This indicates a more important role for IL-17 in the unstable phase of inflammation and a more prominent role for T-Bet+ cells within the chronic phase. CONCLUSION: The present model is highly reproducible and is useful in studying the dynamics of a psoriasis-like inflammation with respect to key components of immunity. It could provide a useful tool to study the immediate biological effects of new therapies like anti-IL-17 drugs on IL-17 production and effects on cutaneous inflammation and epidermal proliferation in vivo. PMID- 24401331 TI - Detecting single-electron events in TEM using low-cost electronics and a silicon strip sensor. AB - There is great interest in developing novel position-sensitive direct detectors for transmission electron microscopy (TEM) that do not rely in the conversion of electrons into photons. Direct imaging improves contrast and efficiency and allows the operation of the microscope at lower energies and at lower doses without loss in resolution, which is especially important for studying soft materials and biological samples. We investigate the feasibility of employing a silicon strip detector as an imaging detector for TEM. This device, routinely used in high-energy particle physics, can detect small variations in electric current associated with the impact of a single charged particle. The main advantages of using this type of sensor for direct imaging in TEM are its intrinsic radiation hardness and large detection area. Here, we detail design, simulation, fabrication and tests in a TEM of the front-end electronics developed using low-cost discrete components and discuss the limitations and applications of this technology for TEM. PMID- 24401332 TI - Strategy to improve the request of uric acid in primary care: preliminary results and evaluation through process and outcome appropriateness indicators. AB - INTRODUCTION: Alerted by the high rates of request of serum uric acid (UA) in primary care patients, we aimed to design a strategy to improve such an indicator, and to monitor such an intervention through process and outcome appropriateness indicators. METHODS: To design the strategy, several meetings were held between the Laboratory, Rheumatology and Primary Care. The intervention consisted of discharging UA from two laboratory profiles ("Health Check" and "Rheumatology"), making it only possible to request the test in an individualized manner. To assess the intervention effectiveness, the ratio of UA/glucose requests, the quantity of allopurinol prescription and the resulting economic savings were calculated and compared for pre- and post-intervention 12 month periods. RESULTS: There was a 70% decrease in the number of UA requests in the post-intervention period, as compared to the pre-intervention interval. The ratio of UA/glucose requests experienced a significant commensurate drop in the post intervention period (p<0.01). There was a significant reduction in the prescription of allopurinol (p<0.01). From an economic perspective, the strategy resulted in a savings of 8190 ?. CONCLUSION: The strategy resulted in a dramatic drop in the number of UA requests and in the prescription of allopurinol. This highlights a likely existence of prior unnecessary treatment of patients with hyperuricemia in the absence of clinical symptoms. PMID- 24401333 TI - Association of sociodemographic, psychopathological and gambling-related factors with treatment utilization for pathological gambling. AB - BACKGROUND/AIMS: Only a small percentage of pathological gamblers utilizes professional treatment for gambling problems. Little is known about which social and gambling-related factors are associated with treatment utilization. The aim of this study was to look for factors associated with treatment utilization for pathological gambling. METHODS: The study followed a sampling design with 3 different recruitment channels, namely (1) a general population-based telephone sample, (2) a gambling location sample and (3) a project telephone hotline. Pathological gambling was diagnosed in a telephone interview. Participants with pathological gambling (n=395) received an in-depth clinical interview concerning treatment utilization, comorbid psychiatric disorders and social characteristics. RESULTS: Variables associated with treatment were higher age [odds ratio (OR) 1.05, 95% confidence interval (CI) 1.03-1.08], an increased number of DSM-IV criteria for pathological gambling (OR 1.34, 95% CI 1.06-1.70), more adverse consequences from gambling (OR 1.10, 95% CI 1.03-1.16) and more social pressure from significant others (OR 1.17, 95% CI 1.07-1.27). Affective disorders were associated with treatment utilization in the univariate analysis (OR 1.81, 95% CI 1.19-2.73), but multivariate analysis showed that comorbid psychiatric disorders were not independently associated. CONCLUSION: These results indicate that individuals with more severe gambling problems utilize treatment at an older age when more adverse consequences have occurred. Further research should focus on proactive early interventions. PMID- 24401335 TI - We can treat Alzheimer's disease successfully in mice but not in men: failure in translation? A perspective. AB - BACKGROUND: Animal models closely resembling the etiopathogenesis of Alzheimer's disease (AD) are needed for research on disease mechanisms and for drug development. No natural model of AD is available, so big hopes arose from transgenic and knockout technology, expecting that modulation and expression of pathogenetically important proteins resemble human brain pathology and functional deficits in the expected morphological and temporal pattern. OBJECTIVE: The real usefulness of these models should be discussed from an objective point of view. RESULTS: Not a single one of the published transgenic rodent models fulfils this hope, and even complex multiple transgenic animals do not suffer from real AD. It is crucial to be aware that all of the commonly used mice and rats are just models, and therefore results from drug efficacy testing have to be interpreted with care. Repeated experience with failed trials of new treatments that previously had been published as successful in animals has led to the wrong conclusion that animal models are of low predictive value or even of no use. Often clinical trials replicate exactly what was shown in the animal proof-of concept studies. CONCLUSION: The value of animal models depends mainly on the careful experimentation and correct interpretation of results. Appropriate planning of experiments will help to increase the predictive value in drug development programs, though this may also increase negative findings. However, the early failure may enable a faster focus on more promising strategies. PMID- 24401334 TI - Evidence for eIF2alpha phosphorylation-independent effects of GSK2656157, a novel catalytic inhibitor of PERK with clinical implications. AB - The endoplasmic reticulum (ER)-resident protein kinase PERK is a major component of the unfolded protein response (UPR), which promotes the adaptation of cells to various forms of stress. PERK phosphorylates the alpha subunit of the translation initiation factor eIF2 at serine 51, a modification that plays a key role in the regulation of mRNA translation in stressed cells. Several studies have demonstrated that the PERK-eIF2alpha phosphorylation pathway maintains insulin biosynthesis and glucose homeostasis, facilitates tumor formation and decreases the efficacy of tumor treatment with chemotherapeutic drugs. Recently, a selective catalytic PERK inhibitor termed GSK2656157 has been developed with anti tumor properties in mice. Herein, we provide evidence that inhibition of PERK activity by GSK2656157 does not always correlate with inhibition of eIF2alpha phosphorylation. Also, GSK2656157 does not always mimic the biological effects of the genetic inactivation of PERK. Furthermore, cells treated with GSK2656157 increase eIF2alpha phosphorylation as a means to compensate for the loss of PERK. Using human tumor cells impaired in eIF2alpha phosphorylation, we demonstrate that GSK2656157 induces ER stress-mediated death suggesting that the drug acts independent of the inhibition of eIF2alpha phosphorylation. We conclude that GSK2656157 might be a useful compound to dissect pathways that compensate for the loss of PERK and/or identify PERK pathways that are independent of eIF2alpha phosphorylation. PMID- 24401336 TI - Emerging paradigms in anti-infective drug design. AB - The need for new drugs to treat microbial infections is pressing. The great progress made in the middle part of the twentieth Century was followed by a period of relative inactivity as the medical needs relating to infectious disease in the wealthier nations receded. Growing realisation that anti-infectives are needed in many parts of the world, to treat neglected diseases as well as to combat the burgeoning risk of resistance to existing drugs, has galvanised a new wave of research into anti-microbial drugs. The transfer of knowledge from the Pharmaceutical industry relating to the importance of understanding how to target drugs successfully within the body, and improved understanding of how pathogens interact with their hosts, is driving a series of new paradigms in anti-infective drug design. Here we provide an overview of those processes as an introduction to a series of articles from experts in this area that emerged from a meeting entitled "Emerging Paradigms in Anti-Infective Drug Design" held in London on the 17th and 18th September 2012. The symposium was organised jointly by British Society for Parasitology (BSP) and the Biological & Medicinal Chemistry sector of the Royal Society of Chemistry (RSC) and held at the London School of Hygiene & Tropical Medicine. The symposium set out to cover all aspects of the identification of new therapeutic modalities for the treatment of neglected and tropical diseases. We aimed to bring together leading scientists from all the disciplines working in this field and cover the pharmacology, medicinal chemistry and drug delivery of potential new medicines. Sessions were held on: "Target diseases and targets for drugs", "Target based medicinal chemistry", "Bioavailability and chemistry", "Targeting intracellular microbes", "Alternative approaches and models", and "New anti-infectives - how do we get there?" This symposium was organised by Simon Croft (LSHTM) and Mike Barrett (University of Glasgow) for the BSP, and David Alker (David Alker Associates) and Andrew Stachulski (University of Liverpool) for the Biological & Medicinal Chemistry sector of the RSC. PMID- 24401337 TI - Novel inhibitors of the Plasmodium falciparum electron transport chain. AB - Due to an increased need for new antimalarial chemotherapies that show potency against Plasmodium falciparum, researchers are targeting new processes within the parasite in an effort to circumvent or delay the onset of drug resistance. One such promising area for antimalarial drug development has been the parasite mitochondrial electron transport chain (ETC). Efforts have been focused on targeting key processes along the parasite ETC specifically the dihydroorotate dehydrogenase (DHOD) enzyme, the cytochrome bc 1 enzyme and the NADH type II oxidoreductase (PfNDH2) pathway. This review summarizes the most recent efforts in antimalarial drug development reported in the literature and describes the evolution of these compounds. PMID- 24401338 TI - Motivating employees. PMID- 24401339 TI - Mounted models as surgical guides? PMID- 24401340 TI - Lip service is no longer enough. PMID- 24401341 TI - Anterior guidance for the natural dentition and fixed prosthodontics: the other side of success. PMID- 24401342 TI - Provisional materials-can you tell one from the other? PMID- 24401343 TI - Combination of esthetic natural tooth restorations with a central incisor implant case. PMID- 24401344 TI - In social media age, watch what you say. PMID- 24401345 TI - Drug supplement interactions significant to dentistry. PMID- 24401347 TI - Message to our patients: you are what you eat, and your mouth shows it. PMID- 24401346 TI - Achieving immediate success with ceramic repairs. PMID- 24401348 TI - What every dentist needs to know about the human microbiome and probiotics. AB - Bacterial cells in the human body outnumber human cells by a ratio of 10:1. Apart from their well-known pathogenic potential, bacteria are proving to be integral to the overall health of the body. Residential microbes have critical roles in diverse processes, such as nutrient harvesting, internal environment regulation, immune system development, neurological modulation, and drug metabolism, as well as providing protection against pathogens. There is a growing body of research on the microbiome and probiotic therapies to restore or augment these functions throughout the body. In particular, increasing numbers of bacterial species and bacterial interactions have been discovered in the oral cavity, and probiotic interventions for common dental problems such as caries, periodontal diseases, and oral malodor are being developed and reviewed. PMID- 24401349 TI - Comparative study of the fluorescence intensity of dental composites and human teeth submitted to artificial aging. AB - The aim of this study was to evaluate quantitatively the fluorescence of resin composites and human teeth, and to determine the stability of fluorescence after aging. Ten specimens were built using a 1 mm thick increment of dentin composite overlapped by a 0.5 mm thick increment of enamel composite. Ten sound human molars were sectioned and silicon carbide-polished to obtain enamel and dentin slabs 1.5 mm in thickness. Fluorescence measurements were carried out by a fluorescence spectrophotometer before and after thermocycling (2000 cycles, 5 degrees C and 55 degrees C). One-way analysis of variance (ANOVA) with repeated measures and Tukey's test were performed at a significance level of 5%. Most of the tested composites showed significant differences in fluorescence both before and after aging (P < 0.05). Opallis was the only composite whose fluorescence was similar to that of human teeth at both periods of evaluation (P > 0.05), and was the only composite that showed comparable results of fluorescence to the tooth structure before and after thermocycling. With the exception of Filtek Supreme, there were significant reductions in fluorescence intensity for all the tested composites (P < 0.05). PMID- 24401351 TI - Clinical observations of dental erosion associated with citrus diet and intake methods. AB - Citrus fruits and juices are an integral part of daily diets the world over; however, excessive and frequent consumption can cause damage to the human dentition. This article describes the characteristics of destruction induced by citrus products. Related factors include the fruits' acidic nature, their inherent highly fibrous content, the method of intake, and the sites of the dentition exposed for prolonged durations. The various features of the defects resulting from the combined chemical and/or mechanical destructive potential of citrus products are demonstrated in relation to intake method. Mitigating and aggravating factors that affect the erosive process are discussed also. PMID- 24401350 TI - Multiple metastases of malignant melanoma in the head and neck: a case report and literature review. AB - Malignant melanoma (MM) with multiple metastases (including the oral mucosa) is an extremely rare condition that is difficult to manage due to its complexity. This article presents the case of a 27-year-old man who first developed MM on the scalp, which subsequently metastasized to the mandible, parotid gland, infratemporal fossa, and the cervical regions of the larynx, kidneys, liver, and lungs. The findings of the present case report are compared with 31 other cases published in the English literature. Multiple metastases of MMs in the head and neck region are rare and generally are associated with a poor prognosis. In such cases, dentists play a role in the diagnosis, prevention, and treatment of sequelae stemming from oncologic treatment, with the aim of improving the patient's quality of life. PMID- 24401352 TI - Polysomnographic analysis of bruxism. AB - The American Academy of Sleep Medicine (AASM) defines sleep bruxism as a stereotyped movement disorder characterized by clenching and grinding of the teeth during sleep. Bruxism is found in 14%-20% of children, 8% of adults <60 years old, and 3% of adults >60 years old. The mandibular movements of bruxism can be confused with rhythmic mandibular movements associated with other sleep disorders, such as arousals/microarousals, limb movement disorder, and obstructive sleep apnea/hypopnea syndrome. Polysomnography (PSG) is the study of sleep disorders based on the recording of physiological events throughout an entire night of sleep. This system involves electroencephalography, electrooculography, and electromyography of the submental/suprahyoid, tibialis anterior, mentalis, masseter, and temporal muscles, through which signs of sleep bruxism can be identified. The aim of the present study was to identify bruxism during a night of sleep in a laboratory. Thirty patients were analyzed clinically and underwent PSG. The descriptive analysis correlated apnea, arousals, and limb movements in the 12 patients who exhibited signs and symptoms of sleep bruxism. Of these patients, 4 were confirmed through PSG to have bruxism. In a comparison between the 4 patients with confirmed bruxism (PSGB group) and the 8 patients confirmed not to have bruxism (NPSGB group), the respiratory event index was lower in the PSGB group (13.17 and 17.95, respectively). The mean leg movement index was higher in the PSGB group than the NPSGB group in total sleep time (21.36 and 8.42, respectively) and in rapid eye movement sleep time (34.54 and 10.30, respectively). PMID- 24401353 TI - The dentist's role in identifying child abuse: an evaluation about experiences, attitudes, and knowledge. AB - This study sought to investigate dentists' experiences, attitudes, and knowledge in recognizing and reporting suspected cases of child abuse. It was designed as a cross-sectional study across dental practices. Data were collected through a self administered questionnaire, which was distributed randomly to 500 dentists. The questionnaire investigated characteristics of the population, education concerning child abuse, experience and attitudes in reporting suspected cases, and the ability to recognize signs of abuse. Approximately 60% of the dentists responded to the survey. Among the dentists who participated in the survey, 87% believed that recognizing child abuse is important, however, 63.2% reported that they did not know how to act in such situations, and 44.2% were unaware of the proper child protection authorities to contact. Among the dentists surveyed, 94.7% reported they did not receive enough education concerning child abuse in their undergraduate studies. While 31.3% of dentists suspected child abuse among their patients, 84% reported their suspicions to the proper authorities. The reason cited most often (33.3%) for not reporting suspected abuse was the fear of litigation and its potential impact on their practice. Only 34.2% of dentists demonstrated knowledge about the potential signs of child abuse. PMID- 24401354 TI - Clinical and demographic overlaps among immunologically mediated oral diseases: a challenge for clinicians. AB - This study sought to assess and compare retrospective demographic and clinical data of oral lesions of lichen planus, pemphigus vulgaris, and mucous membrane pemphigoid from the records of the Department of Oral Pathology and Surgery, School of Dentistry, Universidade Federal de Minas Gerais, Brazil, covering a period of 55 years. Out of 25,435 specimens, these immunologically-mediated diseases accounted for 301 (1.18%) cases, of which 250 (0.98%) were lichen planus, 27 (0.11%) were pemphigus vulgaris, and 24 (0.09%) were mucous membrane pemphigoid. Lichen planus presented mainly as white asymptomatic plaques on buccal mucosa. Pemphigus vulgaris was usually characterized by multiple symptomatic erithematous ulcers on the buccal mucosa. Painful ulcers and/or blisters on the gingiva were the most common presentation for mucous membrane pemphigoid. Desquamative gingivitis was noted for all 3 diseases, but mainly for mucous membrane pemphigoid. Overall, lesions were more frequent in white women >50 years. Oral manifestations of immunologically-mediated diseases are relatively rare, and the correct diagnosis can be a challenge for dentists as the lesions often share similar clinical and demographic features. PMID- 24401355 TI - Conservative treatment for amelogenesis imperfecta: a case report. AB - Amelogenesis imperfecta is a hereditary condition that can alter the thickness, color, and shape of tooth enamel. Recent adhesive materials and techniques have provided less invasive treatment options. This case report presents the treatment of a patient whose anterior teeth had color alterations, white spots, pits, and shape defects. Using a more conservative technique, the mandibular and maxillary anterior teeth were restored using veneer direct composite restorations. After 6 years, the restorations demonstrated no deterioration, and no pathology was seen in association with the rehabilitation. PMID- 24401356 TI - A minimally invasive surgical approach for large cyst-like periapical lesions: a case series. AB - Various conservative approaches have been utilized to manage large periapical lesions. This article presents a relatively new, very conservative technique known as surgical fenestration which is both diagnostic and curative. The technique involves partially excising the cystic lining, gently curetting the cystic cavity, performing copious irrigation, and closing the surgical site. This technique allows for decompression and allows the clinician the freedom to take a biopsy of the lesion, as well as perform other procedures such as root resection and retrograde sealing, if required. As the procedure does not perform a complete excision of the cystic lining, it is both minimally invasive and cost-effective. The technique and the concepts involved are reviewed in 4 cases treated with this novel surgical approach. PMID- 24401357 TI - Nonaggressive central giant cell granuloma mimicking chronic inflammatory enlargement: a case report. AB - This article presents a case of giant cell granuloma in a 24-year-old man. Clinical, histopathological, and radiographic findings are discussed and a differential diagnosis and treatment plan are suggested. Clinical behavior among lesions may vary between nonaggressive and aggressive forms, and even radiographic appearances are not identical. The present case resembled a variety of conditions clinically but was diagnosed histopathologically as giant cell granuloma. This case is presented to emphasize the importance of histopathologic examination to ensure proper diagnosis and treatment. PMID- 24401358 TI - Smoking cessation practices in the dental setting. AB - According to the US Centers for Disease Control, approximately 20.6% of the American adult population currently smokes cigarettes. There is no doubt that tobacco use has a negative effect on oral and general health. Dentists can be effective in assessing their patients' smoking status, health beliefs, and related behavior patterns. A total of 608 patients-smokers, former smokers, and nonsmokers-participated in this study. The Five A's protocol was utilized with follow-up interviews to assess smoking cessation (quit rates) among the patients. Of the 608 subjects, 170 (28%) were current smokers, 140 (23%) were former smokers, and 298 (49%) had never smoked. Females comprised 56% of the study group. Of the 170 smokers who were assessed at baseline, successful follow-ups were performed with 64 (38%). Based on a follow-up of these smokers, the 7-day abstinence quit rate was 22%. Among participants who received nicotine replacement therapy (NRT), 40% quit. Of the participants who did not receive NRT, 19% quit. PMID- 24401359 TI - Effect of moisture and moisture-insensitive primer on bond strength of composite resin to enamel and dentin. AB - This article sought to compare the influence of moisture and the effect of moisture-insensitive primer (MIP) on shear bond strength (SBS). This study divided 160 extracted teeth randomly into 2 groups (n = 80): Group 1 (enamel) and Group 2 (dentin). Groups 1 and 2 were divided into 4 subgroups (n = 20), according to the surface treatment administered. Subgroup A samples were etched and primed, and received composite resin; Subgroup B samples were etched, contaminated with artificial saliva, and primed before application of composite resin; Subgroup C samples were etched, primed, and contaminated before application of composite resin. Subgroup D samples were etched, primed, contaminated, and primer was applied a second time before application of composite resin. All the specimens were stored in distilled water and thermocycled for 500 cycles; at that point, SBS was tested. According to Tukey's test, only the mean values in Subgroups A and C revealed statistically significant differences (P < 0.05). The use of MIP on contaminated etched tooth surfaces achieved comparable bond strength to noncontaminated tooth surfaces and might have a role in restorative dentistry cases where moisture contamination is inevitable. PMID- 24401360 TI - Improved adhesion of Y-TZP ceramics: a novel approach for surface modification. AB - The aim of this study was to evaluate the effect of novel surface treatments of Y TZP ceramics on initial shear bond strengths to resin cement. Eighty-four samples (7 x 6 x 5 mm) were randomly divided into 6 groups (n=14): Group1 (G1), no treatment; Group 2 (G2), air-borne particle abrasion with silica-coated aluminum oxide particles; Group 3 (G3), vitreous application 1 + etching with hydrofluoric acid; Group 4 (G4), vitreous application 1 + tribosilicatization; Group 5 (G5), vitreous application 2 + etching; Group 6 (G6), vitreous application 2 + tribosilicatization. Surface roughness (Ra) evaluation was performed by optical profilometry, scanning electron microscopy, and X-ray spectroscopy. The samples were silanized, and resin cement cylinders (3 x 2 mm) were built on the treated surfaces, light-cured and submitted to shear testing (1 mm/min). The failure mode was evaluated by SEM. Bond strength data were statistically analyzed using 1-way ANOVA and Tukey's test (alpha=0.05). Bond strength results were significantly affected by surface treatments (P = 0.0001). G5 and G3 presented increased Ra parameters and showed highest bond strength results (17.8 +/- 5.5 and 13.3 +/- 4.1, respectively). Failure modes were mainly mixed in all groups except for G1. The results confirmed that the approach of coating surface-conditioned Y-TZP with a vitreous material increased the initial shear bond strength to resin cement. PMID- 24401361 TI - Minimally invasive cosmetic dentistry: smile reconstruction using direct resin bonding. AB - Discrepancies in tooth size and shape can interfere with smile harmony. Composite resin can be used to improve the esthetics of the smile at a low cost while offering good clinical performance. This article presents an approach for restoring and correcting functional, anatomic, and esthetic discrepancies with minimal intervention, using composites and a direct adhesive technique. This conservative restorative procedure provided the patient with maximum personal esthetic satisfaction. PMID- 24401362 TI - Prosthetic rehabilitation of an edentulous patient with cleft palate. AB - It is difficult today to find older patients without their cleft palate prosthetically rehabilitated. This case report presents the rehabilitation by conventional dental prostheses of a cleft palate patient who had no prior treatment. A 52-year-old male presented himself to have his fissured palate obturated and occlusion restored. He reported difficulties in swallowing food and liquids, along with a severe speech disability. The patient's medical history revealed diabetes mellitus type II, hypertension, low vision due to macular atrophic lesions, and xerostomia. The upper and lower arches were completely and partially edentulous, respectively. The treatment plan involved a conventional denture to be placed in the upper arch, and a removable partial denture to be placed in the lower arch. PMID- 24401363 TI - Utilization of iTero digital impression unit for resin composite inlay. AB - Historically, traditional elastomeric impression techniques for indirect fixed procedures have presented challenges for the operator, laboratory, and patient. Recent digital impression unit technology offers a compelling alternative to elastomeric impressions. The iTero system applies parallel confocal imaging to create a virtual impression that can be easily captured, edited, and uploaded electronically to the dental laboratory. Computer-aided design/computer-aided manufacturing technology is applied to the virtual impression to create an unlimited number of identical polyurethane models. This case report is presented from the perspectives of the clinicians and the laboratory technician using an iTero system to treat a left mandibular second premolar with a resin composite inlay. PMID- 24401364 TI - Achieving optimal outcomes with all-zirconia crowns. AB - All-zirconia crowns are enjoying an unprecedented popularity. Dental laboratories are acquiring new equipment and adopting novel techniques, some of which require a learning curve. As a result, some crowns fabricated by computer-aided design/computer-aided manufacturing technology may come back to the dentist with unsatisfactory features. Dentists should carefully examine each crown under magnification prior to delivery to the patient. The dentist and dental laboratory should establish a close partnership with clear communication to yield the most favorable outcome for the patient. PMID- 24401365 TI - Adequacy of inhale/exhale breathhold CT based ITV margins and image-guided registration for free-breathing pancreas and liver SBRT. AB - PURPOSE: To evaluate use of breath-hold CTs and implanted fiducials for definition of the internal target volume (ITV) margin for upper abdominal stereotactic body radiation therapy (SBRT). To study the statistics of inter- and intra-fractional motion information. METHODS AND MATERIALS: 11 patients treated with SBRT for locally advanced pancreatic cancer (LAPC) or liver cancer were included in the study. Patients underwent fiducial implantation, free-breathing CT and breath-hold CTs at end inhalation/exhalation. All patients were planned and treated with SBRT using volumetric modulated arc therapy (VMAT). Two margin strategies were studied: Strategy I uses PTV = ITV + 3 mm; Strategy II uses PTV = GTV + 1.5 cm. Both CBCT and kV orthogonal images were taken and analyzed for setup before patient treatments. Tumor motion statistics based on skeletal registration and on fiducial registration were analyzed by fitting to Gaussian functions. RESULTS: All 11 patients met SBRT planning dose constraints using strategy I. Average ITV margins for the 11 patients were 2 mm RL, 6 mm AP, and 6 mm SI. Skeletal registration resulted in high probability (RL = 69%, AP = 4.6%, SI = 39%) that part of the tumor will be outside the ITV. With the 3 mm ITV expansion (Strategy 1), the probability reduced to RL 32%, AP 0.3%, SI 20% for skeletal registration; and RL 1.2%, AP 0%, SI 7% for fiducial registration. All 7 pancreatic patients and 2 liver patients failed to meet SBRT dose constraints using strategy II. The liver dose was increased by 36% for the other 2 liver patients that met the SBRT dose constraints with strategy II. CONCLUSIONS: Image guidance matching to skeletal anatomy is inadequate for SBRT positioning in the upper abdomen and usage of fiducials is highly recommended. Even with fiducial implantation and definition of an ITV, a minimal 3 mm planning margin around the ITV is needed to accommodate intra-fractional uncertainties. PMID- 24401366 TI - Plasma zinc levels, anthropometric and socio-demographic characteristics of school children in eastern Nepal. AB - BACKGROUND: Zinc deficiency is a major public health problem in many developing countries including Nepal. The present study was designed to assess the prevalence of zinc deficiency and to study the association of zinc deficiency with anthropometric and socio-demographic variables, in school children of eastern Nepal. METHODS: This cross-sectional study included total 125 school children of age group 6-12 years from Sunsari and Dhankuta districts of eastern Nepal. Plasma zinc level was estimated by Flame Atomic Absorption Spectroscopy. RESULTS: The Median interquartile range (IQR) values of zinc in the two districts Sunsari and Dhankuta were 5.9 (4.4, 7.9) MUmol/L and 5.8 (4.3, 8.4) MUmol/L respectively. A total of 55 children (87.3%) in Sunsari and 52 (83.9%) in Dhankuta had zinc deficiency, no significant difference was observed in the Median (IQR) plasma zinc levels (p = 0.9) and zinc deficiency patterns (p = 0.3) of the two districts. Significant differences were observed in the plasma zinc levels (p = 0.02) and zinc deficiency patterns (p = 0.001), of the school children having age groups 6-8 years than in 9-10 and 11-12 years of age, and zinc deficiency patterns between male and female school children (p = 0.04) respectively. CONCLUSIONS: The present study showed higher prevalence of zinc deficiency among school children in eastern Nepal. In our study, zinc deficiency was associated with both sex and age. The findings from the present study will help to populate data for policy implementation regarding consumption and supplementation of zinc. PMID- 24401367 TI - Metals in the pathogenesis of type 2 diabetes. AB - Minerals are one of the components of food, though they are not synthesized in the body but they are essential for optimal health. Several essential metals are required for the proper functioning of many enzymes, transcriptional factors and proteins important in various biochemical pathways. For example Zn, Mg and Mn are cofactors of hundreds of enzymes, and Zn is involved in the synthesis and secretion of insulin from the pancreatic beta-cells. Similarly, Cr enhances the insulin receptor activity on target tissues, especially in muscle cells. Insulin is the key hormone required to maintain the blood glucose level in normal range. In case of insulin deficiency or resistance, blood glucose concentration exceeds the upper limit of the normal range of 126 mg/dl. Persistent increase of blood serum glucose level leads to overt chronic hyperglycemia, which is a major clinical symptom of diabetes mellitus. Poor glycemic control and diabetes alters the levels of essential trace elements such as Zn, Mg, Mn, Cr, Fe etc. by increasing urinary excretion and their concomitant decrease in the blood. Hence, the main purpose of this review is to discuss the important roles of essential trace elements in normal homeostasis and physiological functioning. Moreover, perturbation of essential trace elements is also discussed in perspective of type 2 diabetes pathobiology. PMID- 24401368 TI - Expression of amyloid-associated miRNAs in both the forebrain cortex and hippocampus of middle-aged rat. AB - BACKGROUND: Aging is associated with the gradual cognitive decline and shows the typical senile plaque formation in the brain, which results from the aggregation of beta amyloid (Abeta) peptide following the abnormal proteolytic processing of amyloid precursor protein (APP) by beta-secretase (BACE1) and gamma-secretase. Accumulating evidence indicates that several microRNAs (miRNAs) are involved in the Alzheimer's disease (AD) by regulating the expression of APP and BACE1 proteins. However, the cognitive ability and the expression profile of the APP- and BACE1-associated miRNAs in the middle-aged population are largely unknown. METHODS: The learning and memory ability in rats were determined by Morris Water Maze test. The protein levels of APP and BACE1 were detected by western blotting. The quantitative polymerase chain reaction was used to identify the miRNAs levels in forebrain cortex and the hippocampus. RESULTS: Middle-aged rats have declined learning ability without changes in the memory ability, and increased APP and BACE1 protein expression in the forebrain cortex. Computational analysis using Targetscan and Pictar databases reveals that totally 4 predicted miRNAs have conserved binding site with APP, namely miR-106b, -17-5p, -153, -101. All of them showed decreased expression in both the forebrain cortex and hippocampus. Among the 10 predicted miRNAs targeting BACE1, different expression profiles were identified in the forebrain cortex (decreased: miR-9, -19a, -135a, -15b, -16, 195, -29c, -214; increased: miR-124; no change: miR-141) and the hippocampus (decreased: miR-9, -15b, -16, -195, -29c, -124; increased: miR-19a, -135a, -214, 141) in the middle-aged rats compared with the young rats. CONCLUSION: Our results provided the first evidence that middle-aged rats have begun displaying cognitive disability with abnormal expression of APP- and BACE1-related miRNAs in the hippocampus and forebrain cortex. PMID- 24401369 TI - Endophilin B is required for the Drosophila oocyte to endocytose yolk downstream of Oskar. AB - The nutritional environment is crucial for Drosophila oogenesis in terms of controlling hormonal conditions that regulate yolk production and the progress of vitellogenesis. Here, we discovered that Drosophila Endophilin B (D-EndoB), a member of the endophilin family, is required for yolk endocytosis as it regulates membrane dynamics in developing egg chambers. Loss of D-EndoB leads to yolk content reduction, similar to that seen in yolkless mutants, and also causes poor fecundity. In addition, mutant egg chambers exhibit an arrest at the previtellogenic stage. D-EndoB displayed a crescent localization at the oocyte posterior pole in an Oskar-dependent manner; however, it did not contribute to pole plasm assembly. D-EndoB was found to partially colocalize with Long Oskar and Yolkless at the endocytic membranes in ultrastructure analysis. Using an FM4 64 dye incorporation assay, D-EndoB was also found to promote endocytosis in the oocyte. When expressing the full-length D-endoB(FL) or D-endoB(DeltaSH3) mutant transgenes in oocytes, the blockage of vitellogenesis and the defect in fecundity in D-endoB mutants was restored. By contrast, a truncated N-BAR domain of the D EndoB only partially rescued these defects. Taken together, these results allow us to conclude that D-EndoB contributes to the endocytic activity downstream of Oskar by facilitating membrane dynamics through its N-BAR domain in the yolk uptake process, thereby leading to normal progression of vitellogenesis. PMID- 24401371 TI - Nato3 plays an integral role in dorsoventral patterning of the spinal cord by segregating floor plate/p3 fates via Nkx2.2 suppression and Foxa2 maintenance. AB - During embryogenesis, the dorsal roof plate and the ventral floor plate (FP) act as organizing centers to pattern the developing neural tube. Organizer-secreted morphogens provide signals that are interpreted via the graded expression of transcription factors. These factors establish a combinatorial code, which subsequently determines the fate of neuronal progenitors along the dorsoventral axis. To further separate the fates and promote distinct identities of the neural progenitors, mutual repression takes place among transcription factors expressed in progenitors situated along the dorsoventral axis. The molecular mechanisms acting in the developing spinal cord and underlying the segregation of the progenitor pool containing cells with a mixed FP/p3 fate into separate FP cells and V3 neurons are not fully understood. Using in vivo ectopic expression in chick, we found that Nato3 induces ectopic Foxa2-positive cells and indirectly downregulates Nkx2.2 expression. To examine the role of Nato3 in the FP, Foxa2 Nato3 signaling was blocked in Nato3 null mice and to a greater extent in Nato3 null/Foxa2 heterozygous bigenic mutants. Complementary to the findings obtained by gain of function in chick, the loss of function in mouse indicated that the segregation of the FP/p3 population into its derivatives was interrupted. Together, the data suggest that Nato3 is a novel determinant factor regulating the segregation of the FP and p3 identities, which is an essential step for establishing a definitive FP fate in the embryonic spinal cord. PMID- 24401370 TI - The conserved transmembrane RING finger protein PLR-1 downregulates Wnt signaling by reducing Frizzled, Ror and Ryk cell-surface levels in C. elegans. AB - Wnts control a wide range of essential developmental processes, including cell fate specification, axon guidance and anteroposterior neuronal polarization. We identified a conserved transmembrane RING finger protein, PLR-1, that governs the response to Wnts by lowering cell-surface levels of the Frizzled family of Wnt receptors in Caenorhabditis elegans. Loss of PLR-1 activity in the neuron AVG causes its anteroposterior polarity to be symmetric or reversed because signaling by the Wnts CWN-1 and CWN-2 are inappropriately activated, whereas ectopic PLR-1 expression blocks Wnt signaling and target gene expression. Frizzleds are enriched at the cell surface; however, when PLR-1 and Frizzled are co-expressed, Frizzled is not detected at the surface but instead is colocalized with PLR-1 in endosomes. The Frizzled cysteine-rich domain (CRD) and invariant second intracellular loop lysine are crucial for PLR-1 downregulation. The PLR-1 RING finger and protease-associated (PA) domain are essential for activity. In a Frizzled-dependent manner, PLR-1 reduces surface levels of the Wnt receptors CAM 1/Ror and LIN-18/Ryk. PLR-1 is a homolog of the mammalian transmembrane E3 ubiquitin ligases RNF43 and ZNRF3, which control Frizzled surface levels in an R spondin-sensitive manner. We propose that PLR-1 downregulates Wnt receptor surface levels via lysine ubiquitylation of Frizzled to coordinate spatial and temporal responses to Wnts during neuronal development. PMID- 24401372 TI - Efficient RNA/Cas9-mediated genome editing in Xenopus tropicalis. AB - For the emerging amphibian genetic model Xenopus tropicalis targeted gene disruption is dependent on zinc-finger nucleases (ZFNs) or transcription activator-like effector nucleases (TALENs), which require either complex design and selection or laborious construction. Thus, easy and efficient genome editing tools are still highly desirable for this species. Here, we report that RNA guided Cas9 nuclease resulted in precise targeted gene disruption in all ten X. tropicalis genes that we analyzed, with efficiencies above 45% and readily up to 100%. Systematic point mutation analyses in two loci revealed that perfect matches between the spacer and the protospacer sequences proximal to the protospacer adjacent motif (PAM) were essential for Cas9 to cleave the target sites in the X. tropicalis genome. Further study showed that the Cas9 system could serve as an efficient tool for multiplexed genome engineering in Xenopus embryos. Analysis of the disruption of two genes, ptf1a/p48 and tyrosinase, indicated that Cas9-mediated gene targeting can facilitate direct phenotypic assessment in X. tropicalis embryos. Finally, five founder frogs from targeting of either elastase-T1, elastase-T2 or tyrosinase showed highly efficient transmission of targeted mutations into F1 embryos. Together, our data demonstrate that the Cas9 system is an easy, efficient and reliable tool for multiplex genome editing in X. tropicalis. PMID- 24401373 TI - High-resolution imaging of cardiomyocyte behavior reveals two distinct steps in ventricular trabeculation. AB - Over the course of development, the vertebrate heart undergoes a series of complex morphogenetic processes that transforms it from a simple myocardial epithelium to the complex 3D structure required for its function. One of these processes leads to the formation of trabeculae to optimize the internal structure of the ventricle for efficient conduction and contraction. Despite the important role of trabeculae in the development and physiology of the heart, little is known about their mechanism of formation. Using 3D time-lapse imaging of beating zebrafish hearts, we observed that the initiation of cardiac trabeculation can be divided into two processes. Before any myocardial cell bodies have entered the trabecular layer, cardiomyocytes extend protrusions that invade luminally along neighboring cell-cell junctions. These protrusions can interact within the trabecular layer to form new cell-cell contacts. Subsequently, cardiomyocytes constrict their abluminal surface, moving their cell bodies into the trabecular layer while elaborating more protrusions. We also examined the formation of these protrusions in trabeculation-deficient animals, including erbb2 mutants, tnnt2a morphants, which lack cardiac contractions and flow, and myh6 morphants, which lack atrial contraction and exhibit reduced flow. We found that, compared with cardiomyocytes in wild-type hearts, those in erbb2 mutants were less likely to form protrusions, those in tnnt2a morphants formed less stable protrusions, and those in myh6 morphants extended fewer protrusions per cell. Thus, through detailed 4D imaging of beating hearts, we have identified novel cellular behaviors underlying cardiac trabeculation. PMID- 24401374 TI - Neuropilin 1 (NRP1) hypomorphism combined with defective VEGF-A binding reveals novel roles for NRP1 in developmental and pathological angiogenesis. AB - Neuropilin 1 (NRP1) is a receptor for class 3 semaphorins and vascular endothelial growth factor (VEGF) A and is essential for cardiovascular development. Biochemical evidence supports a model for NRP1 function in which VEGF binding induces complex formation between NRP1 and VEGFR2 to enhance endothelial VEGF signalling. However, the relevance of VEGF binding to NRP1 for angiogenesis in vivo has not yet been examined. We therefore generated knock-in mice expressing Nrp1 with a mutation of tyrosine (Y) 297 in the VEGF binding pocket of the NRP1 b1 domain, as this residue was previously shown to be important for high affinity VEGF binding and NRP1-VEGFR2 complex formation. Unexpectedly, this targeting strategy also severely reduced NRP1 expression and therefore generated a NRP1 hypomorph. Despite the loss of VEGF binding and attenuated NRP1 expression, homozygous Nrp1(Y297A/Y297A) mice were born at normal Mendelian ratios, arguing against NRP1 functioning exclusively as a VEGF164 receptor in embryonic angiogenesis. By overcoming the mid-gestation lethality of full Nrp1-null mice, homozygous Nrp1(Y297A/Y297A) mice revealed essential roles for NRP1 in postnatal angiogenesis and arteriogenesis in the heart and retina, pathological neovascularisation of the retina and angiogenesis-dependent tumour growth. PMID- 24401375 TI - Scaffoldless tissue-engineered dental pulp cell constructs for endodontic therapy. AB - A major cause of apical periodontitis after endodontic treatment is the bacterial infiltration which could have been challenged by the presence of a vital pulp. In this study, self-assembled, scaffoldless, three-dimensional (3D) tissues were engineered from dental pulp cells (DPCs) and assessed as a device for pulp regeneration. These engineered tissues were placed into the canal space of human tooth root segments that were capped on one end with calcium phosphate cement, and the entire system was implanted subcutaneously into mice. Histological staining indicated that after three- and five-month implantations, tooth roots containing 3D scaffoldless engineered tissues maintained a cellular, fibrous tissue throughout, whereas empty tooth roots remained predominantly empty. Immunostaining indicated that the tissue found in the root canals containing scaffoldless DPC engineered tissues was vascular, as characterized by the expression of CD31, and contained odontoblast-like cells organized along the length of the root wall as assessed by immunostaining for dentin sialoprotein. This study shows that 3D self-assembled scaffoldless DPC engineered tissues can regenerate a vital dental pulp-like tissue in a tooth root canal system and are therefore promising for endodontic therapy. PMID- 24401376 TI - Antidepressant effects of crocin and its effects on transcript and protein levels of CREB, BDNF, and VGF in rat hippocampus. AB - BACKGROUND: Antidepressants have been shown to affect levels of brain-derived neurotrophic factor (BDNF) and VGF (non-acronymic) whose transcriptions are dependent on cAMP response element binding protein (CREB) in long term treatment. The aim of this study was to verify the subacute antidepressant effects of crocin, an active constituent of saffron (Crocus sativus L.), and its effects on CREB, BDNF, and VGF proteins, transcript levels and amount of active, phosphorylated CREB (P-CREB) protein in rat hippocampus. METHODS: Crocin (12.5, 25, and 50 mg/kg), imipramine (10 mg/kg; positive control) and saline (1 mL/kg; neutral control) were administered intraperitoneally (IP) to male Wistar rats for 21 days. The antidepressant effects were studied using the forced swimming test (FST) on day 21 after injection. Protein expression and transcript levels of genes in the rat hippocampus were evaluated using western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), respectively. RESULTS: Crocin significantly reduced the immobility time in the FST. Western blot analysis showed that 25 and 50 mg/kg of crocin increased the levels of CREB and BDNF significantly and dose dependently. All doses of crocin increased the VGF levels in a dose-dependent manner. Levels of p-CREB increased significantly by 50 mg/kg dose of crocin. Only 12.5 mg/kg crocin could significantly increase the transcript levels of BDNF. No changes in CREB and VGF transcript levels were observed in all groups. CONCLUSIONS: These results suggest that crocin has antidepressant-like action by increasing CREB, BDNF and VGF levels in hippocampus. PMID- 24401377 TI - Trace elements in cocoa solids and chocolate: an ICPMS study. AB - The concentrations of eight trace elements: lead (Pb), cadmium (Cd), chromium (Cr), manganese (Mn), cobalt (Co), arsenic (As), bismuth (Bi) and molybdenum (Mo), in chocolate, cocoa beans and products were studied by ICPMS. The study examined chocolate samples from different brands and countries with different concentrations of cocoa solids from each brand. The samples were digested and filtered to remove lipids and indium was used as an internal standard to correct matrix effects. A linear correlation was found between the level of several trace elements in chocolate and the cocoa solids content. Significant levels of Bi and As were found in the cocoa bean shells but not in the cocoa bean and chocolate. This may be attributed to environmental contamination. The presence of other elements was attributed to the manufacturing processes of cocoa and chocolate products. Children, who are big consumers of chocolates, may be at risk of exceeding the daily limit of lead; whereas one 10 g cube of dark chocolate may contain as much as 20% of the daily lead oral limit. Moreover chocolate may not be the only source of lead in their nutrition. For adults there is almost no risk of exceeding daily limits for trace metals ingestion because their digestive absorption of metals is very poor. PMID- 24401378 TI - Electrochemical studies of self-assembled monolayers composed of various phenylboronic acid derivatives. AB - Gold electrodes were functionalized with thiolated phenylboronic acids or by sequential immobilization of alkanethiols with terminal carboxylic groups and conjugation with aminophenylboronic acids. The stepwise assembly of organic molecules was characterized by several voltammetric techniques with systematic monitoring of surface coverage of organic molecules anchored to the gold electrodes. The receptor properties and applicability of the obtained monomolecular layers for the voltammetric detection of fructose and fluoride ions in solution were evaluated. The MPBA and APBA modified electrodes can be applied for the voltammetric determination of chosen non-electroactive analytes on the basis of the changes in peak currents of ferricyanide/ferrocyanide couple in the presence of the detected species. PMID- 24401379 TI - Rapid analysis of effluents generated by the dairy industry for fat determination by preconcentration in nylon membranes and attenuated total reflectance infrared spectroscopy measurement. AB - This paper describes a new approach for the determination of fat in the effluents generated by the dairy industry which is based on the retention of fat in nylon membranes and measurement of the absorbances on the membrane surface by ATR-IR spectroscopy. Different options have been evaluated for retaining fat in the membranes using milk samples of different origin and fat content. Based on the results obtained, a method is proposed for the determination of fat in effluents which involves the filtration of 1 mL of the samples through 0.45 um nylon membranes of 13 mm diameter. The fat content is then determined by measuring the absorbance of band at 1745 cm(-1). The proposed method can be used for the direct estimation of fat at concentrations in the 2-12 mg/L interval with adequate reproducibility. The intraday precision, expressed as coefficients of variation CVs, were <= 11%, whereas the interday CVs were <= 20%. The method shows a good tolerance towards conditions typically found in the effluents generated by the dairy industry. The most relevant features of the proposed method are simplicity and speed as the samples can be characterized in a few minutes. Sample preparation does not involve either additional instrumentation (such as pumps or vacuum equipment) or organic solvents or other chemicals. Therefore, the proposed method can be considered a rapid, simple and cost-effective alternative to gravimetric methods for controlling fat content in these effluents during production or cleaning processes. PMID- 24401380 TI - Chemometrics enhanced HPLC-DAD performance for rapid quantification of carbamazepine and phenobarbital in human serum samples. AB - This paper describes development and validation of a simple and efficient bioanalytical procedure for simultaneous determination of phenobarbital and carbamazepine in human serum samples using high performance liquid chromatography with photodiode-array detection (HPLC-DAD) regarding a fast elution methodology in less than 5 min. Briefly, this method consisted of a simple deproteinization step of serum samples followed by HPLC analysis on a Bonus-RP column using an isocratic mode of elution with acetonitrile/K2HPO4 (pH=7.5) buffer solution (45:55). Due to the presence of serum endogenous components as non-calibrated components in the sample, second-order calibration based on multivariate curve resolution-alternating least squares (MCR-ALS), has been applied on a set of absorbance matrices collected as a function of retention time and wavelengths. Acceptable resolution and quantification results were achieved in the presence of matrix interferences and the second-order advantage was fully exploited. The average recoveries for carbamazepine and phenobarbital were 89.7% and 86.1% and relative standard deviation values were lower than 9%. Additionally, computed elliptical joint confidence region (EJCR) confirmed the accuracy of the proposed method and indicated the absence of both constant and proportional errors in the predicted concentrations. The developed method enabled the determination of the analytes in different serum samples in the presence of overlapped profiles, while keeping experimental time and extraction steps at minimum. Finally, the serum concentration levels of carbamazepine in three time intervals were reported for morphine-dependents who had received carbamazepine for treating their neuropathic pain. PMID- 24401381 TI - Development of a new biosensor based on functionalized SBA-15 modified screen printed graphite electrode as a nano-reactor for Gquadruplex recognition. AB - Gquadruplex is an active target for therapeutic purposes because of the evidence which suggest that G-rich region of the human genome may form Gquadruplex structure. The electrochemical biosensor was prepared by modifying screen-printed graphite electrode (SPE) with synthesized SBA-N-propylpipyrazine-N-(2 mercaptopropane-1-one) (SBA@NPPNSH) mesoporous structure to investigate the Gquadruplex DNA structure (G4DNA). Ascorbic acid (AA) is known as an antioxidant agent that induces reductive properties. It is also important for some therapeutic purposes. In this study, AA was used as the model ligand and its ability to interact with Gquadruplex structure was examined. The pore of SBA@NPPNSH structure can act as a nano-reactor and the interaction of G4DNA/AA is accomplished inside these channels. The structure of SBA@NPPNSH was characterized by transmission electron microscope (TEM), X-ray powder diffraction (XRD), thermo gravimetric analysis (TGA) methods and atomic force microscopy (AFM). The interaction of AA with G4DNA was studied in Tris-HCl buffer and also in the presence of [Fe(CN)6](3-) as a redox label using the CV method. CV current decreases with the increasing concentrations of AA due to the interaction of G4DNA/AA. Circular dichroism (CD) spectroscopy was used to examine the ability of AA to form Gquadruplexes from short and long complementary G4DNA strands. Studying the selectivity using different dsDNA sequences revealed that AA could stabilize G4DNA. Thus, the proposed biosensor can distinguish G4DNA structure from other dsDNA structures. PMID- 24401382 TI - Green aspects, developments and perspectives of liquid phase microextraction techniques. AB - Determination of analytes at trace levels in complex samples (e.g. biological or contaminated water or soils) are often required for the environmental assessment and monitoring as well as for scientific research in the field of environmental pollution. A limited number of analytical techniques are sensitive enough for the direct determination of trace components in samples and, because of that, a preliminary step of the analyte isolation/enrichment prior to analysis is required in many cases. In this work the newest trends and innovations in liquid phase microextraction, like: single-drop microextraction (SDME), hollow fiber liquid-phase microextraction (HF-LPME), and dispersive liquid-liquid microextraction (DLLME) have been discussed, including their critical evaluation and possible application in analytical practice. The described modifications of extraction techniques deal with system miniaturization and/or automation, the use of ultrasound and physical agitation, and electrochemical methods. Particular attention was given to pro-ecological aspects therefore the possible use of novel, non-toxic extracting agents, inter alia, ionic liquids, coacervates, surfactant solutions and reverse micelles in the liquid phase microextraction techniques has been evaluated in depth. Also, new methodological solutions and the related instruments and devices for the efficient liquid phase micoextraction of analytes, which have found application at the stage of procedure prior to chromatographic determination, are presented. PMID- 24401383 TI - Fast, simple and efficient supramolecular solvent-based microextraction of mecoprop and dichlorprop in soils prior to their enantioselective determination by liquid chromatography-tandem mass spectrometry. AB - A simple, sensitive, rapid and economic method was developed for the quantification of enantiomers of chiral pesticides as mecoprop (MCPP) and dichlorprop (DCPP) in soil samples using supramolecular solvent-based microextraction (SUSME) combined with liquid chromatography coupled to mass spectrometry (LC-MS/MS). SUSME has been described for the extraction of chiral pesticides in water, but this is firstly applied to soil samples. MCPP and DCPP are herbicides widely used in agriculture that have two enantiomeric forms (R- and S-) differing in environmental fate and toxicity. Therefore, it is essential to have analytical methods for monitoring individual DCPP and MCPP enantiomers in environmental samples. MCPP and DCPP were extracted in a supramolecular solvent (SUPRAS) made up of dodecanoic acid aggregates, the extract was dried under a nitrogen stream, the two herbicides dissolved in acetate buffer and the aqueous extract directly injected in the LC-MS/MS system. The recoveries obtained were independent of soil composition and age of herbicide residues. The detection and quantitation limits of the developed method for the determination of R- and S MCPP and R- and S-DCPP in soils were 0.03 and 0.1 ng g(-1), respectively, and the precision, expressed as relative standard deviation (n=6), for enantiomer concentrations of 5 and 100 ng g(-1) were in the ranges 4.1-6.1% and 2.9-4.1%. Recoveries for soil samples spiked with enantiomer concentrations within the interval 5-180 ng g(-1) and enantiomeric ratios (ERs) of 1, 3 and 9, ranged between 93 and 104% with standard deviations of the percent recovery varying between 0.3% and 6.0%. Because the SUPRAS can solubilize analytes through different type of interactions (dispersion, dipole-dipole and hydrogen bonds), it could be used to extract a great variety of pesticides (including both polar and non-polar) in soils. PMID- 24401384 TI - Focused ultrasound assisted extraction for the determination of PBDEs in vegetables and amended soil. AB - Focused-ultrasound solid-liquid extraction was developed for the extraction of polybrominated diphenyl ethers in vegetables and amended soil. Firstly, solid phase extraction clean-up using 2g and 5 g of Florisil and 2-g silica cartridges were evaluated and elution profile was also optimised. Similar recoveries were obtained for most compounds while better recoveries were obtained for 5-g Florisil in the case of the heavier PBDEs. FUSLE extraction time (2 min) guaranteed quantitative extraction of the target analytes in the four studied matrices (69-130%). Method detection limit values were in the range of 1-5 ng g( 1) for splitless injection in a gas chromatograph coupled to a mass spectrometer and no significant improvement was obtained for large volume injection. Relative standard deviation values were between 1% and 30%. Recoveries obtained using FUSLE were compared with those obtained with microwave assisted extraction and the developed method was also applied to a certify reference material of polybrominated diphenyl ethers and polychlorinared biphenyls in sediment. Similar values were obtained in the case of carrot and pepper matrices (77-130% for FUSLE and 77-112% for MAE). However, MAE provided extraction recoveries higher than 100% for most of the BDE congeners in lettuce and amended soil. PMID- 24401385 TI - Direct GC-(EI)MS determination of fatty acid alkyl esters in olive oils. AB - A new analytical method for fatty acid alkyl esters (FAAEs) determination by GC MS in virgin olive oils is proposed. No sample preparation is required and FAAEs are directly thermo-desorbed and cryo-focalised in the cooled injector of a GC-MS (EI) instrument. The analytical conditions were optimized by Design of Experiment (DoE) techniques (an exploratory Plackett-Burman design followed by a factorial design on three selected variables). After the improvement of method performances, several samples of extra virgin and low quality virgin olive oils were analyzed both by the new method and by the Official EU Method of analysis. The application of Principal Component Analysis to the obtained results confirmed that the ability of the proposed method to discriminate between extra virgin and lower quality olive oils is at least equal to that of the Official Method, but the new method is faster, simpler, requires a much lower amount of organic solvents and significantly enhances method repeatability. PMID- 24401386 TI - Automated in-chip kinetic-catalytic method for molybdenum determination. AB - In this work, the automation of a catalytic spectrophotometric method for the determination of molybdenum is presented. For this purpose, a multisyringe flow injection system was coupled to an integrated microconduit that we have called "chip". Reagents and sample were simultaneously dispensed to the chip where complete mixing, heating, and measurement were carried out. The spectrophotometric method is based on the oxidation of 4-amino-3-hydroxy naphthalenesulphonic acid (AHNA) by hydrogen peroxide catalyzed by Mo (VI). Absorbance of the reaction product was measured at 465 nm. Two optical fibers were used to conduct the light, one from the source to the chip, and the other from the output of the cell to the spectrophotometer. The detection cell was incorporated in the thermostated zone of the chip. The initial rate method, at controlled temperature, was employed to determine the Mo (VI) concentration. The estimated precision was 3.7%, with the working range of 4.0-40 ug L(-1) of Mo (VI), and the limit of detection of 1.2 ug L(-1) of Mo (VI). The system was successfully applied to water samples and pharmaceutical products with a sampling throughput of 20 injections h(-1). PMID- 24401387 TI - Determination of penicillins in milk of animal origin by capillary electrophoresis: is sample treatment the bottleneck for routine laboratories? AB - Capillary electrophoresis (CE) is increasingly being used not only for research purposes but also for routine analyses. The latter, however, are especially difficult when the analytes are present at very low concentrations in complex food samples (e.g. penicillins in milk of animal origin). No study of the difficulties encountered in daily practice in sample treatments for the determination of penicillins (PENs) in milk by CE has to our knowledge been reported. Rather than reviewing the main uses of CE for determining PENs in different types of samples, this paper focuses on the weaknesses of available methods for this purpose, which originate in sample treatment rather than in a lack of robustness of the CE technique. Some problems which, based on our own experience, often confront sample treatment and method development in this context are discussed here. Clearly, the greatest source of error in this context is sample processing, which must provide optimal extraction and preconcentration of analytes, and extracts compatible with the separation technique to be used. In this respect, using time-consuming procedures can cause the loss of variable amounts of analytes in different steps. Interestingly, dramatically simplifying the sample preparation process can detract from sensitivity but lead to increased recoveries. As with any methodological development in routine analysis, acceptable results can only be obtained by considering all potentially influential factors. PMID- 24401388 TI - Sensitive determination of endogenous hexanal and heptanal in urine by hollow fiber liquid-phase microextraction prior to capillary electrophoresis with amperometric detection. AB - Hexanal (Hex) and heptanal (Hep) in human blood have been regarded as potential biomarkers of lung cancer. In this work, a hollow-fiber liquid-phase microextraction (HF-LPME) method has been developed for the preconcentration of these trace aldehydes in urine samples. After derivatization with an electroactive compound 2-thiobarbituric acid, these two non-electroactive aldehydes were converted to electroactive adducts, therefore detectable by capillary zone electrophoresis with amperometric detection (CZE-AD) approach. Experimental conditions of derivatization, extraction, electrophoretic separation and detection were optimized. Under the optimum conditions, the enrichment factors for Hex and Hep could reach 320 and 355, respectively. The limits of detection for Hex and Hep were 2.7 and 0.97 nM, respectively; the average recoveries were in the range of 61-95% and relative standard deviation (RSD) values less than 8.5%. The present method has been applied to quantitative analysis of two biomarkers in human urine in lieu of blood samples, and the assay results showed that the contents of Hex (0.99-6.7 MUM) and Hep (2.5-6.4 MUM) found in the urine sample of the lung cancer patients were significantly higher than those in the healthy volunteers, liver cancer patients, as well as diabetics. The proposed HF-LPME/CZE-AD method may provide a potential alternative for early non-invasive diagnosis of lung cancer disease. PMID- 24401389 TI - A comprehensive factorial design study of variables affecting protein extraction from formalin-fixed kidney tissue samples. AB - Formalin-fixed tissues are an important source of biological samples for biomedical research. However, proteomics analysis of formalin-fixed tissues has been set aside by formalin-induced protein modifications, which reduce protein extraction efficiency. In this study, a two level full factorial experimental design (2(4)) was used to determine the effects of the extracting conditions in the efficiency of protein recovery from formalin-fixed kidney samples. The following variables were assessed: temperature of extraction, pH of extraction, composition of the extracting buffer and the use ultrasonic energy applied with probe. It is clearly demonstrated that when hating and ultrasonic energy are used in conjunction, a 7-fold increase (p < 0.05) in protein extraction is obtained if compared to extracting conditions for which neither heating nor ultrasonic energy are used. The optimization study was done following the amount of protein extracted by UV (Nanodrop((r)) technology, protein ABS at 280 nm) and by 1D SDS PAGE. Extracts obtained with the optimized conditions were subjected to LC-MALDI MS/MS. A total of 112 proteins were identified. PMID- 24401391 TI - Concept and properties of an infrared hybrid single-beam spectrum and its application to eliminate solvent bands and other background interferences. AB - For infrared (IR) spectral measurements, if a quality single-beam background spectrum with desired intensity could be obtained, the contributions from solvent and other background components could be completely suppressed and their bands would not appear in a final transmittance/absorbance spectrum. In order to achieve this ideal but difficult goal, the concept of hybrid single-beam spectrum is introduced in this paper. The hybrid single-beam spectrum (phi h) is defined as a mixture of two single-beam spectra (phi b1 and phi b2) of the same sample but with different pathlengths (b1 and b2), namely, phi h = alphaphi b1+(1 alpha)phi b2, where alpha (0 <= alpha <= 1) is the component factor. The properties of the hybrid spectrum have been investigated. Under conditions of b2 > b1 >= 0.7 b2 and A max <= 0.60 (Amax is the maximum absorbance of b2 sample in the spectral range of interest), all the synthesized hybrid spectra are free from significant distortion regardless of the component factor. Therefore, the hybrid single-beam spectrum with desired intensity can be easily obtained simply by choosing an appropriate component factor. The proposed methodology has been demonstrated experimentally by the complete removal of the interference from the atmospheric water vapor and solvent. PMID- 24401390 TI - Pressurized liquid extraction and dispersive liquid-liquid microextraction for determination of tocopherols and tocotrienols in plant foods by liquid chromatography with fluorescence and atmospheric pressure chemical ionization mass spectrometry detection. AB - Pressurized liquid extraction (PLE) and dispersive liquid-liquid microextraction (DLLME) were used to isolate and preconcentrate tocopherols and tocotrienols from plant foods. The Taguchi experimental method was used to optimize the six factors (three levels for each factor), affecting DLLME, namely: carbon tetrachloride volume, methanol volume, aqueous sample volume, pH of sample, sodium chloride concentration and time of the centrifugation step. The influencing parameters selected were 2 mL of methanol:isopropanol (1:1) (disperser solvent), 150 uL carbon tetrachloride (extraction solvent) and 10 mL aqueous solution. The organic phase was injected into reversed-phase liquid chromatography (LC) with an isocratic mobile phase composed of an 85:15 (v/v) methanol:water mixture and a pentafluorophenyl stationary phase. Detection was carried out using both fluorescence and atmospheric pressure chemical ionization mass spectrometry (APCI MS) in negative ion mode. Quantification was carried out by the standard addition method. Detection limits were in the range 0.2-0.3 ng mL(-1) for the vitamers with base-line resolution. The recoveries obtained using the optimized DLLME were in the 90-108% range, with RSDs lower than 6.7%. The APCI-MS spectra, in combination with fluorescence spectra, permitted the correct identification of compounds in the vegetable and fruit samples. The method was validated according to international guidelines and using two certified reference materials. PMID- 24401392 TI - Development of an automatic high-throughput assay for tetracycline determination by using Eu2O3 nanoparticles and dry-reagent technology. AB - The usefulness of europium oxide nanoparticles (Eu2O3 NPs) as analytical reagent for the direct determination of organic compounds is described for the first time. Tetracycline, which forms a luminescent chelate with europium, has been chosen as a model analyte. Dry reagent chemistry is used in a 96-well format, which considerably speeds up the determination and contributes to its automation. The NPs are immobilized onto polystyrene wells by adding a volume of a Eu2O3 NP dispersion in 2-propanol to each well and drying in an oven until they dry completely. At the moment of analysis, a standard or sample volume (200 MUL) in the appropriate medium is added, and the mixture shaken for 15 min at 37 degrees C. The method allows the determination of tetracycline in the range 20-1000 ng mL(-1), with a detection limit of 8 ng mL(-1). The inter-assay and intra-assay precision, which were assayed at two different tetracycline concentrations and expressed as relative standard deviation, were in the ranges of 6.5-8.2% and 9.2 12.7%, respectively. The study of the selectivity of the system showed that the method is adequate for tetracycline determination in agri-food samples, since most of antibiotics assayed did not interfere the determination. Only other tetracycline antibiotics provided luminescent signal when reacting to Eu2O3 NPs. The method has been applied to the determination of tetracycline in calf urine and in honey samples obtaining recovery values in the ranges of 85.0-110.0% and 99.7-116.7%, respectively. PMID- 24401393 TI - Design and validation of a novel immunological test for enterolactone. AB - Enterolactone (ENL) is produced by the gut microflora from lignans found in edible plants. ENL is estrogenic with no effect on the E-screen test and is a natural Selected Estrogen Receptor Modulator (SERM) with health interests that have to be checked in clinical studies with bioavailability assessment. Two haptens of ENL were synthesized, with a spacer arm at the C5 position having either 2 or 4 carbon atoms (ENLDelta2 and ENLDelta4, respectively). Hapten coupling to bovine serum albumin (BSA) was characterized by MALDI mass spectrometry. Polyclonal antibodies were obtained against the BSA conjugates. Additional conjugates were generated by coupling to swine thyroglobulin (Thyr). Homologous and heterologous competitive ELISAs were developed with Thyr or BSA conjugates as coating. The best assays were validated on biological samples from mice. Both antibodies exhibited the same IC50 at 1.5 ng mL(-1) with a detection limit below 0.5 ng mL(-1). Most cross-reactions with structurally related lignans were lower than 0.03%. This new assay type is faster, more specific and more reliable than existing ones. PMID- 24401394 TI - Rapid immunochromatographic assay for ofloxacin in animal original foodstuffs using native antisera labeled by colloidal gold. AB - An immunochromatographic assay was developed to detect fluoroquinolone antibiotic ofloxacin based on the competitive binding of ofloxacin and the membrane immobilized ofloxacin-protein conjugate to colloidal gold-labeled antibodies in the course of the labeled antibodies, and to test sample flow through the membrane. The specific feature of labeling by colloidal gold is that native antiserum is used instead of purified immunoglobulins or specific antibodies. This makes the synthetic procedure easier, with no sacrifice in the detection limit. The proposed test makes it possible to detect down to 30 ng mL(-1) of ofloxacin, which corresponds to the demands of food safety assessment. The assay time is 10 min. The assay provides reliable information on the ofloxacin content in milk without the sample preparation and in chicken and pork meat with the minimum sample preparation (the separation of the insoluble fraction of the homogenate by centrifugation). The high degree of detection of ofloxacin in foodstuffs by the proposed assay (70-112%) was shown by a comparison with the data obtained with the use of a commercial immunoenzymatic kit. PMID- 24401395 TI - Vapour phase polymerisation of conducting and non-conducting polymers: a review. AB - Vapour phase polymerisation (VPP) is a well established technique in which the monomer is introduced to an oxidant-coated substrate in vapour form. Polymerisation then takes place at the oxidant vapour interface. VPP is a technique that could be used to immobilise materials to the modified electrode surface. This review article concentrates on the VPP of conducting polymers such as Polypyrrole (PPy) polythiophen (PT) and polyaniline (PANi). VPP of conducting polymers and other non-conducting polymers have extensively been investigated. This review article is divided into three main parts as given in Table of contents related to the VPP process of some important conducting polymers such as PPy, PT, PANi and Poly(3,4-ethylenedioxythiophene). A total of 181 references are cited in this review article and it attempts to look into VPP from inception of the method till present day. PMID- 24401396 TI - Optically encoded nanoprobes using single walled carbon nanotube as the building scaffold for magnetic field guided cell imaging. AB - We construct a novel fluorescent, surface enhanced Raman scattering (SERS) encoded and magnetic nanoprobe for live cell imaging. To fabricate this nanoprobe, single walled carbon nanotube (SWNT) is used as the building scaffold while gold nanoparticles (Au NPs), superparamagnetic iron oxide nanoparticles (SPIONs) and quantum dots (QDs) are employed as the building blocks. Here, Au NPs serve as the SERS substrate and QDs act as the fluorescent agent. Au NPs and SPIONs are first adsorbed on the SWNT via electrostatic interactions. Then a silica layer is coated on the SWNT. Finally, QDs are attached on the silica shell. With such a structure, various optical signals can be readily encoded to the nanoprobe simply by using different Raman molecules and QDs with different emission wavelengths. Experimental results show that the as-prepared nanoprobe exhibits well fluorescence and SERS performance. Furthermore, in vitro experiments demonstrate that the nanoprobe can fulfill magnetic field guided fluorescence and SERS dual mode imaging of live cells. As a fascinating optical encoding material and a multifunctional nanoplatform, the presented nanoprobe holds genuine potential in future biosensing applications. PMID- 24401397 TI - Characterization of plasma-enhanced teflon AF for sensing benzene, toluene, and xylenes in water with near-IR surface plasmon resonance. AB - Near-IR surface plasmon resonance is used to characterize Teflon AF films for refractive index-based detection of the aromatic hydrocarbon contaminants benzene, toluene, and xylenes in water. The technique requires no sample preparation, and film sensitivity is found to be enhanced by oxygen plasma etching. A diffusion equation model is used to extract the diffusion and partition coefficients, which indicate film enrichment factors exceeding two orders of magnitude, permitting a limit of detection of 183, 105 and 55 ppb for benzene, toluene, and xylenes, respectively. The effect of other potential interfering contaminants is quantified. PMID- 24401398 TI - Nickel hydroxide nanoparticles-reduced graphene oxide nanosheets film: layer-by layer electrochemical preparation, characterization and rifampicin sensory application. AB - Electrochemical deposition, as a well-controlled synthesis procedure, has been used for subsequently layer-by-layer preparation of nickel hydroxide nanoparticle reduced graphene oxide nanosheets (Ni(OH)2-RGO) on a graphene oxide (GO) film pre cast on a glassy carbon electrode surface. The surface morphology and nature of the nano-hybrid film (Ni(OH)2-RGO) was thoroughly characterized by scanning electron and atomic force microscopy, spectroscopy and electrochemical techniques. The modified electrode appeared as an effective electro-catalytic model for analysis of rifampicin (RIF) by using linear sweep voltammetry (LSV). The prepared modified electrode exhibited a distinctly higher activity for electro-oxidation of RIF than either GO, RGO nanosheets or Ni(OH)2 nanoparticles. Enhancement of peak currents is ascribed to the fast heterogeneous electron transfer kinetics that arise from the synergistic coupling between the excellent properties of RGO nanosheets (such as high density of edge plane sites, subtle electronic characteristics and attractive pi-pi interaction) and unique properties of metal nanoparticles. Under the optimized analysis conditions, the modified electrode showed two oxidation processes for rifampicin at potentials about 0.08 V (peak I) and 0.69 V (peak II) in buffer solution of pH 7.0 with a wide linear dynamic range of 0.006-10.0 umol L(-1) and 0.04-10 umol L(-1) with a detection limit of 4.16 nmol L(-1) and 2.34 nmol L(-1) considering peaks I and II as an analytical signal, respectively. The results proved the efficacy of the fabricated modified electrode for simple, low cost and highly sensitive medicine sensor well suited for the accurate determinations of trace amounts of rifampicin in the pharmaceutical and clinical preparations. PMID- 24401399 TI - A novel sensitive doxorubicin impedimetric immunosensor based on a specific monoclonal antibody-gold nanoaprticle-sol-gel modified electrode. AB - In this work, ultrasensitive electrochemical doxorubicin impedance immunosensor was investigated based on immobilization of a specific monoclonal antibody on gold nanoparticles (GNPs) associated with a thiol base sol-gel (TBSol-Gel) modified gold electrode. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) were employed for characterization of the various layers that were formed at the electrode surface. The redox couples of 1.0 mmol L(-1), Fe(CN)6(4-/3-) species on the electrode surface was followed to study the layers formation and determination process, using electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). After optimization of analytical parameters, the relative charge transfer resistance (Rct) increases linearly with doxorubicin concentration in the ranges of 0.1-1.0 and 2.5-50.0 pg mL(-1), with a detection limit of 0.09 pg mL(-1). A high association constant of 1.4 * 10(11) L mol(-1) was obtained for the affinity of doxorubicin toward the immobilized antibody on the electrode surface. The capability of the proposed immunosensor for the determination of doxorubicin in spiked human serum and urine samples was examined by standard addition method, and the results show that the immunosensor is a useful tool for the determination of doxorubicin in the biological samples. PMID- 24401400 TI - Validated liquid chromatographic determination of a novel ACE inhibitor in the presence of its hydrolytic and oxidative degradation products as per ICH guidelines. AB - Imidapril hydrochloride (IMD) is a recently developed prodrug-type angiotensin converting enzyme (ACE) inhibitor. Due to its instability under both hydrolytic and oxidative conditions, development of rapid, simple and sensitive methods for its determination in the presence of its possible degradation products is essential. We proposed two simple liquid chromatographic methods associated with ultraviolet detection. The first method is an HPTLC-densitometric one in which separation of IMD from its degradation products was achieved followed by densitometric scanning at 220 nm using silica gel F254 plates and chloroform:ethanol:acetic acid (3:0.5:0.1, v/v/v) as the developing system. The second method was based on RP-HPLC in which the separation was performed using C18 analytical column and isocratic elution system with acetonitrile: 0.15% triethylamine (pH=2.2) (40:60, v/v). The optimum flow rate was 1.5 mL min(-1) and the detection was at 220 nm. Validation was conducted in compliance with the ICH guidelines and the methods were successfully applied for IMD determination in its commercial tablets. The obtained results were statistically compared to those obtained by applying reported HPLC method where no significant difference was found in accordance with accuracy and precision. PMID- 24401401 TI - Strategy for determination of LOD and LOQ values--some basic aspects. AB - The paper is devoted to the evaluation of limit of detection (LOD) and limit of quantification (LOQ) values in concentration domain by using 4 different approaches; namely 3sigma and 10sigma approaches, ULA2 approach, PBA approach and MDL approach. Brief theoretical analyses of all above mentioned approaches are given together with directions for their practical use. Calculations and correct calibration design are exemplified by using of electrothermal atomic absorption spectrometry for determination of lead in drinking water sample. These validation parameters reached 1.6 MUg L(-1) (LOD) and 5.4 MUg L(-1) (LOQ) by using 3sigma and 10sigma approaches. For obtaining relevant values of analyte concentration the influence of calibration design and measurement methodology were examined. The most preferred technique has proven to be a method of preconcentration of the analyte on the surface of the graphite cuvette (boost cycle). PMID- 24401402 TI - Green colorimetric recognition of trace sulfide ions in water samples using curcumin nanoparticle in micelle mediated system. AB - In this paper, green curcumin nanoparticles (CURNs) are introduced for colorimetric sensing of sulfide using micelle mediated cloud point extraction for the first time. CURNs are transferred into non-ionic surfactant phase and show strong surface plasmon absorption intensity. The extraction of CURNs to the surfactant rich phase is suppressed in the presence of Cu(2+) but upon addition of sulfide, the extraction of CURNs to the surfactant rich phase is increased again. This increase in the absorbance of surfactant rich phase is related to the sulfide concentration and was used as an analytical signal for the sensing of sulfide. The effect of chemical variables such as pH of the sample solution, concentration of Cu(2+), electrolyte and CURNs on the cloud point extraction was studied. Under optimum conditions, the change in absorption intensity was linearly proportional to the concentration of sulfide in the range of 0.5-200.0 ng mL(-1) with a detection limit of 0.4 ng mL(-1). The relative standard deviations for 10 replicate measurements of 20 ng mL(-1) and 175 ng mL(-1) of sulfide were 4.1% and 1.4% respectively. The method was successfully applied to the determination of sulfide in different water samples. PMID- 24401403 TI - Application of nanoring amino-functionalized magnetic polymer dispersive micro solid-phase extraction and ultra fast liquid chromatography-tandem mass spectrometry in dicyandiamide residue analysis of powdered milk. AB - In this study, a rapid and accurate ultra-fast liquid chromatography-tandem quadrupole mass spectrometry (UFLC-MS/MS) method combined with dispersive micro solid-phase extraction (d-u-SPE) using a core-shell nanoring amino-functionalized magnetic polymer (CS-NR-MP) was established and validated to determine trace dicyandiamide (DCD) in powdered milk. The developed d-u-SPE cleanup procedure can dramatically reduce the matrix in samples, and lead to a significant reduction in absolute matrix effects. Chromatographic separation was performed on an Acquity UPLC BEH Amide column by using water-acetonitrile (9:91, v/v) as the mobile phase within 2 min. DCD was quantitatively analyzed by using DCD-(15)N2(13)C2 as an internal standard. The results showed that the recoveries were between 99.8 and 105.6% with RSDs in the range of 0.5-4.9%. The target compound had good linearity in the range of 0.1-20.0 ug L(-1) with a correlation coefficient (r) of 0.9996. The limit of quantification (LOQ) was 0.06 ug kg(-1). This method can be used for the rapid and sensitive determination of ultratrace DCD residue in powdered milk samples. PMID- 24401404 TI - Evaluation of vancomycin-based synergistic system with amino acid ester chiral ionic liquids as additives for enantioseparation of non-steroidal anti inflammatory drugs by capillary electrophoresis. AB - Recently, chiral ionic liquids (ILs) have drawn increasing attention in chiral separation field; however, few papers reported the application of chiral ILs for chiral separation by capillary electrophoresis (CE), and among the papers, chiral ILs were mainly applied as additives to beta-cyclodextrin derivatives systems to establish synergistic systems. The synergistic system based on antibiotics with chiral ILs as additives has never been reported before. In this paper, two chiral ionic liquids (ILs) based on amino acid ester, L-alanine and L-valine tert butyl ester bis (trifluoromethane) sulfonamide, were first applied to evaluate the synergistic effect with antibiotic selector for CE chiral separation. The vancomycin-based synergistic system with chiral ILs as additives was successfully established and investigated for the enantioseparation of naproxen, carprofen, ibuprofen, ketoprofen and pranoprofen. Compared to vancomycin-alone cases, significant improvement of separation for all the analytes was observed. Several parameters, such as type and proportion of organic modifier, composition and pH of buffer, concentration of chiral ILs and vancomycin were systematically investigated, and then evaluated by means of Statistical Product and Service Solutions (SPSS) to research the influences on the synergistic effect. Finally, the established method was successfully applied to test the chiral impurity of naproxen sample. PMID- 24401405 TI - SPE speciation of inorganic arsenic in rice followed by hydride-generation atomic fluorescence spectrometric quantification. AB - Due to high toxicity, inorganic arsenic (iAs) species are the focus of monitoring effort worldwide. In this work arsenic was first extracted from rice by microwave assisted digestion in HNO3-H2O2, during which As(III) was oxidized to As(V). Silica-based strong anion exchange cartridges were used to separate As(V) from organic forms. After prereduction by iodide, iAs was quantified by hydride generation atomic fluorescence spectrometry (HG-AFS). This method achieved 1.3 ng g(-1) limit of detection (LOD), and 94 +/- 3% and 93 +/- 5% recoveries, respectively, for As(III) and As(V) at 100 ng g(-1). Validation was performed using standard reference material NIST 1568a (102 ng g(-1)) and ERM BC211 (124 ng g(-1)) rice flour. By eliminating chromatography, SPE speciation gained throughput and cost advantages. HG-AFS, at 10% budget and operation cost of a typical inductively-couple plasma mass spectrometer (ICPMS), proved highly sensitive and specific for iAs quantification. PMID- 24401406 TI - A flower-like nickel oxide nanostructure: synthesis and application for choline sensing. AB - Flower-like nickel oxide nanostructure was synthesized by a simple desolvation method. The nanostructure was then employed as the modifier of a carbon paste electrode to fabricate a choline sensor. The mechanism and kinetics of the electrocatalytic oxidation of choline on the modified electrode surface were studied by cyclic voltammetry, steady-state polarization curve, and chronoamperometry. The catalytic rate constant and the charge transfer coefficient of the choline electrooxidation process by an active nickel species, and the diffusion coefficient of choline were reported. An amperometric method was developed for determination of choline with a sensitivity of 60.5 mA mol( 1)Lcm(-2) and a limit of detection of 25.4 MUmol L(-1). The sensor had the advantages of high electrocatalytic activity and sensitivity, and long-term stability toward choline, with a simple fabrication method without complications of immobilization steps and using any enzyme or reagent. PMID- 24401407 TI - Electrochemical sensors using modified electrodes based on copper complexes formed with Algerian humic acid modified with ethylenediamine or triethylenetetramine for determination of nitrite in water. AB - The response and efficiency of new sensors for nitrite ions analysis have been studied electrochemically. These sensors were developed by modifying a carbon paste electrode (CPE) with copper (II) complexes formed with commercial (PFHA) and Algerian (YHA) humic acids and their modified compounds with ethylenediamine (EDA) or triethylenetetramine (TETA). The developed mechanism is based on the electrochemical oxidation of NO2(-) on the modified CPE for different nitrite concentrations. The obtained results showed that the carbon paste electrode modified with copper (II)-modified humic acids complexes (Cu-MHA) exhibited substantial electrocatalytic effect on the oxidation of nitrite anions compared with carbon paste electrode. The sensitivity of the modified CPE towards nitrite concentrations depends on the nature of the humic acid and its modified compounds. The measurements performed by using CPE/Cu-YHA-EDA and CPE/Cu-YHA-TETA gave the best sensitivity and a good linear response of current versus nitrite concentrations. The oxidation peak current of nitrite at CPE/Cu-YHA-TETA and CPE/Cu-YHA-EDA electrodes in weak acid solution is proportional to the concentration of nitrite over the range 0-1.38 * 10(-2) mol L(-1) with a limit of detection (LOD) of 1.46 MUmol L(-1) (Sensitivity=41.06 MUA(mmol L(-1))(-1) and 2.17 MUmol L(-1) (Sensitivity=27.63MUA(mmol L(-1))(-1), respectively. Compared to the sensors published in the literature, our CPE/Cu-YHA-TETA and CPE/Cu-YHA-EDA electrodes exhibit a good catalytic activity towards nitrite oxidation and a low limit of detection over a wide nitrite concentrations range. PMID- 24401408 TI - A combination of dynamic measurement protocol and advanced data treatment to resolve the mixtures of chemically similar analytes with potentiometric multisensor system. AB - Data processing techniques and measuring protocol are very important parts of the multisensor systems methodology. Complex analytical tasks like resolving the mixtures of two components with very similar chemical properties require special attention. We report on the application of non-linear (artificial neural networks, ANNs) and linear (projections on latent structures, PLS) regression techniques to the data obtained from the flow cell with potentiometric multisensor detection of neighouring lanthanides in the Periodic System of the elements (samarium, europium and gadolinium). Quantification of individual components in mixtures is possible with reasonable precision if dynamic components of the response are incorporated thanks to the use of an automated sequential injection analysis system. The average absolute error in prediction of lanthanides with PLS was around 1 * 10(-4)mol/L, while the use of ANNs allows the lowering of prediction errors down to 2 * 10(-5)mol/L in certain cases. The suggested protocol seems to be useful for other analytical applications where simultaneous determination of chemically similar analytes in mixtures is required. PMID- 24401409 TI - Fast determination of trace elements in organic fertilizers using a cup-horn reactor for ultrasound-assisted extraction and fast sequential flame atomic absorption spectrometry. AB - A fast and accurate method based on ultrasound-assisted extraction in a cup-horn sonoreactor was developed to determine the total content of Cd, Co, Cr, Cu, Mn, Ni, Pb and Zn in organic fertilizers by fast sequential flame atomic absorption spectrometry (FS FAAS). Multivariate optimization was used to establish the optimal conditions for the extraction procedure. An aliquot containing approximately 120 mg of the sample was added to a 500 uL volume of an acid mixture (HNO3/HCl/HF, 5:3:3, v/v/v). After a few minutes, 500 uL of deionized water was added and eight samples were simultaneously sonicated for 10 min at 50% amplitude, allowing a sample throughput of 32 extractions per hour. The performance of the method was evaluated with a certified reference material of sewage sludge (CRM 029). The precision, expressed as the relative standard deviation, ranged from 0.58% to 5.6%. The recoveries of analytes were found to 100%, 109%, 96%, 92%, 101%, 104% and 102% for Cd, Cr, Cu, Mn, Ni, Pb and Zn, respectively. The linearity, limit of detection and limit of quantification were calculated and the values obtained were adequate for the quality control of organic fertilizers. The method was applied to the analysis of several commercial organic fertilizers and organic wastes used as fertilizers, and the results were compared with those obtained using the microwave digestion procedure. A good agreement was found between the results obtained by microwave and ultrasound procedures with recoveries ranging from 80.4% to 117%. Two organic waste samples were not in accordance with the Brazilian legislation regarding the acceptable levels of contaminants. PMID- 24401410 TI - Determination of thiol functional groups on bacteria and natural organic matter in environmental systems. AB - Organic thiols (R-SH) are known to react and form complexes with some toxic soft metals such as mercury (Hg) in both biotic and abiotic systems. However, a clear understanding of these interactions is currently limited because quantifying thiols in environmental matrices is difficult due to their low abundance, susceptibility to oxidation, and measurement interference by non-thiol compounds in samples. Here, we report a fluorescence-labeling method using a maleimide containing probe, ThioGlo-1 (TG-1), to determine total thiols directly on bacterial cells and natural organic matter (NOM). We systematically evaluated the optimal thiol labeling conditions and interference from organic compounds such as disulfide, methionine, thiourea, and amine, and inorganic ions such as Na(+), K(+), Ca(2+), Fe(2+), Cl(-), SO4(2-), HCO3(-), and SCN(-), and found that the method is highly sensitive and selective. Only relatively high levels of sulfide (S(2-)) and sulfite (SO3(2-)) significantly interfere with the thiol analysis. The method was successful in determining thiols in a bacterium Geobacter sulfurreducens PCA and its mutants in a phosphate buffered saline solution. The measured value of ~2.1 * 10(4) thiols cell(-1) (or ~0.07 umol g(-1) wet cells) is in good agreement with that observed during reactions between Hg and PCA cells. Using the standard addition, we determined the total thiols of two reference NOM samples, the reduced Elliot soil humic acid and Suwanee River NOM, to be 3.6 and 0.7 umol g(-1), respectively, consistent with those obtained based on their reactions with Hg. PMID- 24401411 TI - Electrochemical preparation of sodium dodecylsulfate doped over-oxidized polypyrrole/multi-walled carbon nanotube composite on glassy carbon electrode and its application on sensitive and selective determination of anticancer drug: pemetrexed. AB - Electrochemical oxidation of pemetrexed (PMX) was studied on bare, carboxylic acid functionalized multi-walled carbon nanotubes and over-oxidized polypyrrole modified (oo-PPy/MWCNTs-COOH/GCE) glassy carbon electrodes by cyclic and adsorptive stripping differential pulse voltammetric techniques. The oo PPy/MWCNTs-COOH/GCE is very sensitive to the oxidation of PMX. The results proved that the over-oxidation of the PPy film gave a negative charge density on porous layer that improved the adsorption for PMX. The effects of pH, concentrations of MWCNTs and monomer, the number of cycles for the electropolymerization and the scan rate for sensor preparation were optimized. The MWCNTs-COOH and oo-PPy based sensor showed an excellent recognition capacity toward PMX. The linear responses have been obtained in the range from 8.00 * 10(-7)M to 1.00 * 10(-4)M with 2.04 * 10(-7)M detection limit for the bare GCE and from 1.00 * 10(-8)M to 1.00 * 10( 7)M with 3.28 * 10(-9)M detection limit for the modified GCE. The oxidation of PMX was controlled by the adsorption process on both types of electrode surfaces. The proposed methods were compared with the literature on UV spectrophotometric assay, which was carried out at an absorption maximum of 225 nm. The proposed method and the designed sensors have been successfully applied for the determination of PMX in pharmaceuticals. PMID- 24401412 TI - Development of soybean certified reference material for pesticide residue analysis. AB - A soybean certified reference material for pesticide residue analysis was developed by the National Metrology Institute of Japan. Three organophosphorus (diazinon, fenitrothion, chlorphyrifos) and one pyrethroid (permethrin) pesticides were sprayed on soybeans three times before harvest. These soybeans were freeze pulverized, homogenized, bottled, and sterilized by gamma-irradiation to prepare the candidate material. Three isotope-dilution mass spectrometric methods that varied in terms of the solvents used for extraction of the target pesticides, the clean-up procedure, and the injection techniques and columns used for quantification via gas chromatography/mass spectrometry were applied to the characterization. Each target pesticide was quantified by two of these analytical methods, and the results were in good agreement. Homogeneity and stability assessment of the material demonstrated that the relative standard uncertainties due to the inhomogeneity and the instability for an expiry date of 55 months were 1.89-4.00% and 6.65-11.5%, respectively. The certified pesticide concentrations with expanded uncertainties (coverage factor k=2, approximate 95% confidence interval) calculated using the results of the characterization and the homogeneity and stability assessment were 21.7 +/- 3.2 MUg/kg for diazinon, 88 +/ 21 MUg/kg for fenitrothion, 11.1 +/- 3.2 MUg/kg for chlorpyrifos, and 20.1 +/- 4.3 MUg/kg for permethrin (as the sum of the constituent isomers). PMID- 24401413 TI - Development of 1,1'-oxalyldiimidazole chemiluminescent biosensor using the combination of graphene oxide and hairpin aptamer and its application. AB - Highly sensitive biosensor with 1,1'-oxalyldiimidazole chemiluminescence (ODI-CL) detection was developed to rapidly quantify Vibrio (V) parahaemolyticus without time-consuming procedures such as multiple long-incubations and washings. When V. parahaemolyticus in Tris-HCl (pH 7) and hairpin DNA aptamer conjugated with TEX615 in DNA free deionized water were consecutively added in PBS buffer (pH 7.4) containing graphene oxides (GOs), V. parahaemolyticus and GOs bind competitively to hairpin DNA aptamer conjugated with TEX615 during 10 min of incubation at room temperature. Brightness of light immediately emitted with the addition of ODI-CL reagents (e.g., ODI, H2O2) after the incubation was dependent on the concentration of V. parahaemolyticus in a sample. The dynamic range of linear calibration curve for the quantification of V. parahaemolyticus in a sample was from 4375 to 70,000 cells/ml. The limit of detection (LOD = background + 3 * standard deviation, 2230 cells/ml) of the biosensor operated with good accuracy, precision, and recovery was lower than those of conventional assay methods such as time-consuming and expensive enzyme-linked immunosorbent assays. PMID- 24401414 TI - Determination of five pyrethroids in tea drinks by dispersive solid phase extraction with polyaniline-coated magnetic particles. AB - The polyaniline-coated magnetic particles with bowl-shaped morphology (Fe3O4/C/PANI microbowls) were successfully prepared and characterized by scanning electron microscopy, transmission electron microscopy and vibrating sample magnetometry. The prepared microbowls were used as the magnetic adsorbent in dispersive solid phase extraction of five pyrethroids, including cyhalothrin, beta-cypermethrin, esfenvalerate, permethrin and bifenthrin in plain tea drinks. The effects of experiment factors, including amount of Fe3O4/C/PANI microbowls, pH value, ultrasound extraction time and desorption conditions, were investigated. The extraction recoveries obtained with 8 mg of magnetic microbowls were satisfactory, and the microbowls can be reused after easy washing. Thus, a simple, selective and effective method for the determination of the pyrethroids was established successfully. The results showed that the method had good linearity (r=0.9992-0.9998), and the limits of detections (LODs) were from 0.025 to 0.032 ng mL(-1). The intra-day and inter-day relative standard deviations (RSDs) were in the range of 2.4-6.1% and 3.5-8.8%, respectively. Recoveries obtained by analyzing the real tea drinks were in the range of 72.1-118.4%. PMID- 24401415 TI - Ligand-free gold nanoparticles as colorimetric probes for the non-destructive determination of total dithiocarbamate pesticides after solid phase extraction. AB - In this work, we describe a simple and sensitive non-destructive method for the determination of the total concentration of dithiocarbamate fungicides (DTCs) in real samples. The proposed method combines for the first time the benefits of an extraction method for sample clean-up and preconcentration with a sensitive colorimetric assay based on gold nanoparticle probes. In this two-step procedure, the target DTCs are isolated from the matrix and preconcentrated by solid phase extraction onto commercially available C18 sorbents. Following elution, the extract containing the target dithiocarbamates, free from most interferences and matrix components, is delivered into an aqueous dispersion of plain citrate capped gold nanoparticles (AuNPs) which aggregate in response to DTCs coordination on AuNPs surface through multiple gold thiolate bonds. This aggregation is evidenced by changes in the spectral properties of the solution involving a decrease in the original absorbance of Au nanoparticles at 522 nm and the appearance of a new absorption band above 700 nm. An ensuing chromatic shift of the solution from wine-red to purple-blue is observed which is visual by naked eye at concentrations as low as 50 MUg L(-1). Further improvement in the detection limits can be accomplished by scaling-down the method to micro-volume conditions alleviating the need to preconcentrate larger sample volumes. Overall, by combining sample clean-up and preconcentration with the strong affinity of DTC thiol group for the gold surface, the total concentration of dithiocarbamate pesticides was successfully determined in various water samples at the low and ultra-low MUg L(-1) levels without resorting to destructive techniques, sophisticated instrumentation or post-synthetic modification of gold nanoparticles. Method application in real samples showed good analytical features in terms of recoveries (81.0-94.0%), precision (5.6-8.9%) and reproducibility (~9%) rendering the method as an attractive alternative to current methodologies for the determination of DTC fungicide residues in samples of environmental interest. PMID- 24401416 TI - Liquid chromatography-tandem mass spectrometry method for determination of panel of neurotransmitters in cerebrospinal fluid from the rat model for tauopathy. AB - Alzheimer's disease (AD) is still being recognized today as an unmet medical need. Currently, there is no cure and early preclinical diagnostic assay available for AD. Therefore much attention is now being directed at the development of novel methods for quantitative determination of AD biomarkers in the cerebrospinal fluid (CSF). Here, we describe the liquid chromatography-tandem mass spectrometry method for determination of 5-hydroxytryptamine (SER), 5 hydroxyindoleacetic acid (5-HIAA), homovanilic acid (HVA), noradrenaline (NADR), adrenaline (ADR), dopamine (DA), glutamic acid (Glu), gamma-aminobutyric acid (GABA), 3,4-dihydroxyphenylacetic acid (DOPAC) and histamine (HIS) in cerebrospinal fluid (CSF) from the rat model for human tauopathy. The benzoyl chloride was used as pre-column derivatization reagents. Neurotransmitters and metabolites were analysed on ultra performance liquid chromatography (UPLC) on C18 column in combination with tandem mass spectrometry. The method is simple, highly sensitive and showed excellent linearity with regression coefficients higher than 0.99. The accuracy was in a range of 93-113% for all analytes. The inter-day precision (n=5 days), expressed as %RSD, was in a range 2-10% for all analytes. Using this method we detected significant changes of CSF levels of two important neurotransmitters/metabolites, ADR and 5-HIAA, which correlates with progression of neurodegeneration in our animal model. PMID- 24401417 TI - Rapid determination of phthalate esters in alcoholic beverages by conventional ionic liquid dispersive liquid-liquid microextraction coupled with high performance liquid chromatography. AB - A very simple, fast and environmentally friendly sample extraction method was proposed for the analysis of phthalate esters (PAEs, di-isobutyl phthalate (DIBP), dibutylphthalate (DBP), butylbenzylphthalate (BBP) and bis(2 ethylhexyl)phthalate (DEHP)) in alcoholic beverages by using conventional ionic liquid dispersive liquid-liquid microextraction. The samples were extracted by 160 MUL 1-octyl-3-methylimidazolium hexafluorophosphate in the presence of appropriate amount of ethanol and 10% (w/v) sodium chloride solution; the enriched analytes in sedimented phases were analyzed by high performance liquid chromatography-diode array detector (HPLC-DAD). Under the optimum conditions, a satisfactory linearity (in the range of 0.02-1 MUg mL(-1) for white spirits and 0.01-0.5 MUg mL(-1) for red wines with the correlation coefficients (r) varying from 0.9983 to 1), acceptable recovery rates (88.5-103.5% for white spirits and 91.6-104.6% for red wines), good repeatability (RSD <= 8.0%) and low detection limits (3.1-4.2 ng mL(-1) for white spirits and 1.5-2.2 ng mL(-1) for red wines) were obtained. The developed method was successfully applied for the determination of the four PAEs in 30 white spirits and 11 red wines collected locally, and the DBP content in 63% (19:30) white spirits exceeded the specific migration limit of 0.3 mg kg(-1) established by international regulation. PMID- 24401418 TI - Measurement of salivary metabolite biomarkers for early monitoring of oral cancer with ultra performance liquid chromatography-mass spectrometry. AB - This study aimed to set-up an ultra performance liquid chromatography electrospray ionization-mass spectrometry (UPLC-ESI-MS) method for the determination of salivary L-phenylalanine and L-leucine for early diagnosis of oral squamous cell carcinoma (OSCC). In addition, the diagnostic accuracy for both biomarkers was established by using receiver operating characteristic (ROC) analysis. Mean recoveries of l-phenylalanine and L-leucine ranged from 88.9 to 108.6% were obtained. Intra- and inter-day precision for both amino acids was less than 7%, with acceptable accuracy. Linear regression coefficients of both biomarkers were greater than 0.99. The diagnostic accuracy for both biomarkers was established by analyzing 60 samples from apparently healthy individuals and 30 samples from OSCC patients. Both potential biomarkers demonstrated significant differences in concentrations in distinguishing OSCC from control (P<0.05). As a single biomarker, L-leucine might have better predictive power in OSCC with T1-2 (early stage of OSCC including stage I and II), and L-phenylalanine might be used for screening and diagnosis of OSCC with T3-4 (advanced stage of OSCC including stage III and IV). The combination of L-phenylalanine and L-leucine will improve the sensitivity (92.3%) and specificity (91.7%) for early diagnosis of OSCC. The possibility of salivary metabolite biomarkers for OSCC diagnosis is successfully demonstrated in this study. This developed method shows advantages with non invasive, simple, reliable, and also provides lower detection limits and excellent precision and accuracy. These non-invasive salivary biomarkers may lead to a simple clinical tool for the early diagnosis of OSCC. PMID- 24401419 TI - Specific and sensitive colorimetric detection of Al3+ using 5 mercaptomethyltetrazole capped gold nanoparticles in aqueous solution. AB - Contamination of food and drinking water by health-risk levels of Al(3+) calls for convenient assays. Here, we report a method to visibly detect Al(3+) at room temperature. Firstly, the chelating ligand of 5-mercaptomethyltetrazole (MMT) was synthesized and modified on the surface of AuNPs through the strong Au-S interaction to form a MMT-AuNP probe, which can remain well-dispersed and stable in an aqueous solution for a long time. Upon the addition of Al(3+), the interparticle crosslinking induced aggregation (color change from red to blue) of MMT-AuNPs was triggered through the Al(3+)-MMT interaction. Under optimal conditions, the absorbance ratio (A620/A520) of MMT-AuNPs is linear within the Al(3+) concentration range from 1.0 to 10.0 MUM, and the detection limit (3sigma) was as low as 0.53 MUM. Moreover, an interference study showed that this MMT-AuNP probe discriminated Al(3+) from a wide range of environmentally dominant metal ions and anions. The practical utility of the new method was demonstrated by determining Al(3+) in several environmental water and human urine specimens, obtaining satisfactory results. Being a rapid, convenient and cost-effective method, it should become a powerful alternative to conventional methods for selective quantification of Al(3+) in routine laboratory practice or rapid on site assay. PMID- 24401420 TI - Implementing the contamination prevention programs in the pesticide industry by infrared spectroscopy. AB - An infrared spectroscopy based methodology has been successfully developed to implement contamination prevention programs in the pesticide industry. Sensitivity of the IR procedure, traditionally considered the Achilles Hell of the technique, has been improved by using a transmission cell with an open upper side, an internal volume of 35 uL and an optical pathlength of 0.5mm, providing detection limits of 32 mg L(-1) for folpet and 48 mg L(-1) for cymoxanil. The manufacturing of folpet and cymoxanil was employed as an example and the IR methodology was validated for the implementation of contamination prevention programs in the pesticide industry. The swab test and rinsate method were employed as sampling methods and results obtained by both were compared and correlated. Samples were analyzed from a qualitative and quantitative point of view. Qualitative information can be obtained by comparing the sample spectra with those of a new IR spectral library with approximately 50 entries of pesticide standards. Positive identification of folpet in all the analyzed samples was obtained. Other pesticides present in swab and rinsate samples positively identified by IR and confirmed by gas chromatography-mass spectrometry (GC-MS), were metalaxyl and chlorpyrifos methyl used in the manufacture of previous formulations. The amount of folpet in the swab and rinsate samples obtained by the developed IR method was compared with those of a reference procedure, being statistically comparable. PMID- 24401421 TI - Combination of UV-vis spectroscopy and chemometrics to understand protein nanomaterial conjugate: a case study on human serum albumin and gold nanoparticles. AB - Study of the interactions between proteins and nanomaterials is of great importance for understanding of protein nanoconjugate. In this work, we choose human serum albumin (HSA) and citrate-capped gold nanoparticles (AuNPs) as a model of protein and nanomaterial, and combine UV-vis spectroscopy with multivariate curve resolution by an alternating least squares (MCR-ALS) algorithm to present a new and efficient method for comparatively comprehensive study of evolution of protein nanoconjugate. UV-vis spectroscopy coupled with MCR-ALS allows qualitative and quantitative extraction of the distribution diagrams, spectra and kinetic profiles of absorbing pure species (AuNPs and AuNPs-HSA conjugate are herein identified) and undetectable species (HSA) from spectral data. The response profiles recovered are converted into the desired thermodynamic, kinetic and structural parameters describing the protein nanoconjugate evolution. Analysis of these parameters for the system gives evidence that HSA molecules are very likely to be attached to AuNPs surface predominantly as a flat monolayer to form a stable AuNPs-HSA conjugate with a core-shell structure, and the binding process takes place mainly through electrostatic and hydrogen-bond interactions between the positively amino acid residues of HSA and the negatively carboxyl group of citrate on AuNPs surface. The results obtained are verified by transmission electron microscopy, zeta potential, circular dichroism spectroscopy and Fourier transform infrared spectroscopy, showing the potential of UV-vis spectroscopy for study of evolution of protein nanoconjugate. In parallel, concentration evolutions of pure species resolved by MCR-ALS are used to construct a sensitive spectroscopic biosensor for HSA with a linear range from 1.8 nM to 28.1 nM and a detection limit of 0.8 nM. PMID- 24401422 TI - Development of search prefilters for infrared library searching of clear coat paint smears. AB - Search prefilters developed from spectral data collected on two 6700 Thermo Nicolet FTIR spectrometers were able to identify the respective manufacturing plant and the production line of an automotive vehicle from its clear coat paint smear using IR transmission spectra collected on a Bio-Rad 40A or Bio-Rad 60 FTIR spectrometer. All four spectrometers were equipped with DTGS detectors. An approach based on instrumental line functions was used to transfer the classification model between the Thermo-Nicolet and Bio-Rad instruments. In this study, 209 IR spectra of clear coat paint smears comprising the training set were collected using two Thermo-Nicolet 6700 IR spectrometers, whereas the validation set consisted of 242 IR spectra of clear coats obtained using two Bio-Rad FTIR instruments. PMID- 24401423 TI - Fe3O4@ionic liquid@methyl orange nanoparticles as a novel nano-adsorbent for magnetic solid-phase extraction of polycyclic aromatic hydrocarbons in environmental water samples. AB - A novel nano-adsorbent, Fe3O4@ionic liquid@methyl orange nanoparticles (Fe3O4@IL@MO NPs), was prepared for magnetic solid-phase extraction (MSPE) of polycyclic aromatic hydrocarbons (PAHs) in environmental water samples. The Fe3O4@IL@MO NPs were synthesized by self-assembly of the ionic liquid 1-octadecyl 3-methylimidazolium bromide (C18mimBr) and methyl orange (MO) onto the surface of Fe3O4 silica magnetic nanoparticles, as confirmed by infrared spectroscopy, ultraviolet-visible spectroscopy and superconducting quantum interface device magnetometer. The extraction performance of Fe3O4@IL@MO NPs as a nano-adsorbent was evaluated by using five PAHs, fluorene (FLu), anthracene (AnT), pyrene (Pyr), benzo(a)anthracene (BaA) and benzo(a)pyrene (BaP) as model analytes. Under the optimum conditions, detection limits in the range of 0.1-2 ng/L were obtained by high performance liquid chromatography-fluorescence detection (HPLC-FLD). This method has been successfully applied for the determination of PAHs in environmental water samples by using the MSPE-HPLC-FLD. The recoveries for the five PAHs tested in spiked real water samples were in the range of 80.4-104.0% with relative standard deviations ranging from 2.3 to 4.9%. PMID- 24401425 TI - Autonomous, waste-free eluent generation and suppression in a single device: electrodialytic eluent reflux for ion chromatography. AB - Eluent reflux provides a new approach to suppress and reflux (recover) eluent without the continuous generation of chromatographic waste. The current work utilized a device containing ion exchange membranes at the electrodes, in order to prohibit electrolysis gases from entering the eluent stream. Two resin beds (separated by a membrane stack) were responsible for suppressing incoming eluent and regenerating the suppressed eluent to nearly its original concentration after detection. A greater than expected dilution in the eluent concentration was observed as a result of the minor leakage of potassium ions through the anion membrane stack into the electrode chamber. The incomplete recovery of the eluent was offset by the addition of a three port valve (DRV) to regulate eluent concentration. Over 48 h of continuous operation (192 injections), the device's performance was stable (RSD of 0.21% with the three port valve, compared to RSD 3.73% without). The device was able to operate for up to four weeks using 1L of eluent. Chromatograms showing the reproducibility of the device are presented for anions. PMID- 24401424 TI - Sputtered bismuth screen-printed electrode: a promising alternative to other bismuth modifications in the voltammetric determination of Cd(II) and Pb(II) ions in groundwater. AB - A commercially available sputtered bismuth screen-printed electrode (BispSPE) has been pioneeringly applied for the simultaneous determination of Cd(II) and Pb(II) ions in a certified groundwater sample by means of differential pulse anodic stripping voltammetry (DPASV) as an alternative to more conventional bismuth screen-printed carbon electrodes (BiSPCEs). BispSPEs can be used for a large set of measurements without any previous plating or activation. The obtained detection and quantification limits suggest that BispSPEs produce a better analytical performance as compared to In-situ BiSPCE for Pb(II) and Cd(II) determination, but also to Ex-situ BiSPCE for Cd(II) determination. The results confirm the applicability of these devices for the determination of low level concentrations of these metal ions in natural samples with very high reproducibility (0.7% and 2.5% for Pb(II) and Cd(II) respectively), and good trueness (0.3% and 2.4% for Pb(II) and Cd(II) respectively). PMID- 24401426 TI - Non-invasive quantification of 5 fluorouracil and gemcitabine in aqueous matrix by direct measurement through glass vials using near-infrared spectroscopy. AB - Fourier transform near infrared spectroscopy (NIRS) was used for quantitative analysis of two cytotoxic drugs used in pharmaceutical infusion, 5-fluorouracil (5FU) and gemcitabine (GEM), at therapeutic concentrations in aqueous matrix. Spectra were collected from 4000 cm(-1) to 13,000 cm(-1) by direct measurement through standard glass vials and calibration models were developed for 5FU and GEM using partial least-squares regression. NIR determination coefficient (R(2)) greater than 0.9992, root-mean-square-error of cross-validation (RMESCV) of 0.483 mg/ml for 5FU and 0.139 mg/ml for GEM and the root mean square error of prediction (RMSEP) of 0.519 for 5FU and 0.108 mg/ml for GEM show a good prediction ability of NIR spectroscopy to predict 5FU and GEM concentrations directly through a glass packaging. According to accuracy profile, the linearity was validated from 7 to 50mg/ml and 2 to 40 mg/ml for 5-fluorouracil and gemcitabine respectively. This new approach for cytotoxic drugs control at hospital has shown the feasibility of near infrared spectroscopy to quantify antineoplastic drugs in aqueous matrix by a direct measurement through glass vial in less than 1 min and by non-invasive measurement perfect to limit exposure of operator to cytotoxic drugs. PMID- 24401427 TI - Quantitative evaluation of besifloxacin ophthalmic suspension by HPLC, application to bioassay method and cytotoxicity studies. AB - Besifloxacin (BSF) is a synthetic chiral fluoroquinolone developed for the topical treatment of ophthalmic infections. The present study reports the development and validation of a microbiological assay, applying the cylinder plate method, for determination of BSF in ophthalmic suspension. To assess this methodology, the development and validation of the method was performed for the quantification of BSF by high performance liquid chromatography (HPLC). The HPLC method showed specificity, linearity in the range of 20-80 ug mL(-1) (r=0.9998), precision, accuracy and robustness. The microbiological method is based on the inhibitory effect of BSF upon the strain of Staphylococcus epidermidis ATCC 12228 used as a test microorganism. The bioassay validation method yielded excellent results and included linearity, precision, accuracy, robustness and selectivity. The assay results were treated statistically by analysis of variance (ANOVA) and were found to be linear (r=0.9974) in the range of 0.5-2.0 ug mL(-1), precise (inter-assay: RSD=0.84), accurate (101.4%), specific and robust. The bioassay and the previously validated high performance liquid chromatographic (HPLC) method were compared using Student's t test, which indicated that there was no statistically significant difference between these two methods. These results confirm that the proposed microbiological method can be used as routine analysis for the quantitative determination of BSF in an ophthalmic suspension. A preliminary stability study during the HPLC validation was performed and demonstrated that BSF is unstable under UV conditions. The photodegradation kinetics of BSF in water showed a first-order reaction for the drug product (ophthalmic suspension) and a second-order reaction for the reference standard (RS) under UVA light. UVA degraded samples of BSF were also studied in order to determine the preliminary in vitro cytotoxicity against mononuclear cells. The results indicated that BSF does not alter the cell membrane and has been considered non-toxic to human mononuclear cells in the experimental conditions tested. PMID- 24401428 TI - Microextraction by packed sorbent and salting-out-assisted liquid-liquid extraction for the determination of aromatic amines formed from azo dyes in textiles. AB - EU legislation prohibits the use of certain azo dyes which, on reduction, form any of 22 aromatic amines listed in Regulation (EC) 1907/2006 at concentrations above the threshold limit of 30 mg Kg(-1). Two different extraction techniques for the determination of aromatic amines formed from azo dyes in textiles in combination with gas chromatography-mass spectrometry (GC-MS) are described. The first one is based on microextraction by packed sorbent (MEPS) and the other approach involves salting-out-assisted liquid-liquid extraction (SALLE). The influence of several parameters on the efficiency of the extraction using MEPS (sorbent material, sample volume, elution solvent, elution volume and washing steps, among others) and SALLE (extraction volume and amount of salt) were investigated. In addition, chromatographic separation was optimized and quadrupole mass spectrometry was evaluated using the synchronous SIM/scan data acquisition mode. The repeatability (n=8, S/N=3) of the methods, calculated as the relative standard deviation (RSD) was below 15 and 11% for all compounds when MEPS and SALLE were used, respectively. Standard additions procedure was used to quantify the aromatic amines in the textil samples. The detection limits in the samples for both methods were lower than the maximum value allowed by legislation. The results obtained in the analysis of textiles revealed the presence of o-anisidine, p-chloroaniline, 4-chloro-o-toluidine, 2-naphthylamine and 3,3'-dimethoxybenzidine in some of them. PMID- 24401429 TI - Rapid and non-invasive quantification of intramuscular fat content of intact pork cuts. AB - Having acquired near infrared (NIR) hyperspectral images of intact pork loin samples through an NIR hyperspectral imaging system, the efficiency of a variety of image processing techniques including texture pattern analysis techniques were applied to process hyperspectral images so as to determine the intramuscular fat (IMF) content non-destructively. After the segmentation of region of interest (ROI), the raw spectral, texture-based spectral and textural characteristics of pork images were extracted by spectral averaging and pattern recognition techniques namely Gabor filter and improved gray level co-occurrence matrix (GLCM), respectively. First derivatives of the non-filtered and the Gabor filtered spectra were also investigated. Full waveband partial least squares regression (PLSR) was employed to determine the optimal parameters of Gabor filter and GLCM, and to select optimal wavelengths for IMF prediction. A stepwise procedure was applied to the optimal wavelengths to further optimize them to key wavelengths. Multiple linear regression (MLR) models were built based on the key wavelengths. Mean spectra and the Gabor filtered spectra outperformed GLCM. The best result, represented by correlation coefficients of calibration (Rc), cross validation (Rcv) and prediction (Rp) of 0.89, 0.89, and 0.86, respectively, was achieved using the first derivative of Gabor filtered spectra at 1193 and 1217 nm. To visualize the IMF content in pork, the distribution maps of IMF content in pork were drawn using a mean spectra-based MLR model. These promising results highlight the great potential of NIR hyperspectral imaging for non-destructive prediction of IMF content of intact pork. PMID- 24401430 TI - Direct analysis of eight chlorophenols in urine by large volume injection online turbulent flow solid-phase extraction liquid chromatography with multiple wavelength ultraviolet detection. AB - A novel method for determining eight chlorophenols (CPs) by large volume injection online turbulent flow solid-phase extraction high performance liquid chromatography in urine samples was developed. An aliquot of 1.0 mL urine sample could be analyzed directly after centrifugation. The analytes were preconcentrated online on a Turboflow C18-P SPE column, eluted in back-flush mode, and then separated on an Acclaim PA2 analytical column. Major parameters such as SPE column type, sample loading flow rate and elution time were optimized in detail. Eight CPs from monochlorophenol to pentacholophenol were measured by multiple-wavelength UV detection at four different wavelengths. The limits of detection (LODs) were between 0.5 and 2 ng/mL. The linearity range was from the limit of quantification to 1000 ng/mL for each compound, with the coefficients of determination (r(2)) ranging from 0.9990 to 0.9996. The reproducibility of intraday and interday relative standard deviations (RSDs) ranged from 0.6% to 4.5% (n=5). The method was successfully applied to analyze eight CPs in urine samples. Good recoveries, ranging from 76.3% to 122.9%, were obtained. This simple, sensitive and accurate method provides an alternative way to rapidly analyze and monitor CPs in urine samples, especially for matters of occupational exposure. PMID- 24401431 TI - Study on pharmacokinetic and tissue distribution of lycorine in mice plasma and tissues by liquid chromatography-mass spectrometry. AB - A fast and simple liquid chromatography-mass spectrometry method for the determination of lycorine in mice plasma and tissues was developed and well used in the pharmacokinetic and tissue distribution study of lycorine after tail vein injection and intraperitoneal administration. Biological samples were processed with ethyl acetate by liquid-liquid extraction, and evodiamine was used as the internal standard. Chromatographic separation was performed on an Amethyst C18 column (4.6 * 150 mm) with a mobile phase consisting of methanol and water. Quantification was performed by selected ion monitoring with m/z 288 [M+H](+) for lycorine and m/z 304 [M+H](+) for the internal standard. Good linearity was observed over the concentration ranges. Limits of quantification were low up to 10.0 ng/mL in plasma samples, 9.0 ng/g for lung, 12.0 ng/g for heart, 18.0 ng/g for spleen and 6.5 ng/g for other tested tissues. The intraday accuracy and precision in plasma and tissues ranged from -7.4% to 9.1%. Recoveries in plasma and tissue were more than 80%. The method was rapid, accurate and fully validated. It was successfully applied to the investigation of the pharmacokinetics and tissue distribution of lycorine in mice. PMID- 24401432 TI - Compositional surface-layered sorbents for pre-concentration of organic substances in the air analysis. AB - We juxtapose methods of synthesis of non-polar surface-layered sorbents on the platform of a carrier, which combines macro-porous coarse-dispersed polytetrafluoroethylene with micro-dispersed activated carbon. Further, we present data about the sorption properties of the said materials alongside perspectives of their analytical applications. Our study established that with respect to efficacy of dynamic sorption from gaseous phases these sorbents outperform bulk-porous analogues in their normal, granular form. PMID- 24401433 TI - Voltammetric assay of butyrylcholinesterase in plasma samples and its comparison to the standard spectrophotometric test. AB - Butyrylcholinesterase (BChE) is an enzyme abundantly constituted in the livers and released into blood where it is soluble. It may be found in the both plasma and serum. BChE can serve as a biochemical marker. BChE activity is typically measured by spectrophotometric Ellman's method. In the present work, voltammetric assay of cholinesterasemia is proposed as a simple and reliable method. In the experiments described here, limits of detections 4.57 pkat for the spectrofotometric test and 1.14 pkat for the voltammetric assay were determined. Interference caused by acetylcholinesterase (AChE) and organic solvents was characterized and counter measurement to the AChE caused interference was proposed. Finally, the both methods were correlated one to each other using mouse plasma spiked with carbofuran resulting in a promising coefficient of determination. In a conclusion, the voltammetric assay seems to be reliable and suitable for routine performance. PMID- 24401435 TI - Comparison of digestion methods for the determination of ruthenium in catalyst materials. AB - A fusion method, an acid digestion method with a high pressure asher (HPA) and two microwave (MW)-assisted acid digestion methods were compared to investigate their suitability for the determination of Ru in catalyst materials. Ru contents in the digested samples were determined with inductively coupled plasma optical emission spectrometry (ICP-OES). Ru powder and three Ru compounds (RuO2 . xH2O, anhydrous RuO2 and RuCl3), possibly present in Ru catalysts, were digested and analyzed to compare the digestion efficiencies of the methods. Significant differences among the digestion efficiencies of the methods were observed; the fusion method having the best digestion efficiency for the compounds studied. The methods were applied for the determination of Ru in alumina- and carbon-supported catalysts. No differences among the methods were observed for these samples. PMID- 24401434 TI - Simultaneous quantitation of 5- and 7-hydroxyflavone antioxidants and their binding constants with BSA using dual chiral capillary electrophoresis (dCCE) and HPLC with fluorescent detection. AB - In this article we present two novel uses of the sensitive techniques HPLC fluorescence and dCCE for both the quantitation and binding studies of the 5- and 7-HFs extracted from the plant Alfalfa with Albumin. Ultrasonic extraction method as an extra energy source is used to enhance the extraction efficiency and speed up. The two antioxidants could be easily separated and quantified after a 10.0 min run time. Multiple calibration curves for their analysis exhibited consistent linearity and reproducibility in the range of 0.20-2.00 mg L(-1) for 5-HF (r >0.9979) and 0.01-0.10 mg L(-1) for 7-HF (r >0.9999). Limits of Detection were 0.500 ug L(-1) and 0.025 ug L(-1) for 5-HF and 7-HF respectively. Lower Limits of Quantification were 131.600 ug L(-1) for 5-HF and 6.579 ug L(-1) for 7-HF. Inter assay imprecision was <10% for both flavones. Mean recovery was 104.76% (range 90%-110%) for 5-HF and 93.18% (range 90%-110%) for 7-HF. Since the intermolecular hydrogen atom transfer in the excited triplet state as well as in the excited singlet state might play an important role in the quenching process of photo excited molecules in biological systems, the binding constants of these HFs with serum albumin have been also estimated to be 1.910 - 2.019 * 10(5) L mol(-1) and 2.390 - 2.500 * 10(5) L mol(-1) for 5-HF and 7-HF respectively. PMID- 24401436 TI - Combination of accelerated solvent extraction and vortex-assisted liquid-liquid microextraction for the determination of dimethyl fumarate in textiles and leathers by gas chromatography-mass spectrometry. AB - A simple and environmentally friendly sample preparation procedure coupled with gas chromatography-mass spectrometry was developed to assay dimethyl fumarate in textiles and leathers. The sample preparation procedure involved an accelerated solvent extraction (ASE) using water as the extract solvent, followed by the extraction and concentration of dimethyl fumarate from the aqueous solution using vortex-assisted liquid-liquid microextraction (VALLME). The parameters affecting the ASE and VALLME were optimized to achieve the maximum extraction efficiency, and the performance of the developed method was evaluated. Good linearity was observed over the range assayed (0.01-1mg/kg) with a regression coefficient of 0.998. The limit of detection and enrichment factor for the VALLME step were 0.001 mg/kg and 53, respectively. The intra- and inter-day precision were below 8.9%, and the recovery was approximately 84-103%. The as-developed method was successfully applied to textiles and leather samples. PMID- 24401437 TI - A quasi non-destructive approach for amber geological provenance assessment based on head space solid-phase microextraction gas chromatography-mass spectrometry. AB - Head space (HS) solid-phase micro-extraction (SPME) combined with gas chromatography-mass spectrometry (GC-MS) was used to analyze the volatile fraction of ambers of different geological origin. In particular, Romanian (romanite) and Baltic (succinite) amber samples were studied. Both types of amber have nearly similar bulk chemical compositions and could probably reflect only some differences of paleobiological and/or diagenetic origin. The present study shows that amber head space fingerprint, obtained by SPME/GC-MS, can provide a simple and quasi non-destructive method capable of romanite/succinite differentiation. Among the numerous compounds present in the head space, a number of few informative variables could be selected that were able to differentiate the ambers as demonstrated by Principal Component and Cluster Analysis. PMID- 24401438 TI - Ion-exchange chromatography combined with direct current amperometric detection at CuNPs/reduced graphene oxide-chitosan composite film modified electrode for determination of monosaccharide composition of polysaccharides from Phellinus igniarius. AB - A novel Cu nanoparticles/reduced graphene oxide-chitosan (CuNPs/r-GO-chitosan) composite film modified glassy carbon electrode (GCE) was fabricated by dispersing CuNPs uniformly on a stable r-GO-chitosan thin film through electrodeposition process. The modified electrode was characterized by cyclic voltammetry, scanning electron microscopy (SEM) and electrochemical impedance spectroscopy (EIS), and exhibited efficiently electrocatalytic oxidation toward monosaccharides with high stability. The good electrocatalytic activity of this modified electrode might be attributed to the synergistic effect of r-GO and CuNPs, and the stability might be attributed to the r-GO and chitosan thin matrix film. When the CuNPs/r-GO-chitosan/GCE was used as an electrochemical sensor in high performance anion exchange chromatography-direct current amperometric detection (HPAEC-DC) flowing system for the determination of monosaccharides under constant working potential of +0.55 V, the detection limits (S/N=3) ranged from 0.006 to 0.02 mg L(-1) for the analyzed sugars, and the dynamic linear ranges spanned from 0.02 to 500 mg L(-1). The proposed method has been applied for the determination of monosaccharide composition of crude polysaccharides from phellinus igniarius real samples, and the results were satisfactory. PMID- 24401439 TI - Polypyrrole/multi-walled carbon nanotube composite for the solid phase extraction of lead(II) in water samples. AB - A multi-walled carbon nanotubes-polypyrrole conducting polymer nanocomposite has been synthesized, characterized and used for the separation and preconcentration of lead at trace levels in water samples prior to its flame atomic absorption spectrometric detection. The analytical parameters like pH, sample volume, eluent, sample flow rate that were affected the retentions of lead(II) on the new nanocomposite were optimized. Matrix effects were also investigated. Limit of detection and preconcentration factors were 1.1 ug L(-1) and 200, respectively. The adsorption capacity of the nanocomposite was 25.0mg lead(II) per gram composite. The validation of the method was checked by using SPS-WW2 Waste water Level 2 certified reference material. The method was applied to the determination of lead in water samples with satisfactory results. PMID- 24401440 TI - Highly selective enrichment of phosphopeptides with high-index facets exposed octahedral tin dioxide nanoparticles for mass spectrometric analysis. AB - High-index facets exposed octahedral tin dioxide (SnO2) nanoparticles were successfully synthesized and applied to selectively enrich phosphopeptides for mass spectrometric analysis. The high selectivity and capacity of the octahedral SnO2 nanoparticles were demonstrated by effectively enriching phosphopeptides from digests of phosphoprotein (alpha- or beta-casein), protein mixtures of beta casein and bovine serum albumin, milk, and human serum samples. The unique octahedral SnO2 with abundant unsaturated coordination Sn atoms exhibited enhanced affinity and selective coordination ability with phosphopeptides due to their high chemical activity. The strong affinity led to highly selective capture and enrichment of phosphopeptides for sensitive detection through the bidentate bonds formed between surface atoms and phosphate. The phosphopeptides could be detected in beta-casein down to 4 * 10(-9)M or in the mixture of beta-casein and BSA with a molar ratio of even 1:100. The performance in selective enrichment of phosphopeptides from drinking milk and human serum showed powerful evidence of high selectivity and efficiency in identifying the low-abundant phosphopeptides from complicated biological samples. This work provided a way to improve the physical and chemical properties of materials by tailoring their exposed facets for selective enrichment of phosphopeptides. PMID- 24401441 TI - Determination of trace/ultratrace rare earth elements in environmental samples by ICP-MS after magnetic solid phase extraction with Fe3O4@SiO2@polyaniline-graphene oxide composite. AB - A novel Fe3O4@SiO2@polyaniline-graphene oxide composite (MPANI-GO) was prepared through a simple noncovalent method and applied to magnetic solid phase extraction (MSPE) of trace rare earth elements (REEs) in tea leaves and environmental water samples followed by inductively coupled plasma mass spectrometry (ICP-MS) detection. The prepared MPANI-GO was characterized by transmission electron microscopy and vibrating sample magnetometer. Various parameters affecting MPANI-GO MSPE of REEs have been investigated. Under the optimized conditions, the limits of detection (LODs, 3sigma) for REEs were in the range of 0.04-1.49 ng L(-1) and the relative standard deviations (RSDs, c=20 ng L(-1), n=7) were 1.7-6.5%. The accuracy of the proposed method was validated by analyzing a Certified Reference Material of GBW 07605 tea leaves. The method was also successfully applied for the determination of trace REEs in tea leaves and environmental water samples. The developed MPANI-GO MSPE-ICP-MS method has the advantages of simplicity, rapidity, high sensitivity, high enrichment factor and is suitable for the analysis of trace REEs in samples with complex matrix. PMID- 24401442 TI - Performance of a portable biosensor for the analysis of ethion residues. AB - Sensitive disposable potentiometric sensors for determination of the organophosphorus pesticide (OPs), ethion and its degradation residues have been constructed. The fabricated screen printed sensors are based on multi-walled carbon nanotube-polyvinyl chloride (MWNT-PVC) composite incorporated with alpha cyclodextrin (alpha-CD) ionophore for butyrylcholine (BuCh) determination. Butyrylcholinesterase (BuChE) activity was measured through monitoring the BuCh hydrolysis using the fabricated sensors. The electrode potential changes linearly with BuChE concentration over the range from 0.04 to 0.4 U in phosphate buffer solution. This approach can also be used to analyze ethion and its degradation products in the concentration range from 0 to 330 ng mL(-1) by measuring the relative inhibition percentage of BuChE. From different ethion degradation products, inhibition by dioxon and monooxon were more potent than the parent pesticide. The proposed method was applied for determination of ethion in different samples with good accuracy and precision. The relative simple fabrication protocol of biosensor, high sensitivity and stability represents a promising approach for determination of environmental pollutants in field conditions. PMID- 24401443 TI - Pollen Raman spectra database: application to the identification of airborne pollen. AB - Raman microspectroscopy allows a non-destructive identification of airborne particles. However, the identification of particles such as pollen is hindered by the absence of a spectral library. Although reference spectra of pollen have been published before, they have always been limited to a certain number of species. In this work, Raman spectra of 34 pollen types are presented and were used to build a pollen spectra primary library. Afterward, the applicability of this database for detecting and identifying pollen in airborne samples was tested. Airborne pollen samples collected during April, May and August were compared with blank pollen spectra by means of Hit Quality Index. Although a much larger library would be required, our results showed that all first hits correspond to the same blank pollen species of the questioned sample from the air. This possibility is an innovative idea and a promising line of investigation for future RAMAN technology development in the area of aerobiology. PMID- 24401444 TI - Preparation of a novel porous poly (trimethylol propane triacrylate-co-ethylene dimethacrylate) monolithic column for highly efficient HPLC separations of small molecules. AB - A novel poly (trimethylol propane triacrylate-co-ethylene dimethacrylate) [poly (TMPTA-co-EDMA)] monolith was prepared by in situ free-radical polymerization in a 50 mm * 4.6mm i.d. stainless steel column and was investigated for high performance liquid chromatography (HPLC). The porous structure of monolith was optimized by changing the conditions of polymerization. The chemical group of the monolithic column was confirmed by a Fourier transform infrared spectroscopy (FT IR) method and the morphology of column structure was characterized by scanning electron microscopy (SEM). The mechanical strength and permeability were also studied. Finally, a series of low-molecular-weight organic compounds were utilized to evaluate the retention behaviors of the monolithic column. The result demonstrated that the prepared column exhibited an RP-chromatographic behavior and good separation performance. The method reproducibility was obtained by evaluating the run-to-run and column-to-column with relative standard deviations (RSDs) less than 0.7% (n=6) and 2.9% (n=6), respectively, which indicated that prepared monolithic columns had good reproducibility and stability. PMID- 24401445 TI - Hybrid organic-inorganic monolithic enzymatic reactor with SBA-15 nanoparticles incorporated. AB - A novel enzymatic reactor was prepared by incorporating SBA-15 nanoparticles into hybrid organic-inorganic monolith and immobilizing trypsin with glutaraldehyde as bridging reagent. Preparation and operation conditions including nanoparticles percentage and residence time were optimized to improve the digestion efficiency. The digestion products were characterized by Matrix Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS) with sequence coverage of 50%, 93% and 71% for bovine serum albumin, myoglobin and cytochrome C, while consuming only about 19s in dynamic mode. Compared with enzymatic reactor without nanoparticles incorporated, the enzymatic reactor with SBA-15 nanoparticles embedded achieved higher digestion efficiency by introducing more trypsin, which was originated from combination of SBA-15 nanoparticles and hybrid organic inorganic monolith. PMID- 24401446 TI - Surface plasmon resonance immunoassay for the detection of the TNFalpha biomarker in human serum. AB - A simple method for the detection of TNF-alpha protein biomarker in human serum with great sensitivity has been developed using a surface plasmon resonance biosensor. Signal amplification based on a sandwich immunoassay including gold nanoparticles was used. Detection in serum proved to be challenging due to high undesirable non-specific binding to the sensor surface stemming from the matrix nature of the sample. After optimization of the assay parameters and, in the case of serum, of a sample dilution buffer to minimize the non-specific binding, very low limits of detection were achieved: 11.6 pg/mL (211 fM) and 54.4 pg/mL (989 fM) for spiked buffer and human serum respectively. The amplification steps with high affinity biotinylated antibodies and streptavidin-fuctionalized nanoparticles greatly enhanced the signal with the advantage of additional specificity. Due to its simplicity and sensitivity, the immunoassay has proved feasible to be used for detection of low concentration biomarkers in real samples. PMID- 24401447 TI - A solid phase microextraction fiber coated with graphene-poly(ethylene glycol) composite for the extraction of volatile aromatic compounds from water samples. AB - Poly(ethylene glycol)-grafted graphene (PEG-g-G) was prepared and used as the solid phase microextraction (SPME) fiber coating for the extraction of seven volatile aromatic compounds (VACs) from water samples followed by the determination with gas chromatography-flame ionization detection. The PEG-g-G coating was characterized by both the thermal gravimetric analysis and scanning electron microscopy. The results verified that the PEG was successfully grafted onto the surface of graphene and the coating had a highly porous structure. Several important experimental parameters that could influence the SPME efficiency were investigated and optimized. Under the optimized conditions, the limits of detection were in the range from 1.0 to 6.0 ng L(-1). The relative standard deviations for intraday and interday variations were in the range of 1.8 5.8% and 5.1-8.3%, and for fiber-to-fiber variations, were between 6.5 and 11.9%, respectively. The results indicated that the PEG-g-G fiber had the advantages of high extraction efficiency and good thermal stability and durability. It can be reused more than 200 times without a significant loss of extraction efficiency. The method was successfully applied to the analysis of seven VACs in tap, river and mineral water samples. PMID- 24401448 TI - Ionic liquid-based extraction followed by graphite-furnace atomic absorption spectrometry for the determination of trace heavy metals in high-purity iron metal. AB - The analysis of high-purity materials for trace impurities is an important and challenging task. The present paper describes a facile and sensitive method for the determination of trace heavy metals in high-purity iron metal. Trace heavy metals in an iron sample solution were rapidly and selectively preconcentrated by the extraction into a tiny volume of an ionic liquid [1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide] for the determination by graphite-furnace atomic absorption spectrometry (GFAAS). A nitrogen-donating neutral ligand, 2,4,6 tris(2-pyridyl)-1,3,5-triazine (TPTZ), was found to be effective in the ionic liquid-based selective extraction, allowing the nearly complete (~99.8%) elimination of the iron matrix. The combination with the optimized GFAAS was successful. The detectability reached sub-MUg g(-1) levels in iron metal. The novel use of TPTZ in ionic liquid-based extraction followed by GFAAS was successfully applied to the determination of traces of Co, Ni, Cu, Cd, and Pb in certified reference materials for high-purity iron metal. PMID- 24401449 TI - Electrochemical oxidation and electroanalytical determination of xylitol at a boron-doped diamond electrode. AB - Xylitol is a reduced sugar with anticariogenic properties used by insulin dependent diabetics, and which has attracted great attention of the pharmaceutical, cosmetics, food and dental industries. The detection of xylitol in different matrices is generally based on separation techniques. Alternatively, in this paper, the application of a boron-doped diamond (BDD) electrode allied to differing voltammetric techniques is presented to study the electrochemical behavior of xylitol, and to develop an analytical methodology for its determination in mouthwash. Xylitol undergoes two oxidation steps in an irreversible diffusion-controlled process (D=5.05 * 10(-5)cm(2)s(-1)). Differential pulse voltammetry studies revealed that the oxidation mechanism for peaks P1 (3.4 <= pH <= 8.0), and P2 (6.0 <= pH <= 9.0) involves transfer of 1H(+)/1e(-), and 1e(-) alone, respectively. The oxidation process P1 is mediated by the (*)OH generated at the BDD hydrogen-terminated surface. The maximum peak current was obtained at a pH of 7.0, and the electroanalytical method developed, (employing square wave voltammetry) yielded low detection (1.3 * 10(-6) mol L( 1)), and quantification (4.5 * 10(-6) mol L(-1)) limits, associated with good levels of repeatability (4.7%), and reproducibility (5.3%); thus demonstrating the viability of the methodology for detection of xylitol in biological samples containing low concentrations. PMID- 24401450 TI - Ultrafast coating procedure for graphene on solid-phase microextraction fibers. AB - Graphene's unsurpassed specific surface area (up to 2630 m(2)/g) makes it be an ideal absorbent. To promote its use as a sorption coating in solid phase microextraction, an ultrafast method was established, able to coat a stable layer of graphene on a metal fiber in only 23s, with adjustable coating thickness between 10 and 40 um by using sleeve barrels. The core idea includes: (1) use of semi-polymerized dimethylsiloxane as a sticky pre-liner to glue graphene and (2) rapid conversion from pre-liner to elastic polydimethylsiloxane (PDMS) to fix the glued graphene. Ultrafast conversion of the pre-liner to PDMS was achieved by direct heating of the metallic fibers. The method produced very stable and durable fibers, capable of being used for at least 120 extractions-desorption cycles and stored at room temperature for at least 20 months. Interestingly, the new method could always coat a layer of mossy graphene on the fibers to largely increase their extraction capacity. Their limit of detection reached 2 pg/L PAHs, being about 3 orders of magnitude better than that of the reported graphene-based fibers. They were applicable to the direct extraction of trace PAHs in beverages, with a linear regression range from 10 to 1000 pg/L, and recoveries of 88.9 105.3%. The relative standard deviations of peak area were 2.9-8.9% for the same fiber and 3.0-10.0% for different fibers. The method is also suitable for re coating a used fiber and extendable to fast coating other solid sorbents on heat resistant supports. PMID- 24401451 TI - Fuzzy clustering evaluation of the discrimination power of UV-Vis and (+/-) ESI MS detection system in individual or coupled RPLC for characterization of Ginkgo Biloba standardized extracts. AB - AIM: Discrimination power evaluation of UV-Vis and (+/-) electrospray ionization/mass spectrometric techniques, (ESI-MS) individually considered or coupled as detectors to reversed phase liquid chromatography (RPLC) in the characterization of Ginkgo Biloba standardized extracts, is used in herbal medicines and/or dietary supplements with the help of Fuzzy hierarchical clustering (FHC). EXPERIMENTAL: Seventeen batches of Ginkgo Biloba commercially available standardized extracts from seven manufacturers were measured during experiments. All extracts were within the criteria of the official monograph dedicated to dried refined and quantified Ginkgo extracts, in the European Pharmacopoeia. UV-Vis and (+/-) ESI-MS spectra of the bulk standardized extracts in methanol were acquired. Additionally, an RPLC separation based on a simple gradient elution profile was applied to the standardized extracts. Detection was made through monitoring UV absorption at 220 nm wavelength or the total ion current (TIC) produced through (+/-) ESI-MS analysis. FHC was applied to raw, centered and scaled data sets, for evaluating the discrimination power of the method with respect to the origins of the extracts and to the batch to batch variability. RESULTS: The discrimination power increases with the increase of the intrinsic selectivity of the spectral technique being used: UV-Vis0.99) and repeatibilty (1-25%) for all the compounds under study. The accuracy of the method measured as the average percentage recovery of the compounds in spiked surface and marine waters was higher than 70% for all compounds studied. Finally, the optimized methodology was applied to real aqueous samples enabled the simultaneous determination of all compounds under study in surface and marine water samples obtained from Valencia region (Spain). PMID- 24401455 TI - Chemometrics-assisted simultaneous voltammetric determination of ascorbic acid, uric acid, dopamine and nitrite: application of non-bilinear voltammetric data for exploiting first-order advantage. AB - For the first time, several multivariate calibration (MVC) models including partial least squares-1 (PLS-1), continuum power regression (CPR), multiple linear regression-successive projections algorithm (MLR-SPA), robust continuum regression (RCR), partial robust M-regression (PRM), polynomial-PLS (PLY-PLS), spline-PLS (SPL-PLS), radial basis function-PLS (RBF-PLS), least squares-support vector machines (LS-SVM), wavelet transform-artificial neural network (WT-ANN), discrete wavelet transform-ANN (DWT-ANN), and back propagation-ANN (BP-ANN) have been constructed on the basis of non-bilinear first order square wave voltammetric (SWV) data for the simultaneous determination of ascorbic acid (AA), uric acid (UA), dopamine (DP) and nitrite (NT) at a glassy carbon electrode (GCE) to identify which technique offers the best predictions. The compositions of the calibration mixtures were selected according to a simplex lattice design (SLD) and validated with an external set of analytes' mixtures. An asymmetric least squares splines regression (AsLSSR) algorithm was applied for correcting the baselines. A correlation optimized warping (COW) algorithm was used to data alignment and lack of bilinearity was tackled by potential shift correction. The effects of several pre-processing techniques such as genetic algorithm (GA), orthogonal signal correction (OSC), mean centering (MC), robust median centering (RMC), wavelet denoising (WD), and Savitsky-Golay smoothing (SGS) on the predictive ability of the mentioned MVC models were examined. The best preprocessing technique was found for each model. According to the results obtained, the RBF-PLS was recommended to simultaneously assay the concentrations of AA, UA, DP and NT in human serum samples. PMID- 24401456 TI - Quantum dots-based ratiometric fluorescence probe for mercuric ions in biological fluids. AB - Fluorescence analysis by means of a single fluorescence signal output usually leads to the signal fluctuation caused by various external factors. Ratiometric fluorescence probes that can significantly eliminate the external effects by self calibration of two different emission bands are preferable for the detection of real samples. In this work, we designed a dual-emission quantum dots (QDs) nanocomposite as a ratiometric probe for the visual detection of Hg(2+). The dual emission QDs nanocomposite consists of two differently sized CdTe/CdS QDs. The red-emitting larger sized CdTe/CdS QDs embeded in silica nanoparticles are insensitive to Hg(2+), while the green-emitting smaller sized ones are covalently conjugated onto the silica nanoparticles surface and sensitive to Hg(2+). The addition of Hg(2+) can only quench green fluorescence in the dual-emission QDs nanocomposites, which triggers the change of fluorescence intensity ratio of two different emission wavelengths and hence induces the evolution of fluorescence color of the probe solution with variation of Hg(2+) concentration. Based on this feature, the dual-emission QDs nanocomposites can be used to develop a ratiometric fluorescence probe for the visual detection of Hg(2+). Under the optimized conditions, the ratiometric fluorescence QDs probe shows a linear relationship between fluorescence intensity ratio and Hg(2+) concentration in the range of 5-300 nM. The detection limit of this probe was found to be 3.1 nM. This ratiometric assay also exhibits a high selectivity and it has been successfully used in the determination of Hg(2+) content in fetal bovine serum and human urine. PMID- 24401457 TI - Optimizing separation conditions of 19 polycyclic aromatic hydrocarbons by cyclodextrin-modified capillary electrophoresis and applications to edible oils. AB - For the first time, the separation of 19 polycyclic aromatic hydrocarbons (PAHs) listed as priority pollutants in environmental and food samples by the United States Environmental Protection Agency (US-EPA) and the European Food Safety Authority was developed in cyclodextrin (CD)-modified capillary zone electrophoresis with laser-induced fluorescence detection (excitation wavelength: 325 nm). The use of a dual CD system, involving a mixture of one neutral CD and one anionic CD, enabled to reach unique selectivity. As solutes were separated based on their differential partitioning between the two CDs, the CD relative concentrations were investigated to optimize selectivity. Separation of 19 PAHs with enhanced resolutions as compared with previous studies on the 16 US-EPA PAHs and efficiencies superior to 1.5 * 10(5) were achieved in 15 min using 10mM sulfobutyl ether-beta-CD and 20mM methyl-beta-CD. The use of an internal standard (umbelliferone) with appropriate electrolyte and sample compositions, rinse sequences and sample vial material resulted in a significant improvement in method repeatability. Typical RSD variations for 6 successive experiments were between 0.8% and 1.7% for peak migration times and between 1.2% and 4.9% for normalized corrected peak areas. LOQs in the low ug/L range were obtained. For the first time in capillary electrophoresis, applications to real vegetable oil extracts were successfully carried out using the separation method developed here. PMID- 24401458 TI - Quantification of animal fat biodiesel in soybean biodiesel and B20 diesel blends using near infrared spectroscopy and synergy interval support vector regression. AB - In this work, multivariate calibration based on partial least squares (PLS) and support vector regression (SVR) using the whole spectrum and variable selection by synergy interval (siPLS and siSVR) were applied to NIR spectra for the determination of animal fat biodiesel content in soybean biodiesel and B20 diesel blends. For all models, prediction errors, bias test for systematic errors and permutation test for trends in the residuals were calculated. The siSVR produced significantly lower prediction errors compared to the full spectrum methods and siPLS, with a root mean squares error (RMSEP) of 0.18%(w/w) (concentration range: 0.00%-69.00%(w/w)) in the soybean biodiesel blend and 0.10%(w/w) in the B20 diesel (concentration range: 0.00%-13.80%(w/w)). Additionally, in the models for the determination of animal fat biodiesel in blends with soybean diesel, PLS and SVR showed evidence of systematic errors, and PLS/siPLS presented trends in residuals based on the permutation test. For the B20 diesel, PLS presented evidence of systematic errors, and siPLS presented trends in the residuals. PMID- 24401459 TI - Determination of plutonium isotopes (238Pu, 239Pu, 240Pu, 241Pu) in environmental samples using radiochemical separation combined with radiometric and mass spectrometric measurements. AB - This paper reports an analytical method for the determination of plutonium isotopes ((238)Pu, (239)Pu, (240)Pu, (241)Pu) in environmental samples using anion exchange chromatography in combination with extraction chromatography for chemical separation of Pu. Both radiometric methods (liquid scintillation counting and alpha spectrometry) and inductively coupled plasma mass spectrometry (ICP-MS) were applied for the measurement of plutonium isotopes. The decontamination factors for uranium were significantly improved up to 7.5 * 10(5) for 20 g soil compared to the level reported in the literature, this is critical for the measurement of plutonium isotopes using mass spectrometric technique. Although the chemical yield of Pu in the entire procedure is about 55%, the analytical results of IAEA soil 6 and IAEA-367 in this work are in a good agreement with the values reported in the literature or reference values, revealing that the developed method for plutonium determination in environmental samples is reliable. The measurement results of (239+240)Pu by alpha spectrometry agreed very well with the sum of (239)Pu and (240)Pu measured by ICP-MS. ICP-MS can not only measure (239)Pu and (240)Pu separately but also (241)Pu. However, it is impossible to measure (238)Pu using ICP-MS in environmental samples even a decontamination factor as high as 10(6) for uranium was obtained by chemical separation. PMID- 24401460 TI - Measurement of strontium isotope ratio in nitric acid extract of peanut testa by ICP-Q-MS after removal of Rb by extraction with pure water. AB - The difference in the distributions of Sr and Rb in peanut seeds was utilized to develop a precise method for Sr isotope ratio measurement by inductively coupled plasma quadruple mass spectrometry (ICP-Q-MS). The testa instead of the whole peanut seed was selected as the sample because apparent enrichment of Sr in comparison to Rb was found in the testa. Furthermore, Rb in the testa was removed by pure water extraction with the aid of sonication to remove the isobaric interference in Sr isotope ratio measurement. The testa taken from one peanut seed was treated as one sample for the analysis. After optimization of the operating conditions, pure water (10 mL for each sample) extraction in 30 min with sonication was able to remove over 95% of Rb in the testa, while after the Rb removal Sr could be completely extracted using 10 mL of 0.3 mol L(-1) HNO3 for each sample. The integration time in ICP-Q-MS measurement was optimized to achieve a lower measurement uncertainty in a shorter time; the results showed that 1s was required and enough for the precise measurement of Sr isotope ratios giving a relative standard uncertainty (n=10) of ca. 0.1%. The present method was applied to peanut seeds grown in Japan, China, USA, India, and South Africa. PMID- 24401461 TI - Highly sensitive and selective determination of cupric ions by using N,N' bis(salicylidene)-o-phenylenediamine as fluorescent chemosensor and related applications. AB - A sensitive and selective copper(II) fluorescence Schiff base chemical sensor receptor 1 (short for N,N'-bis(salicylidene)-o-phenylenediamine) has been prepared. The fluorescence of receptor 1 in pH 8.2 phosphate buffer solution can be dramatically quenched by Cu(2+), whereas it is nearly unaffected by other metal ions. Based on this, a sensitive and selective fluorescent quenching method for Cu(2+) detection has been established. Under the optimum conditions, a good linear relation exists between the quenching efficiency (F0/F) and the concentration of Cu(2+) in the range of 1.0 * 10(-7)-2.5 * 10(-6) mol L(-1). The detection limit (3sigma) for Cu(2+) determination is 2.0 * 10(-8) mol L(-1). The present method has been successfully used for quantification of Cu(2+) in soybean milk powder. Furthermore, the fluorescence switch property of the system was explored, and the system might be applied for determination of glutathione and construction of molecular logic gate. PMID- 24401462 TI - A novel nanoporous film electrode based on electrochemical polymerization of ionic liquid and its application in sensitive determination of magnolol. AB - A polymeric film modified glassy carbon electrode was electrochemically fabricated with potential step technique using 1-butyl-3-[3-(N-pyrrole)propyl] imidazolium tetrafluoroborate ionic liquid as a monomer. Followed by being treated with sodium dodecyl sulfonate solution, a hydrophobic film bearing poly{1 butyl-3-[3-(N-pyrrolyl)propyl]imidazolium dodecyl sulfonate} moiety was modified onto electrode surface. The substitution was confirmed by X-ray photoelectron spectroscopy. The morphology of the polymeric film electrode surface was characterized with scanning electron microscopy. Electrochemical behaviors of magnolol at the hydrophobic polymeric film electrode were systematically investigated with voltammetry. Compared with the unmodified glassy carbon electrode, the oxidation peak shift slightly towards positive potential and the oxidation peak current significantly increased. Under optimal conditions, the oxidation peak current was linearly related to the magnolol concentration in the range of 1.0 * 10(-8) to 1.0 * 10(-6) mol L(-1) and 1.0 * 10(-6) to 5.0 * 10(-5) mol L(-1). The detection limit was estimated to be 4.55 * 10(-9) mol L(-1) (S/N=3). The polymerized ionic liquid film electrode was successfully used to analysis magnolol in M. officinalis. The result was consistent with that obtained by high performance liquid chromatography. PMID- 24401463 TI - Determination of trace heavy metals in environmental and biological samples by solution cathode glow discharge-atomic emission spectrometry and addition of ionic surfactants for improved sensitivity. AB - Solution cathode glow discharge-atomic emission spectrometry (SCGD-AES) was evaluated for its ability to determine toxic heavy metals, including cadmium (Cd), mercury (Hg), lead (Pb), and chromium (Cr), in environmental and biological samples. A significant enhancement in heavy metal signal was observed by addition of a small amount of cetyltrimethylammoniumchloride (CTAC, C16H33 (CH3)3NCl) to the samples. The net intensity of atomic emission lines of Cd, Hg, Pb, and Cr increased by 2.1-, 4.8-, 6.6-, and 2.6-fold, respectively, after addition of 0.15% CTAC to the test solutions. The effects of ionic surfactants (CTAC) compared with non-ionic surfactants, e.g., Triton x-45 and Triton x-100, on the sensitivity of Cd, Hg, Pb, and Cr were also investigated in the present study. The enhancement effect is in the order Triton x-45=3) and mortality. RESULTS: There were a total of 363 ICHs (overall rate 32.3%; HI=267, 24%; PH=96, 8.5%) among the 1122 study patients (mean age 67+/-15 years; median National Institutes of Health Stroke Scale score 17 (IQR 13-20)). Independent predictors for HI included diabetes mellitus (OR 2.27, 95% CI (1.58 to 3.26), p<0.0001), preprocedure IV tissue plasminogen activator (tPA) (1.43 (1.03 to 2.08), p<0.037), Merci thrombectomy (1.47 (1.02 to 2.12), p<0.032), and longer time to puncture (1.001 (1.00 to 1.002), p<0.026). Patients with atrial fibrillation (1.61 (1.01 to 2.55), p<0.045) had a higher risk of PH while the use of IA tPA (0.57 (0.35 to 0.90), p<0.008) was associated with lower chances of PH. Both the presence of HI (2.23 (1.53 to 3.25), p<0.0001) and PH (6.24 (3.06 to 12.75), p<0.0001) were associated with poor functional outcomes; however, only PH was associated with higher mortality (3.53 (2.19 to 5.68), p<0.0001). CONCLUSIONS: Greater understanding about the predictors and consequences of ICH post endovascular stroke therapy is essential to improve risk assessment, patient selection/clinical outcomes, and early prognostication. Our data suggest that patients with atrial fibrillation are particularly prone to severe ICH and question the 'benign' nature of HI suggested by earlier studies. PMID- 24401480 TI - Prediction of gestational diabetes early in pregnancy: targeting the long-term complications. AB - Gestational diabetes (GD), defined as carbohydrate intolerance with onset or first recognition during pregnancy, has a prevalence of 7% and is a growing problem worldwide. Infants born to mothers with GD are more likely to be large for gestational age, incur traumatic birth injury, require a stay in the intensive care unit and develop postnatal metabolic disturbances. As the worldwide epidemic of obesity worsens, more women are entering pregnancy with metabolic alterations and preexisting insulin resistance, which is heightened by the hormonal milieu of pregnancy. The Hyperglycemia Adverse Pregnancy Outcome (HAPO) study has clearly shown that GD-related complications correlate with glycemic control. We will review the current understanding of the physiology of GD and the screening and treatment guidelines that are commonly utilized in clinical care. In addition, we will discuss the need for development of multiparametric models combining maternal clinical risk factors and biomarkers early in pregnancy to better stratify and predict risk of GD-related complications and offer targeted intervention. PMID- 24401481 TI - Trabeculectomy using mitomycin C versus an atelocollagen implant: clinical results of a randomized trial and histopathologic findings. AB - PURPOSE: To assess the efficacy of trabeculectomy with a biodegradable OlogenTM implant (OLO) versus mitomycin C (MMC) in patients in a prospective randomized clinical trial. METHODS: In the MMC group (15 patients), trabeculectomy was performed according to standard protocols. In the OLO group (15 patients) after standard trabeculectomy, the implant was positioned on top of the scleral flap, and no MMC was applied. RESULTS: Mean preoperative intraocular pressure (IOP) levels (OLO: 28.0 +/- 9.4; MMC: 23.9 +/- 5.0 mm Hg; p = 0.21) and medication score (OLO: 3.4 +/- 1.6; MMC: 3.6 +/- 1.5; p = 0.56) were comparable in both groups. One year after surgery, the mean IOP was 15.9 +/- 4.5 mm Hg in the OLO group (p < 0.01, 43% reduction) and 11.0 +/- 2.6 mm Hg in the MMC group (p < 0.01, 54% reduction). The surgical success rate 12 months after surgery was 93.3% in the MMC group and 40% in the OLO group (p = 0.01). CONCLUSIONS: With the atelocollagen-glycosaminoglycan matrix OLO it was not possible to reach the surgical success rate and pressure reduction achieved in the MMC group. PMID- 24401482 TI - TTSS2-deficient hha mutant of Salmonella Typhimurium exhibits significant systemic attenuation in immunocompromised hosts. AB - Non-typhoidal Salmonella (NTS) infections are emerging as leading problem worldwide and the variations in host immune status append to the concern of NTS. Salmonella enterica serovar Typhimurium is one of the causative agents of NTS infections and has been extensively studied. The inactivation of Salmonella pathogenicity island 2 (SPI2) encoded type-III secretion system 2 (TTSS2) has been reported rendering the strain incapable for systemic dissemination to host sites and has also been proposed as live-attenuated vaccine. However, infections from TTSS2-deficient Salmonella have also been reported. In this study, mutant strain MT15 was developed by inactivation of the hemolysin expression modulating protein (hha) in TTSS2-deficient S. Typhimurium background. The MT15 strain showed significant level of attenuation in immune-deprived murine colitis model when tested in iNos(-/-), IL10(-/-), and CD40L(-/-) mice groups in C57BL/6 background. Further, the mutation in hha does not implicate any defect in bacterial colonization to the host gut. The long-term infection of developed mutant strain conferred protective immune responses to suitably immunized streptomycin pre-treated C57BL/6 mice. The immunization enhanced the CD4(+) and CD8(+) cell types involved in bacterial clearance. The serum IgG and luminal secretory IgA (sIgA) was also found to be elevated after the due course of infection. Additionally, the immunized C57BL/6 mice were protected from the subsequent lethal infection of Salmonella Typhimurium. Collectively, these findings implicate the involvement of hemolysin expression modulating protein (Hha) in establishment of bacterial infection. In light of the observed attenuation of the developed mutant strain, this study proposes the possible significance of SPI2-deficient hha mutant as an alternative live-attenuated vaccine strain for use against lethal Salmonella infections. PMID- 24401483 TI - Conference report: community health centers and vulnerable workers. AB - A one-day conference in Washington brought together leaders of community health centers and worker advocates to discuss collaboration. They agreed that health centers could help protect vulnerable workers. They agreed on use of electronic medical records; access to workers compensation; Medical-Legal Partnerships; better understanding of work settings in their communities; and educating clinicians on work and jobs. PMID- 24401484 TI - Editorial input for the right price: tobacco industry support for a sheet metal indoor air quality manual. AB - Following legal action in the 1990s, internal tobacco industry documents became public, allowing unprecedented insight into the industry's relationships with outside organizations. During the 1980s and 1990s, the National Energy Management Institute (NEMI), established by the Sheet Metal Workers International Association and the Sheet Metal and Air Conditioning Contractors' National Association, (SMACNA) received tobacco industry funding to establish an indoor air quality services program. But the arrangement also required NEMI to serve as an advocate for industry efforts to defeat indoor smoking bans by arguing that ventilation was a more appropriate solution to environmental tobacco smoke. Drawing on tobacco industry documents, this paper describes a striking example of the ethical compromises that accompanied NEMI's collaboration with the tobacco industry, highlighting the solicitation of tobacco industry financial support for a SMACNA indoor air quality manual in exchange for sanitizing references to the health impact of environmental tobacco smoke prior to publication. PMID- 24401485 TI - Training for an effective health and safety committee in a small business setting. AB - Health and safety committees are often heralded as a key element of successful health and safety programs, and are thought to represent a means of engaging workers in health and safety efforts. While the understanding of the factors that make these committees effective is growing, there are few resources for how to assist committees in developing these characteristics. This paper describes one approach to creating and implementing a training intervention aimed at improving health and safety committee function at one multilingual worksite. Short-term impacts were evaluated via questionnaire and qualitative observations of committee function. Results indicated high satisfaction with the training as well as modest increases in participation, cooperation, role clarity, and comfort with health and safety skills among committee members. The committee also made considerable achievements in establishing new processes for effective function. Similar interventions may be useful in other workplaces to increase health and safety committee success. PMID- 24401486 TI - Occupational health profile of Brazilian immigrant housecleaners in Massachusetts. AB - The occupational health and safety conditions of a sample of Brazilian housecleaners in Massachusetts are examined in this article. We administered a main survey to a convenience sample of 626 Brazilian immigrant workers of all trades and a supplemental survey to 163 Brazilian housecleaners in Massachusetts in 2005 and 2006. Survey questions addressed housecleaner demographics, socioeconomic status, working conditions, and hazards of housecleaning work. Housecleaners are exposed to a variety of ergonomic, chemical, and biological hazards. Professional housecleaners' work is fast-paced, requires awkward postures, and involves repetitive movements, use of force, and heavy lifting. The most common symptoms reported include back pain, and pain in the muscles, arms, legs, neck, shoulder, hands, fingers, and feet. To reduce exposures to occupational hazards, we propose the substitution of green cleaners for toxic chemical cleaning products, the use of ergonomic equipment, the use of personal protective equipment, and changes in work organization. PMID- 24401487 TI - Climate and environmental change drives Ixodes ricinus geographical expansion at the northern range margin. AB - BACKGROUND: Global environmental change is causing spatial and temporal shifts in the distribution of species and the associated diseases of humans, domesticated animals and wildlife. In the on-going debate on the influence of climate change on vectors and vector-borne diseases, there is a lack of a comprehensive interdisciplinary multi-factorial approach utilizing high quality spatial and temporal data. METHODS: We explored biotic and abiotic factors associated with the latitudinal and altitudinal shifts in the distribution of Ixodes ricinus observed during the last three decades in Norway using antibodies against Anaplasma phagocytophilum in sheep as indicators for tick presence. Samples obtained from 2963 sheep from 90 farms in 3 ecologically different districts during 1978 - 2008 were analysed. We modelled the presence of antibodies against A. phagocytophilum to climatic-, environmental and demographic variables, and abundance of wild cervids and domestic animals, using mixed effect logistic regressions. RESULTS: Significant predictors were large diurnal fluctuations in ground surface temperature, spring precipitation, duration of snow cover, abundance of red deer and farm animals and bush encroachment/ecotones. The length of the growth season, mean temperature and the abundance of roe deer were not significant in the model. CONCLUSIONS: Our results highlight the need to consider climatic variables year-round to disentangle important seasonal variation, climatic threshold changes, climate variability and to consider the broader environmental change, including abiotic and biotic factors. The results offer novel insight in how tick and tick-borne disease distribution might be modified by future climate and environmental change. PMID- 24401488 TI - The immunogenicity and protection effect of the BPL-inactivated CA16 vaccine in different animal systems. AB - We evaluated the effect of a beta-propiolactone (BPL)-inactivated coxsackievirus A16 (CA16) vaccine, using three immunogenicity evaluation and two animal challenge systems. A CA16 virus strain, named 419, was used as the production strain. Another CA16 strain, named 1131, was isolated and used as the challenge strain in intracerebral inoculation of neonatal mice for the calculation of median lethal dose (LD 50). In the passive and maternal antibody-protection challenge systems, all results indicated that the vaccine could protect mouse pups from lethal challenge with the CA16 virus. In the immunogenicity systems, three types of animal (mouse, rat, and cynomolgus monkey), were immunized with the 419/CA16 vaccine. The dose-effect relationship and the antibody-generation routine were described. The CA16 vaccine induced a more potent serum antibody effect in rat than in mouse. The serum antibody titer was detectable more than 63 days after the initial vaccination. We also identified tools to evaluate the effect of the BPL-inactivated CA16 vaccine. PMID- 24401489 TI - MR-guidance--a clinical study to evaluate a shuttle- based MR-linac connection to provide MR-guided radiotherapy. AB - BACKGROUND: The purpose of this clinical study is to investigate the clinical feasibility and safety of a shuttle-based MR-linac connection to provide MR guided radiotherapy. METHODS/DESIGN: A total of 40 patients with an indication for a neoadjuvant, adjuvant or definitive radiation treatment will be recruited including tumors of the head and neck region, thorax, upper gastrointestinal tract and pelvic region. All study patients will receive standard therapy, i.e. highly conformal radiation techniques like CT-guided intensity-modulated radiotherapy (IMRT) with or without concomitant chemotherapy or other antitumor medication, and additionally daily short MR scans in treatment position with the same immobilisation equipment used for irradiation for position verification and imaging of the anatomical and functional changes during the course of radiotherapy. For daily position control, skin marks and a stereotactic frame will be used for both imaging modalities. Patient transfer between the MR device and the linear accelerator will be performed with a shuttle system which uses an air-bearing patient platform for both procedures. The daily acquired MR and CT data sets will be digitally registrated, correlated with the planning CT and compared with each other regarding translational and rotational errors. Aim of this clinical study is to establish a shuttle-based approach for realising MR guided radiotherapy for certain clinical situations. Second objectives are to compare MR-guided radiotherapy with the gold standard of CT image guidance for quality assurance of radiotherapy, to establish an appropriate MR protocol therefore, and to assess the possibility of using MR-based image guidance not only for position verification but also for adaptive strategies in radiotherapy. DISCUSSION: Compared to CT, MRI might offer the advantage of providing IGRT without delivering an additional radiation dose to the patients and the possibility of optimisation of adaptive therapy strategies due to its superior soft tissue contrast. However, up to now, hybrid MR-linac devices are still under construction and not clinically applicable. For the near future, a shuttle-based approach would be a promising alternative for providing MR-guided radiotherapy, so that the present study was initiated to determine feasibility and safety of such an approach. Besides positioning information, daily MR data under treatment offer the possibility to assess tumor regression and functional parameters, with a potential impact not only on adaptive therapy strategies but also on early assessment of treatment response. PMID- 24401490 TI - Facilitators and barriers of adaptation to diabetes: experiences of Iranian patients. AB - BACKGROUND: Diabetes mellitus is one of the most challenging and burdensome chronic diseases of the 21st century and More than 1% of the Iranian urban population older than 20 years develops Type 2 diabetes each year. Living with diabetes mellitus has been described as a dynamic personal transitional adaptation, based on restructuring of the illness perceived experience and management of the self. Adaptation to Type 2 Diabetes mellitus is an integral part of diabetes care.This study explored the experiences of facilitators and barriers adaptation to Type 2 Diabetes by Iranian patients. METHODS: This study was conducted by using qualitative content analysis. Data were collected via in depth, semi-structured and face to face interviews with 15 patients with type2 diabetes. RESULTS: Three themes emerged from collected data, including a) individual context with Beliefs, personal background, and previous experience subthemes. b) supportive system with Family, Society and Health organizations subthemes and c) self-comparison with comparison with other diabetes and comparison with other diseases subthemes. CONCLUSIONS: Identifying and managing Facilitators and Barriers adaptation to Type 2 Diabetes mellitus are an integral part of diabetes care. This study provides a better understanding of the factors from perspective of patients and it can be utilized by health care providers to adapt their health care and education contents to better meet the needs of people with diabetes. PMID- 24401492 TI - Small bowel obstruction secondary to multiple lesions of primary lymphoma. PMID- 24401493 TI - Robert Liston, M.D. (October 28, 1794-December 7, 1847): the fastest knife in the West End. PMID- 24401494 TI - Treatment of a lymphocutaneous fistula with glue. PMID- 24401495 TI - Biological mesh in contaminated fields--overuse without data: a systematic review of their use in abdominal wall reconstruction. AB - Ventral hernia repair in contaminated fields is a significant problem for surgeons. We performed a systematic review regarding the use of biological mesh in contaminated fields for abdominal wall reconstruction. The primary end points were recurrence and infection of the hernia repair. An independent search of scientific papers in the English language was performed by three reviewers. Articles were chosen based on reference to ventral hernias, their use in infected fields, and in human subjects. Papers were scored using the Methodological Index for Non-Randomized Studies and those with a score of 8 or more were combined to evaluate the end points. A total of 16 studies from six different mesh products met our criteria. These papers comprised 554 patients with an overall infection rate of 24 per cent and a recurrence rate of 20 per cent. The largest study used 116 patients. All papers were case series. Overall the data for use of biological mesh products in contaminated fields are limited. Further controlled studies are needed to address this important and clinically relevant question. Caution should be used when using biological mesh products in infected fields because there is a paucity of controlled data and none have U.S. Food and Drug Administration approval for use in infected fields. PMID- 24401496 TI - Duodenal stenosis after injury of a pancreaticoduodenal artery caused by blunt abdominal trauma. PMID- 24401497 TI - Dr. Seishu Hanaoka (1760-1835): surgeon, pharmacist, and anesthesiologist. PMID- 24401498 TI - Prehospital intubation does not decrease complications in the penetrating trauma patient. AB - Intubation in the prehospital setting does not result in a survival benefit in penetrating trauma. However, the effect of prehospital intubation (PHI) on the development of in-hospital complications has yet to be determined. The goal of this study was to determine if PHI in patients with penetrating trauma results in reduced mortality and in-hospital complications. Patient records for all Category 1 trauma activations as a result of penetrating injury admitted to our institution from 2006 to 2010 were reviewed. There were 1615 Category 1 trauma activations with 152 (9.8%) intubated in the field. A total of 1311 survived initial resuscitative efforts to permit hospital admission with 55 (4.2%) being intubated in the field. For patients surviving to admission, prehospital intubation was associated with increased mortality (hazard ratio, 8.266; 95% confidence interval [CI, 4.336 to 15.758; P < 0.001). After correcting for Injury Severity Score, PHI was not protective against pulmonary complications (odds ratio [OR], 0.724; 95% CI, 0.229 to 2.289; P = 0.582), deep vein thrombosis/pulmonary embolus (OR, 0.838; 95% CI, 0.281 to 2.494; P = 0.750), sepsis (OR, 0.572; 95% CI, 0.201 to 1.633; P = 0.297), wound infections (OR, 1.739; 95% CI, 0.630 to 4.782; P = 0.286), or complications of any kind (OR, 1.020; 95% CI, 0.480 to 2.166; P = 0.959). For victims of penetrating trauma, immediate transportation by emergency medical personnel may result in improved outcomes. PMID- 24401499 TI - Bacteroides tectum causing perineal and groin soft tissue infection in a diabetic patient exposed to dogs. PMID- 24401500 TI - Symptomatic gallbladder agenesis: never again unnecessary cholecystectomy. PMID- 24401501 TI - Simultaneous gastric and colonic erosion of gastric band. PMID- 24401502 TI - Step-by-step vascular control for extracapsular resection of complex giant liver hemangioma involving the inferior vena cava. AB - Massive hemorrhage remains an important clinical problem in extracapsular resection of giant liver hemangiomas (GLHs), especially for those involving the proximal hepatic veins and/or inferior vena cava. Between July 2004 and March 2012, 87 patients with a complex GLH scheduled for surgical treatment were included in this study. All patients were underwent vascular preparation (Step 1), advanced hepatic artery clamping (Step 2), and stepwise vascular occlusion (Step 3). Intraoperative blood loss, blood transfusion volume, degree of ischemia reperfusion injury, and postoperative complications were recorded. No patients required urgent vascular preparation to manage intraoperative bleeding. In total, 87, 64, and 21 patients had portal triad (PT), infrahepatic inferior vena cava (IVC), and suprahepatic IVC preparation; and 17, 43, and 11 patients had PT, PT and suprahepatic IVC, and all three (PT, infra-, and suprahepatic IVC) occlusions. The PT, infrahepatic IVC, and SIVC occlusion times were 12.1 +/- 3.7 minutes, 7.9 +/- 2.4 minutes, and 3.2 +/- 1.4 minutes, respectively. Mean blood loss was 291.9 +/- 124.5 mL, and only four patients received blood transfusions. No patients had life-threatening complications or died (Clavien-Dindo Grade 4, 5). Compared with paralleled studies, this technique has an advantage to decrease the blood loss in less liver ischemia time. For complex GLH resections, the described step-by-step vascular control technique was efficacious and feasible for controlling intraoperative bleeding. PMID- 24401503 TI - Does irrigation of the subdiaphragmatic region with ropivacaine reduce the incidence of right shoulder tip pain after laparoscopic cholecystectomy? A prospective randomized, double-blind, controlled study. PMID- 24401504 TI - Resolution of persistent pancreaticopleural fistula after an internal drainage procedure. PMID- 24401505 TI - Surgeon-administered conscious sedation and local anesthesia for ambulatory anorectal surgery. AB - Anorectal procedures are often performed in an outpatient setting using a variety of anesthetic techniques. One technique that has not been well studied is surgeon administered conscious sedation along with local anesthetic. The purpose of this study was to evaluate the use of this technique with emphasis on safety, efficacy, and patient satisfaction. Chart review was performed on 133 consecutive patients who had anorectal procedures at an outpatient surgery center. Additionally, 65 patients were enrolled prospectively and completed a satisfaction survey. Inclusively, charts of 198 patients who underwent outpatient anorectal surgery under conscious sedation and local anesthesia under the direction of a colorectal surgeon from 2004 through 2008 were reviewed. Parameters related to patient and procedural characteristics, safety, efficacy, and satisfaction were evaluated. Surgeon-administered sedation consisted of combined fentanyl and midazolam in 90 per cent. Eighty per cent of procedures were performed in the prone position and 23 per cent were in combination with an endoscopic procedure. Eighty-two per cent were classified as American Society of Anesthesiologists Grade 1 or 2. Transient mild hypoxemia or hypotension occurred in 4 and 3 per cent of the patients, respectively. Mean operative time was 29 minutes with a mean stay in the postanesthesia care unit of 37 minutes. There were no early major cardiac or respiratory complications. Ninety-seven per cent of the patients surveyed reported a high degree of satisfaction. Surgeon administered conscious sedation with local anesthesia was well tolerated for outpatient anorectal surgeries. Additional studies are needed to confirm the safety and efficacy of this technique. PMID- 24401506 TI - Laparoscopic endoscopic single-site surgery versus conventional laparoscopic surgery for acute appendicitis in an adult population. PMID- 24401507 TI - Same-day surgery for laparoscopic appendectomy in appendicitis: is this safe? PMID- 24401508 TI - Laparoscopic total mesorectal excision for ultralow rectal cancer with transanal intersphincteric dissection as a first step: a single-surgeon experience. AB - Laparoscopic intersphincteric resection (ISR) after neoadjuvant chemoradiation is helpful in the management of patients with low rectal cancer. With the advent of this technique, the need for performance of abdominoperineal resection seems to have decreased in patients with very low rectal tumors. The aim of the present study was to evaluate the feasibility of laparoscopic ISR preceded by transanal rectal dissection low rectal cancer. Between December 2009 and June 2011, we performed laparoscopic ISR for 30 patients with very low rectal cancer. Patients received preoperative concurrent chemoradiation (5 days a week for 5 weeks). The surgical procedure was performed 6 weeks after radiotherapy and included total mesorectal excision, ISR, transanal coloanal anastomosis with coloplasty and loop ileostomy. Clinical data of 30 patients were analyzed retrospectively. Thirty patients (21 men, nine women) had a median age of 65 years (range, 37 to 75 years), a median body weight of 67 kg (range, 43 to 96 kg), and body mass index of 24 kg/m(2) (range, 19 to 33 kg/m(2)). The distance of the tumor from the anal verge was 5 cm (range, 2 to 11 cm). The operative time was from 240 to 360 minutes, and estimated blood loss was 100 to 520 mL. There were no conversions and no postoperative mortality. This procedure is feasible and has favorable short-term results for radical treatment of very low rectal disease while preserving anal function. PMID- 24401509 TI - Intramural esophageal bronchogenic cyst with wall hemorrhage results in acute esophageal obstruction: report of two cases. PMID- 24401510 TI - Use of ultrasonography during percutaneous endoscopic gastrostomy. PMID- 24401511 TI - Surgical treatment options for rectal carcinoid cancer: local versus low radical excision. PMID- 24401512 TI - Actinomyces appendicitis: diagnostic dilemma--malignancy or infection? PMID- 24401513 TI - Clinical impact of preoperative cholangitis after biliary drainage in patients who undergo pancreaticoduodenectomy on postoperative pancreatic fistula. AB - The objective of this study was to examine whether the development of cholangitis after preoperative biliary drainage (PBD) can increase the incidence of postoperative pancreatic fistula (POPF). The study population included 185 consecutive patients who underwent pancreaticoduodenectomy from April 2006 to March 2011. All patients were divided into two groups, which consisted of a "no PBD" group (73 patients) and a PBD group (112 patients). Moreover, the PBD group was divided into a "cholangitis" group (21 patients) and a "no cholangitis" group (91 patients). Clinical background, clinical outcome, and postoperative complications were compared between groups. All patients received prophylactic antibiotics using cefmetazole until 1 or 2 days postoperatively. There was no difference between noncholangitis and non-PBD groups except the frequency of overall POPF. Clinically relevant POPF and drain infection occurred in the cholangitis group significantly more than in the noncholangitis group (P < 0.05). Univariate and multivariate analyses showed that development of preoperative cholangitis after preoperative biliary drainage and small pancreatic duct (less than 3 mm diameter) were independent risk factors for clinically relevant POPF. The frequency of clinically relevant POPF was 8 per cent (eight of 99) in patients without two risk factors, 19 per cent (15 of 80) in patients with one risk factor, and 50 per cent (three of six) in patients with both risk factors. The development of preoperative cholangitis after PBD was closely associated with the development of clinically relevant POPF under the limited use of prophylactic antibiotics. PMID- 24401514 TI - Repeat head computed tomography in anticoagulated traumatic brain injury patients: still warranted. AB - Anticoagulation agents are proven risk factors for intracranial hemorrhage (ICH) in traumatic brain injury (TBI). The aim of our study is to describe the epidemiology of prehospital coumadin, aspirin, and Plavix (CAP) patients with ICH and evaluate the use of repeat head computed tomography (CT) in this group. We performed a retrospective study from our trauma registry. All patients with intracranial hemorrhage on initial CT with prehospital CAP therapy were included. Demographics, CT scan findings, number of repeat CT scans, progressive findings, and neurosurgical intervention were abstracted. A comparison between prehospital CAP and no-CAP patients was done using chi(2) and Mann-Whitney U test. A total of 1606 patients with blunt TBI charts were reviewed of whom 508 patients had intracranial bleeding on initial CT scan and 72 were on prehospital CAP therapy. CAP patients were older (P < 0.001), had higher Injury Severity Score and head Abbreviated Injury Scores on admission (P < 0.001), were more likely to present with an abnormal neurologic examination (P = 0.004), and had higher hospital and intensive care unit lengths of stay (P < 0.005). Eighty-four per cent of patients were on antiplatelet therapy and 27 per cent were on warfarin. The CAP patients have a threefold increase in the rate of worsening repeat head CT (26 vs 9%, P < 0.05). Prehospital CAP therapy is high risk for progression of bleeding on repeat head CT. Routine repeat head CT remains an important component in this patient population and can provide useful information. PMID- 24401515 TI - Laparoscopic versus open resection for gastric gastrointestinal stromal tumors: a meta-analysis. AB - We conducted our meta-analysis to compare outcomes between laparoscopic resection and open resection for gastric gastrointestinal stromal tumors (GISTs) from all published comparative studies in the literature. Databases, including PubMed, Embase, Cochrane Library, Ovid, Web of Science, and CNKI, were searched to identify studies comparing outcomes after laparoscopic resection and open resection for gastric GISTs. The meta-analysis was performed by RevMan 5.1. Eleven comparative studies comprising 495 patients were identified. Patients undergoing laparoscopic resection of gastric GISTs were found to have similar operative time (weighted mean difference [WMD], 2.29; 95% confidence interval [CI], -16.01 to 11.43; P = 0.74) and complications rate (odds ratio [OR], 0.76; 95% CI, 0.36 to 1.58; P = 0.46). Less intraoperative blood loss (WMD, -55.91; 95% CI, -90.26 to -21.56; P = 0.001), earlier passing first flatus (WMD, -0.89, 95% CI, -1.60 to -0.18; P = 0.01), earlier having the first liquid diet (WMD, -1.54; 95% CI, -2.44 to -0.64; P = 0.0008), and shorter hospital stay (WMD, -4.25; 95% CI, -5.63 to -2.88; P < 0.00001) were observed in the laparoscopic resection group. The recurrence rate was higher in the group of open resection compared with the group of laparoscopic resection (OR, 0.26; 95% CI, 0.09 to 0.75; P = 0.01). Laparoscopic resection is safe and efficient in the treatment of patients with gastric GISTs as compared with open resection procedure. Laparoscopic resection may be a preferred treatment for gastric GISTs. PMID- 24401516 TI - Intraperitoneal tension-free repair of a small midline ventral abdominal wall hernia: randomized study with a mean follow-up of 3 years. AB - Funding received from Cousin Biotech, Wervicq Sud, France, and CR Bard Inc., Cranston, RI. The aim of this prospective randomized study was to determine the long-term recurrence and complication rates after small abdominal wall hernia repair with two different bilayer prostheses. Hernia repair using prosthetic mesh material has become the preferred method of repair, because the recurrence rates are much lower than with conventional repair techniques. The use of a hernia bilayer patch, composite expanded polytetrafluoroethylene (ePTFE)-polypropylene, with intraperitoneal placement behind the hernia defect, through a small incision, may be efficient, safe, and cost-effective. This study is a randomized, single-institution trial, including 83 selected consecutive patients with primary (umbilical, epigastric) or incisional anterior abdominal wall defects from 2 to 5 cm. Hernia repair was performed by direct local access in ambulatory surgery; the prosthesis used was a circular bilayer with an inner face in ePTFE to avoid bowel adhesion. One group was treated with a Ventralex(r) Hernia Patch (Bard USA). The second group was treated with a Cabs'Air(r) Composite (Cousin Biotech France), which was delivered with two to four fixation sutures and a balloon to properly deploy the mesh intraperitoneally. Patients' characteristics and operative and postoperative data were prospectively collected. The primary outcome was late recurrence. Secondary outcomes included, pain, discomfort and quality of life before and after (3 months) surgery using the SF-12 questionnaire, patient surgeon satisfaction, and early and late complications. Among 98 patients, 83 were included in the study protocol between January 2007 and August 2011. The two groups were comparable according to pre- and intraoperative data. According to surgeon experience, placement of the Cabs'Air(r) device was significantly faster (P = 0.01) and easier. At 3 months, there was significantly less pain and less discomfort for the Cabs'Air(r) group and patient satisfaction rate was higher. This was confirmed by all components of the SF-12 questionnaire. Long-term follow up was available for 77 patients. The mean follow-up was similar for the two groups (42 months; range, 14 to 70 months). At this point, for the Ventralex(r) group, there were four recurrences (11.7%); one mesh infection; one small bowel obstruction; and six cases (15.7%) of severe pain resulting from a mass syndrome (shrinkage) with a sense of the presence of a foreign body. Six reoperations (15.6%) were required with explant of the prosthesis. There were no recurrences or late complications in the comparative group. The Ventralex(r) Hernia Patch is associated with inconsistent deployment, spreading, or shrinkage, which account for late complications and decreases the overlap, which contributes to the recurrence rate. The Cabs'Air(r)-associated balloon facilitates superior deployment of the prosthesis allowing for good fixation with four sutures. PMID- 24401517 TI - The value of cholangiography through Jackson-Pratt drains in the management of postoperative biliary injuries. AB - Iatrogenic biliary injury is the most significant complication after laparoscopic cholecystectomy. We present our experience with an alternative diagnostic approach using transcatheter cholangiography (TCC) through a Jackson-Pratt (JP) drain and discuss potential benefits and limitations of the technique. From March 2002 to February 2012, 40 patients with major postoperative biliary injury underwent biliary reconstruction at our institution. Mean age was 51.7 +/- 18.1 years (range, 19 to 86 years) with 30 (75%) females. Seventeen (42.5%) injuries were detected intraoperatively and in 13 (32.5%) cases, JP drains were placed for biliary drainage. Lesions were classified according to Bismuth grade: I (10 patients [25%]), II (10 patients [25%]), III (six patients [15%]), IV (10 patients [25%]), and V (four patients [10%]). TCC was performed in seven patients with JP drains (53.8%). It fully defined the injury site in three cases of limited magnetic resonance cholangiopancreatography (MRCP) such as common hepatic duct and common bile duct leaks and in four cases (57.1%) that endoscopic retrograde cholangiopancreatography (ERCP) was limited as a result of clipping of the distal common bile duct. TCC showed promising results in cases of limited MRCP and ERCP such as fistulous orifices or leakage. It may represent an alternative adjunct in the diagnostic armamentarium of complex biliary injuries. PMID- 24401518 TI - Blunt assault: 'million dollar baby'. AB - Contrasting reports exist in the literature regarding the management of patients with blunt assault to the head, neck, and face and more importantly for clearing the cervical spine. The purpose of our study was to determine the risk of cervical spine injuries after blunt assault to the head, neck, and face and its association with other injuries. We performed a retrospective case review of all blunt assault trauma admissions to the head, neck, and face at our Level I trauma center. We identified all patients who were assaulted with hands and feet and blunt instruments. A total of 3286 patients with blunt assault to the head, neck, and face were identified of whom 11 (0.003%) were found to have a cervical spine fracture or cervical spine subluxation. None of the patients had a cervical spinal cord injury. The 11 patients composed our study population with a mean age of 39 +/- 7.8 years, 100 per cent were male, and the mean Injury Severity Score was 12 +/- 7.9. Five (45%) patients required surgery for stabilization of the cervical spine. Mortality was reported in only one patient who had a C7 transverse process fracture. Cervical spine injury after blunt assault is rare but does occur and encompasses significant injuries requiring surgical intervention. However, these injuries are the result of direct blows to the cervical spine and we suggest that assaulted patients with no direct trauma to the neck do not require an exhaustive evaluation of the cervical spine. PMID- 24401519 TI - Changing paradigms in acute care surgery: a shift to the hindgut. AB - In this study we sought to identify changes in the etiology and surgical treatment of acute gastrointestinal perforations in the United States over the past 20 years. We performed a retrospective review of the Nationwide Inpatient Sample from January 1, 1988, through December 31, 2007. We first identified all patients with gastrointestinal perforations, the perforated organ, and treatment rendered. During the study period, 550,132 patients experienced a gastrointestinal perforation for a mean rate of 3.9 cases per 1,000 discharges. Total number of perforations rose significantly over the study period, yet surgical procedures were performed in less than half of the patients (47.6%). The most common surgical procedures for gastrointestinal perforation were colorectal in origin (38.3%), upper gastrointestinal tract (30.0%), small intestine (29.2%), esophagus (3.0%), and anus (0.1%). At study end, colorectal procedures for perforation were the most commonly performed (40.4%), whereas upper gastrointestinal procedures experienced the greatest decline. In conclusion, our data demonstrate a decline in procedures for upper gastrointestinal perforation and an increase in colorectal procedures during the two-decade study period. These data should be used to assist in the training of acute care surgeons. PMID- 24401520 TI - Early detection of coagulation abnormalities in patients at nutritional risk: the novel role of thromboelastography. AB - It is believed that malnutrition is common among hospitalized patients and associated with increased risk of morbidity and mortality. It is unclear if it is more likely to cause coagulation disorders in patients with malnutrition. We, therefore, investigate the feasibility of using thromboelastography (TEG) in early detection of coagulation abnormalities in patients at nutritional risk. Fifty successive adult patients with gastrointestinal disease were prospectively divided into one of two groups according to nutritional risk score (less than 3 and 3 or greater). Blood samples were collected at admission for analysis of standard biochemical parameters, routine coagulation tests, and TEG parameters. A total of 62 per cent of patients (n = 31) were at nutritional risk. Serum concentrations of prealbumin, transferrin, total protein, low-density lipoprotein, high-density lipoprotein, and cholesterol were much lower in the nutritional risk group than in the no-risk group (P <= 0.05). There was no significant difference in routine coagulation tests, whereas most of the TEG parameters showed significant differences between the two groups. The overall coagulation function was worse in patients at nutritional risk than in patients with good nutritional status (P <= 0.01). TEG appears to be more sensitive for the detection of coagulation abnormalities compared with routine coagulation tests in patients at nutritional risk. The phenomenon described in this article should be useful in further studies of patients with malnutrition. PMID- 24401521 TI - Reply to 'Hospital volume, margin status, and long-term survival after pancreaticoduodenectomy for pancreatic adenocarcinoma' (Am Surg 2012;78:225-9). PMID- 24401522 TI - Effect of a dedicated acute care operating room on hospital efficiency. PMID- 24401523 TI - Frequency of bile leak after laparoscopic cholecystectomy: audit of a surgical residency program. PMID- 24401524 TI - Ileal perforation in a young female with Churg-Strauss syndrome. PMID- 24401525 TI - Can we decrease the number of trauma patients 'missing in action'? A prospective pilot intervention to improve trauma patient compliance with outpatient follow-up at an urban Level I trauma center. PMID- 24401526 TI - Not a blunt issue, but penetrating--an Israeli experience with abdominal injury in civilian multiple casualty blast incidents. PMID- 24401527 TI - Shock with intestinal ischemia: a rare complication of methamphetamine use. PMID- 24401528 TI - Preparing senior medical students for surgical internship: the value of a half day intervention. PMID- 24401529 TI - Radioembolization with Yttrium-90 microspheres (SIRT) in pancreatic cancer patients with liver metastases: efficacy, safety and prognostic factors. AB - OBJECTIVE: To analyze the clinical efficacy of (90)Y radioembolization in liver metastases from pancreatic cancer, to describe treatment toxicities and to identify biomarkers as predictors of outcome. METHODS: Data from 19 pancreatic cancer patients (9 females/10 males) who had received (90)Y radioembolization for metastatic liver disease between 06/2004 and 01/2011 were analyzed retrospectively. RESULTS: The median age at (90)Y radioembolization was 63 years (range 43-77). In 16 patients, previous palliative gemcitabine-based chemotherapy was given for metastatic disease. Objective response in the liver after (90)Y radioembolization was 47%. Median local progression-free survival in the liver was 3.4 months (range 0.9-45.0). Median overall survival (OS) was 9.0 months (range 0.9-53.0) and 1-year survival was 24%. Cox regression models for baseline biomarkers at (90)Y radioembolization revealed correlations of increased carbohydrate antigen 19-9 (p = 0.02) and C-reactive protein (p = 0.03) with shorter OS. Short-term adverse events (nausea, vomiting, fatigue, fever and abdominal pain) did not exceed grade 3. As long-term adverse events, liver abscesses, gastroduodenal ulceration, cholestasis and cholangitis, ascites and spleen infarction were observed. CONCLUSION: (90)Y radioembolization is able to induce an encouraging local response rate of liver metastases of pancreatic cancer patients. Most short-term toxicities are manageable; however, patients should be followed up carefully for severe long-term toxicities. PMID- 24401531 TI - Melatonin inhibits mTOR-dependent autophagy during liver ischemia/reperfusion. AB - BACKGROUND: Autophagy is a self-digestion system responsible for maintaining cellular homeostasis and interacts with reactive oxygen species produced during ischemia/reperfusion (I/R). Melatonin (MLT) is a potent and endogenous anti oxidant that has beneficial effects in liver I/R injury. In this study, we examined the cytoprotective mechanisms of MLT in liver I/R, focusing on autophagic flux and associated signaling pathways. METHODS: Male C57BL/6 mice were subjected to 70% liver ischemia for 60 min followed by reperfusion. MLT (10 mg/kg, i.p.) was injected 15 min prior to ischemia and again immediately before reperfusion. Rapamycin (Rapa, 1 mg/kg, i.p.), which induces autophagy, was injected 1.5 h before ischemia. RESULTS: Liver I/R increased autophagic flux as indicated by the accumulation of LC3-II and degradation of sequestosome1/p62. This increase was attenuated by MLT. Likewise, electron microscopic analysis showed that autophagic vacuoles were increased in livers of mice exposed to I/R, which was attenuated by MLT. I/R decreased phosphorylation of mammalian target of rapamycin (mTOR) and 4E-BP1 and 70S6K, downstream molecules of the mTOR pathway, but increased expression of calpain 1 and calpain 2. MLT attenuated the decrease in mTOR, 4E-BP1 and 70S6K phosphorylation. Pretreatment of Rapa reversed the effect of MLT on autophagic flux as well as mTOR pathway. CONCLUSION: Our findings suggest that MLT downregulates autophagy via activation of mTOR signaling, which may in turn contribute to its protective effects in liver I/R injury. PMID- 24401532 TI - A preliminary investigation of anticholinesterase activity of some Iranian medicinal plants commonly used in traditional medicine. AB - BACKGROUND: The aim of this study was to evaluate acetylcholinesterase inhibitory activity of some commonly used herbal medicine in Iran to introduce a new source for management of Alzheimer's disease. A total of 18 aqueous-methanolic extract (1:1; v/v) from the following plants: Brassica alba, Brassica nigra, Camellia sinensis, Cinchona officinalis, Citrus aurantifolia, Citrus x aurantium, Ferula assafoetida, Humulus lupulus, Juglans regia, Juniperus sabina, Myristica fragrans, Pelargonium graveolens, Pistacia vera, Punica granatum, Rheum officinale, Rosa damascena, Salix alba, and Zizyphus vulgaris were prepared and screened for their acetylcholinesterase inhibitory activity using in vitro Ellman spectrophotometric method. RESULTS: According to the obtained results, the order of inhibitory activity (IC50 values, MUg /ml) of extracts from highest to the lowest was: C. sinensis (5.96), C. aurantifolia (19.57), Z. vulgaris (24.37), B. nigra (84.30) and R. damascena (93.1). CONCLUSIONS: The results indicated and confirmed the traditional use of these herbs for management of central nervous system disorders. C. sinensis showed the highest activity in inhibition of acetylcholinesterase. However, further investigations on identification of active components in the extracts are needed. PMID- 24401533 TI - {blacktriangledown} Apixaban and {blacktriangledown} rivaroxaban for stroke prevention in AF. AB - In October 2011, DTB reviewed the use of dabigatran, the first new oral anticoagulant licensed for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (AF) and one or more defined risk factors.1 We noted that the potential advantages of dabigatran for many patients with AF and the continuing need to provide warfarin therapy for others, provided an important challenge for the NHS. The use of dabigatran has increased significantly in the UK and two other drugs have been licensed for this indication (?apixaban-Eliquis, Bristol-Myers Squibb/Pfizer; ?rivaroxaban-Xarelto, Bayer plc).2-6 In addition, published drug safety alerts have highlighted the risk of serious haemorrhage associated with the use of these drugs.7-9 Here we review the evidence for apixaban and rivaroxaban for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation. PMID- 24401530 TI - Versican and the regulation of cell phenotype in disease. AB - BACKGROUND: Versican is an extracellular matrix (ECM) proteoglycan that is present in the pericellular environment of most tissues and increases in many different diseases. Versican interacts with cells to influence the ability of cells to proliferate, migrate, adhere and assemble an ECM. SCOPE OF REVIEW: The structure of the versican molecule is briefly reviewed and studies highlighting those factors that promote versican synthesis and degradation and their impact on cell phenotype in disease are discussed. Particular attention is given to vascular disease, but other diseases where versican is important are covered as well, most notably different forms of cancers. Attention is given to mechanisms(s) by which versican influences cell behaviors through either direct or indirect processes. Versican produced by either stromal cells or myeloid cells can have a major impact influencing immunity and inflammation. Finally, studies controlling versican accumulation that either delay or inhibit the progression of disease will be highlighted. MAJOR CONCLUSIONS: Versican is one component of the ECM that can influence the ability of cells to proliferate, migrate, adhere, and remodel the ECM. Targeting versican as a way to control cell phenotype offers a novel approach in the treatment of disease. SIGNIFICANCE: ECM molecules such as versican contribute to the structural integrity of tissues and interact with cells through direct and indirect means to regulate, in part, cellular events that form the basis of disease. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties. PMID- 24401534 TI - Parenchyma, pipes, perfusion and penumbra imaging: the multimodal CT in wake-up stroke basilar thrombosis. PMID- 24401535 TI - Neuroimaging findings in late-onset schizophrenia and bipolar disorder. AB - In recent years, there has been an increasing interest in late-onset mental disorders. Among them, geriatric schizophrenia and bipolar disorder are significant health care risks and major causes of disability. We discussed whether late-onset schizophrenia (LOS) and late-onset bipolar (LOB) disorder can be a separate entity from early-onset schizophrenia (EOS) and early-onset bipolar (EOB) disorder in a subset of late-life schizophrenia or late-life bipolar disorder through neuroimaging studies. A literature search for imaging studies of LOS or LOB was performed in the PubMed database. Search terms used were "(imaging OR MRI OR CT OR SPECT OR DTI OR PET OR fMRI) AND (schizophrenia or bipolar disorder) AND late onset." Articles that were published in English before October 2013 were included. There were a few neuroimaging studies assessing whether LOS and LOB had different disease-specific neural substrates compared with EOS and EOB. These researches mainly observed volumetric differences in specific brain regions, white matter hyperintensities, diffusion tensor imaging, or functional neuroimaging to explore the differences between LOS and LOB and EOS and EOB. The aim of this review was to highlight the neural substrates involved in LOS and LOB through neuroimaging studies. The exploration of neuroanatomical markers may be the key to the understanding of underlying neurobiology in LOS and LOB. PMID- 24401537 TI - Abstracts of the 5th World Congress on Sleep Medicine, 28 September-2 October 2013, Valencia, Spain. PMID- 24401538 TI - Detecting novel SNPs and breed-specific haplotypes at calpastatin gene in Iranian fat- and thin-tailed sheep breeds and their effects on protein structure. AB - Calpastatin has been introduced as a potential candidate gene for growth and meat quality traits. In this study, genetic variability was investigated in the exon 6 and its intron boundaries of ovine CAST gene by PCR-SSCP analysis and DNA sequencing. Also a protein sequence and structural analysis were performed to predict the possible impact of amino acid substitutions on physicochemical properties and structure of the CAST protein. A total of 487 animals belonging to four ancient Iranian sheep breeds with different fat metabolisms, Lori-Bakhtiari and Chall (fat-tailed), Zel-Atabay cross-bred (medium fat-tailed) and Zel (thin tailed), were analyzed. Eight unique SSCP patterns, representing eight different sequences or haplotypes, CAST-1, CAST-2 and CAST-6 to CAST-11, were identified. Haplotypes CAST-1 and CAST-2 were most common with frequency of 0.365 and 0.295. The novel haplotype CAST-8 had considerable frequency in Iranian sheep breeds (0.129). All the consensus sequences showed 98-99%, 94-98%, 92-93% and 82-83% similarity to the published ovine, caprine, bovine and porcine CAST locus sequences, respectively. Sequence analysis revealed four SNPs in intron 5 (C24T, G62A, G65T and T69-) and three SNPs in exon 6 (c.197A>T, c.282G>T and c.296C>G). All three SNPs in exon 6 were missense mutations which would result in p.Gln 66 Leu, p.Glu 94 Asp and p.Pro 99 Arg substitutions, respectively, in CAST protein. All three amino acid substitutions affected the physicochemical properties of ovine CAST protein including hydrophobicity, amphiphilicity and net charge and subsequently might influence its structure and effect on the activity of Ca2+ channels; hence, they might regulate calpain activity and afterwards meat tenderness and growth rate. The Lori-Bakhtiari population showed the highest heterozygosity in the ovine CAST locus (0.802). Frequency difference of haplotypes CAST-10 and CAST-8 between Lori-Bakhtiari (fat-tailed) and Zel (thin tailed) breeds was highly significant (P<0.001), indicating that these two haplotypes might be breed-specific haplotypes that distinguish between fat-tailed and thin-tailed sheep breeds. PMID- 24401539 TI - Is soluble mesothelin-related protein an upfront predictive marker of pleural mesothelioma? A prospective study on Italian workers exposed to asbestos. AB - OBJECTIVE: Soluble mesothelin-related peptide (SMRP) may be useful in the diagnosis and detection of early stage mesothelioma. We investigated the SMRP upfront predictive role for mesothelioma in asbestos-exposed workers. METHODS: A total of 1,715 subjects underwent a first visit and were invited for a follow-up after 1 and 2 years, with a clinical examination and blood sampling. SMRP was measured by an ELISA assay. RESULTS: Median SMRP at the first visit was 0.45 [interquartile range (IQR) i.e. 25th-75th percentile: 0.30-0.67 nmol/l]. In all, 1,676 subjects (97.8%) were followed up for a median period of 47.1 months. SMRP was measured at the first visit and at both follow-up visits in 1,536 subjects. At follow-up, 3 subjects were diagnosed with an epithelioid mesothelioma. In these cases, SMRP at the first visit ranged from 0.17 to 0.52 nmol/l. Malignant pleural mesothelioma was diagnosed 9-17 months after the last SMRP evaluation. No SMRP variation was observed during the follow-up. Other 61 miscellaneous cancers were diagnosed (median SMRP at first visit: 0.50 nmol/l, IQR: 0.34-0.71 nmol/l). CONCLUSIONS: Our results did not support the usefulness of SMRP as an early marker for the detection of the disease for a time interval of 1 year. PMID- 24401540 TI - Combined brachytherapy and external beam radiotherapy without adjuvant androgen deprivation therapy for high-risk prostate cancer. AB - BACKGROUND: To report the outcomes of patients treated with combined iodine-125 (I-125) brachytherapy and external beam radiotherapy (EBRT) for high-risk prostate cancer. METHODS: Between 2003 and 2009, I-125 permanent prostate brachytherapy plus EBRT was performed for 206 patients with high-risk prostate cancer. High-risk patients had prostate-specific antigen >= 20 ng/mL, and/or Gleason score >= 8, and/or Stage >= T3. One hundred and one patients (49.0%) received neoadjuvant androgen deprivation therapy (ADT) but none were given adjuvant ADT. Biochemical failure-free survival (BFFS) was determined using the Phoenix definition. RESULTS: The 5-year actuarial BFFS rate was 84.8%. The 5-year cause-specific survival and overall survival rates were 98.7% and 97.6%, respectively. There were 8 deaths (3.9%), of which 2 were due to prostate cancer. On multivariate analysis, positive biopsy core rates and the number of high-risk factors were independent predictors of BFFS. The 5-year BFFS rates for patients in the positive biopsy core rate <50% and >= 50% groups were 89.3% and 78.2%, respectively (p = 0.03). The 5-year BFFS rate for patients with the any single high-risk factor was 86.1%, compared with 73.6% for those with any 2 or all 3 high-risk factors (p = 0.03). Neoadjuvant ADT did not impact the 5-year BFFS. CONCLUSIONS: At a median follow-up of 60 months, high-risk prostate cancer patients undergoing combined I-125 brachytherapy and EBRT without adjuvant ADT have a high probability of achieving 5-year BFFS. PMID- 24401541 TI - Disruption of Rpp1-mediated soybean rust immunity by virus-induced gene silencing. AB - Phakopsora pachyrhizi, a fungus that causes rust disease on soybean, has potential to impart significant yield loss and disrupt food security and animal feed production. Rpp1 is a soybean gene that confers immunity to soybean rust, and it is important to understand how it regulates the soybean defense system and to use this knowledge to protect commercial crops. It was previously discovered that some soybean proteins resembling transcription factors accumulate in the nucleus of Rpp1 soybeans. To determine if they contribute to immunity, Bean pod mottle virus was used to attenuate or silence the expression of their genes. Rpp1 plants subjected to virus-induced gene silencing exhibited reduced amounts of RNA for 5 of the tested genes, and the plants developed rust-like symptoms after subsequent inoculation with fungal spores. Symptoms were associated with the accumulation of rust fungal RNA and protein. Silenced plants also had reduced amounts of RNA for the soybean Myb84 transcription factor and soybean isoflavone O-methyltransferase, both of which are important to phenylpropanoid biosynthesis and lignin formation, crucial components of rust resistance. These results help resolve some of the genes that contribute to Rpp1-mediated immunity and improve upon the knowledge of the soybean defense system. It is possible that these genes could be manipulated to enhance rust resistance in otherwise susceptible soybean cultivars. PMID- 24401542 TI - Autoimmune polyglandular syndrome presenting with jaundice and thrombocytopenia. AB - OBJECTIVE: To report an uncommon presentation of a rare case of autoimmune polyglandular syndrome type IIIb in an elderly woman. CLINICAL PRESENTATION AND INTERVENTION: A 62-year-old woman presented with anaemic symptoms and jaundice. Blood tests showed macrocytic anaemia due to vitamin B12 deficiency with Coombs negative haemolysis. A thyroid function test was consistent with hypothyroidism. Autoimmune antibody assays were positive for anti-parietal cell, anti-intrinsic factor and anti-thyroid peroxidase antibodies. A final diagnosis of autoimmune thyroiditis with pernicious anaemia, which constituted autoimmune polyglandular syndrome type IIIb, was made and the patient was treated with L-thyroxine, vitamin B12 injection and a blood transfusion. She was discharged uneventfully after a week of hospitalization. CONCLUSION: This case showed that the presence of one autoimmune endocrine disease should prompt clinicians to look for other coexisting autoimmune diseases which may be asymptomatic despite positive autoantibodies. PMID- 24401543 TI - Broncho-hepatico-cutaneous fistula in a case of amoebic liver abscess. AB - Pulmonary complications occur in 7-20% of patients with amoebic liver abscess(ALA) and may present as pleural effusion, empyema, lung abscess or a bronchohepatic fistula. Rupture into a bronchus presents as sudden coughing with expectoration of chocolate-coloured sputum and is usually managed by postural drainage, bronchodilators and anti-amoebic drugs. A young boy presented with a large amoebic liver abscess of about 1 L volume which ruptured into the lung. He required surgical drainage of the liver abscess as even after intubation he was not able to maintain adequate ventilation. Following this he developed a broncho hepatico-cutaneous fistula with drainage of 400-500 mL bile per day and bubbling of air in the abdominal drain. He underwent selective right hepatic duct cannulation with endo-papillotomy, following which the fistula closed gradually. PMID- 24401544 TI - Mediastinal tubercular lymph node eroding into pericardium causing acute pyopericardium and cardiac tamponade. AB - Cardiac tamponade due to tuberculosis is a well-known complication. However, acute erosion of TB lymphadenitis and its caseous material into the pericardium causing pericardial tamponade is rare. We describe a case of extensive mediastinal tubercular lymph node mass in which the caseous necrotic material found its way into pericardial sac causing acute pyopericardium and cardiac tamponade. PMID- 24401547 TI - Physical activity in U.S. youth aged 12-15 years, 2012. AB - KEY FINDINGS: Data from the combined National Health and Nutrition Examination Survey (NHANES) and the NHANES National Youth Fitness Survey, 2012. In 2012, about one-quarter of U.S. youth aged 12-15 years engaged in moderate-to-vigorous physical activity for at least 60 minutes daily. Basketball was the most common activity reported among active boys, followed by running, football, bike riding, and walking. Running was the most common activity among active girls, followed by walking, basketball, dancing, and bike riding. The percentage of male youth who were physically active for at least 60 minutes daily decreased as weight status increased. The 2008 Physical Activity Guidelines for Americans, which have been adopted by the First Lady's Let's Move! initiative and the American Academy of Pediatrics, recommend that youth participate in daily moderate-to-vigorous physical activity for at least 60 minutes (1-5). This report presents the most recent national data from 2012 on self-reported physical activity among youth aged 12-15 years, by sex and weight status. This report also describes the most common types of physical activities--outside of school-based physical education (PE) or gym classes--in which youth engage. PMID- 24401545 TI - A controlled study on gastrointestinal nematodes from two Swedish cattle farms showing field evidence of ivermectin resistance. AB - BACKGROUND: Anthelmintic resistance (AR) is an increasing problem for the ruminant livestock sector worldwide. However, the extent of the problem is still relatively unknown, especially for parasitic nematodes of cattle. The effect of ivermectin (IVM) (Ivomec inj.(r), Merial) was investigated in Swedish isolates of gastrointestinal nematode (GIN) populations showing signs of AR in the field to further characterise the AR status by a range of in vivo and in vitro methods. METHODS: Three groups, each of 11 calves, were infected with an equal mixture of third stage larvae (L3) of Cooperia oncophora and Ostertagia ostertagi. Group A was inoculated with an IVM-susceptible laboratory isolate and groups B and C with isolates originating from 'resistant' cattle farms. Faecal egg counts (FEC) were monitored from 0 to 45 days post infection (d.p.i.), and L3 were harvested continuously for larval migration inhibition testing (LMIT) and species-specific PCR (ITS2). At 31 d.p.i., one calf from each group was necropsied and adult worms were recovered pre-treatment. At 35 d.p.i., calves from all groups were injected with IVM at the recommended dose (0.2 mg/kg bodyweight). At 45 d.p.i., another two animals from each group were sacrificed and established gastrointestinal worms were collected and counted. RESULTS: A few animals in all three groups were still excreting eggs (50-150 per g faeces) 10 days post IVM injection. However, there was no significant difference in the FEC reductions in groups A (95%; 95% CI 81-99), B (98%; 92-100) and C (99%; 97-100) between 35 and 44 d.p.i. Furthermore, LMIT showed no significant difference between the three groups. Approximately 100 adult O. ostertagi were found in the abomasum of one calf (group B), whereas low to moderate numbers (400-12 200) of C. oncophora remained in the small intestine of the calves in all three groups at 45 d.p.i. PCR on L3 harvested from faecal samples up to 10 days post treatment showed a ratio of 100% C. oncophora in the calves inoculated with isolates A and B, whereas C also had 8% O. ostertagi. CONCLUSIONS: Overall, this experiment showed that the animals were successfully treated according to the Faecal egg count reduction test (FECRT) standard (>= 95% reduction). However, several adult worms of the dose limiting species C. oncophora demonstrably survived the IVM treatment. PMID- 24401548 TI - The persistent toxic substances in Korea: environmental fates and human health. PMID- 24401549 TI - Improvement in glaucoma patient quality of life by therapy switch to preservative free timolol/dorzolamide fixed combination. AB - PURPOSE: To assess a change in visual-related quality of life (QoL) in glaucoma patients after switching from preservative-containing medical therapy to preservative-free unit dose timolol/dorzolamide fixed combination (TDFC UD). METHODS: Prospective, noninterventional, multicenter 8-week study. Primary outcome was a change in visual symptoms at week 8, as assessed by the Glaucoma Symptom Scale (GSS). RESULTS: 80 patients completed the study. There was a clinically significant increase in the scores of all GSS-related categories at week 8 when compared to baseline (GSS symptom week 8: +21.15 +/- 37.9%, GSS function week 8: +10.3 +/- 31.6%, both p < 0.001 vs. baseline). Comparison between patients taking only TDFC UD and patients taking TDFC UD plus concomitant medications did not detect differences in any GSS category (p > 0.50 in all comparisons). CONCLUSIONS: Switching to TDFC UD significantly improved the self reported QoL of glaucoma patients. This can be seen even in patients who are taking concomitant ocular treatments. PMID- 24401550 TI - Eligibility for the kidney transplant wait list: a model for conceptualizing patient risk. AB - BACKGROUND: Determining eligibility for a kidney transplant is one of the most important decisions facing nephrologists. It is assumed that the harm of kidney transplantation is minimal and most will benefit. The purpose of this study was to quantify the probability of 'no benefit' as defined by death on the wait list; 'harm', defined by the probability that a transplanted patient would live less than the average wait listed patient; and 'benefit' for the probability a transplanted patient would outlive the average wait listed patient. METHODS: A computerized model was developed to replicate observed patient survival outcomes in deceased donor kidney transplantation. Three sequential periods of risk for the transplanted recipient compared to the wait listed cohort (increased, equivalent and reduced risk) were modeled. RESULTS: The model predicted that wait listed patients with a baseline mortality of 28 deaths per 100 patient years were equally likely to benefit or be harmed with a transplant. However if 20% of patients on the wait list were on hold (assuming a 2.2-fold higher mortality than those who were transplanted), then the baseline mortality rate for equal harm or benefit decreases to 22 deaths per 100 patient years (equivalent life expectancy 4.5 years). CONCLUSION: Patients with limited life expectancies are more likely to suffer some harm than derive benefit from kidney transplantation. PMID- 24401551 TI - Neuroprotective effects of donepezil against cholinergic depletion. AB - INTRODUCTION: Intraparenchymal injections of the immunotoxin 192-IgG-saporin into medial septum and nucleus basalis magnocellularis causes a selective depletion of basal forebrain cholinergic neurons. Thus, it represents a valid model to mimic a key component of the cognitive deficits associated with aging and dementia. Here we administered donepezil, a potent acetylcholinesterase inhibitor developed for treating Alzheimer's disease, 15 days before 192-IgG-saporin injection, and thus we examined donepezil effects on neurodegeneration and cognitive deficits. METHODS: Caspase-3 activity and cognitive performances of lesioned rats pre treated with donepezil or saline were analyzed and compared to the outcomes obtained in pre-treated sham-lesioned rats. RESULTS: Cholinergic depletion increased hippocampal and neocortical caspase-3 activity and impaired working memory, spatial discrimination, social novelty preference, and ultrasonic vocalizations, without affecting anxiety levels and fear conditioning. In lesioned animals, donepezil pre-treatment reduced hippocampal and neocortical caspase-3 activity and improved working memory and spatial discrimination performances and partially rescued ultrasonic vocalizations, without preventing social novelty alterations. CONCLUSIONS: Present data indicate that donepezil pre treatment exerts beneficial effects on behavioral deficits induced by cholinergic depletion, attenuating the concomitant hippocampal and neocortical neurodegeneration. PMID- 24401552 TI - The limit of anemia tolerance during hyperoxic ventilation with pure oxygen in anesthetized domestic pigs. AB - BACKGROUND: During acellular replacement of an acute blood loss, hyperoxic ventilation (HV) increases the amount of O2 physically dissolved in the plasma and thereby improves O2 supply to the tissues. While this effect could be demonstrated for HV with inspiratory O2 fraction (FiO2) 0.6, it was unclear whether HV with pure oxygen (FiO2 1.0) would have an additional effect on the physiological limit of acute normovolemic anemia. METHODS: Seven anesthetized domestic pigs were ventilated with FiO2 1.0 and subjected to an isovolemic hemodilution protocol. Blood was drawn and replaced by a 6% hydroxyethyl starch (HES) solution (130/0.4) until a sudden decrease of total body O2 consumption (VO2) indicated the onset of O2 supply dependency (primary endpoint). The corresponding hemoglobin (Hb) concentration was defined as 'critical Hb' (Hbcrit). Secondary endpoints were parameters of myocardial function, central hemodynamics, O2 transport and tissue oxygenation. RESULTS: HV with FiO2 1.0 enabled a large blood-for-HES exchange (156 +/- 28% of the circulating blood volume) until Hbcrit was met at 1.3 +/- 0.3 g/dl. After termination of the hemodilution protocol, the contribution of O2 physically dissolved in the plasma to O2 delivery and VO2 had significantly increased from 11.7 +/- 2 to 44.2 +/- 9.7% and from 29.1 +/- 4.2 to 66.2 +/- 11.7%, respectively. However, at Hbcrit, cardiovascular performance was found to have severely deteriorated. CONCLUSION: HV with FiO2 1.0 maintains O2 supply to tissues during extensive blood-for-HES exchange. In acute situations, where profound anemia must be tolerated (e.g. bridging an acute blood loss until red blood cells become available for transfusion), O2 physically dissolved in the plasma becomes an essential source of oxygen. However, compromised cardiovascular performance might require additional treatment. PMID- 24401553 TI - New antiangiogenic strategies beyond inhibition of vascular endothelial growth factor with special focus on axon guidance molecules. AB - Since the approval of the first antiangiogenic agent bevacizumab, a neutralizing antibody against the vascular endothelial growth factor (VEGF), antiangiogenic therapies augmented the standard armamentarium of anticancer therapies and proved their clinical efficacy. Nevertheless, antiangiogenic strategies could not fulfill the expected hopes. In clinical routine, therapy responses to antiangiogenic therapies were mostly transient and most of the patients developed evasive resistance mechanisms during therapy. Further, no predictive biomarker for therapy response could be developed, hampering the clinical development of these agents and triggering skepticism. In the past years, knowledge on the biology of angiogenesis increased and the role of tumor hypoxia was better characterized and identified as the driver for angiogenic regulation mechanisms. Besides VEGF, new angiogenic and antiangiogenic factors were characterized and the process of endothelial cell migration, proliferation and vessel formation was better elucidated. Thus, a strong connection to neural development and axon guidance molecules like netrins, Slit proteins, semaphorins, ephrins and their cognate receptors UNC5, Robo1-4, neuropilin and EphB was identified. The aim of this review is to present the importance of these axon guidance molecules with special focus on Robo4 and semaphorins in tumor angiogenesis and to highlight their value as potential targets for new antiangiogenic therapies. PMID- 24401554 TI - Saikosaponin-D enhances radiosensitivity of hepatoma cells under hypoxic conditions by inhibiting hypoxia-inducible factor-1alpha. AB - BACKGROUND: Our previous study revealed that the combination of Saikosaponin-d ( SSd) and radiation is more effective in the treatment of liver cancer than the application of either of these monotherapeutic methods. However, the molecular mechanisms of the radiosensitizing effect of SSd on liver cancer remained ill defined. METHODS: Cells were treated with different interventions; afterward, cell viability, apoptosis, and cell survival of SMMC-7721 and HepG2 hepatoma cells were examined. Xenograft tumor models were established by subcutaneously injecting SMMC-7721 cells. The molecular mechanism was assessed by western blot. RESULTS: SSd dose-dependently increased radiosensitivity of hepatoma cells under hypoxic condition. The growth inhibitory effect of the combined treatment was correlated with cell apoptosis. Further mechanistic analysis indicated that SSd induced the upregulation of p53 and Bax as well as the downregulation of Bcl-2 by attenuating HIF-1alpha expression under hypoxic condition. These effects were enhanced when the HIF-1alpha inhibitor PX-478 was introduced. In vivo data also presented a more significant suppression of tumor xenograft growth from the combined therapy than from either of the monotherapeutic methods. CONCLUSIONS: Our study provides evidence for a radiosensitizing effect of SSd on hepatoma cells under hypoxic conditions by inhibiting HIF-1alpha expression. Thus, SSd can be used as a potential sensitizer in hepatoma radiotherapy. (c) 2014 S. Karger AG, Basel. PMID- 24401555 TI - Using ecological momentary assessment to test the effectiveness of a web-based brief alcohol intervention over time among heavy-drinking students: randomized controlled trial. AB - BACKGROUND: Web-based brief alcohol interventions are effective in reducing alcohol use among students when measured at limited follow-up time points. To date, no studies have tested Web-based brief alcohol intervention effectiveness over time by using a large number of measurements. OBJECTIVE: Testing whether the What Do You Drink (WDYD) Web-based brief alcohol intervention can sustain a reduction in alcohol use among heavy-drinking students aged 18-24 years at 1-, 3 , and 6-month follow-up intervals. METHODS: A purely Web-based, 2-arm, parallel group randomized controlled trial applying an ecological momentary assessment approach with 30 weekly measurements was conducted in the Netherlands (2010 2011). Participants were recruited offline and online. A total of 907 participants were randomized into the experimental condition (n=456) including the single-session and fully automated WDYD intervention, or into the control condition (n=451) including assessment only. Weekly alcohol consumption and frequency of binge drinking were the self-assessed outcome measures. RESULTS: Attrition rates of the 907 participants were 110 (12.1%), 130 (14.3%), and 162 (17.9%) at 1-, 3-, and 6-month follow-up intervals, respectively. Latent growth curve analyses according to the intention-to-treat principle revealed that participants in the experimental condition had significantly lower weekly alcohol consumption compared to participants in the control condition that was sustained at 3-month follow-up (intercept=-2.60, P<.001; slope=0.16, P=.08). Additional linear regression analyses indicated that this intercept difference resulted from significantly higher levels of alcohol units per week for participants in the control condition compared to those in the experimental condition at 1-month (beta=-2.56, SE 0.74, Cohen's d=0.20, P=.001), 3-month (beta=-1.76, SE 0.60, Cohen's d=0.13, P=.003), and 6-month (beta=-1.21, SE 0.58, Cohen's d=0.09, P=.04) follow-up intervals. Latent growth curve analyses further indicated that participants in the experimental condition had a significantly lower frequency of binge drinking compared to participants in the control condition that was sustained at 6-month follow-up (intercept=-0.14, P=.01; slope=0.004, P=.19). This intercept difference resulted from higher levels in this outcome for participants in the control condition relative to participants in the experimental condition at 1-month (beta=-1.15, SE 0.06, Cohen's d=0.16, P=.01), 3-month (beta=-0.12, SE 0.05, Cohen's d=0.09, P=.01), and 6-month (beta=-0.09, SE 0.05, Cohen's d=0.03, P=.045) follow-up intervals. CONCLUSIONS: The WDYD intervention was shown to be effective in preventing an increase in weekly alcohol consumption and frequency of binge drinking directly after the intervention. This effect was sustained 3 and 6 months after the intervention. TRIAL REGISTRATION: Netherlands Trial Register NTR2665; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2665 (Archived by WebCite at http://webcitation.org/6LuQVn12M). PMID- 24401556 TI - Uneven futures of human lifespans: reckonings from Gompertz mortality rates, climate change, and air pollution. AB - The past 200 years have enabled remarkable increases in human lifespans through improvements in the living environment that have nearly eliminated infections as a cause of death through improved hygiene, public health, medicine, and nutrition. We argue that the limit to lifespan may be approaching. Since 1997, no one has exceeded Jeanne Calment's record of 122.5 years, despite an exponential increase of centenarians. Moreover, the background mortality may be approaching a lower limit. We calculate from Gompertz coefficients that further increases in longevity to approach a life expectancy of 100 years in 21st century cohorts would require 50% slower mortality rate accelerations, which would be a fundamental change in the rate of human aging. Looking into the 21st century, we see further challenges to health and longevity from the continued burning of fossil fuels that contribute to air pollution as well as global warming. Besides increased heat waves to which elderly are vulnerable, global warming is anticipated to increase ozone levels and facilitate the spread of pathogens. We anticipate continuing socioeconomic disparities in life expectancy. PMID- 24401558 TI - The appropriate and justified use of medical radiation in cardiovascular imaging: a position document of the ESC Associations of Cardiovascular Imaging, Percutaneous Cardiovascular Interventions and Electrophysiology. AB - The benefits of cardiac imaging are immense, and modern medicine requires the extensive and versatile use of a variety of cardiac imaging techniques. Cardiologists are responsible for a large part of the radiation exposures every person gets per year from all medical sources. Therefore, they have a particular responsibility to avoid unjustified and non-optimized use of radiation, but sometimes are imperfectly aware of the radiological dose of the examination they prescribe or practice. This position paper aims to summarize the current knowledge on radiation effective doses (and risks) related to cardiac imaging procedures. We have reviewed the literature on radiation doses, which can range from the equivalent of 1-60 milliSievert (mSv) around a reference dose average of 15 mSv (corresponding to 750 chest X-rays) for a percutaneous coronary intervention, a cardiac radiofrequency ablation, a multidetector coronary angiography, or a myocardial perfusion imaging scintigraphy. We provide a European perspective on the best way to play an active role in implementing into clinical practice the key principle of radiation protection that: 'each patient should get the right imaging exam, at the right time, with the right radiation dose'. PMID- 24401559 TI - Thalamic volume and thalamo-cortical white matter tracts correlate with motor and verbal memory performance. AB - Cognitive testing and diffusion tensor imaging data from 121 normal subjects were combined to investigate the relationship between thalamic connectivity and cognitive performance. Thalamic regions were segmented based on their cortical connectivity, and regions for both ipsilateral and contralateral thalamocortical connections were identified. White matter tracts corresponding to these regions were identified and the mean fractional anisotropy, and axial and radial diffusivities within each tract were measured. Motor task performance correlated with radial diffusivity in the dominant thalamo-precentral tract. Verbal memory corresponded with the thalamic volume connected to the left temporal lobe. These data support the use of diffusion tractography to identify functionally important regions within the thalamus. Our findings provide the first robust correlation between thalamic volumes and tract characteristics with cognitive performance data in normal subjects. PMID- 24401560 TI - Invited commentary: interpreting associations between exposure biomarkers and pregnancy outcome. AB - Levels of exposure biomarkers vary among individuals because of differences in both environmental exposure and metabolism. However, the ultimate interest is in providing information about the impact of modifying environmental exposures through regulation or behavior change. Using these levels in studies of pregnancy outcomes, as nicely illustrated by the study of Kadhel et al. in this issue of the Journal (Am J Epidemiol. 2014;179(5):536-544), has the usual strength of being integrative across multiple pathways but may reflect reverse causality, in which the underlying disease alters biomarker levels or shared physiological determinants of the biomarker level and the health outcome. Specifically, biomarkers may vary because of spatial differences in exposure, behavioral differences affecting exposure, and metabolic differences across members of the study population. Proper interpretation of such studies calls for a clearer understanding the sources of variation in exposure to more fully consider confounding and reverse causality due to metabolic differences within the study population. PMID- 24401561 TI - Chlordecone exposure, length of gestation, and risk of preterm birth. AB - Persistent organic pollutants have not been conclusively associated with length of gestation or with preterm birth. Chlordecone is an organochlorine pesticide that has been extensively used to control the banana root borer population in the French West Indies. Data from the Timoun Mother-Child Cohort Study conducted in Guadeloupe between 2004 and 2007 were used to examine the associations of chlordecone concentrations in maternal plasma with the length of gestation and the rate preterm birth in 818 pregnant women. Data were analyzed using multivariate linear regression for length of gestation and a Cox model for preterm birth. The median plasma chlordecone concentration was 0.39 ug/L (interquartile range, 0.18-0.83). No correlation was observed with plasma concentrations of p,p'-dichlorodiphenyl dichloroethene (rho = 0.017) or polychlorinated biphenyl 153 (rho = -0.016), the other main organochlorine compounds detected. A 1-log10 increase in chlordecone concentration was associated with a decreased length of gestation (-0.27 weeks; 95% confidence interval: -0.50, -0.03) and an increased risk of preterm birth (60%; 95% confidence interval: 10, 130). These associations may result from the estrogen like and progestin-like properties of chlordecone. These results are of public health relevance because of the prolonged persistence of chlordecone in the environment and the high background rate of preterm births in this population. PMID- 24401562 TI - Assessment of the "case-chaos" design as an adjunct to the case-control design. AB - In 2012, a novel case series method dubbed the "case-chaos" design was proposed as an alternative to case-control studies, whereby controls are artificially created by permutating the exposure information of the cases. Our aim in the current work was to further evaluate the case-chaos method. Using a theoretical example of 2 risk factors, we demonstrated that the case-chaos design yields risk estimations for which the odds ratios obtained for every risk factor are in the same ascending order as the risk factors' exposure prevalences in the case group. Applying the method to data from the European Study of Severe Cutaneous Adverse Reactions (EuroSCAR; 1997-2001), we were not able to obtain sensible results but instead produced results as predicted by our theoretical assessment. We therefore claim that the method is equivalent to declaring risk solely on the basis of prevalences obtained in cases. While the proposers of the case-chaos method view it as a useful adjunct, we show that it cannot produce sensible estimates. PMID- 24401563 TI - No rise in incidence but geographical heterogeneity in the occurrence of primary biliary cirrhosis in North East England. AB - In this study, we examined temporal changes in the incidence of primary biliary cirrhosis (PBC) and investigated associations between PBC incidence and sociodemographic factors and spatial clustering. We included 982 patients aged >=40 years from North East England with incident PBC diagnosed during 1987-2003. Age-standardized incidence rates with 95% confidence intervals were calculated. Negative binomial regression was used to analyze incidence and socioeconomic deprivation. Clustering analysis was performed using point process methods, testing the null hypothesis that disease risk does not vary spatially and that PBC cases occur independently. The age-standardized incidence rate was 53.50 per million persons per year (95% confidence interval: 48.65, 58.35) in 1987-1994 and 45.09 per million persons per year (95% confidence interval: 41.10, 49.07) in 1995-2003. Risk of PBC increased in areas with higher levels of socioeconomic deprivation (P = 0.035). More specifically, risk increased in areas with higher levels of overcrowded homes (P = 0.040), higher levels of households without cars (P < 0.001), and higher levels of non-owner-occupied homes (P < 0.001). Overall, there was evidence of spatial clustering (P = 0.001). The findings confirm that overall incidence of PBC did not rise over time, but sociodemographic variations suggest that certain aspects of deprivation are involved in its etiology. PMID- 24401564 TI - Kadhel et al. respond to "Interpreting exposure biomarkers in pregnancy". PMID- 24401565 TI - Screening vaccine formulations for biological activity using fresh human whole blood. AB - Understanding the relevant biological activity of any pharmaceutical formulation destined for human use is crucial. For vaccine-based formulations, activity must reflect the expected immune response, while for non-vaccine therapeutic agents, such as monoclonal antibodies, a lack of immune response to the formulation is desired. During early formulation development, various biochemical and biophysical characteristics can be monitored in a high-throughput screening (HTS) format. However, it remains impractical and arguably unethical to screen samples in this way for immunological functionality in animal models. Furthermore, data for immunological functionality lag formulation design by months, making it cumbersome to relate back to formulations in real-time. It is also likely that animal testing may not accurately reflect the response in humans. For a more effective formulation screen, a human whole blood (hWB) approach can be used to assess immunological functionality. The functional activity relates directly to the human immune response to a complete formulation (adjuvant/antigen) and includes adjuvant response, antigen response, adjuvant-modulated antigen response, stability, and potentially safety. The following commentary discusses the hWB approach as a valuable new tool to de-risk manufacture, formulation design, and clinical progression. PMID- 24401566 TI - A randomized comparison of gasless laparoscopic appendectomy and conventional laparoscopic appendectomy. AB - INTRODUCTION: The purpose of this study was to compare the clinical outcomes and cost effectiveness of the gasless laparoscopic appendectomy (GLA) and conventional laparoscopic appendectomy (LA). METHODS: From Aug 2010 to Feb 2012, 100 patients with a clinical diagnosis of acute appendicitis in Shanghai Tongji hospital were included in the study and randomly divided into the LA and GLA groups, fifty in the GLA group and 50 in the LA group. The two groups were comparable in age, gender, body mass index, symptom duration, ASA score, and white blood cell count. RESULTS: The mean surgical duration was 70.6 +/- 30.8 min in the GLA group and 62.6 +/- 22.0 min in the LA group (P = 0.138). The total conversion rate was 8% in the GLA group, while no conversions occurred in the LA group. Postoperative complications did not significantly differ between the two groups. Fentanyl consumption was decreased significantly in the GLA group (P = 0.019) postoperatively. The length of the total hospital stay was 4.36 +/- 1.74 days in the GLA group compared with 5.68 +/- 4.44 days in the LA group (P = 0.053). There was a significant decrease in the total hospital cost when the GLA group was compared with the LA group (6659 +/- 1782 vs. 9056 +/- 2680 Yuan, respectively, P < 0.001). CONCLUSION: GLA and conventional LA are comparable in terms of operative duration, complications, and total hospital stay. The obvious advantage of GLA is the significantly reduced hospital cost. The demand for postoperative analgesics may also decrease following GLA. In conclusion, GLA is a safe and feasible procedure in selected patients. TRIAL REGISTRATION: Chinese Clinical Trial Register ChiCTR-TRC-10001203. PMID- 24401567 TI - Schistosoma mansoni infection after three years of mass drug administration in Sierra Leone. AB - BACKGROUND: Schistosoma mansoni was moderately-highly endemic in the northeast of Sierra Leone. The national neglected tropical disease control program started mass drug administration (MDA) with praziquantel (PZQ) in six districts in 2009 targeting primary school children only. The effort was scaled-up to seven districts in 2010 targeting school aged children (SAC) and at-risk adults. A cross-sectional sentinel site survey was conducted in 2012 after three rounds of MDA to evaluate the impact of the national program. METHODS: Twenty-six (26) sentinel sites were randomly selected from the baseline mapping survey sites stratified according to the baseline prevalence into high, moderate or low endemic category. Fifty (50) school children (25 males and 25 females) were randomly selected per site. Fresh stool samples were examined in the field using the Kato Katz technique. The results were compared with the baseline data. RESULTS: Program coverage of 94.8%, 77.1% and 81.7% was reported in 2009, 2010 and 2011 respectively. Independent monitoring in 2011 showed program coverage of 83.9%, not significantly different from the reported result in the same year. The overall prevalence of S. mansoni was 16.3% (95% CI: 14.4-18.4%) and mean intensity was 18.98 epg (95% CI: 11.46-26.50 epg) in 2012, representing 67.2% and 85.9% reduction from the baseline respectively. The proportion of moderately and heavily infected children was 3.3% and 1.2%, a significant reduction from 18.2% and 8.8% at baseline respectively. CONCLUSIONS: Sierra Leone has maintained effective MDA coverage with PZQ since 2009. Three rounds of MDA led to a significant reduction of S. mansoni infection in the country. In line with the significant progress made in controlling schistosomiasis, the national treatment strategy has been reviewed and MDA will be expanded to include school age children in low endemicity districts with the new national objective for the elimination of schistosomiasis. Sierra Leone is well on its way to eliminate schistosomiasis as a public health problem. PMID- 24401569 TI - Smoking-attributable burden of lung cancer in the Philippines. AB - BACKGROUND: In the Philippines, smoking is highly prevalent and tobacco control policies fail to fully implement the WHO Framework Convention on Tobacco Control provisions. To aid in policy change, intervention implementation, monitoring and evaluation, this study aimed to provide the first internally consistent and latest Philippine estimates of the following: disability-adjusted life-years (DALYs) lost due to lung cancer; population-attributable fractions (PAFs) of smoking; and smoking-attributable lung cancer DALYs. METHODS: This study applied the Global Burden of Disease and Comparative Risk Assessment frameworks to secondary data, supplemented by expert opinion. A comprehensive internally consistent assessment of disease epidemiology was conducted using DISMOD II and disease impact was quantified as DALYs. PAFs were calculated using the smoking impact ratio and Monte Carlo uncertainty analyses were conducted. RESULTS: For 2008, lung cancer incidence and mortality estimates were 10 871 cases and 9871 deaths respectively. Lung cancer accounted for an estimated 267 787 DALYs lost, 99% of which were due to years of life lost. Overall, the PAF of smoking was 65% and a total of 173 103 DALYs were smoking-attributable. There were increasing trends in incidence, mortality and DALY rates with age. The majority of incidence (72%), mortality (71%) and disease burden (72%) occurred among men, who also had higher PAF estimates. CONCLUSIONS: Considerable health gains could be achieved if smoking exposure were reduced in the Philippines. Strong enforcement of measures like increasing taxation to the WHO-endorsed rate, expanding smoke-free environments, and requiring large graphic warnings within a comprehensive tobacco control programme is recommended. PMID- 24401568 TI - Hepatitis B virus X protein inhibits autophagic degradation by impairing lysosomal maturation. AB - Deficiency in autophagy, a lysosome-dependent cell degradation pathway, has been associated with a variety of diseases especially cancer. Recently, the activation of autophagy by hepatitis B virus X (HBx) protein, which is implicated in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC), has been identified in hepatic cells. However, the underlying mechanism and the relevance of HBx-activated autophagy to the carcinogenesis caused by HBV remain elusive. Here, by transfection of HBV genomic DNA and HBx in hepatic and hepatoma cells, we showed that HBV- or HBx-induced autophagosome formation was accompanied by unchanged MTOR (mechanistic target of rapamycin) activity and decreased degradation of LC3 and SQSTM1/p62, the typical autophagic cargo proteins. Further functional and morphological analysis indicated that HBx dramatically impaired lysosomal acidification leading to a drop in lysosomal degradative capacity and the accumulation of immature lysosomes possibly through interaction with V-ATPase affecting its lysosome targeting. Moreover, clinical specimen test showed increased SQSTM1 and immature lysosomal hydrolase CTSD (cathepsin D) in human liver tissues with chronic HBV infection and HBV-associated liver cancer. These data suggest that a repressive effect of HBx on lysosomal function is responsible for the inhibition of autophagic degradation, and this may be critical to the development of HBV-associated HCC. PMID- 24401570 TI - New strategy for detection of subclinical coronary atherosclerosis in asymptomatic patients with type 2 diabetes based on cardiac multi-detector computed tomography and treadmill test. AB - BACKGROUND: The current screening strategy for subclinical coronary atherosclerosis in asymptomatic diabetic patients is not sufficient in real clinical practice. A new strategy was investigated that uses cardiac multi detector computed tomography (MDCT) and a treadmill test (TMT). METHODS AND RESULTS: A total of 445 self-referred asymptomatic diabetic patients underwent cardiac MDCT. The treatment plan was determined according to the new strategy that uses MDCT and TMT. All patients underwent clinical follow-up and cardiac events were investigated. The incidence of subclinical atherosclerosis was 49.4%. The group without plaque underwent clinical follow-up without treatment and did not experience any cardiac events in 675.1 person-years of follow-up. Among patients with subclinical atherosclerosis without significant stenosis (n=136) who received medical treatment only, 11 patients experienced cardiac events over 326.4 person-years. The patients with significant stenosis (n=84) underwent TMT. Patients with positive TMT (n=14) underwent coronary angiograms and revascularization therapy was performed in all of them over 39.2 person-years. Patients with negative TMT (n=70) underwent medical treatment, and 27 of them experienced cardiac events. The incidence of cardiac death was 0% during 3 years of follow-up. CONCLUSIONS: The new strategy for detecting subclinical atherosclerosis on MDCT combined with TMT may be a useful method for minimizing the mortality rate from cardiovascular disease in asymptomatic diabetic patients. PMID- 24401571 TI - Robot-assisted coronary artery bypass. PMID- 24401572 TI - Operability assessment and postoperative outcome in chronic thromboembolic pulmonary hypertension. PMID- 24401574 TI - [Selection of muscle relaxants in special patients]. PMID- 24401573 TI - Current venous thromboembolism management and outcomes in Japan. AB - BACKGROUND: Epidemiology and clinical management of acute venous thromboembolism (VTE) are not readily available in Japan. METHODS AND RESULTS: The Japan VTE Treatment Registry (JAVA) is a multicenter cohort study of consecutive patients with an objectively confirmed, symptomatic acute pulmonary embolism (PE), symptomatic acute deep vein thrombosis (DVT), or asymptomatic acute proximal DVT. Of the 1,076 patients enrolled with acute VTE, 68.7% presented with an isolated DVT; 17.0% had PE alone; and 14.4% had both. VTE management was characterized by a high rate of inferior vena cava filter insertion (40.6%), frequent thrombolysis (21.1%), and sub-therapeutic unfractionated heparin-based anticoagulation, followed by warfarin prescription, mostly targeting an international normalized ratio of 2.0 (range, 1.5-2.5). During a mean observation period of 252.5 days, 29 recurrent cases of VTE were documented, yielding an incidence rate of 3.9 per 100 patient-years. A total of 123 patients died during the study period, corresponding to a rate of 16.6 deaths per 100 patient-years. The incidence of major bleeding was 3.2% per patient-year, including 2 fatal hemorrhages and 7 intracranial hemorrhages. CONCLUSIONS: VTE management in Japan is characterized by a highly aggressive strategy in the acute phase, in contrast to protocols that use low-level anticoagulation. The VTE recurrence rates in Japan and Western countries are similar, but mortality is higher in Japan, with significant variability depending on patient and management characteristics. PMID- 24401575 TI - [Side effects of muscle relaxants]. PMID- 24401576 TI - [The methods of administration of muscle relaxants during maintenance of general anesthesia]. PMID- 24401577 TI - [Knowledge on the muscle relaxant effect of residual block]. PMID- 24401578 TI - [New skills in minimally invasive neurosurgery: retractorless surgery]. PMID- 24401579 TI - [Prevalence of REM sleep behavior disorder in patients with brainstem lesions]. AB - OBJECTIVE: To explore the prevalence of REM sleep behavior disorder (RBD) and define the brainstem structures likely to be involved in its pathogenesis in patients with brainstem lesions on magnetic resonance imaging (MRI). METHODS: Sixty-two patients with definite brainstems lesions on brain MRI were recruited from Neurology Department, Peking Union Medical College Hospital. And 66 gender and-age-matched healthy subjects were included as controls. RBD screening questionnaire (RBDSQ) was provided. All patients fulfilling clinical criteria for RBD underwent a two-night polysomnography (PSG) with synchronized audio-visual recording and the evaluations of Zung self-rating depression scale (SDS) and Zung self-rating anxiety scale (SAS). RESULTS: The brainstem group had a mean age of 43+/-16 years (range, 18-65) while the controls a mean age of 41+/-13 years (range, 18-65). In brainstem group, SDS scores were 38+/-4 (range, 35-44); SAS scores 43.0+/-5.8 (range, 36-49). In controls, SDS scores were 64+/-6 (range, 59 68); SAS scores 69.5+/-2.1 (range, 68-71). Five patients in the brainstem group and two in the control group fulfilling the clinical criteria for RBD were confirmed after PSG. All five patients had focal lesion on pontine tegmentum. Treatment with clonazepam at bedtime completely resolved the RBD symptoms. CONCLUSION: RBD is common in patients with brainstem lesions. And its definite diagnosis is based upon clinical symptoms and PSG examination. PMID- 24401580 TI - [The effect of two methods guided fluid therapy to the patient undergoing open gastrointestinal surgery]. AB - OBJECTIVE: To investigate the effect of central venous blood oxygen saturation (ScvO2) and venous-arterial PCO2 (P(cv-a)CO2) guided fluid therapy on tissue perfusion, gastrointestinal function recovering and outcome of the patients who undergoing open gastrointestinal surgery. METHODS: Forty patients undergoing open gastrointestinal surgery were randomly divided into 2 groups (n = 20 each): ScvO2 guided fluid therapy (group S) and P(cv-a) CO2 guided fluid therapy (group P). All the patients were infused 10 ml/kg lactated Ringer's (LR) solution before anesthesia induction, they were all also given a continuous lactated Ringer's (LR) solution's infusion at the speed of 2 ml.kg(-1).h(-1) during the operation. While, 6%HES 130/0.4 (free flex 6%HES 130/0.4, Fresenius Kabi) infusion was different between the 2 groups, when the patients of group S's central venous blood oxygen saturation < 75% or venous-arterial PCO2 in the patients of P group >=6 mm Hg, then infused 6%HES 130/0.4. Arterial and central venous blood gas analyses were performed every 20 minutes after skin incision, measure the venous and arterial lactate value, and record the anal exhaust time after surgery, postoperative complications and mortality in 28 days. RESULTS: Compared with group S, the arterial lactate value in T4 (after operation began 80 min) were significantly decreased in group P (P = 0.013), and venous lactate value in T5 (after operation began 100 min) were also lower (P = 0.044), other lactate value were not different (P > 0.05) . The anal exhaust time was not different between the two groups (P = 0.673). All the patients were survival, and there were no obvious postoperative complications. CONCLUSION: Compared to group S, there was a transient improvement in tissue perfusion in group P, but there were no difference in complications and mortality. PMID- 24401581 TI - [Clinical observation of CT guided two needles puncturing crossed through disc for superior hypogastric block to manage intractable pelvic cancer pain]. AB - OBJECTIVE: To observe the feasibility and clinical efficacy of CT guided two needles puncturing crossed through disc for superior hypogastric block with alcohol to manage intractable pelvic cancer pain. METHODS: Thirty-one cases of advanced pelvic cancer suffering from untreatable pain in lower abdomen in our hospital from December 2009 to May 2012 were analyzed, the patients were treated with both sides of superior hypogastric block with absolute alcohol by CT guided two needles puncturing crossed through L5-S1 interlaminar space. Complications during and after the surgery were recorded. To observe and follow-up visual analog scale pain scores (VAS) and the daily oral morphine consumption on just before operation, at 1 week, 1 and 3 months after operation. RESULTS: No case suffered serious complication. A week later of surgery the curative effect of 20 patients: clinical cure in 17 cases, excellent in 14 cases, the effective rate was 100%. Compared with preoperation, The score of VAS on 1 week, 1 and 3 months after the surgery (2.0+/-0.7, 2.3+/-0.6, 3.0+/-0.4) were strikingly lower than before operation (7.7+/-0.7, P < 0.01); The daily oral dose of morphine of post operation were significantly decreased in the three time points ((35+/-17) mg, (42+/-22) mg and (53+/-19) mg respectively) than the dose of pre-operation ((201+/-119)mg, P < 0.01). CONCLUSION: Superior hypogastric block with alcohol with double needles crossed transdiscal approach may be a safe, simple and effective method for relieving the severe pain of advanced pelvic cancer patients. PMID- 24401582 TI - [Application of apparent diffusion coefficient ratio in the diagnosis of bladder cancer grading pre-operation]. AB - OBJECTIVE: To explore the value of apparent diffusion coefficient (ADC) ratio in the diagnosis of bladder cancer pre-operation by analyzing its differences among different grades of bladder cancer. METHODS: A total of 52 cases of bladder cancer were all definitely diagnosed with histological results.Routine examinations of magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) were performed preoperatively on each patient. ADC map was constructed in work station and ADC values of tumor and internal obturator muscle were measured (b = 800 s/mm(2)).Ratio of ADC was calculated with internal obturator muscle as reference site. Then the relationship between ADC ratio and bladder cancer grade was analyzed. RESULTS: Mean ratio of ADC of all tumors was 0.98+/-0.35, G1 (1.12+/-0.21) and G2 (0.67+/-0.29), the sensitivity and specificity of ADC ratio was 90.2% and 85.3% respectively with an optimal threshold of 0.96. The ratios of ADC of low-grade group were significantly higher than those of high-grade group while the values of non-muscle-invasive group were significantly higher than those of muscle-invasive group. The ratios of ADC of tumor were inversely associated with the malignancy degree of bladder cancer (r = -0.845, P < 0.05). CONCLUSION: The ratio of ADC of bladder cancer reflects the lesion tissue properties. And its measurement plays an important role in the diagnosis of bladder cancer grading pre-operation. PMID- 24401583 TI - [Correlation study of HPV-16 existential status with Th17/Treg cytokines]. AB - OBJECTIVE: To explore the relationship between the presence of HPV-16 DNA and the expression Treg surface marker Foxp3(+), peripheral blood levels of Th17/Treg cell-associated cytokines and explore their roles and significance in cervical cancer progression. METHODS: Between January 2012 and October 2012 at Shengjing Hospital of China Medical University, a total of 142 HPV16 positive patients were divided into cervical cancer (CC, n = 60), cervical intraepithelial neoplasia (CIN, n = 65) and control group (n = 17). Cervical liquid-based cytological (LBC) samples were collected to detect E2 and E6 genes of HPV type 16 using multiple real-time polymerase chain reaction (PCR). E2/E6 ratio was used to evaluate the physical status of HPV-16 DNA in host cell genome. The SP immunohistochemical method was used to detect the expressions of FOXP3 in cervical lesions. The concentrations of Th17/Treg cell-associated cytokines were detected by enzyme linked immunosorbent assay (ELISA). RESULTS: Under the same status of HPV16 DNA in vivo, the levels of Foxp3(+), transforming growth factor-beta (TGF-beta) and interleukin-10 (IL-10) were significantly higher than those of the control group (P < 0.01) while the levels of interleukin-17 (IL-17) and interleukin-21 (IL 21)were significantly lower than those of the control group (P < 0.05) . In the same disease, HPV16 DNA integration rate grew with the increases of Foxp3(+), TGF beta and IL-10 while IL-17 and IL-21 were opposite. In the different status of HPV16 type DNA, the expression of Foxp3(+) was closely correlated with Federation International of Gynecology and Obstetrics (FIGO) stage, histological grade and lymphnode metastasis (P < 0.05) except for age (P > 0.05). CONCLUSION: Treg cytokines, HPV16 integration rate and severity of cervical lesions are positively correlated while Th17 cytokines show opposite effects. Th17/Treg cell-associated cytokines may play an important role in the occurrence and development of cervical cancer. PMID- 24401584 TI - [Segmental cut-off bridge and local floating technology for the treatment of ossification of ligamentum flavum in thoracic spine]. AB - OBJECTIVE: To explore the efficacy and safety of segmental cut-off bridge and local floating technology for the treatment of ossification of ligamentum flavum (OLF) in thoracic spine. METHODS: Retrospective study was performed in 98 patients with thoracic OLF who under went operation. There was 56 males and 42 females with an average age of 45.8 (35-73) years. The average duration of onset was 17 (3-51) months. The main clinical symptoms were numbness and paraesthesia (n = 90), lower limb weakness and walking trouble (n = 46), positive pyramidal tract signs (n = 33) and sphincter function obstacle (n = 9). OLF was screened and diagnosed by radiology, magnetic resonance imaging (MRI), computed tomography (CT) or CT myelography (CTM). A total of 142 OLF nidus were spotted. The lesions involved single segment (n = 32), double segments (n = 56), three segments (n = 6) and >= four segments (n = 4). And the locations were at upper thoracic segment (T1-4) (n = 34), middle thoracic segment (T5-8) (n = 23) and lower thoracic segment (T9-12) (n = 42). The OLF nidus were removed by local floating technology oft windowing at cephalic and caudal ends and a cut-off bridge at both sides of involved segments. Pre- and post-operative Japanese Orthopedic Association (JOA) scores and Epstein grades were recorded to evaluate the outcomes. RESULTS: The mean loss volume of blood was 320 ml and operative duration 155 min. All cases recovered independent activities. The mean follow-up period was 28 (13-48) months. The mean preoperative JOA score was 4.3 (1-8) points and the mean postoperative JOA score 9.7 (5-11) points. The recovery rate was 78.8%. According to Epstein grade, the excellent and good rate was 86.7%. CONCLUSION: As a common cause of thoracic spinal cord compression, OLF should be operated as early as possible. Based upon clinical and imaging findings, the application of segmental cut-off bridge and local floating technology is both safe and efficacious in the treatment of OLF in thoracic spine. PMID- 24401585 TI - [Efficacy evaluation of treating cervical spondylopathy with the Discover artificial cervical disc prosthesis]. AB - OBJECTIVE: To explore the clinical and radiological outcomes of Discover artificial cervical disc arthroplasty and the range of motion status on adjacent segments for cervical spondylosis causing radiculopathy or myelopathy. METHODS: A total of 18 consecutive patients underwent cervical arthroplasty with the Discover artificial cervical disc at our hospital. Clinical and radiological follow-ups were conducted. Their radiographic parameters of treatment and adjacent segments were evaluated at Month 1, 3, 6, 12, 18 post-operation. And the Japanese Orthopedic Association (JOA) score, visual analog scale (VAS) pain score and Odom's scale were recorded and analyzed. RESULTS: During follow-ups over an average of 15 months, there was no occurrence of vascular injury, severe complications or prosthesis displacement and loosening. The score of JOA was 7.2+/-1.8 at preoperation and 16.7+/-4.5 at postoperation. And the score of VAS was 8.15+/-1.65 at preoperation and 2.03+/-1.12 at postoperation. CONCLUSION: Discover artificial cervical disc arthroplasty is efficacious and the patients recover quickly. Targeted cervical segments may be stabilized and their physiological ranges of motion preserved. PMID- 24401586 TI - [Relationship between CNTF gene polymorphism and athletes training adaptation of muscle tissue]. AB - OBJECTIVE: To explore the relationship between CNTF gene polymorphism and athletes training adaptation of muscle tissue. METHODS: A total of 215 new students without a training history CNTF genotype were recruited from a sports college. During training, the changes in test object biceps muscle belly cross sectional area, muscle fatigue and muscle damage related biochemical indices were detected. And the impact of gene polymorphism was analyzed on the detection results. RESULTS: After training, biceps brachii muscle cross-sectional areas showed different degrees of growth and the GG gene type growth was greater than other genotypes (P < 0.05) . At post-training physical examination, all subjects of muscle fatigue and muscle damage index were higher than those of the control group, but no obvious difference existed between examination groups.In basic training at the end of physical examination, the related indices of each group were higher than those of the control group, but the values of lactic acid, blood urea nitrogen and serum CK value were lower for object type GG than those for the other groups [ (234.7+/-57.5) vs (84.7+/-24.7) U, (5.8+/-0.8) vs (4.3+/-0.6) mmol/L, (271.5+/-98.7) vs (59.2+/-35.6) U] (P < 0.05). CONCLUSION: During training, muscle cross-sectional area of GG genotype grows more while the serum levels of muscle injury are significantly lower than those of other groups. In summary, GG genotype has better muscle training adaptation than GA and AA. PMID- 24401587 TI - [A comparative study of complete video-assisted thoracoscopic lobectomy and video assisted mini-thoracotomy in treatment of lung cancer]. AB - OBJECTIVE: To explore the clinical application value of complete video-assisted thoracoscopic (cVATS) lobectomy in the mini-invasive treatment of lung cancer. METHODS: 90 patients with non-small cell lung cancer (NSCLC) who had undergone lobectomy were reviewed. According to surgical approach, complete video-assisted thoracoscopic lobectomy group (cVATS, n = 47) and video-assisted mini-thoracotomy group (VAMT, n = 43) were studied. Numbers of dissected lymph nodes, operation duration, volumes of intraoperative bleeding, duration of postoperative catheter drainage, length of postoperative hospital stay, incidence rates of postoperative complications, postoperative pain scores of patients were compared between the two groups retrospectively. RESULTS: There were no significant differences in numbers of dissected lymph nodes, operation duration, bleeding during operation, incidence rates of postoperative complication between the two groups (P > 0.05). Duration of postoperative catheter drainage and length of postoperative hospital stay of patients in cVATS group were shorter than those in VAMT group (P < 0.05). Pain scores of patients in cVATS group were lower than those at the same time in VAMT group (P < 0.05). CONCLUSION: Complete video-assisted thoracoscopic lobectomy is safe and effective surgical strategy for lung cancer patients with advantage of rapid recovery. PMID- 24401588 TI - [A retrospective study on salvage surgery after local failure of definitive chemoradiotherapy for esophageal carcinomas]. AB - OBJECTIVE: To evaluate the feasibility and efficacy of salvage surgery after local failure of definitive chemoradiotherapy (dCRT) for esophageal carcinomas. METHODS: We retrospectively reviewed the esophageal cancer patients underwent salvage surgery (Group A, 26 cases) or non-surgical therapy (Group B, 11 cases) after local failure of dCRT(cT1-3N0-1M0) between July 2008 and June 2010. RESULTS: The rate of resection was 84.6% in Group A, R0 was 69.2%. There was no mortality after surgery. The rate of postoperative complications is 53.8%, especially pneumonia 30.8%, anastomosis leakage 11.5% and arrhythmia 7.7%. The median survival time is 11.1 months; the 2-year survival rate of Group A was 23.1% in Group A. The non-surgical therapy was given including second-line chemotherapy and esophagus stents; the median survival time is 8.1 months (3.1 15.1) in Group B. The survival rate of Group A was higher than Group B (Kaplan Meier, P = 0.013). CONCLUSION: Salvage surgery provides survival benefit for esophageal cancer patients with local persistent or recurrence after primary dCRT, despite of high morbidity.Salvage surgery should be carried out for patients with good physical condition and complete resection is technically possible. PMID- 24401589 TI - [Cerebral microbleeds detected on T2-weighted gradient echo magnetic resonance and its clinical significance]. AB - OBJECTIVE: To explore the diagnostic value of T2-weighted gradient-echo magnetic resonance imaging (MRI) in cerebral microbleeds (CMBs) and its clinical significance. METHODS: The distribution of CMBs and follow-up observations were performed by routine T1WI, T2WI and T2-weighted gradient echo sequence in 634 patients clinically suspected for stroke. RESULTS: In 149 patients, a total of 1140 CMBs occurred predominantly in cortex-subcortical area (n = 471, 41.31%), basal ganglia (n = 289, 25.35%), thalamus (n = 199, 17.45%), brain stem (n = 90, 7.89%) and cerebellum (n = 91, 7.98%). Among them, 137 patients had various degrees of ischemic brain changes, displayed iso-intensity or hypo-intensity on T1WI, hyper-intensity on T2WI and FLAIR in basal ganglia, white matter around sided ventricle and brain stem. There were 23 patients with cerebral infarction and 5 with CMBs after hemorrhagic brain stroke. And 12 of them had new hemorrhagic stroke in 2-6 months. CONCLUSION: T2-weighted gradient echo MRI has obvious advantages in the detection of CMBs. The presence of CMBs suggests a risk of cerebral hemorrhage. PMID- 24401590 TI - [A prospective study of pessary treatment for pelvic organ prolapse and health related quality-of-life]. AB - OBJECTIVE: To explore the effects of pessary use on symptomatic improvement and quality-of-life (QOL) in women with pelvic organ prolapse (POP). METHODS: For this prospective cohort study, 79 patients with symptomatic POP were evaluated for pessary insertion between October 2011 and February 2013. After 3 and 6 months of consistent pessary use, quality of life was assessed with the Chinese version of Short-Form 12-Item Health Survey (SF-12) and pelvic floor impact questionnaire short form (PFIQ-7). RESULTS: Their average age was (66+/-9) years, average parity (2.4+/-1.1) and average duration of POP (68+/-14) months. Among them, 63 (79.7%) continued pessary use at 3 months and 46 (58.2%) at 6 months. The reasons for dropout were inappropriate size, discomfort and urinary retention. Compared with baseline findings, SF-12 and PFIQ-7 demonstrated significant improvement in patient QOL at 3 months and 6 months. CONCLUSION: Pessary use results in significant changes of QOL for POP patients. And it is a viable noninvasive treatment for pelvic organ prolapse. PMID- 24401591 TI - [Applications of laparoscopic ultrasound in gynecological surgery]. AB - OBJECTIVE: To evaluate the application value of laparoscopic ultrasonography (LUS) in gynecological surgery. METHODS: Retrospective analyses were performed for 52 cases undergoing LUS during laparoscopic extirpation/excision of gynecological tumors. Aloka 7.5-MHz laparoscopic probe was used to detect the residual lesions during laparoscopic operations. The findings of LUS were compared with those of preoperative transvaginal ultrasound and postoperative pathohistological examinations. RESULTS: Preoperative diagnoses were corrected by LUS in 9 cases. And 34 residual lesions located by LUS were successfully removed. CONCLUSION: With a high detection rate and diagnostic accuracy rate in the diagnosis of gynecologic disease, LUS can locate invisible lesions during laparoscopic operations and provide guidance for radical tumor removal. It is a safe and valuable assistance for gynecologic surgery. PMID- 24401593 TI - [A modified goat model of acute spinal cord compression injury from a percutaneous balloon catheter: method feasibility and preliminary observation]. AB - OBJECTIVE: To establish a goat model of acute spinal cord compression injury through a modified percutaneous technique with a Foley double-lumen urine catheter and explore the method feasibility and preliminary observation. METHODS: Twelve adult male Chongming goats were randomly divided into 3 groups:control (A, n = 4), 0.5 ml compression (B, n = 4) and 1 ml compression (C, n = 4). After local anesthesia, all animals received epidural balloon catheter (5Fr) insertion via a percutaneous trans-lumbosacral interlaminar space technique that mimicked the method used in vascular access for angiography. The balloon catheter was advanced under fluoroscopic guidance until its distal tip reached the middle of T6 level.One week later, for groups B and C, the balloon was inflated by half strength contrast material, 0.5 ml and 1 ml, respectively. The balloon was left inflated for 30 min and then deflated. The images of computed tomography (CT) and magnetic resonance (MR) were taken before and after surgical procedures.Quantitative assessment of spine canal occupying rate was accomplished by an off-line software program based on CT results. Motor function was assessed by the modified Tarlov scale. Two animals of each group were sacrificed after a total observation period of 48 h and 72 h respectively.Spinal cords from the injured level were then obtained for pathologic examinations. RESULTS: All animals underwent successful catheterization occupying 6.8%+/-0.7% (Group A), 6.7%+/-0.7% (Group B) and 6.6%+/-0.6% (Group C) of spine canal respectively. After inflation, the occupying rate of groups B and C achieved 43.4%+/-2.5% and 88.1%+/-2.3% respectively.Ventral compression of spinal cord was noted on MR images.Hindlimb movement remained normal after catheter insertion in all groups. All animals in group B and C became paraplegic after inflation. And a positive correlation existed between injection volume and Tarlov score. Pathological findings confirmed neuron atrophy, increased gap around neurons, mild demyelination and vacuolar degeneration both in groups B and C at 48 h after injury. Pathological changes deteriorated at 72 h after injury. CONCLUSION: The results of behavioral evaluation, radiographic images and pathological examination reveal an evidence of acute spinal cord injury. Percutaneous epidural balloon catheter insertion differs from previous techniques by avoiding surgical exposure and associated artifacts, yet it offers injury mechanisms similar to those of human spinal cord injury. As a new means of modeling spinal cord injury in animals, this technique has many potential applications. PMID- 24401592 TI - [Efficacy of local injection of RhTNFR: Fc in collagen-induced arthritis of rats]. AB - OBJECTIVE: To evaluate the efficacy of recombinant human tumor necrosis factor alpha receptor II: IgG fusion protein (RhTNFR:Fc) local injection in collagen induced arthritis (CIA) of rats. METHODS: Twenty-four CIA rats were randomly divided into 3 groups: single therapy (Group I), multiply therapies (Group II) and control (Group III). Group I received normal saline thrice after a single RhTNFR:Fc local treatment while Groups II and III had 4 times of RhTNFR:Fc or normal saline local injection. The severities of right ankle and systemic inflammation were assessed by arthritis index (AI) at baseline and every week after local injection (visits 1, 2, 3 and 4). Serum C reactive protein (CRP) was measured after the last visit. And right ankles were further examined through radiology and pathology. RESULTS: Local or systemic AI of Group I were significantly lower than that of baseline at visit 1 (P < 0.05), but increased during other visits. And local or systemic AI of Group II gradually decreased at each follow-up, but AI of Group III showed no decline. The radiographic scores (5.70+/-0.67 and 4.90+/-0.73), histopathological scores (6.00+/-0.67 and 3.80+/ 0.91) and serum CRP concentration (7.50+/-0.87 and 3.09+/-0.76 ug/ml) of Group I and Group II were lower than those of Group III (6.60+/-1.26, 7.10+/-0.7 and 12.15+/-3.47 ug/ml, P < 0.05). And all these parameters of Group I were higher than those of Group II (P < 0.05). CONCLUSION: Local injection of RhTNFR:Fc can effectively alleviate disease activity of CIA and reduce CRP concentration, radiographic and histopathological scores. Multiple therapies show a better efficacy than single injection. PMID- 24401594 TI - [Study on propofol and fentanyl administrated via common carotid artery in rabbits]. AB - OBJECTIVE: To compare the pharmacodynamic differences of common carotid artery administration with ear vein administration of propofol and fentanyl in rabbits. METHODS: Sixty New Zealand white rabbits were randomly divided into four groups(n = 15):PvFv, PvFa, PaFv and PaFa groups. Propofol 30 mg*kg(-1)*h(-1) and fentanyl 2 ug*kg(-1)*h(-1)were administrated via the ear vein or the common carotid artery. The outcomes were recorded, including the time of consciousness loss and recovery, to electrocerebral silence, dose of propofol and fentanyl, mean arterial pressure, heart rate, respiration rate and SpO2. RESULTS: (1) None of rabbits appeared breathing to be depressed seriously in group PaFa, while respiratory in the other groups were significantly depressed. (2) The dosage of propofol and fentanyl of group PaFa was significantly less than the other groups (P < 0.05). (3) The time of consciousness loss and recovery of group PaFa were shorter than the other three groups. CONCLUSION: Compared to drugs infusion via the ear vein, infusion of propol and fentanyl via the common carotid artery is more advantageous in some aspects, such as rapid anesthesia induction and recovery, smaller dose, and smaller impact on the hemodynamic and respiratory. PMID- 24401595 TI - Identifying critical sites of PrP(c)-PrP(Sc) interaction in prion-infected cells by dominant-negative inhibition. AB - A direct physical interaction of the prion protein isoforms is a key element in prion conversion. Which sites interact first and which parts of PrP(c) are converted subsequently is presently not known in detail. We hypothesized that structural changes induced by PrP(Sc) interaction occur in more than one interface and subsequently propagate within the PrP(C) substrate, like epicenters of structural changes. To identify potential interfaces we created a series of systematically-designed mutant PrPs and tested them in prion-infected cells for dominant-negative inhibition (DNI) effects. This showed that mutant PrPs with deletions in the region between first and second alpha-helix are involved in PrP PrP interaction and conversion of PrP(C) into PrP(Sc). Although some PrPs did not reach the plasma membrane, they had access to the locales of prion conversion and PrP(Sc) recycling using autophagy pathways. Using other series of mutant PrPs we already have identified additional sites which constitute potential interaction interfaces. Our approach has the potential to characterize PrP-PrP interaction sites in the context of prion-infected cells. Besides providing further insights into the molecular mechanisms of prion conversion, this data may help to further elucidate how prion strain diversity is maintained. PMID- 24401596 TI - "Ciliophagy": The consumption of cilia components by autophagy. AB - Chronic obstructive pulmonary disease (COPD) involves aberrant airway inflammatory responses to cigarette smoke (CS) associated with respiratory epithelial cell cilia shortening and impaired mucociliary clearance (MCC). The underlying cellular and molecular mechanisms for CS-associated cilia shortening have remained incompletely understood. We have previously demonstrated increased autophagy in the lungs of COPD patients; however, whether or not this process is selective for specific autophagic targets in the lung was not elucidated. Based on observations that increased morphological and biochemical indicators of autophagy correlate with cilia shortening in our models, we posited that autophagy might regulate cilia length in response to CS in the lung. We demonstrate that CS-induced cilia shortening occurs through an autophagy dependent mechanism mediated by the deacetylase HDAC6 (histone deacetylase 6). Autophagy-impaired (Becn1(+/-), map1lc3b(-/-), or Hdac6(-/Y)) mice resist CS induced cilia shortening. Furthermore, cilia components are identified as autophagic substrates during CS exposure. Assessment of airway cilia function using a 3D MCC assay demonstrates that Becn1(+/-), map1lc3b(-/-), and Hdac6(-/Y) mice or mice injected with the HDAC6 inhibitor tubastatin A are protected from CS associated mucociliary dysfunction. We concluded that an autophagy-dependent pathway regulates cilia length during CS exposure, which identifies new pathways and targets in COPD. PMID- 24401597 TI - Reduced organic anion transporter expression is a risk factor for hepatocellular carcinoma in chronic hepatitis C patients: a propensity score matching study. AB - OBJECTIVES: Recent reports indicated that reduced SLC22A7 (a gene-encoding organic anion transporter 2) expression in noncancerous liver tissue predicts hepatocellular carcinoma (HCC) recurrence after curative resection. Our study aimed to elucidate the association between SLC22A7 expression and HCC development in chronic hepatitis C patients. METHODS: HCC recurrence after local ablation therapy and SLC22A7 expression in noncancerous liver tissue were analyzed in 20 patients. Subsequently, the association between de novo HCC development and SLC22A7 expression was examined at baseline in 38 hepatitis C patients without HCC who subsequently developed HCC as well as in 76 hepatitis C patients who did not develop HCC and were matched for age, gender and stage of fibrosis. RESULTS: In the patients whose HCC had been cured, reduced SLC22A7 expression in noncancerous liver tissue was significantly associated with a high incidence of multifocal HCC recurrence. In patients without HCC at baseline, cumulative incidence of de novo HCC development was significantly higher with a reduced SLC22A7 expression than with a normal expression (p = 0.01). This difference remained significant among patients without known risk factors for HCC like age and advanced fibrosis. CONCLUSION: Reduced SLC22A7 expression in the liver indicates a significant risk for HCC development in chronic hepatitis C, independently of other risk factors. PMID- 24401598 TI - Ultrasound in pulmonology. PMID- 24401599 TI - Transcriptional and proteomic analysis reveal recombinant galectins of Haemonchus contortus down-regulated functions of goat PBMC and modulation of several signaling cascades in vitro. AB - In this study, a combined proteomic and transcriptomic analysis was performed to understand the mechanisms underlying the immunomodulation induced by recombinant galectins of Haemonchus contortus (rHco-gal-m/f) on goat peripheral blood mononuclear cells (PBMC). We demonstrated that rHco-gal-m/f could be distinguished by antisera from goats experimentally infected with H. contortus and bound to the surface of goat PBMC. Following rHco-gal-m/f exposure, 16 differentially expressed proteins were identified, which function in biological processes such as stimulus response, biological regulation and localization. According to Gene Ontology Annotation, 15 proteins (93.8%) had binding activity and 9 proteins (56.3%) had catalytic activity. A series of transcriptomic analyses were performed subsequently to assess the expression change of certain pathway members. The integrated results of proteomic and transcriptomic analysis suggested that the activation of VEGF pathway, free radical producing pathway, NFkappaB pathway and ubiquitin-proteasome pathway was inhibited following exposure to rHco-gal-m/f, while the TLR pathway and CASPASE pathway were activated. Cytokine production and T cell differentiation were also influenced. Cell migration assays and ELISA were performed and the results were in accordance with the change of the proteins and genes. The protein and gene profiles determined here identified several mechanisms underlying the rHco-gal-m/f-induced immunomodulation of goat PBMC. BIOLOGICAL SIGNIFICANCE: This research provided insight into the interactive relationship between parasitic nematode galectins and host PBMC. It also shed new lights on the understanding of molecular mechanisms of helminthic immune evasion. PMID- 24401600 TI - Effect of dietary defatted diatom biomass on egg production and quality of laying hens. AB - BACKGROUND: This study was to determine if feeding laying hens with defatted diatom microalgal biomass (DFA) from biofuel production affected their egg production and health status. METHODS: Five replicates of 5 individually caged ISA Babcock White leghorn hens were fed 4 diets, including a corn-soybean meal control diet, a diet containing 7.5% DFA substituting for soybean meal, and diets containing 7.5% or 15% DFA substituting for corn and soybean meal. Body weights, feed intake, feed conversion ratio (FCR), rate of egg production, egg size, egg mass, and several characteristics of eggs were determined at 4 and 8 wk. Venous blood was sampled at 4 and 8 wk for measurement of 5 biomarkers of health. RESULTS: The 15% DFA diet decreased (P < 0.05) feed intake, egg production, and plasma uric acid concentrations as compared with the control diet, but increased (P < 0.05) egg albumen weight and height compared with the 7.5% DFA diets. The two levels of DFA produced dose-dependent (P < 0.05) changes in three color measures of egg yolk, without affecting four hen plasma biochemical indicators of health. CONCLUSIONS: Feeding laying hens with 7.5% DFA in the corn-soybean meal diet for 8 wk had no adverse effect on their health, egg production, or egg quality, but 15% inclusion reduced feed intake, egg production, and efficiency of feed utilization. PMID- 24401601 TI - Regulation of VASP by phosphorylation: consequences for cell migration. AB - Phosphorylations control all aspects of vasodilator-stimulated phospho-protein (VASP) function. Mapped phosphorylation sites include Y39, S157, S239, T278, and S322, and multiple kinases have been shown to mediate their phosphorylation. Recently, Protein Kinase D1 (PKD1) as a direct kinase for S157 and S322 joined this group. While S157 phosphorylation generally seems to serve as a signal for membrane localization, phosphorylations at S322 or at S239 and T278 have opposite effects on F-actin accumulation. In migrating cells, S322 phosphorylation increases filopodia numbers and length, while S239/T278 phosphorylations decrease these and also disrupt formation of focal adhesions. Therefore, the kinases mediating these phosphorylations can be seen as switches needed to facilitate cell motility. PMID- 24401603 TI - Delayed pulmonary arterial hypertension in relation to pulmonary damage score after pneumonectomy under protective ventilation: experimental study. AB - OBJECTIVE: To characterize pulmonary hemodynamic changes in relation to lung injury at 2 time points [48 h (H48) and 168 h (H168)] after pneumonectomy under intraoperative protective ventilation in order to improve postpneumonectomy pulmonary edema (PPE) prevention. METHOD: Fifteen pigs (25 +/- 1.9 kg) were randomly allocated to nonsurgical (control, n = 5) and surgical (H48 and H168) groups. A left pneumonectomy under volume-controlled one-lung ventilation (OLV) (low tidal volume, positive end-expiratory pressure = 4 cm H2O, inspired oxygen fraction = 50%) was performed in surgical animals. Mean pulmonary artery pressure (MPAP) and pulmonary artery occlusion pressure were recorded. Pulmonary vascular resistance (PVR) was calculated. Pulmonary damage score (PDS) and bronchoalveolar albumin level were evaluated. Data were collected after induction (T0), after OLV (T1), after left pneumonectomy (T2), and at H48 or H168 (T3). RESULTS: Pneumonectomy caused precapillary pulmonary arterial hypertension (PAH) measured at T3 H48 (36.2 +/- 3.67 mm Hg). PAH was delayed temporarily (both after OLV and after pneumonectomy) (p < 0.001), and linked with PVR (r = 0.93; p < 0.05). PDS and bronchoalveolar albumin level varied with MPAP (r = 0.76; p < 0.001 and r = 0.55; p < 0.05). CONCLUSION: Given that PAH is delayed and related to PVR increase, indicating secondary pulmonary vascular bed adaptation limits, pharmacological treatment should focus on a delayed failure in pulmonary capacitance in patients at risk of PPE. PMID- 24401602 TI - A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility. AB - INTRODUCTION: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow up strategy. METHODS: Sixty-six non-HLA SNPs showing a P value <10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. RESULTS: We observed nominal associations for both PPARG rs310746 (PMH = 1.90 * 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 * 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 * 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis. CONCLUSION: Our results suggest a role of PPARG gene in the development of SSc. PMID- 24401605 TI - Variation in brain organization of coral reef fish larvae according to life history traits. AB - In coral reefs, one of the great mysteries of teleost fish ecology is how larvae locate the relatively rare patches of habitat to which they recruit. The recruitment of fish larvae to a reef, after a pelagic phase lasting between 10 and 120 days, depends strongly on larval ability to swim and detect predators, prey and suitable habitat via sensory cues. However, no information is available about the relationship between brain organization in fish larvae and their sensory and swimming abilities at recruitment. For the first time, we explore the structural diversity of brain organization (comparative sizes of brain subdivisions: telencephalon, mesencephalon, cerebellum, vagal lobe and inferior lobe) among larvae of 25 coral reef fish species. We then investigate links between variation in brain organization and life history traits (swimming ability, pelagic larval duration, social behavior, diel activity and cue use relying on sensory perception). After accounting for phylogeny with independent contrasts, we found that brain organization covaried with some life history traits: (1) fish larvae with good swimming ability (>20 cm/s), a long pelagic duration (>30 days), diurnal activity and strong use of cues relying on sensory perception for detection of recruitment habitat had a larger cerebellum than other species. (2) Fish larvae with a short pelagic duration (<30 days) and nocturnal activity had a larger mesencephalon and telencephalon. Lastly, (3) fish larvae exhibiting solitary behavior during their oceanic phase had larger inferior and vagal lobes. Overall, we hypothesize that a well-developed cerebellum may allow fish larvae to improve their chances of successful recruitment after a long pelagic phase in the ocean. Our study is the first one to bring together quantitative information on brain organization and the relative development of major brain subdivisions across coral reef fish larvae, and more specifically to address the way in which this variation correlates with the recruitment process. PMID- 24401604 TI - Human autophagy gene ATG16L1 is post-transcriptionally regulated by MIR142-3p. AB - Multiple genetic studies have implicated the autophagy-related gene, ATG16L1, in the pathogenesis of Crohn disease (CD). While CD-related research on ATG16L1 has focused on the functional significance of ATG16L1 genetic variations, the mechanisms underlying the regulation of ATG16L1 expression are unclear. Our laboratory has described that microRNAs (miRNAs), key regulators of gene expression, are dysregulated in CD. Here, we report miRNA-mediated regulation of ATG16L1 in colonic epithelial cells as well as Jurkat T cells. Dual luciferase reporter assays following the transfection of vectors containing the ATG16L1 3' untranslated region (3'UTR) or truncated 3'UTR fragments suggest that the first half of ATG16L1 3'UTR in the 5' end is more functional for miRNA targeting. Of 5 tested miRNAs with putative binding sites within the region, MIR142-3p, upon transient overexpression in the cells, resulted in decreased ATG16L1 mRNA and protein levels. Further observation demonstrated that the luciferase reporter vector with a mutant MIR142-3p binding sequence in the 3'UTR was unresponsive to the inhibitory effect of MIR142-3p, suggesting ATG16L1 is a gene target of MIR142 3p. Moreover, the regulation of ATG16L1 expression by a MIR142-3p mimic blunted starvation- and L18-MDP-induced autophagic activity in HCT116 cells. Additionally, we found that a MIR142-3p inhibitor enhanced starvation-induced autophagy in Jurkat T cells. Our study reveals MIR142-3p as a new autophagy regulating small molecule by targeting ATG16L1, implying a role of this miRNA in intestinal inflammation and CD. PMID- 24401606 TI - Heme oxygenase-1 mediates oxidative stress and apoptosis in coxsackievirus B3 induced myocarditis. AB - BACKGROUND: Heme oxygenase-1 (HO-1), which is suggested to play a role in defending the organism against oxidative stress-mediated injuries, can be induced by diverse factors including viruses and iron. As coxsackievirus B3 (CVB3) infected SWR/J mice susceptible for chronic myocarditis were found to have a significant iron incorporation and HO-1 upregulation in the myocardium, we aimed to investigate the molecular interplay between HO-1 expression and iron homeostasis in the outcome of viral myocarditis. METHODS AND RESULTS: In susceptible SWR/J mice, but not in resistant C57BL/6 mice, we observed at later stages of CVB3 myocarditis significant iron deposits in macrophages and also in cardiomyocytes, which were spatially associated with oxidative stress, upregulation of HO-1 and caspase-3 activation. HO-1, which is also expressed in cultivated RAW 264.7 macrophages upon incubation with iron and/or CVB3, could be downregulated by inhibition of NO/iNOS using L-NAME. Moreover, specific inhibition of HO-1 by tin mesoporphyrin revealed a suppression of superoxide production in iron and/or CVB3-treated macrophages. The molecular relationship of HO-1 and caspase-3 activation was proven by downregulation with HO-1 siRNA in iron- and/or CVB3-treated cultivated cells. Importantly, iron was found to increase viral replication in vitro. CONCLUSION: These results indicate that HO-1 induces a paracrine signalling in macrophages via reactive oxygen species production, mediating apoptosis of heart muscle cells at later stages of myocarditis. Notably, in genetically susceptible mice iron potentiates the detrimental effects of CVB3 by the NO/HO-1 pathway, thus increasing cardiac pathogenicity. PMID- 24401607 TI - Nanopore analysis reveals differences in structural stability of ovine PrP(C) proteins corresponding to scrapie susceptible (VRQ) and resistance (ARR) genotypes. AB - Species, as well as individuals within species, have unique susceptibilities to prion infection that are likely based on sequence differences in cellular prion protein (PrP(C)). Species barriers to transmission also reflect PrP(C) sequence differences. Defining the structure-activity relationship of PrP(C)/PrP(Sc) with respect to infectivity/susceptibility will benefit disease understanding and assessment of transmission risks. Here, nanopore analysis is employed to investigate genotypes of sheep PrP(C) corresponding to differential susceptibilities to scrapie infection. Under non-denaturing conditions scrapie resistant (ARR) and susceptible (VRQ) genotypes display similar, type I (bumping) predominant event profiles, suggesting a conserved folding pattern. Under increasingly denaturing conditions both proteins shift to type II (intercalation/translocation) events but with different sensitivities to unfolding. Specifically, when pre-incubated in 2M Gdn-HCl, the VRQ variant had more of type II events as compared with the ARR protein, suggesting a more flexible unfolding pattern. Addition of PrP(Sc)-specific polyclonal antibody (YML) to the ARR variant, pre-incubated in 2M Gdn-HCl, reduced the number of type II events with no clear intercalation/translocation peak, whereas for VRQ, type II events above blockades of 90 pA bound YML. A second PrP(Sc)-specific antibody (SN6b) to a different cryptic epitope reduced type II events for VRQ but not the ARR variant. Collectively, the event patterns associated with sequential denaturation, as well as interactions with PrP(Sc)-specific antibodies, support unique patterns and/or propensities of misfolding between the genotypes. Overall, nanopore analysis identifies intermediate conformations that occur during the unfolding pathways of ARR and VRQ genotypes and may help to understand the correlation of structural properties that induce protein misfolding. PMID- 24401608 TI - Hypoxic preconditioning increases survival of cardiac progenitor cells via the pim-1 kinase-mediated anti-apoptotic effect. AB - BACKGROUND: Stem cells transplanted to the ischemic myocardium usually encounter massive cell death within a few days after transplantation, and hypoxic preconditioning (HPC) is currently used as a strategy to prepare stem cells for increased survival and engraftment in the heart. The purpose of this study is to determine whether Pim-1 kinase mediates any beneficial effects of HPC for human cardiac progenitor cells (CPCs). METHODS AND RESULTS: Human CPCs were isolated from an adult heart auricle and were purified by magnetic-activated cell sorting using c-kit magnetic beads; they were hypoxic preconditioned for 6h. Both Pim-1 and p-Akt were determined. CPCs were assigned to one of the following groups: (1) control (without HPC); (2) HPC; or (3) HPC+I (Pim-1 inhibitor). HPC can promote the survival of CPCs. HPC enhances the expression of Pim-1 kinase in a time dependent manner, which causes a reduction of proapoptotic elements (cytochrome c and cleaved caspase-3) and the preservation/modulation of important components of the mitochondria (Bcl-2, Bcl-XL and p-Bad), and attenuates mitochondrial damages. All of these protective effects were blocked by a Pim-1 inhibitor. CONCLUSIONS: Pim-1 plays a pivotal role in the protective effect of HPC for CPCs, and the promotion of the expression of Pim-1 in CPCs can as serve part of molecular therapeutic interventional strategies in the treatment of cardiomyopathy damage by blunting CPC death. PMID- 24401609 TI - Statins and renin-angiotensin system inhibitor combination treatment to prevent cardiovascular disease. AB - Hypercholesterolemia and hypertension are common risk factors for cardiovascular disease (CVD). Updated guidelines emphasize target reductions of overall cardiovascular risks. Experimental studies have shown reciprocal relationships between insulin resistance (IR) and endothelial dysfunction. Hypercholesterolemia and hypertension have a synergistic deleterious effect on IR and endothelial dysfunction. Unregulated renin-angiotensin system (RAS) is important in the pathogenesis of atherosclerosis and hypertension. Various strategies with different classes of antihypertensive medications to reach target goals have failed to reduce residual CVD risk further. Of interest, treating moderate cholesterol elevations with low-dose statins in hypertensive patients reduced CVD risk by 35-40% further. Therefore, statins are important in reducing CVD risk. Unfortunately, statin therapy causes IR and increases the risk of type 2 diabetes mellitus. RAS inhibitors improve both endothelial dysfunction and IR. Further, cross-talk between hypercholesterolemia and RAS exists at multiple steps of IR and endothelial dysfunction. In this regard, combined therapy with statins and RAS inhibitors demonstrates additive/synergistic effects on endothelial dysfunction and IR in addition to lowering cholesterol levels and blood pressure when compared with either monotherapy in patients. This is mediated by both distinct and interrelated mechanisms. Therefore, combined therapy with statins and RAS inhibitors may be important in developing optimal management strategies in patients with hypertension, hypercholesterolemia, diabetes, metabolic syndrome, or obesity to prevent CVD. PMID- 24401610 TI - The Na+/Ca2+ exchange inhibitor SEA0400 limits intracellular Ca2+ accumulation and improves recovery of ventricular function when added to cardioplegia. AB - BACKGROUND: The Na+/Ca2+ exchange inhibitor SEA0400 prevents myocardial injury in models of global ischemia and reperfusion. We therefore evaluated its potential as a cardioplegia additive. METHODS: Isolated rat cardiomyocytes were exposed to hypoxia (45 min) followed by reperfusion. During hypoxia, cells were protected using cardioplegia with (n=25) or without (n=24) SEA0400 (1 MUM), or were not protected with cardioplegia (hypoxic control, n=8). Intracellular Ca2+ levels were measured using Ca2+ sensitive dye (fura-2 AM). Isolated rat hearts were arrested using cardioplegia with (n=7) or without (n=6) SEA0400 (1 MUM) then reperfused after 45 min of ischemia. Left ventricular (LV) function, troponin release, and mitochondrial morphology were evaluated. RESULTS: Cardiomyocytes exposed to hypoxia without cardioplegia had poor survival (13%). Survival was significantly improved when cells were protected with cardioplegia containing SEA0400 (68%, p=0.009); cardioplegia without SEA0400 was associated with intermediate survival (42%). Cardiomyocytes exposed to hypoxia alone had a rapid increase in intracellular Ca2+ (305 +/- 123 nM after 20 minutes of ischemia). Increases in intracellular Ca2+ were reduced in cells arrested with cardioplegia without SEA0400; however cardioplegia containing SEA0400 was associated with the lowest intracellular Ca2+ levels (110 +/- 17 vs. 156 +/- 42 nM after 45 minutes of ischemia, p=0.004). Hearts arrested with cardioplegia containing SEA0400 had better recovery of LV work compared to cardioplegia without SEA0400 (23140 +/- 2264 vs. 7750 +/- 929 mmHg.MUl, p=0.0001). Troponin release during reperfusion was lower (0.6 +/- 0.2 vs. 2.4 +/- 0.5 ng/mL, p=0.0026), and there were more intact (41 +/- 3 vs. 22 +/- 5%, p<0.005), and fewer disrupted mitochondria (24 +/ 2 vs. 33 +/- 3%, p<0.05) in the SEA0400 group. CONCLUSIONS: SEA0400 added to cardioplegia limits accumulation of intracellular Ca2+ during ischemic arrest in isolated cardiomyocytes and prevents myocardial injury and improves recovery of LV function in isolated hearts. PMID- 24401611 TI - Characterization of the biological activity of a potent small molecule Hec1 inhibitor TAI-1. AB - BACKGROUND: Hec1 (NDC80) is an integral part of the kinetochore and is overexpressed in a variety of human cancers, making it an attractive molecular target for the design of novel anticancer therapeutics. A highly potent first-in class compound targeting Hec1, TAI-1, was identified and is characterized in this study to determine its potential as an anticancer agent for clinical utility. METHODS: The in vitro potency, cancer cell specificity, synergy activity, and markers for response of TAI-1 were evaluated with cell lines. Mechanism of action was confirmed with western blotting and immunofluorescent staining. The in vivo potency of TAI-1 was evaluated in three xenograft models in mice. Preliminary toxicity was evaluated in mice. Specificity to the target was tested with a kinase panel. Cardiac safety was evaluated with hERG assay. Clinical correlation was performed with human gene database. RESULTS: TAI-1 showed strong potency across a broad spectrum of tumor cells. TAI-1 disrupted Hec1-Nek2 protein interaction, led to Nek2 degradation, induced significant chromosomal misalignment in metaphase, and induced apoptotic cell death. TAI-1 was effective orally in in vivo animal models of triple negative breast cancer, colon cancer and liver cancer. Preliminary toxicity shows no effect on the body weights, organ weights, and blood indices at efficacious doses. TAI-1 shows high specificity to cancer cells and to target and had no effect on the cardiac channel hERG. TAI-1 is synergistic with doxorubicin, topotecan and paclitaxel in leukemia, breast and liver cancer cells. Sensitivity to TAI-1 was associated with the status of RB and P53 gene. Knockdown of RB and P53 in cancer cells increased sensitivity to TAI-1. Hec1-overexpressing molecular subtypes of human lung cancer were identified. CONCLUSIONS: The excellent potency, safety and synergistic profiles of this potent first-in-class Hec1-targeted small molecule TAI-1 show its potential for clinically utility in anti-cancer treatment regimens. PMID- 24401612 TI - Vascular expression of the chemokine CX3CL1 promotes osteoclast recruitment and exacerbates bone resorption in an irradiated murine model. AB - Circulating osteoclast precursor cells highly express CX3C chemokine receptor 1 (CX3CR1), which is the only receptor for the unique CX3C membrane-anchored chemokine, fractalkine (CX3CL1). An irradiated murine model was used to evaluate the role of the CX3CL1-CX3CR1 axis in osteoclast recruitment and osteoclastogenesis. Ionizing radiation (IR) promoted the migration of circulating CD11b+ cells to irradiated bones and dose-dependently increased the number of differentiated osteoclasts in irradiated bones. Notably, CX3CL1 was dramatically upregulated in the vascular endothelium after IR. IR-induced production of CX3CL1 by skeletal vascular endothelium promoted chemoattraction of circulating CX3CR1+/CD11b+ cells and triggered homing of these osteoclast precursor cells toward the bone remodeling surface, a specific site for osteoclast differentiation. CX3CL1 also increased the endothelium-derived expression of other chemokines including stromal cell-derived factor-1 (CXCL12) and macrophage inflammatory protein-2 (CXCL2) by activating the hypoxia-inducible factor-1 alpha pathway. These effects may further enhance osteoclastogenesis. A series of in vivo experiments confirmed that knockout of CX3CR1 in bone marrow-derived cells and functional inhibition of CX3CL1 using a specific neutralizing antibody significantly ameliorated osteoclastogenesis and prevented bone loss after IR. These results demonstrate that the de novo CX3CL1-CX3CR1 axis plays a pivotal role in osteoclast recruitment and subsequent bone resorption, and verify its therapeutic potential as a new target for anti-resorptive treatment. PMID- 24401614 TI - An age-related decline of CD62L and vaccine response: a role of microRNA 92a? AB - Aging process can affect T cell and antibody response to vaccination and an age related decline in the expression of CD62L on CD8(+) T-lymphocyte is one of the important factors that contribute. A recent report demonstrated that percentage of CD3(+)CD8(+)CD62L(+) cells and CD8(+) T-lymphocyte microRNA-92a levels significantly decline with the age and were positively correlated. These results suggested that the age-related attrition of human naive T cells could be connected to a reduced microRNA-92a in T-lymphocytes and downregulation of the microRNA-92a level might indicate exhaustion of naive T-cells due to alteration of the immunologic condition with aging. Further studies are necessary to evaluate whether targeting microRNA-92a as microRNA mimics could be one of the therapeutic strategies in improving vaccine response in elderly. PMID- 24401613 TI - A novel vascular homing peptide strategy to selectively enhance pulmonary drug efficacy in pulmonary arterial hypertension. AB - A major limitation in the pharmacological treatment of pulmonary arterial hypertension (PAH) is the lack of pulmonary vascular selectivity. Recent studies have identified a tissue-penetrating homing peptide, CARSKNKDC (CAR), which specifically homes to hypertensive pulmonary arteries but not to normal pulmonary vessels or other tissues. Some tissue-penetrating vascular homing peptides have a unique ability to facilitate transport of co-administered drugs into the targeted cells/tissues without requiring physical conjugation of the drug to the peptide (bystander effect). We tested the hypothesis that co-administered CAR would selectively enhance the pulmonary vascular effects of i.v. vasodilators in Sugen5416/hypoxia/normoxia-exposed PAH rats. Systemically administered CAR was predominantly detected in cells of remodeled pulmonary arteries. Intravenously co administered CAR enhanced pulmonary, but not systemic, effects of the vasodilators, fasudil and imatinib, in PAH rats. CAR increased lung tissue imatinib concentration in isolated PAH lungs without increasing pulmonary vascular permeability. Sublingual CAR was also effective in selectively enhancing the pulmonary vasodilation by imatinib and sildenafil. Our results suggest a new paradigm in the treatment of PAH, using an i.v./sublingual tissue-penetrating homing peptide to selectively augment pulmonary vascular effects of nonselective drugs without the potentially problematic conjugation process. CAR may be particularly useful as an add-on therapy to selectively enhance the pulmonary vascular efficacy of any ongoing drug treatment in patients with PAH. PMID- 24401615 TI - [Strengthening the study on the biology and recurrence early-warning monitoring of schizophrenia]. PMID- 24401616 TI - [A study of cerebral cortex in untreated first-episode schizophrenics]. AB - OBJECTIVE: To detect the changes of cortical thickness and cortical surface area in untreated patients of first-episode schizophrenia. METHODS: Fifty-seven untreated patients of first-episode schizophrenia (SCZ) hospitalized from September 2009 to March 2012 at Department of Psychiatry, Third Affiliated Hospital, SUN Yat-sen University and 57 healthy controls (HC) recruited by advertising during the same period underwent a high resolution three-dimensional magnetic resonance imaging of brain structures. And cortical-surface based technique was used to analyze the cortical thickness and cortical surface area. The general linear model (GLM) was employed to detect the differences of cortical thickness and cortical surface area between two groups. RESULTS: were corrected for multiple comparisons by the Monte Carlo simulation method. RESULTS: As compared with HC, the cortical thickness of left superior frontal, left caudal middle cingulate, left lateral occipital, right superior frontal, right superior temporal and right fusiform regions in SCZ decreased by 6.0%, 7.2%, 8.2%, 5.2%, 7.1% and 6.0% respectively. And the largest reductions occurred in left lateral occipital regions. Cortical surface area of each brain regions in SCZ had no significant difference with HC. CONCLUSION: Cortical thickness reductions exist in multiple brain regions in schizophrenia. It may be the neuropathological mechanisms of schizophrenia. PMID- 24401617 TI - [Study of adiponectin, IL-1beta, IL-6 and TNF-alpha in first episode drug naive schizophrenia]. AB - OBJECTIVE: To explore the levels of adiponectin (APN), interleukin-1beta (IL 1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in first episode drug naive schizophrenics and further examine the role of adipocytokines in schizophrenia. METHODS: Ninety-six normal weight schizophrenics and 22 overweight/obese ones from First Affiliated Hospital, Zhengzhou University and 60 healthy controls were enrolled. Serum levels of IL-1beta, IL-6, TNF-alpha and APN were measured with enzyme linked immunosorbent assay (ELISA). RESULTS: Serum levels of IL-1beta, IL-6 and TNF-alpha in normal weight schizophrenics (54 +/- 13, 34 +/- 12, 48 +/- 18) pg/ml and overweight/obese schizophrenics (71 +/- 21, 40 +/- 12, 53 +/- 18) pg/ml were significantly higher than those in the controls (23 +/- 16, 16 +/- 7, 32 +/- 15) pg/ml (P < 0.05). Serum levels of IL-1beta and IL-6 in overweight/obese schizophrenics were significantly higher than those in normal weight schizophrenics (P < 0.05). Serum level of adiponectin in normal weight schizophrenics was significantly higher than that in control group [(12 +/ 4) vs (9 +/- 4) pg/ml, P < 0.05]. CONCLUSION: The serum levels of APN, IL-1beta, IL-6 and TNF-alpha increase in first episode drug naive schizophrenics. It suggests that an inflammatory response mediated by adipocytokines. APN may play a pro-inflammatory role in schizophrenia. PMID- 24401618 TI - [Diagnostic P300 threshold based on the analysis of receiver operating characteristic curve]. AB - OBJECTIVE: To explore the diagnostic application of receiver operating characteristic (ROC) curve of P300 amplitude and latency in schizophrenia. METHODS: ROC curve of P300 amplitude and latency was plotted from 91 first episode schizophrenia (FES) and 141 normal controls (NC). Youden's index and distance were calculated in ROC curve to determine the optimal cutoff point of P300 amplitude and latency for schizophrenic diagnosis. Then the subjects were layered by gender and age for improved diagnostic accuracy. RESULTS: The area under ROC curve for P300 amplitude for predicting schizophrenia was 0.746 (P < 0.001), while P300 latency showed poor power in predicting schizophrenia (P = 0.373). The optimal cutoff point of P300 amplitude was 5.097 uV with a sensitivity of 80.14% and a specificity of 63.74%. After gender and age stratification, Youden' s index was enhanced in all 5 subgroups (from 1.8% to 14.88%) and the sensitivities of corresponding cutoff were enhanced obviously in subgroups of males (25.01%), <= 25 years (22.22%) and >40 years (28.80%) patients. CONCLUSION: P300 amplitude has certain values in schizophrenic diagnosis. Gender and age stratification may enhance the diagnostic efficiency of ROC curve in the diagnosis of frequent schizophrenia. PMID- 24401619 TI - [Value of peripheral perfusion index in the assessment of reactive hyperemia in septic patients]. AB - OBJECTIVE: To explore the changes of peripheral perfusion index (PI) during forearm vascular occlusion test (VOT) and examine its evaluative value of reactive hyperemia in septic patients. METHODS: Twenty-one patients with septic shock, 21 postoperative ones without infection and 18 health volunteers were prospectively recruited to undergo vascular occlusion test. An arrest of forearm blood flow was applied for 3 min with a sphygmomanometer inflated to a pressure approximately 30 mm Hg greater than systolic pressure around forearm. PI was measured and recorded continuously by conventional pulse oximetry during VOT. RESULTS: (1)In all subjects, the PI values decreased to zero during ischemic period. There were no changes in heart rate or blood pressure between baseline and reperfusion. The maximum PI (PI-max) after a release of pneumatic cuff was significantly higher than baseline PI; (2)The change rates of PI-max and PI were significantly lower and the time to PI-max was longer in septic group after reperfusion; (3) A negative relationship existed between PI change rate and sequential organ failure assessment (SOFA) score in septic group. CONCLUSIONS: PI may be used to assess vascular reactive hyperemia in critically ill patients. And the capacity of peripheral vascular reactive hyperemia decreases in septic patients. PMID- 24401620 TI - [A study of the effect of interstitial (125)I seed implantation on ward nurses' hemogram and relevant protection investigations]. AB - OBJECTIVE: To analyze the blood picture changes of the ward nurses who nurse the patients received (125)I seeds implantation. METHODS: 32 ward nurses who nurse the patients for (125)I seeds implantation were involved in the experimental group, the control group included 32 ward nurses from the medical oncology never exposed to (125)I seeds. The WBC count, hemoglobin concentration and platelet counts from the two groups were analyzed statistically, respectively. 30 patients received (125)I seeds implantation were selected randomly and gamma-ray dose from the unshielded group and lead rubber cloth covering group was detected at a distance of 0, 15, 30, 50, 100 cm from patient body surface and at different angles. RESULTS: No significant statistical difference was found between the two groups of WBC count, hemoglobin concentration and platelet count (7.1 +/- 1.7 vs 6.8 +/- 2.0, 132 +/- 11 vs 136 +/- 11, 236 +/- 57 vs 242 +/- 61) . The measured radiation dose was close to the natural background dose (10.2-10.8 uSv/h) at a distance of 50 cm from the body surface [ (12.7 +/- 4.3) uSv/h] and the same as after 0.125 mm lead equivalent (Pb) rubber cloth shield protection[ (11.2 +/- 3.1) uSv/h]. CONCLUSION: Interstitial (125)I seed implantation is safe on the blood picture of the ward nurses after taking appropriate protective measures. PMID- 24401621 TI - [The incidence of awareness with recall during general anesthesia has been lowered: a historical controlled trial]. AB - OBJECTIVE: To evaluate the effect of our prophylaxis job against awareness during general anesthesia and identify the effective methods. To analyze the risk factors of awareness. METHODS: Patients who received general anesthesia requiring muscle relaxants were interviewed postoperatively. The cases with explicit recall (ER) were identified as the cases of awareness. The results of the patients were compared with a historical group of 2025 cases in a previous study. RESULTS: 16 patients in the later group(6305 cases), 0.25%, had ER as compared with 1.38% in the earlier group (P < 0.05). 8330 patients were included in a Logistic analysis and factors associated with awareness were: TIVA technique (OR = 6.671), O2/N2O based anesthesia >30 min (OR = 8.791), obvious intraoperative blood pressure fluctuation (OR = 9.995), midazolam as a premedication (OR = 0.060) , anesthetic gas monitoring (OR = 0.441). CONCLUSION: Attentiveness on the knowledge of awareness and improvement in anesthetic management and monitoring were associated with a significantly reduced incidence of awareness as compared with a historical control population. PMID- 24401622 TI - [Risk factors for delirium of elderly patients undergoing hip fracture operation]. AB - OBJECTIVE: To explore the causes for delirium of elderly patients after hip fracture operation. METHODS: A total of 68 cases of delirium were selected from 458 patients aged over 65 years undergoing hip fracture operation via spinal anesthesia from 2009 to 2011. There were 26 males and 42 females with an average age of 72.9 (66-98) years. Their clinical features, such as gender, operative duration, blood loss volume, saturation of arterial oxygen, were observed. After single factor risk analysis, multiple factor analysis was performed by binary Logistic regression. RESULTS: Delirium occurred at certain timepoints during the first postoperative days. The incidence of delirium was 14.9%. The Logistic stepwise regression analysis showed that significant differences existed between delirium and non-delirium in age (P = 0.042), operative duration (P = 0.042), blood loss volume (P = 0.027), hypoxemia (P = 0.019) and preoperative comorbidity (P = 0.029). CONCLUSION: The independent risk factors for postoperative delirium include age, operative duration, blood loss volume, preoperative comorbidity and hypoxemia. PMID- 24401623 TI - [Magnetic resonance imaging study of effects of accommodation on human lens morphological characters]. AB - OBJECTIVE: To evaluate the effects of accommodation on lens morphological characters. METHODS: From January 2011 to June 2011, magnetic resonance images of eyes were acquired from 30 subjects aged 20 to 24 years during accommodation and at rest. The optimal images were analyzed by Autocad 2010 to obtain the total lens cross-sectional area (CSA) and CSA of anterior and posterior portions of lens, anterior chamber depth, lens thickness, lens diameter, vitreous chamber depth and axial length during accommodation and at rest. Paired-t test was performed. RESULTS: The anterior curvature radius (mm), posterior curvature radius (mm), CSA of anterior portion (mm(2)), CSA of posterior portion (mm(2)), total lens CSA (mm(2)) was (8.7 +/- 0.8), (6.2 +/- 0.5), (7.5 +/- 2.1), (12.0 +/- 2.6), (20 +/- 4) during relaxed accommodation; anterior curvature radius (mm), posterior curvature radius (mm), CSA of anterior portion (mm(2)), CSA of posterior portion (mm(2)), total lens CSA (mm(2)) was (7.1 +/- 1.3), (5.6 +/- 0.5), (14.7 +/- 2.9), (12.2 +/- 2.1) and (27 +/- 4) during accommodation. The total lens CSA (t = -11.556, P < 0.01) and CSA of anterior portion (t = -15.653, P < 0.01) both increased in accommodative states. The CSA of posterior portion of lens (t = -0.437, P > 0.05) under a statistically independent accommodative state. There was significant difference in the anterior chamber depth (t = 4.366, P < 0.01), lens thickness (t = -5.456, P < 0.01) and lens diameter (t = 4.597, P < 0.01) in accommodative states. There were insignificant differences both in vitreous chamber depth (t = 0.428, P > 0.05) and axial length (t = 0.418, P > 0.05) under accommodative states. CONCLUSION: During accommodation, the anterior chamber depth decreases, lens thickness increases and diameter of lens decreases while anterior portions and total lens CSA increase. There are insignificant changes in posterior portions of lens CSA, vitreous chamber depth and axial length. The accommodative changes in CSA indicate that the anterior portion of lens may be related with the properties of anterior capsule and lens material, the position of zonular attachments and the location of fetal nucleus. Helmholtz theory is supported. PMID- 24401624 TI - [Clinical study of delivery method in modified vaginal hysterectomy for large uterus]. AB - OBJECTIVE: To prospectively explore the techniques, feasibility and safety of modified vaginal hysterectomy for large uterus. METHODS: A total of 158 patients undergoing hysterectomy at Beijing Hospital from January 2008 to December 2010 were divided into three groups: 12-16 gestational weeks large uterus for vaginal hysterectomy (n = 65, group 1), 12-16 gestational weeks uterus for abdominal hysterectomy (n = 47, group 2) and <10 gestational weeks uterus for vaginal hysterectomy (n = 46, group 3). The pattern and techniques of delivery in group 1 was based on the location of fibroids/adenomyoma (in anterior wall, posterior wall, uterine horn or broad ligament, cervix) and the direction of overall shape maximum diameter (direction towards abdomen defined as long type while the direction towards lateral pelvic wall wide type). The completion and safety were observed intraoperatively. The outpatient follow-up period was 1 month. RESULTS: A total of 158 cases of hysterectomy were performed successfully. The locations of fibroids/adenomyoma included anterior wall (n = 17), posterior wall (n = 24), unilateral uterine horn (n = 6), broad ligament (n = 3) and cervix (n = 2). in group 1, and there were long (n = 6) and wide (n = 7) types. They were all successfully delivered through vagina through various techniques. No case was converted into laparotomy. The average largest size (judged by as large as number of gestational weeks) and weight of uterus was group 2 and followed by group 1. But the difference of size and weight between two groups was insignificant (P > 0.05). Sorted by mean operative duration, mean amount of bleeding and decrease of hemoglobin, the declining order was the group 2, group 1 and group 3. The amount of bleeding for group 1 was less than that for group 2 (P < 0.05). But it was more than group 3 (P > 0.05). According to postoperative hospitalization duration, flatus time and indwelling catheter time, no statistical differences existed between groups 1 and 3. But the values of group 1 were significantly better than those of group 2 (P < 0.01, <0.05, <0.01). CONCLUSION: Vaginal hysterectomy is a safe and effective option for removing enlarged uterus. This pattern of operation can reduce the postoperative hospitalization time, flatus time and indwelling catheter time. PMID- 24401625 TI - [Measurement of bone tunnel width with computed tomography versus plain radiography after anterior cruciate ligament single-bundle reconstruction]. AB - OBJECTIVE: To compare the measurements of bone tunnel width with computed tomography (CT) and plain radiography two years after anterior cruciate ligament single-bundle reconstruction. METHODS: Twenty patients underwent primary anterior cruciate ligament single-bundle reconstruction with hamstring autografts. There were 10 females and 10 males. Tibial and femoral bone tunnel widths were measured with CT and plain radiography at least two years post-operation. The average follow-up period was 26 months (range, 24-31). The tunnel measurements were taken at the widest point of tibial and femoral tunnels on sagittal and coronal CT and plain radiography perpendicularly to the longitudinal axis of tunnels. All data were statistically analyzed. RESULTS: The tibial tunnel width of one case decreased on CT while all others increased. The average tibial tunnel width on coronal plain radiography was 0.9 +/- 0.6 mm (range, 0.3-2.2) larger than that on CT. And the average width on sagittal plain radiography was 0.9 +/- 0.5 mm (range, 0.1-2.1) larger than that on CT. Both were statistically significant. All femoral tunnel widths increased, except in 2 cases. The average femoral tunnel widths on coronal and sagittal plain radiography were both significantly larger than those on CT. And the difference were 0.7 +/- 0.6 mm (range, 0-1.7) and 0.9 +/- 0.7 mm (range, 0.1-2.7) respectively. CONCLUSION: Bone tunnel measurements on plain radiography are significantly larger than those on CT after anterior cruciate ligament reconstruction. PMID- 24401626 TI - [Multicenter randomized clinical study of high-intensity focused ultrasound and cortical hormone in the treatment of non-neoplastic epithelial disorders of vulva]. AB - OBJECTIVE: To evaluate the efficacy of high-intensity focused ultrasound (HIFU) and cortical hormone in the treatment of non-neoplastic epithelial disorders of vulva. METHODS: A total of 268 cases with pathologically diagnosed non-neoplastic epithelial disorders of vulva were randomly allocated into two groups of high intensity focused ultrasound (HIFU) (n = 119) and cortical hormone (n = 124). And 25 cases became lost to follow-ups. Their signs, symptoms and quality-of-life were assessed before treatment, 1 month post-treatment and 3 months post treatment. And the relationship was analyzed between pathologic type, age, course and efficacies. RESULTS: Their signs, symptoms and quality-of-life improved in both groups after 1 and 3 month. Compared with drug therapy, HIFU showed superior results in lesion amelioration at 1 month with significantly statistical difference and so did lesion amelioration and therapeutic effect at 3 month. And the efficacy of HIFU was better in those with >10-year disease course and pathologically diagnosed lichen sclerosus in 3 months. CONCLUSIONS: HIFU is both safe and effective in the treatment of non-neoplastic epithelial disorders of vulva. PMID- 24401627 TI - [Clinical application of 320-row computed tomography 4D digital subtraction angiography in hepatocellular carcinoma]. AB - OBJECTIVE: To explore the application value of 320-row computed tomography (CT) 4D digital subtraction angiography (DSA) for hepatocellular carcinoma (HCC). METHODS: A total of 40 HCC patients received 320-row CT contrast scans. The 4D DSA images were obtained on the basis of baseline data. The normal anatomy and anatomical variations of hepatic artery, tumor supplying arteries, tumor vessels, tumor staining were observed by comparing DSA (n = 20). RESULTS: 320-row CT 4D DSA could show 6-7 levels of intrahepatic arterial branch. Normal hepatic artery anatomy was found in 35 cases (87.5%, Michels I type) and variations in 5 cases (12.5%). The diagnose accordance rate was 100% between 4D DSA and DSA in showing the anatomy and variation of hepatic artery. Among them, 320-row CT 4D DSA showed tumor staining (n = 40), tumor vessels (n = 28), tumor supplying arteries (n = 26) and two hepatic supplying arteries (n = 3). The number of tumor supplying arteries observed by 4D DSA (n = 20) was 18 versus 19 by DSA. Compared with DSA, the accurate rate of 4D DSA was 94.7% (18/19) in detecting tumor supplying arteries. CONCLUSION: As a noninvasive vascular examination modality, 320-row CT 4D DSA can accurately visualize normal anatomy and variation of hepatic artery, dynamically display tumor staining and reproducibly delineate the three-dimension relationship between tumor and blood vessels. In consistency with DSA in detection blood supply of HCC, 320-row CT 4D DSA provides a rapid, DSA-like and non-invasive alternative. PMID- 24401628 TI - [A comparison of clinical outcomes between standard and total two-field lymphadenectomy for squamous cell carcinoma of the lower thoracic esophagus]. AB - OBJECTIVE: To explore the suitable lymphadenectomy for squamous cell carcinoma of the lower thoracic esophagus. METHODS: From January 2004 to December 2007, 300 patients with lower thoracic esophageal squamous cell carcinoma underwent Ivor Lewis esophagectomy with 2-field lymphadenectomy in our department. All cases were retrospectively analyzed. 143 cases underwent standard lymphadenectomy(standard group), 157 cases underwent total lymphadenectomy(total group). The clinical and pathological characteristics, the status of lymph node metastases, postoperative complications and survival rates were compared between two groups. RESULTS: There were more lymph nodes dissected(30 +/- 10 vs 26 +/- 8, P = 0.001)and higher respiratory failure rate(16.6% vs 0.7%, P = 0.038) in total group than in standard group. The 5-year survival rate was 28.9% and 30.2%, respectively(P = 0.936). CONCLUSION: The total 2-field lymphadenectomy doesn't provides better survival benefit for patients with squamous cell carcinoma of the lower thoracic esophagus, instead more complications occurred. For local advanced tumor, 3-field lymphadenectomy and comprehensive treatment should be considered. PMID- 24401629 TI - [Transaxillary concealing single incision endoscopic thoracic sympathectomy in the treatment of palmar hyperhidrosis: a novel surgical approach]. AB - OBJECTIVE: To evaluate the cosmetic effect and safety of transaxillary concealing single incision endoscopic thoracic sympathectomy in the treatment of palmar hyperhidrosis (PH). METHODS: Retrospective study was conducted for 326 PH cases undergoing transaxillary concealing single incision endoscopic thoracic bilateral sympathectomy during January 2009 and March 2011. RESULTS: All operations were successfully performed without severe complication and mortality. No conversion into open technique was necessary. The mean unilateral operative duration was 5.8 (5-8) min. It was calculated from the time of skin incision to the application of dressing over wound. The mean follow-up period was 25 (8-38) months. All patients achieved excellent cosmetic effects with undetectable incision. CONCLUSION: Transaxillary concealing single incision endoscopic thoracic sympathectomy is a safe and effective procedure for treating primary PH. Incision is undetectable with excellent cosmetic effect. It is worthy of wider popularization. PMID- 24401630 TI - [The feasibility of training anesthesiologists with hemodynamic models of miniature pigs]. AB - OBJECTIVE: To investigate the feasibility of training anesthesiologists with hemodynamic models of miniature pigs. METHODS: Eight miniature experimental pigs were chosen; ECG, SpO2, PetCO2, ABP, CVP, SV, SVV and PAP were monitored after anesthesia. The research was divided into two parts. Part one: the blood of pig was taken from its artery, air was injected into its body thought jugular vein, 15%KCl and 0.75% bupivacaine were given by peripheral vein respectively. The resuscitation would not be implemented unless the monitoring data changes were significantly and were recorded. Trainees looked on only during that time. Part two: Trainees were trained for placement of Swan-Ganz catheter after the sheath had been success- fully intubated into pig's right jugular vein. Trainees were trained for placement of femoral artery guided by ultrasound.Scores related to trainees' performance were written down. RESULTS: (1) Monitoring data (ABP, SV, SVV, CVP, PetCO2, PAP, SpO2 , ECG) changes were significantly ( P < 0.05 or P < 0.01), which indicated that the models had been successfully established. The evaluation scale displays: 81.3% of trainees thought this research improved their under- standing of hemodynamic changes; 78.2% thought that it helped them know how to deal with these circumstances; 71.9% thought this training was meaningful. (2) It was improved for students' skill to place Swan-Ganz catheter (P < 0.05), whereas the skill for placement of artery catheter by ultrasound was not significantly improved (P > 0.05). CONCLUSION: It was feasible to use a hemodynamic model of miniature pigs as an assisted teaching method to improve resident anesthesiologists' ability to understand and cope with clinical hemodynamic changes. PMID- 24401631 TI - [Association between differentiation potential of immortalized human mesenchymal stem cells and cluster of differentiation antigens]. AB - OBJECTIVE: To explore the relationship between multi-differentiation potential of monoclonal immortalized human mesenchymal stem cells (hMSC-TERT) in vivo and their cluster of differentiation antigens (CD). METHODS: Monoclonal hMSC-TERT were isolated using limiting dilution. Direct immunofluorescence staining flow cytometry was used to detect the cluster of differentiation antigens (CD44, CD45, CD105) of these cell lines. Their adipocytic, osteogenic, neuronal differentiation potential in vitro were determined by Oil Red O staining, Von Kossa staining and immunocytochemistry for tubulin-beta III antibody. Then hMSC TERTs were transplanted subcutaneously into severe combined immunodeficiency (SCID) mice. The cell grafts were removed and analyzed by immunohistochemistry for pathologic tissue markers for multi-differentiation potential of hMSC-TERT cells in vivo. RESULTS: CD105+ cell was 84.68% positive in hMSC-TERT-C19 while <5% in other monoclonal cell lines. The positive rate of cytokeratin in grafts formed by hMSC-TERT-C19 cell line in SCID mice was much higher than the others (P < 0.01). CONCLUSION: The positive CD105 of monoclonal hMSC-TERTs may be directly correlated with its epithelial differentiation potential. PMID- 24401632 TI - [Epidemiology of rheumatoid arthritis in middle-aged and elderly population in Luohe City, Henan Province]. AB - OBJECTIVE: To explore the local prevalence of rheumatoid arthritis (RA) among the middle-aged and elderly population. METHODS: A total of 8610 residents were recruited for a two-stage cluster sampling survey through a questionnaire of RA according to 2010 ACR/EULAR classification criteria. Physical examinations and blood tests were performed. RESULTS: The responding rate was 96.10%. Joint score 0, 1, 2, 3, 5 was detected in 13.62%, 7.57%, 2.79%, 1.87% and 0.23% of subjects. The prevalence of joint score 0, 1, 2, 3, 5 was 13.62%, 7.57%, 2.79%, 1.87% and 0.23%. The rate was 17.48% and 14.27% for elevated levels of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), 6.62%, 1.96% and 5.48%, 1.55% for low titer and high titer rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) positive antibody. And 63 RA cases were confirmed. The crude prevalence was 0.76% and 0.71% for standardized prevalence. Compared to males, females had a higher prevalence of RA (1.02% vs 0.39%, P < 0.01). In the population, the awareness rate was 74.60%, cure rate 71.43% and control rate 18.57% respectively. CONCLUSION: The local prevalence of RA in elderly females is higher than that in males. And the treatment and awareness rates are also low. PMID- 24401633 TI - [Impact factor of timeliness lag for seeing a doctor about cataract patient in Wenzhou region of Zhejiang province]. AB - OBJECTIVE: Investigation the impact factor of timeliness lag about cataract patient of operation. METHODS: Through Opportunistic Screening , from January 2007 to January 2012, we extracted people aged 50 or above and carried out the cataract screening in 10 towns of Wenzhou region of Zhejiang province. People extracted was checked by slit lamp microscope and ophthalmoscope directly, and the people who are suit for operation were brought to a first-rate of level three eye hospital and operated by MSICS . At the same time we have made questionnaire about five aspect including basic situation, economic status, basic life status, health and medical status and health needs for the operator and this questionnaire involves twenty-three relevant indexes about the timeliness, these factors of timeliness for patients seeing a doctor are judged. RESULTS: 36 681 people are checked for five years and 10 326 people(10 326 eyes) are suitable for surgery. Through analyzing sixteen relevant indexes about the timeliness , there are ten indexes which have Statistical Significance including in transportation, the distance for nearest medical aid post , care knowledge, population of family, income of family, respondents degree , the highest degree of family members type of work, structure of building, government subsidies. The first reason that the people can't be operated in time are economic difficulties, next are older and making children trouble for seven factors of no operation in time. The people for this three reason is more than 75% for not seeing a doctor in time. CONCLUSION: The key work of blindness prevention and treatment is the cataract surgery for our country.Eye doctors pay attention to new surgical technique , at the same time we should promote MSICS which is technique of low cost and have good effect of the operation. PMID- 24401634 TI - Reassessing hepatocellular carcinoma staging in a changing patient population. AB - OBJECTIVE: Hepatocellular carcinoma (HCC) staging systems were developed using data predominantly from patients who had hepatitis and cirrhosis. Given the recent change in prevalence of viral hepatitis and cirrhosis at oncology centers, which has altered the natural history of HCC, we aimed at comparing the accuracy of HCC staging systems in patients with or without hepatitis and cirrhosis. METHODS: A total of 438 patients were enrolled. Baseline clinicopathologic parameters, Barcelona Clinic Liver Cancer stage, Cancer of the Liver Italian Program score, TNM (6th edition) stage, Okuda stage, and Chinese University Prognostic Index score were prospectively obtained for all patients, and retrospectively analyzed. Kaplan-Meier analysis was used to determine overall survival (OS), Cox regression analyses were performed, and Harrell's Correspondence Index compared the staging systems' ability to predict OS duration. Subgroup analyses of patients with or without hepatitis or cirrhosis were performed. RESULTS: Median patient OS was 13.9 months; 165 patients (37.7%) had no cirrhosis and 256 patients (58.4%) had no hepatitis. Overall, all staging systems were significantly less predictive of OS in patients who did not have cirrhosis or hepatitis. CONCLUSION: Our results advocate the need to further stratify HCC based on cirrhosis and hepatitis status, which may change patient risk-stratification and, ultimately, treatment decisions. PMID- 24401635 TI - Oxygen modulates the glutathione peroxidase activity during the L6 myoblast early differentiation process. AB - AIM: This work aims to study the regulation of the glutathione peroxidase and catalase activities in myoblasts from the L6 line exposed to 21%, 5% and 1% O2 during the cell differentiation. MATERIAL AND METHODS: Rat L6 myoblasts were grown in 1%, 5% or 21% O2 in the presence or absence of N-acetyl cysteine. The cell proliferation was evaluated by determining the doubling time and kinetics of cultures by counting cells. The cell differentiation was analyzed by determining the myogenic fusion index using antibodies against the myosin heavy chain. The glutathione peroxidase and catalase activities were assayed. The p110-PI3K/Thr308 Akt pathway was studied using western blotting. The oxidative status of the cells was carried out by determining TBARS. RESULTS: 5% O2 improves the glutathione peroxidase activity, p110-PI3K/Thr308-Akt pathway and differentiation while 1% O2 alters all these parameters compared to 21% O2. NAC (0.5 mM) can prevent the deleterious effects of hypoxia (1% O2) on the L6 myoblast proliferation and enhances the myoblast differentiation when exposed to 21% O2. TBARS are reduced in 5% O2 compared to both 21% and 1% O2. CONCLUSION: The glutathione peroxidase activity and p110-PI3K/Thr308-Akt are both modulated in the same way by oxygen. PMID- 24401636 TI - The effect of glutamine therapy on outcomes in critically ill patients: a meta analysis of randomized controlled trials. AB - INTRODUCTION: Glutamine supplementation is supposed to reduce mortality and nosocomial infections in critically ill patients. However, the recently published reducing deaths due to oxidative stress (REDOX) trials did not provide evidence supporting this. This study investigated the impact of glutamine-supplemented nutrition on the outcomes of critically ill patients using a meta-analysis. METHODS: We searched for and gathered data from the Cochrane Central Register of Controlled Trials, MEDLINE, Elsevier, Web of Science and ClinicalTrials.gov databases reporting the effects of glutamine supplementation on outcomes in critically ill patients. We produced subgroup analyses of the trials according to specific patient populations, modes of nutrition and glutamine dosages. RESULTS: Among 823 related articles, eighteen Randomized Controlled Trials (RCTs) met all inclusion criteria. Mortality events among 3,383 patients were reported in 17 RCTs. Mortality showed no significant difference between glutamine group and control group. In the high dosage subgroup (above 0.5 g/kg/d), the mortality rate in the glutamine group was significantly higher than that of the control group (relative risk (RR) 1.18; 95% confidence interval (CI), 1.02 to 1.38; P = 0.03). In 15 trials, which included a total of 2,862 patients, glutamine supplementation reportedly affected the incidence of nosocomial infections in the critically ill patients observed. The incidence of nosocomial infections in the glutamine group was significantly lower than that of the control group (RR 0.85; 95% CI, 0.74 to 0.97; P = 0.02). In the surgical ICU subgroup, glutamine supplementation statistically reduced the rate of nosocomial infections (RR 0.70; 95% CI, 0.52 to 0.94; P = 0.04). In the parental nutrition subgroup, glutamine supplementation statistically reduced the rate of nosocomial infections (RR 0.83; 95% CI, 0.70 to 0.98; P = 0.03). The length of hospital stay was reported in 14 trials, in which a total of 2,777 patients were enrolled; however, the patient length of stay was not affected by glutamine supplementation. CONCLUSIONS: Glutamine supplementation conferred no overall mortality and length of hospital stay benefit in critically ill patients. However, this therapy reduced nosocomial infections among critically ill patients, which differed according to patient populations, modes of nutrition and glutamine dosages. PMID- 24401637 TI - Polymorphisms in genes involved in the triglyceride synthesis pathway and marine omega-3 polyunsaturated fatty acid supplementation modulate plasma triglyceride levels. AB - BACKGROUND: Marine omega-3 (n-3) polyunsaturated fatty acids (PUFA) reduce plasma triglyceride (TG) levels. Genetic factors such as single nucleotide polymorphisms (SNPs) could be responsible for the variability of the plasma TG response to n-3 PUFA supplementation. Previous studies have demonstrated that n-3 PUFA supplementation using fish oil modified the expression levels of three genes involved in the TG synthesis pathway (GPAM, AGPAT3 and AGPAT4) in peripheral blood mononuclear cells. METHODS: A total of 210 subjects consumed 5 g/day of a fish oil supplement for 6 weeks. Plasma lipids were measured before and after the supplementation period. Three SNPs in GPAM, 13 SNPs in AGPAT3 and 35 SNPs in AGPAT4 were genotyped. RESULTS: In an ANOVA for repeated measures adjusted for age, sex and BMI, genotype effects on plasma TG levels were observed for rs1838452 in AGPAT3 as well as for rs746731 and rs2293286 in AGPAT4. Genotype * supplementation interaction effects on plasma TG levels were observed for rs2792751 and rs17129561 in GPAM as well as for rs3798943 and rs9458172 in AGPAT4 (p < 0.05). CONCLUSION: These results suggest that SNPs in genes involved in the TG synthesis pathway may influence plasma TG levels after n-3 PUFA supplementation. PMID- 24401638 TI - Inflammatory cytokines and mortality in a cohort of HIV-infected adults with alcohol problems. AB - BACKGROUND: HIV infection leads to chronic inflammation and alterations in levels of inflammatory cytokines. The association between cytokine levels and mortality in HIV infection is not fully understood. METHODS: We analyzed data from a cohort of HIV-infected adults with alcohol problems who were recruited in 2001-2003, and were prospectively followed until 2010 for mortality using the National Death Index. The main independent variables were inflammatory biomarkers [interleukin-6 (IL-6), IL-10, tumor necrosis factor-alpha, C-reactive protein, serum amyloid A, monocyte chemotactic protein-1, and cystatin-C], measured at baseline in peripheral blood and categorized as high (defined as being in the highest quartile) vs. low. A secondary analysis was conducted using inflammatory burden score, defined as the number of biomarkers in the highest quartile (0, 1, 2 or >= 3). Cox models were used to assess the association between both biomarker levels and inflammatory burden with mortality adjusting for potential confounders. RESULTS: Four hundred HIV-infected patients were included (74.8% men, mean age 42 years, 50% hepatitis C virus-infected). As of 31 December 2009, 85 patients had died. In individual multivariable analyses for each biomarker, high levels of IL 6 and C-reactive protein were significantly associated with mortality [hazard ratio=2.49 (1.69-5.12), P<0.01] and [hazard ratio=1.87 (1.11-3.15), P=0.02], respectively. There was also a significant association between inflammatory burden score and mortality [hazard ratio=2.18 (1.29-3.66) for >= 3 vs. 0, P=0.04]. In the fully adjusted multivariable analysis, high levels of IL-6 remained independently associated with mortality [hazard ratio=2.57 (1.58-4.82), P<0.01]. CONCLUSION: High IL-6 levels and inflammatory burden score were associated with mortality in a cohort of HIV-infected adults with alcohol problems. PMID- 24401639 TI - Treatment as prevention among injecting drug users; extrapolating from the Amsterdam cohort study. AB - OBJECTIVE: To determine the potential of treatment as prevention for reducing HIV incidence among injecting drug users (IDU). METHODS: Transmission dynamics of HIV as influenced by cART uptake and demographic changes were studied using an individual-based model. Parameters were based on data of the Amsterdam Cohort Study, and counterfactual treatment scenarios were examined for this city. Demography of the modeled population was also varied to allow for more general conclusions. RESULTS: We estimated that over the complete HIV epidemic among IDU in Amsterdam the historic use of cART has led to only 2% less incidence. As individuals were treated from low CD4 cell counts, their decreased infectiousness was offset by increased infectious lifetime. Large reduction in incidence could result from a test and immediate treat strategy, with elimination of HIV occurring when the average time from infection to starting treatment was less than 2 months. However, substantial proportions of new infections were prevented only if the test and treat intervention was implemented within the first few years after HIV-epidemic onset, especially for a declining IDU population. Ignoring heterogeneity in risk-behavior led to overly optimistic expectations of the prevention effects of treatment. In general, treatment led to much greater reduction in incidence compared with stopping HIV-infected IDU from lending out syringes. CONCLUSION: A test and immediate treat strategy for HIV among IDU could lead to great reductions in incidence. To fully eliminate the spread of HIV, treatment as prevention should be combined with other interventions, with behavioral intervention directed at those not yet HIV infected. PMID- 24401641 TI - Antiretroviral reduction: is it time to rethink the unthinkable? PMID- 24401640 TI - Predictors of virologic response in persons who start antiretroviral therapy during recent HIV infection. AB - OBJECTIVE: Despite evidence supporting antiretroviral therapy (ART) in recent HIV infection, little is known about factors that are associated with successful ART. We assessed demographic, virologic, and immunologic parameters to identify predictors of virologic response. DESIGN: A 24-week observational study of ART on persons enrolled within 6 months of their estimated date of infection (EDI) evaluated baseline demographics and the collection of blood and gut specimens. METHODS: Flow cytometry analyses of blood and gut lymphocytes allowed characterization of CD4 and CD8 T cells at study entry and end. Additional assessments included soluble CD14 (sCD14), lipopolysaccharide, CD4 T-cell counts, and HIV RNA levels. RESULTS: Twenty-nine participants initiated ART, and 17 achieved undetectable HIV RNA by study end. A longer time from EDI to ART, older age, higher sCD14, lower proportions of central memory CD4 T cells, and higher proportions of activated CD8 T cells were associated with detectable viremia. Multivariable logistic regression found only older age and elevated sCD14 were independently associated with persistent viremia. Additionally, we observed that ART in recent infection did not result in discernible recovery of CD4 T cells in the gut. CONCLUSION: In persons who started ART within 3-33 weeks from EDI, age and microbial translocation were associated with detectable HIV RNA. As observed in other cohorts, ART in recent infection did not improve proportions of total CD4 T cells in gut-associated lymphoid tissue (GALT). This lends support to further evaluate the use of more potent ART or regimens that protect the GALT in recent HIV infection. PMID- 24401643 TI - What is the significance of posttreatment control of HIV infection vis-a-vis functional cure? PMID- 24401644 TI - Differential impact of APOBEC3-driven mutagenesis on HIV evolution in diverse anatomical compartments. AB - OBJECTIVE: Previous studies on HIV quasispecies have revealed HIV compartmentalization in various tissues within an infected individual. Such HIV variation is a result of a combination of factors including high replication and mutation rates, recombination, and APOBEC3-host selective pressure. METHODS: To evaluate the differential impact of APOBEC3 editing in HIV-1 compartments, we analyzed the level of G-to-A hypermutation in HIV-1 protease and reverse transcriptase sequences among 30 HAART-treated patients for whom peripheral blood mononuclear cells and body tissues or fluids [cerebral spinal fluid (CSF), rectal tissue, or renal tissue] were collected on the same day. RESULTS: APOBEC3 mediated hypermutation was identified in 36% (11/30) of participants in at least one viral reservoir. HIV hypermutated sequences were often observed in viral sanctuaries (total n = 10; CSF, n = 6; renal tissue, n = 1; rectal tissue n = 3) compared with peripheral blood (total n = 4). Accordingly, APOBEC3 editing generated more G-to-A drug resistance mutations in sanctuaries: three patients' CSF (i.e. G73S in protease; M184I, M230I in reverse transcriptase) and two other patients' rectal tissues (M184I, M230I in reverse transcriptase) while such mutations were absent from paired peripheral blood mononuclear cells. CONCLUSION: APOBEC3-induced mutations observed in peripheral blood underestimate the overall proportion of hypermutated viruses in anatomical compartments. The resulting mutations may favor escape to antiretrovirals in these compartments in conjunction with a lower penetration of drugs in some sanctuaries. On the other side, because hypermutated sequences often harbor inactivating mutations, our results suggest that accumulation of defective viruses may be more dominant in sanctuaries than in peripheral blood of patients on effective HAART. PMID- 24401642 TI - Malignancies in HIV/AIDS: from epidemiology to therapeutic challenges. AB - The incidence of AIDS-defining cancers (ADCs) - Kaposi sarcoma, primary central nervous system lymphoma, non-Hodgkin lymphoma, and cervical cancer - although on the decline since shortly after the introduction of HAART, has continued to be greater even in treated HIV-infected persons than in the general population. Although the survival of newly infected people living with HIV/AIDS now rivals that of the general population, morbidity and mortality associated with non-AIDS defining cancers (NADCs) such as lung, liver, anal, and melanoma are significant and also continue to rise. Increasing age (i.e. longevity) is the greatest risk factor for NADCs, but longevity alone is not sufficient to fully explain these trends in cancer epidemiology. In this review, we briefly review the epidemiology and etiology of cancers seen in HIV/AIDS, and in this context, discuss preclinical research and broad treatment considerations. Investigation of these considerations provides insight into why malignancies continue to be a major problem in the current era of HIV/AIDS care. PMID- 24401645 TI - Implementing the Jadelle implant for women living with HIV in a resource-limited setting: concerns for drug interactions leading to unintended pregnancies. AB - An analysis of 570 HIV-infected women in Swaziland using the Jadelle implant showed that age, condom use, the provider who placed the implant, and CD4 cell count had no effect on unintentional pregnancy rates. Antiretroviral regimen at the time of pregnancy, however, correlated with pregnancy outcomes (P < 0.001). None of the women on nevirapine or lopinavir/ritonavir-based regimens (n = 208 and 13, respectively) became pregnant, whereas 15 women on efavirenz (n = 121; 12.4%) became pregnant. PMID- 24401646 TI - Lower adiponectin is associated with subclinical cardiovascular disease among HIV infected men. AB - OBJECTIVE: To examine whether altered levels of adipokines, adipose-derived peptides associated with myocardial infarction in the general population, may contribute to subclinical coronary atherosclerosis in HIV-infected persons. DESIGN: Nested cohort study. METHODS: We studied HIV-infected (HIV+) and HIV uninfected (HIV-) men in the Multicenter AIDS Cohort Study with noncontrast computed tomography (CT) to measure coronary artery calcium and regional adiposity; 75% additionally underwent coronary CT angiography to measure plaque composition and stenosis. Adiponectin and leptin levels were assessed. Multiple regression models were used to assess associations between adipokine levels and HIV disease parameters, regional adiposity, and plaque adjusted for age, race, HIV serostatus, and cardiovascular disease (CVD) risk factors. RESULTS: Significant findings were limited to adiponectin. HIV-positive men (n=493) had lower adiponectin levels than HIV-negative men (n=250) after adjusting for CVD risk factors (P<0.0001), which became nonsignificant after adjustment for abdominal visceral and thigh subcutaneous adipose tissue. Among HIV-positive men, lower adiponectin levels were associated with higher CD4 T-cell counts (P=0.004), longer duration of antiretroviral therapy (P=0.006), and undetectable HIV RNA levels (P=0.04) after adjusting for age, race, and CVD risk factors; only CD4 cell count remained significant after further adjustment for adipose tissue. In both groups, lower adiponectin levels were associated with increased odds of coronary stenosis more than 50% (P<0.007). Lower adiponectin levels were associated with increased extent of plaque in HIV-positive and of mixed plaque in HIV-negative men. CONCLUSION: Adiponectin levels were lower in HIV-infected men and related to the severity of subclinical atherosclerosis, independent of traditional CVD risk factors. PMID- 24401648 TI - Looking upstream to prevent HIV transmission: can interventions with sex workers alter the course of HIV epidemics in Africa as they did in Asia? AB - BACKGROUND: High rates of partner change in 'upstream' sex work networks have long been recognized to drive 'downstream' transmission of sexually transmitted infections (STIs). We used a stochastic microsimulation model (STDSIM) to explore such transmission dynamics in a generalized African HIV epidemic. METHODS: We refined the quantification of sex work in Kisumu, Kenya, from the 4-cities study. Interventions with sex workers were introduced in 2000 and epidemics projected to 2020. We estimated the contribution of sex work to transmission, and modelled standard condom and STI interventions for three groups of sex workers at feasible rates of use and coverage. RESULTS: Removing transmission from sex work altogether would have resulted in 66% lower HIV incidence (range 54-75%) and 56% lower prevalence (range 44-63%) after 20 years. More feasible interventions reduced HIV prevalence from one-fifth to one-half. High rates of condom use in sex work had the greatest effect, whereas STI treatment contributed to HIV declines at lower levels of condom use. Interventions reaching the 40% of sex workers with most clients reduced HIV transmission nearly as much as less targeted approaches attempting to reach all sex workers. Declines were independent of antiretroviral therapy rollout and robust to realistic changes in parameter values. CONCLUSION: 'Upstream' transmission in sex work remains important in advanced African HIV epidemics even in the context of antiretroviral therapy. As in concentrated Asian epidemics, feasible condom and STI interventions that reach the most active sex workers can markedly reduce the size of HIV epidemics. Interventions targeting 'transactional' sex with fewer clients have less impact. PMID- 24401647 TI - Findings in asymptomatic HIV-infected patients undergoing chest computed tomography testing: implications for lung cancer screening. AB - BACKGROUND: HIV-infected persons have a two-fold to five-fold increased unadjusted risk of lung cancer. In the National Lung Screening Trial (NLST), computed tomography (CT) screening was associated with a reduction in lung cancer mortality among high-risk smokers. These results may not generalize to HIV infected persons, particularly if they are more likely to have false-positive chest CT findings. METHODS: We utilized data including standardized chest CT scans from 160 HIV infected and 139 uninfected Veterans enrolled between 2009 and 2012 in the multicenter Examinations of HIV Associated Lung Emphysema (EXHALE) Study. Abnormal CT findings were abstracted from clinical interpretations of the scans and classified as positive by NLST criteria vs. other findings. Clinical evaluations and diagnoses that ensued were abstracted from the medical record. RESULTS: There was no significant difference by HIV in the proportion of CT scans classified as positive by NLST criteria (29% of HIV infected and 24% of HIV uninfected, P=0.3). However, HIV-infected participants with CD4 cell counts less than 200 cells/MUl had significantly higher odds of positive scans, a finding that persisted in multivariable analysis. Evaluations triggered by abnormal CT scans were also similar in HIV-infected and uninfected participants (all P>0.05). CONCLUSION: HIV status was not associated with an increased risk of abnormal findings on CT or increased rates of follow-up testing in clinically stable outpatients with CD4 cell count more than 200. These data reflect favorably on the balance of benefits and harms associated with lung cancer screening for HIV infected smokers with less severe immunodeficiency. PMID- 24401649 TI - Clinical findings in 19 cases of invasive pulmonary aspergillosis with liver cirrhosis. AB - BACKGROUND: Aspergillus infection was mostly reported with high mortality rates and a bad prognosis in immunocompromised patients, but data were lacking on the clinical characteristics of aspergillus infection in liver cirrhosis. The aim of this study was to retrospectively assess the morbidity and mortality rate, clinical manifestation, risk factors, and medication of invasive pulmonary aspergillosis (IPA) in liver cirrhosis in The First Affiliated Hospital, College of Medicine, Zhejiang University. METHODS: Patients with liver cirrhosis who had been diagnosed with proven or probable IPA by clinical and laboratory parameters from 1st December 2008 to 1st May2012 were retrospectively evaluated for predisposing factors for IPA and clinical outcome. The follow up ended on 30th July2012. IPA was defined according to European Organization for Research and Treatment of Cancer/Mysoses Study group criteria. RESULTS: In total, 6,600 patients with liver cirrhosis were enrolled, and 19 out of these developed IPA. Seventeen out of 19 patients died. Imaging findings such as the halo sign and lower respiratory tract infection symptoms contributed to the early diagnosis of IPA. Possible risk factors for IPA included a high Child-Turcotte-Pugh (CTP) score, broad antibiotic usage and steroid exposure. The use of antifungal compounds may prolong a patient's life. CONCLUSIONS: The mortality of liver cirrhosis with IPA is high. Liver cirrhosis should be considered a risk factor of IPA. Once patients with high CTP scores and steroid and broad spectrum antibiotics exposure present cough and fever, IPA should be taken into consideration and antifungal agents should be used as soon as possible. PMID- 24401651 TI - Neuroanatomy of the human hypothalamic kisspeptin system. AB - Hypothalamic kisspeptin (KP) neurons are key players in the neuronal network that regulates the onset of puberty and the pulsatile secretion of gonadotropin releasing hormone (GnRH). In various mammalian species, the majority of KP synthesizing neurons are concentrated in two distinct cell populations in the preoptic region and the arcuate nucleus (ARC). While studies of female rodents have provided evidence that preoptic KP neurons play a critical sex-specific role in positive estrogen feedback, KP neurons of the ARC have been implicated in negative sex steroid feedback and they have also been hypothesized to contribute to the pulse generator network which regulates episodic GnRH secretion in both females and males. Except for relatively few morphological studies available in monkeys and humans, our neuroanatomical knowledge of the hypothalamic KP systems is predominantly based on observations of laboratory species which are phylogenetically distant from the human. This review article discusses the currently available literature on the topographic distribution, network connectivity, neurochemistry, sexual dimorphism, and aging-dependent morphological plasticity of the human hypothalamic KP neuronal system. PMID- 24401650 TI - The 50th anniversary of the US surgeon general's report on tobacco: what we've accomplished and where we go from here. PMID- 24401652 TI - ZEB2, a new candidate gene for asplenia. PMID- 24401653 TI - Low incidence of ADAMTS13 missense mutation R1060W in adult Egyptian patients with thrombotic thrombocytopenic purpura. AB - Thrombotic thrombocytopenic purpura (TTP) is an acute life-threatening disorder, characterized by thrombocytopenia, microangiopathic hemolytic anemia, widespread microvascular thrombi and consequent clinical sequelae due to ischemic organ damage. TTP is most commonly associated with deficiency or inhibition of von Willebrand factor-cleaving protease (ADAMTS13) activity. ADAMTS13 mutations and polymorphisms have been reported in childhood congenital TTP, but their significance in adult-onset TTP is still under investigation. Two mutations stand out: the single base insertion 4143insA in exon 29 and the missense mutation R1060W in exon 24 have both been observed in several unrelated families, mainly in adult-onset TTP, and over a wide geographic area. Our objective in this study is to identify the prevalence of R1060W missense mutation in exon 24 ADAMTS13 in a sample of adult Egyptian TTP patients. Thirty-one adult-onset TTP patients were included in this study, with a male/female ratio of 1:4. Twenty-six cases (84%) presented with acute idiopathic TTP, 2 cases were drug abusers and 3 cases were pregnant. None of the study cases provided a history of suspicious TTP symptoms during childhood (2 cases gave a history of episodes of thrombocytopenia during childhood). All cases showed statistically significant decreased ADAMTS13 activity compared to normal controls (p < 0.001). The study revealed a high statistical difference regarding the ADAMTS13 inhibitor level in primary versus secondary cases (p = 0.003). None of our Egyptian cases or of the healthy normal controls are positive for exon 24 missense mutation. Larger studies and regional and national TTP registries are recommended. PMID- 24401654 TI - Impaired uterine artery flow associated with the presence of ovarian endometrioma: preliminary results of a prospective study. AB - BACKGROUND: Aim of this prospective, case-control study was to evaluate uterine arteries' blood flow before and after laparoscopic surgery in patients with ovarian endometriosis and its possible correlation with infertility. METHODS: We prospectively enrolled 110 women of reproductive age; 69 with ovarian endometriomas and scheduled for surgery, and 41 controls. At enrolment, a detailed medical, gynecologic and obstetric history was collected. Fertility and pregnancy desire were assessed. All patients underwent complete physical and gynecologic examination. Transvaginal ultrasound with Doppler color flow was performed to evaluate Resistance Index (RI) of uterine arteries during the secretory phase, at enrolment (T0) and 3 months after laparoscopic surgery (T1). RESULTS: Among cases, 27 patients were excluded because they did not meet the inclusion criteria. At enrolment (T0) unilateral or bilateral flow alterations (RI >= 0.8) were found in 38 out of 42 patients with ovarian endometriosis (90%), whereas in the control group only 17 women (41%) had Doppler alterations. The difference in uterine artery RI values between cases and controls was statistically significant (P < 0.0001). A statistically significant improvement in uterine artery flow (P <0.0001) was found 3 months after surgical treatment of endometriosis. Nineteen patients with endometriosis (45%) were infertile before surgery; all of them presented uterine artery Doppler alterations at T0. After surgery the pregnancy rate was significantly higher in patients who presented uterine artery flow normalization than in those with persistent uterine artery flow alterations (p = 0.002). CONCLUSIONS: A strong correlation was found between uterine artery flow abnormalities and ovarian endometriosis. Uterine artery flow improvement following surgery seems to increase the probabilities of achieving pregnancy. PMID- 24401656 TI - Intertester agreement and validity of identifying lumbar pain provocative movement patterns using active and passive accessory movement tests. AB - OBJECTIVE: The purpose of this study was to evaluate the interexaminer agreement and validity of active and passive pain provocation tests in the lumbar spine. METHODS: Two blinded raters examined 36 participants, 18 of whom were asymptomatic and 18 reported subacute nonspecific low back pain (LBP). Two types of pain provocation tests were performed: (1) physiological movements in single (flexion/extension) and, when necessary, combined planes and (2) passive accessory intervertebral movement tests of each lumbar vertebra in prone with the lumbar spine in neutral, flexion, and extension position. RESULTS: The interobserver agreement in both groups was good to excellent for the identification of flexion (kappa = 0.87-1) or extension (kappa = 0.65-0.74) as the most painful pattern of spinal movement. In healthy participants, 0% was identified as having a flexion provocative pattern and 8.8% were identified as having an extension provocative pattern. In the LBP group, 20% were identified as having a flexion provocative pattern vs 60% with an extension provocative pattern. The average interexaminer agreement for passive accessory intervertebral movement tests in both groups was moderate to excellent (kappa = 0.42-0.83). The examiners showed good sensitivity (0.67-0.87) and specificity (0.82-0.85) to distinguish participants with LBP using this combined examination procedure. CONCLUSION: The use of a combination of pain provocative tests was found to have acceptable interexaminer reliability and good validity in identifying the main pain provocative movement pattern and the lumbar segmental level of involvement. These pain provocation tests were able to distinguish participants with LBP from asymptomatic participants and may help clinicians in directing manual therapy treatment. PMID- 24401655 TI - The metazoan protein disaggregase and amyloid depolymerase system: Hsp110, Hsp70, Hsp40, and small heat shock proteins. AB - A baffling aspect of metazoan proteostasis is the lack of an Hsp104 ortholog that rapidly disaggregates and reactivates misfolded polypeptides trapped in stress induced disordered aggregates, preamyloid oligomers, or amyloid fibrils. By contrast, in bacteria, protozoa, chromista, fungi, and plants, Hsp104 orthologs are highly conserved and confer huge selective advantages in stress tolerance. Moreover, in fungi, the amyloid remodeling activity of Hsp104 has enabled deployment of prions for various beneficial modalities. Thus, a longstanding conundrum has remained unanswered: how do metazoan cells renature aggregated proteins or resolve amyloid fibrils without Hsp104? Here, we highlight recent advances that unveil the metazoan protein-disaggregase machinery, comprising Hsp110, Hsp70, and Hsp40, which synergize to dissolve disordered aggregates, but are unable to rapidly solubilize stable amyloid fibrils. However, Hsp110, Hsp70, and Hsp40 exploit the slow monomer exchange dynamics of amyloid, and can slowly depolymerize amyloid fibrils from their ends in a manner that is stimulated by small heat shock proteins. Upregulation of this system could have key therapeutic applications in various protein-misfolding disorders. Intriguingly, yeast Hsp104 can interface with metazoan Hsp110, Hsp70, and Hsp40 to rapidly eliminate disease associated amyloid. Thus, metazoan proteostasis is receptive to augmentation with exogenous disaggregases, which opens a number of therapeutic opportunities. PMID- 24401657 TI - Well-being among Italian medical oncologists: an exploratory study. AB - BACKGROUND: Recently, attention has been focused on physicians' stress and quality-of-life improvement. Due to their relationship with patients, oncologists in particular are overloaded physically, emotionally and psychologically. Previous studies showed that training of communication skills improves the satisfaction and well-being of physicians and patients. AIMS: Our research investigates the relationship between work stress and engagement and personal well-being in physicians working in Italian hospitals. MATERIALS AND METHODS: 176 physicians were included. Doctors filled out self-report questionnaires to evaluate work stress and coping strategies, personal well-being, work engagement and two purpose-built scales to measure the degree of perceived organizational support and the level of specific training of social and relational skills. Descriptive statistics were used to analyze data, as well as correlation analysis (Pearson's r), hierarchical regression analysis (enter step) and analysis of variance (one-way ANOVA). RESULT: Positive and significant correlations were found between variables. Moreover, physicians who obtained higher levels of specific training on social and relational skills reported lower levels of stress. Oncologists experienced greater stress than other physicians in terms of maladaptive coping and lack of additional training. CONCLUSIONS: The study suggests that physicians' well-being is mediated by professional aspects, such as social skills in relationships with patients. PMID- 24401658 TI - On van Gogh and the foxglove plant. PMID- 24401659 TI - The world of "GM-free". AB - The rapid global development of agricultural production systems using seeds derived from genetic modification (GM) has been paralleled by the growth of attempts to keep at least a part of the world's agriculture and food as free from GM-crops and their products as possible. The ideal for some proponents of such "GM-free" activity would be a total absence, usually styled "zero content"; others, perhaps more realistically, opt for a definition usually not precisely defined that allows for minimal trace levels of GM material. The reasons for wanting "GM-free" agriculture and its products are varied; they include philosophical and religious beliefs, concern for human (and animal) health--and for "the environment"-as well as commercial and political interests. With such a variety of motivations, and in the absence of legal rulings, the definitions of "GM-free" vary according to inclination and circumstances. Whatever the precise meaning, the maintenance of a "GM-free" product stream in a world where GM crop production is widespread requires the establishment of identity preservation and segregation systems in which traceability and testing are cornerstones. Inevitably these have cost implications for the supply chain and/or the ultimate consumer. In a number of countries different forms of "GM-free" labels exist for some products; the style of such labels is variable with schemes and labels typically voluntary or privately organized. In more recent years, some governments have begun to regularize the definition and meaning of "GM-free." We conclude our analysis by exploring consumer reactions both to "GM-free" and to "GM-free" labels, and ask who ultimately benefits from preserving a product stream substantially or entirely devoid of GM-content. PMID- 24401660 TI - Increased expression of the leptin receptor in human ovaries affected by endometrioma and detection of high levels of leptin in the ovarian endometriomal fluid. AB - BACKGROUND: This study was designed to investigate leptin levels in the fluid in ovarian endometriomas (OEs) and to compare the expression of leptin and its receptors (OBR) in ovarian tissue affected by endometrioma in infertile women to its expression in the normal ovarian tissue of fertile controls without endometriosis. METHODS: In this case-control observational study, ovarian tissue, blood samples and peritoneal fluid were obtained from 20 women (10 fertile controls without endometriosis or any ovarian disease, who were undergoing tubal ligation surgery, and 10 infertile women with severe endometriosis and OE). The ovarian endometriomal fluid (EF) was aspirated, and peritoneal-implant (PI) biopsies were performed. The tissues removed during the surgeries were immediately frozen in liquid nitrogen to determine expression levels by western blot and leptin levels by ELISA. RESULTS: OBR was expressed at higher levels in the ovarian tissue affected by endometrioma than in the normal ovarian tissue (control = 0.38 +/- 0.05, study = 0.60 +/- 0.09, p = 0.03), but there was no significant difference in leptin levels between these groups (control = 0.57 +/- 0.1, study = 0.35 +/- 0.1, p = 0.18). Positive and significant correlations were observed between leptin and OBR in the OE (r = 0.85, p = 0.004) and in the PI (r = 0.87, p = 0.001). ELISA results demonstrate a greater leptin concentration within the EF compared with the serum and the PF (serum = 14.25 +/- 1.63, PF = 5.98 +/- 2.0, EF = 73.8 +/- 16.2, p = 0.0001), but there was no correlation between these variables. A positive, significant and strong correlation was observed between PF leptin levels and the expression of leptin and OBR in PI (leptin: r = 0.78, p = 0.007/OBR: r = 0.68, p = 0.04) and between the EF leptin levels and the expression of leptin and OBR in the OE (leptin: r = 0.88, p = 0.008/OBR: r = 0.89, p = 0.005). CONCLUSIONS: These data suggest that leptin may play an important role in the physiopathology of OE through a modulatory interaction with its active receptor. PMID- 24401661 TI - Global target mRNA specification and regulation by the RNA-binding protein ZFP36. AB - BACKGROUND: ZFP36, also known as tristetraprolin or TTP, and ELAVL1, also known as HuR, are two disease-relevant RNA-binding proteins (RBPs) that both interact with AU-rich sequences but have antagonistic roles. While ELAVL1 binding has been profiled in several studies, the precise in vivo binding specificity of ZFP36 has not been investigated on a global scale. We determined ZFP36 binding preferences using cross-linking and immunoprecipitation in human embryonic kidney cells, and examined the combinatorial regulation of AU-rich elements by ZFP36 and ELAVL1. RESULTS: Targets bound and negatively regulated by ZFP36 include transcripts encoding proteins necessary for immune function and cancer, and transcripts encoding other RBPs. Using partial correlation analysis, we were able to quantify the association between ZFP36 binding sites and differential target RNA abundance upon ZFP36 overexpression independent of effects from confounding features. Genes with increased mRNA half-lives in ZFP36 knockout versus wild-type mouse cells were significantly enriched for our human ZFP36 targets. We identified thousands of overlapping ZFP36 and ELAVL1 binding sites, in 1,313 genes, and found that ZFP36 degrades transcripts through specific AU-rich sequences, representing a subset of the U-rich sequences ELAVL1 interacts with to stabilize transcripts. CONCLUSIONS: ZFP36-RNA target specificities in vivo are quantitatively similar to previously reported in vitro binding affinities. ZFP36 and ELAVL1 bind an overlapping spectrum of RNA sequences, yet with differential relative preferences that dictate combinatorial regulatory potential. Our findings and methodology delineate an approach to unravel in vivo combinatorial regulation by RNA-binding proteins. PMID- 24401662 TI - Clinical and genetic evaluation of patients with KATP channel mutations from the German registry for congenital hyperinsulinism. AB - Congenital hyperinsulinism (CHI) causes hypoglycemia due to irregular insulin secretion. In infants, a rapid diagnosis and appropriate management to avoid severe hypoglycemia is mandatory. CHI is a heterogeneous condition at the clinical and genetic level, and disease-causing genes have been identified in about half of the patients. The majority of mutations have been identified in the ABCC8 and KCNJ11 genes encoding subunits of the KATP channel responsible for two distinct histological forms. The diffuse form is caused by autosomal recessive or dominant inherited mutations, whereas the focal form is caused by a paternally transmitted recessive mutation and a second somatic event. We report on an unselected cohort of 136 unrelated patients from the German CHI registry. Mutations in either the ABCC8 or KCNJ11 gene were identified in 61 of these patients (45%). In total, 64 different mutations including 38 novel ones were detected in this cohort. We observed biparental (recessive) inheritance in 34% of mutation-positive patients, dominant inheritance in 11% and paternal transmission of a mutation associated with a focal CHI type in 38%. In addition, we observed inheritance patterns that do not exactly follow the classical recessive or dominant mode, further adding to the genetic complexity of this disease. PMID- 24401663 TI - Control of malaria and other vector-borne protozoan diseases in the tropics: enduring challenges despite considerable progress and achievements. AB - Vector-borne protozoan diseases represent a serious public health challenge, especially in the tropics where poverty together with vector-favorable climates are the aggravating factors. Each of the various strategies currently employed to face these scourges is seriously inadequate. Despite enormous efforts, vaccines which represent the ideal weapon against these parasitic diseases-are yet to be sufficiently developed and implemented. Chemotherapy and vector control are therefore the sole effective attempts to minimize the disease burden. Nowadays, both strategies are also highly challenged by the phenomenon of drug and insecticide resistance, which affects virtually all interventions currently used. The recently growing support from international organizations and governments of some endemic countries is warmly welcome, and should be optimally exploited in the various approaches to drug and insecticide research and development to overcome the burden of these prevalent diseases, especially malaria, leishmaniasis, Human African Trypanosomiasis (HAT), and Chagas disease. PMID- 24401665 TI - Sample Size Calculation in Oncology Trials: Quality of Reporting and Implications for Clinical Cancer Research. AB - OBJECTIVES: Sample size calculation (SSC) is a pivotal step in clinical trial conception and design. Herein, we describe the frequency with which oncology phase III trials report the parameters required for SSC. MATERIALS AND METHODS: We systematically searched for phase III trials published in 6 leading journals, which were accompanied by editorials from January 2008 to October 2011. Two blinded investigators extracted required and optional parameters for SSC according to the primary endpoint. RESULTS: We retrieved 140 eligible phase III trials. The median target sample size was 596 subjects (50 to 40,000); in 66.4% of cases, the number of enrolled subjects was at least 90% of the target. The primary endpoint was a continuous variable in 5.7%, categorical in 30.0%, and a time-to-event variable in 64.3% of phase III trials. Although nearly 80% reported a target sample size, only 27.9% of the trials provided all the required parameters for proper SSC. The most commonly reported parameters for sample size computation were alpha (93.6%) and beta (90.7%) errors. The parameters least reported were the expected outcomes in the control or experimental groups, each provided in only 57.9% of trials. CONCLUSIONS: The quality of SSC reporting in phase III cancer trials is poor. Such incomplete reporting may compromise future study designs, pooling of data, and interpretation of results. Lack of transparency in SSC reporting may also have ethical implications. PMID- 24401664 TI - Prematurity and school readiness in a nationally representative sample of Australian children: does typically occurring preschool moderate the relationship? AB - OBJECTIVE: This study aims to examine the relationship between indicators of prematurity and children's cognitive and behavioral school readiness in a nationally representative sample and to investigate whether typically occurring preschool enrollment moderates this relationship, particularly for children from disadvantaged families in Australia. METHODS: The Longitudinal Study of Australian Children is a nationally representative prospective sample of two cohorts of children with sequentially obtained indicators of child health and developmental outcomes. We analyzed information on 8060 children aged 4-5 years who had complete data on birth weight, gestational age, prenatal risks, social factors, and cognitive and behavioral outcomes of school readiness. Multivariate regressions were used to relate three indicators of prematurity (low birth weight, preterm birth, and small for gestational age) to cognitive and behavioral school readiness. RESULTS: Children born preterm, small for gestational age, or with low birth weight have significantly lower cognitive school readiness after controlling for social factors and prenatal risks. None of the premature indicators were associated with behavioral school readiness. All children benefited from attending preschool. Yet, preschool enrollment did not moderate the relationship between prematurity and school readiness. The only exception is for small for gestational age survivors with low educated mothers. Preschool enrollment was associated with an increase in cognitive school readiness skills. CONCLUSIONS: Prematurity was associated with lower cognitive school readiness skills. Typical occurring preschool did not eliminate this association. Findings suggest that simply expanding the preschool enrollment is inadequate to address the developmental needs of premature children from disadvantaged backgrounds. PMID- 24401666 TI - Clinical and Prognostic Significance of Coagulation Assays in Pancreatic Cancer Patients With Absence of Venous Thromboembolism. AB - OBJECTIVES: Activation of coagulation and fibrinolysis is frequently observed in patients with cancer, even with absence of thrombosis. Furthermore, plasma coagulation parameters were associated with tumor progression, metastasis, and prognosis. Few studies have investigated these associations in pancreatic cancer (PA). This study aimed to investigate the clinical and prognostic significance of various plasma coagulation tests in PA patients with absence of venous thromboembolism (VTE). MATERIALS AND METHODS: A total of 139 PA patients with the absence of VTE were included in the analysis. Patients were followed up for at least 12 months until death. Pretreatment coagulation parameters including prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (APTT), fibrinogen (F), antithrombin-III (AT-III), protein C (PC), factor-VIII (F-VIII), and D-dimer (DD) were evaluated. A total of 40 age matched and sex-matched healthy individuals without coagulation disorder were enrolled as the control group. RESULTS: Patients were inclined to have higher levels of PT, INR, APTT, F, F-VIII, and DD and lower levels of AT-III and PC than the control group (P<0.01 for all, except P=0.022 for INR and P=0.015 for AT III). Patients with advanced tumor stages were likely to have higher median DD levels and lower AT-III levels than the control group (P=0.005 and P<0.001, respectively). DD levels were higher in patients with advanced pathology grade (P<0.001). Plasma DD levels (hazards ratio=1.71; 95% confidence interval, 1.07 2.73; P=0.025) were identified as the significantly independent prognostic predictors. CONCLUSIONS: PA patients are susceptible to activation of hemostasis system. Pretreatment plasma DD level was a potential predictor of prognosis in PA patients without VTE. PMID- 24401668 TI - Low Toxicity in Inflammatory Bowel Disease Patients Treated With Abdominal and Pelvic Radiation Therapy. AB - OBJECTIVE: To determine the short-term and long-term toxicity of abdominal and pelvic radiation therapy in a cohort of patients with inflammatory bowel disease (IBD). We hypothesize that with newer techniques, such as intensity-modulated radiation therapy (IMRT) and 3-dimensional conformal radiotherapy (3D-CRT), patients with IBD can safely undergo abdominal and pelvic radiation, with low risk for major acute or late toxicity. MATERIALS AND METHODS: Nineteen consecutive patients with IBD (14 with ulcerative colitis, 5 with Crohn disease) who were treated with abdominal or pelvic external beam radiation therapy at Stanford University from 1997 to 2011 were identified. Fourteen patients were treated with IMRT and 5 were treated with 3D-CRT. Treated sites included prostate (n=8), gastric/esophageal (n=5), rectal/anal (n=3), and liver (n=3) tumors. Charts were reviewed and toxicity was graded according to the Common Terminology Criteria for Acute Events version 4.0. Median follow-up was 32.5 months. Fisher exact test was used to determine if any clinical and/or treatment factors were associated with toxicity outcomes. RESULTS: Acute grade >=3 toxicity occurred in 2 patients (11%). Late grade >=3 toxicity occurred in 1 patient (6%). Acute grade >=2 toxicity occurred in 28% of patients treated with IMRT versus 100% of patients treated with 3D-CRT (P=0.01). Acute grade >=2 gastrointestinal toxicity was lower in patients treated with IMRT versus 3D-CRT (14% vs. 100%, respectively, P=0.002). Late grade >=2 toxicity occurred in 21% of patients. Higher total dose (Gy) and biologically effective dose (Gy) were associated with increased rates of late grade >=2 toxicity (P=0.02 and 0.03, respectively). CONCLUSIONS: These data suggest that select patients with IBD can safely undergo abdominal and pelvic radiation therapy. The use of IMRT was associated with decreased acute toxicity. Acute and late severe toxicity rates were low in this patient population with the use of modern radiation techniques. PMID- 24401667 TI - Extraskeletal Osteosarcoma: An International Rare Cancer Network Study. AB - OBJECTIVES: To report characteristics, treatment, and outcomes for an international cohort of patients with extraskeletal osteosarcoma (ESOS). MATERIALS AND METHODS: Through the Rare Cancer Network, retrospective data on patients with ESOS were collected. Patient characteristics, multimodality treatment information, and survival status were analyzed. RESULTS: Thirty-seven patients in 4 health care institutions were identified. Thirty-one (86%) patients had grade 3 or 4 tumors. Most patients (27 [73%]) had stage III disease. Fourteen (38%) received neoadjuvant chemotherapy or chemoradiation. Of 28 (85%) who underwent surgery, 21 (75%) had free margins achieved and 15 (41%) subsequently received adjuvant chemotherapy. At median follow-up of 45 months, 20 (55%) patients were alive, 13 (43%) of whom were disease free. Univariate analysis showed that poor overall survival was related to stage IV (P<0.001), no surgery (P<0.001), primary size >10 cm (P=0.002), and age (P=0.002). In multivariate analysis, primary size >10 cm (P=0.005) was prognostic for overall survival. For patients without metastases, univariate analysis showed disease-free survival (DFS) related to primary size >10 cm (P=0.003), surgery (P=0.004), local recurrence (P=0.003), and age (P<0.001). In multivariate analysis for DFS, primary size >10 cm (P=0.01) and older age (P<0.001) were significant for worse outcome. CONCLUSIONS: Multimodality treatment remains standard for localized ESOS, with indications for neoadjuvant therapy less clear. Larger tumor size and older age were prognostic of poorer DFS. PMID- 24401669 TI - Intensity-modulated Radiation Therapy for Anal Cancer: Results From a Multi Institutional Retrospective Cohort Study. AB - OBJECTIVES: To assess toxicity and efficacy of intensity-modulated radiation therapy (IMRT) for anal cancer. METHODS: Records of 152 patients were reviewed retrospectively from multiple institutions. Data on disease control and toxicity were collected as well as patient and treatment characteristics. Acute (<6 mo) and late (>=6 mo) severe toxicity (grade >=3) were graded. Four patients were excluded due to the presence of metastatic disease or stage TX. Late toxicity data were available for 120 patients. RESULTS: Median cumulative IMRT dose was 51.25 Gy (median, 28 fractions). All but 2 patients received chemotherapy. With median follow-up of 26.8 months, local control at 3 years was 87%, worse for patients with T3-T4 than T1-T2 disease on univariate analysis (79% vs. 90%; P=0.04). Regional control, distant control, and overall survival were 97%, 91%, and 87%, respectively, at 3 years. Nodal status was associated with regional control, distant control, and overall survival (P<0.01 for each). Most common severe acute toxicity was hematologic (41%), skin (20%), and gastrointestinal tract (11%). Two grade 5 toxicities occurred (hematologic and gastrointestinal tract). Severe late toxicity affected skin (1%) and gastrointestinal tract (3%). CONCLUSIONS: IMRT with chemotherapy resulted in excellent local control. Although T stage predicted worse local control, most T3-T4 disease was controlled with IMRT. Nodal status predicted regional and distant control and overall survival. Severe toxicity was acceptable. PMID- 24401670 TI - Concurrent Chemoradiotherapy With Cisplatin Versus Cetuximab for Squamous Cell Carcinoma of the Head and Neck. AB - OBJECTIVES: We previously reported inferior outcomes for locally advanced head and neck cancer treated with cetuximab (C225) versus cisplatin (CDDP). We now examine if this difference persists when accounting for HPV status and update outcomes on the entire cohort. MATERIALS AND METHODS: From 3/106 to 4/1/08, 174 locally advanced head and neck cancer patients received definitive treatment with RT and CDDP (n=125) or RT and C225 (n=49). Of these, 62 patients had tissue available for HPV analysis. RESULTS: The median follow-up was 47 months. The 3 year loco-regional failure, disease-free survival, and overall survival for CDDP versus C225 were 5.7% versus 40.2% (P<0.0001), 85.1% versus 35.4% (P<0.0001), and 90.0% versus 56.6% (P<0.0001), respectively. In the subset with tissue, there was no difference in rates of HPV or p16 positivity between the 2 groups. In this subset, the 3-year loco-regional failure, disease-free survival, and overall survival for CDDP versus C225 were 5.3% versus 32.0% (P=0.01), 86.8% versus 43.2% (P=0.002), and 86.7% versus 76.9% (P=0.09), respectively. Multivariate analysis continued to show a benefit for CDDP. CONCLUSIONS: With longer follow-up and the inclusion of HPV and p16 status for about one third of patients where tissue was available, we continued to find superior outcomes with concurrent CDDP versus C225. PMID- 24401671 TI - Racial Disparities in Extremity Soft-Tissue Sarcoma Outcomes: A Nationwide Analysis. AB - BACKGROUND: Racial disparities in access and survival have been reported in a variety of cancers. These issues, however, have yet to be explored in detail in patients with soft-tissue sarcomas (STS). The purpose of this paper was to investigate the independent role of race with respect to survival outcomes in STS. METHODS: A total of 7601 patients were evaluated in this study. A SEER registry query for patients over 20 years old with extremity STS diagnosed between 2004 and 2009 (n=7225) was performed. Survival outcomes were analyzed after patients were stratified by race. Multivariable survival models were used to identify independent predictors of sarcoma-specific death. The Wilcoxon rank sum test was used to compare continuous variables. Statistical significance was maintained at P<0.05. RESULTS: This study showed that African American patients were more likely to die of their STS. They were younger at presentation (P=0.001), had larger tumors (P<0.001), had less surgery (P=0.002), received radiotherapy less frequently (P=0.024), had higher family income (P<0.001), and were less likely to be married (P<0.001). African American race by itself was not an independent predictor of death. CONCLUSIONS: African Americans encounter death due to STS at a much larger proportion and faster rate than their respective white counterparts. African Americans frequently present with a larger size tumor, do not undergo surgical resection, or receive radiation therapy as frequently as compared with their white peers. Barriers to timely and appropriate care should be further investigated in this group of at-risk patients. PMID- 24401672 TI - Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases. AB - There is a growing body of evidence indicating that number of human neurodegenerative diseases, including Alzheimer disease, Parkinson disease, fronto-temporal dementias, and amyotrophic lateral sclerosis, propagate in the brain via prion-like intercellular induction of protein misfolding. Prions cause lethal neurodegenerative diseases in humans, the most prevalent being sporadic Creutzfeldt-Jakob disease (sCJD); they self-replicate and spread by converting the cellular form of prion protein (PrP(C)) to a misfolded pathogenic conformer (PrP(Sc)). The extensive phenotypic heterogeneity of human prion diseases is determined by polymorphisms in the prion protein gene, and by prion strain specific conformation of PrP(Sc). Remarkably, even though informative nucleic acid is absent, prions may undergo rapid adaptation and evolution in cloned cells and upon crossing the species barrier. In the course of our investigation of this process, we isolated distinct populations of PrP(Sc) particles that frequently co exist in sCJD. The human prion particles replicate independently and undergo competitive selection of those with lower initial conformational stability. Exposed to mutant substrate, the winning PrP(Sc) conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to the lowest stability. Thus, the evolution and adaptation of human prions is enabled by a dynamic collection of distinct populations of particles, whose evolution is governed by the selection of progressively less stable, faster replicating PrP(Sc) conformers. This fundamental biological mechanism may explain the drug resistance that some prions gained after exposure to compounds targeting PrP(Sc). Whether the phenotypic heterogeneity of other neurodegenerative diseases caused by protein misfolding is determined by the spectrum of misfolded conformers (strains) remains to be established. However, the prospect that these conformers may evolve and adapt by a prion-like mechanism calls for the reevaluation of therapeutic strategies that target aggregates of misfolded proteins, and argues for new therapeutic approaches that will focus on prior pathogenetic steps. PMID- 24401673 TI - Pharmacokinetics of dalteparin during haemodialysis. AB - BACKGROUND/AIMS: Usually, the appropriate dosage of low-molecular-weight heparin during haemodialysis is empirically based on the clinical effect. We studied the pharmacokinetics of dalteparin during standard haemodialysis in different groups of patients to assess the added value of measuring the anti-Xa activity for dose monitoring and adjustments. METHODS: The pharmacokinetics of intravenously administered dalteparin during haemodialysis was studied in 9 patients during 27 haemodialysis sessions. Six patients received a single bolus dose of dalteparin (group 1), and 3 patients received a higher initial bolus dose of dalteparin followed by a second bolus dose after 2 h (group 2). The clinical effect was evaluated by visual inspection for clot formation in the extracorporeal circuit. RESULTS: The pharmacokinetic curve suggests a zero-order process of elimination. The mean decrease in anti-Xa activity (slope) was comparable in all patients. The mean anti-Xa activity at the end of haemodialysis (Clast) was 0.15 IU/ml in group 1 and 0.60 IU/ml in group 2. CONCLUSION: We conclude that measuring anti-Xa activity can be used to monitor the elimination of dalteparin during haemodialysis and is highly reproducible. PMID- 24401674 TI - Reninoma: the importance of renal vein renin ratios for lateralisation and diagnosis. AB - BACKGROUND/AIM: Reninomas are rare juxtaglomerular tumours which can cause severe hypertension and hypokalaemia. Diagnosis can be problematic and these tumours can be difficult to locate on imaging. In this report we aim to demonstrate the value of carefully performed renal vein renin ratios (RVRRs) to assist in locating these tumours. METHOD/RESULTS: We report on 3 patients diagnosed with reninoma in our unit. The patients were all female, young (17, 16 and 30 years), severely hypertensive and hypokalaemic (2.5, 2.5 and 3.1 mmol/l). Plasma renin activity (PRA) was elevated (31.9, 274 and 175 ng/ml/h), and aldosterone was high-normal (19.9 ng/dl) or elevated (207 and 109.3 ng/dl). Renal artery stenosis was excluded by renal artery Doppler, DTPA scan and angiography. Renal CT detected the lesion in 2 patients, with one lesion visible on pre- and post-contrast CT and the other on post-contrast CT only. RVRRs were performed several weeks after withdrawing interfering medications, maintaining a <40 mmol/day low-sodium diet and maintaining recumbency overnight the night before and during the procedure. Ratios before and after captopril or enalaprilat administration were obtained and lateralised the tumours in all 3 cases (dominant/non-dominant ratios of 2.3, 4.3 and 3.8). All of the patients underwent nephrectomy yielding a typical juxtaglomerular tumour and resulting in cure of hypertension and hypokalaemia. CONCLUSIONS: Reninoma should be suspected in young hypertensives (especially females) with significant hypokalaemia and high PRA or direct renin concentration after renovascular hypertension has been excluded. CT imaging and carefully performed RVRRs provide the highest likelihood of locating these tumours. PMID- 24401675 TI - Therapeutic potential of vasopressin-receptor antagonists in heart failure. AB - Arginine vasopressin (AVP) is a 9-amino acid peptide that is secreted from the posterior pituitary in response to high plasma osmolality and hypotension. AVP has important roles in circulatory and water homoeostasis, which are mediated by oxytocin receptors and by AVP receptor subtypes: V(1a) (mainly vascular), V(1b) (pituitary), and V(2) (renal). Vaptans are orally and intravenously active nonpeptide vasopressin-receptor antagonists. Recently, subtype-selective nonpeptide vasopressin-receptor agonists have been developed. A selective V(1a) receptor antagonist, relcovaptan, has shown initial positive results in the treatment of Raynaud's disease, dysmenorrhea, and tocolysis. A selective V(1b) receptor antagonist, nelivaptan, has beneficial effects in the treatment of psychiatric disorders. Selective V2-receptor antagonists including mozavaptan, lixivaptan, satavaptan, and tolvaptan induce highly hypotonic diuresis without substantially affecting the excretion of electrolytes. A nonselective V(1a)/V(2) receptor antagonist, conivaptan, is used in the treatment for euvolaemic or hypervolemic hyponatremia. Recent basic and clinical studies have shown that AVP receptor antagonists, especially V2-receptor antagonists, may have therapeutic potential for heart failure. This review presents current information about AVP and its antagonists. PMID- 24401676 TI - Colchicine-free remission in familial Mediterranean fever: featuring a unique subset of the disease-a case control study. AB - BACKGROUND: To demonstrate and clinically, genetically and demographically characterize familial Mediterranean fever (FMF) patients, maintaining remission despite colchicine abstinence. METHODS: FMF patients were screened for an endurance of prolonged remission (>= 3 years), despite refraining from colchicine. Clinical, demographic and genetic parameters were collected. Data were compared with those of consecutive control FMF subjects, coming to the clinic for their periodic follow up examination. RESULTS: Of 1000 patients screened over 5 years, 33 manifested colchicine-free remission. The mean duration of the remission period was 12.6 +/- 8.1 years. Patients in the remission group had milder severity of FMF, compared to the control group (22 vs. 11 patients with mild disease, respectively, p=0.003) and a longer diagnosis delay (21 +/- 15.7 vs. 13.4 +/- 13.5 years, respectively, p=0.04). Patients experiencing remission suffered mostly of abdominal attacks, low rate of attacks in other sites and low rate of chronic and non-attack manifestations. When the disease resumed activity, it responded well to colchicine, despite using a lower dose, as compared to the control subjects (p<0.001). None of the patients in this group was homozygous for the M694V mutation (p=0.0008). CONCLUSIONS: Prolonged colchicine-free remission defines a rare and milder form of FMF with unique clinical, demographic, and molecular characteristics. PMID- 24401677 TI - Refractory invasive aspergillosis controlled with posaconazole and pulmonary surgery in a patient with chronic granulomatous disease: case report. AB - Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Among primary immunodefiencies, chronic granulomatous disease (CGD) has the highest prevalence of invasive fungal diseases. Voriconazole is recommended for the primary treatment of invasive aspergillosis in most patients. In patients whose aspergillosis is refractory to voriconazole, therapeutic options include changing class of antifungal, for example using an amphotericin B formulation, an echinocandin, combination therapy, or further use of azoles. Posaconazole is a triazole derivative which is effective in Aspergillosis prophylaxis and treatment. Rarely, surgical therapy may be needed in some patients. Lesions those are contiguous with the great vessels or the pericardium, single cavitary lesion that cause hemoptysis, lesions invading the chest wall, aspergillosis that involves the skin and the bone are the indications for surgical therapy.Chronic granulomatous disease (CGD) is an inherited immundeficiency caused by defects in the phagocyte nicotinamide adenine dinucleotidephosphate (NADPH) oxidase complex which is mainstay of killing microorganisms. CGD is characterized by recurrent life-threatening bacterial and fungal infections and by abnormally exuberant inflammatory responses leading to granuloma formation, such as granulomatous enteritis, genitourinary obstruction, and wound dehiscence. The diagnosis is made by neutrophil function testing and the genotyping.Herein, we present a case with CGD who had invasive pulmonary aspergillosis refractory to voriconazole and liposomal amphotericine B combination therapy that was controlled with posaconazole treatment and pulmonary surgery. PMID- 24401678 TI - Reply: To PMID 23969858. PMID- 24401679 TI - Serum concentration of 17alpha-hydroxyprogesterone in children from birth to adolescence. AB - BACKGROUND: Reference intervals (RI) of serum 17alpha- hydroxyprogesterone (17OHP) are useful to confirm congenital adrenal hyperplasia (CAH) in neonates with abnormal screening results and nonclassical forms of CAH in symptomatic children. We aimed to establish serum 17OHP RI in normal children and adolescents using a current 17OHP radioimmunoassay (RIA). METHODS: Serum 17OHP was measured via a current RIA (Diasource) in children, i.e. 111 infants aged <1 year [before (NE-17OHP) and after extraction (E-17OHP)] and 216 children aged 1-17 years. Forty NE serum samples from subjects aged >1 year, covering the whole analytical range, were simultaneously measured to compare 17OHP RIA from Diagnostic System Laboratories (DSL) (withdrawn) and Diasource by Passing Bablok linear regression and ratio plot. The equation obtained was used to correct our own previous RI (DSL RIA) for infancy for the Diasource RIA. Samples from infants aged <1 year were used to verify the calculated RI with evaluator protocol C28-A3. The influence of age, gender, and Tanner's classification (T) was assessed in children aged >1 year by ANOVA. RESULTS: E-17OHP as measured via the Diasource RIA was significantly lower than NE-17OHP in infants aged <1 year (p < 0.0001). The 17OHP measurement from the Diasource RIA was negatively biased compared to the value obtained using the DSL RIA (Diasource (ng/ml) = 0.85 DSL (ng/ml) -0.32 ng/ml, r = 0.952). Most infants (93%) had age- and gender-adjusted NE-17OHP and E 17OHP levels within the recalculated RI. Serum 17OHP significantly increased throughout prepuberty (p < 0.001). Sexual dimorphism was only observed at T IV-V. CONCLUSION: When evaluating 17OHP during childhood, we recommend taking into account the extraction procedure in neonates, the method used, age, and the Tanner's stage. PMID- 24401681 TI - A new animal model of spontaneous autoimmune peripheral polyneuropathy: implications for Guillain-Barre syndrome. AB - BACKGROUND: Spontaneous autoimmune peripheral neuropathy including Guillain-Barre Syndrome (GBS) represents as one of the serious emergencies in neurology. Although pathological changes have been well documented, molecular and cellular mechanisms of GBS are still under-explored, partially due to short of appropriate animal models. The field lacks of spontaneous and translatable models for mechanistic investigations. As GBS is preceded often by viral or bacterial infection, a condition can enhance co-stimulatory activity; we sought to investigate the critical role of T cell co-stimulation in this autoimmune disease. RESULTS: Our previous study reported that transgene-derived constitutive expression of co-stimulator B7.2 on antigen presenting cells of the nervous tissues drove spontaneous neurological disorders. Depletion of CD4+ T cells in L31 mice accelerated the onset and increased the prevalence of the disease. In the current study, we further demonstrated that L31/CD4-/- mice exhibited both motor and sensory deficits, including weakness and paresis of limbs, numbness to mechanical stimuli and hypersensitivity to thermal stimulation. Pathological changes were characterized by massive infiltration of macrophages and CD8+ T cells, demyelination and axonal damage in peripheral nerves, while changes in spinal cords could be secondary to the PNS damage. In symptomatic L31/CD4-/- mice, the disruption of the blood neural barriers was observed mainly in peripheral nerves. Interestingly, the infiltration of immune cells was initiated in pre-symptomatic L31/CD4-/- mice, prior to the disease onset, in the DRG and spinal roots where the blood nerve barrier is virtually absent. CONCLUSIONS: L31/CD4-/- mice mimic most parts of clinical and pathological signatures of GBS in human; thus providing an unconventional opportunity to experimentally explore the critical events that lead to spontaneous, autoimmune demyelinating disease of the peripheral nervous system. PMID- 24401680 TI - Constitutive patterns of gene expression regulated by RNA-binding proteins. AB - BACKGROUND: RNA-binding proteins regulate a number of cellular processes, including synthesis, folding, translocation, assembly and clearance of RNAs. Recent studies have reported that an unexpectedly large number of proteins are able to interact with RNA, but the partners of many RNA-binding proteins are still uncharacterized. RESULTS: We combined prediction of ribonucleoprotein interactions, based on catRAPID calculations, with analysis of protein and RNA expression profiles from human tissues. We found strong interaction propensities for both positively and negatively correlated expression patterns. Our integration of in silico and ex vivo data unraveled two major types of protein RNA interactions, with positively correlated patterns related to cell cycle control and negatively correlated patterns related to survival, growth and differentiation. To facilitate the investigation of protein-RNA interactions and expression networks, we developed the catRAPID express web server. CONCLUSIONS: Our analysis sheds light on the role of RNA-binding proteins in regulating proliferation and differentiation processes, and we provide a data exploration tool to aid future experimental studies. PMID- 24401682 TI - Biomechanical evaluation of the quadriceps tendon autograft for anterior cruciate ligament reconstruction: a cadaveric study. AB - BACKGROUND: Recently, many surgeons have chosen the quadriceps tendon (QT) as an autograft for anterior cruciate ligament (ACL) reconstruction. However, there have not been biomechanical studies that quantitatively evaluated knee function after reconstruction using a QT autograft. PURPOSE: To measure the 6 degrees of freedom knee kinematics and in situ graft forces after reconstruction with a QT autograft compared with a quadrupled semitendinosus and gracilis (QSTG) tendon autograft. STUDY DESIGN: Controlled laboratory study. METHODS: Ten human cadaveric knees (age, 54-64 years) were tested in 3 conditions: (1) intact, (2) ACL deficient, and (3) after ACL reconstruction using a QT or QSTG autograft. With use of a robotic/universal force-moment sensor testing system, knee kinematics and in situ forces in the ACL and autografts were obtained at 5 knee flexion angles under externally applied loads: (1) 134-N anterior tibial load, (2) 134-N anterior tibial load with 200-N axial compression, and (3) 10-N.m valgus and 5-N.m internal tibial torque. RESULTS: Under the anterior tibial load, both autografts restored anterior tibial translation to within 2.5 mm of the intact knee and in situ forces to within 20 N of the intact ACL at 15 degrees , 30 degrees , and 60 degrees . Adding compression did not change these findings. With the combined rotatory load, the anterior tibial translation and graft in situ forces were again not significantly different from the intact ACL. There were no significant differences between the grafts under any experimental condition. CONCLUSION: Reconstruction of the ACL with a QT autograft restored knee function to similar levels as that reconstructed with a QSTG autograft under loads simulating clinical examinations. CLINICAL RELEVANCE: The positive biomechanical results of this cadaveric study lend support to the use of a QT autograft for ACL reconstruction, as it could restore knee function immediately after surgery under applied loads that mimic clinical examinations. PMID- 24401683 TI - Biomechanical comparison of an all-soft suture anchor with a modified Brostrom Gould suture repair for lateral ligament reconstruction. AB - BACKGROUND: Anatomic repair is indicated for patients who have recurrent lateral ankle instability despite nonoperative measures. HYPOTHESIS: There is no difference in repair stiffness, failure torque, or failure angle between specimens repaired with all-soft suture anchors versus the modified Brostrom Gould technique with sutures only. STUDY DESIGN: Controlled laboratory study. METHODS: In 10 matched pairs of human cadaveric ankles, the anterior talofibular ligament (ATFL) was incised from its origin on the fibula. After randomization, 1 ankle was repaired to its anatomic insertion using two 1.4-mm JuggerKnot all-soft suture anchors; the other ankle was repaired with a modified Brostrom-Gould technique using 2-0 FiberWire. All were augmented using the inferior extensor retinaculum. All ankles were mounted to the testing machine in 20 degrees of plantar flexion and 15 degrees of internal rotation and loaded to failure after the repair. Stiffness, failure torque, and failure angle were recorded and compared using a paired Student t test with a significance level set at P < .05. RESULTS: There was no significant difference in failure torque, failure angle, or stiffness. No anchors pulled out of bone. The primary mode of failure was pulling through the ATFL tissue. CONCLUSION: There was no statistical difference in strength or stiffness between a 1.4-mm all-soft suture anchor and a modified Brostrom-Gould repair with 2-0 FiberWire. The primary mode of failure was at the tissue level rather than knot failure or anchor pullout. CLINICAL RELEVANCE: The particular implant choice (suture only, tunnel, anchor) in repairing the lateral ligament complex may not be as important as the time to biological healing. The suture-only construct as described in the Brostrom-Gould repair was as strong as all-soft suture anchors, and the majority of the ankles failed at the tissue level. For those surgeons whose preference is to use anchor repair, this novel all-soft suture anchor may be an alternative to other larger anchors, as none failed by pullout. PMID- 24401684 TI - Antiepileptic drugs and neurocognitive development. PMID- 24401685 TI - Neuralgic amyotrophy and hepatitis E virus infection. AB - OBJECTIVE: To determine whether there is an association between an acute preceding hepatitis E virus (HEV) infection and neuralgic amyotrophy (NA), and if so, whether patients with HEV-related NA differ from patients without an associated HEV infection. METHODS: HEV testing was conducted in a retrospective cohort of 28 Cornish patients with NA (2011-2013) and a prospective cohort of 38 consecutive Dutch patients with NA (2004-2007). Acute-phase serum samples were analyzed for the presence of anti-HEV immunoglobulin (Ig) M and IgG and HEV RNA (quantitative real-time PCR). RESULTS: Five cases (10.6%) of acute hepatitis E infection were identified in a total group of 47 patients with NA of whom serum samples were available. In 4 patients, HEV RNA was detected in serum samples taken at presentation. All patients with HEV-associated NA had clinical and electrophysiologic evidence of bilateral brachial plexus involvement. Anti-HEV IgM positivity was not related to age, sex, disease severity, disease course, or outcome. CONCLUSIONS: Acute hepatitis E is found in 10% of patients with NA from the United Kingdom and the Netherlands. Further research is required to investigate the role of HEV in NA in other geographical locations and to determine pathophysiologic mechanisms. PMID- 24401686 TI - Myoinositol and glutamate complex neurometabolite abnormality after mild traumatic brain injury. AB - OBJECTIVE: To obtain quantitative neurometabolite measurements, specifically myoinositol (mI) and glutamate plus glutamine (Glx), markers of glial and neuronal excitation, in deep gray matter structures after mild traumatic brain injury (mTBI) using proton magnetic resonance spectroscopy ((1)H-MRS) and to compare these measurements against normal healthy control subjects. METHODS: This study approved by the institutional review board is Health Insurance Portability and Accountability Act compliant. T1-weighted MRI and multi-voxel (1)H-MRS imaging were acquired at 3 tesla from 26 patients with mTBI an average of 22 days postinjury and from 13 age-matched healthy controls. Two-way analysis of variance was used to compare patients and controls for mean N-acetylaspartate, choline, creatine (Cr), Glx, and mI levels as well as the respective ratios to Cr within the caudate, globus pallidus, putamen, and thalamus. RESULTS: Quantitative putaminal mI was higher in patients with mTBI compared with controls (p = 0.02). Quantitative neurometabolite ratios of putaminal mI and Glx relative to Cr, mI/Cr, and Glx/Cr were also higher among patients with mTBI compared with controls (p = 0.01 and 0.02, respectively). No other differences in neurometabolite levels or ratios were observed in any other brain region evaluated. CONCLUSION: Increased putaminal mI, mI/Cr, and Glx/Cr in patients after mTBI compared with control subjects supports the notion of a complex glial and excitatory response to injury without concomitant neuronal loss, evidenced by preserved N-acetylaspartate levels in this region. PMID- 24401687 TI - In utero exposure to levetiracetam vs valproate: development and language at 3 years of age. AB - OBJECTIVE: To compare the cognitive and language development of children born to women with epilepsy (WWE) exposed in utero to levetiracetam (LEV) or sodium valproate (VPA) and control children born to women without epilepsy not taking medication during pregnancy. METHODS: The children, aged between 36 and 54 months, were recruited from the United Kingdom and assessed using the Griffiths Mental Development Scales and the Reynell Language Development Scale. Maternal demographic and epilepsy information was also collected for use in statistical regression. This is an observational study with researchers not involved in the clinical management of the mothers enrolled. RESULTS: After controlling for confounding variables, children exposed to LEV in utero (n = 53) did not differ from unexposed control children (n = 131) on any scale administered. Children exposed to VPA (n = 44) in utero scored, on average, 15.8 points below children exposed to LEV on measures of gross motor skills (95% confidence interval [CI] 24.5 to -7.1, p < 0.001), 6.4 points below on comprehension language abilities (95% CI -11.0 to -1.8, p = 0.005), and 9.5 points below on expressive language abilities (95% CI -14.7 to -4.4, p < 0.001). CONCLUSION: The current study indicates that children exposed to LEV in utero were superior in their language and motor development in comparison to children exposed to VPA. This information should be used collaboratively between health care professionals and WWE when deciding on women's preferred choice of antiepileptic drug. PMID- 24401688 TI - Epicardial metastasis of rectal neuroendocrine tumour. PMID- 24401689 TI - Effect of hypogammaglobulinemia after lung transplantation: a single-institution study. AB - OBJECTIVES: Recent studies suggest hypogammaglobulinemia (HGG) is frequently associated with infection after solid organ transplantation, although the effects of HGG after lung transplantation are not well recognized. We investigated the incidence and degree of HGG after lung transplantation and its association with infection. METHODS: A retrospective cohort study analysing pre- and post transplant IgA, IgG and IgM levels and infectious events in patients undergoing living-donor lobar and cadaveric lung transplantation at Kyoto University Hospital between June 2008 and March 2013. RESULTS: Overall, post-transplant immunoglobulin (Ig) levels were significantly lower than pretransplant levels. In almost all patients who received transplants for bronchiolitis obliterans (BO) after haematopoietic stem cell transplantation (HSCT), interstitial lung diseases and bronchiectasis, post-transplant IgA and IgG levels decreased and were significantly lower than pretransplant levels; pre- and post-transplant IgA and pretransplant IgG levels were significantly lower in patients transplanted for BO after HSCT than in the others. Post-transplant IgG levels in patients transplanted for BO after HSCT also tended to be lower than those in the others, but not significantly. Nineteen of 29 patients had HGG after lung transplantation (65.5%) and had more infections than the normal gammaglobulinemia group, although there was no significant difference. Among them, 2 patients transplanted for BO after HSCT with quite low HGG had severe pneumonia and finally died. CONCLUSIONS: Post-transplant Ig levels were significantly lower than pretransplant levels. Although without significant difference, HGG patients had more infections, above all, those with severe HGG transplanted for BO after HSCT could have lethal infections. Ig levels in HGG should be monitored carefully because severe HGG was associated with poor prognosis. PMID- 24401690 TI - Abnormal origin of the right coronary artery in a patient with left ventricular non-compaction. PMID- 24401691 TI - In-hospital mortality risk assessment in elective and non-elective cardiac surgery: a comparison between EuroSCORE II and age, creatinine, ejection fraction score. AB - OBJECTIVES: Age, creatinine, ejection fraction (ACEF) score is a simplified algorithm for prediction of mortality after elective cardiac surgery. Although mainly conceived for elective cardiac surgery, no information is available on its performance in non-elective surgery and on comparison with the new EuroSCORE II. This study was undertaken to compare the performance of ACEF score and EuroSCORE II within classes of urgency. METHODS: Complete data on 13 871 consecutive patients who underwent major cardiac surgery in a 6-year period were retrieved from three prospective institutional databases. Discriminatory power was assessed using the c-index and h with Delong, bootstrap and Venkatraman methods. Calibration was evaluated with calibration curves and associated statistics. RESULTS: The in-hospital mortality rate was 2.5%. The discriminatory power of ACEF score within elective and non-elective surgery was similar (area under the curve (AUC) 0.71, 95% confidence interval (CI) 0.67-0.74 and AUC 0.68, 95% CI 0.62-0.73, respectively) but significantly lower than that of EuroSCORE II (AUC 0.80, 95% CI 0.77-0.83 for elective surgery; AUC 0.82, 95% CI 0.78-0.85 for non elective surgery). The calibration patterns were different in the two subgroups, but the summary statistics underscored a miscalibration in both of them (U statistic and Spiegelhalter Z-test P-values <0.05). Even the calibration of EuroSCORE II was insufficient, although it was demonstrated to be well calibrated in the first tertile of predicted risk. CONCLUSIONS: This study demonstrated that the performance of ACEF score in predicting in-hospital mortality in elective and non-elective cardiac surgery is comparable. Nonetheless, it is not as satisfactory as the new EuroSCORE II, as its discrimination is significantly lower and it is also miscalibrated. PMID- 24401692 TI - Relationship between plaque pH and different caries-associated variables in a group of adolescents with varying caries prevalence. AB - The pH response of the dental biofilm after a sugar challenge can be considered to mirror the acidogenic potential and thereby the caries risk of an individual. The aim of this cross-sectional study was to evaluate the relationship between plaque pH and different caries variables in adolescents with varying caries prevalence. One hundred individuals, aged 14-15 years, were examined regarding different caries-related variables: (i) caries score (DSm, DSi, DSm + i, DTm), (ii) salivary secretion rate and buffer capacity, (iii) oral microflora of plaque and saliva, (iv) plaque amount, (v) plaque pH and (vi) dietary intake, oral hygiene habits and fluoride use. Plaque pH was assessed using the microtouch method before and after a 1-min mouthrinse with 10 ml 10% sucrose. Depending on the minimum pH, the participants were divided into three groups: low pH (<=5.3), medium pH (>5.3-6.3) and high pH (>6.3). Statistically significant differences between the three groups (p < 0.01) were found for initial caries (DSi) and combined manifest and initial caries (DSm + i). A statistically significant difference was also found in the log values for salivary lactobacilli (p = 0.02) within the three groups, and for the total number of bacteria in plaque (p = 0.04); for both variables, the low-pH group had the highest values. The only covariate significantly associated was the Cariogram score in the medium-pH group (p < 0.01) and the number of meals per day in the high-pH group (p = 0.02). To conclude, plaque pH measured by the microtouch method is a method that can be used for discriminating between individuals with varying caries prevalence. PMID- 24401694 TI - Human brown adipose tissue: regulation and anti-obesity potential. AB - Brown adipose tissue (BAT) is the site of sympathetically activated adaptive thermognenesis during cold exposure and after hyperphagia, thereby controlling whole-body energy expenditure (EE) and body fat. Radionuclide imaging studies have demonstrated that adult humans have metabolically active BAT composed of mainly beige/brite adipocytes, recently identified brown-like adipocytes. The inverse relationship between the BAT activity and body fatness suggests that BAT is, because of its energy dissipating activity, protective against body fat accumulation in humans as it is in small rodents. In fact, either repeated cold exposure or daily ingestion of some food ingredients acting on transient receptor potential channels recruits BAT in parallel with increased EE and decreased body fat. In addition to the sympathetic nervous system, several endocrine factors are also shown to recruit BAT. Thus, BAT is a promising therapeutic target for combating human obesity and related metabolic disorders. PMID- 24401695 TI - Emergency medicine in the United Arab Emirates. AB - It has been a decade since emergency medicine was recognized as a specialty in the United Arab Emirates (UAE). In this short time, emergency medicine has established itself and developed rapidly in the UAE. Large, well-equipped emergency departments (EDs) are usually located in government hospitals, some of which function as regional trauma centers. Most of the larger EDs are staffed with medically or surgically trained physicians, with board-certified emergency medicine physicians serving as consultants overseeing care.Prehospital care and emergency medical services (EMS) operate under the auspices of the police department. Standardized protocols have been established for paramedic certification, triage, and destination decisions. The majority of ambulances offer basic life support (BLS/Type 2) with a growing minority offering advanced life support (ALS/Type 3).Medicine residency programs were established 5 years ago and form the foundation for training emergency medicine specialists for UAE.This article describes the full spectrum of emergency medicine in the UAE: prehospital care, EMS, hospital-based emergency care, training in emergency medicine, and disaster preparedness. We hope that our experience, our understanding of the challenges faced by the specialty, and the anticipated future directions will be of importance to others advancing emergency medicine in their region and across the globe. PMID- 24401693 TI - Stem cell derived basal forebrain cholinergic neurons from Alzheimer's disease patients are more susceptible to cell death. AB - An early substantial loss of basal forebrain cholinergic neurons (BFCNs) is a constant feature of Alzheimer's disease (AD) and is associated with deficits in spatial learning and memory. Induced pluripotent stem cells (iPSCs) derived from patients with AD as well as from normal controls could be efficiently differentiated into neurons with characteristics of BFCNs. We used BFCNs derived from iPSCs to model sporadic AD with a focus on patients with ApoE3/E4 genotypes (AD-E3/E4). BFCNs derived from AD-E3/E4 patients showed typical AD biochemical features evidenced by increased Abeta42/Abeta40 ratios. AD-E3/E4 neurons also exhibited altered responses to treatment with gamma-secretase inhibitors compared to control BFCNs or neurons derived from patients with familial AD. BFCNs from patients with AD-E3/E4 also exhibited increased vulnerability to glutamate mediated cell death which correlated with increased intracellular free calcium upon glutamate exposure. The ability to generate BFCNs with an AD phenotype is a significant step both for understanding disease mechanisms and for facilitating screening for agents that promote synaptic integrity and neuronal survival. PMID- 24401696 TI - Does online haemodiafiltration reduce intra-dialytic patient symptoms? AB - INTRODUCTION: Patients often suffer from symptoms during dialysis. Haemodiafiltration (HDF) therapy has been suggested to be superior to standard haemodialysis (HD). To understand patients' experiences, we quantified the burden and duration of dialysis-associated symptoms to determine whether there was any difference between the modalities. METHODS: Symptom questionnaires (83.3%) were returned by 623 dialysis outpatients. Symptom scores were analysed using a visual analogue score. We compared symptom burdens during HD and HDF treatments and also whether the scores changed following a modality change to HDF. RESULTS: Among the patients, 55.7% were men, the median age was 65 years, 39.7% were diabetic, 26.4% were treated by HDF and the median unadjusted Charlson co-morbidity score was 6 (IQR 4-8). Fatigue (77.3%), intra-dialytic hypotension (76.4%), cramps (74.3%) and dizziness (63%) were the commonest symptoms reported, followed by headache (53.6%) and pruritus (52.2%). Although most symptoms were reported less frequently with HDF [median headache frequency score: HD: 1 (IQR 1-4) vs. HDF: 0 (IQR 0-2), p < 0.005]. There was no evidence of a reduction in symptom scores in patients switching from HD to HDF compared to those remaining on HD. CONCLUSION: Patient self-reporting shows that most patients frequently suffer symptoms. There was no evidence that switching to HDF improved symptoms in patients established on HD. PMID- 24401697 TI - Comparisons of pattern visually evoked potentials elicited by different response time liquid crystal display screens. AB - PURPOSE: To evaluate the usefulness of a liquid crystal display (LCD) with higher driving frequency and shorter response time (2 ms) as a visual stimulator to elicit pattern reversal visually evoked potentials (p-VEPs). METHOD: p-VEPs were recorded from 12 eyes of 12 healthy volunteers (28.3 +/- 9 years). The p-VEPs elicited by a conventional cathode ray tube (CRT) screen were compared to those elicited by a high-speed LCD screen (2-ms LCD, GD245HQbid, Acer, Taipei, Taiwan). The luminance changes of each monitor were measured with a photodiode. RESULTS: During the reversal phase the luminance of the 2-ms LCD screen with 97% contrast was transiently reduced, which can elicit an electroretinogram (ERG) and therefore a flash VEP. The 2-ms LCD with 81% contrast checkerboard had a minimal luminance reduction during the reversal phase, and therefore no ERGs were elicited. No significant differences in the amplitude of P100 and the implicit times of N75 and P100 were observed in the p-VEPs elicited by a CRT or the 2-ms LCD screens as stimulators. CONCLUSION: The luminance change can elicit flash VEPs, and this artifact can be minimized by using a 2-ms LCD screen with reduced contrast of the checkerboard stimulus. PMID- 24401698 TI - Extensive cartilaginous metaplasia of recurrent posterior fossa ependymoma: case report and review of the literature. AB - Cartilaginous metaplasia in ependymomas is extremely rare and only few cases have been reported in the literature. We describe a case of a 5-year-old patient with a 5th recurrence of 4th ventricle ependymoma. He was previously treated with 4 resections, chemotherapy and radiotherapy. Histopathology revealed well differentiated chondroid tissue occupying almost the entire lesion. Near total resection was achieved for the 5th time, but the patient died 3 months later achieving a total survival of 48 months, the 3rd longest reported in literature. Multiple resections of tumour recurrence provided a new insight in this very rare tumour, as it gave us the opportunity to observe the progression of tumour aggressiveness from grade II to grade III and finally to chondroid metaplasia. Cartilaginous metaplasia in posterior fossa ependymomas is a very atypical and challenging tumour with poor overall prognosis. PMID- 24401700 TI - Nickel removal by biosorption onto medlar male flowers coupled with photocatalysis on the spinel ZnMn2O4. AB - Ni2+ is a highly toxic above 0.07 mg/L and its removal is of high significance. The biosorption of Ni2+ onto medlar male flowers (MMF) was studied in relation with the physical parameters like pH, contact time, biosorbent dosage, Ni2+ concentration and temperature. The interaction biosorbent-Ni2+ was examined by the FTIR technique. The equilibrium was achieved within 40 min and the data were well fitted by the Langmuir and Redlich-Peterson (R-P) models. The maximum Ni2+ uptake capacity was 17.073 mg/g at 25 degrees C and the Ni2+ removal follows a pseudo-second order kinetic with activation energy of 13.3 kJ/mol. The thermodynamic parameters: DeltaS degrees , DeltaH degrees and DeltaG degrees showed that the biosorption was spontaneous and endothermic. MMF was used as a post treatment technique and the biosorption was coupled with the visible light driven Ni2+ reduction over the spinel ZnMn2O4. The effect of the pH, ZnMn2O4 loading and light intensity on the photoactivity was investigated. 77.5% of Ni2+ was reduced after ~140 min under optimal conditions. The Ni2+ removal reached a rate conversion of 96% of with the coupled system biosorption/photocatalysis is very promising for the water treatment. PMID- 24401699 TI - BK virus replication in patients with anti-neutrophil cytoplasmic antibody associated vasculitis. AB - BACKGROUND: BK virus (BKV) is an important cause of renal dysfunction in kidney transplant (KTX) recipients. Immunosuppression intensity is a major risk factor for BKV replication in these patients. The prevalence of BKV replication in immunosuppressed patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) without transplant is not known. METHODS: Consecutive patients (n = 37) with a diagnosis of GPA (n = 25) or MPA (n = 12) without history of KTX were evaluated for plasma BKV replication by quantitative PCR (group A). Descriptive data were collected. BKV replication in this nontransplant immunosuppressed vasculitis cohort was compared with a historical cohort of vasculitis KTX recipients (group B). RESULTS: Group A patients had mean disease duration of 75 months. Mean age was 57 years and 54% were female. Mean time from vasculitis onset to BKV testing was 36 months, and 19/37 patients were tested within 24 months of induction therapy. At the time of BKV testing, 73% were on prednisone (P) with azathioprine, mycophenolate mofetil (MMF), methotrexate or leflunomide. None of the nontransplanted vasculitis patients had detectable plasma BKV. Among 35 patients in group B, 16 were tested for BKV; 5/16 (31%) had detectable virus in plasma at a mean of 6 months after TX (p = 0.002). Most (94%) were on maintenance therapy with MMF, P and tacrolimus. CONCLUSION: Immunosuppressed patients with GPA/MPA without KTX had no evidence of plasma BKV. However, BKV was common in GPA/MPA patients after KTX, suggesting that replication may be related to differences in immunosuppression, alloimmune activation or differences in host defense mechanisms. PMID- 24401701 TI - Guidelines for a new year. PMID- 24401702 TI - P-glycoprotein: a focus on characterizing variability in cardiovascular pharmacotherapeutics. AB - According to the report of Agency for Healthcare Research and Quality in 2008, drug-related adverse outcomes exceed 2.7 million events per year. Therefore, it is requisite to understand the etiologies of those unpleasant outcomes. Polypharmacy especially in the elderly is considered one of the major sources of drug-related side effects. The drug-related membrane transporters play an indispensable role in the pharmacokinetics, safety, and efficacy of the drugs. P glycoprotein, also known as P-gp, is considered one of the core drug transporters in vivo. Since its discovery in 1976, P-gp gained a tremendous attention of researchers and clinicians. The core objective of this review is to highlight the clinical correlation between the P-gp and a number of cardiovascular drugs and to address the drug-drug interaction in case of using those cardiovascular drugs with P-gp-related drugs whether substrates, inhibitors, or inducers. Bearing in mind that P-gp is found in liver and intestine, as well as cytochrome P450, a strong association between the 2 systems is expected. Yet, plenty of the drugs that can behave as substrates to P-gp can act as substrates to CYP450 too. Consequently, probable drug-drug interaction can occur between drugs that work on both systems. In other words, whenever these classes of medications prescribed together cautious monitoring of drug's level and eventually dose adjustment might be necessary to avoid drug-drug interactions, failure of therapy, or drug toxicity; especially with the use of drugs that possess narrow therapeutic index like digoxin. PMID- 24401703 TI - Prevalence of hyperuricemia and the relationship between serum uric acid and metabolic syndrome in the Asian Mongolian area. AB - AIM: To investigate the prevalence of hyperuricemia and the association between the serum uric aci (SUA) levels and incidence of metabolic syndrome (MetS) in the Mongolian area of China. METHODS: This cross-sectional survey was based on a population of 1,426 subjects (809 men and 617 women) 20-80 years of age who were recruited from Inner Mongolia, China. Metabolic and anthropometric indicators were measured according to standard methods. Hyperuricemia was defined as an SUA level of >=7.0 mg/dL for men and >=6.0 mg/dL for women. MetS was diagnosed based on the consensus criteria released in 2009 from a joint collaboration organization. RESULTS: The prevalence of hyperuricemia was 17.7% in men and 5.2% in women. The prevalence of MetS in men was higher than that observed in women(36.7% vs. 17.8%). Waist circumference, BMI and the level of triglycerides were most strongly correlated with the SUA level in both sexes. Men with hyperuricemia had an increased risk of MetS [OR(95%CI)=2.95(2.00-4.35)], while men with a "normal" SUA level(>5.0 mg/dL and <6.3 mg/dL) had a higher risk of MetS, central obesity and hypertriglyceridemia than men in the lower level group (<=5 mg/dL). Women with a higher SUA level(>=4.3 mg/dL) had an increased risk of MetS, central obesity, hypertriglyceridemia and hypertension compared with women in the lowest tertile SUA group (<=3.5 mg/dL). CONCLUSIONS: The SUA level is significantly associated with various metabolic indicators. In this study, waist circumference and the level of triglycerides were most strongly correlated with the SUA level in both sexes. Individuals with a normal level of SUA had an increased risk of MetS and other metabolic disorders. Further research on appropriate cut-off values for pre-hyperuricemia is expected, and the early detection of hyperuricemia is essential for the prevention of MetS. PMID- 24401704 TI - TrigNER: automatically optimized biomedical event trigger recognition on scientific documents. AB - BACKGROUND: Cellular events play a central role in the understanding of biological processes and functions, providing insight on both physiological and pathogenesis mechanisms. Automatic extraction of mentions of such events from the literature represents an important contribution to the progress of the biomedical domain, allowing faster updating of existing knowledge. The identification of trigger words indicating an event is a very important step in the event extraction pipeline, since the following task(s) rely on its output. This step presents various complex and unsolved challenges, namely the selection of informative features, the representation of the textual context, and the selection of a specific event type for a trigger word given this context. RESULTS: We propose TrigNER, a machine learning-based solution for biomedical event trigger recognition, which takes advantage of Conditional Random Fields (CRFs) with a high-end feature set, including linguistic-based, orthographic, morphological, local context and dependency parsing features. Additionally, a completely configurable algorithm is used to automatically optimize the feature set and training parameters for each event type. Thus, it automatically selects the features that have a positive contribution and automatically optimizes the CRF model order, n-grams sizes, vertex information and maximum hops for dependency parsing features. The final output consists of various CRF models, each one optimized to the linguistic characteristics of each event type. CONCLUSIONS: TrigNER was tested in the BioNLP 2009 shared task corpus, achieving a total F-measure of 62.7 and outperforming existing solutions on various event trigger types, namely gene expression, transcription, protein catabolism, phosphorylation and binding. The proposed solution allows researchers to easily apply complex and optimized techniques in the recognition of biomedical event triggers, making its application a simple routine task. We believe this work is an important contribution to the biomedical text mining community, contributing to improved and faster event recognition on scientific articles, and consequent hypothesis generation and knowledge discovery. This solution is freely available as open source at http://bioinformatics.ua.pt/trigner. PMID- 24401705 TI - Dopamine gates sensory representations in cortex. AB - The prefrontal cortex (PFC) maintains information about relevant sensory stimuli, in a process thought to rely on dopamine release. In a recent paper, Jacob et al. (J Neurosci 33: 13724-13734, 2013) demonstrated one way in which dopamine might facilitate this process. The authors recorded from PFC neurons in monkeys during local application of dopamine. They found that dopamine increases the gain of sensory-evoked responses in putative pyramidal neurons in PFC, potentially by inhibiting local interneurons. PMID- 24401706 TI - Partially dissociable roles of OFC and ACC in stimulus-guided and action-guided decision making. AB - Recently, the functional specialization of prefrontal areas of the brain, and, specifically, the functional dissociation of the orbitofrontal cortex (OFC) and the anterior cingulate cortex (ACC), during decision making have become a particular focus of research. A number of neuropsychological and lesion studies have shown that the OFC and ACC have dissociable functions in various dimensions of decision making, which are supported by their different anatomical connections. A recent single-neuron study, however, described a more complex picture of the functional dissociation between these two frontal regions during decision making. Here, I discuss the results of that study and consider alternative interpretations in connection with other findings. PMID- 24401708 TI - Intersegmental dynamics shape joint coordination during catching in typically developing children but not in children with developmental coordination disorder. AB - Factors shaping joint coordination during multijoint movements were studied using a one-handed ball-catching task. Typically developing (TD) boys between 9 and 12 yr of age, at which catching becomes consistently successful, and boys with developmental coordination disorder (DCD) of the same age participated in the study. The arm was initially stretched down. Catching was performed by flexing the shoulder and elbow and extending the wrist in the parasagittal plane. Catching success rate was substantially lower in children with DCD. Amplitudes and directions of joint motions were similar in both groups. Group differences were found in shoulder and elbow coordination patterns. TD children performed the movement predominantly by actively accelerating into flexion, one joint at a time first the elbow and then the shoulder-and allowing passive interaction torque (IT) to accelerate the other joint into extension. Children with DCD tended to accelerate both joints into flexion simultaneously, suppressing IT. The results suggest that the TD joint coordination was shaped by the tendency to minimize active control of IT despite the complexity of the emergent joint kinematics. The inefficient control of IT in children with DCD points to deficiency of the internal model of intersegmental dynamics. Together, the findings advocate that joint coordination throughout a multijoint movement is a by-product of the control strategy that benefits from movement dynamics by actively accelerating a single joint and using IT for rotation of the other joint. Reduction of control dependent noise is discussed as a possible advantage of this control strategy. PMID- 24401707 TI - Intrinsic and synaptic homeostatic plasticity in motoneurons from mice with glycine receptor mutations. AB - Inhibitory synaptic inputs to hypoglossal motoneurons (HMs) are important for modulating excitability in brainstem circuits. Here we ask whether reduced inhibition, as occurs in three murine mutants with distinct naturally occurring mutations in the glycine receptor (GlyR), leads to intrinsic and/or synaptic homeostatic plasticity. Whole cell recordings were obtained from HMs in transverse brainstem slices from wild-type (wt), spasmodic (spd), spastic (spa), and oscillator (ot) mice (C57Bl/6, approximately postnatal day 21). Passive and action potential (AP) properties in spd and ot HMs were similar to wt. In contrast, spa HMs had lower input resistances, more depolarized resting membrane potentials, higher rheobase currents, smaller AP amplitudes, and slower afterhyperpolarization current decay times. The excitability of HMs, assessed by "gain" in injected current/firing-frequency plots, was similar in all strains whereas the incidence of rebound spiking was increased in spd. The difference between recruitment and derecruitment current (i.e., DeltaI) for AP discharge during ramp current injection was more negative in spa and ot. GABAA miniature inhibitory postsynaptic current (mIPSC) amplitude was increased in spa and ot but not spd, suggesting diminished glycinergic drive leads to compensatory adjustments in the other major fast inhibitory synaptic transmitter system in these mutants. Overall, our data suggest long-term reduction in glycinergic drive to HMs results in changes in intrinsic and synaptic properties that are consistent with homeostatic plasticity in spa and ot but not in spd. We propose such plasticity is an attempt to stabilize HM output, which succeeds in spa but fails in ot. PMID- 24401709 TI - Perception-action dissociation generalizes to the size-inertia illusion. AB - Two objects of similar visual aspects and of equal mass, but of different sizes, generally do not elicit the same percept of heaviness in humans. The larger object is consistently felt to be lighter than the smaller, an effect known as the "size-weight illusion." When asked to repeatedly lift the two objects, the grip forces were observed to adapt rapidly to the true object weight while the size-weight illusion persisted, a phenomenon interpreted as a dissociation between perception and action. We investigated whether the same phenomenon can be observed if the mass of an object is available to participants through inertial rather than gravitational cues and if the number and statistics of the stimuli is such that participants cannot remember each individual stimulus. We compared the responses of 10 participants in 2 experimental conditions, where they manipulated 33 objects having uncorrelated masses and sizes, supported by a frictionless, air bearing slide that could be oriented vertically or horizontally. We also analyzed the participants' anticipatory motor behavior by measuring the grip force before motion onset. We found that the perceptual illusory effect was quantitatively the same in the two conditions and observed that both visual size and haptic mass had a negligible effect on the anticipatory gripping control of the participants in the gravitational and inertial conditions, despite the enormous differences in the mechanics of the two conditions and the large set of uncorrelated stimuli. PMID- 24401710 TI - The effects of expectancy on corticospinal excitability: passively preparing to observe a movement. AB - The corticospinal tract excitability is modulated when preparing movements. Earlier to movement execution, the excitability of the spinal cord increases waiting for supraspinal commands to release the movement. Movement execution and movement observation share processes within the motor system, although movement observation research has focused on processes later to movement onset. We used single and paired pulse transcranial magnetic stimulation on M1 (n = 12), and electrical cervicomedullary stimulation (n = 7), to understand the modulation of the corticospinal system during the "preparation" to observe a third person's movement. Subjects passively observed a hand that would remain still or make an index finger extension. The observer's corticospinal excitability rose when "expecting to see a movement" vs. when "expecting to see a still hand." The modulation took origin at a spinal level and not at the corticocortical networks explored. We conclude that expectancy of seeing movements increases the excitability of the spinal cord. PMID- 24401711 TI - Coordination between digit forces and positions: interactions between anticipatory and feedback control. AB - Humans adjust digit forces to compensate for trial-to-trial variability in digit placement during object manipulation, but the underlying control mechanisms remain to be determined. We hypothesized that such digit position/force coordination was achieved by both visually guided feed-forward planning and haptic-based feedback control. The question arises about the time course of the interaction between these two mechanisms. This was tested with a task in which subjects generated torque (+/- 70 N.mm) on a virtual object to control a cursor moving to target positions to catch a falling ball, using a virtual reality environment and haptic devices. The width of the virtual object was varied between large (L) and small (S). These object widths result in significantly different horizontal digit relative positions and require different digit forces to exert the same task torque. After training, subjects were tested with random sequences of L and S widths with or without visual information about object width. We found that visual cues allowed subjects to plan manipulation forces before contact. In contrast, when visual cues were not available to predict digit positions, subjects implemented a "default" digit force plan that was corrected after digit contact to eventually accomplish the task. The time course of digit forces revealed that force development was delayed in the absence of visual cues. Specifically, the appropriate digit force adjustments were made 250-300 ms after initial object contact. This result supports our hypothesis and further reveals that haptic feedback alone is sufficient to implement digit force-position coordination. PMID- 24401712 TI - Dynamic-clamp analysis of wild-type human Nav1.7 and erythromelalgia mutant channel L858H. AB - The link between sodium channel Nav1.7 and pain has been strengthened by identification of gain-of-function mutations in patients with inherited erythromelalgia (IEM), a genetic model of neuropathic pain in humans. A firm mechanistic link to nociceptor dysfunction has been precluded because assessments of the effect of the mutations on nociceptor function have thus far depended on electrophysiological recordings from dorsal root ganglia (DRG) neurons transfected with wild-type (WT) or mutant Nav1.7 channels, which do not permit accurate calibration of the level of Nav1.7 channel expression. Here, we report an analysis of the function of WT Nav1.7 and IEM L858H mutation within small DRG neurons using dynamic-clamp. We describe the functional relationship between current threshold for action potential generation and the level of WT Nav1.7 conductance in primary nociceptive neurons and demonstrate the basis for hyperexcitability at physiologically relevant levels of L858H channel conductance. We demonstrate that the L858H mutation, when modeled using dynamic clamp at physiological levels within DRG neurons, produces a dramatically enhanced persistent current, resulting in 27-fold amplification of net sodium influx during subthreshold depolarizations and even greater amplification during interspike intervals, which provide a mechanistic basis for reduced current threshold and enhanced action potential firing probability. These results show, for the first time, a linear correlation between the level of Nav1.7 conductance and current threshold in DRG neurons. Our observations demonstrate changes in sodium influx that provide a mechanistic link between the altered biophysical properties of a mutant Nav1.7 channel and nociceptor hyperexcitability underlying the pain phenotype in IEM. PMID- 24401713 TI - Comparison of the contractile responses to irregular and regular trains of stimuli during microstimulation of single human motor axons. AB - During voluntary contractions, human motoneurons discharge with a physiological variability of ~20%. However, studies that have measured the contractile responses to microstimulation of single motor axons have used regular trains of stimuli with no variability. We tested the hypothesis that irregular (physiological) trains of stimuli produce greater contractile responses than regular (nonphysiological) trains of identical mean frequency but zero variability. High-impedance tungsten microelectrodes were inserted into the common peroneal nerve and guided into fascicles supplying a toe extensor muscle. Selective microstimulation was achieved for 14 single motor axons. Contractile responses were measured via an angular displacement transducer over the relevant toe. After the responses to regular trains of 10 stimuli extending from 2 to 100 Hz were recorded, irregular trains of 10 stimuli, based on the interspike intervals recorded from single motor units during voluntary contractions, were delivered. Finally, the stimulation sequences were repeated following a 2-min period of continuous stimulation at 10 Hz to induce muscle fatigue. Regular trains of stimuli generated a sigmoidal increase in displacement with frequency, whereas irregular trains, emulating the firing of volitionally driven motoneurons, displayed significantly greater responses over the same frequency range (8-24 Hz). This was maintained even in the presence of fatigue. We conclude that physiological discharge variability, which incorporates short and long interspike intervals, offers an advantage to the neuromuscular system by allowing motor units to operate on a higher level of the contraction-frequency curve and taking advantage of catch-like properties in skeletal muscle. PMID- 24401714 TI - The cortical representation of the speech envelope is earlier for audiovisual speech than audio speech. AB - Visual speech can greatly enhance a listener's comprehension of auditory speech when they are presented simultaneously. Efforts to determine the neural underpinnings of this phenomenon have been hampered by the limited temporal resolution of hemodynamic imaging and the fact that EEG and magnetoencephalographic data are usually analyzed in response to simple, discrete stimuli. Recent research has shown that neuronal activity in human auditory cortex tracks the envelope of natural speech. Here, we exploit this finding by estimating a linear forward-mapping between the speech envelope and EEG data and show that the latency at which the envelope of natural speech is represented in cortex is shortened by >10 ms when continuous audiovisual speech is presented compared with audio-only speech. In addition, we use a reverse-mapping approach to reconstruct an estimate of the speech stimulus from the EEG data and, by comparing the bimodal estimate with the sum of the unimodal estimates, find no evidence of any nonlinear additive effects in the audiovisual speech condition. These findings point to an underlying mechanism that could account for enhanced comprehension during audiovisual speech. Specifically, we hypothesize that low level acoustic features that are temporally coherent with the preceding visual stream may be synthesized into a speech object at an earlier latency, which may provide an extended period of low-level processing before extraction of semantic information. PMID- 24401715 TI - Synbiotic supplementation in nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled pilot study. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Oral administration of synbiotic has been proposed as an effective treatment of NAFLD because of its modulating effect on the gut flora, which can influence the gut-liver axis. OBJECTIVE: The objective was to evaluate the effects of supplementation with synbiotic on hepatic fibrosis, liver enzymes, and inflammatory markers in patients with NAFLD. DESIGN: In a randomized, double-blind, placebo-controlled clinical trial conducted as a pilot study, 52 patients with NAFLD were supplemented twice daily for 28 wk with either a synbiotic or a placebo capsule. Both groups were advised to follow an energy balanced diet and physical activity recommendations. RESULTS: At the end of the study, the alanine aminotransferase (ALT) concentration decreased in both groups; this reduction was significantly greater in the synbiotic group. At the end of the study, the following significant differences [means (95% CIs)] were seen between the synbiotic and placebo groups, respectively: ALT [-25.1 (-26.2, -24) compared with -7.29 (-9.5, -5.1) IU/L; P < 0.001], aspartate aminotransferase [ 31.33 (-32.1, -30.5) compared with -7.94 (-11.1, -4.8) IU/L; P < 0.001], gamma glutamyltransferase [-15.08 (-15.5, -14.7) compared with -5.21 (-6.6, -3.9) IU/L; P < 0.001], high-sensitivity C-reactive protein [-2.3 (-3, -1.5) compared with 1.04 (-1.5, -0.6) mmol/L; P < 0.05], tumor necrosis factor-alpha [-1.4 (-1.7, 1.1) compared with -0.59 (-0.8, -0.3) mmol/L; P < 0.001], total nuclear factor kappa-B p65 [-0.016 (-0.022, -0.011) compared with 0.001 (-0.004, -0.007) mmol/L; P < 0.001], and fibrosis score as determined by transient elastography [- 2.98 ( 3.6, -2.37) compared with -0.77 (-1.32, -0.22) kPa; P < 0.001]. CONCLUSIONS: Synbiotic supplementation in addition to lifestyle modification is superior to lifestyle modification alone for the treatment of NAFLD, at least partially through attenuation of inflammatory markers in the body. Whether these effects will be sustained with longer treatment durations remains to be determined. PMID- 24401716 TI - Season of birth, neonatal vitamin D status, and cardiovascular disease risk at 35 y of age: a cohort study from Sweden. AB - BACKGROUND: Lower vitamin D status during gestation may be associated with cardiovascular disease risk later in life. No studies have assessed this hypothesis with a follow-up time reaching beyond childhood. OBJECTIVE: The objective was to assess the link between season of birth, neonatal 25 hydroxyvitamin D3 [25(OH)D3] status, and adult cardiovascular disease risk. DESIGN: Markers of cardiovascular and metabolic disease risk were measured in 284 subjects aged 35 y, born either at the end of the winter or at the end of the summer of 1975. In 275 of these 284 subjects, concentrations of neonatal 25(OH)D3 were measured in dried blood samples by using a highly sensitive liquid chromatography-tandem mass spectroscopy method. RESULTS: Subjects born after the winter had lower neonatal 25(OH)D3 concentrations than did those born after the summer (31.5 compared with 48.5 nmol/L; P < 0.001). In regression analyses adjusted for sex, season of birth, postnatal age at neonatal sample collection, preterm birth, maternal age, education, smoking, fish consumption per week, exercise per week, and current 25-hydroxyvitamin D, higher neonatal 25(OH)D3 (per 50 nmol/L) was associated with 25.8% (95% CI: 1.0%, 58.4%) higher fasting insulin in adult life, 29.6% (5.1%, 58.4%) higher triglycerides, and 4.64 (95% CI: 1.93, 7.36) mmol/L higher serum cholesterol in women. Neonatal 25(OH)D3 (per 1 nmol/L) was directly associated with risk of adult overweight (OR: 1.03; 95% CI: 1.01, 1.05) and with adult obesity in women (OR: 1.09; 95% CI: 1.02, 1.17). Neonatal 25(OH)D3 was not associated with adult aortic pulse wave velocity, blood pressure, fasting glucose, HDL, LDL, or C-reactive protein. Season of birth was not associated with any of the adult outcomes. CONCLUSIONS: Higher neonatal 25(OH)D3 was associated with higher fasting insulin, triglyceride, and cholesterol (in women) concentrations and with a higher risk of overweight at 35 y of age but not with other adult cardiovascular disease risk factors. PMID- 24401717 TI - Associations of maternal obesity and psychosocial factors with breastfeeding intention, initiation, and duration. AB - BACKGROUND: Psychosocial factors influence breastfeeding outcomes, but little is known about these characteristics and how they influence breastfeeding behavior of obese women, who are a group that experiences poor breastfeeding outcomes. OBJECTIVES: Our objectives were to determine whether 1) maternal prepregnancy body mass index (BMI) is associated with social knowledge of, social influence toward, maternal confidence in, and behavioral beliefs about breastfeeding; 2) BMI and these psychosocial factors predict outcomes of intention to breastfeed, ever breastfed, and the duration of breastfeeding; and 3) BMI and psychosocial factors are associated with these breastfeeding outcomes independent of each other. DESIGN: Participants (n = 2824) in the Infant Feeding Practices Study II provided data on psychosocial characteristics and breastfeeding outcomes. In this prospective cohort study, data were analyzed by using logistic and proportional hazards regression models. RESULTS: Prepregnancy BMI was associated with confidence in (P < 0.0001), social influence toward (P = 0.02), and social knowledge of (P < 0.0001) breastfeeding but not with behavioral beliefs about breastfeeding (P = 0.45). Obese women did not differ from under- and normal weight women in the intention to breastfeed (P = 0.07) but had lower odds of ever breastfeeding (P = 0.04) and were at greater risk of an earlier cessation of exclusive (P = 0.0009) and any (P = 0.03) breastfeeding. Only the association with exclusive breastfeeding remained significant after controlling for psychosocial factors (P = 0.01). All psychosocial factors were positively associated with each breastfeeding outcome. CONCLUSIONS: Despite their intentions to breastfeed, women with high prepregnancy BMI had psychosocial characteristics associated with poor breastfeeding outcomes. However, these characteristics did not fully explain the association between maternal obesity and breastfeeding outcomes. PMID- 24401719 TI - Investigating the role of cardiovascular biomarkers in children with pre-dialysis chronic kidney disease: a substitute to echocardiography to detect increased left ventricular mass? AB - BACKGROUND: Children with chronic kidney disease (CKD) are at increased risk of future cardiovascular (CV) events. Our aim in this prospective single-centre cross-sectional analysis was to assess the relationship of a novel panel of CV biomarkers with left ventricular hypertrophy (LVH). METHODS: A panel of five CV biomarkers (asymmetric dimethyl arginine, high sensitivity C-reactive protein, homocysteine, N-terminal pro-B type natriuretic peptide and uric acid) were measured on the same day as an echocardiogram assessment, in paediatric patients with pre-dialysis stages 3-5 of CKD. RESULTS: Of 73 children aged 5-18 years, LVH, all eccentric, was identified in 38%. Systolic blood pressure (BP), glomerular filtration rate (GFR) and higher intake of calcium-based phosphate binders were significantly worse in children with LVH. In multivariate models analysing each biomarker one at a time with confounders [GFR, systolic BP z score, anti-hypertensive medication (yes/no) and elemental calcium intake], clinic systolic BP z-score and elemental calcium intake consistently displayed a significant relationship with indexed left ventricular mass (LVMI). None of the evaluated CV biomarkers displayed a significant relationship with LVMI. CONCLUSIONS: In our cohort of children with moderately severe pre-dialysis CKD we have identified no suitable biomarkers to detect LVH. We would therefore recommend that echocardiographic determination of LVMI remains the technique of choice for detection of LVH in children with CKD. PMID- 24401718 TI - Index-based dietary patterns and risk of head and neck cancer in a large prospective study. AB - BACKGROUND: Head and neck cancer (HNC) is the seventh most common cancer worldwide. Although diet has been proposed to play an important role in HNC, few associations with diet have been convincing other than alcohol intake. Studies of dietary patterns that examine overall diets may provide broader insight than studies of individual foods. Little is known about the association between dietary patterns and risk of HNC. OBJECTIVE: We prospectively evaluated the association between 2 index-based dietary patterns [ie, the Healthy Eating Index 2005 (HEI-2005) and alternate Mediterranean Diet Score (aMED)] and risk of head and neck squamous cell carcinoma. DESIGN: We included 494,967 participants from the NIH-AARP Diet and Health study (1995-2006). HRs (95% CIs) were estimated by using Cox regression. Scores for the HEI-2005 and aMED were calculated on the basis of diet assessed by using a baseline food-frequency questionnaire. Higher scores reflected adherence to dietary recommendations for healthy eating. Our main outcome was the incidence of HNC, including cancer of the larynx, oral cavity, and orohypopharynx. RESULTS: A total of 1868 HNC cases were identified during follow-up. Higher HEI-2005 scores were associated with reduced risk of HNC in men [HR: 0.74 (95% CI: 0.61, 0.89) for highest compared with lowest quintiles; P-trend = 0.0008] and women [HR: 0.48; 95% CI: 0.33, 0.70; P-trend < 0.0001]. High aMED scores were also associated with lower HNC risk in men (HR: 0.80; 95% CI: 0.64, 1.01; P-trend = 0.002) and women (HR: 0.42; 95% CI: 0.24, 0.74; P-trend < 0.0001). Associations were similar among subsites. We did not find significant interactions between smoking and alcohol intake and each index on HNC risk. CONCLUSIONS: HEI-2005 and aMED scores were associated inversely with risk of HNC. Large interventional studies are required to assess the causality before conveying definite public health messages. PMID- 24401720 TI - Comparative effectiveness study on human papillomavirus detection methods used in the cervical cancer screening programme. AB - OBJECTIVES: To compare the short-term and long-term effectiveness of human papillomavirus (HPV) tests in Norwegian Cervical Cancer Screening Programme (NCCSP). DESIGN: Nationwide register-based prospective follow-up study. SETTING: In 2005, the NCCSP implemented HPV testing in follow-up of unsatisfactory, atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) cytology. PARTICIPANTS: 19 065 women with repeat cytology and HPV test after unsatisfactory ASC-US or LSIL screening result in 2005-2009. INTERVENTIONS: Through individual registry linkages we observed how women were treated in the regular medical care. MAIN OUTCOME MEASURES: We estimated cumulative incidence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in 6 months and 3 years after repeat cytology and HPV test. Patients diagnosed with CIN2+ in 6 months and 3 years were assessed for initial HPV positivity. RESULTS: 5392 had ASC-US/LSIL and 13 673 had normal/unsatisfactory repeat cytology; for HPV detection 4715 used AMPLICOR HPV Test (Roche Diagnostics, Basel, Switzerland), 9162 Hybrid Capture 2 (HC2) High Risk HPV DNA Test (QIAGEN, Gaithersburg, Maryland, USA) and 5188 PreTect HPV Proofer (NorChip, Klokkarstua, Norway). Among those with ASC-US/LSIL repeat cytology, 3-year risk of CIN2+ was 15-fold in Amplicor/HC2-positives compared with Amplicor/HC2-negatives and sevenfold in Proofer-positives compared with Proofer-negatives; a 3-year risk of CIN2+ was 2.1% (95% CI 0.7% to 3.4%) in Amplicor-negatives and 7.2% (95% CI 5.4% to 8.9%) in Proofer-negatives. Close to 100% of patients with CIN2+ diagnosed within 6 months tested positive to HPV (all methods). Considering all patients diagnosed with CIN2+ in 3-year follow-up, 97% were initially positive in the Amplicor group and more than 94% in the HC2 group, compared with less than 80% in the Proofer group. CONCLUSIONS: While the long term evaluation of new screening routines showed a good overall performance of triage-HPV DNA testing, the management of HPV-negative women with persistent ASC US/LSIL was suboptimal. PMID- 24401721 TI - Efficacy of coupled plasma filtration adsorption (CPFA) in patients with septic shock: a multicenter randomised controlled clinical trial. AB - OBJECTIVES: Coupled plasma filtration adsorption (CPFA, Bellco, Italy), to remove inflammatory mediators from blood, has been proposed as a novel treatment for septic shock. This multicenter, randomised, non-blinded trial compared CPFA with standard care in the treatment of critically ill patients with septic shock. DESIGN: Prospective, multicenter, randomised, open-label, two parallel group and superiority clinical trial. SETTING: 18 Italian adult, general, intensive care units (ICUs). PARTICIPANTS: Of the planned 330 adult patients with septic shock, 192 were randomised to either have CPFA added to the standard care, or not. The external monitoring committee excluded eight ineligible patients who were erroneously included. INTERVENTIONS: CPFA was to be performed daily for 5 days, lasting at least 10 h/day. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was mortality at discharge from the hospital at which the patient last stayed. Secondary endpoints were: 90-day mortality, new organ failures and ICU free days within 30 days. RESULTS: There was no statistical difference in hospital mortality (47.3% controls, 45.1% CPFA; p=0.76), nor in secondary endpoints, namely the occurrence of new organ failures (55.9% vs 56.0%; p=0.99) or free-ICU days during the first 30 days (6.8 vs 7.5; p=0.35). The study was terminated on the grounds of futility. Several patients randomised to CPFA were subsequently found to be undertreated. An a priori planned subgroup analysis showed those receiving a CPFA dose >0.18 L/kg/day had a lower mortality compared with controls (OR 0.36, 95% CI 0.13 to 0.99). CONCLUSIONS: CPFA did not reduce mortality in patients with septic shock, nor did it positively affect other important clinical outcomes. A subgroup analysis suggested that CPFA could reduce mortality, when a high volume of plasma is treated. Owing to the inherent potential biases of such a subgroup analysis, this result can only be viewed as a hypothesis generator and should be confirmed in future studies. CLINICALTRIALSGOV: NCT00332371; ISRCTN24534559. PMID- 24401722 TI - Disease manifestations of Helicobacter pylori infection in Arctic Canada: using epidemiology to address community concerns. AB - OBJECTIVES: Helicobacter pylori infection, linked to gastric cancer, is responsible for a large worldwide disease burden. H pylori prevalence and gastric cancer rates are elevated among indigenous Arctic communities, but implementation of prevention strategies is hampered by insufficient information. Some communities in northern Canada have advocated for H pylori prevention research. As a first step, community-driven research was undertaken to describe the H pylori-associated disease burden in concerned communities. DESIGN: Participants in this cross-sectional study completed a clinical interview and gastroscopy with gastric biopsies taken for histopathological examination in February 2008. SETTING: Study procedures were carried out at the health centre in Aklavik, Northwest Territories, Canada (population ~600). PARTICIPANTS: All residents of Aklavik were invited to complete a clinical interview and gastroscopy; 194 (58% female participants; 91% Aboriginal; age range 10-80 years) completed gastroscopy and had gastric biopsies taken. PRIMARY AND SECONDARY OUTCOME MEASURES: This analysis estimates the prevalence of gastric abnormalities detected by endoscopy and histopathology, and associations of demographic and clinical variables with H pylori prevalence. RESULTS: Among 194 participants with evaluable gastric biopsies, 66% were H pylori-positive on histology. Among H pylori-positive participants, prevalence was 94% for acute gastritis, 100% for chronic gastritis, 21% for gastric atrophy and 11% for intestinal metaplasia of the gastric mucosa, while chronic inflammation severity was mild in 9%, moderate in 47% and severe in 43%. In a multivariable model, H pylori prevalence was inversely associated with previous gastroscopy, previous H pylori therapy and aspirin use, and was positively associated with alcohol consumption. CONCLUSIONS: In this population, H pylori-associated gastric histopathology shows a pattern compatible with elevated risk of gastric cancer. These findings demonstrate that local concern about health risks from H pylori is warranted and provide an example of how epidemiological research can address health priorities identified by communities. PMID- 24401724 TI - Intraindividual variation in urinary iodine concentrations: effect of adjustment on population distribution using two and three repeated spot urine collections. AB - OBJECTIVES: To determine the effect of adjustment for intraindividual variation on estimations of urinary iodine concentrations (UIC), prevalence of iodine deficiency and population distribution of iodine status. SETTING: Community dwelling older adults from New South Wales, Australia. PARTICIPANTS: 84 healthy men and women aged 60-95 years were recruited prior to introduction of the mandatory iodine fortification programme. PRIMARY AND SECONDARY OUTCOME MEASURES: UIC data were collected from three spot urine samples, each 1 week apart. Repeated measures analysis of variance were determined between-person (sb) and total (sobs) SDs. Adjusted UIC values were calculated as ((person's UIC-group mean)*(sb/sobs))+group mean, and a corrected UIC distribution was calculated. RESULTS: The sb/sobs for using three samples and two samples were 0.83 and 0.79, respectively. Following adjustment for intraindividual variation, the proportion with UIC <50 MUg/L reduced from 33% to 19%, while the proportion with UIC >=100 MUg/L changed from 21% to 17%. The 95th centile for UIC decreased from 176 to 136 MUg/L. Adjustment by taking averages yielded a lesser degree of contraction in the distribution than the analysis of variance method. CONCLUSIONS: The addition of information about intraindividual variability has potential for increasing the interpretability of UIC data collected to monitor the iodine status of a population. PMID- 24401723 TI - Worldwide variation in human growth and the World Health Organization growth standards: a systematic review. AB - OBJECTIVE: The World Health Organization (WHO) has established a set of growth curves for use as international standards in children up to age 5. The WHO's position is that all economically advantaged children who were breastfed as infants grow similarly. As a result, a single set of growth charts can be used to judge growth in any child, regardless of race or ethnicity. The goal of this study was to compare mean heights, weights and head circumferences from a variety of studies with the WHO's data. DESIGN: We compared data from the WHO's Multicentre Growth Reference Study (MGRS) with data from studies performed in 55 countries or ethnic groups. DATA SOURCES: PubMed, WHO Global Database on Child Growth and Malnutrition, SciELO, Google Scholar, Textbooks and Ministries of Statistics and Public Health. ELIGIBILITY CRITERIA: Large recent studies (1988 2013) of economically advantaged groups, including comparisons with cohorts of breastfed children wherever possible. RESULTS: Height varied somewhat among different national and ethnic groups. Means were generally within 0.5 of an SD of the MGRS means. Weight varied more than height, but the low MGRS means were seen as endorsing slenderness in the midst of an obesity epidemic. The mean head circumference varied widely. In many groups, means were consistently 0.5-1 SD above the MGRS mean. Head size in breastfed children at any age examined was far closer to local norms than to the MGRS means. CONCLUSIONS: Height and weight curves may not be optimal fits in all cases. The differences between national or ethnic group head circumference means were large enough that using the WHO charts would put many children at risk for misdiagnosis of macrocephaly or microcephaly. Our findings indicate that the use of a single international standard for head circumference is not justified. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (# CRD42013003675). PMID- 24401725 TI - Hardiness and Outcome of Self-catheterisation Training (HOST): protocol for an observational study exploring the effects of personality traits in women on ability to learn clean intermittent self-catheterisation. AB - INTRODUCTION: Clean intermittent self-catheterisation (CISC) is the recommended first-line management of voiding dysfunction; however, psychological factors involved in acceptance and take up are often neglected. There is a tendency to discuss the success of CISC in relation to factors that affect teaching and learning, with subsequent success or failure being attributed to these. There is limited research investigating what extent, personality traits impact on a woman's willingness to learn CISC and subsequent mastery of the technique. METHOD AND ANALYSIS: All women attending a tertiary urogynaecology department as eligible for CISC will be invited to participate in the study. Over the 14-month recruitment period, an estimated 130 women will be involved. The participants will complete a series of self-reported questionnaires. Personality types will be assessed using The Hardiness Scale and State-Trait Anxiety Inventory. The impact of urinary symptoms and CISC on quality of life (QoL) will be measured using an electronic pelvic-floor assessment questionnaire (ePAQ). Success and mastery will be measured by recording the number of hospital appointments and the length of time taken to learn. Confidence will be measured using the Likert scale. A sample of 20 women will be invited to participate in semi-structured in-depth interviews to explore women's views and experiences of CISC. ETHICS AND DISSEMINATION: Regulatory approvals will be in place prior to the start of the study. Good clinical practice guidelines will be followed throughout. Eligibility and training for CISC will be undertaken in accordance to individualised care plans in line with unit protocol and will not be influenced by the study. Trial data will be anonymised and participant confidentiality will be maintained. The Study findings will be disseminated through publications in relevant journals and will be presented at multiprofessional conferences and scientific meetings. PMID- 24401726 TI - The acceptance of hearing disability among adults experiencing hearing difficulties: a cross-sectional study. AB - OBJECTIVE: This study developed the Hearing Disability Acceptance Questionnaire (HDAQ) and tested its construct and concurrent validities. DESIGN: Cross sectional. PARTICIPANTS: A total of 90 participants who were experiencing hearing difficulties were recruited in the UK. OUTCOME MEASURES: The HDAQ was developed based on the Tinnitus Acceptance Questionnaire (TAQ). Participants completed self report measures regarding hearing disability acceptance, hearing disability, symptoms of anxiety and depression and a measure of stages of change. RESULTS: The HDAQ has a two-factor structure that explains 75.69% of its variance. The factors identified were activity engagement and avoidance and suppression. The scale showed a sufficient internal consistency (Cronbach's alpha=0.86). The HDAQ also had acceptable concurrent validity with regard to self-reported hearing disability, self-reported anxiety and depression and readiness to change measures. CONCLUSIONS: Acceptance is likely an important aspect of coping with chronic health conditions. To our knowledge, no previously published and validated scale measures the acceptance of hearing disability; therefore, the HDAQ might be useful in future research. However, the role of acceptance in adjusting to hearing disability must be further investigated. PMID- 24401727 TI - Treatment of antipsychotic-associated obesity with a GLP-1 receptor agonist- protocol for an investigator-initiated prospective, randomised, placebo controlled, double-blinded intervention study: the TAO study protocol. AB - INTRODUCTION: Antipsychotic medication is widely associated with dysmetabolism including obesity and type 2 diabetes, cardiovascular-related diseases and early death. Obesity is considered the single most important risk factor for cardiovascular morbidity and mortality. Interventions against antipsychotic associated obesity are limited and insufficient. Glucagon-like peptide-1 (GLP-1) receptor agonists are approved for the treatment of type 2 diabetes, but their bodyweight-lowering effects have also been recognised in patients with non diabetes. The primary endpoint of this trial is weight loss after 3 months of treatment with a GLP-1 receptor agonist (exenatide once weekly) in patients with non-diabetic schizophrenia with antipsychotic-associated obesity. Secondary endpoints include physiological and metabolic measurements, various psychopathological and cognitive measures, and structural and functional brain MRI. METHODS AND ANALYSIS: 40 obese patients with schizophrenia or schizoaffective disorder treated with antipsychotic drugs will be randomised to subcutaneous injection of exenatide once weekly (2 mg) or placebo for 3 months, adjunctive to their antipsychotic treatment. ETHICS AND DISSEMINATION: The trial has been approved by the Danish Health and Medicines Authority, the National Committee on Health Research Ethics and the Danish Data Protection Agency. Trial participation presupposes theoral and written patient informed consent. An external, independent monitoring committee (Good Clinical Practice Unit at Copenhagen University Hospital) will monitor the study according to the GCP Guidelines. Trial data, including positive, negative and inconclusive results, will be presented at national and international scientific meetings and conferences. Papers will be submitted to peer-reviewed journals. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01794429; National Committee on Health Research Ethics project number: 36378; EudraCT nr: 2012-005404-17; The Danish Data Protection Agency project number: RHP-2012-027. PMID- 24401728 TI - Seasonal variation in musculoskeletal extremity injuries in school children aged 6-12 followed prospectively over 2.5 years: a cohort study. AB - OBJECTIVES: The type and level of physical activity in children vary over seasons and might thus influence the injury patterns. However, very little information is available on the distribution of injuries over the calendar year. This study aims to describe and analyse the seasonal variation in extremity injuries in children. DESIGN: Prospective cohort study. SETTING: 10 public schools in the municipality of Svendborg, Denmark. PARTICIPANTS: A total of 1259 school children aged 6-12 years participating in the Childhood Health, Activity, and Motor Performance School Study Denmark. METHODS: School children were surveyed each week during 2.5 school-years. Musculoskeletal injuries were reported by parents answering automated mobile phone text questions (SMS-Track) on a weekly basis and diagnosed by clinicians. Data were analysed for prevalence and incidence rates over time with adjustments for gender and age. RESULTS: Injuries in the lower extremities were reported most frequently (n=1049). There was a significant seasonal variation in incidence and prevalence for lower extremity injuries and for lower and upper extremity injuries combined (n=1229). For the upper extremities (n=180), seasonal variation had a significant effect on the risk of prevalence. Analysis showed a 46% increase in injury incidence and a 32% increase in injury prevalence during summer relative to winter for lower and upper extremity injuries combined. CONCLUSIONS: There are clear seasonal differences in the occurrence of musculoskeletal extremity injuries among children with almost twice as high injury incidence and prevalence estimates during autumn, summer and spring compared with winter. This suggests further research into the underlying causes for seasonal variation and calls for preventive strategies to be implemented in order to actively prepare and supervise children before and during high-risk periods. PMID- 24401729 TI - Self-management support using an Internet-linked tablet computer (the EDGE platform)-based intervention in chronic obstructive pulmonary disease: protocol for the EDGE-COPD randomised controlled trial. AB - INTRODUCTION: The potential for telehealth-based interventions to provide remote support, education and improve self-management for long-term conditions is increasingly recognised. This trial aims to determine whether an intervention delivered through an easy-to-use tablet computer can improve the quality of life of patients with chronic obstructive pulmonary disease (COPD) by providing personalised self-management information and education. METHODS AND ANALYSIS: The EDGE (sElf management anD support proGrammE) for COPD is a multicentre, randomised controlled trial designed to assess the efficacy of an Internet-linked tablet computer-based intervention (the EDGE platform) in improving quality of life in patients with moderate to very severe COPD compared with usual care. Eligible patients are randomly allocated to receive the tablet computer-based intervention or usual care in a 2:1 ratio using a web-based randomisation system. Participants are recruited from respiratory outpatient clinics and pulmonary rehabilitation courses as well as from those recently discharged from hospital with a COPD-related admission and from primary care clinics. Participants allocated to the tablet computer-based intervention complete a daily symptom diary and record clinical symptoms using a Bluetooth-linked pulse oximeter. Participants allocated to receive usual care are provided with all the information given to those allocated to the intervention but without the use of the tablet computer or the facility to monitor their symptoms or physiological variables. The primary outcome of quality of life is measured using the St George's Respiratory Questionnaire for COPD patients (SGRQ-C) baseline, 6 and 12 months. Secondary outcome measures are recorded at these intervals in addition to 3 months. ETHICS AND DISSEMINATION: The Research Ethics Committee for Berkshire South Central has provided ethical approval for the conduct of the study in the recruiting regions. The results of the study will be disseminated through peer review publications and conference presentations. TRIAL REGISTRATION: Current controlled trials ISRCTN40367841. PMID- 24401730 TI - Spinal dumbbell-shaped peripheral primitive neuroectodermal tumor in a child. PMID- 24401731 TI - Impact of changing U.S. demographics on the decline in smoking prevalence, 1980 2010. AB - INTRODUCTION: U.S. smoking prevalence has been declining over the last several decades. During this time, the population has also experienced changes in its demographic composition, as Americans are living longer and becoming increasingly racially and ethnically diverse. Since smoking rates vary across age and race/ethnicity groups, demographics alone could contribute to changes in smoking prevalence among the general population. We examined the effect of changing age and race/ethnicity distributions on total smoking prevalence from 1980 to 2010. METHODS: Using the National Health Interview Survey weighting scheme, we applied the distribution of smokers across age and race/ethnicity categories for the years 1980 and 2010 to the distribution of adults in those categories for both years. The total number of smokers was summed to determine resulting smoking prevalence. RESULTS: The combined effect of aging and the changing racial/ethnic composition of the U.S. population has contributed 2.1% points to the decline in smoking prevalence. If the age and racial/ethnic demographic composition had not changed since 1980, smoking prevalence would have been 21.3% in 2010 (with rounding)--statistically significantly higher than the reported 19.3%. Of the 3 demographic factors we considered (age, race, and ethnicity), ethnicity- specifically the rising share of Hispanics in the population--is the most important contributor to declines in smoking. CONCLUSIONS: Our changing demographics have had an impact on smoking prevalence over the last 3 decades. Future declines in smoking may be driven even more by the aging of the population and increasing racial and ethnic diversity. PMID- 24401732 TI - Decitabine impact on the endocytosis regulator RhoA, the folate carriers RFC1 and FOLR1, and the glucose transporter GLUT4 in human tumors. AB - BACKGROUND: In 31 solid tumor patients treated with the demethylating agent decitabine, we performed tumor biopsies before and after the first cycle of decitabine and used immunohistochemistry (IHC) to assess whether decitabine increased expression of various membrane transporters. Resistance to chemotherapy may arise due to promoter methylation/downregulation of expression of transporters required for drug uptake, and decitabine can reverse resistance in vitro. The endocytosis regulator RhoA, the folate carriers FOLR1 and RFC1, and the glucose transporter GLUT4 were assessed. RESULTS: Pre-decitabine RhoA was higher in patients who had received their last therapy >3 months previously than in patients with more recent prior therapy (P = 0.02), and varied inversely with global DNA methylation as assessed by LINE1 methylation (r = -0.58, P = 0.006). Tumor RhoA scores increased with decitabine (P = 0.03), and RFC1 also increased in patients with pre-decitabine scores <=150 (P = 0.004). Change in LINE1 methylation with decitabine did not correlate significantly with change in IHC scores for any transporter assessed. We also assessed methylation of the RFC1 gene (alias SLC19A1). SLC19A1 methylation correlated with tumor LINE1 methylation (r = 0.45, P = 0.02). There was a small (statistically insignificant) decrease in SLC19A1 methylation with decitabine, and there was a trend towards change in SLC19A1 methylation with decitabine correlating with change in LINE1 methylation (r = 0.47, P <0.15). While SLC19A1 methylation did not correlate with RFC1 scores, there was a trend towards an inverse correlation between change in SLC19A1 methylation and change in RFC1 expression (r = -0.45, P = 0.19). CONCLUSIONS: In conclusion, after decitabine administration, there was increased expression of some (but not other) transporters that may play a role in chemotherapy uptake. Larger patient numbers will be needed to define the extent to which this increased expression is associated with changes in DNA methylation. PMID- 24401733 TI - Stability against brushing abrasion and the erosion-protective effect of different fluoride compounds. AB - This study aimed to analyse the impact of brushing on the protective effect of different fluoride solutions on enamel and dentin erosion. Bovine enamel and dentin specimens were rinsed once with TiF4, AmF, SnF2 (0.5 M F, 2 min) or water (control). Specimens were either left unbrushed or brushed with 10, 20, 50, 100 or 500 brushing strokes in an automatic brushing machine (2 N, non-fluoridated toothpaste slurry). Ten specimens per group were eroded with hydrochloric acid (HCl) (pH 2.3) for 60 s, and calcium release into the acid was determined by atomic absorption spectroscopy. Additionally, enamel and dentin surfaces were analysed by X-ray energy-dispersive spectroscopy (EDS) (n = 6/group) and scanning electron microscopy (SEM) (n = 2/group) before brushing and after 500 brushing strokes. Statistical analysis (p < 0.05) was performed by three- and one-way ANOVA (calcium release) or repeated measures ANOVA (EDS). TiF4, AmF and SnF2 reduced the erosive calcium loss in unbrushed specimens to 58-67% (enamel) and 23 31% (dentin) of control. Calcium release increased with increasing brushing strokes prior to erosion and amounted to 70-88% (enamel) and 45-78% (dentin) of control after 500 brushing strokes. Brushing reduced the surface concentration of fluoride (AmF), tin (SnF2) and titanium (TiF4). SEM revealed that surface precipitates were affected by long-term brushing. Brushing reduced the protective potential of TiF4, AmF and SnF2 solutions. However, considering a small number of brushing strokes, the protective effect of fluoride solutions is only slightly affected by brushing abrasion. PMID- 24401734 TI - Expression of CXCR4 is associated with progression and invasion in patients with nasal-surface basal cell carcinoma. AB - BACKGROUND: Basal cell carcinoma (BCC) is the most common type of skin cancer with an increasing incidence worldwide that imposes a considerable burden on public health. C-X-C chemokine receptor (CXCR4) plays a vital role in initiation, progression and metastasis of several types of cancers. The aim of the present study was to investigate the expression and clinical significance of CXCR4 in BCC. METHODS: In this study, 80 samples of primary BCC were assessed for CXCR4 expression using immunohistochemistry. The mRNA and protein expression levels of CXCR4 were evaluated by real-time reverse transcription polymerase chain reaction and Western blot analysis, respectively. RESULTS: CXCR4-positive staining was detected in 70% of BCC samples. Overexpression of CXCR4 was significantly associated with tumor size (>2 vs. 2 cm, p = 0.002) and pathological type (invasive vs. noninvasive, p = 0.007). CXCR4 was also upregulated at transcriptional and translational levels. CONCLUSION: Our study revealed that the expression of CXCR4 was associated with progression and invasion in patients with BCC. It may be a considerable biomarker to assess invasiveness of nasal-surface BCC and to guide clinical management of such tumors. PMID- 24401735 TI - Noise annoyance through railway traffic - a case study. AB - This paper describes an assessment of noise caused by railway traffic in a large Latin American city. Measurements were taken of noise levels generated by trains passing through residential neighborhoods with and without blowing their horns. Noise maps were also calculated showing noise pollution generated by the train traffic. In addition - annoyance of the residents - affected by railway noise, was evaluated based on interviews. The measurements indicated that the noise levels generated by the passage of the train with its horn blowing are extremely high, clearly exceeding the daytime limits of equivalent sound pressure level - Leq = 55 dB(A) - established by the municipal laws No 10.625 of the city of Curitiba. The Leq = 45 dB (A) which is the limit for the night period also are exceeded during the passage of trains. The residents reported feeling affected by the noise generated by passing trains, which causes irritability, headaches, poor concentration and insomnia, and 88% of them claimed that nocturnal noise pollution is the most distressing. This study showed that the vast majority of residents surveyed, (69%) believe that the noise of the train can devalue their property. PMID- 24401736 TI - Parameters affecting the severity and outcome of pyogenic digital flexor tenosynovitis. PMID- 24401737 TI - Segmental neurofibromatosis of the upper extremity: a case report. PMID- 24401738 TI - Extravasation injuries: a review. AB - Extravasation injuries are common emergencies in clinical practice. If they are not recognized and treated promptly, they can lead to deleterious functional and cosmetic outcomes. There is a vast range of agents involved in these injuries and marked paucity of evidence to support their specific management. Following an extensive literature review, we outline management principles for clinicians involved in the care of patients with extravasation injuries. Key parameters in deciding appropriate management plans include the volume/toxicity of the agent, the necrosis interval of the injury, patient-related factors, as well as the facilities and expertise available in the setting of individual cases of extravasation. PMID- 24401739 TI - Morphology of the proximal and middle phalanx of fingers with regard to the Ascension PyroCarbon PIP total joint. AB - The Ascension PyroCarbon prosthesis has been used in proximal interphalangeal joint osteoarthritis. The dimensions of the intramedullary distal metadiaphyseal canal (isthmus) of the proximal phalanx and the base of the middle phalanx of cadaver fingers were investigated radiographically (n = 304) and macroscopically (n = 152). In up to 30% of the phalanges, the isthmus was smaller than the stem of the smallest proximal component size. The distal component head was always smaller than the middle phalanx base. Insertion and success of the Ascension PyroCarbon prosthesis is strongly dependent on bone morphology. A critical examination of the isthmus in radiographs is recommended in planning. If the isthmus is clearly smaller than the smallest proximal component, insertion of the prosthesis could be inadvisable. A clear mismatch between the distal component and the middle phalanx base should be avoided due to the potential risk for late subsidence and failure of the prosthesis. PMID- 24401740 TI - Comparative clinical study of locking screws versus smooth locking pegs in volar plating of distal radius fractures. AB - The present study was performed to test the null hypothesis on no difference in stability of fixation after volar plating of intra-articular distal radius fractures (AO C2-C3) with either locking smooth pegs or locking screws in a clinical setting. A retrospective evaluation included adult patients with C2-C3 AO fractures treated with a volar plate with locking smooth pegs or locking screws. Radiographic assessment was performed to evaluate extra- and intra articular parameters in the early postoperative period and after bone union. Twenty-seven consecutive patients were included. Thirteen cases had fixation with locking screws and 14 had fixation with locking smooth pegs. Both groups had bone fragment displacement after fixation. However, there were no significant differences between the groups either in extra- or intra-articular parameters defined by Kreder et al. (1996). Our study shows that, in a clinical setting, there is no difference in stability fixation between locking screws or smooth locking pegs in C2-C3 distal radius fractures. PMID- 24401741 TI - How we do it: retraction suture for interphalangeal joint surgery. PMID- 24401742 TI - A study of 60 patients with percutaneous trigger finger releases: clinical and ultrasonographic findings. AB - We present the clinical results and ultrasonographic findings of 61 trigger digits treated with percutaneous A1 pulley release. An endoscopic carpal tunnel knife was used for the release in the outpatient department. The mean follow-up period was 3.5 months. A total of 55 digits (90%) had complete relief of their triggering postoperatively. Six digits (10%) had Grade 2 triggering clinically in the early postoperative period.The complications included six cases of insufficient release (10%), scar sensitivity in one patient, short-term hypoaesthesia in three digits (5%), and flexor tendon laceration noted on postoperative ultrasonography in eight digits (13%). No neurovascular damage was noted on the postoperative ultrasonography. Ultrasonograpy provides information about tendon laceration and changes in thickness of the pulleys and confirm A1 pulley release after surgery, but it does not alter clinical decision-making. We believe that pre- and postoperative ultrasonograpy does not need to be included as a routine examination. PMID- 24401743 TI - Reconstruction of the median and musculocutaneous nerves with a nerve graft combined with end-to-side neurorrhaphy: A case report. PMID- 24401744 TI - Severity grading in radial dysplasia. AB - A functional scoring method to grade the usefulness and quality of the upper limbs in congenital radial dysplasia is presented. It is based on the author's examinations of 44 arms with congenital deficiency of the radius. The hand (H), wrist (W) and proximal parts (P) of the extremity are each scored from 0 to 10 points for severity. The scoring is expressed similarly to the TNM (tumour, nodes, metastasis) tumour classification, for example as H5W4P2. The maximum severity index is 30 points. A severity grade of mild is between 1 and 8 points, moderate between 9 and 16 points and severe 17 points and over. In the author's series, the grades were mild in eight, moderate in 21 and severe in 15 cases. The functional severity grading should allow better comparison of radially deficient limbs and the results of treatment between groups of patients. PMID- 24401745 TI - Distal radio-ulnar joint instability in children and adolescents after wrist trauma. AB - This study retrospectively evaluated the medical records and radiographs of patients younger than aged 25 that were referred for a second opinion due to ulnar-sided wrist pain and persistent distal radio-ulnar (DRU) joint instability. We identified 85 patients with a major wrist trauma before the age of 18. Median age at trauma was 14 years. Median time between trauma and diagnosis of DRUJ instability was 3 years. Sixty-seven patients (79%) had sustained a fracture at the initial trauma. The two most common skeletal injuries related to the DRUJ instability were Salter-Harris type II fractures (24%) and distal radius fractures (19%). In 19 patients (22%), the secondary DRUJ instability was caused by malunion or growth arrest. Eighteen patients (21%) had no fracture; in spite of this, they presented with subsequent symptomatic DRUJ instability. Fourteen of these 18 patients had a triangular fibrocartilage complex (TFCC) tear, confirmed by arthroscopy, open surgery, or magnetic resonance imaging. In conclusion, late DRUJ instability due to wrist fractures or isolated TFCC tears was found to be common in children and adolescents. LEVEL OF EVIDENCE: IV. PMID- 24401746 TI - Diabetic conditions differentially affect the endothelial function, arterial stiffness and carotid atherosclerosis. AB - AIM: The levels of fasting and postprandial plasma glucose, HbA1c and other risk factors for atherosclerosis have distinct effects in patients with and those without diabetes mellitus. The aim of this study was to determine the impact of diabetic surrogate markers on the endothelial function, arterial stiffness and carotid atherosclerosis in individuals with and without diabetes. METHODS: A total of 320 Japanese subjects(mean age: 61.2 +/- 12.1 years) were recruited in this study. Demographic, clinical and laboratory parameters, including 75 g OGTT(155 subjects) results, were examined. The endothelial function was evaluated according to the flow-mediated vasodilation of the brachial artery(%FMD). In addition, arterial stiffness was evaluated according to the brachial-ankle pulse wave velocity(baPWV), and carotid atherosclerotic changes were estimated according to the maximum intima-media thickness(max-IMT) and resistive index of the common carotid artery(CCA-RI). A multiple regression analysis was performed to identify independent determinants of these vascular surrogate markers. RESULTS: None of the glucose-related parameters were associated with the %FMD. In contrast, the presence of T2DM, the HbA1c level and an increased plasma glucose level at 60 minutes during 75 g OGTT were associated with an increased baPWV. The HbA1c level was also correlated with an increased max-IMT. The fasting plasma glucose(FPG) level and the presence of T2DM correlated with an increased CCA-RI. In the subjects with T2DM, the protective effects of high-density lipoprotein cholesterol(HDL-C) on the %FMD and baPWV were abolished. CONCLUSIONS: Various glucose metabolism parameters have different effects the degree of arterial stiffness and presence of carotid atherosclerosis, but not the endothelial function, suggesting that pharmacological intervention has the potential to preserve the endothelial function in diabetic individuals. In addition, the presence of T2DM blunts the vascular protective effects of HDL-C on the endothelial function and progression of arterial stiffness. PMID- 24401747 TI - Optimising treatment of end-stage renal disease in the elderly. AB - The features of ageing complicate the management of end-stage renal disease. These complicate all dialysis modalities and will greatly affect the ability to cope with interventional treatments and quality of life. The presence of other illnesses and comorbidity associated with kidney disease mean that many patients have a poor prognosis. It is therefore important to consider the impact of dialysis on lifestyle and whether survival will actually be improved for frail older patients. This review article considers how haemodialysis and peritoneal dialysis can be adjusted for older patients, and, in particular, how the use of assistance makes peritoneal dialysis more feasible. Most importantly, older patients should be given realistic information about their prognosis and how they can cope with different treatment options, and then they should be involved in the decisions about their management. PMID- 24401748 TI - miR-34a is essential for p19(Arf)-driven cell cycle arrest. AB - The Arf tumor suppressor gene product, p19(Arf), regulates cell proliferation in incipient cancer cells and during embryo development. Beyond its commonly accepted p53-dependent actions, p19(Arf) also acts independently of p53 in both contexts. One such p53-independent effect with in vivo relevance includes its repression of Pdgfrbeta, a process that is essential for vision in the mouse. We have utilized cell culture-based and mouse models to define a new role for miR 34a in this process. Ectopic expression of Arf in cultured cells enhanced the expression of several microRNAs predicted to target Pdgfrbeta synthesis, including the miR-34 family. Because miR-34a has been implicated as a p53 dependent effector, we investigated whether it also contributed to p53 independent effects of p19(Arf). Indeed, in mouse embryo fibroblasts (MEFs) lacking p53, Arf-driven repression of Pdgfrbeta and its blockade of Pdgf-B stimulated DNA synthesis were both completely interrupted by anti-microRNA against miR-34a. Ectopic miR-34a directly targeted Pdgfrbeta and a plasmid reporter containing wild-type Pdgfrbeta 3'UTR sequence, but not one in which the miR-34a target sequence was mutated. Although miR-34a expression has been linked to p53-a well-known effector of p19(Arf)-Arf expression and its knockdown correlated with miR-34a level in MEFs lacking p53. Finally, analysis of the mouse embryonic eye demonstrated that Arf controlled expression of miR-34a, and the related miR-34b and c, in vivo during normal mouse development. Our findings indicate that miR-34a provides an essential link between p19(Arf) and its p53 independent capacity to block cell proliferation driven by Pdgfrbeta. This has ramifications for developmental and tumor suppressor roles of Arf. PMID- 24401750 TI - MOSAL: software tools for multiobjective sequence alignment. AB - : Multiobjective sequence alignment brings the advantage of providing a set of alignments that represent the trade-off between performing insertion/deletions and matching symbols from both sequences. Each of these alignments provide a potential explanation of the relationship between the sequences. We introduce MOSAL, a software tool that provides an open-source implementation and an on-line application for multiobjective pairwise sequence alignment. PMID- 24401749 TI - The research agenda on oral health inequalities: the IADR-GOHIRA initiative. AB - The World Health Organization asserts that oral health is a basic human right, yet this is a right enjoyed by few. Oral disease is a major problem in high income countries, where the cost of treating oral diseases often exceeds that for major non-communicable diseases. In low-to-middle income countries, oral diseases are a severe and growing public health problem. Furthermore, major inequalities exist both within and between countries in terms of disease severity and prevalence, and major social gradients exist in the prevalence of oral disease. The International Association for Dental Research (IADR) has responded to the challenge of poor oral health and oral health inequalities through the Global Oral Health Inequalities: the Research Agenda (GOHIRA) initiative. In a Call to Action it has set out the priorities for research that can lead to a reduction in oral health inequalities. Three key challenges have been identified, namely gaps in knowledge and an insufficient focus on social policy, the separation of oral health from general health, and inadequate evidence-based data. Ten key research priorities have been identified with due regard to the differing needs of the variety of global health care systems, and a set of prioritized outcomes and a timeline for implementation have been defined. In the wider context of the proposals set out above, five immediate priorities for action have been proposed. PMID- 24401751 TI - Association between cardiotrophin 1 levels and central blood pressure in untreated patients with essential hypertension. AB - BACKGROUND: Cardiotrophin 1 (CT-1) is an interleukin 6-related cytokine recently implicated in cardiac hypertrophy and vascular damage in essential hypertension (EH). We aimed first to determine CT-1 levels in naive, untreated patients with grade I EH (UH) as compared with normotensive (NT) individuals and, second, to investigate a possible association of CT-1 levels with indices of arterial stiffness. METHODS: We enrolled 45 consecutive untreated patients recently diagnosed with grade I EH by means of office and ambulatory blood pressure (BP) measurements and 25 age- and sex-matched NT subjects. CT-1 levels were measured with a commercially available enzyme-linked immunosorbent assay kit, and indices of arterial stiffness were determined by applanation tonometry. RESULTS: CT-1 levels were significantly elevated in UH patients compared with NT subjects (P < 0.001). Furthermore, CT-1 levels correlated positively with office, ambulatory and central BP. A significant bivariable correlation was also found between CT-1 levels and pulse wave velocity (P = 0.02). In the multivariable analysis, central systolic and diastolic BP proved the only significant predictors of CT-1 levels after controlling for other related factors. CONCLUSIONS: To our knowledge, this is the first study that correlates CT-1 levels with ambulatory and central BP, as well as with pulse wave velocity in patients with essential hypertension. Thus, studying the effects of CT-1 in the cardiovascular system in patients with EH represents a promising area of investigation in the future. PMID- 24401752 TI - Impact of a social franchising program on uptake of oral rehydration solution plus zinc for childhood diarrhea in myanmar: a community-level randomized controlled trial. AB - BACKGROUND: Diarrhea's impact on childhood morbidity can be reduced by administering oral rehydration solution (ORS) with zinc; challenges to wider use are changing health-seeking behavior and ensuring access. METHODS: We conducted a randomized controlled trial to increase ORS plus zinc uptake in rural Myanmar. Village tracts, matched in 52 pairs, were randomized to standard ORS access vs. a social franchising program training community educators and supplying ORS plus zinc. RESULTS: Intervention and control communities were comparable on demographics, prevalence of diarrhea and previous use of ORS. One year after randomization, ORS plus zinc use was 13.7% in the most recent case of diarrhea in intervention households compared with 1.8% in control households (p < 0.001) (N = 3605). A significant increase in ORS plus zinc use was noted in the intervention (p = 0.044) but not in the control (p = 0.315) group. CONCLUSIONS: Social franchising increased optimal treatment of childhood diarrhea in rural Myanmar. Scale-up stands to reduce morbidity among children in similar settings. TRIAL REGISTRATION: Current Controlled Trials ISRCTN73606238. PMID- 24401753 TI - Co-morbidities in children presenting with chronic suppurative otitis media--a South African study. AB - BACKGROUND: Chronic suppurative otitis media (CSOM) is common among children in southern Africa. Managing associated co-morbidities may result in earlier disease resolution. METHODS: Children <13 years of age with otorrhoea lasting >4 weeks were recruited to the study. Each child underwent a full clinical examination, a blood count, an HIV test and CD4 cell count, if found to be infected. RESULTS: The study included 86 children, and the median age was 4.6 years. HIV infection was present in 45 of 83 children (54.2%), of which 23 (51.1%) were receiving antiretroviral treatment at the time of presentation. Underweight was present in 22 of 85 (25.9%) children and in 17 of the 45 (37.8%) HIV-infected children. One or more clinical signs (not aural-related) were found in 46 of 86 (53.4%) children. Cholesteatoma was found in 23 of 113 (20.4%) ears, and 9 of 86 (10.5%) children had serious associated aural or intracranial complications. CONCLUSIONS: A high percentage of children with CSOM have associated pathology that needs to be diagnosed to optimally manage CSOM. PMID- 24401754 TI - A Randomized controlled trial on safety and efficacy of single intramuscular versus staggered oral dose of 600 000IU Vitamin D in treatment of nutritional rickets. AB - OBJECTIVE: Comparison of efficacy and safety of two different regimens of vitamin D-600 000 IU as a single intramuscular dose, and 60 000IU orally once a week for 10 weeks-in treatment of nutritional rickets. METHODS: Children with nutritional rickets (age: 0.5-5 years, n = 61) were randomized to receive either 60 000IU vitamin D orally once a week for 10 weeks or 600 000IU single intramuscular injection. Serum calcium, phosphate, alkaline phosphatase, urinary calcium/creatinine ratio, serum 25 hydroxy vitamin D and radiological score were compared at 12-week follow-up. RESULTS: No difference was found in efficacy of the two regimens on comparing biochemical and radiological parameters. Serum 25 hydroxy vitamin D >100 ng/ml was found in two children in the oral group and one child in the intramuscular group. No child developed hypercalcemia or hypercalciuria after starting treatment. CONCLUSION: Staggered oral and one-time intramuscular administrations of 600 000IU vitamin D are equally effective and safe in treatment of nutritional rickets. PMID- 24401755 TI - High lactate dehydrogenase 5 expression correlates with high tumoral and stromal vascular endothelial growth factor expression in gastric cancer. AB - BACKGROUND: Lactate dehydrogenase 5 (LDH5) is a major lactate dehydrogenase isoenzyme catalyzing the transformation of pyruvate to lactate to provide anaerobic energy. Vascular endothelial growth factor (VEGF) is expressed in both tumor and stromal cells in gastric cancer. Our aim was to study the prognostic effect of LDH5, and tumoral and stromal expression of the angiogenic factor VEGF in gastric cancer, and the intercorrelation of tissue expression of both factors. METHODS: Tissue microarray analysis of 382 consecutive gastric cancer resection specimens was used for immunohistochemistry of LDH5 and VEGF, and expression of LDH5, tumoral VEGF, and stromal VEGF was categorized into low and high groups. RESULTS: High expression was observed for LDH5 in 57.9% (219/378), tumoral VEGF in 35.7% (136/381), and stromal VEGF in 58.5% (223/381) of the specimens. Regarding high expression of LDH5 and VEGF, significant associations with intestinal type, advanced gastric cancer, lymph node metastasis, higher TNM stage, and upper-third location were noted. Positive intercorrelations occurred among the expression of LDH5 and VEGF. Results of survival analyses revealed a significant association of high expression of LDH5 and VEGF with lower survival (overall and disease-free survival). Five-year survival rates were significantly lower in tumors with high LDH5 and tumoral VEGF expression in diffuse- or mixed type cancers and high expression of stromal VEGF in intestinal-type cancer. CONCLUSION: The results of our study showed that high LDH5 and VEGF expression in both tumor and stroma was a prognostic factor for patients with gastric cancers, especially diffuse- or mixed-type cancers. Therefore, LDH5 expression may play a role in the regulation of tumoral and stromal VEGF expression in gastric cancer. Our results suggest the potential use of LDH5 expression as a biomarker for response to VEGF-targeted therapy. PMID- 24401756 TI - Erosion/abrasion-preventing potential of NaF and F/Sn/chitosan toothpastes in dentine and impact of the organic matrix. AB - The study investigated the erosion/abrasion-preventing potential of experimental NaF (1,400 ppm F(-)) and amine fluoride (AmF)/NaF/SnCl2/chitosan (1,400 ppm F(-), 3,500 ppm Sn(2+), 0.5% chitosan) toothpastes relative to placebo and SnF2 gel (970 ppm F(-), 3,000 ppm Sn(2+)), and the impact of the demineralised dentine matrix on toothpaste effects. The study was a cyclic erosion/intervention experiment (10 days). Samples were stored in mineral salt solution either without or with collagenase (from Clostridium histolyticum type VII; 100 U/ml) for continuous removal of the organic matrix. To produce a comparable order of tissue loss, erosion was performed 6 * 30 s/day with 0.5% citric acid in the latter and 6 * 90 s/day with 1% citric acid in the former. Intervention was toothpaste slurry immersion (2 * 2 min/day); half of the samples were additionally brushed for 15 s within this time (brushing machine, load 200 g). Tissue loss was determined profilometrically (mean +/- SD; um). Tissue loss values (without/with brushing) for placebo, NaF, AmF/NaF/SnCl2/chitosan and SnF2 gel, respectively, were 11.6 +/- 3.1/12.2 +/- 2.5, 12.7 +/- 3.1/10.7 +/- 4.5, 8.7 +/- 2.1/9.7 +/- 2.1 and 8.8 +/- 1.8/10.9 +/- 1.8 in the presence of the organic matrix and 10.7 +/- 3.2/11.9 +/- 2.1, 8.2 +/- 4.0/10.1 +/- 4.1, 8.7 +/- 2.9/9.1 +/- 1.8 and 8.4 +/- 1.9/7.5 +/- 1.5 in the absence of the organic matrix. Relative to placebo, the NaF formulation had no significant effects; the AmF/NaF/SnCl2/chitosan formulation significantly reduced tissue loss between 20 and 25% except when applied without brushing in the absence of the organic matrix. The effects of the formulations were similar both in the presence and absence of the organic matrix. Sn(2+)/F(-)-containing formulations have the potential to reduce erosion/abrasion even in the absence of demineralised collagen; seeking for more effective formulations is desirable. PMID- 24401757 TI - Baha-mediated rehabilitation of patients with unilateral deafness: selection criteria. AB - The aim of our study was to identify clinical criteria for optimizing rehabilitation of patients with unilateral deafness using the Baha device. We made a retrospective study of 102 patients with unilateral deafness requesting auditory rehabilitation over a period of 5 years. All subjects underwent a series of stereo audiometric tests, with and without Baha worn on a headband, and were then referred to a hearing care specialist for a real life trial of 15 days. The Glasgow Health Status Inventory (GHSI) questionnaire was administered. Patients refusing the implantation were retrospectively submitted to a questionnaire specifically designed to ask the reasons for refusal. We measured stereo audiometric test results, age, aetiology of deafness, duration of auditory deprivation on the rehabilitated ear, and GHSI score. At the conclusion of testing, the implantation rate was 29%. During preoperative testing, the improvement in understanding of speech-in-noise was 22 +/- 11% for patients agreeing to the implantation versus 13 +/- 11% for patients refusing the implantation. Age, aetiology of deafness and duration of auditory deprivation had no influence on the implantation decision. Speech-in-noise testing and aided stereo audiometric gain were the only two measures showing statistically significant differences between the groups agreeing to and refusing the implantation. There were multiple reasons for refusal of the implantation. Among these, the four principal reasons were: absence of perceived benefit during stereo audiometric testing (59%), requirement for surgery (35%), cost of the solution (44%), and aesthetics (41%). Hence, no other criteria except the preoperative improvement in understanding of speech-in-noise and the aided gain from Baha worn on a headband were found to be predictive of the patient's acceptance of surgical implantation of a bone-anchored implant/abutment for Baha. Speech-in-noise testing with and without Baha worn on a headband has a role to play in deciding on the implantation of a bone-anchored hearing solution. PMID- 24401758 TI - Extremely low-frequency electromagnetic fields cause DNA strand breaks in normal cells. AB - BACKGROUND: Extremely low frequency electromagnetic fields aren't considered as a real carcinogenic agent despite the fact that some studies have showed impairment of the DNA integrity in different cells lines. The aim of this study was evaluation of the late effects of a 100 Hz and 5.6 mT electromagnetic field, applied continuously or discontinuously, on the DNA integrity of Vero cells assessed by alkaline Comet assay and by cell cycle analysis. Normal Vero cells were exposed to extremely low frequency electromagnetic fields (100 Hz, 5.6 mT) for 45 minutes. The Comet assay and cell cycle analysis were performed 48 hours after the treatment. RESULTS: Exposed samples presented an increase of the number of cells with high damaged DNA as compared with non-exposed cells. Quantitative evaluation of the comet assay showed a significantly (<0.001) increase of the tail lengths, of the quantity of DNA in tail and of Olive tail moments, respectively. Cell cycle analysis showed an increase of the frequency of the cells in S phase, proving the occurrence of single strand breaks. The most probable mechanism of induction of the registered effects is the production of different types of reactive oxygen species. CONCLUSIONS: The analysis of the registered comet indices and of cell cycle showed that extremely low frequency electromagnetic field of 100 Hz and 5.6 mT had a genotoxic impact on Vero cells. PMID- 24401759 TI - The neurite growth inhibitory protein Nogo-A has diverse roles in adhesion and migration. PMID- 24401760 TI - Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology. AB - ITPKB phosphorylates inositol 1,4,5-trisphosphate into inositol 1,3,4,5 tetrakisphosphate and controls signal transduction in various hematopoietic cells. Surprisingly, it has been reported that the ITPKB messenger RNA level is significantly increased in the cerebral cortex of patients with Alzheimer's disease, compared with control subjects. As extracellular signal-regulated kinases 1/2 activation is increased in the Alzheimer brain and as ITPKB is a regulator of extracellular signal-regulated kinases 1/2 activation in some hematopoietic cells, we tested whether this increased activation in Alzheimer's disease might be related to an increased activity of ITPKB. We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased beta-secretase 1 activity leading to overproduction of amyloid-beta peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-beta peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and beta-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-beta40 peptide production and tau hyperphosphorylation. No impact on pathology was observed in the 5X familial Alzheimer's disease mouse model when a catalytically inactive ITPKB protein was overexpressed. Together, our results point to the ITPKB/inositol 1,3,4,5 tetrakisphosphate/extracellular signal-regulated kinases 1/2 signalling pathway as an important regulator of neuronal cell apoptosis, APP processing and tau phosphorylation in Alzheimer's disease, and suggest that ITPKB could represent a new target for reducing pathology in human patients with Alzheimer's disease with ITPKB expression. PMID- 24401761 TI - A calcium prerinse required to form calcium fluoride in plaque from a sodium fluoride rinse. AB - The purpose of this study is to determine whether a calcium (Ca) prerinse used before a 228 ug/g (ppm) fluoride (F) rinse would induce the formation of 'calcium fluoride-like' (CaF2-like) deposits in human dental plaque. Sixty minutes after the use of the Ca prerinse/F rinse, plaque samples were collected from 10 volunteers, homogenized, and split into 2 aliquots. The plaque mass from one aliquot was then extracted with a 'plaque-like' solution that extracted all the CaF2-like deposits. The total F in both aliquots was then determined and compared. The results demonstrated that, as in previous studies, the Ca prerinse induced large increases in plaque fluid and total plaque F. However, unlike previous results without the Ca prerinse, 30% of the plaque F deposits were CaF2 or CaF2-like. Given that maintaining an elevated F concentration in the vicinity of a developing lesion may play an important role in the cariostatic effect of this ion, and the potential advantages of CaF2-like deposits as an F source, these results suggest that a Ca prerinse may increase the cariostatic effect of topical agents. PMID- 24401762 TI - Increasing glutamate promotes ischemia-reperfusion-induced ventricular arrhythmias in rats in vivo. AB - BACKGROUND: Glutamate mediates cerebral ischemia injury via N-methyl-D-aspartate (NMDA) receptor-coupled ion channels, but the activities of glutamate in the heart remain unclear. AIMS: To investigate whether or not glutamate contributes to ischemia- and reperfusion (IR)-induced arrhythmias. METHODS: Myocardial IR was induced by occlusion of the left anterior descending coronary artery for 30 min and reperfusion for another 30 min. A score system was used to quantify arrhythmias. MK801 (a noncompetitive NMDA receptor antagonist), dihydrokainate (DHK, a glutamate transporter inhibitor) and gabapentin (GBP, a glutamate release inhibitor) were used before ischemia. Serum glutamate levels, Ca(2+)-ATPase activity, SERCA2a protein expression and myocardial mitochondrial Ca(2+) content were assayed. RESULTS: Myocardial IR caused a significant increase in serum glutamate and high incidences of ventricular arrhythmias. GBP and MK801 significantly ameliorated ventricular arrhythmias, improved SERCA2a expression and sarcoplasmic reticulum Ca(2+)-ATPase activity and reduced Ca(2+) accumulated in mitochondria. By contrast, DHK significantly exacerbated reperfusion-related arrhythmias and mitochondrial Ca(2+) overload while it decreased SERCA2a expression and activity. CONCLUSION: This study showed that glutamate mediates reperfusion arrhythmias, and the corresponding mechanism may be associated with Ca(2+) overload via the NMDA receptor. Reperfusion arrhythmias may be prevented by inhibiting the release of glutamate or by antagonizing NMDA receptors. PMID- 24401763 TI - Transformation efficiency and formation of transformation products during photochemical degradation of TCE and PCE at micromolar concentrations. AB - BACKGROUND: Trichloroethene and tetrachloroethene are the most common pollutants in groundwater and two of the priority pollutants listed by the U.S. Environmental Protection Agency. In previous studies on TCE and PCE photolysis and photochemical degradation, concentration ranges exceeding environmental levels by far with millimolar concentrations of TCE and PCE have been used, and it is not clear if the obtained results can be used to explain the degradation of these contaminants at more realistic environmental concentration levels. METHODS: Experiments with micromolar concentrations of TCE and PCE in aqueous solution using direct photolysis and UV/H2O2 have been conducted and product formation as well as transformation efficiency have been investigated. SPME/GC/MS, HPLC/UV and ion chromatography with conductivity detection have been used to determine intermediates of degradation. RESULTS: The results showed that chloride was a major end product in both TCE and PCE photodegradation. Several intermediates such as formic acid, dichloroacetic acid, dichloroacetaldehyede, chloroform, formaldehyde and glyoxylic acid were formed during both, UV and UV/H2O2 treatment of TCE. However chloroacetaldehyde and chloroacetic acid were only detected during direct UV photolysis of TCE and oxalic acid was only formed during the UV/H2O2 process. For PCE photodegradation, formic acid, di- and trichloroacetic acids were detected in both UV and UV/H2O2 systems, but formaldehyde and glyoxylic acid were only detected during direct UV photolysis. CONCLUSIONS: For water treatment UV/H2O2 seems to be favorable over direct UV photolysis because of its higher degradation efficiency and lower risk for the formation of harmful intermediates. PMID- 24401764 TI - Antiepileptic drugs and suicide: a systematic review of adverse effects. AB - BACKGROUND: Since the FDA (Food and Drug Administration) report on antiepileptic drugs (AEDs) and suicide risk was released (2008), several studies have been published on this controversial relationship. This systematic review (SR) gives an updated approach to this health issue. SUMMARY: We searched 6 databases. We ultimately included 11 publications: 4 cohort studies, 1 case-crossover study, 2 community case-control studies, and 4 SRs. Overall, 1 SR described studies already included; 3 studies reported a 2- to 4-fold overall increase in risk; 1 study reported an increased risk of suicide among epilepsy patients on AEDs with high risk of depression; 1study showed a protective effect among epilepsy patients; 2 studies were conducted with patients with bipolar disorder (1 showed a protective effect, whereas the other showed a 3-fold increase in risk of suicide), and the other 3 studies reported results for single AEDs. Several biases affected the published results. KEY MESSAGES: There is no clear evidence of an association between the use of AEDs and an increased risk of suicide because of the heterogeneity in the studies at the clinical and methodological level. A future study should cover all indications for use, retrieve information from a healthcare database, and include a defined set of covariates to avoid bias. PMID- 24401765 TI - Effects of prochlorperazine on normal vestibular ocular and perceptual responses: a randomised, double-blind, crossover, placebo-controlled study. AB - BACKGROUND: The present study investigated whether prochlorperazine affects vestibulo-ocular reflex (VOR) and vestibulo-perceptual function. METHODS: We studied 12 healthy naive subjects 3 h after a single dose of oral prochlorperazine 5 mg in a randomised, placebo-controlled, double-blind, crossover study in healthy young subjects. Two rotational tests in yaw were used: (1) a threshold task investigating perceptual motion detection and nystagmic thresholds (acceleration steps of 0.5 degrees /s(2)) and (2) suprathreshold responses to velocity steps of 90 degrees /s in which vestibulo-ocular and vestibuloperceptual time constants of decay, as well as VOR gain, were measured. RESULTS: Prochlorperazine had no effect upon any measure of nystagmic or perceptual vestibular function compared to placebo. This lack of effects on vestibular-mediated motion perception suggests that the drug is likely to act more as an anti-emetic than as an antivertiginous agent. PMID- 24401766 TI - Quantifying interface and bulk contributions to spin-orbit torque in magnetic bilayers. AB - Spin-orbit interaction-driven phenomena such as the spin Hall and Rashba effect in ferromagnetic/heavy metal bilayers enables efficient manipulation of the magnetization via electric current. However, the underlying mechanism for the spin-orbit interaction-driven phenomena remains unsettled. Here we develop a sensitive spin-orbit torque magnetometer based on the magneto-optic Kerr effect that measures the spin-orbit torque vectors for cobalt iron boron/platinum bilayers over a wide thickness range. We observe that the Slonczewski-like torque inversely scales with the ferromagnet thickness, and the field-like torque has a threshold effect that appears only when the ferromagnetic layer is thinner than 1 nm. Through a thickness-dependence study with an additional copper insertion layer at the interface, we conclude that the dominant mechanism for the spin orbit interaction-driven phenomena in this system is the spin Hall effect. However, there is also a distinct interface contribution, which may be because of the Rashba effect. PMID- 24401767 TI - Comprehensive analysis of miRNA expression in T-cell subsets of rheumatoid arthritis patients reveals defined signatures of naive and memory Tregs. AB - Disturbed expression of microRNAs (miRNAs) in regulatory T cells (Tregs) leads to development of autoimmunity in experimental mouse models. However, the miRNA expression signature characterizing Tregs of autoimmune diseases, such as rheumatoid arthritis (RA) has not been determined yet. In this study, we have used a microarray approach to comprehensively analyze miRNA expression signatures of both naive Tregs (CD4+CD45RO-CD25++) and memory Tregs (CD4+CD45RO+CD25+++), as well as conventional naive (CD4+CD45RO-CD25-) and memory (CD4+CD45RO+CD25-) T cells (Tconvs) derived from peripheral blood of RA patients and matched healthy controls. Differential expression of selected miRNAs was validated by TaqMan based quantitative reverse transcription-PCR. We found a positive correlation between increased expression of miR-451 in T cells of RA patients and disease activity score (DAS28), erythrocyte sedimentation rate levels and serum levels of interleukin-6. Moreover, we found characteristic, disease- and treatment independent, global miRNA expression signatures defining naive Tregs, memory Tregs, naive Tconvs and memory Tconvs. The analysis allowed us to define miRNAs characteristic for a general naive phenotype (for example, miR-92a) and a general memory phenotype (for example, miR-21, miR-155). Importantly, the analysis allowed us to define miRNAs that are specifically expressed in both naive and memory Tregs, defining as such miRNA signature characterizing the Treg phenotype (that is, miR-146a, miR-3162, miR-1202, miR-1246 and miR-4281). PMID- 24401768 TI - Partial extensively drug-resistant tuberculosis in an HIV-infected child: a case report and review of literature. AB - Tuberculosis (TB) is one of the most common opportunistic infections that affects patients with HIV. HIV and TB coinfection have a synergistic effect on each other, with one disease worsening the effects and treatment of the other. In the recent past, varying levels of drug resistance are also found in patients coinfected with HIV and TB, but rarely is it reported in children in India. The present case documents partial extensively drug-resistant TB in an 8-year-old child. PMID- 24401769 TI - Adductor canal block versus femoral nerve block for total knee arthroplasty: a prospective, randomized, controlled trial. AB - BACKGROUND: This prospective double-blinded, randomized controlled trial compared adductor canal block (ACB) with femoral nerve block (FNB) in patients undergoing total knee arthroplasty. The authors hypothesized that ACB, compared with FNB, would exhibit less quadriceps weakness and demonstrate noninferior pain score and opioid consumption at 6 to 8 h postanesthesia. METHODS: Patients received an ACB or FNB as a component of a multimodal analgesic. Quadriceps strength, pain score, and opioid consumption were assessed on both legs preoperatively and at 6 to 8, 24, and 48 h postanesthesia administration. In a joint hypothesis test, noninferiority was first evaluated on the primary outcomes of strength, pain score, and opioid consumption at 6 to 8 h; superiority on each outcome at 6 to 8 h was then assessed only if noninferiority was established. RESULTS: Forty-six patients received ACB; 47 patients received FNB. At 6 to 8 h postanesthesia, ACB patients had significantly higher median dynamometer readings versus FNB patients (median [interquartile range], 6.1 kgf [3.5, 10.9] (ACB) vs. 0 kgf [0.0, 3.9] (FNB); P < 0.0001), but was not inferior to FNB with regard to Numeric Rating Scale pain scores (1.0 [0.0, 3.5] ACB vs. 0.0 [0.0, 1.0] FNB; P = 0.019), or to opioid consumption (32.2 [22.4, 47.5] ACB vs. 26.6 [19.6, 49.0]; P = 0.0115). At 24 and 48 h postanesthesia, there was no significant statistical difference in dynamometer results, pain scores, or opioid use between the two groups. CONCLUSION: At 6 to 8 h postanesthesia, the ACB, compared with the FNB, exhibited early relative sparing of quadriceps strength and was not inferior in both providing analgesia or opioid intake. PMID- 24401770 TI - Sedation using propofol induces similar diaphragm dysfunction and atrophy during spontaneous breathing and mechanical ventilation in rats. AB - BACKGROUND: Mechanical ventilation is crucial for patients with respiratory failure. The mechanical takeover of diaphragm function leads to diaphragm dysfunction and atrophy (ventilator-induced diaphragmatic dysfunction), with an increase in oxidative stress as a major contributor. In most patients, a sedative regimen has to be initiated to allow tube tolerance and ventilator synchrony. Clinical data imply a correlation between cumulative propofol dosage and diaphragm dysfunction, whereas laboratory investigations have revealed that propofol has some antioxidant properties. The authors hypothesized that propofol reduces markers of oxidative stress, atrophy, and contractile dysfunction in the diaphragm. METHODS: Male Wistar rats (n = 8 per group) were subjected to either 24 h of mechanical ventilation or were undergone breathing spontaneously for 24 h under propofol sedation to test for drug effects. Another acutely sacrificed group served as controls. After sacrifice, diaphragm tissue was removed, and contractile properties, cross-sectional areas, oxidative stress, and proteolysis were examined. The gastrocnemius served as internal control. RESULTS: Propofol did not protect against diaphragm atrophy, oxidative stress, and protease activation. The decrease in tetanic force compared with controls was similar in the spontaneous breathing group (31%) and in the ventilated group (34%), and both groups showed the same amount of muscle atrophy. The gastrocnemius muscle fibers did not show atrophy. CONCLUSIONS: Propofol does not protect against ventilator induced diaphragmatic dysfunction or oxidative injury. Notably, spontaneous breathing under propofol sedation resulted in the same amount of diaphragm atrophy and dysfunction although diaphragm activation per se protects against ventilator-induced diaphragmatic dysfunction. This makes a drug effect of propofol likely. PMID- 24401771 TI - Nitrous oxide-related postoperative nausea and vomiting depends on duration of exposure. AB - BACKGROUND: Inclusion of nitrous oxide in the gas mixture has been implicated in postoperative nausea and vomiting (PONV) in numerous studies. However, these studies have not examined whether duration of exposure was a significant covariate. This distinction might affect the future place of nitrous oxide in clinical practice. METHODS: PubMed listed journals reporting trials in which patients randomized to a nitrous oxide or nitrous oxide-free anesthetic for surgery were included, where the incidence of PONV within the first 24 postoperative hours and mean duration of anesthesia was reported. Meta-regression of the log risk ratio for PONV with nitrous oxide (lnRR PONVN2O) versus duration was performed. RESULTS: Twenty-nine studies in 27 articles met the inclusion criteria, randomizing 10,317 patients. There was a significant relationship between lnRR PONVN2O and duration (r = 0.51, P = 0.002). Risk ratio PONV increased 20% per hour of nitrous oxide after 45 min. The number needed to treat to prevent PONV by avoiding nitrous oxide was 128, 23, and 9 where duration was less than 1, 1 to 2, and over 2 h, respectively. The risk ratio for the overall effect of nitrous oxide on PONV was 1.21 (CIs, 1.04-1.40); P = 0.014. CONCLUSIONS: This duration-related effect may be via disturbance of methionine and folate metabolism. No clinically significant effect of nitrous oxide on the risk of PONV exists under an hour of exposure. Nitrous oxide-related PONV should not be seen as an impediment to its use in minor or ambulatory surgery. PMID- 24401772 TI - Visual acuity in a species of coral reef fish: Rhinecanthus aculeatus. AB - Coral reef fish present the human observer with an array of bold and contrasting patterns; however, the ability of such fish to perceive these patterns is largely unexamined. To understand this, the visual acuity of these animals - the degree to which they can resolve fine detail - must be ascertained. Behavioural studies are few in number and anatomical analysis has largely focused on estimates of ganglion cell density to predict the visual acuity in coral reef fish. Here, we report visual acuity measures for the triggerfish Rhinecanthus aculeatus. Acuity was first assessed using a series of behavioural paradigms and the figures were then contrasted with those obtained anatomically, based on photoreceptor and ganglion cell counts. Behavioural testing indicated an upper behavioural acuity of 1.75 cycles.degree(-1), which is approximately the same level of acuity as that of the goldfish (Carassiusauratus). Anatomical estimates were then calculated from wholemount analysis of the photoreceptor layer and Nissl staining of cells within the ganglion cell layer. Both of these anatomical measures gave estimates that were substantially larger (7.75 and 3.4 cycles.degree(-1) for the photoreceptor cells and ganglion cells, respectively) than the level of acuity indicated by the behavioural tests. This indicates that in this teleost species spatial resolution is poor compared to humans (30-70 cycles.degree(-1)) and it is also not well indicated by anatomical estimates. PMID- 24401774 TI - [Ethical responsibilities on the publication of scientific articles]. PMID- 24401773 TI - Pulmonary rehabilitation improves exercise capacity and dyspnea in air pollution related respiratory disease. AB - Air pollution in Japan caused respiratory disease, such as chronic bronchitis and asthma, in many individuals in the 1960s. Although air pollution has decreased, many victims of air pollution-related respiratory disease are limited in their activities of daily living because of respiratory symptoms. The purpose of this study was to evaluate the efficacy of pulmonary rehabilitation in victims of air pollution-related chronic bronchitis or asthma. Subjects were enrolled in a 12 week (2-week inpatient followed by 10-week outpatient) pulmonary rehabilitation program. The program comprised conditioning, strength training, endurance training, and patient education. We assessed the Modified Medical Research Council (MMRC) dyspnea grade, pulmonary function, peripheral muscle force, incremental shuttle walk distance (ISWD), and physical activity at baseline and immediately after the program. Twenty-nine subjects (mean age 74.2 +/- 10.1 years, 11 males) completed the program, including 11 subjects with COPD and 18 subjects with asthma. Following rehabilitation, the participants (n = 29) showed significant improvements in MMRC dyspnea grade, vital capacity % predicted, quadriceps force and ISWD (all P < 0.05). Sub-group analyses revealed that all these variables were significantly improved in subjects with asthma. In contrast, subjects with COPD showed significant improvements only in quadriceps force and ISWD (both P < 0.05). Thus, pulmonary rehabilitation is an effective method of improving exercise capacity and dyspnea in officially acknowledged victims of air pollution-related asthma. In conclusion, we recommend that patients with chronic bronchitis or asthma, resulting from exposure to air pollution, are referred for pulmonary rehabilitation. PMID- 24401775 TI - Expression of the hemagglutinin HA1 subunit of the equine influenza virus using a baculovirus expression system. AB - Equine influenza virus is a leading cause of respiratory disease in horses worldwide. Disease prevention is by vaccination with inactivated whole virus vaccines. Most current influenza vaccines are generated in embryonated hens' eggs. Virions are harvested from allantoic fluid and chemically inactivated. Although this system has served well over the years, the use of eggs as the substrate for vaccine production has several well-recognized disadvantages (cost, egg supply, waste disposal and yield in eggs). The aim of this study was to evaluate a baculovirus system as a potential method for producing recombinant equine influenza hemagglutinin to be used as a vaccine. The hemagglutinin ectodomain (HA1 subunit) was cloned and expressed using a baculovirus expression vector. The expression was determined by SDS-PAGE and immunoblotting. A high yield, 20MUg/ml of viral protein, was obtained from recombinant baculovirus infected cells. The immune response in BALB/c mice was examined following rHA1 inoculation. Preliminary results show that recombinant hemagglutinin expressed from baculovirus elicits a strong antibody response in mice; therefore it could be used as an antigen for subunit vaccines and diagnostic tests. PMID- 24401776 TI - [Detection of a clonal complex with Brucella abortus biovar 2 genotype as founder in B. abortus isolates from Argentina]. AB - Brucella abortus is the causative agent of bovine brucellosis, a worldwide zoonosis. Up to date, eight biovars of B. abortus have been described. In Argentina, biovar 1 is the most frequently isolated. However, biovar 2, which is more pathogenic than biovar 1, is also found. Molecular methods for subtyping isolates are necessary for allowing epidemiological surveillance and control of eradication programs. Due to the genetic homogeneity of the genus Brucella, the development of molecular typing tools has been difficult. The publication of microorganism genomes facilitates the design of this approach. The aim of this work was to employ a Multiple Locus VNTR Analysis (MLVA) scheme for strains from Argentina isolated in our laboratory. From the 56 isolates analyzed, 47 different genotypic profiles were obtained. All the strains typed as biovar 2 showed the same profile. This scheme allowed assigning each isolate to the biovar it belongs to. All the genotypes were related using the goeBURST analysis and biovar 2 was proposed as founder. PMID- 24401777 TI - [Surveillance of Haemophilus influenzae serotypes in Argentina from 2005 to 2010 during the Haemophilus influenzae type b conjugate vaccine era]. AB - The introduction of the Haemophilus influenzae type b vaccine in the immunization programs of many countries has greatly reduced this invasive disease and the carriage caused by this serotype, also increasing other capsular types and non capsular isolations. There were 313 isolations of H. influenzae under study, which were recovered from a sterile site coming from pediatric and adult patients carrying the invasive disease. Patients were treated at 90 different hospitals belonging to the Red Nacional de Laboratorios para Meningitis e Infecciones Respiratorias Agudas Bacterianas (National Lab Network for Meningitis and Acute Bacterial Respiratory Infections) from 2005 to 2010 for the following disorders: pneumonia, 40.3% (n=126), meningitis, 30.0% (n=94) and bacteremia, 26.5% (n=83). In pediatric patients (n=279), the highest frequency of isolations corresponded to children under the age of 2 years, 74.5% (n=208). Regarding type distribution, 61.3% corresponded to non-capsular H. influenzae (n=192), 20.1% to type b (n=63), 11.2% to type a (n=35), 4.8% to type f, and 2.6% to other types. Capsular H. influenzae was predominant in meningitis whereas non-capsular H. influenzae in pneumonia and bacteremia. The biotype was determined in 306 isolations. The totality (100%) of type a (n=35) was biotype II whereas 66.7% of type b (n=63) was biotype I. Slide agglutination and PCR tests were used in 220 isolations. There was a match of 0.982 (IC: 0.92-1.00) between them. During the last year, there was a great increase in type b, showing the importance of clinical and laboratory-based surveillance of the invasive disease caused by H. influenzae. PMID- 24401778 TI - [Taxonomic study of clinic isolates of Trichophyton in Rosario, Argentina]. AB - Due to the pleomorphism and cultural variability displayed by species of the genus Trichophyton, the identification methods based solely on morphological features are usually insufficient for their classification. The goal of the present work was to test a set of phenotypic methods in order to identify fungal isolates that belong to the aforementioned genus. These methods were based on a molecular taxonomic technique used as standard. Clinical isolates (56) were used as samples along with 6 reference strains. Macro and micromorphological studies were performed as well as biochemical and physiological tests such as in vitro hair perforation, nutritional requirements in Trichophyton agar media, urease production and growth on bromocresol purple-milk. solids-glucose (BCP-MS-G) agar. Additionally, PCR fingerprinting using the (GACA)4 primer was employed. As a result of the PCR method, specific profiles were observed for Microsporum canis, Epidermophyton floccosum, Trichophyton rubrum and Trichophyton interdigitale. Identical profiles were obtained for Arthroderma benhamiae y Trichophyton erinacei. Of the total number of clinical isolates, 39 matched the T. rubrum profile while 13 corresponded to A. benhamiae and 4 to T. interdigitale. The most useful phenotypic test to differentiate between T. rubrum and T. mentagrophytes complex strains was alkalinization of the BCP-MS-G medium. Phenotypic tests did not allow differentiation among the T. mentagrophytes complex species. On the other hand, the molecular technique allowed characterization of T. rubrum isolates as well as of those observed in our study and included in the T. mentagrophytes complex: T. interdigitale and Trichophyton sp., the anamorph of A. benhamiae. PMID- 24401779 TI - [Streptococcus gallolyticus subsp. pasteurianus isolated from cerebrospinal fluid in a pediatric patient]. AB - Streptococcus gallolyticus subsp. pasteurianus is known to cause bacterial meningitis in adults, and most of the few pediatric cases observed occurred in neonates. We report the case of a 9-month old boy with a history of repeated hospitalizations due to respiratory diseases, who presented meningitis and bacteremia by Streptococcus gallolyticus subsp. pasterianus. To our knowledge, this is the first reported case in Santa Fe to this date. PMID- 24401780 TI - [Evaluation of the Epsilometer (Etest) method for the detection of tetracycline susceptibility in Paenibacillus larvae, the causal agent of American foulbrood disease of honeybees]. AB - American foulbrood (AFB) is a bacterial disease caused by the spore-forming, grampositive bacterium Paenibacillus larvae, which affects honeybee broods worldwide. The aim of this work was to compare the Epsilometer test (Etest) to the agar dilution method for testing a collection of 22 P. larvae strains to tetracycline by using MYPGP and Iso- Sensitest agars. Results showed that a categorical agreement of 100% was found when using Iso-Sensitest, while a categorical agreement of 86.36% was found (with 3 minor errors) when MYPGP was tested. In conclusion, the Etest could be a rapid and reliable method for testing MIC values of tetracycline in P. larvae only when used in combination with Iso Sensitest agar. Nevertheless, these results should be confirmed with future studies involving a larger number of isolates. PMID- 24401781 TI - Macrolide resistance in Streptococcus pneumoniae isolated from Argentinian pediatric patients suffering from acute otitis media. AB - Macrolide-resistant Streptococcus pneumoniae emerged in Argentina in 1995, representing 26% of invasive infection isolates in children under 5 years old. The objectives of this study were to describe the prevalence of ermB and mefA genes in macrolide-resistant S. pneumoniae isolates from acute otitis media (AOM) and to determine their genetic relatedness. Between May 2009 and August 2010, 126 S. pneumoniae isolates from 324 otherwise healthy children with a first episode of AOM were included. Twenty six of these isolates (20.6%) were resistant to erythromycin. Most frequent serotypes were: 14 (46.2%), 6A (23.1%), 19F (7.7%) and 9V (7.7%). Twenty (76.9%) carried the mefA gene, 5 (19.2%) have the ermB gene, and 1 (3.9%) both ermB + mefA. Ten clonal types were identified, mostly related to Sweden(15A)-25/ST782 (SLV63), CloneB(6A)/ST473 and England(14)-9/ ST9. This is the first study assessing the mechanisms of macrolide resistance in pneumococci isolates from pediatric AOM in Argentina and their genetic relatedness. PMID- 24401783 TI - Production of anticandidal cotton textiles treated with oak gall extract. AB - Candida albicans, one of the most dreadful fungal pathogens threatening humans, could not be easily prevented. The anticandidal activity of oak gall extract, Quercus infectoria (QIE), was investigated as a potential natural alternative to synthetic and chemical fungicides. QIE anticandidal potentiality was confirmed using both qualitative and quantitative assays. Cotton textiles were treated with QIE and then evaluated as anticandidal fabrics. QIE-treated textiles had a potent anticandidal activity, which could completely inhibit the inoculated C. albicans cells. The durability of anticandidal activity in QIE-treated textiles almost completely disappeared after the fourth laundering cycle. QIE could be recommended, however, as a potent anticandidal agent for preparing antiseptic solutions and emulsions and as a finishing agent for manufacturing anticandidal disposable diapers and hygienic clothes. PMID- 24401782 TI - Multiple enzymatic profiles of Vibrio parahaemolyticus strains isolated from oysters. AB - The enzymatic characterization of vibrios has been used as a virulence indicator of sanitary interest. The objective of this study was to determine the enzymatic profile of Vibrio parahaemolyticus strains (n=70) isolated from Crassostrea rhizophorae oysters. The strains were examined for the presence of gelatinase (GEL), caseinase (CAS), elastase (ELAS), phospholipase (PHOS), lipase (LIP), amilase (AML) and DNase. All enzymes, except elastase, were detected in more than 60% of the strains. The most recurrent enzymatic profiles were AML + DNase + PHOS + GEL + LIP (n=16; 22.9%) and AML + CAS + DNase + PHOS + GEL + LIP (n=21; 30%). Considering the fact that exoenzyme production by vibrios is closely related to virulence, one must be aware of the bacteriological risk posed to human health by the consumption of raw or undercooked oysters. PMID- 24401784 TI - A species-specific method for detecting pathogenic Streptomyces species from soil and potato tubers in Argentina. AB - Potato common scab is caused by several soil-inhabiting pathogenic Streptomyces species. In the present study, a species-specific PCR method was used to detect Streptomyces species in potato tuber lesions and soils. Total genomic DNA from soil samples from six locations and tuber samples from four potato cultivars (Spunta, Shepody, Innovator and Russet Burbank) were assessed. Streptomyces scabies, Streptomyces acidiscabies, and Streptomyces turgidiscabies were detected in soybean, tobacco and potato soils and in all potato varieties except Russet Burbank. The phylogenetic analysis of the sequences obtained confirmed the identification. The method proposed proved to be time-saving and cost effective for the rapid detection of Streptomyces species. This is the first report of the detection of S. acidiscabies and S. turgidiscabies in soils and potato tubers from Argentina. PMID- 24401785 TI - [High quality protein maize fermentation with Lactobacillus plantarum (CPQBA 087 11 DRM) isolated from traditional maize sourdough in Colombia]. PMID- 24401786 TI - Sodium balance is not just a renal affair. AB - PURPOSE OF REVIEW: The equilibration theory of extracellular body fluids is tightly linked to sodium (Na) metabolism. It is accepted that with changes in salt intake, renal sodium elimination will prevent any change in interstitial Na content and concentration. This review summarizes recent anomalous findings regarding salt and water homeostasis that are inconsistent with current assumptions. RECENT FINDINGS: Recent findings from chemical analysis studies of laboratory animals, as well as noninvasive quantitative Na MRI (Na-MRI) studies in patients, have shown that remarkable amounts of Na are stored in muscle and in skin without commensurate water retention. Furthermore, an ultra-long Na balance study in humans suggests the presence of endogenous clocks that generate weekly and monthly infradian rhythmicity of Na storage independent of salt intake. Animal experiments suggest that fluids in the skin interstitium are hypertonic compared with plasma, and that interstitial osmotic stress induces local extrarenal immune cell and lymph-capillary driven mechanisms for electrolyte clearance and maintenance of the internal environment. SUMMARY: Recent quantitative evidence challenges current ideas on salt and water homeostasis, and suggests that Na homeostasis cannot be maintained without additional previously unappreciated extrarenal regulatory mechanisms. PMID- 24401787 TI - What should be the goal blood pressure in nondiabetic chronic kidney disease? AB - PURPOSE OF REVIEW: To summarize the available evidence on whether a lower blood pressure (BP) treatment target can ameliorate the progression of nondiabetic chronic kidney disease (CKD), and prevent cardiovascular events in CKD patients. RECENT FINDINGS: The three prospective, randomized controlled trials which addressed the question of progression of CKD suggest that a lower BP treatment goal (<130/80 mmHg) may lead to better preservation of renal function, but only in those patients with proteinuria of more than 300 mg/day. However, the evidence is not conclusive. We are not aware of adequately powered, randomized trials that have assessed the efficacy of lower target BP levels for the prevention of cardiovascular events specifically in nondiabetic CKD patients. The available circumstantial evidence (e.g., subgroup analyses of CKD patients in cardiovascular trials) fails to reveal a clear benefit of a lower BP goal. SUMMARY: There is currently no convincing evidence to recommend a lower than standard BP treatment target of less than 140/90 mmHg for all patients with nondiabetic CKD. A lower treatment target of less than 130/80 mmHg may delay renal disease progression but only in patients with proteinuria. PMID- 24401788 TI - Role of epidermal growth factor receptor in vascular structure and function. AB - PURPOSE OF THE REVIEW: The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase with a wide implication in tumor biology, wound healing and development. Besides acting as a growth factor receptor activated by ligands such as EGF, the EGFR can also be transactivated and thereby mediate cross-talk with different signaling pathways. The aim of this review is to illustrate the Janus faced function of the EGFR in the vasculature with its relevance for vascular biology and disease. RECENT FINDINGS: Over recent years, the number of identified signaling partners of the EGFR has steadily increased, as have the biological processes in which the EGFR is thought to be involved. Recently, new models have allowed investigation of EGFR effects in vivo, shedding some light on the overall function of the EGFR in the vasculature. At the same time, EGFR inhibitors and antibodies have become increasingly established in cancer therapy, providing potential therapeutic tools for decreasing EGFR signaling. SUMMARY: The EGFR is a versatile signaling pathway integrator associated with vascular homeostasis and disease. In addition to modulating basal vascular tone and tissue homeostasis, the EGFR also seems to be involved in proinflammatory, proliferative, migratory and remodeling processes, with enhanced deposition of extracellular matrix components, thereby promoting vascular diseases such as hypertension or atherosclerosis. PMID- 24401789 TI - Update on intravenous iron choices. AB - PURPOSE OF REVIEW: Iron deficiency is a major factor in the prevalence and severity of anemia in patients with chronic kidney disease (CKD). We review the pathophysiology impairing normal intestinal iron absorption in CKD and compare the characteristics of newer intravenous (i.v.) iron agents to the longstanding i.v. iron products in the market. RECENT FINDINGS: The newer iron products, ferumoxytol, ferric carboxymaltose, and iron isomaltoside, more avidly bind iron, minimizing the release of labile iron during infusions, thus permitting large dose infusions. These irons also have more complex carbohydrate shells than their predecessors, which may also diminish reactions. Newer agents can be routinely administered at higher single doses, in as little as 15 min, with an acceptable safety profile. SUMMARY: Newer i.v. iron products permit the rapid, and sometimes complete, repletion of iron-deficient patients with a single dose. However, further studies examining the long-term risks and benefits of i.v. iron repletion are needed. PMID- 24401790 TI - Interaction of removal Ethidium Bromide with Carbon Nanotube: Equilibrium and Isotherm studies. AB - Drinking water resources may be contaminated with Ethidium Bromide (EtBr) which is commonly used in molecular biology laboratories for DNA identification in electrophoresis. Carbon nanotubes are expected to play an important role in sensing, pollution treatment and separation techniques. In this study adsorption of Ethidium Bromide on single-walled carbon nanotubes (SWCNTs) and carboxylate group functionalized single-walled carbon nanotube (SWCNT-COOH) surfaces have been investigated by UV-vis spectrophotometer. The effect of contact time, initial concentration and temperature were investigated. The adsorbents exhibits high efficiency for EtBr adsorption and equilibrium can be achieved in 6 and 3 min for SWCNTs and SWCNT-COOH, respectively. The effect of temperature on adsorption of EtBr by toward adsorbents shows the process in this research has been endothermic. The results showed that the equilibrium data were well described by the Langmuir isotherm model, with a maximum adsorption capacity of 0.770 and 0.830 mg/g for SWCNTs and SWCNT-COOH, respectively. The adsorption of EtBr on SWCNT-COOH is more than SWCNTs surfaces. A comparison of kinetic models was evaluated for the pseudo first-order, pseudo second-order models. Pseudo second-order was found to agree well with the experimental data. PMID- 24401791 TI - Self-reported head injury and risk of late-life impairment and AD pathology in an AD center cohort. AB - AIMS: To evaluate the relationship between self-reported head injury and cognitive impairment, dementia, mortality, and Alzheimer's disease (AD)-type pathological changes. METHODS: Clinical and neuropathological data from participants enrolled in a longitudinal study of aging and cognition (n = 649) were analyzed to assess the chronic effects of self-reported head injury. RESULTS: The effect of self-reported head injury on the clinical state depended on the age at assessment: for a 1-year increase in age, the OR for the transition to clinical mild cognitive impairment (MCI) at the next visit for participants with a history of head injury was 1.21 and 1.34 for the transition from MCI to dementia. Without respect to age, head injury increased the odds of mortality (OR = 1.54). Moreover, it increased the odds of a pathological diagnosis of AD for men (OR = 1.47) but not women (OR = 1.18). Men with a head injury had higher mean amyloid plaque counts in the neocortex and entorhinal cortex than men without. CONCLUSIONS: Self-reported head injury is associated with earlier onset, increased risk of cognitive impairment and dementia, increased risk of mortality, and AD-type pathological changes. PMID- 24401792 TI - Inferior alveolar nerve transection enhanced formalin-induced nocifensive responses in the upper lip: systemic buprenorphine had more antinociceptive efficacy over morphine. AB - This study was designed to investigate the efficacy of a partial MU-opioid agonist, buprenorphine, against the formalin-induced hyperalgesia in the upper lip in chronically inferior alveolar nerve (IAN)-transected rats. Subcutaneous injection of diluted formalin into the upper lip in the IAN-transected rats showed an increased number of pain-related behavior (PRB; face-rubbing behavior) in every phase up to 45 min (p < 0.01) compared with that in the nontransected sham control rats. The numbers of c-Fos-immunoreactive (IR) cells in the superficial layers of the trigeminal nucleus caudalis (VcI/II) at the rostral (0 0.7 mm caudal to the obex) and middle levels (1.4-2.2 mm caudal to the obex) 2 h after the formalin injection in the IAN-transected rats were significantly increased compared with those in the control rats. The PRB in phases 1 and 2 (0 15 and 15-30 min after formalin injection) in rats with preadministration of morphine (3 mg/kg i.p.) or buprenorphine (100 ug/kg i.p.) was significantly (p < 0.05) smaller than those in the control rats. There was no significant difference in the efficacy between morphine and buprenorphine at these doses. The antinociceptive efficacy in phase 2 of buprenorphine (100 ug/kg) was higher (p < 0.05) than that of morphine (3 mg/kg) in the IAN-transected rats. The number of c Fos-IR cells in the VcI/II at every level (0-3.6 mm caudal to the obex) after formalin injection was significantly decreased (p < 0.01) with preadministration of morphine (3 mg/kg) or buprenorphine (100 ug/kg) in the control rats. In the IAN-transected rats, the number of c-Fos-IR cells in the caudal VcI/II (2.2-3.6 mm caudal to the obex) after formalin injection was significantly decreased (p < 0.01) with preadministration of buprenorphine (100 ug/kg) but not so much (2.2 2.9 mm caudal to the obex, p < 0.05; 2.9-3.6 mm caudal to the obex, p > 0.05) with preadministration of morphine (3 mg/kg). These results indicate that IAN transection enhanced formalin-induced nocifensive responses in the upper lip, the dermatome of the intact nerve neighboring the IAN. Systemic preadministration of buprenorphine had more antinociceptive effects on the formalin-induced nocifensive behavior in the upper lip compared with morphine in the IAN transected rats. PMID- 24401793 TI - Use of the Finnish Information System on Occupational Exposure (FINJEM) in epidemiologic, surveillance, and other applications. AB - This paper reviews the use of the Finnish Information System on Occupational Exposure (Finnish job-exposure matrix, FINJEM) in different applications in Finland and other countries. We describe and discuss studies on FINJEM and studies utilizing FINJEM in regard to the validity of exposure estimates, occupational epidemiology, hazard surveillance and prevention, the assessment of health risks and the burden of disease, the assessment of exposure trends and future hazards, and the construction of job-exposure matrices (JEMs) in countries other than Finland. FINJEM can be used as an exposure assessment tool in occupational epidemiology, particularly in large register-based studies. It also provides information for hazard surveillance at the national level. It is able to identify occupations with high average exposures to chemical agents and can therefore serve the priority setting of prevention. However, it has only limited use at the workplace level due to the variability of exposure between workplaces. The national estimates of exposure and their temporal trends may contribute to the assessment of both the recent and future burden of work-related health outcomes. FINJEM has also proved to be useful in the construction of other national JEMs, for example in the Nordic Occupational Cancer study in the Nordic countries. FINJEM is a quantitative JEM, which can serve many purposes and its comprehensive documentation also makes it potentially useful in countries other than Finland. PMID- 24401794 TI - Alzheimer's disease and cancer: current epidemiological evidence for a mutual protection. PMID- 24401795 TI - Parametrically amplified bright-state polariton of four- and six-wave mixing in an optical ring cavity. AB - We report experimental studies of bright-state polaritons of four-wave mixing (FWM) and six-wave mixing (SWM) signals through cascade nonlinear optical parametric amplification processes in an atom-cavity composite system for the first time. Also, the coexisting cavity transmission modes of parametrically amplified FWM and SWM signals are observed. Finally, electromagnetically induced absorption by the FWM cavity modes in the probe beam is investigated. The investigations can find potential applications in multi-channel narrow-band long distance quantum communication. PMID- 24401800 TI - Impaired bone metabolism in glycogen storage disease type 1 is associated with poor metabolic control in type 1a and with granulocyte colony-stimulating factor therapy in type 1b. AB - BACKGROUND: Glycogen storage disease type 1 (GSD1) is a rare and genetically heterogeneous metabolic defect of gluconeogenesis due to mutations of either the G6PC gene (GSD1a) or the SLC37A4 gene (GSD1b). Osteopenia is a known complication of GSD1. OBJECTIVES: The aim of this study was to investigate the effects of poor metabolic control and/or use of GSD1-specific treatments on bone mineral density (BMD) and metabolism in GSD1 patients. METHODS: In a multicenter, cross-sectional case-control study, we studied 38 GSD1 (29 GSD1a and 9 GSD1b) patients. Clinical, biochemical and instrumental parameters indicative of bone metabolism were analyzed; BMD was evaluated by dual-emission X-ray absorptiometry and quantitative ultrasound. RESULTS: Both GSD1a and GSD1b patients showed reduced BMD compared with age-matched controls. In GSD1a patients, these abnormalities correlated with compliance to diet and biochemical indicators of metabolic control. In GSD1b patients, BMD correlated with the age at first administration and the duration of granulocyte colony-stimulating factor (G-CSF) therapy. CONCLUSIONS: Our data indicate that good metabolic control and compliance with diet are highly recommended to improve bone metabolism in GSD1a patients. GSD1b patients on G-CSF treatment should be carefully monitored for the risk of osteopenia/osteoporosis. PMID- 24401801 TI - Ultrasonographic evaluation of gastric content during labour under epidural analgesia: a prospective cohort study. AB - BACKGROUND: Women in labour are considered at risk of gastric content aspiration partly because the stomach remains full before delivery. Ultrasonographic measurement of antral cross-sectional area (CSA) is a validated method of gastric content assessment. Our aim was to determine gastric content volume and its changes in parturients during labour under epidural analgesia using bedside ultrasonography. METHODS: The cut-off value corresponding to an increased gastric content was determined by ultrasound measurement of antral CSA in six pregnant women in late pregnancy before and after ingestion of 250 ml of non-clear liquid. Antral CSA was then measured twice in 60 parturients who presented in spontaneous labour: when the anaesthesiologist was called for epidural analgesia catheter placement, and at full cervical dilatation. Patient-controlled epidural analgesia was performed with a solution of ropivacaine and sufentanil. RESULTS: After liquid ingestion, antral CSA (mm(2)) increased from 90 (range, 80-151) to 409 (range, 317-463). A CSA of 320 was taken as cut-off value. The feasibility rate of antral CSA determination was 96%. CSA decreased from 319 [Q1 158-Q3 469] to 203 [Q1 123-Q3 261] during labour (P=2*10(-7)). CSA was >320 in 50% of parturients at the beginning of labour vs 13% at full cervical dilatation (P=0.006). CONCLUSIONS: Bedside ultrasonographic antral CSA measurement is feasible in pregnant women during labour and easy to perform. The observed decrease in antral CSA during labour suggests that gastric motility is preserved under epidural anaesthesia. The procedure could be used to assess individual risk of gastric content aspiration during labour. PMID- 24401802 TI - Effect of adductor canal block on pain in patients with severe pain after total knee arthroplasty: a randomized study with individual patient analysis. AB - BACKGROUND: Total knee arthroplasty (TKA) is associated with varying degrees of pain. A considerable proportion (25-40%) of patients experience severe pain, despite a comprehensive multimodal analgesic regimen. We hypothesized that adductor canal block (ACB) would reduce pain in this patient category compared with placebo. METHODS: Fifty patients with severe pain, defined as having a visual analogue scale (VAS) pain score of >60 during active flexion of the knee on the first or the second postoperative day after TKA, were included in this randomized, double-blind, placebo-controlled trial. All the patients had received a comprehensive multimodal analgesic regimen. Group A received an ACB with ropivacaine 0.75%, 30 ml at time 0 and isotonic saline after 45 min. Group B received an ACB with isotonic saline at time 0 and ropivacaine 0.75%, 30 ml after 45 min. RESULTS: A 32-mm difference in VAS pain score, during active flexion of the knee (primary endpoint), was observed in favour of Group A, 95% confidence interval (CI): 23-42, P<0.0001. At rest, the difference in VAS pain score was 15 mm in favour of Group A, 95% CI: 8-23 mm, P=0.0001. Individual patient analysis revealed that 25% of the patients had no effect during active flexion. At rest, however, only 8% had more than mild pain after ACB compared with 57% at inclusion. CONCLUSIONS: ACB reduced VAS with 32 mm, during active flexion of the knee, in patients with severe pain after TKA, but a large proportion (78%) still had at least moderate, movement-related pain. Clinical trial registration www.clinicaltrials.gov, NCT01549704. PMID- 24401803 TI - Surgical management of Gorlin syndrome: a 4-decade experience using local excision technique. AB - Basal cell nevus syndrome (aka Gorlin syndrome, Gorlin-Goltz syndrome, nevoid basal cell carcinoma syndrome, and fifth phacomatosis) is a rare but well described autosomal dominant condition with variable penetrance. We present a female patient who has been successfully treated using local surgical excision and diligent skin surveillance for more than 4 decades, demonstrating that simple local incision is an efficacious and reasonable surgical alternative that may circumvent the specialization and expense of Mohs technique. PMID- 24401804 TI - Vascular variations of the transverse upper gracilis flap in consideration for breast reconstruction. AB - PURPOSE: The transverse upper gracilis (TUG) myocutaneous flap has served as an alternative to abdominally based autologous breast reconstruction since its introduction by Yousif et al in 1992. The reliability of the overlying skin paddle of the gracilis myocutaneous flap depends on the perforator anatomy as well as the vascular pedicle. Although much attention recently has been given to variations in the septocutaneous as well as myocutaneous perforators, we believe that relevant variations in pedicle anatomy have been underappreciated. We would like to report our experience with pedicle variability. METHODS: A retrospective review of records was performed on patients undergoing a TUG flap for autologous breast reconstruction from July 2006 and November 2011 by a single surgeon (L.C.W.). RESULTS: A total of 36 TUG flaps were performed on 24 patients. Twelve patients underwent bilateral simultaneous TUG reconstruction, and 12 patients underwent unilateral TUG reconstruction. Pedicle variability was found in 6 (17%) of 36 dissections. In 5.5% of dissections, there was a split pedicle and 11% were found to have a double main pedicle. There was 1 partial flap loss that resulted in a failed breast reconstruction. Four limbs had some degree of resultant lymphedema as a consequence of flap harvest. CONCLUSIONS: Although still a viable alternative to abdominally based autologous reconstruction, we find that the variability of the main pedicle has been quite underestimated in earlier reports. We also present a logical algorithm for flap dissection when the microsurgeon encounters such aberrancies. PMID- 24401805 TI - Expression Patterns of HIF-1alpha Under Hypoxia in Vascular Smooth Muscle Cells of Venous Malformations. AB - PURPOSE: The molecular pathophysiology of venous malformations (VMs), which are a type of vascular malformation, is poorly understood. Until now, it is known that VM lesions are related to the process of angiogenesis. Because angiogenesis is induced under hypoxic conditions, hypoxia is thought to be important in VM lesion formation. Therefore, we examined the implications of hypoxia on the biological behavior of VM vascular smooth muscle cells (VSMCs). In doing so, we investigated the expression patterns of hypoxia-inducible factor-1alpha (HIF-1alpha), which plays a key role in hypoxia-induced angiogenesis, to provide a further understanding of the molecular mechanisms involved in VM. METHODS: Vascular smooth muscle cells from 5 normal veins and 5 VM lesions were cultured under moderate hypoxic conditions (3% O2, 5% CO2). The effects of hypoxia on HIF-1alpha expression were measured by immunocytochemical staining, reverse transcription polymerase chain reaction, and real-time reverse transcription-polymerase chain reaction. RESULTS: Overall, the expression of HIF-1alpha in cells was high after exposure to hypoxia for 6 or 12 hours, but decreased after 24 hours of hypoxia. HIF-1alpha expression in VM VSMCs was 2 times higher than that in normal VSMCs. Immunocytochemically, HIF-1alpha was mainly located in the nucleus and the intensity in VM VSMCs was stronger after 6 and 12 hours of hypoxia when compared to the expression pattern of HIF-1alpha in VSMCs from normal tissue. This suggested that VM tissue is more susceptible to the effects of hypoxia than normal tissue. CONCLUSIONS: These results indicate that the high expression of HIF-1alpha in VM VSMCs under hypoxic conditions could be an important factor for stimulating downstream angiogenesis in VM. Furthermore, the results of this investigation could provide the basis for future studies of VM pathophysiology, and ultimately lead to the development of new therapeutic approaches. PMID- 24401806 TI - Infantile hemangiomas exhibit neural crest and pericyte markers. AB - Infantile hemangiomas (IHs) are the most common benign tumors of infancy and occur with greater than 60% prevalence on the head and neck. Despite their prevalence, little is known about the pathogenesis of this disease. Given the predilection of hemangioma incidence on the face and its nonrandom distribution on embryological fusion plates, we postulated that IHs are derived from pericytes of the neural crest. We performed an analysis on 15 specimens at various stages of the IH progression. Experiments performed included immunohistochemical staining, immunofluorescent staining, quantitative real-time polymerase chain reaction, and flow cytometry. We analyzed a number of cell markers using these methods, including cell markers for the neural crest, pericytes, endothelial cells, stem cells, and the placenta. We observed that neural crest markers such as NG2 and nestin were expressed in the hemangioma samples, in addition tomultiple pericytes markers including delta-like kinase, smooth muscle actin, calponin, and CD90. Stem cell markers such as c-myc, oct4, nanog, and sox2 were also more highly expressed in hemangioma samples compared to controls. Our work demonstrates that hemangiomas express pericyte, neural crest, and stem cell markers suggesting a possible pathogenetic mechanism. PMID- 24401807 TI - Comparison of Laser Doppler and Laser-Assisted Indocyanine Green Angiography Prediction of Flap Survival in a Novel Modification of the McFarlane Flap. AB - BACKGROUND: The McFarlane rat ischemic dorsal skin flap model has been commonly used for clinical vector studies, as well as the testing of noninvasive diagnostics. However, variability of this model secondary to flap contact with the wound bed has led many to question its validity. Here we present a novel modification to the McFarlane skin flap using sterile silicone. We also use this model to test the prognostic efficacy of laser-assisted indocyanine green (ICG) angiography and laser Doppler imaging (LDI). METHODOLOGY: A 3 * 9-cm dorsal skin flap with a cranially based pedicle was created, centered 1 cm distal to the scapulae. The flap was undermined, and in one of the 2 groups, a sterile silicone sheet was placed onto the wound bed. All flaps were then reapproximated with sutures 1-cm intervals. Clinical assessment and perfusion imaging was performed immediately postoperative, and at 24, 48, and 72 hours postsurgery. Postoperative day 7 clinical assessment was obtained before euthanasia. RESULTS: A comparative study using silicone blocked versus unblocked models (n = 6 per group) showed that, clinically, both models had equivalent flap survival [8.5 (0.913) vs 9.5 (1.01) cm]. However, a statistically significant increase in perfusion in the mid third of unblocked models was observed on POD3 [20.28% (2.7%) vs blocked 13.45% (2.5%), P < 0.05], with a similar increase in the distal third on POD7 [18.73% (2.064%) vs 10.91% (4.19%), P < 0.05]. A prognostic study comparing LDI and ICG angiography prediction of POD7 survival at early time points (n = 10) found that LDI underpredicted flap survival at early time points [84.2% (12.03%) on POD0, 87.35% (16.11%) on POD1]. In contrast, ICG was more proficient [100.1% (10.1%) on POD0]. CONCLUSIONS: We present a modification of the McFarlane skin flap model that results in similar clinical results, but with a noted reduction in perfusion inconsistencies noted in unblocked models. The ICG angiography is superior to LDI in predicting POD7 flap necrosis within the first 48 hours postinjury. Future work will focus on histologic validation of our model, and vector efficacy testing. PMID- 24401808 TI - Merkel cell carcinoma of the head and neck: challenges in implementing best practice. AB - OBJECTIVE: Merkel cell carcinoma (MCC) is a rare, aggressive skin tumor. Controversies regarding optimal management persist due to inadequate data and knowledge regarding tumor biology. Head and neck MCC increases both oncological and reconstructive challenges, compounded by predominantly elderly patients. We review our practice and outcomes, review evidence, and discuss the difficulties in delivering best practice management. METHODS: All patients with primary head and neck MCC, managed by a single multidisciplinary team between January 2001 and December 2010, were identified through retrospective analysis of a pathology coding database. A literature review was performed. RESULTS: Twenty patients, with a mean age of 83.5 years (40-99 years) and presenting with mean symptom duration of 5 months, had primary tumors involving the nose (n = 2), periorbital region (n = 5), cheek (n = 6), and the temple and scalp (n = 7). Mean tumor size was 2.1 cm (range, 0.5-7.5 cm). Reconstructive techniques were direct closure (n = 8), skin grafting (n = 7), local flaps (n = 4), and free anterolateral thigh flap (n = 1). Two (10%) patients presented with nodal disease. Eight (40%) patients re-presented with nodal recurrence at a mean of 7 months with 6 undergoing salvage neck dissections. Adjuvant radiotherapy was completed in 5 cases, and chemotherapy used for palliation in 1 case. Most of the patients declined radiotherapy due to adverse effects or frailty. CONCLUSIONS: Our series demonstrates the profound challenges in managing head and neck MCC, including tailoring definitive primary treatment and current consensus management to elderly patients. Regional nodal assessment and management remains crucial to achieving this goal. PMID- 24401809 TI - Lateral gastrocnemius myocutaneous flap transposition to the midlateral femur: extending the arc of rotation. AB - We report the successful use of an extended lateral gastrocnemius myocutaneous flap for coverage of the midlateral femur using successive delayed elevations. A 62-year-old man underwent wide resection of a liposarcoma of the right anterior thigh with free flap reconstruction and subsequent radiation therapy 10 years before. Four years later, the patient fractured his irradiated femur and was treated with a retrograde intramedullary nail, which subsequently became infected, causing osteomyelitis of the distal femur, septic arthritis of the knee joint, and nonunion of his pathologic fracture. Although advised by numerous surgeons to undergo above-knee amputation, we offered our motivated patient a multidisciplinary approach to clear his infection and pathology; implanted new orthopedic hardware; performed delayed flap reconstruction; and rehabilitated him back to painless, unassisted ambulation. The extended lateral gastrocnemius myocutaneous flap used provided perfused soft tissues and durable coverage for the patient's exposed orthopedic hardware of the midlateral femur, 14 cm above the joint line of the knee. By using this flap to cover a femur defect well above published heights, our patient avoided amputation after years of worsening incapacitation. PMID- 24401810 TI - Adipose-derived stem cells promote proliferation, migration, and tube formation of lymphatic endothelial cells in vitro by secreting lymphangiogenic factors. AB - Adipose-derived stem cells (ADSCs) are a promising new therapeutic modality for several diseases and have been applied to various clinical fields because of their multidifferentiation potential and capacity for growth-factor secretion. Recently, 2 in vivo studies showed ADSCs to have potential applications in lymphedema therapy. However, it remains unclear whether ADSCs have direct effects on lymphatic endothelial cells (LECs). In this study, human LECs were treated with murine ADSC-derived conditioned media. Changes in LEC proliferation, migration, and tube formation were assessed by WST-8 assay, transwell chamber assay, and Matrigel-based tube formation assay, respectively, with recombinant human vascular endothelial growth factor-C used as a positive control. Additionally, the expression of several lymphangiogenic factors in ADSCs was examined by quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Factors secreted by ADSCs induced LEC proliferation, migration, and tube formation more potently than recombinant human vascular endothelial growth factor-C. We confirmed by quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay that some of the lymphangiogenic factors of ADSCs were dramatically up-regulated under serum-starved conditions. These data indicate that ADSCs could directly contribute to lymphangiogenesis via secretory factors in vitro and may thus provide a therapeutic modality for patients with lymphedema. PMID- 24401811 TI - Seroma Formation in Rat Latissimus Dorsi Resection in the Presence of Biologics: The Role of Quilting. AB - BACKGROUND: Seroma formation is a well-recognized complication associated with many operative procedures. Despite its ubiquity, a lack of definitive scientific understanding of the etiology, natural history, and biochemistry of seromas remains. We endeavored to create and examine seromas in a rat model in the setting of commonly used biologic implants and to examine the role of quilting sutures/mechanical fixation in mitigating seroma development. METHODS: Female Sprague-Dawley rats were assigned to either Quilting or Nonquilting groups then subdivided into one of 3 porcine dermal implant groups (Permacol Surgical Implant, Strattice Reconstructive Tissue Matrix, or XCM Biologic Tissue Matrix) or control group. A 5-cm midline back incision was made, the skin reflected and the latissimus dorsi muscle resected bilaterally. Implants were sutured into the surgical bed using a running suture. The skin of nonquilted rats was closed with a running subcuticular suture. Quilted rats underwent placement of absorbable quilting sutures spaced 2 cm apart between the skin and underlying implant or muscle before skin closure. Postoperatively, rats were monitored for seroma formation with fluid aspirated as needed. At 28 or 90 days, rats were euthanized. Seroma and implants were examined grossly and under light microscopy. RESULTS: Of nonquilted rats, 42/54 (78%) developed seromas compared with 19/46 (41%) of quilted rats (P < 0.05), defined by bursa cavity present at necropsy. When a biologic implant was present, 28/35 (80%) of nonquilted rats developed seromas compared with 12/33 (36%) of quilted rats (P < 0.05). In the control group, 14/19 (74%) of nonquilted rats developed seromas compared with 7/13 (54%) of quilted rats. This difference was not statistically significant. Bursa presence was confirmed histologically in all cases, with no difference in bursa character seen between groups. CONCLUSIONS: This study confirms a reliable rat model of seroma formation, with most of the rats exhibiting at least subclinical seromas. There was no difference in seroma formation rate in the presence of biologic implants, and no differences in bursa character between implants. Mechanical fixation with quilting sutures decreased seroma rate significantly in all subgroups. All rats with seromas at necropsy had histological evidence of a bursa with no difference in appearance between groups. PMID- 24401812 TI - The Effect of Differentiation Grade of Cutaneous Squamous Cell Carcinoma on Excision Margins, Local Recurrence, Metastasis, and Patient Survival: A Retrospective Follow-Up Study. AB - BACKGROUND: The incidence of cutaneous squamous cell carcinoma (SCC) is increasing worldwide. Despite a growing body of literature on prognostic factors, it remains unclear how tumor differentiation grade influences patient survival. The aim of this study was to investigate a possible correlation between cutaneous SCC differentiation, local recurrence, metastasis, and patient survival. MATERIALS AND METHODS: All consecutive patients treated for cutaneous SCC between 2001 and 2008 were retrospectively analyzed. Univariate survival analysis was used to assess the association of different tumor characteristics with survival. RESULTS: One hundred thirty-one patients with 155 SCCs were included (median follow-up, 81 months; range, 27-125 months). Although no significant correlation between tumor differentiation grade and local recurrence could be found, it was an independent prognostic factor for metastatic disease and overall survival (OS). Metastasis-free survival at 5 years was significantly higher in well differentiated tumors (70%) compared to moderately (51%) and poorly differentiated SCCs (26%; P = 0.012); identical percentages were found for OS (P = 0.005). Furthermore, patients with incomplete excision of the first tumor showed an increased relative risk of dying of SCC of 4.0 (95% confidence interval, 2.4-6.6; P < 0.001) compared to excision with clear margins. CONCLUSIONS: Studies that investigated the relationship between SCC differentiation grade and patient survival are scarce and inconsistent. The present study indicates tumor differentiation grade is an independent prognostic factor for OS. This finding suggests poor differentiation of cutaneous SCC alone is sufficient to upstage the primary tumor in the TNM classification system. PMID- 24401813 TI - Immediate permanent implant reconstruction following mastectomy with capsule preservation in patients with prior augmentation mammoplasty. AB - Prior breast augmentation in patients desiring post-mastectomy reconstruction provides a unique opportunity for capsular preservation and immediate, single step implant reconstruction. We report a case series of a single-surgeon experience with immediate implant reconstruction after skin-sparing mastectomy in patients with prior subpectoral augmentation. Final implant volumes, complications, and outcomes were examined. Twenty patients (15 bilateral, total 35 breasts) were included. Eighteen (90%) patients were treated for cancer. Mean augmentation-to-reconstruction interval was 9 years (range, 3-19 years). Mean patient age was 45.1 years (range, 37-64 years). Eight patients (40%) received postoperative chemotherapy and two (10%) radiation. Mean mastectomy weight was 321 g. Mean weight of the implants removed was 346 g. Mean volume of new implants was 487 mL. All patients underwent capsulotomy (100% superior, 85% medial, 30% inferior, 5% lateral). Mean operative time was less than 1 hour for bilateral reconstruction. With average follow-up of 25.6 months, 2 patients were re operated on for asymmetry (implant malposition, synmastia). Thirty-day complications included 1 implant loss due to infection, 1 drain placement with implant salvage, 1 hematoma requiring evacuation, and 1 cellulitis treated with antibiotics. There were no late complications and no capsular contractures. None have required further oncologic surgery. No cancer recurrences have been detected. In patients who desire prosthetic reconstruction similar to their original submuscular augmentation, capsule preservation and implant replacement with a larger prosthetic inserted within the old capsule is safe, fast, and aesthetically pleasing without compromising oncologic principles. PMID- 24401814 TI - Embryonic cerebrospinal fluid activates neurogenesis of neural precursors within the subventricular zone of the adult mouse brain. AB - INTRODUCTION: There is a nondeveloped neurogenic potential in the adult mammalian brain, which could be the basis for neuroregenerative strategies. Many research efforts have been made to understand the control mechanisms which regulate the transition from a neural precursor to a neuron in the adult brain. Embryonic cerebrospinal fluid (CSF) is a complex fluid which has been shown to play a key role in neural precursor behavior during development, working as a powerful neurogenic inductor. We tested if the neurogenic properties of embryonic CSF are able to increase the neurogenic activity of neuronal precursors from the subventricular zone (SVZ) in the brains of adult mice. RESULTS: Our results show that mouse embryonic CSF significantly increases the neurogenic activity in precursor cells from adult brain SVZ. This intense neurogenic effect was specific for embryonic CSF and was not induced by adult CSF. CONCLUSIONS: Embryonic CSF is a powerful neurogenesis inductor in homologous neuronal precursors in the adult brain. This property of embryonic CSF could be a useful tool in neuroregeneration strategies. PMID- 24401815 TI - Interaction between a CSK gene variant and fish oil intake influences blood pressure in healthy adults. AB - Blood pressure is a heritable determinant of cardiovascular disease (CVD) risk. Recent genome-wide association studies have identified several single-nucleotide polymorphisms (SNPs) associated with blood pressure, including rs1378942 in the c Src tyrosine kinase (CSK) gene. Fish oil supplementation provides inconsistent protection from CVD, which may reflect genetic variation. We investigated the effect of rs1378942 genotype interaction with fish oil dosage on blood pressure measurements in the MARINA (Modulation of Atherosclerosis Risk by Increasing doses of N-3 fatty Acids) study, a parallel, double-blind, controlled trial in 367 participants randomly assigned to receive treatment with 0.45, 0.9, and 1.8 g/d eicosapentaenoic acid [EPA (20:5n-3)] and docosahexaenoic acid [DHA (22:6n 3)] (1.51:1) or an olive oil placebo for 12 mo. A total of 310 participants were genotyped. There were no significant associations with blood pressure measures at baseline; however, the interaction between genotype and treatment was a significant determinant of systolic blood pressure (SBP) (P = 0.010), diastolic blood pressure (DBP) (P = 0.037), and mean arterial blood pressure (MABP) (P = 0.014). After the 1.8 g/d dose, noncarriers of the rs1378942 variant allele showed significantly lower SBP (P = 0.010), DBP (P = 0.016), and MABP (P = 0.032) at follow-up, adjusted for baseline values, than did carriers. We found no evidence of SNP genotype association with endothelial function (brachial artery diameter and flow-mediated dilatation), arterial stiffness (carotid-femoral pulse wave velocity and digital volume pulse), and resting heart rate. A high intake of EPA and DHA could help protect noncarriers but not carriers of the risk allele. Dietary recommendations to reduce blood pressure in the general population may not necessarily benefit those most at risk. This trial was registered at controlled-trials.com as ISRCTN66664610. PMID- 24401816 TI - Higher urinary lignan concentrations in women but not men are positively associated with shorter time to pregnancy. AB - Phytoestrogens have been associated with subtle hormonal changes, although effects on fecundity are unknown. Our objective was to evaluate the association between male and female urinary phytoestrogen (isoflavone and lignan) concentrations and time to pregnancy (TTP) in a population-based cohort of 501 couples desiring pregnancy and discontinuing contraception. Couples were followed for 12 mo or until pregnancy. Fecundability ORs (FORs) and 95% CIs were estimated after adjusting for age, body mass index, race, site, creatinine, supplement use, and physical activity in relation to female, male, and joint couple concentrations. Models included the phytoestrogen of interest and the sum of the remaining individual phytoestrogens. FORs <1 denote a longer TTP and FORs >1 a shorter TTP. Urinary lignan concentrations were higher, on average, among female partners of couples who became pregnant during the study compared with women who did not become pregnant (median enterodiol: 118 vs. 80 nmol/L; P < 0.10; median enterolactone: 990 vs. 412 nmol/L; P < 0.05) and were associated with significantly shorter TTP in models based on both individual and couples' concentrations (couples' models: enterodiol FOR, 1.13; 95% CI: 1.02, 1.26; enterolactone FOR, 1.11; 95% CI: 1.01, 1.21). Male lignan concentrations were not associated with TTP, nor were isoflavone concentrations. Sensitivity analyses showed that associations observed are unlikely to be explained by potential unmeasured confounding by lifestyle or other nutrients. Our results suggest that female urinary lignan concentrations at levels characteristic of the U.S. population are associated with a shorter TTP among couples who are attempting to conceive, highlighting the importance of dietary influences on fecundity. PMID- 24401817 TI - Dietary fat and fatty acid profile are associated with indices of skeletal muscle mass in women aged 18-79 years. AB - Age-related loss of skeletal muscle mass results in a reduction in metabolically active tissue and has been related to the onset of obesity and sarcopenia. Although the causes of muscle loss are poorly understood, dietary fat has been postulated to have a role in determining protein turnover through an influence on both inflammation and insulin resistance. This study was designed to investigate the cross-sectional relation between dietary fat intake, as dietary percentage of fat energy (PFE) and fatty acid profile, with indices of skeletal muscle mass in the population setting. Body composition [fat-free mass (FFM; in kg)] and the fat free mass index (FFMI; kg FFM/m(2)) was measured by using dual-energy X-ray absorptiometry in 2689 women aged 18-79 y from the TwinsUK Study and calculated according to quintile of dietary fat (by food-frequency questionnaire) after multivariate adjustment. Positive associations were found between the polyunsaturated-to-saturated fatty acid (SFA) ratio and indices of FFM, and inverse associations were found with PFE, SFAs, monounsaturated fatty acids (MUFAs), and trans fatty acids (TFAs) (all as % of energy). Extreme quintile dietary differences for PFE were -0.6 kg for FFM and -0.28 kg/m(2) for FFMI; for SFAs, MUFAs, and TFAs, these were -0.5 to -0.8 kg for FFM and -0.26 to -0.38 kg/m(2) for FFMI. These associations were of a similar magnitude to the expected decline in muscle mass that occurs over 10 y. To our knowledge, this is the first population-based study to demonstrate an association between a comprehensive range of dietary fat intake and FFM. These findings indicate that a dietary fat profile already associated with cardiovascular disease protection may also be beneficial for conservation of skeletal muscle mass. PMID- 24401818 TI - Dietary iron intake and body iron stores are associated with risk of coronary heart disease in a meta-analysis of prospective cohort studies. AB - The link between iron intake as well as body iron stores and coronary heart disease (CHD) has been contentiously debated, and the epidemiologic evidence is inconsistent. We aimed to quantitatively summarize the literature on the association between dietary iron intake/body iron stores and CHD risk by conducting a meta-analysis of prospective cohort studies. PubMed was used to find studies published through June 2013 in peer-reviewed journals. Embase or a hand search of relevant articles was used to obtain additional articles. The pooled RRs of CHD incidence and mortality with 95% CIs were calculated by using either a random-effects or fixed-effects model, as appropriate. Twenty-one eligible studies (32 cohorts) including 292,454 participants with an average of 10.2 y of follow-up were included. Heme iron was found to be positively associated with CHD incidence (RR: 1.57; 95% CI: 1.28, 1.94), whereas total iron was inversely associated (RR: 0.85; 95% CI: 0.73, 0.999). Neither heme-iron nor total iron intakes were significantly associated with CHD mortality. Both transferrin saturation and serum iron were inversely related to CHD incidence [RR (95% CI): 0.76 (0.66, 0.88) and 0.68 (0.56, 0.82), respectively], but only transferrin saturation was inversely associated with CHD mortality (RR: 0.85; 95% CI: 0.73, 0.99). In conclusion, total iron intake and serum iron concentrations were inversely associated with CHD incidence, but heme iron intake was positively related to CHD incidence. Elevated serum transferrin saturation concentration was inversely associated with both CHD incidence and mortality. Future research is needed to establish the causal relation and to elucidate potential mechanisms. PMID- 24401821 TI - Water molecule-driven reversible single-crystal to single-crystal transformation of a multi-metallic coordination polymer with controllable metal ion movement. AB - A single-crystal to single-crystal (SC-SC) transformation process driven by water molecules has been exhibited by a multi-metallic coordination polymer. The in situ heating single crystal X-ray diffraction technique was applied to study the control of metal ion movement in the reversible SC-SC transformation process. PMID- 24401819 TI - Mixed matrix membranes: a new asset for blood purification therapies. PMID- 24401822 TI - A Combined Fabrication and Instrumentation Platform for Sample Preparation. AB - While potentially powerful, access to molecular diagnostics is substantially limited in the developing world. Here we present an approach to reduced cost molecular diagnostic instrumentation that has the potential to empower developing world communities by reducing costs through streamlining the sample preparation process. In addition, this instrument is capable of producing its own consumable devices on demand, reducing reliance on assay suppliers. Furthermore, this instrument is designed with an "open" architecture, allowing users to visually observe the assay process and make modifications as necessary (as opposed to traditional "black box" systems). This open environment enables integration of microfluidic fabrication and viral RNA purification onto an easy-to-use modular system via the use of interchangeable trays. Here we employ this system to develop a protocol to fabricate microfluidic devices and then use these devices to isolate viral RNA from serum for the measurement of human immunodeficiency virus (HIV) viral load. Results obtained from this method show significantly reduced error compared with similar nonautomated sample preparation processes. PMID- 24401823 TI - Stroke and unsteadiness - a cross-sectional study from primary health care. AB - BACKGROUND: Dizziness is seldom the only symptom among patients who develop stroke but patients, hospitalized for vertigo are at higher risk of stroke than the general population. The proportions of patients who have remaining dizziness after a stroke seem to be unclear. OBJECTIVES: To study the frequency of dizziness among stroke patients referred to rehabilitation in primary health care and to study the relation between dizziness and gender, age, activity and self rated health. METHODS: Patients with first-time stroke who were referred to rehabilitation in primary health care after the initial hospital stay were included. Dependence/independence in daily activities and self-rated health was measured. A question about whether the patient had experienced any dizziness or unsteadiness was asked. RESULTS: Sixty three patients were included in the study, (39 men, 24 women) aged 36-85 years. The majority of patients were dizzy (70%). Being female increased the risk of being dizzy substantially (OR 9.43). Patients with dizziness had poorer self-rated health than patients without dizziness (p = 0.001). CONCLUSION: Dizziness is a common symptom among patients with stroke, especially among female patients, and is associated with lower self-rated health. Therefore, it is important to address dizziness in the rehabilitation of stroke patients. PMID- 24401824 TI - Cardiac autonomic status is associated with spasticity in post-stroke patients. AB - BACKGROUND: Whether post-stroke spasticity is associated with autonomic status is unclear. The purpose of our study was to determine whether spasticity in post stroke patients is associated with heart rate variability (HRV), an indicator of sympathetic and parasympathetic regulation. OBJECTIVE: To determine whether HRV is associated with spasticity in post-stroke patients. METHODS: Our cross sectional observational study included 21 post-stroke patients with varying degrees of knee spasticity. We measured patients' heart rate variability (HRV) during the morning and afternoon of the same day using the modified Ashworth assessment and the pendulum test. The relationship between HRV and the spasticity parameters was evaluated based on the Pearson correlation coefficient (r). RESULTS: The data for the morning measurements showed that the relaxation index negatively correlated with the high frequency (HF) power of HRV (r = -0.47, P < 0.05), and positively correlated with the low frequency (LF) power of HRV (r = 0.47, P < 0.05) and the LF/HF power ratio (r = 0.55, P < 0.05). Similar correlations were observed between the diurnal differences of HRV and the relaxation index. No correlation was observed among the data for the afternoon measurements. CONCLUSIONS: Higher parasympathetic tone and lower sympathetic tone are associated with a higher degree of knee spasticity in post-stroke patients. Further studies are warranted to confirm our findings and investigate the pathological mechanisms involved. PMID- 24401825 TI - MS related employment and disease modifying treatment in the German working population: 1994-2009. AB - BACKGROUND: Relapses in MS may affect the acquisition and maintenance of employment due to associated neurological deficits. Several disease modifying drugs (DMD) like interferons or glatiramer reduce the frequency of relapses and decrease their severity in MS. OBJECTIVE: To investigate the influence of DMD on employment prevalence and employment rate with relapsing remitting Multiple Sclerosis (RR-MS) in the German working population from 1994 to 2009. METHODS: Database assessment of working patients with MS and German labour market statistic database. RESULTS: Four DMD have been introduced in Germany for the treatment of RR-MS during the observation time: Interferon beta-1b (Betaferon) was approved 1996 whereas interferon beta-1a has been available in intramuscular formulation since 1997 (Avonex) and subcutaneous formulation since 1998 (Rebif). The non-interferon glatiramer (Copaxone) was introduced in 2001. Both general employment and employment with MS have increased during this period. The employment increase with RR-MS was higher than in general population only after the availability of all four DMD during the time period 2002-2009 (p = 0.008). The overall mean employment prevalence of RR-MS subjects was 0.82 +/- 0.03 among 1,000 workers. The annual prescription volume of all DMD rose every year since their introduction until the end of our observation of about 10% annually. Employment increases among RR-MS patients highly correlated with the time frame of DMD availability (correlation rate 0.88, p < 0.0001). The employment rate with DMD was higher than without treatment (p < 0.0001). CONCLUSION: The introduction of DMD may have positively influenced the employment with MS. PMID- 24401826 TI - Frequency of domain-specific cognitive impairment in sub-acute and chronic stroke. AB - BACKGROUND: Functional contributions of cognitive impairment may vary by domain and severity. OBJECTIVE: (1) To characterize frequency of cognitive impairment by domain after stroke by severity (mild: -1.5 <= z-score < -2; severe: Z <= -2) and time (sub-acute: < 90d; chronic: 90d-2yrs); and (2) To assess the association of cognitive impairment with function in chronic stroke. METHODS: Cognitive function was characterized among 215 people with sub-acute or chronic stroke (66.8 years, 43.3% female). Z-scores by cognitive domain were determined from normative data. Function was defined as the number of IADLs minimally independent. RESULTS: 76.3% of sub-acute and 67.3% of chronic stroke participants had cognitive impairment in >= 1 domain (p-for-difference = 0.09). Severe impairment was most common in psychomotor speed (sub-acute: 53.5%; chronic: 33.7%). Impairment in executive function was common (sub-acute: 39.5%; chronic: 30.7%) but was usually mild. Severe impairment in psychomotor speed, visuospatial function, and language and any impairment in executive function and memory was associated with IADL impairment (p < 0.03). CONCLUSIONS: Mild cognitive impairment is common after stroke but is not associated with functional disability. Impairment in psychomotor speed, executive function, and visuospatial function is common and associated with functional impairment so should be a focus of screening and rehabilitation post-stroke. PMID- 24401827 TI - Adult functioning of mothers with traumatic brain injury at high risk of child abuse: a pilot study. AB - BACKGROUND: There is little information regarding the impact that traumatic brain injury (TBI) has on the functioning of mothers at risk of child abuse. OBJECTIVE: This study evaluated adult functioning (e.g. child abuse, substance use, criminal convictions, and mental health problems) of mothers, at high risk for child abuse, who also had a history of TBI compared with those without TBI. It was hypothesised that mothers with a history of TBI would engage in higher rates of dysfunctional behaviour compared to those with no history of TBI. METHOD: Participants were 206 women engaged in a child abuse prevention programme for mothers who are highly socially disadvantaged, and at high risk for child abuse. Using historical data collected as part of the referral, and self report intake process, this study compared child abuse, mental health problems (depression, anxiety, substance use) and rates of criminal offending for mothers with a history of TBI versus those with no history of TBI. RESULTS: Mothers with TBI were no more likely than those without TBI to have engaged in child abuse. However, mothers with a history of TBI were significantly more likely to have one or more mental health problems, engage in substance use and have a history of criminal offending. CONCLUSIONS: Parents with TBI who have been identified as high risk for engaging in child abuse have increased risk for mental health problems and criminal offending. These issues need to be considered when designing parenting programmes in order for intervention strategies to be effective. PMID- 24401828 TI - Evaluation of intrarater and interrater reliability of the Wisconsin Gait Scale with using the video taped stroke patients in a Turkish sample. AB - OBJECTIVE: To establish the intrarater and interrater reliability of Wisconsin Gait Scale (WGS) in hemiplegic patients. DESIGN: Repeated-measures reliability study using video data of stroke patients. SETTING: Rehabilitation department of the university hospital. PARTICIPITANTS: Nineteen hemiplegic patients with 3-9 months stroke history and two physiatrists and two physical therapists. INTERVENTIONS: Video recordings were assessed twice, at an interval of 2 days, by the two physiatrists and two physical therapists. MAIN OUTCOME MEASURE: Wisconsin Gait Scale. RESULTS: Internal consistency coefficients for the WGS were excellent; Cronbach scores were 0.91 and 0.94 for the first and third days. Coefficient of Repeatability (CR) for observers' WGS assessments were ranged between 4.23-5.76 and intraclass correlation coefficients for total WGS score were indicated very high interrater reliability at the begining and end, respectively 0.91 and 0.96. Intraclass correlation coefficients for fourteen items of WGS ranged from 0.81 to 1. "Hip hiking at mid-swing", "Circumduction at mid-swing" and "Hip extension of the affected leg" were the items with lowest correlation coefficients. Intrarater reliability for total WGS scores ranged from 0.75 to 0.90. CONCLUSION: WGS was found excellent in reliability and may provide an objective means to document the findings from observational gait analysis, which is frequently used in clinical practice by rehabilitation teams. PMID- 24401829 TI - Effect of real-time cortical feedback in motor imagery-based mental practice training. AB - BACKGROUND: Mental practice using motor imagery of limb movement may facilitate motor recovery in persons who have experienced cerebrovascular accident (CVA). However, the lack of a feedback mechanism that can monitor the quality of the motor imagery affects patients' engagement and motivation to participate in the mental practice training program. OBJECTIVE: This study investigates the effect of novel real-time motor imagery-associated cortical activity feedback on motor imagery-based mental practice training. METHODS: Ten healthy volunteers were randomly assigned into intervention and control groups. Both groups participated in a five-visit motor imagery-based mental practice training program managed over a period of two months. The intervention group received mental practice training with real-time feedback of movement-associated cortical activity-beta band (16-28 Hz) event-related desynchronization (ERD) in electroencephalography (EEG), using a novel custom-made brain-computer interface (BCI) system. The control group received the mental practice training program without EEG cortical feedback. Motor excitability was assessed by measuring the frequency power magnitude of the EEG rhythmic activity associated with physical execution of wrist extension before and after the motor imagery-based mental practice training. RESULTS: The EEG frequency power magnitude associated with the physical execution of wrist extension was significantly lower (i.e. more desynchronized) after the mental practice training in the intervention group that received real-time cortical feedback (P < 0.05), whereas no significant difference in EEG frequency power magnitude associated with the physical execution of wrist extension was observed before and after mental practice training in the control group who did not receive feedback. CONCLUSIONS: The mental practice training program with motor imagery-associated cortical feedback facilitated motor excitability during the production of voluntary motor control. Motor imagery-based mental practice training with movement-associated cortical activity feedback may provide an effective strategy to facilitate motor recovery in brain injury patients, particularly during the early rehabilitation stage when full participation in physical and occupational therapy programs may not be possible due to excessive motor weakness. PMID- 24401830 TI - Motor imagery group practice for gait rehabilitation in individuals with post stroke hemiparesis: a pilot study. AB - BACKGROUND: Stroke is the leading cause of adult disability, with walking impairment being a devastating indicator of chronic post-stroke hemiparesis. Limited resources exist for individual treatments; therefore, the delivery of safe group exercise therapy is highly desired. OBJECTIVE: To examine whether the application of group-based motor imagery practice to community-dwelling individuals with chronic hemiparesis improves gait. METHODS: Sixteen individuals with chronic hemiparesis from two community centers participated in the study, with eight from each center. Four participants in each center received five weeks of the experimental intervention, consisting of group-based motor imagery exercises of gait tasks, followed by five weeks of control treatment of motor imagery exercises for the affected upper extremity. Four other subjects in each center received the same treatments in reverse order. Pre- and post intervention measurements included clinical and biomechanical gait parameters. RESULTS: Comparisons within (pre- vs. post) and between treatments (experimental vs. control) indicated no significant change in any gait variable. Nevertheless, the verbal reports of most participants alluded to satisfaction with the experimental intervention and to an increase in self-confidence. CONCLUSIONS: Despite the lack of evidence for the effectiveness of group-based motor imagery practice in improving gait among individuals with chronic hemiparesis, the contrast between the measured outcomes and the positive verbal reports merits further inquiry. PMID- 24401831 TI - Does effect of rehabilitation based on sensory conflicts in patients with vestibular deficits exceed learning effect? AB - OBJECTIVE: The purpose was to assess learning and rehabilitation effect and their influence on Sensory Organization Test results in young and elderly patients with peripheral, central and mixed vestibular pathology. MATERIAL AND METHODS: 26 patients with different vestibular system deficits participated in this study. Rehabilitation was held five days a week, for two weeks. To assess learning effect, SOT was administered to each patient twice and compared: 1) on the day preceding the beginning of rehabilitation (SOT1), and 2) on the first day of rehabilitation (SOT2). To evaluate rehabilitation effect, results of SOT2 were compared to SOT3 (administered on the last day of rehabilitation). RESULTS: Learning effect showed similar improvement in CS in all groups but young. Rehabilitation caused further improvement in CS in all groups but central pathology. This improvement was similar between those groups. There was no significant difference found between learning and rehabilitation effect in CS. CONCLUSIONS: The results of our study indicate that none of the groups achieved significant benefit from rehabilitation based on sensory conflicts that would overcome the learning effect. However, the lack of significant advantage of rehabilitation over learning does not mean that it does not exist. PMID- 24401832 TI - A comparison of hemisphere-specific training pattern in Inter-limb Learning Transfer (ILT) for stroke patients with hemiparesis. AB - BACKGROUND: Stroke patients have major problems with impaired upper-extremity function. Unfortunately, many patients do not experience a full recovery from movement deficits in the upper extremities. OBJECTIVES: The purpose of this study was to compare the effectiveness of inter-limb learning transfer (ILT) to the contralateral upper limb after both hemisphere-specific and -unspecific ipsilateral upper limb training for stroke patients with hemiparesis. METHODS: Twenty-four stroke patients with hemiparesis participated. The hemisphere specific training group performed reaching movements in a customized training setting in which non-dominant limb training participants began from a single starting location and proceeded to one of three target locations (1S3T condition); the dominant limb training participants started from one of three starting locations and proceeded to a single target location (3S1T condition). The hemisphere-unspecific training group performed these movements starting under reverse-start and target conditions. RESULTS: The non-dominant to dominant limb transfer, the hemisphere-specific training group performance time decreased significantly as compared with the pre-training session (p < 0.05). Also, the isolation contraction ratio was decreased significantly from that of the pre training session in the biceps brachii muscles and increased significantly in the upper trapezius muscles (p < 0.05). And, dominant to non-dominant limb transfer in the hemisphere-specific training group significantly increased RMS amplitudes from the pre-training session in the biceps brachii and triceps muscles (p < 0.05). Also, the isolation contraction ratio was increased significantly from that of the pre-training session in the biceps brachii muscles and decreased significantly in the upper trapezius muscles (p < 0.05). However, the hemisphere unspecific training group showed no significant differences in inter-limb learning transfer (ILT). CONCLUSION: The transfer of hemisphere-specific training from one arm to the other had a more positive influence on functional recovery than did hemisphere-unspecific training for patients with stroke and hemiparesis. PMID- 24401833 TI - Pharmacogenomic characterization of gemcitabine response--a framework for data integration to enable personalized medicine. AB - OBJECTIVES: Response to the oncology drug gemcitabine may be variable in part due to genetic differences in the enzymes and transporters responsible for its metabolism and disposition. The aim of our in-silico study was to identify gene variants significantly associated with gemcitabine response that may help to personalize treatment in the clinic. METHODS: We analyzed two independent data sets: (a) genotype data from NCI-60 cell lines using the Affymetrix DMET 1.0 platform combined with gemcitabine cytotoxicity data in those cell lines, and (b) genome-wide association studies (GWAS) data from 351 pancreatic cancer patients treated on an NCI-sponsored phase III clinical trial. We also performed a subset analysis on the GWAS data set for 135 patients who were given gemcitabine+placebo. Statistical and systems biology analyses were performed on each individual data set to identify biomarkers significantly associated with gemcitabine response. RESULTS: Genetic variants in the ABC transporters (ABCC1, ABCC4) and the CYP4 family members CYP4F8 and CYP4F12, CHST3, and PPARD were found to be significant in both the NCI-60 and GWAS data sets. We report significant association between drug response and variants within members of the chondroitin sulfotransferase family (CHST) whose role in gemcitabine response is yet to be delineated. CONCLUSION: Biomarkers identified in this integrative analysis may contribute insights into gemcitabine response variability. As genotype data become more readily available, similar studies can be conducted to gain insights into drug response mechanisms and to facilitate clinical trial design and regulatory reviews. PMID- 24401834 TI - PharmGKB summary: ifosfamide pathways, pharmacokinetics and pharmacodynamics. PMID- 24401835 TI - Interference with PD-L1/PD-1 co-stimulation during antigen presentation enhances the multifunctionality of antigen-specific T cells. AB - The release of cytokines by T cells strongly defines their functional activity in vivo. The ability to produce multiple cytokines has been associated with beneficial immune responses in cancer and infectious diseases, while their progressive loss is associated with T-cell exhaustion, senescence and anergy. Consequently, strategies that enhance the multifunctional status of T cells are a key for immunotherapy. Dendritic cells (DCs) are professional antigen presenting cells that regulate T-cell functions by providing positive and negative co stimulatory signals. A key negative regulator of T-cell activity is provided by binding of programmed death-1 (PD-1) receptor on activated T cells, to its ligand PD-L1, expressed on DCs. We investigated the impact of interfering with PD-L1/PD 1 co-stimulation on the multifunctionality of T cells, by expression of the soluble extracellular part of PD-1 (sPD-1) or PD-L1 (sPD-L1) in human monocyte derived DCs during antigen presentation. Expression, secretion and binding of these soluble molecules after mRNA electroporation were demonstrated. Modification of DCs with sPD-1 or sPD-L1 mRNA resulted in increased levels of the co-stimulatory molecule CD80 and a distinct cytokine profile, characterized by the secretion of IL-10 and TNF-alpha, respectively. Co-expression in DCs of sPD-1 and sPD-L1 with influenza virus nuclear protein 1 (Flu NP1) stimulated Flu NP1 memory T cells, with a significantly higher number of multifunctional T cells and increased cytokine secretion, while it did not induce regulatory T cells. These data provide a rationale for the inclusion of interfering sPD-1 or sPD-L1 in DC based immunotherapeutic strategies. PMID- 24401836 TI - Injection parameters and virus dependent choice of promoters to improve neuron targeting in the nonhuman primate brain. AB - We, like many others, wish to use modern molecular methods to alter neuronal functionality in primates. For us, this requires expression in a large proportion of the targeted cell population. Long generation times make germline modification of limited use. The size and intricate primate brain anatomy poses additional challenges. We surved methods using lentiviruses and serotypes of adeno associated viruses (AAVs) to introduce active molecular material into cortical and subcortical regions of old-world monkey brains. Slow injections of AAV2 give well-defined expression of neurons in the cortex surrounding the injection site. Somewhat surprisingly we find that in the monkey the use of cytomegalovirus promoter in lentivirus primarily targets glial cells but few neurons. In contrast, with a synapsin promoter fragment the lentivirus expression is neuron specific at high transduction levels in all cortical layers. We also achieve specific targeting of tyrosine hydroxlase (TH)- rich neurons in the locus coeruleus and substantia nigra with a lentvirus carrying a fragment of the TH promoter. Lentiviruses carrying neuron specific promoters are suitable for both cortical and subcortical injections even when injected quickly. PMID- 24401837 TI - Tuberculosis drug discovery in the post-post-genomic era. AB - The expectation that genomics would result in new therapeutic interventions for infectious diseases remains unfulfilled. In the post-genomic era, the decade immediately following the availability of the genome sequence of Mycobacterium tuberculosis, tuberculosis (TB) drug discovery relied heavily on the target-based approach but this proved unsuccessful leading to a return to whole cell screening. Genomics underpinned screening by providing knowledge and many enabling technologies, most importantly whole genome resequencing to find resistance mutations and targets, and this resulted in a selection of leads and new TB drug candidates that are reviewed here. Unexpectedly, many new targets were found to be 'promiscuous' as they were inhibited by a variety of different compounds. In the post-post-genomics era, more advanced technologies have been implemented and these include high-content screening, screening for inhibitors of latency, the use of conditional knock-down mutants for validated targets and siRNA screens. In addition, immunomodulation and pharmacological manipulation of host functions are being explored in an attempt to widen our therapeutic options. PMID- 24401840 TI - Prevalence of CD44-positive glomerular parietal epithelial cells reflects podocyte injury in adriamycin nephropathy. AB - BACKGROUND/AIMS: Recent study suggests that activation of parietal epithelial cells (PECs) contributes to pathogenesis of glomerulosclerosis and the activation marker CD44 increases in evolving glomerulosclerosis. Here we examined the pathogenic roles of CD44+ epithelial cells in mouse adriamycin nephropathy (ADRN), a representative rodent model for idiopathic focal segmental glomerulosclerosis (FSGS). We also evaluated whether the prevalence of CD44+ PECs reflects different levels of podocyte injuries. METHODS: As a model of FSGS with different degrees of podocyte injury, ADRN models in mice of different ages were utilized. Immunohistochemistry and immunofluorescence were used to determine roles of CD44 expression. RESULTS: By immunohistochemistry, CD44 expression became positive in claudin-1+ PECs and an increase in CD44+ PECs was associated with reduced expression of synaptopodin and podocin in diseased glomeruli. Furthermore, immunofluorescence staining demonstrated co-expression with osteopontin, a CD44 ligand that plays a significant role in the progression of glomerulosclerosis, thereby suggesting interactions between these molecules. Analysis of the number of WT-1+ podocytes and the levels of electron microscopic foot process effacement revealed a milder degree of podocyte injury in younger ADRN models compared to older ones. Comparative immunohistochemical analysis indicated that the prevalence of CD44+ PECs consistently reflects different degrees of podocyte injury within each different-aged ADRN model. CONCLUSION: CD44+ PECs play significant roles in progressive glomerulosclerosis and the prevalence of the cells reflects different degrees of podocyte injury in ADRN. PMID- 24401838 TI - Rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells. AB - Human cancers modeled in Genetically Engineered Mouse Models (GEMMs) can provide important mechanistic insights into the molecular basis of tumor development and enable testing of new intervention strategies. The inherent complexity of these models, with often multiple modified tumor suppressor genes and oncogenes, has hampered their use as preclinical models for validating cancer genes and drug targets. In our newly developed approach for the fast generation of tumor cohorts we have overcome this obstacle, as exemplified for three GEMMs; two lung cancer models and one mesothelioma model. Three elements are central for this system; (i) The efficient derivation of authentic Embryonic Stem Cells (ESCs) from established GEMMs, (ii) the routine introduction of transgenes of choice in these GEMM-ESCs by Flp recombinase-mediated integration and (iii) the direct use of the chimeric animals in tumor cohorts. By applying stringent quality controls, the GEMM-ESC approach proofs to be a reliable and effective method to speed up cancer gene assessment and target validation. As proof-of-principle, we demonstrate that MycL1 is a key driver gene in Small Cell Lung Cancer. PMID- 24401839 TI - Telomerase governs immunomodulatory properties of mesenchymal stem cells by regulating FAS ligand expression. AB - Bone marrow mesenchymal stem cells (BMMSCs) are capable of differentiating into multiple cell types and regulating immune cell response. However, the mechanisms that govern the immunomodulatory properties of BMMSCs are still not fully elucidated. Here we show that telomerase-deficient BMMSCs lose their capacity to inhibit T cells and ameliorate the disease phenotype in systemic sclerosis mice. Restoration of telomerase activity by telomerase reverse transcriptase (TERT) transfection in TERT(-/-) BMMSCs rescues their immunomodulatory functions. Mechanistically, we reveal that TERT, combined with beta-catenin and BRG1, serves as a transcriptional complex, which binds the FAS ligand (FASL) promoter to upregulate FASL expression, leading to an elevated immunomodulatory function. To test the translational value of these findings in the context of potential clinical therapy, we used aspirin treatment to upregulate telomerase activity in BMMSCs, and found a significant improvement in the immunomodulatory capacity of BMMSCs. Taken together, these findings identify a previously unrecognized role of TERT in improving the immunomodulatory capacity of BMMSCs, suggesting that aspirin treatment is a practical approach to significantly reduce cell dosage in BMMSC-based immunotherapies. PMID- 24401841 TI - Evidence for spin selectivity of triplet pairs in superconducting spin valves. AB - Spin selectivity in a ferromagnet results from a difference in the density of up- and down-spin electrons at the Fermi energy as a consequence of which the scattering rates depend on the spin orientation of the electrons. This property is utilized in spintronics to control the flow of electrons by ferromagnets in a ferromagnet (F1)/normal metal (N)/ferromagnet (F2) spin valve, where F1 acts as the polarizer and F2 the analyser. The feasibility of superconducting spintronics depends on the spin sensitivity of ferromagnets to the spin of the equal spin triplet Cooper pairs, which arise in superconductor (S)-ferromagnet (F) heterostructures with magnetic inhomogeneity at the S-F interface. Here we report a critical temperature dependence on magnetic configuration in current-in-plane F S-F spin valves with a holmium spin mixer at the S-F interface providing evidence of a spin selectivity of the ferromagnets to the spin of the triplet Cooper pairs. PMID- 24401842 TI - Detection and follow-up, after partial liver resection, of the urinary paracetamol metabolites by proton NMR spectroscopy. AB - BACKGROUND: Combination drug therapy is often used to achieve optimal analgesia in surgery. Paracetamol can be used as one component of an analgesic regime following hepatic resection. OBJECTIVE: This study was designed to investigate paracetamol and its metabolites by proton NMR spectroscopy in patient urine and to assess whether N-acetyl-p-benzoquinone imine (NAPQI, a hepatotoxic metabolite) formation is increased after liver resection. METHOD: We studied the excretion of acetaminophen and its metabolites by 5 patients who were operated on for partial liver resection by proton NMR spectroscopy. As an intravenous infusion 1 g of paracetamol was given over 15 min every 6 h during 48 h. The first injection was given in the operating theatre after liver resection was completed. Urine samples were collected before injection (T1) and 24 and 48 h after the first injection (T2 and T3); the samples were frozen and kept at -20 degrees C up to the analysis by NMR spectroscopy. RESULTS: Metabolites of the paracetamol were detected for all patients. Among the discerned metabolites, 4 were identified as metabolites of paracetamol: paracetamol glucuronide, paracetamol sulfate, N-acetyl-L cysteinyl paracetamol (metabolite of NAPQI) and paracetamol. Their ratios, respectively, were: 46-82.9, 12.6-30.0, 0.5-5.5 and 1.43-3.54%. CONCLUSION: This study showed that there was no increase in the formation of toxic metabolite (NAPQI) after treatment with paracetamol in these few cases of liver resections. A larger study is necessary to confirm these results. PMID- 24401843 TI - A top-down approach to prepare silicoaluminophosphate molecular sieve nanocrystals with improved catalytic activity. AB - Silicoaluminophosphate SAPO-34 molecular sieve nanocrystals have been prepared by a post-synthesis milling and recrystallization method, which is further proven to be universally applicable to other SAPO molecular sieves. The obtained SAPO-34 with reduced Si enrichment on the external surface shows considerably improved catalytic performance in the MTO reaction. PMID- 24401844 TI - pH-responsive single-chain polymer nanoparticles utilising dynamic covalent enamine bonds. AB - Structurally dynamic single-chain polymer nanoparticles that can reversibly undergo a coil to particle transition via formation and cleavage of intramolecular dynamic enamine cross-links are reported. PMID- 24401845 TI - Proteomic mapping of proteins released during necrosis and apoptosis from cultured neonatal cardiac myocytes. AB - Cardiac injury induces myocyte apoptosis and necrosis, resulting in the secretion and/or release of intracellular proteins. Currently, myocardial injury can be detected by analysis of a limited number of biomarkers in blood or coronary artery perfusate. However, the complete proteomic signature of protein release from necrotic cardiac myocytes is unknown. Therefore, we undertook a proteomic based study of proteins released from cultured neonatal rat cardiac myocytes in response to H2O2 (necrosis) or staurosporine (apoptosis) to identify novel specific markers of cardiac myocyte cell death. Necrosis and apoptosis resulted in the identification of 147 and 79 proteins, respectively. Necrosis resulted in a relative increase in the amount of many proteins including the classical necrotic markers lactate dehydrogenase (LDH), high-mobility group B1 (HMGB1), myoglobin, enolase, and 14-3-3 proteins. Additionally, we identified several novel markers of necrosis including HSP90, alpha-actinin, and Trim72, many of which were elevated over control levels earlier than classical markers of necrotic injury. In contrast, the majority of identified proteins remained at low levels during apoptotic cell death, resulting in no candidate markers for apoptosis being identified. Blotting for a selection of these proteins confirmed their release during necrosis but not apoptosis. We were able to confirm the presence of classical necrotic markers in the extracellular milieu of necrotic myocytes. We also were able to identify novel markers of necrotic cell death with relatively early release profiles compared with classical protein markers of necrosis. These results have implications for the discovery of novel biomarkers of necrotic myocyte injury, especially in the context of ischemia-reperfusion injury. PMID- 24401846 TI - Direct evidence of intracrine angiotensin II signaling in neurons. AB - The existence of a local renin-angiotensin system (RAS) in neurons was first postulated 40 years ago. Further studies indicated intraneuronal generation of ANG II. However, the function and signaling mechanisms of intraneuronal ANG II remained elusive. Since ANG II type 1 receptor (AT1R) is the major type of receptor mediating the effects of ANG II, we used intracellular microinjection and concurrent Ca(2+) and voltage imaging to examine the functionality of intracellular AT1R in neurons. We show that intracellular administration of ANG II produces a dose-dependent elevation of cytosolic Ca(2+) concentration ([Ca(2+)]i) in hypothalamic neurons that is sensitive to AT1R antagonism. Endolysosomal, but not Golgi apparatus, disruption prevents the effect of microinjected ANG II on [Ca(2+)]i. Additionally, the ANG II-induced Ca(2+) response is dependent on microautophagy and sensitive to inhibition of PLC or antagonism of inositol 1,4,5-trisphosphate receptors. Furthermore, intracellular application of ANG II produces AT1R-mediated depolarization of hypothalamic neurons, which is dependent on [Ca(2+)]i increase and on cation influx via transient receptor potential canonical channels. In summary, we provide evidence that intracellular ANG II activates endolysosomal AT1Rs in hypothalamic neurons. Our results point to the functionality of a novel intraneuronal angiotensinergic pathway, extending the current understanding of intracrine ANG II signaling. PMID- 24401848 TI - WLIP derived from Lasiosphaera fenzlii Reich exhibits anti-tumor activity and induces cell cycle arrest through PPAR-gamma associated pathways. AB - White-line-inducing principle (WLIP), a lipodepsipeptide isolated from Lasiosphaera fenzlii Reich., which is one of the puffballs, for the first time, has been reported to exhibit anti-microbial activity. However, there are no reports regarding the anti-tumor effects of WLIP. In this study, we reported the anti-cancer effects of WLIP on K562 cells, and its potential effect on the PPAR gamma activation pathway. The obtained results showed that WLIP exerted strong anti-proliferative effect on K562 cells. Moreover, WLIP was found to increase apoptosis and induce G0/Gl arrest. Modeling results from the Surflex-Dock program suggested that PPAR-gamma might be the potential anti-tumor target of WLIP, which was confirmed by the experiments that WLIP increased the activity in luciferase reporter assay and the expression of PPAR-gamma in Western blot. Besides, WLIP was able to down-regulate the expression of Bcl-xL, Cyclin-D1 in K562 cells. In summary, our novel observations suggested that WLIP might have a potential implication in cancer prevention and treatment, and also showed for the first time that the anti-tumor effect of WLIP might be mediated through modulation of the PPAR-gamma activation pathway. PMID- 24401847 TI - Protein kinase G increases antioxidant function in lung microvascular endothelial cells by inhibiting the c-Abl tyrosine kinase. AB - Oxidant injury contributes to acute lung injury (ALI). We previously reported that activation of protein kinase GI (PKGI) posttranscriptionally increased the key antioxidant enzymes catalase and glutathione peroxidase 1 (Gpx-1) and attenuated oxidant-induced cytotoxicity in mouse lung microvascular endothelial cells (MLMVEC). The present studies tested the hypothesis that the antioxidant effect of PKGI is mediated via inhibition of the c-Abl tyrosine kinase. We found that activation of PKGI with the cGMP analog 8pCPT-cGMP inhibited c-Abl activity and decreased c-Abl expression in wild-type but not PKGI(-/-) MLMVEC. Treatment of wild-type MLMVEC with atrial natriuretic peptide also inhibited c-Abl activation. Moreover, treatment of MLMVEC with the c-Abl inhibitor imatinib increased catalase and GPx-1 protein in a posttranscriptional fashion. In imatinib-treated MLMVEC, there was no additional effect of 8pCPT-cGMP on catalase or GPx-1. The imatinib-induced increase in antioxidant proteins was associated with an increase in extracellular H2O2 scavenging by MLMVEC, attenuation of oxidant-induced endothelial barrier dysfunction, and prevention of oxidant induced endothelial cell death. Finally, in the isolated perfused lung, imatinib prevented oxidant-induced endothelial toxicity. We conclude that cGMP, through activation of PKGI, inhibits c-Abl, leading to increased key antioxidant enzymes and resistance to lung endothelial oxidant injury. Inhibition of c-Abl by active PKGI may be the downstream mechanism underlying PKGI-mediated antioxidant signaling. Tyrosine kinase inhibitors may represent a novel therapeutic approach in oxidant-induced ALI. PMID- 24401849 TI - Surgical statistics: let's act fast and grasp the opportunity. PMID- 24401850 TI - Reply to letter: "Prehospital intravenous fluid administration is associated with higher mortality in trauma patients: a National Trauma Data Bank analysis". PMID- 24401851 TI - Degradation behavior of Mg-based biomaterials containing different long-period stacking ordered phases. AB - Long-period stacking ordered (LPSO) phases play an essential role in the development of magnesium alloys because they have a direct effect on mechanical and corrosion properties of the alloys. The LPSO structures are mostly divided to 18R and 14H. However, to date there are no consistent opinions about their degradation properties although both of them can improve mechanical properties. Herein we have successfully obtained two LPSO phases separately in the same Mg-Dy Zn system and comparatively investigated the effect of different LPSO phases on degradation behavior in 0.9 wt.% NaCl solution. Our results demonstrate that a fine metastable 14H-LPSO phase in grain interior is more effective to improve corrosion resistance due to the presence of a homogeneous oxidation film and rapid film remediation ability. The outstanding corrosion resistant Mg-Dy-Zn based alloys with a metastable 14H-LPSO phase, coupled with low toxicity of alloying elements, are highly desirable in the design of novel Mg-based biomaterials, opening up a new avenue in the area of bio-Mg. PMID- 24401852 TI - The reliability and validity of patient-reported chronic obstructive pulmonary disease exacerbations. AB - PURPOSE OF REVIEW: Despite the increasing awareness of their pathogenesis and clinical consequences, research on and clinical management of acute exacerbations of chronic obstructive lung disease (AECOPDs) have been hindered by the lack of a consistent and reliable definition. Symptom-based definitions of exacerbations are sensitive to events and account for unreported exacerbations. Event (healthcare utilization)-based definitions are somewhat more definitive but miss unreported events. Objective quantification of symptoms in AECOPD is now possible with the development of the Exacerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT-PRO), a patient-reported outcome (PRO) measure. RECENT FINDINGS: Several studies have revealed that unreported AECOPDs are more frequent than reported events and are associated with long-term adverse consequences. New antibiotic development for AECOPD has been hampered by the lack of validated measures for resolution of exacerbations. As a result of these observations, a unique collaborative effort between academia, industry and regulatory agencies resulted in the development of the EXACT-PRO. It consists of 14 questions that generate a score between 0 and 100, and it has been shown to have excellent reliability and validity. SUMMARY: In the absence of a reliable biomarker, the definition and measurement of exacerbations has been subjective and imprecise. PRO measures such as EXACT can provide much needed objectivity in assessing symptom-defined exacerbations, which may translate into a uniform outcome measure in clinical trials. With further development and validation, it may have a role in clinical practice in the earlier detection of exacerbations, stratification of an exacerbation severity and the assessment of clinical response to treatment. PMID- 24401853 TI - Electronic cigarettes: the good, the bad and the unknown. PMID- 24401854 TI - Is renal dysfunction associated with adverse stroke outcome after thrombolytic therapy? AB - BACKGROUND: Renal dysfunction is a prevalent comorbidity in acute stroke patients requiring thrombolytic therapy. Reports studying the relationship between renal dysfunction and risk of postthrombolytic symptomatic intracerebral hemorrhage (SICH) are contradictory. We aimed to compare the safety and effectiveness of thrombolytic therapy in acute stroke patients with and without renal dysfunction. METHODS: Based on the prospective stroke registries of 4 hospitals in Taiwan from 2007-2012, we identified acute stroke patients who received thrombolytic therapy. Clinically significant renal dysfunction was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2). Renal dysfunction was further defined as stage 3 (30 <= eGFR < 60 ml/min/ 1.73 m(2)), stage 4 (15 <= eGFR < 30 ml/min/1.73 m(2)) and stage 5 (<15 ml/min/1.73 m(2)). The rates of SICH and poor outcome (defined as modified Rankin scale score >=4) at 3 months after thrombolytic therapy were compared in patients with and without renal dysfunction. SICH was determined according to the definition of the National Institute of Neurological Disorders and Stroke. Multivariable logistic regression was used to determine the effect of renal dysfunction on outcome. Patients with different stages of renal dysfunction were further analyzed to determine the effect of disease severity on outcome. RESULTS: Of the 657 stroke patients with thrombolysis, 239 (36%) had renal dysfunction, including 212 patients in stage 3, 17 patients in stage 4 and 10 patients in stage 5 of renal dysfunction. Patients with renal dysfunction were older and more likely to have hypertension, ischemic heart disease, congestive heart failure and prior antiplatelet use than those without. There were no differences in SICH (8 vs. 7%, p = 0.580) and poor outcome (41 vs. 39%, p = 0.758) between patients with and without renal dysfunction. After multivariable analysis, renal dysfunction was not associated with SICH (odds ratio: 1.03, 95% confidence interval: 0.55-1.92) and poor outcome. Pretreatment stroke severity was the only factor significantly associated with both SICH and poor outcome at 3 months. When stratifying renal dysfunction into stage 3 and stage >=4, there was no significant increase in SICH as the severity of renal dysfunction increased after multivariable adjustment. CONCLUSIONS: Renal dysfunction did not increase the risk of SICH and poor outcome at 3 months after stroke thrombolysis. Further study comparing directly the risk and benefit of thrombolytic therapy versus no therapy in stroke patients with renal dysfunction is warranted. PMID- 24401855 TI - Longitudinal study of murine microbiota activity and interactions with the host during acute inflammation and recovery. AB - Although alterations in gut microbiota composition during acute colitis have been repeatedly observed, associated functional changes and the recovery from dysbiosis received little attention. In this study, we investigated structure and function of the gut microbiota during acute inflammation and recovery in a dextran sodium sulfate (DSS)-colitis mouse model using metatranscriptomics, bacterial 16S rRNA gene amplicon sequencing and monitoring of selected host markers. Parallel to an increase of host markers of inflammation during acute colitis, we observed relative abundance shifts and alterations in phylotype composition of the dominant bacterial orders Clostridiales and Bacteroidales, and an increase of the low abundant Enterobacteriales, Deferribacterales, Verrucomicrobiales and Erysipelotrichales. During recovery, the microbiota began to resume, but did not reach its original composition until the end of the experiment. Microbial gene expression was more resilient to disturbance, with pre perturbation-type transcript profiles appearing quickly after acute colitis. The decrease of Clostridiales during inflammation correlated with a reduction of transcripts related to butyrate formation, suggesting a disturbance in host microbe signalling and mucosal nutrient provision. The impact of acute inflammation on the Clostridiales was also characterized by a significant downregulation of their flagellin-encoding genes. In contrast, the abundance of members of the Bacteroidales increased along with an increase in transcripts related to mucin degradation. We propose that acute inflammation triggered a selective reaction of the immune system against flagella of commensals and temporarily altered murine microbiota composition and functions relevant for the host. Despite changes in specific interactions, the host-microbiota homeostasis revealed a remarkable ability for recovery. PMID- 24401856 TI - Metabolite transfer with the fermentation product 2,3-butanediol enhances virulence by Pseudomonas aeruginosa. AB - The respiratory tract of cystic fibrosis (CF) patients harbor persistent microbial communities (CF airway microbiome) with Pseudomonas aeruginosa emerging as a dominant pathogen. Within a polymicrobial infection, interactions between co habitant microbes can be important for pathogenesis, but even when considered, these interactions are not well understood. Here, we show with in vitro experiments that, compared with glucose, common fermentation products from co habitant bacteria significantly increase virulence factor production, antimicrobial activity and biofilm formation of P. aeruginosa. The maximum stimulating effect was produced with the fermentation product 2,3-butanediol, which is a substrate for P. aeruginosa, resulting in a metabolic relationship between fermenters and this pathogen. The global transcription regulator LasI LasR, which controls quorum sensing, was upregulated threefold with 2,3 butanediol, resulting in higher phenazine and exotoxin concentrations and improved biofilm formation. This indicates that the success of P. aeruginosa in CF airway microbiomes could be governed by the location within the food web with fermenting bacteria. Our findings suggest that interbacterial metabolite transfer in polymicrobial infections stimulates virulence of P. aeruginosa and could have a considerable impact on disease progression. PMID- 24401857 TI - Swapping symbionts in spittlebugs: evolutionary replacement of a reduced genome symbiont. AB - Bacterial symbionts that undergo long-term maternal transmission experience elevated fixation of deleterious mutations, resulting in massive loss of genes and changes in gene sequences that appear to limit efficiency of gene products. Potentially, this dwindling of symbiont functionality impacts hosts that depend on these bacteria for nutrition. One evolutionary escape route is the acquisition of a novel symbiont with a robust genome and metabolic capabilities. Such an acquisition has occurred in an ancestor of Philaenus spumarius, the meadow spittlebug (Insecta: Cercopoidea), which has replaced its ancient association with the tiny genome symbiont Zinderia insecticola (Betaproteobacteria) with an association with a symbiont related to Sodalis glossinidius (Gammaproteobacteria). Spittlebugs feed exclusively on xylem sap, a diet that is low both in essential amino acids and in sugar or other substrates for energy production. The new symbiont genome has undergone proliferation of mobile elements resulting in many gene inactivations; nonetheless, it has selectively maintained genes replacing functions of its predecessor for amino-acid biosynthesis. Whereas ancient symbiont partners typically retain perfectly complementary sets of amino-acid biosynthetic pathways, the novel symbiont introduces some redundancy as it retains some pathways also present in the partner symbionts (Sulcia muelleri). Strikingly, the newly acquired Sodalis-like symbiont retains genes underlying efficient routes of energy production, including a complete TCA cycle, potentially relaxing the severe energy limitations of the xylem-feeding hosts. Although evolutionary replacements of ancient symbionts are infrequent, they potentially enable evolutionary and ecological novelty by conferring novel metabolic capabilities to host lineages. PMID- 24401858 TI - Leucoagaricus gongylophorus uses leaf-cutting ants to vector proteolytic enzymes towards new plant substrate. AB - The mutualism between leaf-cutting ants and their fungal symbionts revolves around processing and inoculation of fresh leaf pulp in underground fungus gardens, mediated by ant fecal fluid deposited on the newly added plant substrate. As herbivorous feeding often implies that growth is nitrogen limited, we cloned and sequenced six fungal proteases found in the fecal fluid of the leaf cutting ant Acromyrmex echinatior and identified them as two metalloendoproteases, two serine proteases and two aspartic proteases. The metalloendoproteases and serine proteases showed significant activity in fecal fluid at pH values of 5-7, but the aspartic proteases were inactive across a pH range of 3-10. Protease activity disappeared when the ants were kept on a sugar water diet without fungus. Relative to normal mycelium, both metalloendoproteases, both serine proteases and one aspartic protease were upregulated in the gongylidia, specialized hyphal tips whose only known function is to provide food to the ants. These combined results indicate that the enzymes are derived from the ingested fungal tissues. We infer that the five proteases are likely to accelerate protein extraction from plant cells in the leaf pulp that the ants add to the fungus garden, but regulatory functions such as activation of proenzymes are also possible, particularly for the aspartic proteases that were present but without showing activity. The proteases had high sequence similarities to proteolytic enzymes of phytopathogenic fungi, consistent with previous indications of convergent evolution of decomposition enzymes in attine ant fungal symbionts and phytopathogenic fungi. PMID- 24401859 TI - Diversity and methane oxidation of active epibiotic methanotrophs on live Shinkaia crosnieri. AB - Shinkaia crosnieri is a galatheid crab that predominantly dwells in deep-sea hydrothermal systems in the Okinawa Trough, Japan. In this study, the phylogenetic diversity of active methanotrophs in the epibiotic microbial community on the setae of S. crosnieri was characterized by reverse transcription polymerase chain reaction (RT-PCR) of a functional gene (pmoA) encoding a subunit of particulate methane monooxygenase. Phylogenetic analysis of pmoA transcript sequences revealed that the active epibiotic methanotrophs on S. crosnieri setae consisted of gammaproteobacterial type Ia and Ib methanotrophs. The effect of different RNA stabilization procedures on the abundance of pmoA and 16S rRNA transcripts in the epibiotic community was estimated by quantitative RT-PCR. Our novel RNA fixation method performed immediately after sampling effectively preserved cellular RNA assemblages, particularly labile mRNA populations, including pmoA mRNA. Methane consumption in live S. crosnieri was also estimated by continuous-flow incubation under atmospheric and in situ hydrostatic pressures, and provided a clear evidence of methane oxidation activity of the epibiotic microbial community, which was not significantly affected by hydrostatic pressure. Our study revealed the significant ecological function and nutritional contribution of epibiotic methanotrophs to the predominant S. crosnieri populations in the Okinawa Trough deep-sea hydrothermal systems. In conclusion, our study gave clear facts about diversity and methane oxidation of active methanotrophs in the epibiotic community associated with invertebrates. PMID- 24401860 TI - Breath gas metabolites and bacterial metagenomes from cystic fibrosis airways indicate active pH neutral 2,3-butanedione fermentation. AB - The airways of cystic fibrosis (CF) patients are chronically colonized by patient specific polymicrobial communities. The conditions and nutrients available in CF lungs affect the physiology and composition of the colonizing microbes. Recent work in bioreactors has shown that the fermentation product 2,3-butanediol mediates cross-feeding between some fermenting bacteria and Pseudomonas aeruginosa, and that this mechanism increases bacterial current production. To examine bacterial fermentation in the respiratory tract, breath gas metabolites were measured and several metagenomes were sequenced from CF and non-CF volunteers. 2,3-butanedione was produced in nearly all respiratory tracts. Elevated levels in one patient decreased during antibiotic treatment, and breath concentrations varied between CF patients at the same time point. Some patients had high enough levels of 2,3-butanedione to irreversibly damage lung tissue. Antibiotic therapy likely dictates the activities of 2,3-butanedione-producing microbes, which suggests a need for further study with larger sample size. Sputum microbiomes were dominated by P. aeruginosa, Streptococcus spp. and Rothia mucilaginosa, and revealed the potential for 2,3-butanedione biosynthesis. Genes encoding 2,3-butanedione biosynthesis were disproportionately abundant in Streptococcus spp, whereas genes for consumption of butanedione pathway products were encoded by P. aeruginosa and R. mucilaginosa. We propose a model where low oxygen conditions in CF lung lead to fermentation and a decrease in pH, triggering 2,3-butanedione fermentation to avoid lethal acidification. We hypothesize that this may also increase phenazine production by P. aeruginosa, increasing reactive oxygen species and providing additional electron acceptors to CF microbes. PMID- 24401861 TI - Connecting thermal physiology and latitudinal niche partitioning in marine Synechococcus. AB - Marine Synechococcus cyanobacteria constitute a monophyletic group that displays a wide latitudinal distribution, ranging from the equator to the polar fronts. Whether these organisms are all physiologically adapted to stand a large temperature gradient or stenotherms with narrow growth temperature ranges has so far remained unexplored. We submitted a panel of six strains, isolated along a gradient of latitude in the North Atlantic Ocean, to long- and short-term variations of temperature. Upon a downward shift of temperature, the strains showed strikingly distinct resistance, seemingly related to their latitude of isolation, with tropical strains collapsing while northern strains were capable of growing. This behaviour was associated to differential photosynthetic performances. In the tropical strains, the rapid photosystem II inactivation and the decrease of the antioxydant beta-carotene relative to chl a suggested a strong induction of oxidative stress. These different responses were related to the thermal preferenda of the strains. The northern strains could grow at 10 degrees C while the other strains preferred higher temperatures. In addition, we pointed out a correspondence between strain isolation temperature and phylogeny. In particular, clades I and IV laboratory strains were all collected in the coldest waters of the distribution area of marine Synechococus. We, however, show that clade I Synechococcus exhibit different levels of adaptation, which apparently reflect their location on the latitudinal temperature gradient. This study reveals the existence of lineages of marine Synechococcus physiologically specialised in different thermal niches, therefore suggesting the existence of temperature ecotypes within the marine Synechococcus radiation. PMID- 24401862 TI - Host-specificity among abundant and rare taxa in the sponge microbiome. AB - Microbial communities have a key role in the physiology of the sponge host, and it is therefore essential to understand the stability and specificity of sponge symbiont associations. Host-specific bacterial associations spanning large geographic distance are widely acknowledged in sponges. However, the full spectrum of specificity remains unclear. In particular, it is not known whether closely related sponges host similar or very different microbiota over wide bathymetric and geographic gradients, and whether specific associations extend to the rare members of the sponge microbiome. Using the ultra-deep Illumina sequencing technology, we conducted a comparison of sponge bacterial communities in seven closely related Hexadella species with a well-resolved host phylogeny, as well as of a distantly related sponge Mycale. These samples spanned unprecedentedly large bathymetric (15-960 m) gradients and varying European locations. In addition, this study included a bacterial community analysis of the local background seawater for both Mycale and the widespread deep-sea taxa Hexadella cf. dedritifera. We observed a striking diversity of microbes associated with the sponges, spanning 47 bacterial phyla. The data did not reveal any Hexadella microbiota co-speciation pattern, but confirmed sponge-specific and species-specific host-bacteria associations, even within extremely low abundant taxa. Oligotyping analysis also revealed differential enrichment preferences of closely related Nitrospira members in closely related sponges species. Overall, these results demonstrate highly diverse, remarkably specific and stable sponge bacteria associations that extend to members of the rare biosphere at a very fine phylogenetic scale, over significant geographic and bathymetric gradients. PMID- 24401863 TI - Metaproteomic analysis of a winter to spring succession in coastal northwest Atlantic Ocean microbial plankton. AB - In this study, we used comparative metaproteomics to investigate the metabolic activity of microbial plankton inhabiting a seasonally hypoxic basin in the Northwest Atlantic Ocean (Bedford Basin). From winter to spring, we observed a seasonal increase in high-affinity membrane transport proteins involved in scavenging of organic substrates; Rhodobacterales transporters were strongly associated with the spring phytoplankton bloom, whereas SAR11 transporters were abundant in the underlying waters. A diverse array of transporters for organic compounds were similar to the SAR324 clade, revealing an active heterotrophic lifestyle in coastal waters. Proteins involved in methanol oxidation (from the OM43 clade) and carbon monoxide (from a wide variety of bacteria) were identified throughout Bedford Basin. Metabolic niche partitioning between the SUP05 and ARCTIC96BD-19 clades, which together comprise the Gamma-proteobacterial sulfur oxidizers group was apparent. ARCTIC96BD-19 proteins involved in the transport of organic compounds indicated that in productive coastal waters this lineage tends toward a heterotrophic metabolism. In contrast, the identification of sulfur oxidation proteins from SUP05 indicated the use of reduced sulfur as an energy source in hypoxic bottom water. We identified an abundance of Marine Group I Thaumarchaeota proteins in the hypoxic deep layer, including proteins for nitrification and carbon fixation. No transporters for organic compounds were detected among the thaumarchaeal proteins, suggesting a reliance on autotrophic carbon assimilation. In summary, our analyses revealed the spatiotemporal structure of numerous metabolic activities in the coastal ocean that are central to carbon, nitrogen and sulfur cycling in the sea. PMID- 24401865 TI - Treatment of angiofibromas in tuberous sclerosis complex: the effect of topical rapamycin and concomitant laser therapy. AB - Facial angiofibromas are the most troublesome cutaneous manifestations of the tuberous sclerosis complex and are difficult to treat. Lasers are most commonly used to treat these skin lesions, but results are disappointing with frequent recurrences. Recently, treatment of facial angiofibromas with topical rapamycin has been reported to yield promising results. We observed the need of laser ablation in addition to topical rapamycin to get best results for the treatment of angiofibromas in 4 cases. The result showed that topical rapamycin ointment was enough when the papules were yet small in size, i.e. less than a few millimeters, but additional laser ablation was needed for large papules approximately larger than 4 mm. Considering the natural course of facial angiofibromas, we believe that topical rapamycin can be best used in childhood patients. In adults, topical rapamycin was useful for treating the still present small papules and for preventing recurrences after laser treatment. PMID- 24401864 TI - Aerobic nitrous oxide production through N-nitrosating hybrid formation in ammonia-oxidizing archaea. AB - Soil emissions are largely responsible for the increase of the potent greenhouse gas nitrous oxide (N2O) in the atmosphere and are generally attributed to the activity of nitrifying and denitrifying bacteria. However, the contribution of the recently discovered ammonia-oxidizing archaea (AOA) to N2O production from soil is unclear as is the mechanism by which they produce it. Here we investigate the potential of Nitrososphaera viennensis, the first pure culture of AOA from soil, to produce N2O and compare its activity with that of a marine AOA and an ammonia-oxidizing bacterium (AOB) from soil. N. viennensis produced N2O at a maximum yield of 0.09% N2O per molecule of nitrite under oxic growth conditions. N2O production rates of 4.6+/-0.6 amol N2O cell(-1) h(-1) and nitrification rates of 2.6+/-0.5 fmol NO2(-) cell(-1) h(-1) were in the same range as those of the AOB Nitrosospira multiformis and the marine AOA Nitrosopumilus maritimus grown under comparable conditions. In contrast to AOB, however, N2O production of the two archaeal strains did not increase when the oxygen concentration was reduced, suggesting that they are not capable of denitrification. In (15)N-labeling experiments we provide evidence that both ammonium and nitrite contribute equally via hybrid N2O formation to the N2O produced by N. viennensis under all conditions tested. Our results suggest that archaea may contribute to N2O production in terrestrial ecosystems, however, they are not capable of nitrifier denitrification and thus do not produce increasing amounts of the greenhouse gas when oxygen becomes limiting. PMID- 24401866 TI - Where macro meets micro. AB - Reconciling or somehow linking the macroscopic and microscopic approaches to chemical and physical processes has been a challenge unaddressed for many years. One approach, presented here, treats the issue by examining individual phenomena well described by a macro approach that fails when applied to small systems. The key to the approach is determining the approximate system size below which the breakdown of the macro description is observable. The most developed example is the failure of the Gibbs phase rule for sufficiently small atomic clusters. Other examples, such as the onset, at sufficient size, of the insulator-to-metal transition, are discussed, as are some still more challenging phenomena. PMID- 24401867 TI - Large fetal pulmonary arteriovenous malformation detected at midtrimester scan with subsequent high cardiac output syndrome and favorable postnatal outcome. AB - Prenatal diagnosis of pulmonary arteriovenous malformations (PAVM), caused by abnormal communications between pulmonary arteries and pulmonary veins, is rarely described. We report a case of a PAVM between the right pulmonary artery and the left atrium, referred to our prenatal unit at 22 + 1 weeks of gestation, with severe cardiomegaly, dilation of the right pulmonary artery and a right pulmonary vein and retrograde flow in the ductus arteriosus. The fistula was located in the right lung and showed a broad, disturbed flow at color Doppler with high velocity and low pulsatility. The fetus was monitored weekly and cardiac function remained sufficient until 36 + 1 weeks of gestation, when increasing cardiomegaly prompted delivery by cesarean section. The newborn was transferred to the neonatal intensive care unit, intubated and the fistula was surgically removed. The boy could be discharged at the 43rd day of life and showed an uneventful course until the last follow-up at the age of 4 years, with no residual mental or physical handicaps and a normal cardiac function. Despite adverse outcomes described in previously reported cases of large PAVM complicated by severe cardiomegaly at midtrimester scan, our case had a good outcome. PMID- 24401868 TI - Microfluidic flow-focusing in ac electric fields. AB - We demonstrate the control of droplet sizes by an ac voltage applied across microelectrodes patterned around a flow-focusing junction. The electrodes do not come in contact with the fluids to avoid electrochemical effects. We found several regimes of droplet production in electric fields, controlled by the connection of the chip, the conductivity of the dispersed phase and the frequency of the applied field. A simple electrical modelling of the chip reveals that the effective voltage at the tip of the liquid to be dispersed controls the production mechanism. At low voltages (? 600 V), droplets are produced in dripping regime; the droplet size is a function of the ac electric field. The introduction of an effective capillary number that takes into account the Maxwell stress can explain the dependance of droplet size with the applied voltage. At higher voltages (? 600 V), jets are observed. The stability of droplet production is a function of the fluid conductivity and applied field frequency reported in a set of flow diagrams. PMID- 24401869 TI - Interventions using electronic medical records improve follow up of infants born to hepatitis C virus infected mothers. AB - BACKGROUND: The American Academy of Pediatrics recommends hepatitis C virus (HCV) antibody testing for all HCV- exposed infants at age >= 18 months. However, many of these infants are not appropriately tested. In 2006, the pediatric infectious disease service (PIDS) at our institution implemented interventions using electronic medical records (EMR) to improve appropriate HCV testing for HCV exposed infants. METHODS: Two-part study: During the first period (January 1, 1993, to December 31, 2005), medical records of all infants born to mothers with HCV were retrospectively reviewed for patient's demographics and infant's HCV testing. PIDS interventions included contacting the primary care physician through EMR requesting HCV testing for children without proper testing. During the second period (January 1, 2006, to December 31, 2011), interventions using EMR were implemented prospectively, including PIDS consultations during birth hospitalization for all HCV-exposed infants, addition of HCV exposure to the EMR problem list and communication with PCPs via the EMR to assure appropriate HCV testing. RESULTS: About 67,112 infants were born during the study period; 280 had maternal HCV infection and 193 continued to receive medical care at our institution. PIDS interventions using EMR resulted in a significant improvement of appropriate HCV testing among HCV-exposed infants from 8% (10/121) to 50% (36/72); P <0.0001. It also resulted in the identification of 5 new HCV-infected children; 3 of them were born before 2006 and previously undiagnosed. CONCLUSIONS: Interventions using EMR improved the identification and appropriate HCV follow up of infants born to HCV-infected mothers. PMID- 24401870 TI - Automated glycopeptide assembly by combined solid-phase peptide and oligosaccharide synthesis. AB - Current strategies for the synthesis of glycopeptides require multiple manual synthetic steps. Here, we describe a synthesis concept that merges solid phase peptide and oligosaccharide syntheses and can be executed automatically using a single instrument. PMID- 24401871 TI - Unemployment and coronary heart disease among middle-aged men in Sweden: 39 243 men followed for 8 years. AB - BACKGROUND: Although unemployment may be a stressful life event, its association with coronary heart disease (CHD) remains unclear. This study examines the association between unemployment and later hospitalisation due to CHD. METHODS: The study was based on a Swedish military conscription cohort of 18 to 20-year old men from 1969/1970 (n=49 321) with information provided on health status and health behaviours. Information on unemployment in middle age was obtained from national registers. CHD information was obtained from hospital registers and the cause of death register. Cox proportional hazard analyses were run on the 39 243 individuals who were in paid employment in 1996 and 1997. RESULTS: It was found that >=90 days of unemployment was associated with subsequent CHD during 8 years follow-up (crude HR=1.47, 95% CI 1.23 to 1.75). Controlling for known risk factors for CHD reduced the association but a significant association remained (HR=1.24, 95% CI 1.04 to 1.48); >=90 days of unemployment was significantly associated with CHD during the first 4 years (HR adjusted for known risk factors=1.31, 95% CI 1.01 to 1.71). CONCLUSIONS: Unemployment was associated with increased risk of CHD after adjustment for confounders. We interpret the increased risk of CHD associated with unemployment as potentially the somatic result of a process started by stress. PMID- 24401872 TI - The value of repeat kidney biopsy in quiescent Argentinian lupus nephritis patients. AB - BACKGROUND: The duration of maintenance therapy after induction therapy for lupus nephritis has not been rigorously established. A common practice is to maintain immunosuppression for 1-2 years after complete remission, and longer for partial remission. The present work addresses whether a repeat kidney biopsy might be informative in deciding who should continue immunosuppression after complete or partial remission. METHODS: The practice in a large Buenos Aires nephrology unit is to repeat a kidney biopsy before finalizing the decision to withdraw or continue immunosuppression. This work reports on a cohort of 25 Hispanic patients that had two or more kidney biopsies, the last occurring after at least 24 months of clinically quiescent disease. RESULTS: Despite normalization of serum creatinine and reduction of proteinuria to <500 mg/d, 30% of patients still had significant activity at the last biopsy. Conversely, 60% of patients with ongoing proteinuria (500-1000 mg/d), or stable but abnormal serum creatinine, had no activity by biopsy. Univariate association analyses demonstrated that improvement in the activity index (AI) of the last biopsy was associated with choice of induction therapy (cyclophosphamide or mycophenolate), improvement in serum creatinine over the first six months of treatment, and improvement in complement component C4. By multivariate regression analyses, two AI prediction models emerged. Cyclophosphamide plus change in serum creatinine or cyclophosphamide plus change in C4 accounted for 50% of the improvement in AI. CONCLUSION: These data suggest that a repeat biopsy may be useful in making the decision to withdraw or continue maintenance immunosuppression. PMID- 24401873 TI - Technical skills assessment: time to take it seriously. PMID- 24401874 TI - Wound dehiscence after abdominoperineal resection for low rectal cancer is associated with decreased survival. AB - BACKGROUND: Abdominoperineal resection for low rectal adenocarcinoma is a common procedure with high morbidity, including perineal wound complications. OBJECTIVE: The purpose of this study was to determine risk factors for perineal wound dehiscence and to investigate the effect of wound dehiscence on survival. DESIGN: This was a retrospective medical chart review. SETTINGS: The study was conducted in a tertiary care university medical center. PATIENTS: Patients included in the study were those with low rectal adenocarcinoma who underwent abdominoperineal resection between January 2001 and June 2012. MAIN OUTCOMES MEASURES: We assessed the incidence of perineal wound dehiscence, as well as survival, after surgery. RESULTS: A total of 249 patients underwent abdominoperineal resection for rectal carcinoma. The mean age was 62.6 years (range, 23.0-98.0 years), 159 (63.8%) were male, and the mean BMI was 27.9 (range, 16.7-58.5). There were 153 patients (61.1%) who survived for 5 years after surgery. Sixty-nine patients (27.7%) developed wound dehiscence. Multivariable analysis revealed the following associations with dehiscence: BMI (OR, 1.09; 95% CI, 1.03-1.15; p = 0.002), IBD (OR, 6.6; 95% CI, 1.4-32.5; p = 0.02), history of other malignant neoplasm (OR, 3.1; 95% CI, 1.5-6.6), and abdominoperineal resection for cancer recurrence (OR, 2.8; 95% CI, 1.2-6.3; p = 0.01). In the survival analysis, wound dehiscence was associated with decreased survival (mean survival time for dehiscence vs no dehiscence, 66.6 months vs 76.6 months; p = 0.01). This relationship persisted in the multivariable analysis (HR, 1.7; 95% CI, 1.1-2.8; p = 0.02). LIMITATIONS: This was a retrospective, observational study from a single center. CONCLUSIONS: The adjusted risk of death was 1.7 times higher in patients who experienced dehiscence than in those who did not. Attention to perineal wound closure with consideration of flap creation should at least be given to patients with a history of malignant neoplasm, those with IBD, those with rectal cancer recurrence, and women undergoing posterior vaginectomy. Preoperative weight loss should also reduce dehiscence risk. PMID- 24401875 TI - Patient expectations of functional outcomes after rectal cancer surgery: a qualitative study. AB - BACKGROUND: Rectal cancer patients' expectations of health and function may affect their disease- and treatment-related experience, but how patients form expectations of postsurgery function has received little study. OBJECTIVE: We used a qualitative approach to explore patient expectations of outcomes related to bowel function after sphincter-preserving surgery for rectal cancer. DESIGN: This was a cohort study of patients who were about to undergo sphincter preserving surgery for rectal cancer. SETTINGS: The study was conducted through individual telephone interviews with participants. PATIENTS: Twenty-six patients (14 men and 12 women) with clinical TNM stage I to III disease were enrolled. MAIN OUTCOME MEASURES: The semistructured interview script contained open-ended questions on patient expectations of postoperative bowel function and its perceived impact on daily function and life. Two researchers analyzed the interview transcripts for emergent themes using a grounded theory approach. RESULTS: Participant expectations of bowel function reflected 3 major themes: 1) information sources, 2) personal attitudes, and 3) expected outcomes. The expected outcomes theme contained references to specific symptoms and participants' descriptions of the certainty, importance, and imminence of expected outcomes. Despite multiple information sources and attempts at maintaining a positive personal attitude, participants expressed much uncertainty about their long-term bowel function. They were more focused on what they considered more important and imminent concerns about being cancer free and getting through surgery. LIMITATIONS: This study was limited by context in terms of the timing of interviews (relative to the treatment course). The transferability to other contexts requires further study. CONCLUSIONS: Patient expectations of long-term functional outcomes cannot be considered outside of the overall context of the cancer experience and the relative importance and imminence of cancer- and treatment-related events. Recognizing the complexities of the expectation formation process offers opportunities to develop strategies to enhance patient education and appropriately manage expectations, attend to immediate and long-term concerns, and support patients through the treatment and recovery process. PMID- 24401876 TI - Do anastomotic leaks impair postoperative health-related quality of life after rectal cancer surgery? A case-matched study. AB - BACKGROUND: Anastomotic leaks after colorectal resections for cancer are a leading cause of postoperative morbidity, mortality, and long hospital stay. Few data exist on the potentially deleterious effect of the anastomotic leaks after proctectomy for cancer on patient health-related quality of life. OBJECTIVE: The aim of this study was to explore the effect of clinically evident anastomotic leaks on health-related quality of life after rectal cancer excision. DESIGN: This is a case-matched study. SETTINGS: This study was conducted in a Greek academic surgical department. PATIENTS: Included were 25 patients undergoing low anterior resection complicated by an anastomotic leak (Clavien classification II, n = 14, and III, n = 11) and 50 patients undergoing low anterior resection with an uncomplicated course. MAIN OUTCOME MEASURES: Health-related quality-of-life data were prospectively collected at fixed assessment time points (baseline, 3, 6, and 12 months postoperatively) by the use of validated questionnaires (Medical Outcomes Study Short Form 36, Gastrointestinal Quality of Life Index, European Organization of Research and Treatment of Cancer Quality of Life Questionnaire C30, and European Organization of Research and Treatment of Cancer Quality of Life Questionnaire-CR29). RESULTS: "Leak" patients required a longer hospitalization. Although the numbers of initially constructed defunctioning loop ileostomies were not significantly different between cases and controls, "leak" patients were required to remain with a stoma significantly more often at all postoperative assessment time points. No differences were observed in the baseline scores between the 2 groups. Physical function of "leak" patients was significantly worse at all postoperative assessment time points. At 6 and 12 months, their emotional and social function and overall quality-of-life scores were significantly decreased in comparison with the patients with an uncomplicated course. "Leak" patients experienced significantly more "stoma related problems" and "sore skin" around the stoma site. LIMITATIONS: Limited number of patients, restriction of follow-up to the end of the first year, and heterogeneity in terms of the presentation, severity, and management of anastomotic leaks were the limitations of this study. CONCLUSIONS: Anastomotic leaks have an adverse effect on postoperative health-related quality of life. PMID- 24401877 TI - The first 1000 patients on an internet-based colorectal neoplasia database across private and public medicine in Australia: development of a binational model for the Colorectal Surgical Society of Australia and New Zealand. AB - BACKGROUND: Collection of multi-institutional data pertaining to the treatment of bowel cancer has been hindered by poor clinician compliance with data entry and the lack of incentive to participate. OBJECTIVE: This study aimed to establish if a novel browser-based model of data collection results in complete data capture. DESIGN: A Web-based data collection interface was custom written, offering automated reporting modules for clinical outcome to participants and an automated reporting system for outstanding data fields, and summary reporting of surgical quality outcomes. The software was combined with a clinical feedback system incorporating fortnightly data review meetings, at the time of clinical multidisciplinary meetings. PATIENTS AND SETTING: Selected were 932 consecutive patients with opt-out consent from 3 hospital sites, including public and private medicine. MAIN OUTCOME MEASURES: The primary outcomes measured were the analysis of data completeness and accuracy and ensuring that the highest-quality data were used for clinical audit of the surgical practices of Australian colorectal surgeons for the purpose of quality assurance. RESULTS: A total of 932 men and women, 22 to 94 years of age, treated for colorectal neoplasia were evaluated. We obtained 100% completion (>27,000 data points) of perioperative data registered by 8 specialist colorectal surgeons and a full-time database manager. CONCLUSIONS: Data completeness and validity are essential for clinical databases to serve the purpose of quality assurance, benchmarking, and research. The results confirm the safety and efficacy of colorectal cancer surgery in both the public and private sector in Australia. The combination of a simple multiuser interface, defined data points, automated result-reporting modules, and data deficiency reminder module resulted in 100% data compliance in nearly 1000 clinical episodes. The unprecedented success of this model has lead to the Colorectal Surgical Society of Australia and New Zealand adopting this model for data collection for Australia and New Zealand as the binational database. PMID- 24401878 TI - Crohn's disease and pregnancy: the impact of perianal disease on delivery methods and complications. AB - BACKGROUND: The optimal delivery method in patients with Crohn's disease is unknown, and there is no large-scale evidence on which to base decisions. OBJECTIVE: The aim of this study was to compare delivery methods and outcomes in patients with and without Crohn's disease. DESIGN AND PATIENTS: The Nationwide Inpatient Sample and International Classification of Diseases, Ninth Revision codes were used to identify childbirth deliveries. Patients were stratified by the presence or absence of Crohn's disease and perianal disease (anorectal fistula or abscess, rectovaginal fistula, anal fissure, and anal stenosis). SETTINGS: A large population-cohort database was used for the analysis. MAIN OUTCOME MEASURES: The primary outcomes measured were cesarean delivery and perineal lacerations. RESULTS: Of 6,794,787 pregnant women who delivered, 2882 had a diagnosis of Crohn's disease. Rates of cesarean delivery were higher in patients who had Crohn's disease with (83.1%) and without (42.8%) perianal disease in comparison with patients who did not have Crohn's disease with (38.9%) and without (25.6%) perianal disease (p < 0.001). Rates of 4th degree perineal lacerations were similar between patients who had or did not have Crohn's disease without perianal disease (1.4% vs 1.3%), but these rates increased significantly in patients with perianal disease (12.3%, p < 0.001). On multivariate analysis, perianal disease (OR, 10.9; 95% CI, 8.3-4.1; p < 0.001) and smoking (OR, 1.6; 95% CI, 1.5-1.7; p < 0.001) were independently associated with higher rates of 4th degree laceration. Crohn's disease was not independently associated with 4th degree laceration. LIMITATIONS: This was a retrospective study with the inherent limitations of large databases. CONCLUSIONS: Patients with Crohn's disease have higher rates of cesarean delivery. Perianal disease predicts severe perineal laceration independent of the presence of Crohn's disease. In the absence of perianal disease, the method of delivery in women with Crohn's disease should be predicated on obstetric indication. PMID- 24401879 TI - Ureteral injuries in colorectal surgery: an analysis of trends, outcomes, and risk factors over a 10-year period in the United States. AB - BACKGROUND: Iatrogenic ureteral injuries during colorectal surgical procedures are rare. Little is known about their incidence, associated outcomes, and predisposing factors. OBJECTIVE: The purpose of this study was to examine the trends of iatrogenic ureteral injuries in the United States over a decade, as well as their outcomes and risk factors. DESIGN: This was a retrospective study. SETTINGS: The nationwide inpatient sample from 2001 to 2010 was analyzed. PATIENTS: Included were patients with colorectal cancer, benign polyps, diverticular disease, or inflammatory bowel disease undergoing colorectal surgery. MAIN OUTCOME MEASURES: Trends of iatrogenic ureteral injuries occurring in colon and rectal surgical procedures were examined over a 10-year period. Mortality, morbidity, length of stay and total charge associated with ureteral injuries were analyzed on multivariate analysis. Finally, a predictive model for ureteral injuries was built using patient, hospital, and operative variables. RESULTS: An estimated 2,165,848 colorectal surgical procedures were performed in the United States over the study period, and 6027 ureteral injuries were identified (0.28%). The rate of ureteral injuries was higher in the second half of the decade (2006-2010) compared with the first half (2001-2005; 3.1/1000 vs 2.5/1000; p < 0.001). Ureteral injuries were independently associated with higher mortality (OR, 1.45; p < 0.05), morbidity (OR, 1.66; p < 0.001), longer length of stay (mean difference, 3.65 days; p < 0.001), and higher hospital charges by $31,497 (p< 0.001). Risk factors for ureteral injuries included rectal cancer (OR, 1.85), adhesions (OR, 1.83), metastatic cancer (OR, 1.76), weight loss/malnutrition (OR, 1.08), and teaching hospitals (OR, 1.05). Protective factors included the use of laparoscopy (OR, 0.91), transverse colectomy (OR, 0.90), and right colectomy (OR, 0.43). LIMITATIONS: This was a retrospective study from an administrative database. CONCLUSIONS: Iatrogenic ureteral injuries are rare complications in colorectal surgery; however, their incidence appears to be rising. Ureteral injuries are associated with higher mortality, morbidity, hospital charge, and length of stay, and their incidence can be predicted by several factors. PMID- 24401880 TI - Obesity increases the risk of postoperative peripheral neuropathy after minimally invasive colon and rectal surgery. AB - BACKGROUND: Abdominal surgery in the obese can be a major challenge in the perioperative period. Peripheral neuropathy is an uncommon but well-described complication after abdominal surgery. OBJECTIVE: Our aim was to evaluate the incidence of postoperative peripheral neuropathy after colorectal surgery and to identify its risk factors. DESIGN: A retrospective review of a prospectively maintained database of consecutive patients undergoing colorectal operations was performed. The incidence of postoperative nerve injury was compared between minimally invasive and open surgeries. BMI and other potential risk factors for developing peripheral neuropathy were evaluated. SETTINGS: This investigation was conducted at a single institution. PATIENTS: Over a 7-year period, 1514 colorectal operations were performed. 945(62.4%) of these operations were performed either laparoscopically or via hand-assisted laparoscopy, 166 (11.0%) were robotic assisted, and 403 (26.6%) were open procedures. Twenty-three patients (1.5%) developed peripheral neuropathy in the postoperative period. MAIN OUTCOME MEASURES: Forward stepwise logistic regression was used for multivariate analysis. RESULTS: All 23 of the patients with peripheral neuropathy had sensory deficits, and 1 patient had both sensory and motor deficits. All of the symptoms resolved without any residual neurologic deficits within 1 year. Twenty-two of the 23 patients with peripheral neuropathy were in the minimally invasive surgery group (incidence, 2%). One patient from the open group had peripheral neuropathy. By logistic regression analysis, only BMI was an independent predictor for peripheral neuropathy (p = 0.016) in minimally invasive surgery. LIMITATIONS: A limitation of our study is that postoperative neuropathy identification depended on reporting of symptoms, and there was no objective method of assessment. In addition, because of the relatively small number of patients with postoperative neuropathy, the study may be underpowered to detect significant differences in potential risk factors for developing neuropathy. CONCLUSIONS: The incidence of postoperative peripheral neuropathy was 2.0% in minimally invasive surgery and 0.2% in open surgery. Minimally invasive surgery, age, lithotomy positioning, operative time, and Pfannenstiel incision all significantly increased the risk of peripheral neuropathy. However, only obesity was an independent risk factor for peripheral neuropathy in patients undergoing minimally invasive colorectal surgery. Preventive measures should be instituted and documented in obese patients undergoing minimally invasive colorectal procedures. PMID- 24401881 TI - Process control to measure process improvement in colorectal surgery: modifications to an established enhanced recovery pathway. AB - BACKGROUND: After more than a decade of improvement, our enhanced recovery pathway had patients who had undergone laparoscopic colectomy going home a mean 3.7 days postoperatively. We wondered if adding a transverse abdominus plane block and intravenous acetaminophen to an established pathway would improve outcomes and resource use. OBJECTIVE: The aim of this study was to evaluate the impact of modification of an enhanced recovery pathway on patient outcomes. DESIGN: This was a case-matched study. METHODS: After the addition of transverse abdominus plane blocks and acetaminophen to the enhanced recovery pathway 12 months ago, review of a prospective database was performed. Patients were matched by procedure type, age, and sex. SETTINGS: This study was performed at a tertiary referral center. PATIENTS: Patients undergoing elective major laparoscopic colorectal surgery from 2010 to 2012 were included. MAIN OUTCOME MEASURES: The primary outcome measures were hospital length of stay, readmission rate, postoperative complications, and the cost of the hospital episode before and after the amendment of our enhanced recovery pathway. RESULTS: Two hundred eight elective major laparoscopic cases were evaluated. Both groups were similar in demographics and comorbidities. Length of stay was significantly shorter once transverse abdominus plane blocks and acetaminophen were introduced (p < 0.01), dropping from 3.7 to 2.6 days. There were significantly more complications in the prechange group (p = 0.02), but no significant differences in readmissions or mortality. Direct costs were similar, but there was a $500 increase in total margin per case (p = 0.004) with the pathway changes. With the use of statistical process control to examine the effect on outliers, there was significantly less variation in the mean length of stay (2.29 vs 1.90 days, p < 0.01) after the addition of transverse abdominus plane blocks and intravenous acetaminophen. LIMITATIONS: The single-surgeon, single-institution design was a limitation of this study. CONCLUSIONS: The addition of a transverse abdominus plane block and acetaminophen significantly reduced length of stay more than that seen with a previously established pathway. Statistical process control demonstrated that our pathway changes significantly reduced the spread of outliers around our mean length of stay. PMID- 24401882 TI - Perirenal fat surface area as a risk factor for morbidity after elective colorectal surgery. AB - BACKGROUND: Visceral obesity appears to be an emerging parameter affecting postoperative outcome after abdominal surgery. However, total visceral fat remains time consuming to calculate, and there is still a lack of data about its value as an independent risk factor in colorectal surgery. OBJECTIVES: The aim of this study was to validate the simple measurement of perirenal fat surface as a surrogate of visceral obesity, and to test the value of perirenal fat surface as a risk factor for morbidity in colorectal surgery and to compare it with the predictive value of other obesity parameters such as BMI and waist-hip ratio. DESIGN: This is a prospective observational cohort study. SETTING: The study was conducted at a tertiary university hospital. PATIENTS: Two hundred twenty-four consecutive patients (130 male) undergoing elective colorectal surgery with a mean age of 65.2 years (SD, +/-12.9) were identified. INTERVENTION: Elective colorectal resections were performed. MAIN OUTCOME MEASURES: We assessed complications as the primary outcome measure. Secondary outcome measures were the conversion rates, duration of operation, and length of hospital stay. RESULTS: Perirenal fat surface was validated as a surrogate of visceral fat and a strong correlation between the 2 was confirmed (Spearman correlation coefficient rho = 0.96). The overall postoperative complication rate was 22.8% (51/224) with 14.7% moderate complications (grade I and II) and 7.6% severe complications (grade III IV), with a mortality rate of 0.5%. Multivariate analysis confirmed perirenal fat surface as an independent risk factor for postoperative complications (OR, 3.87; 95% CI, 1.73-8.64; p = 0.001), whereas BMI and waist-hip ratio were not statistically associated with postoperative complications (OR, 1.16; 95% CI, 0.51 2.66; p = 0.72). LIMITATIONS: This study was limited by its sample size. CONCLUSION: Perirenal fat surface is an excellent and easy-to-reproduce indicator of visceral fat volume. Furthermore, perirenal fat surface is an independent risk factor for postoperative outcome in colorectal surgery that appears to be of higher predictive value than BMI and waist-hip ratio. PMID- 24401883 TI - Virtual reality simulator training for laparoscopic colectomy: what metrics have construct validity? AB - BACKGROUND: Virtual reality simulation for laparoscopic colectomy has been used for training of surgical residents and has been considered as a model for technical skills assessment of board-eligible colorectal surgeons. However, construct validity (the ability to distinguish between skill levels) must be confirmed before widespread implementation. OBJECTIVE: This study was designed to specifically determine which metrics for laparoscopic sigmoid colectomy have evidence of construct validity. DESIGN: General surgeons that had performed fewer than 30 laparoscopic colon resections and laparoscopic colorectal experts (>200 laparoscopic colon resections) performed laparoscopic sigmoid colectomy on the LAP Mentor model. All participants received a 15-minute instructional warm-up and had never used the simulator before the study. Performance was then compared between each group for 21 metrics (procedural, 14; intraoperative errors, 7) to determine specifically which measurements demonstrate construct validity. Performance was compared with the Mann-Whitney U-test (p < 0.05 was significant). RESULTS: Fifty-three surgeons; 29 general surgeons, and 24 colorectal surgeons enrolled in the study. The virtual reality simulators for laparoscopic sigmoid colectomy demonstrated construct validity for 8 of 14 procedural metrics by distinguishing levels of surgical experience (p < 0.05). The most discriminatory procedural metrics (p < 0.01) favoring experts were reduced instrument path length, accuracy of the peritoneal/medial mobilization, and dissection of the inferior mesenteric artery. Intraoperative errors were not discriminatory for most metrics and favored general surgeons for colonic wall injury (general surgeons, 0.7; colorectal surgeons, 3.5; p = 0.045). LIMITATIONS: Individual variability within the general surgeon and colorectal surgeon groups was not accounted for. CONCLUSIONS: The virtual reality simulators for laparoscopic sigmoid colectomy demonstrated construct validity for 8 procedure-specific metrics. However, using virtual reality simulator metrics to detect intraoperative errors did not discriminate between groups. If the virtual reality simulator continues to be used for the technical assessment of trainees and board eligible surgeons, the evaluation of performance should be limited to procedural metrics. PMID- 24401884 TI - Electrically stimulated gracilis neosphincter for end-stage fecal incontinence: the long-term outcome. AB - BACKGROUND: Electrically stimulated gracilis neosphincter is an established treatment for patients with end-stage fecal incontinence. Few data, however, describe its long-term efficacy. OBJECTIVE: This study aimed to assess the long term functional outcome associated with this procedure. DESIGN: Patients who underwent gracilis neosphincter construction between1989 and 2001 were identified from a prospectively recorded database. Demographics and pretreatment anorectal physiologic data were available for all patients. SETTINGS: This study was conducted at an academic colorectal unit in a tertiary center. PATIENTS: Sixty patients (median age, 42 years; 46 females) with fecal incontinence and a Williams continence score >=5 were recruited to the study. The causes of incontinence included obstetric injury (n = 22), anal surgery (n = 17), atresia (n = 7), idiopathic incontinence (n = 6), anorectal excision (n = 4), and ileoanal pouch incontinence (n = 4). MAIN OUTCOME MEASURE: The primary outcomes measured were the Williams continence score and the proportion of patients with a Williams score <=3 who avoided permanent stoma formation. RESULTS: Continence improved for the cohort postoperatively at 2 years (2(2-5); p < 0.001) but no significant difference was found between continence scores preoperatively and at 13 years (5(3-6); p = not significant). However, a sustained improvement at 13 years was noted for patients in the anal surgery (3(2-5);p < 0.001) and obstetric injury groups (4.5(3-6); p = 0.001). Twenty-six patients (43%) had a Williams score <=3 and avoided permanent stoma after 13 years. Eighteen patients developed postoperative rectal evacuatory disorder; 10 of them required a conduit to facilitate colonic irrigation. Postoperative evacuatory disorder was more frequent in patients with a history of obstetric injury (p = 0.008). LIMITATIONS: This study was limited by the lack of bowel diaries and quality-of-life scores. CONCLUSION: Gracilis neosphincter is associated with clinically significant and sustained symptom improvement in patients with end-stage fecal incontinence secondary to obstetric injury or anal surgery. These data support the continued use of this procedure in highly selected patients. PMID- 24401885 TI - Long-term results of mucosal advancement flap combined with platelet-rich plasma for high cryptoglandular perianal fistulas. AB - BACKGROUND: The long-term closure rate of high perianal fistulas after surgical treatment remains disappointing. OBJECTIVE: The goal of this study was to improve the long-term closure rate of high cryptoglandular perianal fistulas combining mucosal advancement flap with platelet-rich plasma. DESIGN: This study was retrospective in design. SETTING: This study was conducted at 2 secondary and 1 tertiary referral hospitals. PATIENTS: Patients presenting with high cryptoglandular perianal fistulas involving the middle/upper third of the anal sphincter complex were included. INTERVENTIONS: A staged surgical treatment was performed; After seton placement, a mucosal advancement flap was combined with platelet-rich plasma. MAIN OUTCOME MEASURES: Recurrence was the main outcome. Incontinence was the secondary outcome. RESULTS: We operated on 25 patients between 2006 and 2012. Thirteen (52%) patients had previous fistula surgery. The median follow-up period was 27 months. One patient (4.0%) was lost to follow-up after 4 months. Freedom from recurrence at 2 years was 0.83 (95% CI, 0.62-0.93). Two of the 4 patients with a recurrence (8%) had a repeated treatment and healed. One patient (4.0%) refused another treatment, but agreed to stay in follow-up. One patient (4.0%) requested a colostomy, resulting in closure of the fistula. Complications occurred in 1 patient (4.0%). Incontinence numbers were low with a median Vaizey score of 3.0 out of a maximum of 24. LIMITATIONS: The study was limited by its retrospective design, lack of preoperative incontinence data, selection bias, and phone interview follow-up. CONCLUSION: The long-term outcome results of patients with primary and recurrent high cryptoglandular perianal fistulas treated with a seton followed by mucosal advancement flap and platelet rich plasma show low recurrence, complication, and incontinence rates. Therefore, this technique seems to be a valid option as treatment. Larger and preferably randomized controlled studies are needed to further explore this surgical technique. PMID- 24401886 TI - Use of dynamic 3-dimensional transvaginal and transrectal ultrasonography to assess posterior pelvic floor dysfunction related to obstructed defecation. AB - BACKGROUND: New ultrasound techniques may complement current diagnostic tools, and combined techniques may help to overcome the limitations of individual techniques for the diagnosis of anorectal dysfunction. A high degree of agreement has been demonstrated between echodefecography (dynamic 3-dimensional anorectal ultrasonography) and conventional defecography. OBJECTIVE: Our aim was to evaluate the ability of a combined approach consisting of dynamic 3-dimensional transvaginal and transrectal ultrasonography by using a 3-dimensional biplane endoprobe to assess posterior pelvic floor dysfunctions related to obstructed defecation syndrome in comparison with echodefecography. DESIGN AND SETTING: This was a prospective, observational cohort study conducted at a tertiary-care hospital. PATIENTS: Consecutive female patients with symptoms of obstructed defecation were eligible. INTERVENTION: Each patient underwent assessment of posterior pelvic floor dysfunctions with a combination of dynamic 3-dimensional transvaginal and transrectal ultrasonography by using a biplane transducer and with echodefecography. MAIN OUTCOME MEASURES: Kappa (kappa) was calculated as an index of agreement between the techniques. Diagnostic accuracy (sensitivity, specificity, and positive and negative predictive values) of the combined technique in detection of posterior dysfunctions was assessed with echodefecography as the standard for comparison. RESULTS: A total of 33 women were evaluated. Substantial agreement was observed regarding normal relaxation and anismus. In detecting the absence or presence of rectocele, the 2 methods agreed in all cases. Near-perfect agreement was found for rectocele grade I, grade II, and grade III. Perfect agreement was found for entero/sigmoidocele, with near-perfect agreement for rectal intussusception. Using echodefecography as the standard for comparison, we found high diagnostic accuracy of transvaginal and transrectal ultrasonography in the detection of posterior dysfunctions. LIMITATIONS: This combined technique should be compared with other dynamic techniques and validated with conventional defecography. CONCLUSIONS: Dynamic 3 dimensional transvaginal and transrectal ultrasonography is a simple and fast ultrasound technique that shows strong agreement with echodefecography and may be used as an alternative method to assess patients with obstructed defecation syndrome. PMID- 24401887 TI - Evaluation of novel local anesthetic wound infiltration techniques for postoperative pain following colorectal resection surgery: a meta-analysis. AB - BACKGROUND: Novel local anesthetic blocks have become increasingly popular in the multimodal pain management following abdominal surgery, but have not been evaluated in a procedure-specific manner in colorectal surgery. OBJECTIVE: This study aims to evaluate the efficacy of novel local anesthetic techniques in colorectal surgery. DATA SOURCES: Electronic literature search of PubMed, EMBASE, and Cochrane databases (date range, January 1990 to February 2013) STUDY SELECTION: Randomized controlled trials comparing a novel local anesthetic technique with placebo/routine analgesia in adults undergoing open or laparoscopic colonic or rectal resection were selected. INTERVENTIONS: This is a meta-analysis of randomized controlled trials evaluating novel local anesthetic wound infiltration techniques such as wound catheter, transversus abdominis plane block, and intraperitoneal instillation in colorectal surgical procedures. The comparator group was defined as placebo/routine analgesia. OUTCOME MEASURES: The primary outcome was opiate requirement at 24 hours. Secondary outcomes included opiate requirements at 48 hours, pain numerical rating score at 24 and 48 hours at rest and on movement, recovery (length of stay, nausea and vomiting, time until bowel movement and diet resumption), and complications. Subgroup analysis was performed to evaluate specific local anesthetic techniques and open and laparoscopic surgery. RESULTS: Twelve randomized controlled trials compared local anesthetic techniques with placebo/routine analgesia. Local anesthetic techniques demonstrated a significant reduction in opiate requirement at 48 hours. Local anesthetic techniques were also associated with lower pain scores on movement at 24 and 48 hours, shorter length of stay, and earlier resumption of diet. LIMITATIONS: The diverse study design led to statistical heterogeneity in several analyses. CONCLUSIONS: Novel local anesthetic wound infiltration techniques in colorectal surgery appear to reduce opiate requirements, to reduce pain scores, and to improve recovery in comparison with placebo/routine analgesia. PMID- 24401888 TI - Prone jackknife position is not necessary to achieve a cylindrical abdominoperineal resection: demonstration of the lithotomy position. AB - This video demonstrates a laparoscopic abdominal perineal resection for a fixed 4.8-cm mass involving the posterior and left rectal walls and left puborectalis, 2 cm from the anal verge (see Video, Supplemental Digital Content 1, http://links.lww.com/DCR/A127). We detail the steps of the procedure, all completed in lithotomy, including lateral-to-medial dissection; identification and protection of the left ureter and presacral nerves; division of the inferior mesenteric artery; medial-to-lateral dissection, with meeting the previous dissection plane; total mesorectal excision and pelvic dissection; perineal dissection and layered closure; and abdominal inspection and colostomy creation. Total operative time was 181 minutes. The specimen total mesorectal excision was complete with a negative circumferential radial margin (greater than 1 cm). Final pathology was T3N2M0. PMID- 24401890 TI - Advancing standards of rectal cancer care: lessons from Europe adapted to the vast expanse of North America. PMID- 24401889 TI - Optimizing rectal cancer management: analysis of current evidence. PMID- 24401891 TI - New technique of en bloc resection of colorectal tumor using laparoscopy and endoscopy cooperatively (laparoscopy and endoscopy cooperative surgery - colorectal). AB - BACKGROUND AND AIM: Various factors make complete en bloc resection by endoscopic techniques alone of some laterally spreading colorectal tumors difficult or unsafe. Drawing on recent radical developments in endoscopic and laparoscopic techniques for managing colorectal lesions, we aimed to develop a safe resection procedure by using a combination of laparoscopy and endoscopy. We have named this procedure laparoscopic endoscopic cooperative colorectal surgery. PATIENTS: We have performed this procedure on 3patients who had laterally spreading colorectal tumors. The factors contraindicating endoscopic submucosal dissection were submucosal fibrosis because of previous endoscopic mucosal resection in 1 patient and multiple surrounding diverticula in 2 patients. TECHNIQUE: The patient is placed under general anesthesia and 5 ports are inserted. Following confirmation of the tumor location by endoscopy and laparoscopy, the colon wall at this site is exposed. First, a mucosa-to-submucosa dissection circumferential to the lesion with an appropriate safety margin is performed endoscopically. Complete full thickness dissection and excision is then performed by using ultrasonic activating scissors, endoscopy, and laparoscopy cooperatively. The excised lesion is withdrawn intraluminally with endoscopic forceps. The opened colon is then closed with laparoscopic linear staplers. RESULTS: The mean operating time and blood loss in this series were 205 minutes and 13 mL. There were no intraoperative or postoperative complications. Histological examination revealed tubular adenomas with severe dysplasia and adequate surgical margins in all cases. CONCLUSION: Laparoscopic endoscopic cooperative colorectal surgery involves removal of a minimal length of colon and is a feasible procedure for en bloc resection of some colonic lateral spreading tumors that would be difficult to resect endoscopically. PMID- 24401892 TI - Sacrectomy via the abdominal approach during pelvic exenteration. AB - BACKGROUND: Sacrectomy is sometimes necessary to achieve negative margins in pelvic exenteration procedures. This is typically done with the patient in the prone position. Some of the limitations of the prone approach include its limited access to the lateral pelvic sidewall structures and suboptimal vascular control in comparison with the access and the vascular control of a combined abdominolithotomy approach. OBJECTIVE: This article describes a technique for performing a low sacrectomy (below the sacroiliac joint) through a transabdominal approach without the need to turn the patient prone intraoperatively. PROCEDURE: The procedure involves 2 approaches: abdominal and perineal. The abdominal phase incorporates the complete mobilization of both lateral pelvic sidewalls and their neurovascular bundles to the intended lateral margins. The anterior margin is dependent on the extent of tumor resection necessary and may incorporate the vagina, bladder, prostate, or even part of the pubic bone. The perineal phase involves freeing all the muscular and ligamentous attachments of the posterior sacrum up to the level of S2/3. The sacrectomy is completed by using an osteotome transabdominally. It begins in the midline and extends laterally until the ischial spine and incorporates the sacrospinous through to the sacrotuberous ligaments and the whole pelvic floor. CONCLUSIONS: Transabdominal low sacrectomy is technically feasible and may be associated with numerous practical advantages in comparison with a low sacrectomy performed with the patient in the prone position for involvement of the lower half of the sacrum. PMID- 24401893 TI - Canadian Association of General Surgeons, the American College of Surgeons, the Canadian Society of Colorectal Surgeons and the American Society of Colorectal Surgeons Evidence Based Reviews in Surgery - colorectal surgery. PMID- 24401894 TI - Patient responses to different neuromodulatory treatments. PMID- 24401895 TI - The authors reply. PMID- 24401898 TI - Beneficial effects of short-term calorie restriction against cisplatin-induced acute renal injury in aged rats. AB - BACKGROUND: The therapeutic use of the antineoplastic drug cisplatin (DDP) in the elderly is limited by its nephrotoxic effects. The aim of this study was to examine the effect of short-term calorie restriction (CR) on DDP-induced nephrotoxicity in aged rats. METHODS: A group of 25-month-old male Sprague-Dawley rats were divided into two groups: ad libitum (AL) and CR, which were fed 60% of the food consumed by AL rats for 8 weeks. The two groups were each further randomly divided into two subgroups: OAL control, OAL+DDP, OCR control, and OCR+DDP. A single dose of DDP (6 mg/kg) was injected intraperitoneally. Functional and structural changes of the kidneys were evaluated quantitatively by biochemical, histopathological, and morphometric analyses. RESULTS: At the end of the 8 weeks, rats in the OCR group lost 14.8% more body mass than rats in the OAL group. Pretreatment with CR had several effects: (1) it reduced the levels of blood urea nitrogen and serum creatinine, (2) it reduced the magnitude of the renal tubular epithelial damage, and (3) it significantly reduced the incidence of activated caspase-3 and TUNEL-positive cells in kidneys injured by DDP. However, SIRT1 had the opposite trend after DDP application between the two groups. CONCLUSIONS: Short-term CR exhibits a renoprotective effect in experimental DDP-induced renal injury, the mechanism of which may involve CR antiapoptotic effects and promotion of SIRT1. PMID- 24401899 TI - An overview of the risk factors associated with multiple oral premalignant lesions with a case report of extensive field cancerization in a female patient. AB - BACKGROUND: Field cancerization is a well-known and well-documented process of malignant transformation first coined by Slaughter et al. in 1953. Tobacco chewing was associated with the greatest increase in the risk of multiple oral premalignant lesions and may be the major source of field cancerization of the oral cavity in the Indian population. The field cancerization will probably help clinicians in complementing evaluation of pathologic biopsy specimens. MATERIAL AND METHODS: We present a case report of field cancerization in a 63-year-old Indian female. She presented with an intra-oral generalized hyperkeratotic verruciform type white lesions involving right and left buccal mucosa, lower labial mucosa, upper and lower vestibule, dorsal, ventral and right lateral border of the tongue, hard and soft palate. Microscopic examination revealed features of verrucous carcinoma in one area, squamous cell carcinoma in another and carcinoma in situ in other areas. Based on the overall features in various areas of the oral cavity, the lesion was diagnosed as field cancerization. CONCLUSION: Reviewing the literature revealed the presence of a field with genetically altered cells appear to be induced by tobacco (smoking/smokeless form). The large number of premalignant cells in the fields may increase cancer risk considerably. Thus screening and monitoring of the field may have serious implications for oral cancer prevention. PMID- 24401900 TI - Pathophysiology of anemia in chronic kidney diseases: A review. AB - Backgroud. Anemia is one of the laboratory and clinical findings of chronic kidney diseases (CKD). The presence of anemia in patients with CKD has a wide range of clinically important consequences. Some of the symptoms that were previously attributed to reduced renal function are, in fact, a consequence of anemia. Anemia contributes to increased cardiac output, the development of left ventricular hypertrophy, angina, and congestive heart failure. According to current knowledge, anemia also contributes to the progression of CKD and is one of the factors that contribute to the high morbidity and mortality in patients with chronic renal failure and their reduced survival. METHODS: MEDLINE search was performed to collect both original and review articles addressing anemia in CKD, pathophysiology of renal anemia, erythropoiesis, erythropoietin, iron metabolism, inflammation, malnutrition, drugs, renal replacement therapy and anemia management CONCLUSION: The present review summarized current knowledge in the field of the pathophysiology of renel anemia. Understanding the pathophysiology of anemia in CKD is crucial for the optimal treatment of anemia according to recent clinical practice guidelines and recommendation, and correct recognition of causes of resistence to treatment of erythropoietin stimulating agents (ESA). PMID- 24401901 TI - Cerebrospinal fluid biomarkers in clinical subtypes of early-onset Alzheimer's disease. AB - BACKGROUND/AIMS: Accurate diagnosis of sporadic early-onset Alzheimer's disease (EOAD) can be challenging, and cerebrospinal fluid (CSF) biomarkers may assist in this process. We compared CSF indices between three EOAD subtypes: amnestic, logopenic progressive aphasia (LPA), and posterior cortical atrophy (PCA). METHODS: We identified 21 amnestic EOAD, 20 LPA, and 12 PCA patients with CSF data, which included amyloid beta1-42 (Abeta42), total tau (t-tau), phospho tau181 (p-tau), and Abeta42/t-tau index (ATI) levels. RESULTS: Abeta42 and ATI levels were similar across groups, but t-tau and p-tau levels were significantly lower in PCA patients. CONCLUSIONS: The Abeta42 and ATI data confirm the commonality of the Abeta pathology in EOAD. The lower tau indices in PCA patients may reflect differences in the distribution of neurofibrillary tangles or rates of neurodegeneration. PMID- 24401902 TI - Prevalence and clinical relevance of allergic rhinitis in patients with classic asthma and cough variant asthma. AB - BACKGROUND: A clinically relevant relationship between classic asthma and allergic rhinitis has been reported. However, the possible link between cough variant asthma (CVA) and allergic rhinitis remains unknown. OBJECTIVES: To clarify the prevalence and clinical relevance of perennial allergic rhinitis or seasonal allergic rhinitis in CVA patients compared to classic asthma patients. METHODS: We retrospectively studied adult patients with classic asthma (n = 190) and those with CVA (n = 83). The prevalence of perennial allergic rhinitis or seasonal allergic rhinitis and associations of concomitant perennial or seasonal allergic rhinitis with asthma severity, forced expiratory volume in 1 s (% predicted), fractional exhaled nitric oxide (FeNO) levels, and eosinophil proportions in sputum and blood were analyzed in the two groups. RESULTS: The prevalence of perennial allergic rhinitis and/or seasonal allergic rhinitis was significantly higher in classic asthma patients than in CVA patients (all p < 0.05). Concomitant perennial allergic rhinitis was associated with higher FeNO levels and eosinophil proportions in sputum and blood in classic asthma patients (p = 0.035, p = 0.036, and p = 0.008, respectively) and with higher asthma severity, FeNO levels, and sputum eosinophil proportions in CVA patients (p = 0.031, p = 0.007, and p = 0.010, respectively). Concomitant seasonal allergic rhinitis was only associated with higher sputum eosinophil proportions in CVA patients with active rhinitis symptoms during the sensitized pollen season (p = 0.025). CONCLUSIONS: Perennial allergic rhinitis may be relevant for CVA patients as well as classic asthma patients by consistently augmenting eosinophilic lower airway inflammation. PMID- 24401903 TI - Transmembrane protein with unknown function 16A overexpression promotes glioma formation through the nuclear factor-kappaB signaling pathway. AB - Ion channels have been suggested to be important in the development and progression of tumors, however, chloride channels have rarely been analyzed in tumorigenesis. More recently, transmembrane protein with unknown function 16A (TMEM16A), hypothesized to be a candidate calcium-activated Cl- channel, has been found to be overexpressed in a number of tumor types. Although several studies have implicated the overexpression of TMEM16A in certain tumor types, the exact role of TMEM16A in gliomas and the underlying mechanisms in tumorigenesis, remain poorly understood. In the present study, the role of TMEM16A in gliomas and the potential underlying mechanisms were analyzed. TMEM16A was highly abundant in various grades of gliomas and cultured glioma cells. Knockdown of TMEM16A suppressed cell proliferation, migration and invasion. Furthermore, nuclear factor-kappaB (NF-kappaB) was activated by overexpression of TMEM16A. In addition, TMEM16A regulated the expression of NF-kappaB-mediated genes, including cyclin D1, cyclin E and c-myc, involved in cell proliferation, and matrix metalloproteinases (MMPs)-2 and MMP-9, which are associated with the migration and invasion of glioma cells. Collectively, results of the present study provide evidence for the involvement of TMEM16A in gliomas and the potential mechanism through which TMEM16A promotes glioma formation. PMID- 24401904 TI - Plasmon-enhanced water splitting on TiO2-passivated GaP photocatalysts. AB - Integrating plasmon resonant nanostructures with photocatalytic semiconductors shows great promise for high efficiency photocatalytic water splitting. However, the electrochemical instability of most III-V semiconductors severely limits their applicability in photocatalysis. In this work, we passivate p-type GaP with a thin layer of n-type TiO2 using atomic layer deposition. The TiO2 passivation layer prevents corrosion of the GaP, as evidenced by atomic force microscopy and photoelectrochemical measurements. In addition, the TiO2 passivation layer provides an enhancement in photoconversion efficiency through the formation of a charge separating pn-region. Plasmonic Au nanoparticles deposited on top of the TiO2-passivated GaP further increases the photoconversion efficiency through local field enhancement. These two enhancement mechanisms are separated by systematically varying the thickness of the TiO2 layer. Because of the tradeoff between the quickly decaying plasmonic fields and the formation of the pn-charge separation region, an optimum performance is achieved for a TiO2 thickness of 0.5 nm. Finite difference time domain (FDTD) simulations of the electric field profiles in this photocatalytic heterostructure corroborate these results. The effects of plasmonic enhancement are distinguished from the natural catalytic properties of Au by evaluating similar photocatalytic TiO2/GaP structures with catalytic, non-plasmonic metals (i.e., Pt) instead of Au. This general approach of passivating narrower band gap semiconductors enables a wider range of materials to be considered for plasmon-enhanced photocatalysis for high efficiency water splitting. PMID- 24401906 TI - The endothelial protein C receptor impairs the antibacterial response in murine pneumococcal pneumonia and sepsis. AB - Pneumococcal pneumonia is a frequent cause of gram-positive sepsis and has a high mortality. The endothelial protein C receptor (EPCR) has been implicated in both the activation of protein C (PC) and the anti-inflammatory actions of activated (A)PC. The aim of this study was to determine the role of the EPCR in murine pneumococcal pneumonia and sepsis. Wild-type (WT), EPCR knockout (KO) and Tie2 EPCR mice, which overexpress EPCR on the endothelium, were infected intranasally (pneumonia) or intravenously (sepsis) with viable Streptococcus pneumoniae and euthanised at 24 or 48 hours after initiation of the infection for analyses. Pneumonia did not alter constitutive EPCR expression on pulmonary endothelium but was associated with an influx of EPCR positive neutrophils into lung tissue. In pneumococcal pneumonia EPCR KO mice demonstrated diminished bacterial growth in the lungs and dissemination to spleen and liver, reduced neutrophil recruitment to the lungs and a mitigated inflammatory response. Moreover, EPCR KO mice displayed enhanced activation of coagulation in the early phase of disease. Correspondingly, in pneumococcal sepsis EPCR KO mice showed reduced bacterial growth in lung and liver and attenuated cytokine release. Conversely, EPCR overexpressing mice displayed higher bacterial outgrowth in lung, blood, spleen and liver in pneumococcal sepsis. In conclusion, EPCR impairs antibacterial defense in both pneumococcal pneumonia and sepsis, which is associated with an enhanced pro-inflammatory response. PMID- 24401905 TI - Snail1-dependent control of embryonic stem cell pluripotency and lineage commitment. AB - Embryonic stem cells (ESCs) exhibit the dual properties of self-renewal and pluripotency as well as the ability to undergo differentiation that gives rise to all three germ layers. Wnt family members can both promote ESC maintenance and trigger differentiation while also controlling the expression of Snail1, a zinc finger transcriptional repressor. Snail1 has been linked to events ranging from cell cycle regulation and cell survival to epithelial-mesenchymal transition (EMT) and gastrulation, but its role in self-renewal, pluripotency or lineage commitment in ESCs remains undefined. Here we demonstrate using isogenic pairs of conditional knockout mouse ESCs, that Snail1 exerts Wnt- and EMT independent control over the stem cell transcriptome without affecting self-renewal or pluripotency-associated functions. By contrast, during ESC differentiation, an endogenous Wnt-mediated burst in Snail1 expression regulates neuroectodermal fate while playing a required role in epiblast stem cell exit and the consequent lineage fate decisions that define mesoderm commitment. PMID- 24401907 TI - Frequency of mitochondrial mutations in non-syndromic hearing loss as well as possibly responsible variants found by whole mitochondrial genome screening. AB - Mutations in mitochondrial DNA (mtDNA) are reported to be responsible for the pathogenesis of maternally inherited hearing loss. Complete mtDNA sequencing may detect pathogenic mutations, but whether they are indeed pathogenic can be difficult to interpret because of normal ethnic-associated haplogroup variation and other rare variations existing among control populations. In this study, we performed systemic mutational analysis of mtDNA in 394 Japanese patients with hearing loss. Two different cohorts were analyzed in this study: Cohort 1, 254 maternally inherited patients; and Cohort 2, 140 patients with various inheritance modes. After screening of the entire mtDNA genome with direct sequencing, we evaluated the frequency of previously reported mutations and the frequency and pathogenicity of the novel variants. As a result, the 'Confirmed' mitochondrial mutations were found predominantly in Cohort 1 rather than in Cohort 2 (14.6 vs 0.7%). 1555A>G (n=23) is the most common mutation, followed by the 3243A>G (n=11) mutations. On the basis of prediction analysis, we detected 10 novel homoplasmic mitochondrial variants. After further classification, the 3595A>G and 6204A>G variants were found to be new candidate mutations possibly associated with hearing loss. PMID- 24401908 TI - A shared haplotype for dentatorubropallidoluysian atrophy (DRPLA) in Italian families testifies of the recent introduction of the mutation. AB - To clarify the population history of dentatorubropallidoluysian atrophy (DRPLA) in Italy and to date back the introduction of the mutation, we reconstructed extended haplotypes flanking the CAG repeat in 10 patients of Italian ancestry, analyzing their similarity/dissimilarity as a function of distance from the CAG repeat. Our aim was to compare the hypothesis of a single, recent genealogy connecting all the observed haplotypes with the alternative hypothesis of multiple introductions by more distantly related haplotypes from outer sources. Polymorphic DNA markers were chosen to cover a region of 153 kb flanking the CAG repeat, that is, informative for dating the age of the DNA segment unaffected by recombination. In all patients, an expansion of the ATN1 CAG segment was confirmed residing onto the same narrow haplotype described to be associated with the CAG expansion in the Japanese and Portuguese populations. We also observed the disruption of the DRPLA haplotype at longer distances, on both sides of the CAG. Our results are compatible with a single founder in the last 600 years, most likely before the last 270 years. These estimates for the Sicilian population largely overlap a period in which the Japanese haplotype with the DRPLA mutation could have been introduced by the Portuguese maritime travelers. PMID- 24401909 TI - Truncated UDP-glucuronosyltransferase (UGT) from a Crigler-Najjar syndrome type II patient colocalizes with intact UGT in the endoplasmic reticulum. AB - Mutations in the gene encoding bilirubin UDP-glucuronosyltransferase (UGT1A1) are known to cause Crigler-Najjar syndrome type II (CN-II). We previously encountered a patient with a nonsense mutation (Q331X) on one allele and with no other mutations in the promoter region or other exons, and proposed that CN-II is inherited as a dominant trait due to the formation of a heterologous subunit structure comprised of the altered UGT1A1 gene product (UGT1A1-p.Q331X) and the intact UGT1A1. Here, we investigated the molecular basis of CN-II in this case by expressing UGT1A1-p.Q331X in cells. UGT1A1-p.Q331X overexpressed in Escherichia coli or mammalian cells directly bound or associated with intact UGT1A1 in vitro or in vivo, respectively. Intact UGT1A1 was observed as a dimer using atomic force microscopy. Fluorescent-tagged UGT1A1-p.Q331X and intact UGT1A1 were colocalized in 293T cells, and fluorescence recovery after photobleaching analysis showed that UGT1A1-p.Q331X was retained in the endoplasmic reticulum (ER) without rapid degradation. These findings support the idea that UGT1A1 p.Q331X and UGT1A1 form a dimer and provide an increased mechanistic understanding of CN-II. PMID- 24401910 TI - The mutation spectrum of the phenylalanine hydroxylase (PAH) gene and associated haplotypes reveal ethnic heterogeneity in the Taiwanese population. AB - Phenylalanine hydroxylase (PAH) deficiency is responsible for most cases of phenylketonuria (PKU). In this study of the PAH mutation spectrum in the Taiwanese population, 139 alleles were identified including 34 different mutations. The V190G, Q267R and F392I mutations are first reported in this study. The most common mutations, R241C, R408Q and Ex6-96A>G, account for 23.2%, 12.0% and 9.2%, of the mutant alleles, respectively. Haplotype analysis shows that R241C and Ex6-96A>G are exclusively associated with haplotype 4.3 to suggest founder effects. On the other hand, R408Q is found on two distinct haplotypes suggesting recurrent mutations. The spectrum of PAH mutations in Taiwan shows various links to those of other Asian regions, yet remarkable differences exist. Notably, R408Q, E286K and -4173_-407del, accounting for 21% of all mutant alleles in Taiwan, are very rare or are undetected among PKU cohorts of other Asian regions to suggest local founder effects. Moreover, the low homozygosity value of 0.092 hints at a high degree of ethnic heterogeneity within the Taiwanese population. Our study of PAH mutation spectrum and the associated haplotypes is useful for subsequent study on the origin and migration pattern via Taiwan, an island at the historical crossroad of migration of ancient populations. PMID- 24401912 TI - USB-driven microfluidic chips on printed circuit boards. AB - A technology is presented to fabricate a microfluidic chip in which the microchannels and the microelectrodes of sensors are integrated directly into the copper sheet on a printed circuit board. Then, we demonstrate an application of the generation of oil-in-water and water-in-oil emulsion droplets on this microfluidic chip driven by a USB interface, and the droplet size is detected by the microelectrodes on the downstream microchannel. The integration of the microfluidic chip is improved by the direct connection of the channels to the microelectrodes of the driving unit and of the sensors on the same substrate, and it is a promising way to integrate microfluidics into a more complex micro electrical-mechanical system (MEMS). PMID- 24401911 TI - Thymic stromal lymphopoietin variation, filaggrin loss of function, and the persistence of atopic dermatitis. AB - IMPORTANCE: Atopic dermatitis (AD) is a common chronic illness of childhood. OBJECTIVE: To evaluate the association between thymic stromal lymphopoietin (TSLP) variation and the persistence of skin symptoms of AD. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study was conducted in the general community. Participants included 796 children enrolled in the Pediatric Eczema Elective Registry. EXPOSURE Evaluation of TSLP variation. MAIN OUTCOMES AND MEASURES: Self reported outcome of whether a child's skin had no symptoms of AD and required no medications for 6 months at 6-month intervals. RESULTS: We evaluated 14 variants of TSLP. The variant rs1898671 was significantly associated with the outcome in white children (P = .01). As measured by overlapping CIs, similar odds ratios (ORs) were noted among whites (OR, 1.72; 95% CI, 1.11-2.66) and African Americans (1.33; 0.52-3.45). Further within the subcohort of individuals with a filaggrin protein (FLG) loss-of-function mutation, those with TSLP variation were more likely to have less-persistent disease (OR, 4.92; 95% CI, 2.04-11.86). CONCLUSIONS AND RELEVANCE: The TSLP variation is associated with less persistent AD. Therefore, TSLP may be a potential therapeutic target for the treatment of AD, especially in individuals with diminished barrier function due to FLG mutations. This is an attractive hypothesis that can be tested in clinical trials. PMID- 24401913 TI - Bouncing back: remission from depression in a 12-year panel study of a representative Canadian community sample. AB - PURPOSE: This study sought to investigate time to remission from depression in a community-based sample of adults followed for 12 years. METHODS: Data were derived from the National Population Health Survey (1994/5-2006/7 and 1996/7 2008/9). Fully 1,128 adults were included who were depressed at baseline according to DSM-III/CIDI-SF criteria. Kaplan-Meier and Cox proportional hazards procedures were used to determine time to remission and the demographic (e.g., gender and marital status), psychosocial (e.g., social support and adverse childhood experience) and health-related (e.g., pain, health conditions and alcohol use) factors with which it is associated. RESULTS: More than three quarters of the sample (77 %) no longer screened positive for depression at 2 years, and nearly the entire sample (94 %) had remitted by 12 years. Adverse childhood experiences (i.e., childhood abuse and parental additions), lack of social support, the presence of pain and health conditions (i.e., migraines, arthritis and back pain) each predicted more time to remission. The only factor associated with time to remission in the multivariate analysis was a history of childhood physical abuse. CONCLUSIONS: Most community members with depression get better after 2 years and nearly all will have remitted, at least once, by 12 years. The results of this study may help guide the development of interventions for chronic depression that focus on early prevention of childhood abuse. PMID- 24401914 TI - Another time point, a different story: one year effects of a social media intervention on the attitudes of young people towards mental health issues. AB - PURPOSE: This study extends an evaluation of a brief, social media intervention, called In One Voice, for raising mental health awareness and improving attitudes of youth and young adults towards mental health issues. METHODS: A successive independent samples design assessed market penetration and attitudinal changes among the young people who completed an online questionnaire 1 year after (T3: n = 438) the intervention. This is compared with two samples that completed a survey either immediately before (T1: n = 403) or 2 months after (T2: n = 403) the campaign launch. RESULTS: The proportion of respondents who remembered the campaign grew from 24.8 % at T2 to 48.6 % at T3. Elevated website activity on mindcheck.ca was sustained 1 year after In One Voice had ended. Small but significant reductions in personal stigma and social distance were detected from T1 and T3, which were not observed at T2. Respondents' self-rated ability to help others with mental health issues and to engage in positive behaviors relating to mental health issues (e.g., seeking information) did not improve significantly from T1 to T3. CONCLUSIONS: Improved attitudes towards mental health issues were observed among young people 1 year following a brief social media campaign. The campaign was less effective at providing the tools young people need to feel capable of helping someone who may be experiencing mental health issues, and motivating them to engage in constructive behaviors related to mental health. PMID- 24401915 TI - Biliary complications after liver transplantation from donation after cardiac death donors: an analysis of risk factors and long-term outcome from a single center. PMID- 24401916 TI - Reply to letter: "Influence of margins on overall survival after hepatic resection for colorectal metastasis: a meta-analysis". PMID- 24401917 TI - Using in situ simulation to evaluate operational readiness of a children's hospital-based obstetrics unit. AB - INTRODUCTION: Relocating obstetric (OB) services to a children's hospital imposes demands on facility operations, which must be met to ensure quality care and a satisfactory patient experience. We used in situ simulations to prospectively and iteratively evaluate operational readiness of a children's hospital-based OB unit before it opened for patient care. METHODS: This project took place at a 314-bed, university-affiliated children's hospital. We developed 3 full-scale simulation scenarios depicting a concurrent maternal and neonatal emergency. One scenario began with a standardized patient experiencing admission; the mannequin portrayed a mother during delivery. We ran all 3 scenarios on 2 dates scheduled several weeks apart. We ran 2 of the scenarios on a third day to verify the reliability of key processes. During the simulations, content experts completed equipment checklists, and participants identified latent safety hazards. Each simulation involved a unique combination of scheduled participants who were supplemented by providers from responding ancillary services. RESULTS: The simulations involved 133 scheduled participants representing OB, neonatology, and anesthesiology. We exposed and addressed operational deficiencies involving equipment availability, staffing, interprofessional communication, and systems issues such as transfusion protocol failures and electronic order entry challenges. Process changes between simulation days 1 to 3 decreased the elapsed time between transfusion protocol activation and blood arrival to the operating room and labor/delivery/recovery/postpartum setting. CONCLUSIONS: In situ simulations identified multiple operational deficiencies on the OB unit, allowing us to take corrective action before its opening. This project may guide other children's hospitals regarding care processes likely to require significant focus and possible modification to accommodate an OB service. PMID- 24401918 TI - Using simulation to study difficult clinical issues: prenatal counseling at the threshold of viability across American and Dutch cultures. AB - OBJECTIVE: Prenatal counseling at the threshold of viability is a challenging yet critically important activity, and care guidelines differ across cultures. Studying how this task is performed in the actual clinical environment is extremely difficult. In this pilot study, we used simulation as a methodology with 2 aims as follows: first, to explore the use of simulation incorporating a standardized pregnant patient as an investigative methodology and, second, to determine similarities and differences in content and style of prenatal counseling between American and Dutch neonatologists. METHODS: We compared counseling practice between 11 American and 11 Dutch neonatologists, using a simulation-based investigative methodology. All subjects performed prenatal counseling with a simulated pregnant patient carrying a fetus at the limits of viability. The following elements of scenario design were standardized across all scenarios: layout of the physical environment, details of the maternal and fetal histories, questions and responses of the standardized pregnant patient, and the time allowed for consultation. RESULTS: American subjects typically presented several treatment options without bias, whereas Dutch subjects were more likely to explicitly advise a specific course of treatment (emphasis on partial life support). American subjects offered comfort care more frequently than the Dutch subjects and also discussed options for maximal life support more often than their Dutch colleagues. CONCLUSIONS: Simulation is a useful research methodology for studying activities difficult to assess in the actual clinical environment such as prenatal counseling at the limits of viability. Dutch subjects were more directive in their approach than their American counterparts, offering fewer options for care and advocating for less invasive interventions. American subjects were more likely to offer a wider range of therapeutic options without providing a recommendation for any specific option. PMID- 24401919 TI - An in situ standardized patient-based simulation to train postpartum hemorrhage and team skills on a labor and delivery unit. PMID- 24401920 TI - Short-term and long-term impact of the central line workshop on resident clinical performance during simulated central line placement. AB - INTRODUCTION: The Central Line Workshop (CLW) was introduced at our institution to better train residents in safe placement of the central venous catheter (CVC). This study sought to determine if immediate performance improvements from the CLW are sustained 3 months after the training for residents with various levels of experience. METHODS: Twenty-six emergency medicine residents completed the CLW, which includes online modules and experiential sessions in anatomy, ultrasound, sterile technique, and procedural task training. Demonstration of the synthesis of these skills including placement of both internal jugular and subclavian CVCs was assessed using a task trainer. Each resident was also tested approximately 3 months before and 3 months after the CLW. Residents were assessed using a validated CVC proficiency scale. RESULTS: Residents' CVC proficiency scores (percentage of items performed correctly during the assessment station) improved after CLW (0.6 vs. 0.93, P < 0.05). At 3 months after CLW testing, there was apparent skill decay from the CLW but overall improvement compared with baseline testing (0.6 vs. 0.8, P < 0.05). There was no significant difference in procedure time after CLW training. The postgraduate year 1 group showed the greatest improvement of CVC skill after CLW training. CONCLUSIONS: Resident CVC placement performance improved immediately after the CLW. Although performance 3 months after the CLW revealed evidence of skill decay, it was improved when compared with initial baseline assessment. Novice learners had the greatest benefit from the CLW. PMID- 24401921 TI - Achieving optimal clinical outcomes in ultrasound-guided central venous catheterizations of the internal jugular vein after a simulation-based training program for novice learners. AB - INTRODUCTION: The aim of this study was to determine the number of ultrasound guided (USG) central venous catheterization (CVC) of the internal jugular vein (IJV) residents had to perform, after a simulation-based training program, to achieve optimal clinical outcomes. METHODS: We conducted a single-center, prospective, observational study in the medical intensive care unit of a university-affiliated teaching hospital. Residents participated in a formal training program, consisting of a simulation-based workshop and 5 supervised USG CVC insertions on patients. Subsequent USG CVC of the IJV performed by residents during their rotation were assessed. Data on the overall success (OS), first pass success (FP) and mechanical complication (MC) rates were serially collected over 2 years, spanning 4 cohorts of residents. RESULTS: Thirty-two residents performed a total of 337 USG CVC of the IJV. Residents had previously performed an average of 9 CVC via the landmark technique. None had performed USG CVC before. Results showed that residents improved in their OS, FP, and MC rates as they performed more USG CVC. Residents needed to perform 7 USG CVCs to achieve optimal clinical outcomes of high OS and FP as well as low MC rates. There was a significant improvement in OS, FP, and MC rates for the eighth and subsequent USG CVCs compared with the first 7 USG CVCs (82% vs. 99% [P < 0.001], 70% vs. 92% [P < 0.001] and 11% vs. 0%, respectively). CONCLUSIONS: After a formal training program consisting of a simulation-based workshop and 5 supervised USG CVCs on critically ill adults, residents were able to achieve optimal clinical outcomes after performing 7 procedures. PMID- 24401922 TI - Progress toward improving medical school graduates' skills via a "boot camp" curriculum. AB - INTRODUCTION: Medical school graduates are expected to possess a broad array of clinical skills. However, concerns have been raised regarding the preparation of medical students to enter graduate medical education. We designed a simulation based "boot camp" experience for students entering internal medicine residency and compared medical student performance with the performance of historical controls who did not complete boot camp. METHODS: This was a cohort study of a simulation-based boot camp educational intervention. Twenty medical students completed 2 days (16 hours) of small group simulation-based education and individualized feedback and skills assessment. Skills included (a) physical examination techniques (cardiac auscultation); technical procedures including (b) paracentesis and (c) lumbar puncture; (d) recognition and management of patients with life-threatening conditions (intensive care unit clinical skills/mechanical ventilation); and (e) communication with patients and families (code status discussion). Student posttest scores were compared with baseline scores of postgraduate year 1 (PGY-1) historical controls to assess the effectiveness of the intervention. RESULTS: Boot camp-trained medical students performed significantly better than PGY-1 historical controls on each simulated skill (P<0.01). Results remained significant after controlling for age, sex, and US Medical Licensing Examination step 1 and 2 scores (P<0.001). CONCLUSIONS: A 2-day simulation-based boot camp for graduating medical students boosted a variety of clinical skills to levels significantly higher than PGY-1 historical controls. Simulation-based education shows promise to help ensure that medical school graduates are prepared to begin postgraduate training. PMID- 24401923 TI - Unexpected consequences of simulator use in medical education: a cautionary tale. AB - Reform of medical education in Vienna in the early 19th century led to bodies of patients who had died being used as obstetric simulators. It was unpleasant, but it was thought that learning on a cadaver simulator would be superior to learning on phantoms (artificial simulators). Unfortunately, the change was associated with a significant increase in maternal mortality from puerperal fever and thousands of women died before Ignaz Philipp Semmelweis recognized that the condition was transmitted from the cadaver to the parturient and could be prevented by careful hand washing. A hundred fifty years later, the spread of infection on the hands of health care professionals is still a cause for concern. The apparently simple skill of cleaning hands and adherence to hand hygiene guidelines should be included in scenarios. We also need to make sure that current simulation-based training does not have unwanted consequences. PMID- 24401924 TI - Errors and error-producing conditions during a simulated, prehospital, pediatric cardiopulmonary arrest. AB - INTRODUCTION: Management of pediatric cardiac arrest challenges the skills of prehospital care providers. Errors and error-producing conditions are difficult to identify from retrospective records. The objective of this study was to identify errors committed by prehospital care providers and the underlying causes of those errors during a simulated pediatric cardiopulmonary arrest followed by a structured debriefing. METHODS: Performance criteria were defined prospectively by an advisory panel. Prehospital care providers from 6 emergency medical service agencies in Michigan participated in a simulation of an infant cardiopulmonary arrest using their own drugs, equipment, and protocols in a mobile trailer. Simulations were video recorded and played back during debriefings that were conducted immediately after the event to facilitate error analysis. Observed errors and subjects' explanations were analyzed by thematic qualitative assessment methods and descriptive statistics. RESULTS: One hundred ninety-four subjects, including paramedics, emergency medical technicians, and emergency medical responders in various crew configurations, participated in 60 simulation sessions during a 5-month period (April to August of 2010). Error types were classified into 4 clinically important themes as follows: failure to provide adequate ventilation, failure to provide effective circulation, failure to achieve vascular access rapidly, and medication errors. Multiple underlying causes of medication dosing and other errors were identified, including cognitive, procedural, communication, teamwork, and systems factors. CONCLUSIONS: We systematically observed many types of errors and identified some of the underlying causes during a simulated, prehospital, pediatric cardiopulmonary arrest. There were numerous, multifactorial, and sometimes, synergistic causes of medication dosing errors. Emergency medical service officials can use these findings to prevent future errors. PMID- 24401925 TI - Ignaz Semmelweis redux? AB - The story of Ignaz Semmelweis suggests a lesson to beware of unintended consequences, especially with in situ simulation. In situ simulation offers many important advantages over center-based simulation such as learning about the real setting, putting participants at ease, saving travel time, minimizing space requirements, involving patients and families. Some substantial disadvantages include frequent distractions, lack of privacy, logistics of setup, availability of technology, and supply costs. Importantly, in situ simulation amplifies some of the safety hazards of simulation itself including maintaining control of simulated medications and equipment, limiting the use of valuable hospital resources, preventing incorrect learning from simulation shortcuts, and profoundly upsetting patients and their families. Mitigating these hazards by labeling effectively, publishing policies and procedures, securing simulation supplies and equipment, educating simulation staff, and informing participants of the risks are all methods that may lessen the potential for an accident. Each requires a serious effort of analysis, design, and implementation. PMID- 24401926 TI - Alterations in bone mineral density and bone turnover markers in newly diagnosed adults with lymphoma receiving chemotherapy: a 1-year prospective pilot study. AB - BACKGROUND: Bone mineral density (BMD) loss is poorly defined in lymphoma patients. The aim of this study was to measure the extent of BMD loss in newly diagnosed lymphoma patients receiving chemotherapy. PATIENTS AND METHODS: This was a prospective, single-center study conducted in patients aged>=18 years with previously confirmed lymphoma treated by chemotherapy. Patients with low baseline BMD defined as Z/T-score less than or equal to -2.5 and/or history of osteoporotic fractures were excluded. BMD was measured at baseline before initiating chemotherapy and 1 year later. Predictive factors of BMD loss were investigated. RESULTS: Forty-one lymphoma patients (31 males and 10 females) receiving chemotherapy were enrolled. The median age at diagnosis was 59 (range: 19-86) years. Histological subtypes were predominantly diffuse large B-cell lymphoma (58%), mostly stage III-IV (54%). All patients received chemotherapy and 22% of patients received second-line treatment due to relapse or progressive disease. Thirty-two patients were evaluable at 1 year. The mean BMD changes were: -2.7%+/-3.9% for lumbar spine (P<0.001), -2.2%+/-7.6% for femoral neck (P<0.01) and -2.6%+/-4.5% for total hip (P<0.0001). In multivariate analysis, predictive factors of BMD loss at baseline were (i) at lumbar spine: female gender (P=0.01), higher lactate dehydrogenase level (P=0.04) and lower creatinine clearance (P=0.01); (ii) at total hip: lower albumin (P=0.01), higher corrected serum calcium (P<0.01), lower alkaline phosphatase (AP) (P<0.01) and autologous stem cell transplant (P=0.03); and (iii) at femoral neck: higher corrected serum calcium (P=0.02) and lower bone AP (P=0.01). CONCLUSION: Adult patients with known lymphoma receiving chemotherapy experienced significant BMD loss at 1 year. PMID- 24401927 TI - Muscle dysfunction in cancer patients. AB - BACKGROUND: Muscle dysfunction is a prevalent phenomenon in the oncology setting where patients across a wide range of diagnoses are subject to impaired muscle function regardless of tumor stage and nutritional state. Here, we review the current evidence describing the degree, causes and clinical implications of muscle dysfunction in cancer patients. The efficacy of exercise training to prevent and/or mitigate cancer-related muscle dysfunction is also discussed. DESIGN: We identified 194 studies examining muscular outcomes in cancer patients by searching PubMed and EMBASE databases. RESULTS: Muscle dysfunction is evident across all stages of the cancer trajectory. The causes of cancer-related muscle dysfunction are complex, but may involve a wide range of tumor-, therapy- and/or lifestyle-related factors, depending on the clinical setting of the individual patient. The main importance of muscle dysfunction in cancer patients lies in the correlation to vital clinical end points such as cancer-specific and all-cause mortality, therapy complications and quality of life (QoL). Such associations strongly emphasize the need for effective therapeutic countermeasures to be developed and implemented in oncology practice. Significant progress has been made over the last decade in the field of exercise oncology, indicating that exercise training constitutes a potent modulator of skeletal muscle function in patients with cancer. CONCLUSION: There are clear associations between muscle dysfunction and critical clinical end points. Yet there is a discrepancy between timing of exercise intervention trials, which can improve muscle function, and study populations in whom muscle function are proven prognostic important for clinical end points. Thus, future exercise trials should in early-stage patients, be powered to evaluate clinical outcomes associated with improvements in muscle function, or be promoted in advanced stage settings, aiming to reverse cancer related muscle dysfunction, and thus potentially improve time-to-progression, treatment toxicity and survival. PMID- 24401928 TI - Phase III trial of nonpegylated liposomal doxorubicin in combination with trastuzumab and paclitaxel in HER2-positive metastatic breast cancer. AB - BACKGROUND: Nonpegylated liposomal doxorubicin liposomal doxorubicin, (MyocetTM; Sopherion Therapeutics, Inc Canada, and Cephalon, Europe) (NPLD; Myocet((r))) in combination with trastuzumabHerceptin((r)) (Hoffmann-La Roche) has shown promising activity and cardiac safety. We conducted a randomized phase III trial of first-line NPLD plus trastuzumab and paclitaxel (Pharmachemie B.V.) (MTP) versus trastuzumab plus paclitaxel (TP) in patients with human epidermal growth factor 2 receptor (HER2)-positive metastatic breast cancer. PATIENTS AND METHODS: Patients were randomly assigned to NPLD (M, 50 mg/m(2) every 3 weeks for six cycles), trastuzumab (T, 4 mg/kg loading dose followed by 2 mg/kg weekly), and paclitaxel (P, 80 mg/m(2) weekly) or T + P at the same doses until progression or toxicity. The primary efficacy outcome was progression-free survival (PFS). RESULTS: One hundred and eighty-one patients were allocated to receive MTP, and 183 to TP. Median PFS was 16.1 and 14.5 months with MTP and TP, respectively [hazard ratio (HR) 0.84; two-sided P = 0.174]. In patients with estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors, PFS was 20.7 and 14.0 months, respectively [HR 0.68; 95% confidence interval (CI) 0.47-0.99]. Median overall survival (OS) was 33.6 and 28.9 months with MTP and TP, respectively (HR 0.79; two-sided P = 0.083). In ER- and PR-negative tumors, OS was 38.2 and 27.9 months, respectively (HR 0.63; 95% CI 0.42-0.93). The frequency of adverse events was higher with MTP, but there was no significant difference in cardiac toxicity between treatment arms. CONCLUSION(S): The trial failed to demonstrate a significant clinical improvement with the addition of M to TP regimen. The clinical benefit observed in an exploratory analysis in the ER- and PR-negative population deserves consideration for further clinical trials. CLINICAL TRIAL NUMBER: NCT00294996. PMID- 24401929 TI - Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study. AB - BACKGROUND: There is a need to develop surrogates for treatment efficacy in the neoadjuvant setting to speed-up drug development and stratify patients according to outcome. Preclinical studies showed that chemotherapy induces an antitumor immune response. In order to develop new surrogates for drug efficacy, we assessed the prognostic value of tumor-infiltrating lymphocytes (TIL) on residual disease after neoadjuvant chemotherapy (NACT) in patients with triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Three hundred four TNBC patients with residual disease after NACT were retrospectively identified in three different hospitals. Hematoxylin and eosin-stained slides from surgical postchemotherapy specimens were evaluated for intratumoral (It-TIL) and stromal (Str-TIL) TIL. Cases were classified as High-TIL if It-TIL and/or Str-TIL >60%. RESULTS: TIL were assessable for 278 cases. Continuous It-TIL and Str-TIL variables were strong prognostic factors in the multivariate model, both for metastasis-free [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.77-0.96, P = 0.01 and HR 0.85, 95% CI 0.75-0.98, P = 0.02 for Str-TIL and It-TIL, respectively] and overall survival (HR 0.86, 95% CI 0.77-0.97, P = 0.01 and HR 0.86, 95% CI 0.75 0.99, P = 0.03 for Str-TIL and It-TIL, respectively). The 5-year overall survival rate was 91% (95% CI 68% to 97%) for High-TIL patients (n = 27) and 55% (95% CI 48% to 61%) for Low-TIL patients (HR 0.19, 95% CI 0.06-0.61, log-rank P = 0.0017). The major prognostic impact of TIL was seen for patients with large tumor burden following NACT (residual tumor >2 cm and/or node metastasis). In all but one High-TIL case, It-TIL and Str-TIL values were lower on the prechemotherapy sample. CONCLUSIONS: The presence of TIL in residual disease after NACT is associated with better prognosis in TNBC patients. This parameter may represent a new surrogate of drug efficacy to test investigational agents in the neoadjuvant setting and a new prognostic marker to select patients at high risk of relapse. PMID- 24401930 TI - Preoperative chemotherapy in advanced resectable OCSCC: long-term results of a randomized phase III trial. AB - BACKGROUND: Data on preoperative chemotherapy in resectable oral cavity cancer are conflicting. We present the long-term results of a randomized trial of induction chemotherapy in resectable oral cavity cancer. PATIENTS AND METHODS: A randomized, parallel, multicentre trial evaluated the impact of three cycles of cisplatin 100 mg/m2 and fluorouracil 1000 mg/m2 (120-h infusion administered every 21 days) in stage T2-T4, N0-N2, previously untreated patients with advanced disease. Control group received upfront surgery. Postoperative radiation was offered to both arms when pathologic risk features were identified. The co primary end points were the occurrence of locoregional or distant tumour relapse, and death. RESULTS: Among the 198 enrolled patients, with a median follow-up of 11.5 years, there was no difference in the incidence of locoregional relapse between chemotherapy and control group (P=0.6337), nor in distant metastasis development (P=0.1527). There was also no difference between groups in overall survival (P=0.3402). Patients with a pathological complete response (pCR) had higher probability of survival than those without (10-year OS: 76.2% versus 41.3%, P=0.0004). Late toxicities in patients with a minimum follow-up of 60 months (42 in each group) were similar between arms, except from fibrosis (cumulative incidence 40% versus 22% in chemotherapy arm) and grade 2 dysphagia (14% versus 5%). CONCLUSIONS: Long-term follow-up of this randomized trial confirmed the absence of survival benefit with preoperative chemotherapy in oral cavity cancer. Late toxicity was similar in the two arms except for fibrosis and dysphagia, which were less in the chemotherapy arm. The survival benefit for patients achieving a pCR was maintained. PMID- 24401931 TI - Association of cardiovascular risk factors with disease severity in cerebral cavernous malformation type 1 subjects with the common Hispanic mutation. AB - BACKGROUND: Cerebral cavernous malformations (CCM) are enlarged vascular lesions affecting 0.1-0.5% of the population worldwide and causing hemorrhagic strokes, seizures, and neurological deficits. Familial CCM type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and is characterized by multiple brain lesions whose number and size increase with age. The number of lesions varies widely for unknown reasons, even among carriers of similar ages with the same mutation. The purpose of this study was to investigate whether cardiovascular (CV) risk factors influence potential markers of familial CCM1 disease severity, such as lesion count and history of intracerebral hemorrhage. METHODS: We analyzed baseline data from 185 Hispanic subjects, enrolled in the Brain Vascular Malformation Consortium study between June 2010 and March 2013. All subjects were carriers of the founder Q455X 'Common Hispanic Mutation' (CHM) in the KRIT1 gene, and had a clinical diagnosis of CCM or had an affected first- or second-degree relative with CCM. We performed a cross-sectional study, collecting detailed clinical information of CCM1-CHM subjects and cerebral susceptibility-weighted magnetic resonance imaging to assess lesion count. Linear or logistic regression analysis of log-lesion count or history of intracerebral hemorrhage and CV risk factors (age, gender, obesity, diabetes, hypertension, hyperlipidemia and smoking status) and related quantitative traits (body mass index, glycosylated hemoglobin levels, blood pressure, lipids levels and pack-years of cigarette smoking) was performed accommodating familial clustering. RESULTS: CCM1-CHM subjects were mainly female (63.8%) and symptomatic at presentation (63.2%). Lesion count was highly variable (mean +/- SD: 57.7 +/- 110.6; range: 0-713); 90% of CCM1-CHM subjects had multiple lesions at enrollment. Age (p < 0.001) was positively correlated with lesion count and male gender (p = 0.035) was associated with a greater number of lesions. Obesity (p = 0.001) and higher body mass index (p = 0.002) were associated with fewer lesions. No association with hypertension was detected, however, systolic blood pressure (p = 0.002) was associated with fewer lesions. No significant association with lesion count was observed for diabetes, hyperlipidemia, smoking status or for related quantitative traits. History of intracerebral hemorrhage was not significantly associated with any CV risk factors, however, we found borderline associations of hemorrhage with obesity (p = 0.062), systolic blood pressure (p = 0.083) and pack-years of cigarette smoking (p = 0.055). After correction for multiple testing, age and obesity remained significantly associated with lesion count in CCM1-CHM subjects. CONCLUSIONS: These results suggest that several CV risk factors explain some of the variability in lesion count in Hispanic CCM1-CHM subjects. Although age, gender, obesity, body mass index and systolic blood pressure may influence familial CCM1 disease severity, further longitudinal studies in larger sample sizes are essential to confirm these findings. PMID- 24401932 TI - Structured mRNA induces the ribosome into a hyper-rotated state. AB - During protein synthesis, mRNA and tRNA are moved through the ribosome by the process of translocation. The small diameter of the mRNA entrance tunnel only permits unstructured mRNA to pass through. However, there are structured elements within mRNA that present a barrier for translocation that must be unwound. The ribosome has been shown to unwind RNA in the absence of additional factors, but the mechanism remains unclear. Here, we show using single molecule Forster resonance energy transfer and small angle X-ray scattering experiments a new global conformational state of the ribosome. In the presence of the frameshift inducing dnaX hairpin, the ribosomal subunits are driven into a hyper-rotated state and the L1 stalk is predominantly in an open conformation. This previously unobserved conformational state provides structural insight into the helicase activity of the ribosome and may have important implications for understanding the mechanism of reading frame maintenance. PMID- 24401933 TI - Poison running through my veins. PMID- 24401934 TI - [Nasopharyngeal space-occupying lesion with middle ear effusion. Malignant or benign?]. AB - Warthin tumors (cystadenolymphoma, cystadenoma lymphomatosum papilliferum) account for approximately 10-15 % of all benign salivary gland tumors and are bilateral in approximately 10-15 %, as well as extraparotideal in approximately 8 % of cases. Nasopharyngeal Warthin tumors are extremely rare; however they should be borne in mind as a consideration of differential diagnostics. Furthermore, parotid glands and cervical lymph nodes should be examined as associated synchronous or metachronous manifestations are possible. Palpation, sonography and other radiological imaging of the cervical region, if applicable, might be required. PMID- 24401935 TI - Sitting height and sitting height/height ratio references for Turkish children. AB - Sitting height (SHt) measurements and sitting height/height (SHt/Ht) ratio are important criteria in the diagnosis of growth problems and particularly in the diagnosis of dysproportionate growth. It is known that body proportions are related to genetic influences and show variations among different populations. This study aimed to provide reference data on SHt and SHt/Ht ratios for Turkish children of ages 6-18 years. SHt measurements were performed on a sample of 1,100 boys and 1,020 girls between 6 and 18 years of age attending primary and secondary schools located in six different districts of Istanbul city. Criteria advanced by WHO for establishing reference standards for growth were observed in the study design. The sample consisted of a mixture of children measured only once and those measured at follow-up over different periods of time. Parallel to increase in Ht, SHt increased with age. Mean value for SHt/Ht ratio was 55-56% at ages 6 to 8.5 years in both sexes. In girls, this value started to decrease at age 11.5 years and remained between 53% and 54% thereafter. In the boys, a decrease to 52-53% was noted in the SHt/Ht ratio after age 12 years. In both sexes, SHt/Ht ratio decreased with puberty, demonstrating that growth in trunk length exceeded growth in limb length in midpubertal ages. These changes occurred at an earlier age in the girls. Values obtained for SHt/Ht ratios in Turkish children were high as compared to Dutch children and low as compared to Chinese children. CONCLUSION: This study, by providing reference data on sitting height and sitting height/height ratios in Turkish children of ages between 6 and 18 years, will be useful in the diagnosis and follow-up of children with growth problems. This study also supports the view that body proportions are influenced by genetic makeup. PMID- 24401936 TI - Leopard syndrome: a report of five cases from one family in two generations. AB - This is the first reported family with Leopard syndrome (LS) from Bosnia and Herzegovina. We report five cases of LS from two generations of the same family. In the present series of patients from one family, all patients carry the same recurrent mutation Y279C in the PTPN11 gene, exhibiting different phenotypes and a variable expression of multiple lentigines. The diagnosis may be on clinical basis as the diagnostic clues of LS are: multiple lentigines and cafe-au-lait spots, short stature, distinctive face, congenital heart disease, conduction abnormalities, abnormal genitalia, and sensorineural deafness. CONCLUSION: the clinical diagnosis of LS should be molecularly confirmed in the patient. PMID- 24401937 TI - A call to craft. AB - Educational institutions must begin training tissue engineers to think as both biomedical investigators and fabricators. PMID- 24401938 TI - Mastering translational medicine: interdisciplinary education for a new generation. AB - Graduate-level education in translational medicine will require more than just scientific research. PMID- 24401940 TI - Altered placebo and drug labeling changes the outcome of episodic migraine attacks. AB - Information provided to patients is thought to influence placebo and drug effects. In a prospective, within-subjects, repeated-measures study of 66 subjects with episodic migraine, we investigated how variations in medication labeling modified placebo and drug effects. An initial attack with no treatment served as a control. In six subsequent migraine attacks, each participant received either placebo or Maxalt (10-mg rizatriptan) administered under three information conditions ranging from negative to neutral to positive (told placebo, told Maxalt or placebo, told Maxalt) (N = 459 documented attacks). Treatment order was randomized. Maxalt was superior to placebo for pain relief. When participants were given placebo labeled as (i) placebo, (ii) Maxalt or placebo, and (iii) Maxalt, the placebo effect increased progressively. Maxalt had a similar progressive boost when labeled with these three labels. The efficacies of Maxalt labeled as placebo and placebo labeled as Maxalt were similar. The efficacy of open-label placebo was superior to that of no treatment. Relative to no treatment, the placebo, under each information condition, accounted for more than 50% of the drug effect. Increasing "positive" information incrementally boosted the efficacy of both placebo and medication during migraine attacks. The benefits of placebo persisted even if placebo was honestly described. Whether treatment involves medication or placebo, the information provided to patients and the ritual of pill taking are important components of care. PMID- 24401939 TI - A generally applicable translational strategy identifies S100A4 as a candidate gene in allergy. AB - The identification of diagnostic markers and therapeutic candidate genes in common diseases is complicated by the involvement of thousands of genes. We hypothesized that genes co-regulated with a key gene in allergy, IL13, would form a module that could help to identify candidate genes. We identified a T helper 2 (TH2) cell module by small interfering RNA-mediated knockdown of 25 putative IL13 regulating transcription factors followed by expression profiling. The module contained candidate genes whose diagnostic potential was supported by clinical studies. Functional studies of human TH2 cells as well as mouse models of allergy showed that deletion of one of the genes, S100A4, resulted in decreased signs of allergy including TH2 cell activation, humoral immunity, and infiltration of effector cells. Specifically, dendritic cells required S100A4 for activating T cells. Treatment with an anti-S100A4 antibody resulted in decreased signs of allergy in the mouse model as well as in allergen-challenged T cells from allergic patients. This strategy, which may be generally applicable to complex diseases, identified and validated an important diagnostic and therapeutic candidate gene in allergy. PMID- 24401941 TI - A blood-resistant surgical glue for minimally invasive repair of vessels and heart defects. AB - Currently, there are no clinically approved surgical glues that are nontoxic, bind strongly to tissue, and work well within wet and highly dynamic environments within the body. This is especially relevant to minimally invasive surgery that is increasingly performed to reduce postoperative complications, recovery times, and patient discomfort. We describe the engineering of a bioinspired elastic and biocompatible hydrophobic light-activated adhesive (HLAA) that achieves a strong level of adhesion to wet tissue and is not compromised by preexposure to blood. The HLAA provided an on-demand hemostatic seal, within seconds of light application, when applied to high-pressure large blood vessels and cardiac wall defects in pigs. HLAA-coated patches attached to the interventricular septum in a beating porcine heart and resisted supraphysiologic pressures by remaining attached for 24 hours, which is relevant to intracardiac interventions in humans. The HLAA could be used for many cardiovascular and surgical applications, with immediate application in repair of vascular defects and surgical hemostasis. PMID- 24401942 TI - Piperine reverses chronic unpredictable mild stress-induced behavioral and biochemical alterations in rats. AB - Previous studies in our laboratory have demonstrated that piperine produced antidepressant-like action in various mouse models of behavioral despair, which was related to the serotonergic system. The present study aimed to examine the behavioral and biochemical effects of piperine in rats exposed to chronic unpredictable mild stress (CUMS). The results showed that CUMS caused depression like behavior in rats, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test. In addition, it was found that serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) contents in the hippocampus and frontal cortex were significantly decreased in CUMS-treated rats. Treating the animals with piperine significantly suppressed behavioral and biochemical changes induced by CUMS. The results suggest that piperine produces an antidepressant-like effect in CUMS-treated rats, which is possibly mediated by increasing 5-HT and BDNF contents in selective brain tissues. PMID- 24401943 TI - Treatment of superficial vascular lesions with the KTP 532-nm laser: experience with 647 patients. AB - Superficial vascular lesions are a common dermatological diagnosis but are often difficult to treat. Numerous lasers (especially the dye laser) and intense pulsed light sources have been used, but there have been very few reports on the effectiveness of the potassium-titanyl phosphate (KTP) laser. We have extensive experience of this modality at our institution, and the purpose of this survey is to report on the safety and efficacy of the KTP laser. Using an in-house database, we retrospectively collected data from patients who had undergone treatment with the KTP laser for superficial vascular lesions. Patients of Fitzpatrick skin type I-IV were included. Exclusion criteria were Fitzpatrick skin type V, patients with obvious suntan and those on potentially phototoxic medications or minocycline therapy. Diagnoses included discrete or matted telangiectasia, strawberry naevus, spider angioma, rosaceal erythema, rosaceal telangiectasia, telangiectatic naevus, angioma, combined rosaceal erythema/telangiectasia, port-wine stain, venous lake haemangioma and hereditary haemorrhagic telangiectasia. Patients underwent an initial test treatment and further treatment at 6-week intervals as required. Clinical photographs were taken pre- and post-treatment, and outcome was graded by patient and physician. Adverse effects were recorded including scarring, hypo- or hyperpigmentation, marked swelling, blistering, scabbing and bruising. Six hundred forty-seven patients with 13 diagnoses on 9 different body sites were recorded. Four hundred eighty-six were female, and the median age was 39.5 years. Of the lesions treated, 33.7 % (n = 218) were discrete telangiectases and 31.8 % (n = 206) were spider angiomas. A 92.7 % of lesions were on the face. Four hundred thirteen (77.6 %) patients who had outcomes recorded at 6 weeks were graded as "clearance" or "marked improvement". Only 38 (5.8 %) patients experienced adverse effects, all of which were minor; the main adverse effect was swelling. Unlike the dye laser, there was only one case of bruising out of 647 patients. This is the largest survey of patients to have undergone KTP laser treatment reported in the literature. Our results show that the KTP laser is a safe and effective modality for the treatment of superficial vascular lesions. PMID- 24401944 TI - Characterization on ablation performance of various surgical fibers. AB - Laser light has been widely used as a surgical tool to treat benign prostate hyperplasia (BPH). Various surgical parameters still need to be tested and optimized to accomplish better clinical outcomes. The purpose of the current study is to investigate the effect of fiber core size on ablation performance at various laser power levels. Three optical fibers (600, 775, and 850 MUm) were tested in vitro with a customized 532-nm laser system with power ranging from 120 to 180 W. Ablation performance was evaluated in light of total energy, irradiance, and volumetric energy density. Irrespective fiber size, crater dimension, and ablation volume linearly increased with the incident irradiance. However, each fiber created different geometry of ablation craters (i.e., deep columnar shape for 600 MUm vs. shallow funnel shape for 850 MUm). Smaller fiber size demonstrated the efficient energy usage for tissue removal. In-depth comprehension of fiber performance can help accomplish predictable and efficient surgical procedures for BPH therapy. PMID- 24401945 TI - Conformational changes of graphene nanosheets induced by metal: melting metal can spin a graphene cocoon to encapsulate itself. AB - Graphene nanosheets can be driven to change their conformation by melting metal and, finally, a cocoon coating can be constructed to encapsulate the metal sphere. Interaction beween metal and oxygenated defects plays a leading role in conformational changes of graphene nanosheets. PMID- 24401946 TI - Performance of coagulation tests in patients on therapeutic doses of rivaroxaban. A cross-sectional pharmacodynamic study based on peak and trough plasma levels. AB - Knowledge of anticoagulation status during rivaroxaban therapy is desirable in certain clinical situations. It was the study objective to determine coagulation tests most useful for assessing rivaroxaban's anticoagulant effect. Peak and trough blood samples from 29 patients taking rivaroxaban 20 mg daily were collected. Mass spectrometry and various coagulation assays were performed. "On therapy range" was defined as the rivaroxaban concentrations determined by LC MS/MS. A "misprediction percentage" was calculated based on how often results of each coagulation assay were in the normal reference range, while the rivaroxaban concentration was in the "on-therapy" range. The on-therapy range was 8.9-660 ng/ml. The misprediction percentages for prothrombin time (PT) and activated partial thromboplastin time (aPTT), using multiple reagents and coagulometers, ranged from 10%-52% and 31%-59%, respectively. PT, aPTT and activated clotting time (ACT) were insensitive to trough rivaroxaban: 59%, 62%, and 80% of samples had a normal result, respectively. Over 95% of PT and ACT values were elevated at peak. Four different rivaroxaban calibrated anti-Xa assays had R2 values >0.98, demonstrating strong correlations with rivaroxaban drug levels. In conclusion, PT, aPTT and ACT are often normal in patients on therapeutic doses of rivaroxaban. However, PT and ACT may have clinical utility at higher drug plasma levels. Rivaroxaban calibrated anti-factor Xa assays can accurately identify low and high on-therapy rivaroxaban drug levels and, therefore, have superior utility in all clinical situations where assessment of anticoagulation status may be beneficial. PMID- 24401947 TI - beta-catenin deacetylation is essential for WNT-induced proliferation of breast cancer cells. AB - Deregulation of the WNT signaling pathway is associated with the development and progression of breast cancer. beta-catenin mutations have been found to constitutively activate beta-catenin-T-cell factor (TCF) signaling in other types of cancer. beta-catenin acetylation regulates beta-catenin-TCF4 interaction in WNT signaling, but it remains unknown whether the acetylation of beta-catenin is involved in WNT-induced proliferation of breast cancer cells. In this study, a lower level of acetylated beta-catenin (K345) was observed in breast cancer tissues. WNT3A stimulated the downregulation of beta-catenin acetylation and promoted the proliferation of MCF7 cells. The K345Q mutation in beta-catenin inhibited WNT-induced cell growth and axin2/TCF7 upregulation in breast cancer cells. By contrast, K345R mutants could mimic deacetylated beta-catenin to generate the WNT-elicited phenotype. Additionally, the acetylation of beta catenin may prime beta-catenin for phosphorylation. Further investigation revealed that the deacetylase HDAC6 was responsible for WNT-induced deacetylation of beta-catenin in breast cancer cells. In conclusion, the epigenetic modification of beta-catenin may be essential for WNT signaling in breast cancer progression, and blocking the occurrence of beta-catenin acetylation may provide a novel therapeutic approach for breast cancer. PMID- 24401949 TI - Paper-based microfluidics with high resolution, cut on a glass fiber membrane for bioassays. AB - In this report, we describe a simple, low-cost, straight forward and highly reproducible fabrication method of microfluidic systems. This system was cut on a glass fiber membrane by a common cutter without using any other sophisticated equipment or organic solvents. This format represents a novel type of paper-based microfluidics with high resolution of the microchannel down to ~137 MUm, comparable to those made by conventional photolithography. We successfully applied this method to microfluidics to create a star micro-array format of multiplexed urine tests in this study. PMID- 24401950 TI - Factor XIII deficiency management: a review of the literature. AB - Factor XIII (FXIII) deficiency is a rare congenital bleeding disorder estimated to affect 1 in 2 million live births. Treatment often involves prophylaxis with FXIII concentrate and is especially important in preventing intracranial hemorrhage (ICH) and maintaining pregnancy in women of childbearing age. The rarity of this condition and lack of good quality evidence has resulted in a literature largely based on case reports/case series. A review of the literature was conducted in order to provide information about the optimal management of FXIII deficiency. Articles were identified by searching MEDLINE from 1961 to June 2012. Eligible studies included details on patients with FXIII deficiency that received treatment. Information collected included dose, frequency, duration, hemostatic efficacy and adverse events. Of 606 abstracts reviewed, 43 articles, including a total of 328 patients met the selection criteria. Common bleeding manifestations included umbilical cord bleeding, ICH and hematomas. Patients were generally placed on prophylactic factor replacement therapy upon diagnosis of severe or symptomatic FXIII deficiency, which decreased and/or prevented bleeding episodes. Patients with FXIII deficiency that received prophylactic treatment successfully maintained pregnancies. Alternative treatments included the use of cryoprecipitate or frozen plasma when FXIII concentrate was not available or affordable. Recent studies of a new recombinant FXIII concentrate show promising results in regards to safety and efficacy. There are limited data to guide the optimal treatment of FXIII deficiency. Larger patient registries and international collaborations are needed to improve the evidence and enhance clinical outcomes in this rare bleeding disorder. PMID- 24401948 TI - Self-consumption: the interplay of autophagy and apoptosis. AB - Autophagy and apoptosis control the turnover of organelles and proteins within cells, and of cells within organisms, respectively, and many stress pathways sequentially elicit autophagy, and apoptosis within the same cell. Generally autophagy blocks the induction of apoptosis, and apoptosis-associated caspase activation shuts off the autophagic process. However, in special cases, autophagy or autophagy-relevant proteins may help to induce apoptosis or necrosis, and autophagy has been shown to degrade the cytoplasm excessively, leading to 'autophagic cell death'. The dialogue between autophagy and cell death pathways influences the normal clearance of dying cells, as well as immune recognition of dead cell antigens. Therefore, the disruption of the relationship between autophagy and apoptosis has important pathophysiological consequences. PMID- 24401951 TI - The effect of left ventricular remodelling on soluble ST2 in a cohort of hypertensive subjects. AB - Soluble ST2 is a biomarker of cardiomyocyte stretch that is useful in the diagnosis and prognosis of coronary artery disease. Its role in the field of hypertension and hypertensive heart failure (HHF) has not yet been well investigated. We studied the effect of left ventricular remodelling on the concentration of soluble ST2 in a cohort of 210 subjects with hypertension (HT). Left ventricular hypertrophy (LVH) was considered present when echocardiographic left ventricular mass indexed for height in metres (m) was greater than 46.2 g m( 1 2.7) in women and 49.2 g m(-1 2.7) in men. Subjects were subdivided into three groups: those without LVH (HT, n = 83); those with LVH (hypertension with left ventricular hypertrophy (HTLVH), n = 50) and those with HHF, n=77). Plasma ST2 and NT-pro BNP were measured using electrochemiluminescence type immunoassay. Subjects with HHF had higher plasma ST2 concentrations compared to HTLVH (134.7 +/- 57.3 ng ml(-1) versus 23.0 +/- 8.3 ng ml(-1), P < 0.001) and those with HT (134.7 +/- 57.3 ng ml(-1) versus 14.5 +/- 4.9 ng ml(-1), P < 0.0001). NT-pro BNP levels were similar when HTLVH was compared with HT (P = 0.68), but subjects with HHF had significantly higher NT-pro BNP compared to HTLVH (P < 0.0002). Soluble ST2 had strong correlation with clinical and echocardiograhic parameters, and correlated well with NT-pro BNP (r = 0.41, P < 0.0001). Plasma ST2 is a useful biomarker in not only differentiating HHF from HT with or without LVH, but also distinguishes hypertensive LVH from HT without LVH. PMID- 24401952 TI - Differential gene expression of bradykinin receptors 1 and 2 in peripheral monocytes from patients with essential hypertension. AB - Bradykinin participates in various hypertensive processes, exerted via its type 1 and type 2 receptors (BKR1 and BKR2). The aim of the study was to investigate BKR1 and BK2R gene expression in peripheral monocytes in patients with essential hypertension compared with healthy individuals. Seventeen hypertensive patients (9 males, age 56 +/- 7 years) and 12 healthy individuals (7 males, age 55 +/- 6) participated. Mononuclear cells isolated using anti-CD14+ antibodies and mRNAs of BKR1 and BKR2 were estimated by real-time quantitative reverse transcription-PCR. Both BKR1 and BKR2 showed significantly upregulated gene expression in the group of hypertensive patients. Specifically, BKR1 gene expression was 142.1 +/- 42.2 in hypertensives versus 20.2 +/- 8 in controls (P = 0.024) and BKR2 was 1222.2 +/ 361.6 in hypertensives versus 259.5 +/- 99.1 in controls (P = 0.038). Antihypertensive treatment resulted in a decrease in BKR1 (from 142.1 +/- 42.2 to 55.2 +/- 17.1, P = 0.065) and in BKR2 (from 1222.2 +/- 361.6 to 256.8 +/- 81.8, P = 0.014) gene expression. BKR1 and BKR2 gene expression on peripheral monocytes is upregulated in essential hypertension. This may lead to functional changes in monocytes and contribute to the development of target organ damage in hypertensive patients. PMID- 24401953 TI - Attenuated NOx responses and myocardial ischemia, a possible risk for structural vascular disease in African men: the SABPA study. AB - Chronically elevated blood pressure has been associated with impaired NO-mediated vasodilation and structural vascular disease risk. This study aimed to determine whether significant associations exist regarding NO metabolite (NOx) responses, cardiovascular function and structural vascular disease in a cohort of African and Caucasian men. The study included 81 African and 94 Caucasian male teachers stratified via median splits into low and high NOx ethnic groups. Ambulatory blood pressure, electrocardiogram monitoring and ultrasound carotid intima-media thickness (CIMT) images were obtained. Cardiovascular measurements and fasting blood for NOx responses were measured during rest and on challenging the cardiovascular system with the Stroop colour-word conflict test. African men displayed significantly higher resting NOx as well as higher number of 24 h silent ischemic events than their Caucasian counterparts. Low NOx African men displayed enhanced alpha-adrenergic and ECG ST segment depression acute mental stress responses as well as 24 h silent ischemic events associated with CIMT (adjusted R(2) = 0.47; beta = 0.25; confidence interval (CI) = 0.13, 0.41). African men demonstrated a vulnerable cardiovascular profile. Novel findings revealed alpha-adrenergic-driven blood pressure responses and less NO bioavailability during acute stress. The association between myocardial ischemia and CIMT in this group emphasized their risk for future coronary artery disease and cerebrovascular events. PMID- 24401954 TI - Heart rate and heart rate variability in resistant versus controlled hypertension and in true versus white-coat resistance. AB - Sympathetic nervous system has an important role in resistant hypertension. Heart rate (HR) is a marker of sympathetic activity, but its association with resistant hypertension has not been assessed. We aimed to evaluate differences in HR values and variability between resistant and controlled patients and between true and white-coat resistant hypertensives (RHs). We compared office and ambulatory HR, nocturnal dip and s.d. in 14,627 RHs versus 11,951 controlled patients (on ? 3 drugs) and in 8730 true (24 h blood pressure (BP) ? 130 and/or 80 mm Hg) versus 4825 white-coat (24-h BP < 130/80 mm Hg) RHs. After adjusting for age, gender, body mass index, diabetes status and beta blocker use, HR values and variability were significantly elevated in resistant versus controlled patients and in true versus white-coat RHs. In logistic regression models, after adjustment for confounders, office HR (odds ratio for each increase in tertile: 1.337; 95% confidence interval: 1.287-1.388; P < 0.001), nocturnal dip (0.958; 0.918-0.999; P = 0.035) and night time s.d. (1.115; 1.057-1.177; P = 0.013) were all significantly associated with the presence of resistant hypertension. Moreover, night time HR (1.160; 1.065-1.265; P < 0.001), nocturnal dip (0.876; 0.830-0.925; P < 0.001) and 24-h s.d. (1.148; 1.092-1.207; P < 0.001) were all significantly associated with true resistant hypertension. In conclusion, both increased HR and variability are associated with resistant hypertension and with true resistance. These suggest the involvement of the sympathetic nervous system in the development of resistance to antihypertensive treatment. PMID- 24401955 TI - Lack of changes in carotid artery compliance with systemic nitric oxide synthase inhibition. AB - Proximal large elastic arteries (ascending aorta and carotid artery) have an important role in buffering the pulsatile pressure generated from the left ventricle, which forwards continuous peripheral blood flow and protects the brain microcirculation from end-organ damage. Although compliance of distal conduit arteries (extremities' arteries) is attenuated by the nitric oxide synthase (NOS) inhibition, it is yet unknown whether compliance of proximal elastic arteries changes by the systemic NOS inhibition. To address this question, we measured central artery compliance in 17 young adults (26+/-1 years) who underwent intravenous infusions of N(G)-monomethyl-L-arginine (L-NMMA) or saline (placebo) on separate days. Following the systemic NOS inhibition, the mean arterial pressure (MAP), total peripheral resistance and aortic augmentation index were significantly increased. However, carotid artery compliance was not affected significantly (from 0.10+/-0.01 to 0.11+/-0.01 mm2) per mmHg) and the beta stiffness index (an index of arterial compliance adjusted for the distending pressure) tended to decrease (from 6.63+/-0.35 to 6.06+/-0.42 a.u., P=0.07). These parameters were not altered with saline infusion. Changes in the beta stiffness index tended to correlate negatively with the corresponding changes in MAP (r = -0.31, P=0.07). These results suggest that carotid artery compliance remains unchanged during the systemic NOS inhibition in spite of systemic vasoconstriction. PMID- 24401957 TI - The plant secretory pathway: an essential factory for building the plant cell wall. AB - For building and maintaining the complex structure of the surrounding wall throughout their life, plant cells rely on the endomembrane system, which functions as the main provider and transporter of cell wall constituents. Efforts to understand the mechanisms of synthesis and transport of cell wall materials have been generating valuable information for diverse practical applications. Nonetheless, the identity of the endomembrane components necessary for the transport of cell wall enzymes and polysaccharides is not well known. Evidence indicates that plant cells can accomplish secretion of cell wall constituents through multiple pathways during development or under stress conditions and, that compared with other eukaryotes, they rely on a highly diversified toolkit of proteins for membrane traffic. This suggests that production of the cell wall in plants consists of intricate and highly regulated pathways. In this review, we summarize important discoveries that have allowed the activities of the plant secretory pathway to be linked to the production and deposition of cell wall synthesizing enzymes and polysaccharides. PMID- 24401958 TI - Excess electrons in ice: a density functional theory study. AB - We present a density functional theory study of the localization of excess electrons in the bulk and on the surface of crystalline and amorphous water ice. We analyze the initial stages of electron solvation in crystalline and amorphous ice. In the case of crystalline ice we find that excess electrons favor surface states over bulk states, even when the latter are localized at defect sites. In contrast, in amorphous ice excess electrons find it equally favorable to localize in bulk and in surface states which we attribute to the preexisting precursor states in the disordered structure. In all cases excess electrons are found to occupy the vacuum regions of the molecular network. The electron localization in the bulk of amorphous ice is assisted by its distorted hydrogen bonding network as opposed to the crystalline phase. Although qualitative, our results provide a simple interpretation of the large differences observed in the dynamics and localization of excess electrons in crystalline and amorphous ice films on metals. PMID- 24401956 TI - High CO2 triggers preferential root growth of Arabidopsis thaliana via two distinct systems under low pH and low N stresses. AB - Biomass allocation between shoots and roots is an important strategy used by plants to optimize growth in various environments. Root to shoot mass ratios typically increase in response to high CO2, a trend particularly evident under abiotic stress. We investigated this preferential root growth (PRG) in Arabidopsis thaliana plants cultivated under low pH/high CO2 or low nitrogen (N)/high CO2 conditions. Previous studies have suggested that changes in plant hormone, carbon (C) and N status may be related to PRG. We therefore examined the mechanisms underlying PRG by genetically modifying cytokinin (CK) levels, C and N status, and sugar signaling, performing sugar application experiments and determining primary metabolites, plant hormones and expression of related genes. Both low pH/high CO2 and low N/high CO2 stresses induced increases in lateral root (LR) number and led to high C/N ratios; however, under low pH/high CO2 conditions, large quantities of C were accumulated, whereas under low N/high CO2 conditions, N was severely depleted. Analyses of a CK-deficient mutant and a starchless mutant, in conjunction with sugar application experiments, revealed that these stresses induce PRG via different mechanisms. Metabolite and hormone profile analysis indicated that under low pH/high CO2 conditions, excess C accumulation may enhance LR number through the dual actions of increased auxin and decreased CKs. PMID- 24401959 TI - Surveillance imaging in children with malignant CNS tumors: low yield of spine MRI. AB - Magnetic resonance imaging (MRI) is routinely obtained in patients with central nervous system (CNS) tumors, but few studies have been conducted to evaluate this practice. We assessed the benefits of surveillance MRI and more specifically spine MRI in a contemporary cohort. We evaluated MRI results of children diagnosed with CNS tumors from January 2000 to December 2011. Children with at least one surveillance MRI following the diagnosis of medulloblastoma (MB), atypical teratoid rhabdoid tumor (ATRT), pineoblastoma (PB), supratentorial primitive neuroectodermal tumor, supratentorial high-grade glioma (World Health Organization grade III-IV), CNS germ cell tumors or ependymoma were included. A total of 2,707 brain and 1,280 spine MRI scans were obtained in 258 patients. 97% of all relapses occurred in the brain and 3% were isolated to the spine. Relapse was identified in 226 (8%) brain and 48 (4%) spine MRI scans. The overall rate of detecting isolated spinal relapse was 9/1,000 and 7/1,000 for MB patients. MRI performed for PB showed the highest rate for detecting isolated spinal recurrence with 49/1,000. No initial isolated spinal relapse was identified in patients with glioma, supratentorial primitive neuroectodermal tumor and ATRT. Isolated spinal recurrences are infrequent in children with malignant CNS tumors and the yield of spine MRI is very low. Tailoring surveillance spine MRI to patients with higher spinal relapse risk such as PB, MB with metastatic disease and within 3 years of diagnosis could improve allocation of resources without compromising patient care. PMID- 24401961 TI - Accuracy in reporting past psychiatric symptoms: the role of cross-sectional studies in psychiatric research. PMID- 24401962 TI - Intravenous fluids: the tale goes on. PMID- 24401960 TI - Phenotypic and functional characterization of Glioblastoma cancer stem cells identified through 5-aminolevulinic acid-assisted surgery [corrected]. AB - 5-aminolevulinic acid (5-ALA) introduction in the surgical management of Glioblastoma (GBM) enables the intra-operatively identification of cancer cells in the mass by means of fluorescence. Here, we analyzed the phenotype of GBM cells isolated from distinct tumour areas determined by 5-ALA (tumour core, 5-ALA intense and vague layers) and the potency of 5-ALA labelling in identifying GBM cells and cancer stem cells (CSCs) in the mass. 5-ALA identified distinct layers in the mass, with less differentiated cells residing in the core of the tumour. 5 ALA was able to stain up to 68.5% of CD133(+) cells in the 5-ALA intense layer and, although 5-ALA(+) cells retrieved from different tumour areas contained a similar proportion of CD133(+) cells (range 27.5-35.6%), those from the vague layer displayed the lowest ability to self-renew. In conclusion, our data demonstrate that a substantial amount of GBM cells and CSCs in the mass are able to avoid 5-ALA labelling and support the presence of heterogenic CSC populations in the GBM mass. PMID- 24401963 TI - Investing in antimicrobial resistance research. PMID- 24401965 TI - Demystifying encephalitis: guidelines for an emergency not to miss. PMID- 24401966 TI - Non-motor symptoms: the core of multi-morbid Parkinson's disease. PMID- 24401967 TI - Imaging and neurobiological changes in late-life depression. PMID- 24401968 TI - Hospital-based work experience for applicants to medicine. PMID- 24401969 TI - Tying the knot: helping patients who want to get married in hospital. PMID- 24401970 TI - Hypomagnesaemia: clinical relevance and management. PMID- 24401971 TI - Improving patient handover between teams using a business improvement model: PDSA cycle. AB - BACKGROUND: Medical admission units are continuously under pressure to move patients off the unit to outlying medical wards and allow for new admissions. In a typical district general hospital, doctors working in these medical wards reported that, on average, three patients each week arrived from the medical admission unit before any handover was received, and a further two patients arrived without any handover at all. A quality improvement project was therefore conducted using a 'Plan, Do, Study, Act' cycle model for improvement to address this issue. METHOD: P - Plan: as there was no framework to support doctors with handover, a series of standard handover procedures were designed. D - Do: the procedures were disseminated to all staff, and championed by key stakeholders, including the clinical director and matron of the medical admission unit. RESULTS: S - STUDY: Measurements were repeated 3 months later and showed no change in the primary end points. A - ACT: The post take ward round sheet was redesigned, creating a checkbox for a medical admission unit doctor to document that handover had occurred. Nursing staff were prohibited from moving the patient off the ward until this had been completed. This later evolved into a separate handover sheet. Six months later, a repeat study revealed that only one patient each week was arriving before or without a verbal handover. CONCLUSIONS: Using a 'Plan, Do, Study, Act' business improvement tool helped to improve patient care. PMID- 24401972 TI - Audiovestibular impairment presenting as a portent of vertebrobasilar infarction. AB - Acute audiovestibular symptoms (hearing loss and vertigo) can be caused by labyrinthine disorders such as viral labyrinthitis, cerebrovascular diseases, perilymphatic fistula and acoustic neuroma. If neurological symptoms are not present, it is more likely that viral labyrinthitis is the cause, especially in the absence of abnormal findings on imaging (Lee et al, 2002). PMID- 24401973 TI - Erythroderma is not all psoriasis: a case of Sezary syndrome. PMID- 24401974 TI - Life-threatening constipation. PMID- 24401975 TI - Recurrent pneumonia as a result of Mounier-Kuhn syndrome. PMID- 24401976 TI - Idiopathic calcinosis cutis. PMID- 24401977 TI - Percivall Pott: surgeon remembered by his three eponyms. PMID- 24401978 TI - Mitigating the risk of skin cancer associated with thiopurine use. PMID- 24401980 TI - Should anaesthetists routinely use a gabapentinoid perioperatively? PMID- 24401981 TI - Prognostic factors for small cell neuroendocrine carcinoma of the uterine cervix: an institutional experience. AB - OBJECTIVE: This study aimed to determine the clinicopathologic characteristics that affected the survival in patients with small cell neuroendocrine carcinoma of the uterine cervix (SNEC). MATERIALS AND METHODS: All patients with SNEC treated at Chiang Mai University Hospital between January 1995 and October 2011 were retrospectively reviewed with histologic confirmation of SNEC diagnosis. The prognostic predictors for survival were assessed using competing risk regression analysis concerning the probabilities of competing events. RESULTS: One hundred thirty histologically confirmed patients with SNEC met the study criteria. The median overall survival and median cancer-specific survival (CSS) for entire group were 47.8 and 58.1 months, respectively. Five-year CSS for patients with early-stage disease was 62.6% and for patients with advanced-stage disease was 18.1% (P < 0.001). Among the patients with surgically treated early-stage disease, those with adjuvant chemotherapy had a better 5-year survival rate than those with surgery alone, those with adjuvant radiotherapy, and those with adjuvant chemoradiation therapy (P = 0.041). In multivariable analyses, decreased survival in patients with early-stage disease was associated with age older than 60 years at diagnosis (hazards ratio [HR], 4.9; P = 0.007) and deep stromal invasion (HR, 2.9; P = 0.011). Among the patients with advanced-stage disease, decreased survival was associated with age at diagnosis (older than 60 years: HR, 9.9; P < 0.001 and younger than 45 years: HR, 3.4; P = 0.035) and International Federation of Gynecology and Obstetrics stage IV (HR, 7.4; P = 0.024). CONCLUSIONS: International Federation of Gynecology and Obstetrics stage, age at diagnosis, and deep stromal invasion were important prognostic factors for CSS in patients with SNEC. Adjuvant chemotherapy may provide survival benefits in surgically treated patients with early-stage SNEC. PMID- 24401982 TI - The significance of combination chemotherapy in epithelial ovarian cancer. AB - OBJECTIVE: Since the publication of International Collaborative Ovarian Neoplasm 3, various practice patterns have evolved with respect to practice patterns and survival among women with epithelial ovarian cancer in British Columbia, Canada. The objectives of this study were to evaluate different strategies for first-line chemotherapy in ovarian cancer and to determine their effect on survival at a population level. METHODS AND MATERIALS: This was a retrospective population based cohort study of 854 women with epithelial ovarian cancer in British Columbia from 2005 to 2008. Details were ascertained on stage, grade, histotype, performance status, surgeon type, extent of debulking, first-line chemotherapy including type and number of cycles, and cause and date of death. A Cox regression model was used to evaluate the association of covariates on overall survival. RESULTS: Of the 817 women eligible for chemotherapy, 729 (89.2%) received treatment, including 106 (14.5%) women who received single-agent carboplatin and 623 (85.5%) women who received combination platinum-based chemotherapy. Chemotherapy was evaluated as a time-varying covariate. Median numbers of single-agent carboplatin and combination chemotherapy cycles were 5 (range, 1-11) and 6 (range, 1-12), respectively. After adjustment for demographic, disease, and treatment factors, the covariates significantly associated with survival were stage, performance status, extent of debulking, and chemotherapy type. Single-agent carboplatin had a mortality hazards ratio of 5.15 (95% confidence interval, 2.39-11.11) relative to combination chemotherapy. CONCLUSIONS: In this population-based study, first-line platinum-based combination chemotherapy was associated with improved survival compared with single-agent carboplatin after adjustment for covariates in ovarian cancer. Higher rates of combination chemotherapy may improve outcomes at a population level. PMID- 24401983 TI - Value and advantages of preoperative sentinel lymph node imaging with SPECT/CT in cervical cancer. AB - OBJECTIVE: Precise detection of sentinel lymph nodes (SLNs) seems to be a crucial factor for optimized treatment of cervical cancer. We assess the use of single photon emission computed tomography combined with computed tomography (SPECT/CT) as an alternative to lymphoscintigraphy (LSG) for preoperative identification of SLN. METHODS: This study was performed in a prospective, unicentric setting. Patients with cervical carcinoma were scheduled for surgery and additional SLN labeling by peritumoral injection of 10 MBq technetium-99m-nanocolloid and patent blue. Thirty minutes after injection, LSG and SPECT/CT were carried out. We evaluated the number of SLNs detected intraoperatively in LSG and SPECT/CT and the histologic findings of SLN and non-SLN. Subsequently, we determined the impact of these results on the therapeutic approach. RESULTS: This represents the largest study about SPECT/CT for SLN detection in cervical cancer so far. Between August 2008 and March 2013, 59 cervical cancer patients underwent intraoperative SLN detection. In addition, 51 of these patients underwent preoperative LSG and SPECT/CT. Imaging with SPECT/CT detected singular SLN at significantly higher rate (47/51, 92.2%) than that with planar LSG (43/51, 84.3%, P = 0.044). Furthermore, SPECT/CT performed better than LSG regarding the total number of detected SLN (SPECT/CT median, 3 [0-18]; LSG median, 2 [0-15]) and detection rates per pelvic side (SPECT/CT 76.9%, LSG 69.2%, P < 0.01). Whenever SLN detection succeeded, histologic evaluation of SLN correctly predicted the lymph node status per patient's side. Using this type of diagnostic approach for lymph node staging, we reached sensitivity of 100% and negative predictive value of 100% at a rate of false-negative results of 0% even in tumors larger than 4 cm. CONCLUSIONS: Single photon emission computed tomography combined with computed tomography imaging leads to improved rates of SLN detection and better anatomic correlation compared with planar LSG. Thus, intraoperative detection of SLN can be improved by preoperative SPECT/CT imaging. This enhances the clinical value of SLN technique and improves the oncologic safety of SLN concept. PMID- 24401984 TI - Growth differentiation factor-15 as biomarker in uterine sarcomas. AB - OBJECTIVE: The aim of this study was to investigate and validate circulating growth differentiation factor-15 (GDF-15) as a discriminating biomarker between highly malignant uterine sarcomas and benign uterine leiomyomas. In addition, we investigated whether GDF-15 differed between uterine sarcomas and benign adnexal tumors, ovarian or endometrial cancer, and borderline tumors of the ovary. MATERIALS AND METHODS: Preoperative blood samples from 19 women with a diagnosis of uterine sarcoma were analyzed for GDF-15 with immunoassay and compared with samples from 50 patients operated on for leiomyoma uteri and with samples from 20 premenopausal and 20 postmenopausal controls. Our previously presented preoperative GDF-15 concentrations in women with borderline (n = 43), benign (n = 144), and malignant ovarian tumors (n = 125), as well as endometrial cancer (n = 510), were used for comparison. RESULTS: The median circulating GDF-15 concentration was elevated in the uterine sarcoma group (943 ng/L) compared with the myoma uteri group (647 ng/L), the premenopausal and postmenopausal controls (363 and 545 ng/L), and the women with benign ovarian tumors (591 ng/L, all P <= 0.007) but was not significantly different from the ovarian borderline tumor (718 ng/L) or ovarian (1242 ng/L) or endometrial cancer (1076 ng/L) groups.High GDF-15 levels were significantly associated with leiomyosarcomas (P = 0.036), advanced disease (International Federation of Gynecology and Obstetrics stage III/IV, P = 0.013), large tumors (>=10 cm, P = 0.009), and poor survival (P = 0.022). CONCLUSIONS: Circulating GDF-15 may be a promising novel biomarker for the preoperative identification of malignant pelvic disease. Further large prospective studies are needed to evaluate the clinical usefulness of GDF-15 as a discriminator between benign leiomyomas and aggressive sarcomas and as a marker to guide surgical and systemic therapy. PMID- 24401985 TI - Outcomes of women with atypical glandular cells on preoperative cytology and endometrial cancer. AB - OBJECTIVE: This study aims to examine the prognostic importance of preoperative cervical cytologic diagnosis with atypical glandular cells (AGC) or malignant cells (MC) as a predictor of poor outcomes in endometrial cancer. MATERIALS AND METHODS: A total of 563 patients were surgically staged for endometrial adenocarcinoma from 2002 to 2012 at our institution. Of these patients, 106 were included to perform a case-control study (39 patients with AGC or MC and 67 controls). Included patients were not significantly different from excluded patients and were matched for age, race, and body mass index. Outcome variables included presence of extrauterine disease (International Federation of Gynecology and Obstetrics stage >=II) and high intermediate risk (HIR) disease. Further analysis sought to improve the prediction combining AGC or MC with other factors, such as grade and CA-125 levels. Standard statistical analyses were used. RESULTS: Among the patients with AGC or MC, 53.8% had HIR disease compared with 30.3% with normal cervical cytologic diagnosis (odds ratio [OR], 2.68; 95% confidence interval [CI], 1.18-6.09; P = 0.02). Extrauterine disease was found in 43.6% of patients with AGC or MC compared with that of 15.2% in patients with normal cervical cytologic diagnosis (OR, 4.33; 95% CI, 1.72-10.90; P < 0.01). Multivariate analysis confirmed that AGC or MC was an independent predictor of HIR disease (OR, 8.41; 95% CI, 1.34-52.78; P = 0.02) and extrauterine disease (OR, 4.78; 95% CI, 1.26-18.1; P = 0.02). The combination of elevated CA-125 levels with AGC or MC cervical cytologic diagnosis increased the statistical prediction of extrauterine disease (OR, 13.3; 95% CI, 3.1-56.8; P < 0.01) and HIR disease (OR, 5.83; 95% CI, 1.44-23.71; P = 0.02). CONCLUSIONS: Patients with AGC or MC on preoperative cervical cytology are at risk for extrauterine and HIR disease. These preoperative findings should warn surgeons of the potential of extrauterine or occult metastatic disease. PMID- 24401986 TI - Abnormal breathing of sudden cardiac arrest victims described by laypersons and its association with emergency medical service dispatcher-assisted cardiopulmonary resuscitation instruction. AB - BACKGROUND: Current guidelines for cardiopulmonary resuscitation (CPR) emphasise that emergency medical service (EMS) dispatchers should identify sudden cardiac arrest (CA) with abnormal breathing and assist lay rescuers performing CPR. However, lay rescuers description of abnormal breathing may be inconsistent, and it is unclear how EMS dispatchers provide instruction for CPR based on the breathing status of the CA victims described by laypersons. METHODS AND RESULTS: To investigate the incidence of abnormal breathing and the association between the EMS dispatcher-assisted CPR instruction and layperson CPR, we retrospectively analysed 283 witnessed CA cases whose information regarding breathing status of CA victims was available from population-based prospective cohort data. In 169 cases (59.7%), laypersons described that the CA victims were breathing in various ways, and that the victims were 'not breathing' in 114 cases (40.3%). Victims described as breathing in various ways were provided EMS dispatch-instruction for CPR less frequently than victims described as 'not breathing' (27.8% (47/169) vs 84.2% (96/114); p<0.001). Multivariate logistic regression showed that EMS dispatch-instruction for CPR was associated significantly with layperson CPR (adjusted OR, 11.0; 95% CI, 5.72 to 21.2). CONCLUSIONS: This population-based study indicates that 60% of CA victims showed agonal respiration, which was described as breathing in various ways at the time of EMS call. Although EMS dispatch-instruction was associated significantly with an increase in layperson CPR, abnormal breathing was associated with a much lower rate of CPR instruction and, in turn, was related to a much lower rate of bystander CPR. PMID- 24401987 TI - Enhanced ventricular pump function and decreased reservoir backflow sustain rise in pulmonary blood flow after reduction of lung liquid volume in fetal lambs. AB - Although a reduction in lung liquid volume increases fetal pulmonary blood flow, the changes in central flow patterns that sustain this increased pulmonary perfusion are unknown. To address this issue, eight anesthetized late-gestation fetal sheep were instrumented with pulmonary trunk (PT), ductus arteriosus (DA), and left pulmonary artery (PA) micromanometer catheters and transit-time flow probes, with blood flow profile and wave intensity analyses performed at baseline and after withdrawal of lung liquid via an endotracheal tube. Reducing lung liquid volume by 19 +/- 6 ml/kg (mean +/- SD) augmented right ventricular power by 34% (P < 0.001), with distribution of an accompanying increase in mean PT blood flow (245 +/- 63 ml/min, P < 0.001) to the lungs (169 +/- 91 ml/min, P = 0.001) and across the DA (77 +/- 92 ml/min, P = 0.04). However, although PT and DA flow increments were confined to systole and were related to an increased magnitude of flow-increasing, forward-running compression waves, the rise in PA flow spanned both systole (108 +/- 66 ml/min) and diastole (61 +/- 32 ml/min). Flow profile analysis showed that the step-up in PA diastolic flow was associated with diminished PA diastolic backflow and accompanied by a lesser degree of diastolic right-to-left DA shunting. These data suggest that an increased pulmonary blood flow after reduction of lung liquid volume is associated with substantial changes in PT-DA-PA interactions and underpinned by two main factors: 1) enhanced right ventricular pump function that increases PA systolic inflow and 2) decreased PA diastolic backflow that arises from a fundamental change in PA reservoir function, thereby resulting in greater passage of systolic inflow through the lungs. PMID- 24401988 TI - Stress-induced stimulation of choline transport in cultured choroid plexus epithelium exposed to low concentrations of cadmium. AB - The choroid plexus epithelium forms the blood-cerebrospinal fluid barrier and accumulates essential minerals and heavy metals. Choroid plexus is cited as being a "sink" for heavy metals and excess minerals, serving to minimize accumulation of these potentially toxic agents in the brain. An understanding of how low doses of contaminant metals might alter transport of other solutes in the choroid plexus is limited. Using primary cultures of epithelial cells isolated from neonatal rat choroid plexus, our objective was to characterize modulation of apical uptake of the model organic cation choline elicited by low concentrations of the contaminant metal cadmium (CdCl2). At 50-1,000 nM, cadmium did not directly decrease or increase 30-min apical uptake of 10 MUM [(3)H]choline. However, extended exposure to 250-500 nM cadmium increased [(3)H]choline uptake by as much as 75% without marked cytotoxicity. In addition, cadmium induced heat shock protein 70 and heme oxygenase-1 protein expression and markedly induced metallothionein gene expression. The antioxidant N-acetylcysteine attenuated stimulation of choline uptake and induction of stress proteins. Conversely, an inhibitor of glutathione synthesis l-buthionine-sulfoximine (BSO) enhanced stimulation of choline uptake and induction of stress proteins. Cadmium also activated ERK1/2 MAP kinase. The MEK1 inhibitor PD98059 diminished ERK1/2 activation and attenuated stimulation of choline uptake. Furthermore, inhibition of ERK1/2 activation abated stimulation of choline uptake in cells exposed to cadmium with BSO. These data indicate that in the choroid plexus, exposure to low concentrations of cadmium may induce oxidative stress and consequently stimulate apical choline transport through activation of ERK1/2 MAP kinase. PMID- 24401989 TI - Role of the lateral parabrachial nucleus in the control of sodium appetite. AB - In states of sodium deficiency many animals seek and consume salty solutions to restore body fluid homeostasis. These behaviors reflect the presence of sodium appetite that is a manifestation of a pattern of central nervous system (CNS) activity with facilitatory and inhibitory components that are affected by several neurohumoral factors. The primary focus of this review is on one structure in this central system, the lateral parabrachial nucleus (LPBN). However, before turning to a more detailed discussion of the LPBN, a brief overview of body fluid balance-related body-to-brain signaling and the identification of the primary CNS structures and humoral factors involved in the control of sodium appetite is necessary. Angiotensin II, mineralocorticoids, and extracellular osmotic changes act on forebrain areas to facilitate sodium appetite and thirst. In the hindbrain, the LPBN functions as a key integrative node with an ascending output that exerts inhibitory influences on forebrain regions. A nonspecific or general deactivation of LPBN-associated inhibition by GABA or opioid agonists produces NaCl intake in euhydrated rats without any other treatment. Selective LPBN manipulation of other neurotransmitter systems [e.g., serotonin, cholecystokinin (CCK), corticotrophin-releasing factor (CRF), glutamate, ATP, or norepinephrine] greatly enhances NaCl intake when accompanied by additional treatments that induce either thirst or sodium appetite. The LPBN interacts with key forebrain areas that include the subfornical organ and central amygdala to determine sodium intake. To summarize, a model of LPBN inhibitory actions on forebrain facilitatory components for the control of sodium appetite is presented in this review. PMID- 24401990 TI - Na+/H+ and Na+/NH+4 activities of zebrafish NHE3b expressed in Xenopus oocytes. AB - Zebrafish Na(+)/H(+) exchanger 3b (zNHE3b) is highly expressed in the apical membrane of ionocytes where Na(+) is absorbed from ion-poor fresh water against a concentration gradient. Much in vivo data indicated that zNHE3b is involved in Na(+) absorption but not leakage. However, zNHE3b-mediated Na(+) absorption has not been thermodynamically explained, and zNHE3b activity has not been measured. To address this issue, we overexpressed zNHE3b in Xenopus oocytes and characterized its activity by electrophysiology. Exposure of zNHE3b oocytes to Na(+)-free media resulted in significant decrease in intracellular pH (pH(i)) and intracellular Na(+) activity (aNa(i)). aNa(i) increased significantly when the cytoplasm was acidified by media containing CO2-HCO3(-) or butyrate. Activity of zNHE3b was inhibited by amiloride or 5-ethylisopropyl amiloride (EIPA). Although the activity was accompanied by a large hyperpolarization of ~50 mV, voltage clamp experiments showed that Na(+)/H(+) exchange activity of zNHE3b is electroneutral. Exposure of zNHE3b oocytes to medium containing NH3/NH4(+) resulted in significant decreases in pH(i) and aNa(i) and significant increase in intracellular NH4(+) activity, indicating that zNHE3b mediates the Na(+)/NH4(+) exchange. In low-Na(+) (0.5 mM) media, zNHE3b oocytes maintained aNa(i) of 1.3 mM, and Na(+)-influx was observed when pHi was decreased by media containing CO2 HCO3(-) or butyrate. These results provide thermodynamic evidence that zNHE3b mediates Na(+) absorption from ion-poor fresh water by its Na(+)/H(+) and Na(+)/NH4(+) exchange activities. PMID- 24401992 TI - The Open Connectome Project Data Cluster: Scalable Analysis and Vision for High Throughput Neuroscience. AB - We describe a scalable database cluster for the spatial analysis and annotation of high-throughput brain imaging data, initially for 3-d electron microscopy image stacks, but for time-series and multi-channel data as well. The system was designed primarily for workloads that build connectomes- neural connectivity maps of the brain-using the parallel execution of computer vision algorithms on high performance compute clusters. These services and open-science data sets are publicly available at openconnecto.me. The system design inherits much from NoSQL scale-out and data-intensive computing architectures. We distribute data to cluster nodes by partitioning a spatial index. We direct I/O to different systems reads to parallel disk arrays and writes to solid-state storage-to avoid I/O interference and maximize throughput. All programming interfaces are RESTful Web services, which are simple and stateless, improving scalability and usability. We include a performance evaluation of the production system, highlighting the effec tiveness of spatial data organization. PMID- 24401991 TI - delta-Opioid receptor activation stimulates normal diet intake but conversely suppresses high-fat diet intake in mice. AB - The central opioid system is involved in a broadly distributed neural network that regulates food intake. Here, we show that activation of central delta-opioid receptor not only stimulated normal diet intake but conversely suppressed high fat diet intake as well. [D-Pen(2,5)]-enkephalin (DPDPE), an agonist selective for the delta-receptor, increased normal diet intake after central administration to nonfasted male mice. The orexigenic activity of DPDPE was inhibited by blockade of cyclooxygenase (COX)-2, lipocalin-type prostaglandin D synthase (L PGDS), D-type prostanoid receptor 1 (DP(1)), and neuropeptide Y (NPY) receptor type 1 (Y1) for PGD(2) and NPY, respectively, suggesting that this was mediated by the PGD(2)-NPY system. In contrast, DPDPE decreased high-fat diet intake in mice fed a high-fat diet. DPDPE-induced suppression of high-fat diet intake was blocked by antagonists of melanocortin 4 (MC(4)) and corticotropin-releasing factor (CRF) receptors but not by knockout of the L-PGDS gene. These results suggest that central delta-opioid receptor activation suppresses high-fat diet intake via the MC-CRF system, independent of the orexigenic PGD(2) system. Furthermore, orally administered rubiscolin-6, an opioid peptide derived from spinach Rubisco, suppressed high-fat diet intake. This suppression was also blocked by centrally administered naltrindole, an antagonist for the delta receptor, suggesting that rubiscolin-6 suppressed high-fat diet intake via activation of central delta-opioid receptor. PMID- 24401993 TI - Efficacy of intra-articular bevacizumab for relapsing diffuse-type giant cell tumour. PMID- 24401994 TI - Safety of synthetic and biological DMARDs: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis. AB - OBJECTIVES: To update the evidence for the safety of synthetic disease-modifying antirheumatic drugs (sDMARDs), glucocorticoids (GC) and biological DMARDs (bDMARDs) in patients with rheumatoid arthritis (RA) to inform the European League Against Rheumatism (EULAR) recommendations for the management of RA. METHODS: Systematic literature review (SLR) of observational studies (including registries). Interventions were any bDMARD (anakinra, infliximab, etanercept, adalimumab, rituximab, abatacept, tocilizumab, golimumab or certolizumab pegol) or sDMARD (methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, gold/auranofin, azathioprine, chlorambucil, chloroquine, cyclosporin, cyclophosphamide, mycophenolate, minocycline, penicillamine, tacrolimus or tofacitinib) and a comparator was required. Information on GCs was collected from the included studies. All safety outcomes were included. RESULTS: Forty-nine observational studies addressing diverse safety outcomes of therapy with bDMARDs met eligibility criteria. Substantial heterogeneity precluded meta-analysis of any of the outcomes. Patients on tumour necrosis factor inhibitors (TNFi) compared to patients on conventional sDMARDs had a higher risk of serious infections (adjusted HR (aHR) 1.1-1.8), a higher risk of tuberculosis, and an increased risk of infection by herpes zoster cannot be excluded. Patients on TNFi did not have an increased risk for malignancies in general, lymphoma or non melanoma skin cancer, but the risk of melanoma may be slightly increased (aHR 1.5). From the studies identified on conventional sDMARDs, no new safety signals were found. CONCLUSIONS: The findings from this SLR confirm the known safety pattern of sDMARDs and bDMARDs for the treatment of RA. PMID- 24401995 TI - Different treatment orders achieved similar clinical results: a retrospective study for retreatment of epidermal growth factor receptor tyrosine kinase inhibitors in 120 patients with non-small-cell lung cancer. AB - BACKGROUND: It was reported the retreatment of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) may bring benefit to non-small-cell lung cancer (NSCLC) patients who benefited previously. Nevertheless, the treatment order in most of the prior literature was gefitinib (G) to erlotinib (E), and little was known about whether other treatment order may also bring benefit to the patients. METHODS: One hundred and twenty NSCLC patients who received EGFR TKIs treatment twice were enrolled in this study. The safety and effectiveness of the second EGFR-TKIs administration, as well as the influencing factors that contribute to this process, were analyzed retrospectively. RESULTS: Forty-nine (40.8%) patients were retreated with same kind of EGFR-TKIs: 30 (25%) were G and 19 (15.8%) were E. Seventy-one (59.2%) patients switched to another kind: 55 (45.8%) were G to E and 16 (13.4%) were the reverse. Notably, no differences in clinical benefits were found among the four different treatment orders. For the second administration, the adverse effects of all patients were generally classified as grade I-II and the 1-year survival rate reached 32.5%. The objective response rate, disease control rate, median progression-free survival (PFS), and overall survival was 10.0% (12/120), 52.5% (63/120), 2.3 (95% CI 1.5 3.0) months and 8.0 (95% CI 7.0-8.5) months, respectively. The univariate and multivariate analyses revealed that those patients who benefited from prior EGFR TKIs were easier to get benefit from the second administration, and the strongest beneficial indicators of the retreatment were PFS of the initial EGFR-TKIs (>=6 months, HR 0.611, 95% CI 0.354-0.901, P = 0.0076) and time interval between the two EGFR-TKIs treatment (>=4 months, HR 0.529, 95% CI 0.328-0.852, P = 0.0088). CONCLUSION: Those patients who benefited from prior EGFR-TKIs were easier to get benefit from the second administration. A time interval of >=4 months may improve the retreatment, but differences in clinical benefit were not found among different treatment orders. If the retrospective result could be validated further in the future, it would be helpful for rational administration of EGFR TKIs. PMID- 24401996 TI - Vascular endothelial growth factor polymorphisms affect gene expression and tumor aggressiveness in patients with breast cancer. AB - Vascular endothelial growth factor (VEGF) is one of the key modulators of angiogenesis. The highly polymorphic promoter and 5' untranslated region of VEGF have been associated with susceptibility to and aggressiveness of several types of cancer. To examine the functional role of VEGF polymorphisms at -634 and -1498 positions, VEGF mRNA and protein in breast cancer tissues were analyzed by quantitative polymerase chain reaction and immunohistochemistry. A dual luciferase assay was performed to determine promoter activity. The VEGF-634CC genotype demonstrated the highest VEGF mRNA expression. High VEGF mRNA expression was correlated with a tumor size of >2 cm, the presence of lymphovascular invasion and the presence of axillary nodal metastasis. The promoter containing the -1,498T/-634C haplotype exhibited the highest basal promoter activity. These findings suggest that the interaction between -1,498T and -634C polymorphisms increases VEGF expression and is involved in breast cancer aggressiveness. PMID- 24401997 TI - Pericentrosomal localization of the TIG3 tumor suppressor requires an N-terminal hydrophilic region motif. AB - Tazarotene-induced gene 3 (TIG3) is a tumor suppressor protein that has a key role in controlling cell proliferation. TIG3 is observed at reduced levels in epidermal squamous cell carcinoma, and the restoration of expression in skin cancer cells reduces cell survival. TIG3 suppresses cell survival through mechanisms that involve localization at the plasma membrane and at the centrosome. TIG3 interacts at the plasma membrane to activate enzymes involved in keratinocyte terminal differentiation, and at the centrosome to inhibit daughter centrosome separation during mitosis leading to cessation of cell proliferation and induction of apoptosis. An important goal is identifying the motifs required for TIG3 localization at these intracellular sites as a method to understand the function of TIG3 at each location. TIG3 encodes an N-terminal hydrophilic region (amino acids 1-135) and a C-terminal membrane-anchoring domain (amino acids 135 164). We show that the C-terminal hydrophobic domain targets intact TIG3 to the plasma membrane, but when isolated as an independent element localizes at the mitochondria. We further demonstrate that a segment of the N-terminal hydrophilic region targets the centrosome. These studies provide important insights regarding the mechanisms that guide subcellular localization of this keratinocyte survival regulator. PMID- 24401998 TI - Dermal clusters of mature dendritic cells and T cells are associated with the CCL20/CCR6 chemokine system in chronic psoriasis. PMID- 24401999 TI - Metals in honeys from different areas of southern Italy. AB - The aim of the study was to quantify the cadmium (Cd), lead (Pb), chromium (Cr) and arsenic (As) contents in ninety honey samples from nine areas of southern Italy. Results showed that As content was below the detection limit, while Cd, Pb, and Cr contents were below the recommended maximum acceptable levels. Mean Cd, Pb, and Cr contents were 0.013, 0.289 and 0.707 mg kg(-1), respectively. The metal contents in honey varied greatly depending on considered area. Correlations between the metals were statistically significant (p < 0.05), suggesting that polluting sources involve the simultaneous presence of metals in honey. PMID- 24402000 TI - Effects of dispersant and oil on survival and swimming activity in a marine copepod. AB - Knowledge of lethal and sublethal effects of crude oil and dispersants on mesozooplankton are important to understanding ecosystem impacts of oil spills in marine environments. Here we (1) establish median lethal concentrations for water accommodated fractions of Corexit EC9500A dispersant, MC-252 crude oil (WAF), and dispersed crude oil (CEWAF) for the coastal copepod Labidocera aestiva, and (2) assess acute effects on L. aestiva swimming activity. Mortality assays with L. aestiva support that copepods are more sensitive than other zooplankton taxa to dispersant toxicity, while WAF and CEWAF are generally similar in their toxicity to this copepod species and other zooplankton. Acute effects on L. aestiva activity included impaired swimming upon WAF and CEWAF exposure. These results highlight that copepods are particularly sensitive to dispersant exposure, with acute effects on survival most evident with dispersant alone, and on swimming behavior when dispersant is mixed with crude oil. PMID- 24402001 TI - Pain catastrophizing, pain intensity, and dyadic adjustment influence patient and partner depression in metastatic breast cancer. AB - OBJECTIVE: Metastatic breast cancer can be challenging for couples given the significant pain and distress caused by the disease and its treatment. Although the use of catastrophizing (eg, ruminating, exaggerating) as a pain coping strategy has been associated with depression in breast cancer patients, little is known about the effects of pain intensity on this association. Moreover, even though social relationships are a fundamental resource for couples coping with cancer, no studies have examined whether the quality of the spousal relationship affects the association between catastrophizing and depression. This study prospectively examined these associations. METHODS: Couples (N=191) completed surveys at the start of treatment for metastatic breast cancer (baseline), and 3 and 6 months later. RESULTS: Multilevel models using the couple as the unit of analysis showed patients and partners (ie, spouses or significant others) who had high levels (+1 SD) of dyadic adjustment (DAS-7) experienced fewer depressive symptoms than those who had low levels (-1 SD) of dyadic adjustment (P's<0.01). Moreover, at low levels of dyadic adjustment, when patients engaged in high levels of catastrophizing and had high levels of pain, both patients and partners reported significantly (P=0.002) higher levels of depression than when patients engaged in high levels of catastrophizing but had low levels of pain. DISCUSSION: Findings showed that catastrophizing and pain exacerbate depression in couples experiencing marital distress. Programs that seek to alleviate pain and depressive symptoms in metastatic breast cancer may benefit from targeting both members of the couple, screening for marital distress, and teaching more adaptive pain coping strategies. PMID- 24402002 TI - Contemporary view of the clinical relevance of magnesium homeostasis. AB - Magnesium is one of the most abundant cations in the body and is essential for a wide variety of metabolically important reactions. Serum magnesium concentration is regulated by the balance between intestinal absorption and renal excretion. Hypomagnesaemia is relatively common, with an estimated prevalence in the general population ranging from 2.5 to 15%. It may result from inadequate magnesium intake, increased gastrointestinal or renal loss or redistribution from extracellular to intracellular space. Drug-induced hypomagnesaemia, particularly related to proton-pump inhibitor (PPI) therapy, is being increasingly recognized. Although most patients with hypomagnesaemia are asymptomatic, manifestations may include neuromuscular, cardiovascular and metabolic features. Due to the kidney's ability to increase fractional excretion to nearly 100% when the renal magnesium threshold is exceeded, clinically significant hypermagnesaemia is uncommon, generally occurring only in the setting of renal insufficiency and excessive magnesium intake. Symptoms include hypotension, nausea, facial flushing, ileus and flaccid muscle paralysis. In most cases, simply withdrawing exogenous magnesium is sufficient to restore normal magnesium concentrations, although occasionally administration of intravenous calcium or even dialysis may be required. PMID- 24402003 TI - Accuracy of reports of lifetime mental and physical disorders: results from the Baltimore Epidemiological Catchment Area study. AB - IMPORTANCE: Our understanding of how mental and physical disorders are associated and contribute to health outcomes in populations depends on accurate ascertainment of the history of these disorders. Recent studies have identified substantial discrepancies in the prevalence of mental disorders among adolescents and young adults depending on whether the estimates are based on retrospective reports or multiple assessments over time. It is unknown whether such discrepancies are also seen in midlife to late life. Furthermore, no previous studies have compared lifetime prevalence estimates of common physical disorders such as diabetes mellitus and hypertension ascertained by prospective cumulative estimates vs retrospective estimates. OBJECTIVE: To examine the lifetime prevalence estimates of mental and physical disorders during midlife to late life using both retrospective and cumulative evaluations. DESIGN, SETTING, AND PARTICIPANTS: Prospective population-based survey (Baltimore Epidemiologic Catchment Area Survey) with 4 waves of interviews of 1071 community residents in Baltimore, Maryland, between 1981 and 2005. MAIN OUTCOMES AND MEASURES: Lifetime prevalence of selected mental and physical disorders at wave 4 (2004-2005), according to both retrospective data and cumulative evaluations based on 4 interviews from wave 1 to wave 4. RESULTS Retrospective evaluations substantially underestimated the lifetime prevalence of mental disorders as compared with cumulative evaluations. The respective lifetime prevalence estimates ascertained by retrospective and cumulative evaluations were 4.5% vs. 13.1% for major depressive disorder, 0.6% vs. 7.1% for obsessive-compulsive disorder, 2.5% vs. 6.7% for panic disorder, 12.6% vs. 25.3% for social phobia, 9.1% vs. 25.9% for alcohol abuse or dependence, and 6.7% vs. 17.6% for drug abuse or dependence. In contrast, retrospective lifetime prevalence estimates of physical disorders ascertained at wave 4 were much closer to those based on cumulative data from all 4 waves. The respective prevalence estimates ascertained by the 2 methods were 18.2% vs. 20.2% for diabetes, 48.4% vs. 55.4% for hypertension, 45.8% vs. 54.0% for arthritis, 5.5% vs. 7.2% for stroke, and 8.4% vs. 10.5% for cancer. CONCLUSIONS AND RELEVANCE: One-time, cross-sectional population surveys may consistently underestimate the lifetime prevalence of mental disorders. The population burden of mental disorders may therefore be substantially higher than previously appreciated. PMID- 24402004 TI - Association between helplessness, disability, and disease activity with health related quality of life among rheumatoid arthritis patients in a multiethnic Asian population. AB - To investigate the association between helplessness, disability, and disease activity with health-related quality of life (HRQoL) in a multiethnic cohort of rheumatoid arthritis (RA) patients in Singapore. This cross-sectional study was conducted at Tan Tock Seng Hospital, Department of Rheumatology, Allergy and Immunology, from October 2010 to October 2011. All patients fulfilled the American College of Rheumatology 1987 criteria for RA. Socio-demographics, clinical, and patient-reported outcome (PRO) variables were collected. HRQoL outcomes were Short Form 36 (SF-36) physical and mental component summary (PCS and MCS) scores and Short Form 6 Dimensions (SF-6D) utilities. Stepwise multiple linear regression analyses were performed using HRQoL outcomes as dependent variables in separate models and with adjustment for helplessness (Rheumatology Attitudes Index, RAI), disability (Health Assessment Questionnaire, HAQ), and disease activity (Disease Activity in 28 joints) followed by socio-demographic, clinical, and PRO variables. Complete data were provided by 473 consenting subjects [mean (SD) age: 60.02 (11.04) years, 85 % female, 77 % Chinese]. After adjustment for all measured covariates, only RAI and HAQ scores remained significantly associated with SF-36 MCS (beta: -0.9, p < 0.001; beta: -7.0, p < 0.001) and SF-6D utilities (beta: -0.005, p < 0.001; beta: -0.081, p < 0.001), respectively, while only HAQ scores were significantly associated with SF-36 PCS (beta: -7.7, p < 0.001). Interventions to address the sense of helplessness and to prevent or reduce disability could improve HRQoL of RA patients. PMID- 24402005 TI - Methodological shortcomings make conclusion highly sensitive to relevant changes in review protocol. PMID- 24402006 TI - Quality of life, depression, and sexual dysfunction in spouses of female patients with fibromyalgia. AB - The aim of this study was to investigate the effects of the quality of life and psychological condition of female patients with fibromyalgia and their spouses on sexual function. A total of 32 female patients diagnosed with fibromyalgia and their spouses were analyzed. Thirty married couples were included in the study as the control group. The demographic data of the fibromyalgia patients were recorded, a visual analog scale was used to evaluate the level of pain, and the Fibromyalgia Impact Questionnaire was used to evaluate the impact of the symptoms on the quality of life of the patients. The quality of life of both the patients and the control group were evaluated using the Short Form 36 (SF-36), and psychological variables were evaluated using the Beck Depression Inventory (BDI) and Beck Anxiety Inventory. Sexual function was assessed using the Female Sexual Function Index for female participants and the International Index of Erectile Function (IIEF) for male participants. The IIEF erectile dysfunction scores were significantly lower in the spouses of female patients with fibromyalgia than in the control group (p < 0.05), and the BDI scores were significantly higher in the spouses of the female patients with fibromyalgia (p < 0.05). Among the SF-36 scores, the emotional and physical roles were significantly lower in the spouses of the female patients with fibromyalgia (p = 0.003 and p = 0.004, respectively). In all spouses of FMS patients and controls, there was a significantly negative correlation between erectile function, the BDI score, and to be married with FMS patient and positive correlations between erectile function and emotional role, social function, mental health, SF-36 pain score, and general health (p < 0.05 for all). In a linear regression model, BDI, to be married with FMS patient and general health were found to affect erectile function (beta regression coefficient = -0.572, SE = 0.082, p = 0.001; beta regression coefficient = 0.332, SE = 1.619, p = 0.007; beta regression coefficient = 0.445, SE = 0.065, p = 0.005, respectively). Being a spouse of a patient with fibromyalgia might significantly interfere with quality of life and lead to a high rate of sexual dysfunction. Spouses of patients with fibromyalgia might also be investigated for sexual dysfunction and quality of life. Treatment programs for this group should be considered. PMID- 24402007 TI - Critical body residues, Michaelis-Menten analysis of bioaccumulation, lethality and behaviour as endpoints of waterborne Ni toxicity in two teleosts. AB - Traditionally, water quality guidelines/criteria are based on lethality tests where results are expressed as a function of waterborne concentrations (e.g. LC50). However, there is growing interest in the use of uptake and binding relationships, such as biotic ligand models (BLM), and in bioaccumulation parameters, such as critical body residue values (e.g. CBR50), to predict metal toxicity in aquatic organisms. Nevertheless, all these approaches only protect species against physiological death (e.g. mortality, failed recruitment), and do not consider ecological death which can occur at much lower concentrations when the animal cannot perform normal behaviours essential for survival. Therefore, we investigated acute (96 h) Ni toxicity in two freshwater fish species, the round goby (Neogobius melanostomus) and rainbow trout (Oncorhynchus mykiss) and compared LC, BLM, and CBR parameters for various organs, as well as behavioural responses (spontaneous activity). In general, round goby were more sensitive. Ni bioaccumulation displayed Michaelis-Menten kinetics in most tissues, and round goby gills had lower Kd (higher binding affinity) but similar Bmax (binding site density) values relative to rainbow trout gills. Round goby also accumulated more Ni than did trout in most tissues at a given exposure concentration. Organ specific 96 h acute CBR values tended to be higher in round goby but 96 h acute CBR50 and CBR10 values in the gills were very similar in the two species. In contrast, LC50 and LC10 values were significantly higher in rainbow trout. With respect to BLM parameters, gill log KNiBL values for bioaccumulation were higher by 0.4-0.8 log units than the log KNiBL values for toxicity in both species, and both values were higher in goby (more sensitive). Round goby were also more sensitive with respect to the behavioural response, exhibiting a significant decline of 63-75 % in movements per minute at Ni concentrations at and above only 8 % of the LC50 value; trout exhibited no clear behavioural response. Across species, diverse behavioral responses may be more closely related to tissue Ni burdens than to waterborne Ni concentrations. To our knowledge, this is the first study to link Ni bioaccumulation with behavioural endpoints. In future it would be beneficial to expand these analyses to a wider range of species to determine whether Ni bioaccumulation, specifically in the gills, gut and whole fish, may be a good predictor of behavioural changes from metal exposure; which in the wild can lead to ecological death. PMID- 24402008 TI - Splenic parenchymal heterogeneity at dual-bolus single-acquisition CT in polytrauma patients-6-months experience from Oxford, UK. AB - Dual-bolus single-acquisition CT (DBSA-CT) has been advocated in the work up of polytrauma cases, providing rapid acquisition and simultaneous visceral and vascular assessment. Splenic heterogeneity has been observed with this technique. The aim of this study was to investigate this phenomenon and assess predisposing factors and impact on image interpretation through a 6-month retrospective audit between March and September 2011. Seventy-three polytrauma patients underwent standardized DBSA-CT. Splenic enhancement was assessed quantitatively using ROIs and image quality using a 5-point visual analog scale; a score of >=3 was considered diagnostic. Hematoma density was measured in splenic injuries. Age, hemodynamic status, and aortic density were investigated as predictors of splenic heterogeneity. Seventy-three patients were imaged with 98.6 % blunt traumas. There were 5 (6.9 %) splenic injuries. Eight (11 %) had coexisting visceral and vascular injuries. PMID- 24402009 TI - Core curriculum illustration: cerebral venous thrombosis. PMID- 24402010 TI - Traumatic lumbar hernias: do patient or hernia characteristics predict bowel or mesenteric injury? AB - Traumatic lumbar hernias are rare but important injuries to diagnose in blunt abdominal trauma, both because of delayed complications of the hernia itself and because of well-documented association with bowel and mesenteric injuries. No study to our knowledge has determined whether specific features of the hernia size of the wall defect, inferior or superior location, or the side of the hernia bear any predictive value on the presence of underlying bowel and mesenteric injury. A retrospective query of the radiology information system yielded 21 patients with lumbar hernias which were diagnosed on CT. These were reviewed by three radiologists to confirm the presence of an acute lumbar hernia and to determine the size and location of the hernia. The patients' medical records were reviewed to determine the presence of operatively confirmed bowel and/or mesenteric injuries, which occurred in 52 % of patients. A significant (p < 0.001) difference was found in the frequency of bowel and/or mesenteric injury with hernia defects greater than 4.0 cm (100 %) and those less than 4.0 cm (17 %). Larger hernias also resulted in more procedures (p = 0.042) and a trend towards longer ICU stay, but no difference in injury severity score (ISS) or overall hospital stay. No significant difference was seen in the frequency of bowel and/or mesenteric injuries based on side or location of the hernia, though distal colonic injuries were more commonly seen with left-sided hernias (50 %) compared to right-sided hernias (18 %). Although based on a small patient population, these results suggest that larger traumatic lumbar hernias warrant particularly close evaluation for an underlying bowel and/or mesenteric injury. PMID- 24402011 TI - The role of interferon induced with helicase C domain 1 (IFIH1) in the development of type 1 diabetes mellitus. AB - Type 1 diabetes mellitus (T1DM) is a chronic, progressive, autoimmune disease characterized by metabolic decompensation frequently leading to dehydration and ketoacidosis. Viral pathogens seem to play a major role in triggering the autoimmune destruction that leads to the development of T1DM. Among several viral strains investigated so far, enteroviruses have been consistently associated with T1DM in humans. One of the mediators of viral damage is the double-stranded RNA (dsRNA) generated during replication and transcription of viral RNA and DNA. The IFIH1 gene encodes a cytoplasmic receptor of the pattern-recognition receptors (PRRs) family that recognizes dsRNA, playing a role in the innate immune response triggered by viral infection. Binding of dsRNA to this PRR triggers the release of proinflammatory cytokines, such as interferons (IFNs), which exhibit potent antiviral activity, protecting uninfected cells and inducing apoptosis of infected cells. The IFIH1 gene appears to play a major role in the development of some autoimmune diseases, and it is, therefore, a candidate gene for T1DM. Within this context, the objective of the present review was to address the role of IFIH1 in the development of T1DM. PMID- 24402012 TI - Leptin receptor gene polymorphisms are associated with adiposity and metabolic alterations in Brazilian individuals. AB - OBJECTIVE: The aim of the study was to investigate whether adiposity and metabolic markers, such as leptin, glucose, and lipids, are influenced by leptin (LEP) and leptin receptor (LEPR) gene polymorphisms in a sample of our population. SUBJECTS AND METHODS: A group of 326 individuals of Caucasian European descent, aged 30 to 80 years, 87 men and 239 women, 148 obese and 178 non-obese, was randomly selected at two clinical hospitals in the city of Sao Paulo, Brazil. All individuals declared their ethnic group as white during the initial interview. Anthropometric measurements, body mass index (BMI), and fat mass were evaluated. Blood samples were drawn for DNA extraction and measurements of leptin, soluble leptin receptor, glucose, and lipids. LEP -2548G>A and LEPR Lys109Arg (c.326A>G), Gln233Arg (c.668A>G) and Lys656Asn (c.1968G>C) polymorphisms were detected by PCR-RFLP. RESULTS: Increased leptin and serum lipids, and LEPR Arg223Arg (GG genotype) were associated with higher risk for obesity (p < 0.05), while reduced risk was found in LEPR Arg109Arg (GG genotype) carriers (OR: 0.38, 95%CI: 0.19-0.77, p = 0.007). Multiple linear regression analysis showed a relationship between LEPR 223Arg, increased waist circumference, and leptinemia (p < 0.05), while LEPR 109Arg was associated with high total cholesterol and triglycerides (p < 0.05). LEPR haplotype 3 (AGG: 109Lys/233Arg/656Lys) carriers have increased risk for obesity (OR: 2.56, 95% CI: 1.19-5.49, p = 0.017). Moreover, this haplotype was associated with increased BMI, waist circumference, and leptinemia (p < 0.05). CONCLUSIONS: LEPR polymorphisms are associated with obesity, hyperleptinemia, and atherogenic lipid profile, suggesting their potential role for leptin resistance and cardiovascular risk. Moreover, LEPR haplotype 3 confers susceptibility to adiposity and hyperleptinemia in our population. PMID- 24402013 TI - Prevalence of thyroid diseases in patients with acromegaly: experience of a Brazilian center. AB - OBJECTIVES: Acromegaly is frequently associated with thyroid diseases. In this study, we evaluated the frequency of thyroid disorders in a series of acromegalic patients. SUBJECTS AND METHODS: We evaluated 106 acromegalic patients using thyroid ultrasonography (US) and measurements of GH, IGF-I, free T4, TSH and anti thyroperoxidase antibody levels. IGF-I was expressed in mass units and age related standard deviation scores (SD-scores). Fine-needle aspiration biopsy (FNAB) was performed on thyroid nodules with a diameter greater than one centimeter or with suspicious characteristics. RESULTS: Thyroid disorders were found in 75 patients. Eleven patients had diffuse goiter, 42 patients had nodular goiter, and 22 patients had unspecific morphological abnormalities. Four patients (3.8%) had thyroid carcinoma. Considering the patients with diffuse or nodular goiter, thyroid volume was greater in patients with active acromegaly, and was positively correlated with GH, IGF-I, and IGF-I SD-score. CONCLUSIONS: Our study confirmed that benign thyroid diseases are frequent in acromegalic patients. The prevalence of thyroid cancer was higher than in the overall population. We suggest that thyroid US should be routinely performed in patients with acromegaly. PMID- 24402014 TI - [Dyslipidemia and correlates in adults living in Ribeirao Preto, SP: results of the EPIDCV Project]. AB - OBJECTIVE: To identify the prevalence and correlates of dyslipidemia in adults living in the city of Ribeirao Preto, SP, Brazil, in 2007. MATERIALS AND METHODS: A cross-sectional population-based epidemiological study was carried out using a three-stage cluster sampling. The variability introduced in the third sampling fraction was corrected, resulting in a weighted sample of 2,471 participants. Dyslipidemia prevalence, defined as abnormal values in at least one of four lipid fractions was estimated in both genders, according sociodemographic, behavioral, and health-related variables. To identify correlates, prevalence ratios were estimated using Poisson regression, in crude and adjusted models. All the estimates were calculated taking into account the sampling design effect. RESULTS: High prevalence of dyslipidemia was found (61.9%; CI(95%): 58.5%-65.3%). Income and fiber consumption, in males, and sitting time and saturated fatty acids, in females, were kept in the final models, as well as age and central obesity, which were consistently associated with the outcome, in both genders. CONCLUSIONS: Public intervention policies toward the adoption of healthy food consumption, as well as control central obesity and sedentary behavior might contribute to decrease the prevalence of dyslipidemia and cardiovascular morbidity and mortality in Ribeirao Preto. PMID- 24402015 TI - Exenatide improves type 2 diabetes concomitant with non-alcoholic fatty liver disease. AB - OBJECTIVE: To investigate the effects of exenatide on blood glucose, body weight and hepatic enzymes in patients with type 2 diabetes mellitus (T2DM) and concomitant non-alcoholic fatty liver disease (NAFLD). SUBJECTS AND METHODS: One hundred and seventeen patients with T2DM and NAFLD were randomly divided into exenatide group and metformin group. Patients were treated with exenatide and metformin, respectively, for 12 weeks. RESULTS: After 12 weeks of treatment, body weight, body mass index (BMI), waist-to-hip ratio, HbA1c, FPG, 2-h PPG, ALT, AST, gamma-GT, and hs-CRP were significantly reduced, and the AST/ALT ratio and adiponectin were markedly increased in both groups. BMI, waist-to-hip ratio, 2-h PPG, ALT, AST, gamma-GT, and hs-CRP were markedly lower, and AST/ALT ratio and adiponectin in the exenatide group were dramatically higher than in the metformin group. CONCLUSION: Compared with metformin, exenatide is better to control blood glucose, reduces body weight and improves hepatic enzymes, attenuating NAFLD in patients with T2DM concomitant with NAFLD. PMID- 24402016 TI - Reappraisal of serum insulin-like growth factor-I (IGF-1) measurement in the detection of isolated and combined growth hormone deficiency (GHD) during the transition period. AB - OBJECTIVE: To evaluate the accuracy of serum IGF-1 in the detection of isolated (IGHD) or combined growth hormone deficiency (CGHD) at the transition phase. SUBJECTS AND METHODS: Forty nine patients with GHD during childhood [16 with IGHD (10 men) and 33 with CGHD (24 men); age 23.2 +/- 3.5 yrs.] were submitted to an insulin tolerance test (ITT) with a GH peak < 5 ug/L used for the diagnosis of GHD at the transition phase. Pituitary function and IGF-1 measurements were evaluated in the basal sample of the ITT. Transition patients were reclassified as GH-sufficient (SGH; n = 12), IGHD (n = 7), or CGHD (n = 30). RESULTS: Five (31%) patients with IGHD and 32 (97%) with CGHD at childhood persisted with GHD at retesting. One patient with IGHD was reclassified as CGHD, whereas 3 patients with CGHD were reclassified as IGHD. Mean GH peak was 0.2 +/- 0.3 ug/L in the CGHD, 1.3 +/- 1.5 ug/L in the IGHD, and 18.1 +/- 13.1 ug/L in the SGH group. Serum IGF-1 level was significantly higher in the SGH (272 +/- 107 ng/mL) compared to IGHD (100.2 +/- 110) and CGHD (48.7 +/- 32.8) (p < 0.01). All patients reclassified as CGHD, 86% reclassified as IGHD, and 8.3% reclassified as SGH had low IGF-1 level, resulting in 97.3% sensitivity and 91.6% specificity in the detection of GHD at the transition period; the cutoff value of 110 ng/mL showed 94.5% sensitivity and 100% specificity. Mean IGF-1 values did not differ in IGHD or CGHD associated with one, two, three, or four additional pituitary deficiencies. CONCLUSION: IGF-1 measurement is accurate to replace ITT as initial diagnostic test for IGHD and CGHD detection at the transition phase. PMID- 24402017 TI - [Determinant factors associated with weight loss in adults on diet interventions]. AB - OBJECTIVE: To analyze the determinants for weight loss (> 5%) resulting from outpatient individual appointments. SUBJECTS AND METHODS: A retrospective cohort study was conduct in 318 overweight/obese patients seeking individual care to lose weight. RESULTS: Fifteen percent of the patients did not lose weight; 35.1% had lost < 5%; 35.4% had lost between 5 and 10%; and 13.9% had lost > 10%. Patients who lost > 5% body weight (-7.6 +/- 3.3 kg, n = 156) had a greater number of visits at a shorter interval, and greater frequency of visits with a registered dietitian and multidisciplinary care. This group had a lower prescription of anti-obesity drugs and their total calorie intake was higher than the other patients. In multivariate Cox regression, only the interval between appointments and the total number of visits remained inversely associated with weight loss. CONCLUSIONS: The determinants of > 5% weight loss were fewer visits with a shorter interval between appointments. PMID- 24402018 TI - Static balance in patients presenting diabetes mellitus type 2 with and without diabetic polyneuropathy. AB - OBJECTIVES: To contrast the static balance in patients presenting diabetes mellitus type 2 (DM2) with and without polyneuropathy (DPN); and to correlate the rates from the scale Diabetic Neuropathy Examination (DNE) with the mean ratio of the center of pressure (CoP). SUBJECTS AND METHODS: Twenty patients, aged between 40 and 54, presenting DM2 and classified, according to DNE scale, in groups with (n = 10) and without (n = 10) DPN, were compared. Static balance was evaluated by means of the CoP mean ratio on a Wii Balance Board(r) under the conditions of open and closed eyes. After normality verification (Shapiro-Wilk), balance between both groups was compared by means of the Student t test and Mann-Whitney U test, as applicable. DNE rating was correlated with the mean ratio of CoP in the group with DPN, considering a significance level p < 0.05. RESULTS: Significant differences (p = 0.049) were found under the condition of closed eyes, with greater CoP ratio in the group with DPN (0.548 cm vs. 0.442 cm). The group with DPN showed a tendency (p = 0.059) towards a greater CoP mean ratio under the open eyes condition (0.351 cm vs. 0.239 cm). There was a strong correlation (r = 0.751) between the DNE rating and the CoP mean ratio under the closed eyes condition (p = 0.012). CONCLUSIONS: Patients showing DPN demonstrated worse static balance than patients without DPN in the closed eyes condition. Furthermore, the higher the rating in DNE, the stronger the displacement of CoP, which may be associated with higher risk of falls. PMID- 24402019 TI - [Correlation between iodine urinary levels and pathological changes in thyroid glands]. AB - OBJECTIVES: To determine iodine nutrition in the population and to correlate levels of iodine found in random samples of urine with pathological changes observed in thyroids collected in this population. MATERIALS AND METHODS: Urinary iodine was determined in 30 random samples of urine and the pathological study was carried out in 55 thyroid glands from corpses received by the Department of Forensic Medicine of Vitoria, Espirito Santo, Brazil from May to August 2011. RESULTS: In 29 urine samples (96.7%) urinary iodine was above the maximum limit recommended by the World Health Organization (WHO), of 300 mg/L. Fourteen thyroids (25.5%) showed the presence of histological changes compatible with thyroiditis. Higher levels of iodine in urine were observed in females and in of thyroid that showed inflammation (thyroiditis). CONCLUSIONS: We conclude that, in this population, there is excess iodine intake, and greater incidence of inflammatory thyroid disease. PMID- 24402020 TI - [Screening for autoimmune polyglandular syndrome in a cohort of patients with type 1 diabetes mellitus]. AB - OBJECTIVE: To characterize a cohort of patients with type 1 diabetes mellitus (T1DM) on the presence of other autoimmune disorders that could establish the diagnosis of autoimmune polyglandular syndrome (APS). SUBJECTS AND METHODS: We included 151 patients with T1DM. The following clinical parameters were analyzed: gender, current age, disease duration, previous history of autoimmune disorders, and familial history for diabetes mellitus. Each patient was analyzed to detect autoimmune markers of thyroiditis, adrenocortical insufficiency, gastritis, and celiac disease, as well as possible associated dysfunctions. RESULTS: A cohort with 51.7% males, average current age of 33.4 +/- 13 years and disease duration of 14.4 +/- 9.6 years was analyzed. Previous history of autoimmunity was found in 2%, and familial history for diabetes mellitus in 31.1% of the cohort. Frequency of autoimmune markers was 24% for thyroiditis, 9.4% for adrenocortical insufficiency, 17.2% for gastritis, and 2% for celiac disease. APS was diagnosed on 25.2% of the patients. APS and autoimmune thyroiditis risk was higher in females. Disease duration correlated directly with gastric autoantibodies, and inversely with positive islet cell, glutamic acid decarboxylase, and tyrosine phosphatase antibodies. We noticed a correlation between autoimmune markers for thyroiditis and gastritis, as well as between celiac disease and adrenocortical insufficiency. CONCLUSION: Considering APS prevalence and prognosis, the need for APS screening in patients with T1DM is emphasized. Early diagnosis of other autoimmune disorders will enable us to adjust each patient treatment and follow up. PMID- 24402021 TI - Nonadenomatous nonencapsulated thymic parathyroid tissue concomitant with primary hyperparathyroidism due to ectopic parathyroid adenoma. AB - Primary hyperparathyroidism due to ectopic parathyroid adenoma is not infrequent. Primary hyperparathyroidism caused by unusual thymic nonadenomatous nonencapsulated parathyroid tissue has been reported before. Both can cause unsuccessful neck explorations. Here we presented for the first time a patient with hyperparathyroidism due to ectopic parathyroid adenoma concomitant to the presence of thymic nonadenomatous nonencapsulated parathyroid tissue. PMID- 24402022 TI - [Myxedema coma in a patient with type 1 neurofibromatosis: rare association]. AB - Myxedema coma, a rare but fatal emergency, is an extreme expression of hypothyroidism. We describe a 51-year-old male patient who has discontinued hypothyroidism treatment 10 months earlier and developed lethargy, edema, and cold intolerance symptoms. He also had a previous diagnosis of neurofibromatosis. After admission, he progressed to respiratory insufficiency and coma. The prompt recognition of the condition, thyroid hormone replacement, and management of the complications (hypoventilation, cardiogenic shock associated with swinging heart, adrenal and renal insufficiency and sepsis), resulted in a favorable evolution. PMID- 24402024 TI - Retraction note. Translational research into gut microbiota: new horizons in obesity treatment. PMID- 24402023 TI - The unusual association of Graves' disease, chronic spontaneous urticaria, and premature ovarian failure: report of a case and HLA haplotype characterization. AB - Chronic spontaneous urticaria (CSU), defined as the occurrence of spontaneous wheals for more than six weeks, has been associated with autoimmune diseases. Herein, we report the unusual association of CSU, Graves' disease, and premature ovarian failure. Human leukocyte antigen (HLA) studies were performed. A 36-year old woman presented symptoms and signs of hyperthyroidism for three months. In the same period, the patient complained of widespread urticarial wheals, intensely itchy, and poorly responsive to therapy with antihistaminic agents. Hyperthyroidism was confirmed biochemically, and treatment with methimazole was started. As hyperthyroidism improved, a marked improvement in her urticaria was also observed. However, the patient continued to complain of amenorrhea. Endocrine evaluation, at the age 38, was consistent with premature ovarian failure. This is the first report of coexistence of GD, CSU, and POF. The genetic background of such unusual association is a specific combination of HLA. PMID- 24402025 TI - Arterial stiffness should be evaluated with other inflammatory markers in patients with subclinical hypothyroidism. PMID- 24402027 TI - Remote ischaemic conditioning and ischaemic heart disease. AB - As clinical evidence builds regarding the efficacy of remote ischaemic conditioning's ability to attenuate myocardial injury arising from acute coronary syndromes and cardiac surgery, this article describes the conditioning phenomenon, current clinical evidence and how ischaemic conditioning may be used in future clinical practice. PMID- 24402030 TI - Recognizing and managing retinal vein occlusion. AB - Retinal vein occlusion is the second most common retinal vascular disease after diabetic retinopathy and represents a significant cause of irreversible sight loss and disability in persons over the age of 50 years (The Branch Vein Occlusion Study Group, 1984). PMID- 24402031 TI - Chirality meets visible-light photocatalysis in a molecular cerium vanadium oxide cluster. AB - The first example of a molecular cerium vanadium oxide photocatalyst is presented. A cerium vanadium oxide cluster, (nBu4N)2[(Ce(dmso)3)2V(IV)V(V)11O33Cl] * 2DMSO (1), was obtained by bottom-up self-assembly. The compound exhibits high visible-light photooxidative activity towards indigo with quantum efficiencies >10%. Initial mechanistic studies of the photooxidation reaction are presented. The structure of compound 1 is based on chiral, C2-symmetric cluster anions and both enantiomers are present in the crystal lattice. Retrosynthetic analysis suggests that chiral building blocks are spontaneously formed by symmetry breaking during self-assembly. The assembly of 1 based on the chiral building blocks is discussed conceptually. Consequences of this assembly mechanism for the development of chiral molecular catalysts and photocatalysts are described. PMID- 24402032 TI - Steady state analysis of the genetic regulatory network incorporating underlying molecular mechanisms for anaerobic metabolism in Escherichia coli. AB - A Gene Regulatory Network (GRN) represents complex connections between genes in a cell which interact with each other through their RNA and protein expression products, thereby determining the expression levels of mRNA and proteins required for functioning of the cell. Microarray experiments yield the log fold change in mRNA abundance and quantify the expression levels for a GRN at the genome level. While Boolean or Bayesian modeling along with expression and location data are useful in analyzing microarray data, they lack underlying mechanistic details present in GRNs. Our objective is to understand the role of molecular mechanisms in quantifying a GRN. To that effect, we analyze under steady state, the complete GRN for the central metabolic pathway during anaerobiosis in Escherichia coli. We simulate the microarray experiments using a steady state gene expression simulator (SSGES) that models molecular mechanistic details such as dimerization, multiple-site binding, auto-regulation and feedback. Given a GRN, the SSGES provided the log fold change in mRNA expression values as the output, which can be compared to data from microarray experiments. We predict the log fold changes for mutants obtained by knocking out crucial transcriptional regulators such as FNR (F), ArcA (A), IHFA-B (I) and DpiA (D) and observe a high degree of correlation with previously reported experimental data. We also predict the microarray expression values for hitherto unknown combinations of deletion mutants. We hierarchically cluster the predicted log fold change values for these mutants and postulate that E. coli has evolved from a predominantly lactate secreting (FAID mutant) into a mixed acid secreting phenotype as seen in the wild type (WT) during anaerobiosis. Upon simulating a model without incorporating the mechanistic details, not only the correlation with the experimental data reduced considerably, but also the clustering of expression data indicated WT to be closer to the quadruple mutant FAID. This clearly demonstrates the significance of incorporating mechanistic data while quantifying the expression profile of a GRN which can help in predicting the effect of a gene mutant and understanding the evolution of transcriptional control. PMID- 24402033 TI - Surface interaction of L-alanine on hematite: an astrobiological implication. AB - In the present work, surface interaction of L-alanine (L-ala) has been investigated on hematite (alpha-Fe2O3), an abundant mineral on Mars, as a function of time (5 min-48 h), pH (4.0 and 6.20 +/- 0.10) and concentration (1 * 10(-3) M-10 * 10(-3) M) with optical absorbance and energy-dispersive spectroscopy (EDS). Adsorption parameters (XM and KL) were calculated from Langmuir adsorption isotherms. L-alanine has maximum affinity (65.31 %) in its zwitterionic form at pH 6.20, while it is only 29.86 % adsorbed at pH 4.0. Possible astrobiological implications are discussed. PMID- 24402034 TI - A new criterion for demarcating life from non-life. AB - Criteria for demarcating life from non-life are important for deciding whether new candidate systems, either discovered extraterrestrially or constructed in the laboratory, are genuinely alive or not. They are also important for understanding the origin of life and its evolution. Current criteria are either too restrictive or too extensive. The new criterion proposed here poses that a system is living when it is capable of utilizing active causation, at evolutionary or behavioural timescales. Active causation is produced when the organism uses an estimate of its own Darwinian fitness to modulate the variance of stochasticity that drives hereditary or behavioural changes. The changes are subsequently fed back to the fitness estimate and used in the next cycle of a feedback loop. The ability to use a self-estimated fitness in this way is an evolved property of the organism, and the way in which fitness is estimated is therefore controlled and stabilized by Darwinian evolution. The hereditary and behavioural trajectories resulting from this mechanism combine predictability with unpredictability, and the mechanism produces a form of self-directed agency in living organisms that is absent from non-living systems. PMID- 24402035 TI - Reducing survey burden: feasibility and validity of PROMIS measures in multiple sclerosis. AB - BACKGROUND: Patient-reported outcomes are important for clinical research and care, yet administering and scoring the questionnaires requires considerable effort and time. The Patient Reported Outcomes Measurement Information System (PROMIS) could considerably reduce administrative obstacles and lessen survey burden for participants. OBJECTIVE: Assess the feasibility and validity of PROMIS, compared to commonly-used legacy measures for multiple sclerosis (MS). METHODS: In this cross-sectional survey, 133 participants with confirmed MS completed legacy surveys and PROMIS Computerized Adaptive Tests (CATs) for depression, anxiety, pain, fatigue and physical function. We conducted a multi trait, multi-method analysis and verified results with confirmatory factor analysis. RESULTS: The correlations between PROMIS and the corresponding legacy measures were large (0.67 to 0.87). The multi-trait, multi-method criteria were generally well met, providing good evidence of the validity of PROMIS measures. PROMIS surveys asked fewer questions and required substantially less time to complete than the legacy scales. CONCLUSIONS: Our results provide evidence of the construct validity of PROMIS for use with MS patients. Several aspects of the PROMIS CATs made them an important resource, including: (a) less time was required to complete them; (b) missing data was reduced; and (c) the automatic scoring referenced the general population. Our findings support the use of PROMIS in MS research and may have broader implications for clinical care, as well. PMID- 24402036 TI - Disease course heterogeneity and OCT in multiple sclerosis. AB - BACKGROUND: The heterogeneity of the disease course in multiple sclerosis (MS) remains a challenge for patient management and clinical trials. OBJECTIVE: The objective of this paper is to investigate the relationship between disease course heterogeneity and retinal layer thicknesses in MS. METHODS: A total of 230 MS patients and 63 healthy control subjects were included. Spectral-domain OCT scanning of the peripapillary and macular regions was performed, followed by automated eight-layer segmentation. Generalised estimation equations were used for comparisons. Receiver operating characteristic (ROC) curves were calculated for distinguishing a benign from a typical disease course. RESULTS: Primary progressive patients showed relative preservation of inner retinal layers, compared to the relapsing onset MS types. Only in MS eyes without optic neuritis did patients with typical MS show more severe thinning of the inner retinal layers (RNFL to INL) compared to patients with a benign disease course, even after an average disease course of 20 years. CONCLUSION: The thicknesses, particularly of the innermost retinal layers (RNFL, GCC), were significantly related to the heterogeneous disease course in MS. The relative preservation of these layers in primary progressive and benign MS suggests rather limited susceptibility of the retina to neurodegeneration, which may be relevant for future neurodegenerative treatment trials employing OCT as a secondary outcome measure in primary progressive MS. PMID- 24402037 TI - Utility of aquaporin-4 antibody assay in patients with neuromyelitis optica spectrum disorders. PMID- 24402038 TI - Cranberry versus placebo in the prevention of urinary infections in multiple sclerosis: a multicenter, randomized, placebo-controlled, double-blind trial. AB - OBJECTIVE: Our aim was to assess the usefulness of cranberry extract in multiple sclerosis (MS) patients suffering from urinary disorders. METHODS: In total, 171 adult MS outpatients with urinary disorders presenting at eight centers were randomized (stratification according to center and use of clean intermittent self catheterization) to cranberry versus placebo in a 1-year, prospective, double blind study that was analyzed using a sequential method on an intent-to-treat basis. An independent monitoring board analyzed the results of the analyses each time 40 patients were assessed on the main endpoint. Cranberry extract (36 mg proanthocyanidins per day) or a matching placebo was taken by participants twice daily for 1 year. The primary endpoint was the time to first symptomatic urinary tract infection (UTI), subject to validation by a validation committee. RESULTS: The second sequential analyses allowed us to accept the null hypothesis (no difference between cranberry and placebo). There was no difference in time to first symptomatic UTI distribution across 1 year, with an estimated hazard ratio of 0.99, 95% CI [0.61, 1.60] (p = 0.97). Secondary endpoints and tolerance did not differ between groups. CONCLUSION: Taking cranberry extract versus placebo twice a day did not prevent UTI occurrence in MS patients with urinary disorders. Trial Registration NCT00280592. PMID- 24402039 TI - Antinuclear antibodies in pediatric acquired demyelinating diseases of the central nervous system. PMID- 24402040 TI - Isolated bilateral horizontal gaze palsy as first manifestation of multiple sclerosis. AB - Predilection sites for infratentorial multiple sclerosis lesions are well known and frequently involve the fasciculus longitudinalis medialis leading to classical internuclear ophthalmoplegia. We report a very rare oculomotor disorder due to a demyelinating central nervous system (CNS) lesion in the medial part of the lower pontine tegmentum. A 36-year-old man presented with sudden onset of blurred vision. Clinically there was limited eye adduction and abduction to either side, which corresponds to bilateral horizontal gaze palsy. Brain magnetic resonance imaging (MRI) showed a demyelinating CNS lesion affecting the fasciculus longitudinalis medialis, abducens nuclei or abducens fibres in the medial part of the lower pontine tegmentum. Furthermore there were six further demyelinating white matter lesions fulfilling all Barkhof criteria for multiple sclerosis. Demyelinating CNS lesions causing isolated bilateral horizontal gaze palsy are exceptional and usually associated with further focal neurological deficits, which was not the case in the presenting patient. This is a unique video report of isolated bilateral horizontal gaze palsy as the initial manifestation of demyelinating CNS disease, which lead to definite diagnosis of relapsing remitting multiple sclerosis. PMID- 24402041 TI - Improved short-term outcomes with off-pump reoperative coronary artery bypass grafting. AB - OBJECTIVE: Reoperative coronary surgery patients are usually sicker and older, and the procedure is more technically demanding. Comparisons between coronary surgery with (coronary artery bypass [CAB] surgery on cardiopulmonary bypass [CPB]) and without (off-pump CAB [OPCAB]) the pump have been conducted; however, few studies showed results in reoperative cases. We investigate the potential superiority of one technique over the other in redo coronary surgeries. METHODS: Our institutional Society of Thoracic Surgery database was used to gather the data for 266 isolated reoperative coronary artery surgeries from January 2004 to July 2011. These were divided into the CAB surgery in CPB group (n = 204) and the OPCAB group (n = 62). RESULTS: Baseline characteristics of the two groups were similar, except for a significantly higher prevalence of cerebrovascular disease among the off-pump group (P = 0.01). There was also a trend toward fewer vessels bypassed among the same group (P = 0.07). Risk adjustment was done using multivariable analyses for detection of independent effects. The use of CPB was an independent predictor of increased rates of postoperative events (odds ratio, 3.9; P = 0.004) and atrial fibrillation (odds ratio, 5.9; P < 0.005) and longer intensive care unit (0.006) and hospital stay (0.004). CONCLUSIONS: Redo OPCAB seems to offer favorable short-term outcomes compared with redo CAB. Our results suggest a reduced rate of overall postoperative events, decreased new postoperative atrial fibrillation, reduced hours stayed in the intensive care unit, and fewer days stayed from surgery to discharge. This was not associated with an increase in morbidity and mortality. A randomized study with a larger number of patients and with a longer follow-up is needed. PMID- 24402042 TI - Outcome characteristics of multiple-valve surgery: comparison with single-valve procedures. AB - OBJECTIVE: Multiple-valve (MUV) procedures currently exhibit higher operative mortality than do single-valve procedures, but a paucity of scientific information exists to explain the observation. This topic was examined using The Society of Thoracic Surgeons Database. METHODS: All patients in the The Society of Thoracic Surgeons data set undergoing valve surgery (except pulmonary valve and aortic root operations) from 1993 through 2007 were identified (N = 623,039). Baseline characteristics and postoperative outcomes were contrasted between all seven combinations of single-valve and MUV procedures involving aortic, mitral, and tricuspid valves. Seven independent logistic regression analyses were performed, based on the seven procedures, and multivariable risk factors for mortality were compared, with emphasis on single-valve versus MUV procedures. RESULTS: Baseline characteristics for MUV procedures (n = 67,926) shared many similarities to those for single-valve procedures (n = 555,113), including age, ejection fraction, and comorbidities. Preoperative renal failure, New York Heart Association class III to IV, nonelective presentation, and reoperation were slightly more common in MUV subsets, and coronary bypass was less frequent. Operative mortality was almost double for MUV as compared with single-valve procedures (10.7% vs 5.7%, P = 0.0001). Categorical predictors with the largest odds ratios for mortality were emergency status, renal failure, and second reoperation. However, predictors for mortality were generally consistent in order and magnitude between the single-valve and MUV subgroups. CONCLUSIONS: Despite similarities in preoperative profiles of the patients undergoing single-valve and MUV procedures, mortality for MUV surgery remains considerably higher. Determinants of operative mortality and morbidity differ little across the procedural groups, and these findings serve as a benchmark for future studies, as well as suggest a continued search for explanations of poorer MUV outcomes. PMID- 24402043 TI - Estrogen receptor beta in prostate cancer: friend or foe? AB - Prostate cancer is the commonest, non-cutaneous cancer in men. At present, there is no cure for the advanced, castration-resistant form of the disease. Estrogen has been shown to be important in prostate carcinogenesis, with evidence resulting from epidemiological, cancer cell line, human tissue and animal studies. The prostate expresses both estrogen receptor alpha (ERA) and estrogen receptor beta (ERB). Most evidence suggests that ERA mediates the harmful effects of estrogen in the prostate, whereas ERB is tumour suppressive, but trials of ERB selective agents have not translated into improved clinical outcomes. The role of ERB in the prostate remains unclear and there is increasing evidence that isoforms of ERB may be oncogenic. Detailed study of ERB and ERB isoforms in the prostate is required to establish their cell-specific roles, in order to determine if therapies can be directed towards ERB-dependent pathways. In this review, we summarise evidence on the role of ERB in prostate cancer and highlight areas for future research. PMID- 24402044 TI - Is BRAFV600E mutation a marker for central nodal metastasis in small papillary thyroid carcinoma? AB - Utilizing BRAF(V600E) mutation as a marker may reduce unnecessary prophylactic central neck dissection (pCND) in clinically nodal negative (cN0) neck for small (<=2 cm) classical papillary thyroid carcinoma (PTC). We aimed to assess whether BRAF is a significant independent predictor of occult central nodal metastasis (CNM) and its contribution to the overall prediction after adjusting for other significant preoperative clinical factors in small PTC. Primary tumor tissue (paraffin-embedded) from 845 patients with small classical cN0 PTC who underwent pCND was tested for BRAF mutation. Clinicopathologic factors were compared between those with and without BRAF. BRAF was evaluated to see if it was an independent factor for CNM. Prediction scores were generated using logistic regression models and their predictability was measured by the area under the ROC curve (AUC). The prevalence of BRAF was 628/845 (74.3%) while the rate of CNM was 285/845 (33.7%). Male sex (odds ratio (OR): 2.68, 95% CI: 1.71-4.20), large tumor size (OR: 2.68, 95% CI: 1.80-4.00), multifocality (OR: 1.49, 95% CI: 1.07-2.09), lymphovascular permeation (OR: 10.40, 95% CI: 5.18-20.88), and BRAF (OR: 1.65, 95% CI: 1.10-2.46) were significant independent predictors of CNM, while coexisting Hashimoto's thyroiditis (OR: 0.56, 95% CI: 0.40-0.80) was an independent protective factor. The AUC for prediction score based on tumor size and male sex was similar to that of prediction score based on tumor size, male sex, and BRAF status (0.68 vs 0.69, P=0.60). Although BRAF was an independent predictor of CNM, knowing its status did not substantially improve the overall prediction. A simpler prediction score based on male sex and tumor size might be sufficient. PMID- 24402045 TI - Overexpression of cysteine cathepsin L is a marker of invasion and metastasis in ovarian cancer. AB - Cysteine cathepsins (CTSs) are involved in the degradation and remodeling of the extracellular matrix and are associated with cellular transformation, differentiation, motility and adhesion in cancer development. Previous studies indicate that CTSs may be involved in ovarian cancer invasion and metastasis. However, due to the lack of large sample clinical studies and direct experimental evidence for the relationship between the expression of CTSs and invasion and metastasis, the diagnostic and prognostic value of CTSs in ovarian cancer progression has not been elucidated. In the present study, we observed that expression levels of CTSB, CTSL and CC in malignant ovarian tumors were significantly higher than the expression levels in benign tumors and normal ovarian tissues, yet their associations with clinicopathological features varied. In particular, CTSL was related to lymph node metastasis, CC was related to liver metastasis and omental metastasis, and CTSB and CTSL expression levels were found to be independent prognostic factors in ovarian cancer. Further study indicated that the serum level of CTSL was significantly higher in patients with ovarian malignant tumors than the levels in benign tumors and healthy controls, and the levels were elevated in low grade and advanced stage compared to the levels in high grade and early stage disease, suggesting that the serum level of CTSL may be a useful serum marker for the diagnosis of ovarian cancer. Furthermore, the expression of CTSL in ovarian cancer cells can greatly enhance the ability of cell invasion and metastasis, although no change was observed for cell adhesion. Taken together, we demonstrated that the overexpression of CTSL is involved in tumor invasion and metastasis, and the CTSL level in serum may be a marker for invasion and metastasis in ovarian cancer. PMID- 24402047 TI - Internal fixation of femoral head fractures (Pipkin I) using hip arthroscopy. AB - A hip arthroscopy technique for the reduction and internal fixation of a displaced femoral head fracture is presented. Open treatment is often required for femoral head fractures. However, it is shown below how large fragments of a femoral head fracture-dislocation were reduced and internally fixated using hip arthroscopy. This was performed in the supine position using skeletal traction. The accessory distal anterior portal was used for internal fixation when a hip was positioned in abduction with external rotation. A satisfactory outcome was reported. Recovery was immediate and cosmetics were excellent. We conclude that hip arthroscopy is a valuable option for managing femoral head fracture dislocations (Pipkin I). PMID- 24402046 TI - BNIP3 plays crucial roles in the differentiation and maintenance of epidermal keratinocytes. AB - Transcriptome analysis of the epidermis of Hes1(-/-) mouse revealed the direct relationship between Hes1 (hairy and enhancer of split-1) and BNIP3 (BCL2 and adenovirus E1B 19-kDa-interacting protein 3), a potent inducer of autophagy. Keratinocyte differentiation is going along with activation of lysosomal enzymes and organelle clearance, expecting the contribution of autophagy in this process. We found that BNIP3 was expressed in the suprabasal layer of the epidermis, where autophagosome formation is normally observed. Forced expression of BNIP3 in human primary epidermal keratinocytes (HPEKs) resulted in autophagy induction and keratinocyte differentiation, whereas knockdown of BNIP3 had the opposite effect. Intriguingly, addition of an autophagy inhibitor significantly suppressed the BNIP3-stimulated differentiation of keratinocytes, suggesting that BNIP3 plays a crucial role in keratinocyte differentiation by inducing autophagy. Furthermore, the number of dead cells increased in the human epidermal equivalent of BNIP3 knockdown keratinocytes, which suggests that BNIP3 is important for maintenance of skin epidermis. Interestingly, although UVB irradiation stimulated BNIP3 expression and cleavage of caspase3, suppression of UVB-induced BNIP3 expression led to further increase in cleaved caspase3 levels. This suggests that BNIP3 has a protective effect against UVB-induced apoptosis in keratinocytes. Overall, our data provide valuable insights into the role of BNIP3 in the differentiation and maintenance of epidermal keratinocytes. PMID- 24402048 TI - Sex comparison of familial predisposition to anterior cruciate ligament injury. AB - PURPOSE: In an effort to identify risk factors for anterior cruciate ligament (ACL) injury, many potential risk factors have been proposed, including familial predisposition. However, no study has evaluated familial predisposition in male or females separately. The purpose of this study was to determine whether a familial predisposition to ACL injury exists in both males and females. METHODS: One hundred and twenty (78 males and 42 females) patients who had undergone surgical ACL reconstruction were recruited as the ACL group, and 107 patients (67 males and 40 females) that had undergone arthroscopic partial menisectomy, with no previous history of ACL injury, were recruited as the referent control group. A familial ACL injury and subject particulars questionnaire was completed. RESULTS: When all subjects were combined, the ACL group (20.0 %, 24 of 120) did not demonstrate a higher familial (first-degree relative) prevalence (n.s.) of ACL injury compared to the referent control group (15.0 %; 16 of 107 patients). When the data were stratified by sex, the male ACL group (19.2 %, 15 of 78) demonstrated a significantly higher familial (first-degree relative) prevalence (P = 0.02) of ACL injury compared to the male referent control group (7.5 %; 5 of 67 patients). There were no differences among the females (n.s.). DISCUSSION: The results of this study show that male patients with ACL tears are more likely to have a first-degree relative with an ACL tear compared to male referent control subjects. Future research is warranted to better delineate sex-specific risk factors for ACL injuries could help guide intervention programs aimed at preventative treatment strategies, especially in high-risk families. PMID- 24402049 TI - A data integration and visualization resource for the metabolic network of Synechocystis sp. PCC 6803. AB - Data integration is a central activity in systems biology. The integration of genomic, transcript, protein, metabolite, flux, and computational data yields unprecedented information about the system level functioning of organisms. Often, data integration is done purely computationally, leaving the user with little insight in addition to statistical information. In this article, we present a visualization tool for the metabolic network of Synechocystis sp. PCC 6803, an important model cyanobacterium for sustainable biofuel production. We illustrate how this metabolic map can be used to integrate experimental and computational data for Synechocystis sp. PCC 6803 systems biology and metabolic engineering studies. Additionally, we discuss how this map, and the software infrastructure that we supply with it, can be used in the development of other organism-specific metabolic network visualizations. In addition to the Python console package VoNDA (http://vonda.sf.net), we provide a working demonstration of the interactive metabolic map and the associated Synechocystis sp. PCC 6803 genome-scale stoichiometric model, as well as various ready-to-visualize microarray data sets, at http://f-a-m-e.org/synechocytis. PMID- 24402050 TI - Global selection on sucrose synthase haplotypes during a century of wheat breeding. AB - Spike number per unit area, number of grains per spike, and thousand kernel weight (TKW) are important yield components. In China, increases in wheat (Triticum aestivum) yields are mainly due to increases in grain number per spike and TKW. TKW mainly depends on starch content, as starch accounts for about 70% of the grain endosperm. Sucrose synthase catalysis is the first step in the conversion of sucrose to starch, that is, the conversion of sucrose to fructose and UDP-glucose by the wheat sucrose synthase genes (TaSus1 and TaSus2) that are located on chromosomes 7A/7B/7D and 2A/2B/2D, respectively. A total of 1,520 wheat accessions were genotyped at the six loci. Two, two, five, and two haplotypes were identified at the TaSus2-2A, TaSus2-2B, TaSus1-7A, and TaSus1-7B loci, respectively. Their main variations were detected within the introns. Significant differences between the haplotypes correlated with TKW differences among 348 modern Chinese cultivars from the core collection. Frequency changes for favored haplotypes showed gradual increases in cultivars released since beginning of the last century in China, Europe, and North America. Geographic distributions and time changes of favored haplotypes were characterized in six major wheat production regions worldwide. Strong selection bottlenecks to haplotype variations occurred at polyploidization and domestication and during breeding of wheat. Genetic-effect differences between haplotypes at the same locus influence the selection time and intensity. This work shows that the endosperm starch synthesis pathway is a major target of indirect selection in global wheat breeding for higher yield. PMID- 24402052 TI - Toward Millions of File System IOPS on Low-Cost, Commodity Hardware. AB - We describe a storage system that removes I/O bottlenecks to achieve more than one million IOPS based on a user-space file abstraction for arrays of commodity SSDs. The file abstraction refactors I/O scheduling and placement for extreme parallelism and non-uniform memory and I/O. The system includes a set associative, parallel page cache in the user space. We redesign page caching to eliminate CPU overhead and lock-contention in non-uniform memory architecture machines. We evaluate our design on a 32 core NUMA machine with four, eight-core processors. Experiments show that our design delivers 1.23 million 512-byte read IOPS. The page cache realizes the scalable IOPS of Linux asynchronous I/O (AIO) and increases user-perceived I/O performance linearly with cache hit rates. The parallel, set-associative cache matches the cache hit rates of the global Linux page cache under real workloads. PMID- 24402051 TI - ErbB receptors and their growth factor ligands in pediatric intestinal inflammation. AB - The ErbB tyrosine kinases (epidermal growth factor receptor (EGFR), ErbB2/HER2, ErbB3, and ErbB4) are cell surface growth factor receptors widely expressed in many developing mammalian tissues, including in the intestinal tract. Signaling elicited by these receptors promotes epithelial cell growth and survival, and ErbB ligands have been proposed as therapeutic agents for intestinal diseases of pediatric populations, including inflammatory bowel disease (IBD), necrotizing enterocolitis (NEC), and inflammation associated with total parenteral nutrition (TPN). Furthermore, emerging evidence points to reduced ErbB ligand expression and thus reduced ErbB activity in IBD, NEC, and TPN models. This review will discuss the current understanding of the role of ErbB receptors in the pathogenesis and potential treatment of pediatric intestinal inflammation, with focus on the altered signaling in disease and the molecular mechanisms by which exogenous ligands are protective. PMID- 24402053 TI - Environmental exposure and mitochondrial epigenetics: study design and analytical challenges. AB - The environment can influence human health and disease in many harmful ways. Many epidemiological studies have been conducted with the aim of elucidating the association between environmental exposure and human disease at the molecular and pathological levels, and such associations can often be through induced epigenetic changes. One such mechanism for this is through environmental factors increasing oxidative stress in the cell, and this stress can subsequently lead to alterations in DNA molecules. The two cellular organelles that contain DNA are the nucleus and mitochondria, and the latter are particularly sensitive to oxidative stress, with mitochondrial functions often disrupted by increased stress. There has been a substantial increase over the past decade in the number of epigenetic studies investigating the impact of environmental exposures upon genomic DNA, but to date there has been insufficient attention paid to the impact upon mitochondrial epigenetics in studying human disease with exposure to environment. Here, in this review, we will discuss mitochondrial epigenetics with regard to epidemiological studies, with particular consideration given to study design and analytical challenges. Furthermore, we suggest future directions and perspectives in the field of mitochondrial epigenetic epidemiological studies. PMID- 24402054 TI - The contributions of twin studies to the understanding of brain ageing and neurocognitive disorders. AB - PURPOSE OF REVIEW: A number of studies of older twins have been published to inform about the relative contributions of genetic and environmental factors and their interactions in determining cognitive ageing and dementia. This review attempts to collate the salient findings from these studies. RECENT FINDINGS: Most data come from eight studies, with the majority being Scandinavian. These studies suggest that cognitive functions have moderate to high heritability in late life, with genetic influences varying for different cognitive domains. The heritability of mild cognitive impairment is, however, low, and that of dementia moderate, suggesting significant environmental influences, and possibly some measurement error. Brain structures continue to have high heritability into late life, although the genetic component of the variance does decrease with age. The co-twin control studies support the role of mid-life lifestyle factors for cognitive ageing and late-life dementia. SUMMARY: The potential of twin studies to understand ageing and dementia is only beginning to be realized. More longitudinal studies are needed, and novel strategies of genomics and epigenetics can further exploit this powerful method to inform the field. PMID- 24402057 TI - Caries management through the Atraumatic Restorative Treatment (ART) approach and glass-ionomers: update 2013. PMID- 24402056 TI - Seasonal variations in species composition, abundance, biomass and production rate of tintinnids (Ciliata: Protozoa) along the Hooghly (Ganges) River Estuary, India: a multivariate approach. AB - The study is the first documentation of seasonal variations in species composition, abundance and diversity of tintinnid (Ciliata: Protozoa), in relation to water quality parameters along the stretch of the Hooghly (Ganges) River Estuary (HRE), eastern coastal part of India. A total of 26 species (22 agglomerated and 4 non-agglomerated) belonging to 8 genera has been identified from 8 study sites where Tintinnopsis (17 species) represented the most dominant genera, contributing up to 65 % of total tintinnid community followed by Tintinnidium (2 species), Leprotintinnus (2 species) and Dadayiella, Favella, Metacylis, Eutintinnus and Helicostomella (each with solitary species). The maximum (1,666 ind. l(-1)) and minimum (62 ind. l(-1)) abundance of tintinnids was recorded during post-monsoon and monsoon, respectively. A distinct seasonal dynamics in terms of biomass (0.005-2.465 MUg C l(-1)) and daily production rate (0.04-3.13 MUg C l(-1) day(-1)) was also noticed, accounting highest value during pre-monsoon. Chlorophyll a and nitrate were found to be potential causative factors for the seasonal variations of tintinnids as revealed by a stepwise multiple regression model. The result of ANOVA showed a significant variation between species abundance and months (F = 2.36, P <= 0.05). k-dominance curves were plotted to determine the comparison of tintinnid dominance between the investigated stations. Based on a principal component analysis (PCA), three main groups were delineated with tintinnid ciliates and environmental parameters. The changes in lorica morphology in terms of temperature and salinity, recorded for three dominant species, provided information on the ecological characteristics of the species assemblage in this estuarine system. PMID- 24402055 TI - Methylome-wide association study of schizophrenia: identifying blood biomarker signatures of environmental insults. AB - IMPORTANCE: Epigenetic studies present unique opportunities to advance schizophrenia research because they can potentially account for many of its clinical features and suggest novel strategies to improve disease management. OBJECTIVE: To identify schizophrenia DNA methylation biomarkers in blood. DESIGN, SETTING, AND PARTICIPANTS: The sample consisted of 759 schizophrenia cases and 738 controls (N = 1497) collected in Sweden. We used methyl-CpG-binding domain protein-enriched genome sequencing of the methylated genomic fraction, followed by next-generation DNA sequencing. We obtained a mean (SD) number of 68 (26.8) million reads per sample. This massive data set was processed using a specifically designed data analysis pipeline. Critical top findings from our methylome-wide association study (MWAS) were replicated in independent case control participants using targeted pyrosequencing of bisulfite-converted DNA. MAIN OUTCOMES AND MEASURES: Status of schizophrenia cases and controls. RESULTS: Our MWAS suggested a considerable number of effects, with 25 sites passing the highly conservative Bonferroni correction and 139 sites significant at a false discovery rate of 0.01. Our top MWAS finding, which was located in FAM63B, replicated with P = 2.3 * 10-10. It was part of the networks regulated by microRNA that can be linked to neuronal differentiation and dopaminergic gene expression. Many other top MWAS results could be linked to hypoxia and, to a lesser extent, infection, suggesting that a record of pathogenic events may be preserved in the methylome. Our findings also implicated a site in RELN, one of the most frequently studied candidates in methylation studies of schizophrenia. CONCLUSIONS AND RELEVANCE: To our knowledge, the present study is one of the first MWASs of disease with a large sample size using a technology that provides good coverage of methylation sites across the genome. Our results demonstrated one of the unique features of methylation studies that can capture signatures of environmental insults in peripheral tissues. Our MWAS suggested testable hypotheses about disease mechanisms and yielded biomarkers that can potentially be used to improve disease management. PMID- 24402058 TI - Discrepancies in degree of conversion measurements by FTIR. AB - The purpose of this study was to evaluate the influence of the internal standard peak on the measured degree of conversion (DC) for methacrylate-based resins analyzed by Fourier-transform infrared spectroscopy (FTIR). The influence of different baseline measurement methods was also determined. Different blends were prepared, mixing BisGMA/BisEMA and BisGMA/TEGDMA at proportions of 0% to 100%, in weight. Camphoroquinone and ethyl-4-dimethylamino-benzoate were used to permit the light activation of blends. Degree of conversion was evaluated using FTIR equipped with an attenuated total reflectance (ATR) device. Samples were dispensed onto ATR crystal and light activated for 40 s. The DC was calculated by relating the height of the peak 1637 cm-1 to the intensity of different internal standard peaks (1715, 1608, or 1582 cm-1), measured using two different baseline methods, before and after polymerization. Data were compared by ANOVA at 5% significance. The relationship between DC and monomer ratio was obtained by regression analysis. Double-bond conversion ranged from 32.75% to 78.50% for BisGMA/BisEMA blends, and from 32.75% to 76.22% for BisGMA/TEGDMA blends. For the BisGMA/BisEMA blends, the DC showed a linear association with the composition of the comonomer blends, independent of the internal standard peak and baseline method used. In contrast, the trends in DC for BisGMA/TEGDMA blends were different for each method of measurement. The internal standard peaks and measurement baseline should be taken into account when using FTIR to calculate the DC of methacrylate-based resins, especially comonomer blends containing a high degree of monomers that lack aromatic rings. PMID- 24402059 TI - Success and survival rates of mandibular overdentures supported by two or four implants: a systematic review. AB - This systematic review evaluated the influence played by the number of implants on the results of rehabilitation treatment with mandibular overdentures on 2 or 4 implants. The literature search was conducted using PubMed, Embase and Cochrane databases. Specific terms were used in performing a search from January 1980 to January 2013. The search strategy was applied by two reviewers who extracted the data and compared the results. Discrepancies were resolved by discussion. Great heterogeneity was seen among the selected studies, in regard to survival rates, prosthesis failure and function rates. A medium degree of quality and methodological consistency was found in one study, and no studies showed a high degree. When considering the prosthesis success rate for 2 implants, there was a variation of 23% to 100%. However, when considering the survival rate, the result was 92% to 100%. For 4 implants, prosthesis survival rates showed less variation, i.e., 97.7% to 100%. Ball attachments were the most common type of abutment for 2 implants; however, there was a higher prevalence of bar abutments for 4 implants. Rehabilitations with 2 implants showed more complications and required more maintenance according to the connection type. Given the limitations of this review, mandibular overdentures with 4 implants showed better results with respect to survival and success rates, especially those with a bar connection. Further studies comparing these two treatment types are necessary to improve the scientific evidence in this area. PMID- 24402060 TI - Anatomic relationship of the pectoralis major and minor muscles: a cadaveric study. AB - BACKGROUND: Although the anatomy of the individual pectoralis major and minor muscles has been described previously, never before has the anatomic relationship between these muscles been investigated. OBJECTIVE: The authors identify the anatomic relationship of the costal origins of the pectoralis major and minor muscles. METHODS: Bilateral thoracic wall dissection was completed in 102 cadavers. In each dissection, the chest wall soft tissue was removed, and the distance between costal origins of the pectoralis major and the pectoralis minor muscles was measured. RESULTS: In 49 female and 53 male cadavers, 202 pectoralis major muscles were lifted to expose the costal origins of the pectoralis major and minor muscles. Distances between pectoralis major and pectoralis minor muscles were separated into 3 categories: less than 1 cm, between 1 and 3 cm, and greater than 3 cm. Forty-nine (24%) pectoralis muscle dissections displayed a distance of less than 1 cm between costal muscle origins. Eighty-three dissections (41%) showed an intermediate distance of between 1 and 3 cm, while the remaining 70 (35%) were over 3 cm. No significant difference was observed in these percentages with regard to sex. Ten cadavers displayed asymmetry in pectoralis muscle origin distance. Eight specimens displayed shared fibers between pectoralis major and minor muscles. CONCLUSIONS: The anatomic relationship between the costal origin of the pectoralis major and minor muscles is highly variable. Understanding this spatial relationship has important implications for cosmetic and reconstructive breast surgery. PMID- 24402061 TI - Modular automated solid phase synthesis of dermatan sulfate oligosaccharides. AB - Dermatan sulfates are glycosaminoglycan polysaccharides that serve a multitude of biological roles as part of the extracellular matrix. Orthogonally protected D galactosamine and L-iduronic acid building blocks and a photo-cleavable linker are instrumental for the automated synthesis of dermatan sulfate oligosaccharides. Conjugation-ready oligosaccharides were obtained in good yield. PMID- 24402062 TI - Electrochemical detection of the Fc-STAT3 phosphorylation and STAT3-Fc-STAT3 dimerization and inhibition. AB - Signal transducer and activator of transcription 3 (STAT3) protein is involved in regulatory functions in cell proliferation, differentiation and survival, and is linked to cancer phenotype and tumorigenesis. Towards developing new methodologies for screening STAT3 interactions, the electrochemical method based on the use of redox active protein was proposed. The electrochemical signal, due to the redox (ferrocene)-labeled STAT3 protein immobilized on a gold surface, was modulated due to protein dimerization with the unlabeled STAT3 molecule. The dramatic decrease in current density from 2.7 MUA cm(-2) to 0.5 MUA cm(-2) was observed following the STAT3-ferrocene-STAT3 dimerization. The electrochemical approach was further extended for screening the potential dimerization inhibitors. Previously published potent salicylic acid derivatives were the most promising candidates for inhibition of STAT3 dimerization in this assay. We expect that other SH2-containing proteins may be monitored by the proposed electrochemical method. PMID- 24402063 TI - Adaptive tele-therapies based on serious games for health for people with time management and organisational problems: preliminary results. AB - Attention Deficit with Hyperactivity Disorder (ADHD) is one of the most prevalent disorders within the child population today. Inattention problems can lead to greater difficulties in completing assignments, as well as problems with time management and prioritisation of tasks. This article presents an intelligent tele therapy tool based on Serious Games for Health, aimed at the improvement of time management skills and the prioritisation of tasks. This tele-system is based on the use of decision trees within Django, a high-level Python Web framework. The technologies and techniques used were selected so as to boost user involvement and to enable the system to be easily customised. This article shows the preliminary results of the pilot-phase in an experiment performed to evaluate the use of adaptive tele-therapies within a group of typically developing children and adolescents aged between 12 and 19 years old without ADHD. To do so, we relied on the collection of parameters and the conduct of surveys for assessing time management skills, as well as measuring system usability and availability. The results of a time management survey highlighted that the users involved in the trial did not use any specific or effective time management techniques, scoring 1.98 and 2.30 out of 5 points in this area for ages under 15 and over 16 years old, respectively. The final calculations based on the usability questionnaire resulted in an average score of 78.75 out of 100. The creation of a customisable tool capable of working with different skills, in conjunction with the replication of the current study, may help to understand these users' needs, as well as boosting time management skills among teenagers with and without ADHD. PMID- 24402064 TI - Determinants of sedentary behavior, motivation, barriers and strategies to reduce sitting time in older women: a qualitative investigation. AB - Sedentary behavior defined as time spent non-exercising seated or reclining posture has been identified has a health risk and associated with frailty and disablement for older adults. Older adults are the most sedentary segment of society. To date no study has investigated the determinants of sedentary behavior in older adults. This study reports a qualitative investigation of the determinants of sedentary behavior, strategies and motivator to reduce sitting time by structured interviews in a group of community dwelling older women (N = 11, age 65 and over). Older women expressed the view that their sedentary behavior is mostly determined by pain which acts both as an incentive to sit and a motivator to stand up, lack of energy in the afternoon, pressure from direct social circle to sit and rest, societal and environmental typecasting that older adult are meant to sit, lack of environmental facilities to allow activity pacing. This qualitative investigation highlighted some factors that older adults consider determinants of their sedentary behavior. Some are identical to those affecting physical activity (self-efficacy, functional limitations, ageist stereotyping) but some appear specific to sedentary behavior (locus of control, pain) and should be further investigated and considered during intervention design. Tailored interventions that pay attention to the pattern of sedentary behavior of individuals appear to be supported by the views of older women on their sedentary behavior. PMID- 24402065 TI - Can tobacco control be transformative? Reducing gender inequity and tobacco use among vulnerable populations. AB - Tobacco use and exposure is unequally distributed across populations and countries and among women and men. These trends and patterns reflect and cause gender and economic inequities along with negative health impacts. Despite a commitment to gender analysis in the preamble to Framework Convention on Tobacco Control there is much yet to be done to fully understand how gender operates in tobacco control. Policies, program and research in tobacco control need to not only integrate gender, but rather operationalize gender with the goal of transforming gender and social inequities in the course of tobacco control initiatives. Gender transformative tobacco control goes beyond gender sensitive efforts and challenges policy and program developers to apply gender theory in designing their initiatives, with the goal of changing negative gender and social norms and improving social, economic, health and social indicators along with tobacco reduction. This paper outlines what is needed to progress tobacco control in enhancing the status of gendered and vulnerable groups, with a view to reducing gender and social inequities due to tobacco use and exposure. PMID- 24402066 TI - From the editor. Wide range of innovations occurring in ambulatory care today. PMID- 24402067 TI - Evaluation of a worksite wellness program designed to reduce cardiovascular risks. AB - We evaluated a multifactorial worksite wellness program designed to improve lifestyle and reduce cardiovascular risks at a small professional services company. Program participation (N = 60 employees) consisted of an enrollment session, a 6-month period of wellness program activities, and a disenrollment session. Lifestyle and biometric measures were obtained at enrollment and disenrollment. Over 6-months, percentage of dietary fat intake decreased (P < .01); daily fruit and vegetable servings and fiber intake increased (P = .02); systolic and diastolic blood pressure decreased (P = .04 and 0.01, respectively), and high-density lipoprotein increased (P < .01). This worksite wellness program achieved meaningful improvements in dietary intake and reduction in cardiovascular risks. PMID- 24402068 TI - Primary care as a platform for full continuum health care risk management. AB - Health care clinical and financial risk is a multivectored problem, requiring multivectored solutions that extend beyond primary care. Worksite clinics have emerged that leverage empowered primary care, but incorporate a range of tactics aimed at driving appropriate care and cost by disrupting health care's perverse incentives. This article describes some of those approaches and shows evidence of the performance that can result. PMID- 24402069 TI - Medical group practice characteristics influencing inappropriate emergency department and avoidable hospitalization rates. AB - The inappropriate use of emergency departments (EDs) and ambulatory care sensitive hospital admission rates by patients attributed to a national sample of 212 medical group practices is documented, and the characteristics of practices that influence these rates are identified. Hospital-owned practices have higher nonemergent and emergent primary care treatable ED rates and higher ambulatory care sensitive hospitalization rates. Practices with electronic health records have lower inappropriate ED rates but those in rural areas have significantly higher rates. Practices with lower operating costs have higher inappropriate ED and ambulatory care sensitive rates, raising questions about the costs of preventing these incidents at the medical group practice level. PMID- 24402070 TI - Commentary on medical group practice characteristics influencing inappropriate emergency department and avoidable hospitalization rates. PMID- 24402071 TI - Ambulatory and chronic disease care by physician assistants and nurse practitioners. AB - As the US population increases and ages, more patients require care. A reengineered health care system relies on physician assistants and nurse practitioners; however, the extent to which they care for medical conditions is marginally known. We analyzed ambulatory visits by provider type and diagnosis focusing on chronic diseases to identify differences in patients seen by each type of provider. Both physician assistants and nurse practitioners attended 14% of 777 million weighted visits. Overall, diabetes and hypertension accounted for 2% to 4% of visits. The distribution of visits for chronic disease diagnoses appears to be similar for all 3 providers (physicians, nurse practitioners, and physician assistants). These findings may improve organizational efficiency in ambulatory systems. PMID- 24402072 TI - Practical and policy implications of a changing health care workforce for chronic disease management. PMID- 24402073 TI - Community health workers in Canada: innovative approaches to health promotion outreach and community development among immigrant and refugee populations. AB - This article provides results from an empirical case study that showcases a community health worker practice targeting immigrants and refugees in Canada. The study focuses on the Multicultural Health Brokers practice, which offers an innovative approach to health promotion outreach and community development addressing broad social determinants of health. This article offers new evidence of both the role of community health worker interventions in Canada and community health workers as an invisible health and human services workforce. It also discusses the Multicultural Health Brokers contribution both to the "new public health" vision in Canada and to a practice that fosters feminist urban citizenship. PMID- 24402074 TI - Turning patient-centeredness from ideal to real: lessons from 2 success stories. AB - The Institute of Medicine's 2001 Crossing the Quality Chasm report established patient-centeredness as 1 of 6 core principles for health system redesign. Yet, turning aspiration into accomplishment has proven arduous. Patient-centered care has components that challenge established professional norms, and the term itself has not always been clearly defined. However, these barriers can be overcome using Rogers' principles of diffusion of innovation, as is shown by 2 case histories. One involves care at an urban academic medical center, the other outpatient care at multiple physician sites located in urban, suburban, and rural locations. At the University of Pittsburgh Medical Center, the Patient- and Family-Centered Care Methodology and Practice has become the new "operating system" in 60 clinical areas, using a 6-step approach to engage patients and families as codesigners of ideal care. Meanwhile, the Health Coach Program at Mercy Clinics, Inc, Des Moines, Iowa, has used a "high-tech/high-touch" combined approach to change the organizational culture through patient-centered initiatives. By doing so, it has put the organization in a position to accept risk for populations of patients. Importantly, both programs have been financially and clinically successful, are accepted by frontline physicians and senior management, and are nationally recognized. Common principles include physician leadership, comfort with uncertainty during innovation, organizational structures that send a consistent message about expectations, and quality improvement as a constant cycle with no end point. PMID- 24402075 TI - The annual wellness visit shared medical appointment: innovative delivery of preventive care to the elderly. AB - The Hartford HealthCare Medical Group instituted 3 types of shared medical appointments (SMAs) in 2013, one being for the Medicare Annual Wellness Visit (AWV). While traditionally there have been 2 types of SMAs-either a chronic disease follow-up model or an annual physical examination model, the SMA AWV offers a preventive care focus in a dedicated visit for the elderly population, without co-pays and without logistics of conducting a physical examination. This article reviews the benefits and challenges of SMAs, including those specific to conducting the AWV, as well as the overall patient experience with the AWV SMA. PMID- 24402076 TI - Two useful tools: to improve patient engagement and transition from the hospital. AB - We use an Internet-based health assessment and feedback system to examine the range of needs and diverse experiences of 520 hospitalized adults in transition and the factors most strongly associated with their self-reported health confidence. Our results strongly suggest that patient engagement prior to admission and the quality of care coordination and communication during hospitalization can greatly enhance successful transition from the hospital back to the community. Hospitals are complex institutions. This report illustrates how the Internet or a straightforward graphic can make the complexity less overwhelming to patients and efficiently increase their health confidence for transitions. PMID- 24402077 TI - Association between self-reported depression and screening colonoscopy participation. AB - The impact of depression on participation in screening colonoscopy is poorly characterized. This study attempts to understand this relationship by conducting a cross-sectional analysis on a nationally representative sample of adults aged 50 to 75 years without a history of colorectal cancer or inflammatory bowel disease from the 2009 Medical Expenditures Panel Survey. Multivariable analysis shows that the odds of having a current colonoscopy is 1.3 times higher for individuals with depression compared with those without depression (odds ratio = 1.3; 95% confidence interval = 1.1-1.7). These findings suggest that depression may not be a risk factor for underutilization of CRC screening. PMID- 24402079 TI - Galantamine reverses scopolamine-induced behavioral alterations in Dugesia tigrina. AB - In planaria (Dugesia tigrina), scopolamine, a nonselective muscarinic receptor antagonist, induced distinct behaviors of attenuated motility and C-like hyperactivity. Planarian locomotor velocity (pLMV) displayed a dose-dependent negative correlation with scopolamine concentrations from 0.001 to 1.0 mM, and a further increase in scopolamine concentration to 2.25 mM did not further decrease pLMV. Planarian hyperactivity counts was dose-dependently increased following pretreatment with scopolamine concentrations from 0.001 to 0.5 mM and then decreased for scopolamine concentrations >= 1 mM. Planarian learning and memory investigated using classical Pavlovian conditioning experiments demonstrated that scopolamine (1 mM) negatively influenced associative learning indicated by a significant decrease in % positive behaviors from 86 % (control) to 14 % (1 mM scopolamine) and similarly altered memory retention, which is indicated by a decrease in % positive behaviors from 69 % (control) to 27 % (1 mM scopolamine). Galantamine demonstrated a complex behavior in planarian motility experiments since co-application of low concentrations of galantamine (0.001 and 0.01 mM) protected planaria against 1 mM scopolamine-induced motility impairments; however, pLMV was significantly decreased when planaria were tested in the presence of 0.1 mM galantamine alone. Effects of co-treatment of scopolamine and galantamine on memory retention in planaria via classical Pavlovian conditioning experiments showed that galantamine (0.01 mM) partially reversed scopolamine (1 mM)-induced memory deficits in planaria as the % positive behaviors increased from 27 to 63 %. The results demonstrate, for the first time in planaria, scopolamine's effects in causing learning and memory impairments and galantamine's ability in reversing scopolamine-induced memory impairments. PMID- 24402080 TI - Electrophysiology and pharmacology of tandem domain potassium channel TREK-1 related BDNF synthesis in rat astrocytes. AB - In the present study, the functional properties and pharmacology of two-pore domain potassium channel (K2P) TREK-1 in primary cultured rat brain astrocytes were investigated. Western blot, patch clamping techniques, and ELISA were used to detect the distribution and function of TREK-1 as well as the expression of brain-derived neurotrophic factor (BDNF) on the primary cultured astrocytes. It was shown that TREK-1 protein expressed in astrocytes was 2.4-fold higher than it was expressed in microglia. Single channel recording via patch clamping showed that the TREK-1 outward currents in astrocytes could be activated by arachidonic acid (AA) or chloroform with the conductance of 113 +/- 14 and 120 +/- 13 pS, respectively. The current was also sensitive to mechanical stretch and intracellular acidification. Negative pressure (-30 cm H2O) and acidification of intracellular solution (pH 6.8 or 6.3) both enhanced TREK-1 channel open probability significantly. Further pharmacological studies showed that TREK-1 antagonist penfluridol inhibited AA-induced currents, and both penfluridol and methionine (TREK-1 blockers) significantly increased BDNF level in astrocytes by 50 %. These results indicated that TREK-1 channel current was a major component of K2P currents in astrocytes. TREK-1 channels might play important roles in regulating the function of astrocytes and might be used as a drug target for neuroprotection. PMID- 24402081 TI - Evaluation of the gastroprotective activity of the extracts, fractions, and pure compounds obtained from aerial parts of Rubus imperialis in different experimental models. AB - Previous phytochemical studies carried out with Rubus imperialis Chum. Schl. (Rosaceae) have demonstrated the presence of triterpenes (niga-ichigoside F1 and 2beta,3beta,19alpha-trihydroxyursolic acid) in this species. The literature indicates that triterpenes are closely related to some pharmacological activities, including antiulcer activity. Therefore, in view of the previous promising results with this species, this work extends the phytochemical studies, as well as investigates its gastroprotective action in different models using rodents. The hydroalcoholic extract was tested using the following protocols in mice: ethanol/HCl and nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer, acetic acid-induced chronic ulcer, ligature pylorus model, and free mucus quantification in mucosa. Isolated triterpenes were investigated in the ethanol/HCl-induced ulcer model. The results of this study show that R. imperialis extract (100, 250, or 500 mg) displays gastroprotective activity in the ethanol-induced ulcer model with a percentage of inhibition of gastric lesions of 70, 71, and 86 %, respectively. The extract also significantly reduced the ulcerative lesions in the indomethacin-induced ulcer. In this model, the percentage of inhibition of ulcer was 41, 44, and 70 %, respectively. Regarding the model of gastric secretion, a reduction of gastric juice volume and total acidity was observed, as well as an increase in gastric pH; however, gastric mucus production was not altered by treatment with the extract. It was also observed that the ethyl acetate fraction presented higher activity, leading to the isolation of niga-ichigoside F1 and 2beta,3beta-19-alpha-trihydroxyursolic acid, which presented antiulcer activity comparable to that of omeprazole, with an inhibition percentage of 98 and 99 %, respectively. These results demonstrate that R. imperialis extract and isolated compounds (niga-ichigoside F1 and 2beta,3beta-19-alpha-trihydroxyursolic acid) produce gastroprotective effects, and this activity seems, at least in part, to be related to antisecretory effects. PMID- 24402082 TI - Upregulation of E2F transcription factor 3 is associated with poor prognosis in hepatocellular carcinoma. AB - E2F transcription factor 3 (E2F3), a member of the E2F transcription factor family and a member of the genes involved in the regulation of cell cycle, is an oncogene with strong proliferative potential. E2F3 is involved in many processes and plays important roles in the development of several types of cancer, while its relationship with prognosis in hepatocellular carcinoma (HCC) has yet to be reported. In the present study, based on 4 independent microarray data sets which covered 385 cases of HCC and 327 cases of normal livers retrieved from the Oncomine database, we demonstrated that E2F3 was upregulated at least 1.5-fold and on average 2.3-fold in HCC when compared with normal controls. Comprehensive bioinformatics analysis consisting of protein-protein interaction, gene co occurrence, microRNA-mRNA interaction and biological process annotation indicated that E2F3 interacted with a large number of genes, proteins and microRNAs which were all associated with poor prognosis in patients with HCC and other types of cancer, suggesting that E2F3 may also serve as a biomarker for poor prognosis. Taken together, for the first time, we show that the overexpression of E2F3 may be associated with unfavorable prognosis in HCC. PMID- 24402083 TI - Effects of fish size on the response of antioxidant systems of Oreochromis niloticus following metal exposures. AB - The size of a fish is an important factor in its physiology, and metal uptake is affected by animal physiology. In this study, small and large tilapias (Oreochromis niloticus) differing approximately twofold in length and fivefold in weight were compared for their antioxidant response. Both groups were exposed to Cu or Cr (1.0 MUg/mL) in a freshwater (-80 mg CaCO3/L, conductivity 1.77 mS/cm) using 2 exposure protocols (20 MUM for 48 h and 10 MUM for 6 days). Following the exposures, the antioxidant enzyme activities (superoxide dismutase, SOD; catalase, CAT; glutathione peroxidase, GPX; glutathione reductase, GR and glutathione S-transferase, GST) and glutathione (GSH) levels were measured in the liver of fish. Results showed that small fish was affected from exposure conditions much more than large ones as their antioxidant parameters significantly decreased even in controls. Metal exposures of small fish caused significant increases in SOD and CAT activity in acute Cu or Cr exposures. Subchronic Cr exposure of small fish also caused significant increases in CAT, GPx and GST activities, while there was no significant change in Cu-exposed ones. Large fish, however, showed different antioxidant responses as their levels mostly decreased. This study demonstrated that the response of antioxidant system in the liver of tilapia varied in relation to fish sizes and emphasized using different size groups in environmental monitoring and also in evaluation of fish biomarkers. PMID- 24402084 TI - Onset of complications following cervical manipulation due to malpractice in osteopathic treatment: a case report. AB - The aim of this study is to correlate cervical disc herniation with manipulation performed by a non-physician osteopath on a patient complaining of neck pain. The authors report a case in which a woman - treated with osteopathic spinal manipulation - developed cervical-brachial neuralgia following the cervical disc herniation. The patient then underwent surgery and was followed by physiotherapists. A clinical condition characterized by limitation of neck mobility, with pain and sensory deficit in the right arm and II-III fingers, still persists. The patient consulted the authors to establish whether cervical disc herniation could be attributed to manipulation. Adverse events or side effects of spinal manipulative therapy are relatively common and usually benign. Most of these side effects are mild or moderate, but sometimes they can be severe. Cervical manipulation can provoke complications less often than thoracic or lumbar manipulation. Furthermore, many diseases can be absolutely and relatively contraindicated to osteopathic treatment. Therefore, the knowledge of a patient's clinical conditions is essential before starting a manipulative treatment; otherwise the osteopath could be accused of malpractice. It is the authors' opinion that a cause-effect relationship exists between the manipulative treatment and the development of disc herniation. PMID- 24402085 TI - Response to European Society of Hypertension and European Society of Cardiology guidelines and the muted enthusiasm for home blood pressure monitoring. PMID- 24402086 TI - Pharmacokinetic modeling of enterohepatic circulation of mycophenolic acid in renal transplant recipients. AB - Several factors contribute to mycophenolic acid (MPA) between-patient variability. Here we characterize the metabolic pathways of MPA and quantify the effect of combining genetic polymorphism of multidrug-resistant-associated protein-2, demographics, biochemical covariates, co-medication (cyclosporine (CsA) vs. macrolides), and renal function on MPA, 7-O-MPA-glucuronide (MPAG), and acyl-glucuronide (AcMPAG) disposition, in renal transplant recipients, after mycophenolate mofetil. Complete pharmacokinetic profiles from 56 patients (five occasions) were analyzed. Enterohepatic circulation was modeled by transport of MPAG to the absorption site. This transport significantly decreased with increasing CsA trough concentrations (CtroughCsA). MPAG and AcMPAG plasma clearances significantly decreased with renal function. No significant influence of multidrug-resistant-associated protein-2 C24T single-nucleotide polymorphism was found. The model adequately predicted the increase in MPAG/AcMPAG exposures in CsA and macrolide patients with decreased renal function. This resulted in higher MPA exposures in macrolide patients versus CsA patients, and increased MPA exposures with renal function from 25 to 10 ml/min, in macrolide patients, owing to enhanced MPAG enterohepatic circulation. Lower-percentage enterohepatic circulation occurred with higher CtroughCsA and renal function values. The lack of MPA protein-binding modeling did not permit evaluation of the impact of renal function and CtroughCsA on MPA exposures in CsA patients. Thus, dose tailoring of covariates is recommended for target MPA exposure. PMID- 24402087 TI - Establishing 3-nitrotyrosine as a biomarker for the vasculopathy of Fabry disease. AB - The endothelial dysfunction of Fabry disease results from alpha-galactosidase A deficiency leading to the accumulation of globotriaosylceramide. Vasculopathy in the alpha-galactosidase A null mouse is manifested as oxidant-induced thrombosis, accelerated atherogenesis, and impaired arterial reactivity. To better understand the pathogenesis of Fabry disease in humans, we generated a human cell model by using RNA interference. Hybrid endothelial cells were transiently transfected with small interfering RNA (siRNA) specifically directed against alpha galactosidase A. Knockdown of alpha-galactosidase A was confirmed using immunoblotting and globotriaosylceramide accumulation. Endothelial nitric oxide synthase (eNOS) activity was correspondingly decreased by >60%. Levels of 3 nitrotyrosine (3NT), a specific marker for reactive nitrogen species and quantified using mass spectrometry, increased by 40- to 120-fold without corresponding changes in other oxidized amino acids, consistent with eNOS-derived reactive nitrogen species as the source of the reactive oxygen species. eNOS uncoupling was confirmed by the observed increase in free plasma and protein bound aortic 3NT levels in the alpha-galactosidase A knockout mice. Finally, 3NT levels, assayed in biobanked plasma samples from patients with classical Fabry disease, were over sixfold elevated compared with age- and gender-matched controls. Thus, 3NT may serve as a biomarker for the vascular involvement in Fabry disease. PMID- 24402089 TI - What is the evidence for intraluminal colonization of hemodialysis catheters? AB - Hemodialysis catheter-related bloodstream infections are potentially devastating, leading to increased morbidity, mortality, and cost of care. Prospective studies published over the past 15 years shed light on the pathogenesis of these infections. The data suggest that the intraluminal microbial colonization of hemodialysis catheters often precedes bloodstream infection. This finding supports strategies aimed at preventing or eradicating intraluminal colonization. PMID- 24402088 TI - Genotype-phenotype associations in WT1 glomerulopathy. AB - WT1 mutations cause a wide spectrum of renal and extrarenal manifestations. Here we evaluated disease prevalence, phenotype spectrum, and genotype-phenotype correlations of 61 patients with WT1-related steroid-resistant nephrotic syndrome relative to 700 WT1-negative patients, all with steroid-resistant nephrotic syndrome. WT1 patients more frequently presented with chronic kidney disease and hypertension at diagnosis and exhibited more rapid disease progression. Focal segmental glomerulosclerosis was equally prevalent in both cohorts, but diffuse mesangial sclerosis was largely specific for WT1 disease and was present in 34% of cases. Sex reversal and/or urogenital abnormalities (52%), Wilms tumor (38%), and gonadoblastoma (5%) were almost exclusive to WT1 disease. Missense substitutions affecting DNA-binding residues were associated with diffuse mesangial sclerosis (74%), early steroid-resistant nephrotic syndrome onset, and rapid progression to ESRD. Truncating mutations conferred the highest Wilms tumor risk (78%) but typically late-onset steroid-resistant nephrotic syndrome. Intronic (KTS) mutations were most likely to present as isolated steroid resistant nephrotic syndrome (37%) with a median onset at an age of 4.5 years, focal segmental glomerulosclerosis on biopsy, and slow progression (median ESRD age 13.6 years). Thus, there is a wide range of expressivity, solid genotype phenotype associations, and a high risk and significance of extrarenal complications in WT1-associated nephropathy. We suggest that all children with steroid-resistant nephrotic syndrome undergo WT1 gene screening. PMID- 24402090 TI - The soluble urokinase receptor is not a clinical marker for focal segmental glomerulosclerosis. AB - The soluble urokinase receptor (suPAR) promotes proteinuria and induces focal segmental glomerulosclerosis (FSGS)-like lesions in mice. A serum suPAR concentration cutoff of 3000 pg/ml has been proposed as a clinical biomarker for patients with FSGS. Interestingly, several studies in patients with glomerulopathy found an inverse correlation between the estimated glomerular filtration rate (eGFR) and suPAR. As patients with FSGS present at different eGFRs, we studied the relationship between eGFR and suPAR in a cohort of 476 non FSGS patients and 54 patients with biopsy-proven idiopathic FSGS. In the non-FSGS patients, eGFR was the strongest significant determinant of suPAR. The proposed cutoff for suPAR in FSGS patients was exceeded in 17%, 39%, and 88% in patients with eGFRs of more than 60, 45-60, and 30-45 ml/min per 1.73 m(2), respectively. In patients with eGFR of <30 ml/min per 1.73 m(2), suPAR exceeded the cutoff in 95% of patients. Levels of suPAR in patients with idiopathic FSGS overlapped with non-FSGS controls and for any given eGFR did not discriminate FSGS cases from non FSGS controls. In the overall cohort, there was a negative association between idiopathic FSGS and suPAR, and idiopathic FSGS was not an independent predictor of FSGS concentration over 3000 pg/ml. Thus, this study does not support an absolute, eGFR-independent, suPAR concentration cutoff as a biomarker for underlying FSGS pathology and questions the validity of relative, eGFR-dependent suPAR cutoff values. PMID- 24402091 TI - Ablation of proximal tubular suppressor of cytokine signaling 3 enhances tubular cell cycling and modifies macrophage phenotype during acute kidney injury. AB - Suppressor of cytokine signaling 3 (SOCS-3) is an important intracellular negative regulator of several signaling pathways. We found that SOCS-3 is highly expressed in renal proximal tubules during acute kidney injury. To test the impact of this, conditional proximal tubular knockout mice (SOCS 3(sglt2Delta/sglt2Delta)) were created. These mice had better kidney function than their wild-type counterparts in aristolochic acid nephropathy and after ischemia/reperfusion injury. Kidneys of these knockout mice showed significantly more proximal tubular cell proliferation during the repair phase. A direct effect of SOCS-3 on tubular cell cycling was demonstrated by in vitro experiments showing a JAK/STAT pathway-dependent antimitotic effect of SOCS-3. Furthermore, acute damaged kidneys of the knockout mice contained increased numbers of F4/80(+) cells. Phenotypic analysis of these F4/80(+) cells indicated a polarization from classically activated to alternatively activated macrophages. In vitro, SOCS-3-overexpressing renal epithelial cells directly induced classical activation in cocultured macrophages, supporting the observed in vivo phenomenon. Thus, upregulation of SOCS-3 in stressed proximal tubules plays an important role during acute kidney injury by inhibition of reparative proliferation and by modulation of the macrophage phenotype. Antagonizing SOCS-3 could have therapeutic potential for acute kidney injury. PMID- 24402092 TI - Uremic pruritus. AB - Uremic pruritus or chronic kidney disease-associated pruritus (CKD-aP) remains a frequent and compromising symptom in patients with advanced or end-stage renal disease, strongly reducing the patient's quality of life. More than 40% of patients undergoing hemodialysis suffer from chronic pruritus; half of them complain about generalized pruritus. The pathogenesis of CKD-aP remains obscure. Parathormone and histamine as well as calcium and magnesium salts have been suspected as pathogenetic factors. Newer hypotheses are focusing on opioid receptor derangements and microinflammation as possible causes of CKD-aP, although until now this could not be proven. Pruritus may be extremely difficult to control, as therapeutic options are limited. The most consequential approaches to treatment are: topical treatment with or without anti-inflammatory compounds or systemic treatment with (a) gabapentin, (b) MU-opioid receptor antagonists and kappa-agonists, (c) drugs with an anti-inflammatory action, (d) phototherapy, or (e) acupuncture. A stepwise approach is suggested starting with emollients and gabapentin or phototherapy as first-line treatments. In refractory cases, more experimental options as MU-opioid-receptor-antagonists (i.e., naltrexone) or kappa-opioid-receptor agonist (nalfurafine) may be chosen. In desperate cases, patients suitable for transplantation might be set on 'high urgency'-status, as successful kidney transplantation will relieve patients from CKD-aP. PMID- 24402093 TI - Renal expression of FGF23 and peripheral resistance to elevated FGF23 in rodent models of polycystic kidney disease. AB - Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis and is linked to cardiovascular disease and all-cause mortality in chronic kidney disease. FGF23 rises in patients with CKD stages 2-3, but in patients with autosomal dominant polycystic kidney disease, the increase of FGF23 precedes the first measurable decline in renal function. The mechanisms governing FGF23 production and effects in kidney disease are largely unknown. Here we studied the relation between FGF23 and mineral homeostasis in two animal models of PKD. Plasma FGF23 levels were increased 10-fold in 4-week-old cy/+ Han:SPRD rats, whereas plasma urea and creatinine concentrations were similar to controls. Plasma calcium and phosphate levels as well as TmP/GFR were similar in PKD and control rats at all time points examined. Expression and activity of renal phosphate transporters, the vitamin D3-metabolizing enzymes, and the FGF23 co-ligand Klotho in the kidney were similar in PKD and control rats through 8 weeks of age, indicating resistance to FGF23, although phosphorylation of the FGF receptor substrate 2alpha protein was enhanced. In the kidneys of rats with PKD, FGF23 mRNA was highly expressed and FGF23 protein was detected in cells lining renal cysts. FGF23 expression in bone and spleen was similar in control rats and rats with PKD. Similarly, in an inducible Pkd1 knockout mouse model, plasma FGF23 levels were elevated, FGF23 was expressed in kidneys, but renal phosphate excretion was normal. Thus, the polycystic kidney produces FGF23 but is resistant to its action. PMID- 24402094 TI - Treatment with erythropoiesis-stimulating agents in chronic kidney disease patients with cancer. AB - Treatment of anemia remains an important component in the care of patients with nondialysis chronic kidney disease (CKD) and end-stage renal disease (ESRD). Erythropoietin-stimulating agents (ESAs) remains a key anemia treatment strategy in this patient population. However, anemia management in this group can become more complicated by prior or current history of malignancy. There has been a great deal of work both scientifically and in clinical trials in oncology that have revealed certain concerns and risks of ESA use in patients with cancer. In this review, we will bring together knowledge from nephrology and oncology literature to help nephrologists understand the implications for ESA treatment when CKD/ESRD is complicated by cancer. We also suggest an approach to the management of anemia in this patient group with active or previous malignancy. PMID- 24402095 TI - Utility of renal biopsy in the clinical management of renal disease. AB - Characterizing chronic kidney disease (CKD) at all stages is an essential part of rational management and the renal biopsy plays a key role in defining the processes involved. There remain no global guidelines available to the renal community on indications for this important diagnostic, prognostic, and relatively safe test. Although most nephrologists recognize several clear indications for a renal biopsy, it is still underutilized. It not only helps the clinician to manage the patient with CKD, but it can also help clarify the epidemiology of CKD, and aid research into the pathobiology of disease with the aim of discovering new therapies. It may be useful for instance in elderly patients with CKD, those with diabetes and presumed 'hypertensive nephropathy', and in some patients with advanced CKD as part of the pretransplant work-up. In some populations (for example, immunoglobulin A nephropathy and ANCA vasculitis), renal biopsy allows disease classification that may predict CKD progression and response to therapy. For the individual, interval renal biopsy may be of use in providing ongoing therapeutic and prognostic information. Molecular advances will change the landscape of renal pathology and add a new dimension to the diagnostic precision of kidney biopsy. Organizing the multiplicity of information available in a renal biopsy to maximize benefits to the patient, as well as to the epidemiologist and researcher, is one of the challenges that face the nephrology community. PMID- 24402096 TI - Acute inhibition of NCC does not activate distal electrogenic Na+ reabsorption or kaliuresis. AB - Na(+) reabsorption from the distal renal tubule involves electroneutral and electrogenic pathways, with the latter promoting K(+) excretion. The relative activities of these two pathways are tightly controlled, participating in the minute-to-minute regulation of systemic K(+) balance. The pathways are interdependent: the activity of the NaCl cotransporter (NCC) in the distal convoluted tubule influences the activity of the epithelial Na(+) channel (ENaC) downstream. This effect might be mediated by changes in distal Na(+) delivery per se or by molecular and structural adaptations in the connecting tubule and collecting ducts. We hypothesized that acute inhibition of NCC activity would cause an immediate increase in Na(+) flux through ENaC, with a concomitant increase in renal K(+) excretion. We tested this using renal clearance methodology in anesthetized mice, by the administration of hydrochlorothiazide (HCTZ) and/or benzamil (BZM) to exert specific blockade of NCC and ENaC, respectively. Bolus HCTZ elicited a natriuresis that was sustained for up to 110 min; urinary K(+) excretion was not affected. Furthermore, the magnitude of the natriuresis was no greater during concomitant BZM administration. This suggests that ENaC-mediated Na(+) reabsorption was not normally limited by Na(+) delivery, accounting for the absence of thiazide-induced kaliuresis. After dietary Na(+) restriction, HCTZ elicited a kaliuresis, but the natiuretic effect of HCTZ was not enhanced by BZM. Our findings support a model in which inhibition of NCC activity does not increase Na(+) reabsorption through ENaC solely by increasing distal Na(+) delivery but rather by inducing a molecular and structural adaptation in downstream nephron segments. PMID- 24402097 TI - Increased progression to kidney fibrosis after erythropoietin is used as a treatment for acute kidney injury. AB - Treatment of renal ischemia-reperfusion (IR) injury with recombinant human erythropoietin (rhEPO) reduces acute kidney injury and improves function. We aimed to investigate whether progression to chronic kidney disease associated with acute injury was also reduced by rhEPO treatment, using in vivo and in vitro models. Rats were subjected to bilateral 40-min renal ischemia, and kidneys were studied at 4, 7, and 28 days postreperfusion for renal function, tubular injury and repair, inflammation, and fibrosis. Acute injury was modulated using rhEPO (1,000 or 5,000 IU/kg, intraperitoneally) at the time of reperfusion. Renal tubular epithelial cells or fibroblasts in culture were subjected to hypoxia or oxidative stress, with or without rhEPO (200 IU/ml), and fibrogenesis was studied. The results of the in vivo model confirmed functional and structural improvement with rhEPO at 4 days post-IR (P < 0.05). At 7 days post-IR, fibrosis and myofibroblast stimulation were increased with IR with and without rhEPO (P < 0.01). However, at 28 days post-IR, renal fibrosis and myofibroblast numbers were significantly greater with IR plus rhEPO (P < 0.01) compared with IR only. Mechanistically, rhEPO stimulated profibrotic transforming growth factor-beta, oxidative stress (marker 8-hydroxy-deoxyguanosine), and phosphorylation of the signal transduction protein extracellular signal-regulated kinase. In vitro, rhEPO protected tubular epithelium from apoptosis but stimulated epithelial-to mesenchymal transition and also protected and activated fibroblasts, particularly with oxidative stress. In summary, although rhEPO was protective of renal function and structure in acute kidney injury, the supraphysiological dose needed for renoprotection contributed to fibrogenesis and stimulated chronic kidney disease in the long term. PMID- 24402100 TI - Collagen fleece failed to prevent intrapleural adhesions in a canine model: failure of murine models to translate into a large animal model. AB - Intrapleural and anti-adhesive materials were investigated in murine models, but not in a large animal model before clinical application. Our results failed to show any anti-adhesion effect of collagen fleece and suggested the thoracic physiology in murine models would not translate into a large animal model. PMID- 24402101 TI - Blockage of the renin-angiotensin system in peritoneal dialysis. PMID- 24402098 TI - Deletion of alpha-subunit exon 11 of the epithelial Na+ channel reveals a regulatory module. AB - Epithelial Na(+) channel (ENaC) subunits (alpha, beta, and gamma) found in functional complexes are translated from mature mRNAs that are similarly processed by the inclusion of 13 canonical exons. We examined whether individual exons 3-12, encoding the large extracellular domain, are required for functional channel expression. Human ENaCs with an in-frame deletion of a single alpha subunit exon were expressed in Xenopus oocytes, and their functional properties were examined by two-electrode voltage clamp. With the exception of exon 11, deletion of an individual exon eliminated channel activity. Channels lacking alpha-subunit exon 11 were hyperactive. Oocytes expressing this mutant exhibited fourfold greater amiloride-sensitive whole cell currents than cells expressing wild-type channels. A parallel fivefold increase in channel open probability was observed with channels lacking alpha-subunit exon 11. These mutant channels also exhibited a lost of Na(+) self-inhibition, whereas we found similar levels of surface expression of mutant and wild-type channels. In contrast, in-frame deletions of exon 11 from either the beta- or gamma-subunit led to a significant loss of channel activity, in association with a marked decrease in surface expression. Our results suggest that exon 11 within the three human ENaC genes encodes structurally homologous yet functionally diverse domains and that exon 11 in the alpha-subunit encodes a module that regulates channel gating. PMID- 24402102 TI - Mesangial cells: renal function protagonists or coadjuvants? PMID- 24402103 TI - Reviewing the Brazilian protocol for treatment of secondary hyperparathyroidism. PMID- 24402104 TI - Detection of podocyturia in patients with lupus nephritis. AB - INTRODUCTION: The podocyturia has been detected in glomerular diseases, such as lupus nephritis (LN), in which proteinuria is an important manifestation, and its occurrence seems to be limited to the active phase of the disease. OBJECTIVE: To evaluate podocyturia in LN patients, and the possible association with clinical disease activity. METHODS: We evaluated 56 patients with LN, that were classified in three groups according to the degree of clinical activity: Group B, no activity (n = 17), Group C with mild (n = 29) and Group D, moderate to severe activity (n = 10). The control group was composed by 29 healthy subjects (Group A). The podocyturia was studied by indirect immunofluorescence using primary antibodies to podocyte: anti-podocin, nephrin and synaptopodin, and a secondary antibody conjugated with FITC. We also evaluated serum creatinine levels, urinary protein/creatinine (P/C) ratio, hematuria and leucocituria. RESULTS: The podocyturia with anti-podocin and anti-sinaptopodin correlated statistically with the P/C ratio (p = 0.001 and p = 0.013, respectively). The podocyturia with anti podocin, as well as the P/C ratio showed significant correlation (p < 0.001) with the degree of lupus disease activity, unlike the other two antibodies, anti nephrin and anti-synaptopodin. CONCLUSION: Our findings show that podocyturia with anti-podocin could be useful in monitoring disease activity in LN patients. PMID- 24402105 TI - The effect of hypoxia and reoxygenation in the response of mesangial cells to angiotensin II in vitro. AB - INTRODUCTION: Mesangial cells (MC) may be involved in the glomerular alterations induced by ischemia/reperfusion injury. OBJECTIVE: To evaluate the response of immortalized MC (IMC) to 30 minutes of hypoxia followed by reoxygenation periods of 30 minutes (H/R30) or 24 hours (H/R24). METHODS: The intracellular calcium concentration ([Ca+2]i) was measured before (baseline) and after adding angiotensin II (AII, 10-5 M) in the presence and absence of glybenclamide (K ATP channel blocker). We estimated the level of intracellular ATP, nitric oxide (NO) and PGE2. RESULTS: ATP concentration decreased after hypoxia and increased after reoxygenation. Hypoxia and H/R induced increases in basal [Ca+2]i. AII induced increases in [Ca+2]i in normoxia (97 +/- 9%), hypoxia (72 +/- 10%) or HR30 (85 +/ 17%) groups, but there was a decrease in the response to AII in group H/R24 since the elevation in [Ca+2]i was significantly lower than in control (61 +/- 10%, p < 0.05). Glybenclamide did not modify this response. It was observed a significant increase in NO generation after 24 hours of reoxygenation, but no difference in PGE2 production was observed. Data suggest that H/R injury is characterized by increased basal [Ca+2]i and by an impairment in the response of cells to AII. Results suggest that the relative insensibility to AII may be at least in part mediated by NO but not by prostaglandins or vasodilator K ATP channels. CONCLUSION: H/R caused dysfunction in IMC characterized by increases in basal [Ca+2]i during hypoxia and reduction in the functional response to AII during reoxygenation. PMID- 24402106 TI - Prevalence and associated factors with abdominal obesity in hemodialysis patients in Goiania--GO. AB - INTRODUCTION: The presence of excess weight, especially visceral obesity contributes to the increased risk of metabolic and cardiovascular complications in patients with chronic kidney disease. OBJECTIVE: To determine the prevalence and associated factors with abdominal obesity in patients on hemodialysis (HD). METHODS: Cross-sectional study with 344 patients older than 18 years. Abdominal obesity was defined as waist circumference > 94 cm in men and > 80 cm in women. The independent variables involved socioeconomic, demographic, lifestyle, duration of HD, food consumption and body mass index (BMI). The analysis of associated factors was performed by multiple Poisson regression, remaining in the final model variables with p < 0.05. RESULTS: The prevalence of abdominal obesity was 44.77% and was more prevalent in women (55.71%) than in men (37.25%), p = 0.001. The end result of the multivariate analysis identified factors associated with abdominal obesity in men and women: age over 40 years, protein intake below 1.2 g/kg/day and BMI > 25 kg/m2. In men the economic class D/E remained associated with abdominal obesity, p < 0.05. CONCLUSION: There was a high prevalence of abdominal obesity in hemodialysis patients. Age greater than 40 years, lower socioeconomic classes, below the recommended protein intake and overweight were associated with abdominal obesity. PMID- 24402107 TI - Evaluation of the use of captopril on peritoneal fibrosis induced in rats by the use of glucose solution 4.25%. AB - INTRODUCTION: Chronic renal failure has alarming incidence all over the world in this century. Among the modalities of dialytic treatment, peritoneal dialysis has a major spot. This method of dialytic treatment may present complications, and among those is peritoneal fibrosis. It occurs in patients submitted to peritoneal dialysis along years. It's most dangerous form is sclerosing encapsulant peritonitis, wich leads to a need of change in modality and many times lead to death. OBJECTIVE: Study the influence of using captopril on the peritoneal fibrosis induced in rats using solution with glucoses 4.25%. METHODS: Prospective controlled study in 20 non-uremic Wistar rats. The animals received a peritoneal infusion of 10 ml/100g of peritoneal dialysis solution glucose 4.25% on a daily basis. The animals were divided in two groups: experimental and control. The experimental group received captopril 30 mg/kg/d, by a gastric tube. The control group did not receive any drug. The follow-up was 21 and 49 days. At the end, one surgical procedure was performed to get histological samples of visceral and parietal peritoneum. The samples were analyzed using Hematoxylin Eosin and Sirius Red, to evaluate the severity of the fibrosis. RESULTS: The analysis showed that the intensity of the fibrosis, the peritoneal thickness and the cell number in experimental and control groups were not statistically significant different in experimental and control groups. CONCLUSION: Our findings indicate that captopril do not decrease the intensity of fibrosis on the peritoneal membrane that happens on rats on peritoneal dialysis. PMID- 24402108 TI - Association between the level of quality of life and nutritional status in patients undergoing chronic renal hemodialysis. AB - INTRODUCTION: The chronic kidney disease and undergoing hemodialysis (HD) cause limitation in patients' life interfering in their life's quality and the nutritional care is fundamental to the disease treatment. OBJECTIVE: The objective is the goal is to analyze the association between quality of life through the instrument (SF-36) with dietary intake, nutritional status in patients with chronic kidney disease in HD through quantitative research and transversal. METHODS: Realized valuation anthropometric, collection of the results of biochemical tests, application of the questionnaire SF-36 and dietary anamnesis (food recall of 24h). RESULTS: The sample consisted of thirty adult patients with age between 28 to 76 years. The disease related with chronic kidney disease was found more hypertension systemic arterial (53.3%) The average body mass index was 25.04 +/- 4.50 kg/m2. By fold cutaneous arm, 73.3% were in malnutrition. The end nutritional diagnosis of malnutrition was 80% among the patients studied. The time of diagnosis of renal disease had a mean of 4.84 +/- 3.51 years. By the middle of biochemical tests only phosphorus creatinine were adequate. In the mean the scores of SF-36 the lowest value found was limited to physical aspects (16.67 +/- 29.60) and the largest for the social aspect (68.17 +/- 33.67). CONCLUSION: The average energy consumption and protein was below the recommended. Got positive correlation of calories, protein, fiber, calcium and carbohydrate, with quality of life. It was concluded that feeding is associated with quality of life of renal patients undergoing hemodialysis. PMID- 24402109 TI - Influence of deceased donor hemodynamic factors in transplant recipients renal function. AB - INTRODUCTION: The incidence of delayed graft function (DGF) and unsatisfactory creatinine clearance (UCC) after renal transplantation is significantly higher in Brazil, when compared with that observed in United States or Europe. Deceased donor (DD) characteristics should directly influence the occurrence of these two outcomes. OBJECTIVE: This study aim to evaluate the influence of DD characteristics on DGF and UCC incidence in Brazil. METHODS: DD clinical and laboratory variables were correlated with outcome's incidence. RESULTS: We evaluated 787 DD whose organs were transplanted in 1298 patients. We noted a high prevalence of vasoactive drugs use (90.2%), hypernatremia (66.6%) and renal dysfunction (34.8%). The incidence of DGF and UCC was 60.6% and 55.2%, respectively. We observed a progressive increase in DGF risk for age groups over 30 years and for cold ischemia time (CIT) greater than 24 hours. DGF risk was two times higher in recipients of donor kidney final serum creatinine (Cr) over than 1.5 mg/dl. Hypertension and CIT over 36 hours was associated with an increasing of 82% and 99% in UCC risk, respectively. Donor age above 40 years was associated with a progressive increase in UCC risk. CONCLUSION: DD age, renal function, hypertension and prolonged CIT were associated with increased risk DGF and UCC. PMID- 24402110 TI - Evaluation of metabolic syndrome and associations with inflammation and graft function in renal transplant recipients. AB - INTRODUCTION: Cardiovascular disease (CVD) is a major determinant of mortality in renal transplant recipients (RTR). Metabolic syndrome (MS) and chronic inflammation are currently considered non traditional risk factors for cardiovascular disease. This study evaluates the frequency of these conditions their associations with graft function. OBJECTIVE: To evaluate the prevalence of metabolic syndrome (MS) and inflammation and their associations with graft function in renal transplant recipients. METHODS: A cross-sectional study was carried out with 200 RTR. MS was defined by the NCEP-ATP III criteria. Inflammation was assessed by CRP levels. Renal function was assessed by GFR estimation using the MDRD equation. RESULTS: MS occurred in 71 patients (35.5%). Patients with MS had higher CPR and decreased GFR levels. Inflammation was present in 99 patients (49.5%). Mean waist perimeter, body mass index, triglycerides and serum total cholesterol were significantly higher in inflamed patients. An association between MS and inflammation was demonstrated, 48 (67.6%) patients with MS were inflamed and among those without MS the rate of inflamed patients was 39.5% (51 patients) (p < 0.001). A significantly higher percentage of patients with MS in the group of patients in chronic renal disease stages III and IV was observed. CONCLUSION: In RTR there is a significant association among MS and inflammation. MS is negatively associated with graft function. The clinical implications of these findings must be evaluated in longitudinal studies. PMID- 24402111 TI - [Clinical protocol and therapeutic guidelines for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease]. PMID- 24402112 TI - Vitamin D and kidney disease: what we know and what we do not know. AB - Vitamin D deficiency is common in the chronic kidney disease (CKD) population. CKD has been recognized as a significant public health problem and CKD patients are at increased risk of total and cardiovascular morbidity and mortality. There are increasing epidemiological data suggesting that vitamin D deficiency may play a role in overall morbidity and mortality associated with CKD. The vitamin D hormonal system is classically implicated in the regulation of calcium homeostasis and bone metabolism but there is ample evidence to support the claim that extra renal conversion of 25(OH)D to 1.25(OH)2 has significant biological roles beyond those traditionally ascribed to vitamin D. Based on the current state of evidence this review intends to give an update on novel biological and clinical insights with relevance to the steroid hormone vitamin D specifically in patients with kidney disease. PMID- 24402113 TI - Acute nephrotoxicity of cisplatin: molecular mechanisms. AB - The nephrotoxic drugs have been responsible for about 20% of AKI episodes in inpatients and outpatients. The cisplatin nephrotoxicity is a major limiting factors in 20% of patients who have received the drug, triggering injuries in renal tubular epithelial cells. Cisplatin toxicity is determined by the target tissue and cells accumulation besides the interaction with various subcellular structures and macromolecules. Cisplatin accumulates and interferes with the functioning of different organelles such as mitochondria, lysosomes, endoplasmic reticulum, nuclei and cell membranes, causing inflammation and cell death. This review aims to define the pathophysiology and biochemistry of the cisplatin nephrotoxicity, reviewing the main molecular mechanisms that lead to tubular cisplatin toxicity. PMID- 24402114 TI - [Recurrent urinary tract infection due to enterovesical fistula secondary to colon diverticular disease: a case report]. AB - INTRODUCTION: Enterovesical fistula are pathological connections between the bladder and pelvic intestinal segments. It consists of a rare complication of neoplastic and inflammatory pelvic disorders, in addition to iatrogenic or traumatic injuries, and correlates with both high morbidity and mortality indexes. CASE REPORT: Male patient, 61 years old, admitted at the hospital clinics featuring abdominal pain and distension, vomiting and fecal retention. Patient's pathological precedents include high blood pressure, diabetes mellitus, vesical dysfunction and recurrent urinary tract infection on the past three years. Magnetic resonance imaging of abdomen and pelvis revealed enterovesical fistula in association with colon diverticular disease of the sigmoid. Management of choice consisted of partial colectomy with bowel lowering and partial cystectomy with surgical double-J stent insertion. DISCUSSION: Although consisting of a gastrointestinal primary affection, patients with enterovesical fistula usually search for medical help charging urinary tract features. In this particular case, our patient was admitted with gastrointestinal symptoms, reasoned by diagnostic delay, as the patient had already attended at multiple centers with urinary symptoms. CONCLUSION: Despite being an unusual affection, recurrent urinary tract infection associated with colon diverticular disease must always be considered at differential diagnosis of recurrent urinary tract infection as it concurs with high morbidity and mortality. PMID- 24402116 TI - A multiscale model of interleukin-6-mediated immune regulation in Crohn's disease and its application in drug discovery and development. AB - In this study, we have developed a multiscale systems model of interleukin (IL)-6 mediated immune regulation in Crohn's disease, by integrating intracellular signaling with organ-level dynamics of pharmacological markers underlying the disease. This model was linked to a general pharmacokinetic model for therapeutic monoclonal antibodies and used to comparatively study various biotherapeutic strategies targeting IL-6-mediated signaling in Crohn's disease. Our work illustrates techniques to develop mechanistic models of disease biology to study drug-system interaction. Despite a sparse training data set, predictions of the model were qualitatively validated by clinical biomarker data from a pilot trial with tocilizumab. Model-based analysis suggests that strategies targeting IL-6, IL-6Ralpha, or the IL-6/sIL-6Ralpha complex are less effective at suppressing pharmacological markers of Crohn's than dual targeting the IL-6/sIL-6Ralpha complex in addition to IL-6 or IL-6Ralpha. The potential value of multiscale system pharmacology modeling in drug discovery and development is also discussed.CPT: Pharmacometrics & Systems Pharmacology (2014) 3, e89; doi:10.1038/psp.2013.64; advance online publication 8 January 2014. PMID- 24402117 TI - Scale reduction of a systems coagulation model with an application to modeling pharmacokinetic-pharmacodynamic data. AB - Bridging systems biology and pharmacokinetics-pharmacodynamics has resulted in models that are highly complex and complicated. They usually contain large numbers of states and parameters and describe multiple input-output relationships. Based on any given data set relating to a specific input-output process, it is possible that some states of the system are either less important or have no influence at all. In this study, we explore a simplification of a systems pharmacology model of the coagulation network for use in describing the time course of fibrinogen recovery after a brown snake bite. The technique of proper lumping is used to simplify the 62-state systems model to a 5-state model that describes the brown snake venom-fibrinogen relationship while maintaining an appropriate mechanistic relationship. The simplified 5-state model explains the observed decline and recovery in fibrinogen concentrations well. The techniques used in this study can be applied to other multiscale models. PMID- 24402118 TI - Reproducibility of connectivity based parcellation: primary visual cortex. PMID- 24402119 TI - Exploring a structural protein-drug interactome for new therapeutics in lung cancer. AB - The pharmacology of drugs is often defined by more than one protein target. This property can be exploited to use approved drugs to uncover new targets and signaling pathways in cancer. Towards enabling a rational approach to uncover new targets, we expand a structural protein-ligand interactome () by scoring the interaction among 1000 FDA-approved drugs docked to 2500 pockets on protein structures of the human genome. This afforded a drug-target network whose properties compared favorably with previous networks constructed using experimental data. Among drugs with the highest degree and betweenness two are cancer drugs and one is currently used for treatment of lung cancer. Comparison of predicted cancer and non-cancer targets reveals that the most cancer-specific compounds were also the most selective compounds. Analysis of compound flexibility, hydrophobicity, and size showed that the most selective compounds were low molecular weight fragment-like heterocycles. We use a previously developed screening approach using the cancer drug erlotinib as a template to screen other approved drugs that mimic its properties. Among the top 12 ranking candidates, four are cancer drugs, two of them kinase inhibitors (like erlotinib). Cellular studies using non-small cell lung cancer (NSCLC) cells revealed that several drugs inhibited lung cancer cell proliferation. We mined patient records at the Regenstrief Medical Record System to explore the possible association of exposure to three of these drugs with occurrence of lung cancer. Preliminary in vivo studies using the non-small cell lung cancer (NCLSC) xenograft model showed that losartan- and astemizole-treated mice had tumors that weighed 50 (p < 0.01) and 15 (p < 0.01) percent less than the treated controls. These results set the stage for further exploration of these drugs and to uncover new drugs for lung cancer therapy. PMID- 24402120 TI - The association between metabolic syndrome and hepatocellular carcinoma: systemic review and meta-analysis. AB - BACKGROUND: The metabolic syndrome (MetS) and/or its individual components have been linked to the development of cancer. Recent studies have suggested a similar link to hepatocellular carcinoma (HCC). The aim of this study was to evaluate the direction and magnitude of the association between the MetS and HCC. METHODS: Two reviewers independently conducted a systemic search to identify the available evidence from databases from January 1980 to June 2012. Search terms included "Metabolic syndrome," "insulin resistance syndrome," "metabolic abnormalities" combined with "hepatocellular carcinoma," and "liver cancer." No language restriction was applied to the search. Only studies reporting an effect measure for the association between MetS and HCC were eligible for inclusion. Publication bias was assessed using the Begg and Egger tests, with a visual inspection of funnel plot. All analyses were performed using Comprehensive Meta-analysis version 2 software. RESULTS: Four studies (3 cohort and 1 case control) with a total of 829,651 participants were included in the analysis. The age range of participants was between 30 and 84 years. The combined analysis showed an overall 81% increased risk of HCC in cases with MetS (relative risk, 1.81; 95% confidence interval, 1.37-2.41). After excluding the single case-control study from analysis, the overall risk ratio remained statistically significant (relative risk, 1.49; 95% confidence interval, 1.27-1.74). Funnel plot inspection, Begg and Egger tests showed no evidence of publication bias for combined analysis. CONCLUSIONS: Though studies are scarce, currently available epidemiologic data are suggestive of significantly higher risk of HCC among patients with MetS. PMID- 24402121 TI - Primary sclerosing cholangitis and its relationship to the colon in a black cohort of inflammatory bowel disease patients. AB - BACKGROUND: Recent studies have identified subgroups of inflammatory bowel disease (IBD) patients at increased likelihood for developing primary sclerosing cholangitis (PSC). Most studies look at predominantly white populations. GOALS: The aim of our study was to determine the characteristics of PSC in a black cohort of patients and its relationship to disease location in IBD. STUDY: A retrospective analysis was performed on IBD patients over the age of 18 years. RESULTS: Of the 209 black patients identified as having IBD, 7 (3.5%) had a concomitant diagnosis of PSC; 5/138 (3.6%) ulcerative colitis (UC) patients, and 2/71 (2.8%) Crohn's disease patients (CD). Numerically, more males developed PSC in both the UC and CD subgroups. Age at diagnosis of IBD tended to be younger among PSC cohorts. All PSC-UC patients had pancolitis (P<0.0001), and all PSC-CD patients had a colonic component to their disease. In the UC cohort, PSC patients were statistically more likely to be on immunosuppressive therapy (P<0.0001). CONCLUSIONS: With greater research, physicians will better recognize IBD phenotypes at highest risk of PSC and hopefully identify complications of PSC, including cholangiocarcinoma. PMID- 24402122 TI - Ik6 expression provides a new strategy for the therapy of acute lymphoblastic leukemia. AB - Our previous study demonstrated that the dominant-negative Ikaros isoform 6 (Ik6) is overexpressed in Chinese children with newly diagnosed B-acute lymphoblastic leukemia (B-ALL) and is strongly associated with a poor outcome. The purpose of the present study was to further explore the function of Ik6 in B-ALL. The association between Ik6 expression as detected by real-time PCR and efficacy of chemotherapy was evaluated. The effect of the alteration in Ik6 on leukemic cell lines was assessed by in vitro gain-of-function and loss-of-function techniques. PCR analysis showed that Ik6 expression was decreased when patients completed induction chemotherapy and reached complete remission. Ik6 expression was significantly increased when patients suffered relapse. Stable transfection of Ik6 into the Nalm-6 cell line revealed that Ik6 enhanced proliferation of Nalm-6 cells through the promotion of G0/G1-to-S-phase transition and enhanced chemoresistance to chemotherapeutics through anti-apoptotic effects. However, Ik6 expression did not affect the invasion of Nalm-6 cells. In contrast, silencing of Ik6 in Sup-B15 cells significantly inhibited proliferation and increased chemosensitivity. The present study suggests that Ik6 may be a biological marker of chemosensitivity and relapse and Ik6 may provide a potential therapeutic strategy for ALL. PMID- 24402123 TI - Recent developments of dual-energy CT in oncology. AB - Dual-energy computed tomography (DECT) can amply contribute to support oncological imaging: the DECT technique offers promising clinical applications in oncological imaging for tumour detection and characterisation while concurrently reducing the radiation dose. Fast image acquisition at two different X-ray energies enables the determination of tissue- or material-specific features, the calculation of virtual unenhanced images and the quantification of contrast medium uptake; thus, tissue can be characterised and subsequently monitored for any changes during treatment. DECT is already widely used, but its potential in the context of oncological imaging has not been fully exploited yet. The technology is the subject of ongoing innovation and increasingly with respect to its clinical potential, particularly in oncology. This review highlights recent state-of-the-art DECT techniques with a strong emphasis on ongoing DECT developments relevant to oncologic imaging, and then focuses on clinical DECT applications, especially its prospective uses in areas of oncological imaging. KEY POINTS: * Dual-energy CT (DECT) offers fast, robust, quantitative and functional whole-body imaging. * DECT provides improved tumour detection and more detailed tissue differentiation and characterisation. * DECT affords therapy monitoring with complementary information and reduced radiation dose. * The use of DECT in oncology is of increasing clinical importance. * The potential of DECT in oncology has not been fully exploited yet. PMID- 24402125 TI - Association of polymorphisms of exon 2 of the growth hormone gene with production performance in Huoyan goose. AB - Primers based on the cDNA sequence of the goose growth hormone (GH) gene in GenBank were designed to amplify exon 2 of the GH gene in Huoyan goose. A total of 552 individuals were brooded in one batch and raised in Liaoning and Jiangsu Provinces, China. Single nucleotide polymorphisms (SNPs) of exon 2 in the GH gene were detected by the polymerase chain reaction (single strand conformation polymorphism method). Homozygotes were subsequently cloned, sequenced and analyzed. Two SNP mutations were detected, and 10 genotypes (referred to as AA, BB, CC, DD, AB, AC, AD, BC, BD and CD) were obtained. Allele D was predominant, and the frequencies of the 10 genotypes fit the Hardy-Weinberg equilibrium in the male, female and whole populations according to the chi-square test. Based on SNP types, the 10 genotypes were combined into three main genotypes. Multiple comparisons were carried out between different genotypes and production traits when the geese were 10 weeks old. Some indices of production performance were significantly (p < 0.05) associated with the genotype. Particularly, geese with genotype AB or BB were highly productive. Thus, these genotypes may serve as selection markers for production traits in Huoyan geese. PMID- 24402124 TI - Acyl-homoserine lactone quorum sensing in the Roseobacter clade. AB - Members of the Roseobacter clade are ecologically important and numerically abundant in coastal environments and can associate with marine invertebrates and nutrient-rich marine snow or organic particles, on which quorum sensing (QS) may play an important role. In this review, we summarize current research progress on roseobacterial acyl-homoserine lactone-based QS, particularly focusing on three relatively well-studied representatives, Phaeobacter inhibens DSM17395, the marine sponge symbiont Ruegeria sp. KLH11 and the dinoflagellate symbiont Dinoroseobacter shibae. Bioinformatic survey of luxI homologues revealed that over 80% of available roseobacterial genomes encode at least one luxI homologue, reflecting the significance of QS controlled regulatory pathways in adapting to the relevant marine environments. We also discuss several areas that warrant further investigation, including studies on the ecological role of these diverse QS pathways in natural environments. PMID- 24402127 TI - Analysis of the rs10046 polymorphism of aromatase (CYP19) in premenopausal onset of human breast cancer. AB - The CYP19 gene encodes aromatase, an enzyme catalyzing the conversion of androgens to estrogens. Studies analyzing associations between single nucleotide polymorphisms in CYP19 and breast cancer risk have shown inconsistent results. The rs10046 polymorphism is located in the 3' untranslated region of the CYP19 gene, but the influence of this polymorphism on breast cancer risk is unclear. In this study, we investigated the impact of rs10046 SNP on breast cancer risk, age at onset and association with clinical characteristics in an Austrian population of 274 breast cancer patients and 253 controls. The results show that a significantly increased fraction of patients with the TT genotype of rs10046 develop breast cancer under the age of 50 (41.8% of TT patients, compared to 26.6% of C carriers; p = 0.018, Chi-square test). No rs10046 genotypes were significantly associated with increased breast cancer risk or patient characteristics other than age at onset. These results suggest that the rs10046 polymorphism in the CYP19 gene may have an effect on breast cancer susceptibility at an age under 50 in the investigated population. PMID- 24402126 TI - Meta-omic platforms to assist in the understanding of NAFLD gut microbiota alterations: tools and applications. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide as a result of the increasing prevalence of obesity, starting from early life stages. It is characterized by a spectrum of liver diseases ranging from simple fatty liver (NAFL) to steatohepatitis (NASH), with a possible progression to fibrosis, thus increasing liver-related morbidity and mortality. NAFLD development is driven by the co-action of several risk factors, including obesity and metabolic syndrome, which may be both genetically induced and diet-related. Recently, particular attention has been paid to the gut-liver axis, which may play a physio-pathological role in the onset and progression of the disease. The gut microbiota is intended to act as a bioreactor that can guarantee autonomous metabolic and immunological functions and that can drive functional strategies within the environment of the body in response to external stimuli. The complexity of the gut microbiota suggests that it behaves as an organ. Therefore, the concept of the gut-liver axis must be complemented with the gut-microbiota-liver network due to the high intricacy of the microbiota components and metabolic activities; these activities form the active diet-driven power plant of the host. Such complexity can only be revealed using systems biology, which can integrate clinical phenomics and gut microbiota data. PMID- 24402128 TI - Increased glutamine in patients undergoing long-term treatment for schizophrenia: a proton magnetic resonance spectroscopy study at 3 T. AB - IMPORTANCE: The N-methyl-d-aspartic acid receptor hypofunction model of schizophrenia predicts a paradoxical increase in synaptic glutamate release. In vivo measurement of glutamatergic neurotransmission in humans is challenging, but glutamine, the principal metabolite of synaptic glutamate, can be quantified with proton magnetic resonance spectroscopy (1H-MRS). Although a few studies have measured glutamate, glutamine, and glutamine to glutamate ratio, it is not clear which of these 1H-MRS indices of glutamatergic neurotransmission is altered in schizophrenia. OBJECTIVE: To examine glutamine, glutamate, and glutamine to glutamate ratio in the dorsal anterior cingulate, as well as their relationships with symptoms and cognition in schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional design using 3-T 1H-MRS in participants recruited from university based psychiatric outpatient clinics who underwent neuroimaging at an affiliated research facility. Participants were 84 patients with a DSM-IV-TR diagnosis of schizophrenia and 81 psychiatrically healthy volunteers, matched in age, sex, ethnicity, and occupational level to the head of household of family of origin. MAIN OUTCOMES AND MEASURES: Glutamine, glutamate, and glutamine to glutamate ratio. Also symptoms and cognition. RESULTS: Glutamine was increased in the schizophrenia group (P = .01) as well as the glutamine to glutamate ratio (P = .007) but not glutamate (P = .89). Glutamine levels were positively correlated with severity of psychotic symptoms (P = .02). Choline was also increased in schizophrenia (P = .002). CONCLUSIONS AND RELEVANCE: Elevated glutamine, which was directly related to psychotic symptoms, is consistent with increased glutamatergic synaptic release in schizophrenia, as predicted by the N-methyl-d aspartic acid receptor hypofunction model. Further understanding the underlying mechanism of glutamatergic dysfunction in schizophrenia may lead to new pharmacological strategies to treat psychosis. PMID- 24402129 TI - Expression of the pituitary stem/progenitor marker GFRalpha2 in human pituitary adenomas and normal pituitary. AB - PURPOSE: Recent studies suggest that adult pituitary stem cells may play a role in pituitary tumorigenesis. We sought to explore whether the Glial cell-line derived neurotrophic factor receptor alpha 2 (GFRalpha2), a recently described pituitary stem/progenitor marker, might be differentially expressed in pituitary adenomas versus normal pituitary. METHODS: The expression of GFRalpha2 and other members of the GFR receptor family (GFRalpha1, alpha3, alpha4) were analyzed using RT-PCR, western blot, and immunohistochemistry in 39 pituitary adenomas, 14 normal pituitary glands obtained at autopsy, and cDNA from 3 normal pituitaries obtained commercially. RESULTS: GFRalpha2 mRNA was ~2.6 fold under-expressed in functioning adenomas (p < 0.01) and ~3.5 fold over-expressed in non-functioning adenomas (NFAs) (p < 0.05) compared to normal pituitary. Among NFAs, GFRalpha2 was significantly over-expressed (~5-fold) in the gonadotropinoma subtype only (p < 0.05). GFRalpha2 protein expression appeared to be higher in most NFAs, although there was heterogeneity in protein expression in this group. GFRalpha2 protein expression appeared consistently lower in functioning adenomas by IHC and western blot. In normal pituitary, GFRalpha2 was localized in Rathke's remnant, the putative pituitary stem cell niche, and in corticotropes. CONCLUSION: Our results suggest that the pituitary stem cell marker GFRalpha2 is under-expressed in functioning adenomas and over-expressed in NFAs, specifically gonadotropinomas. Further studies are required to elucidate whether over expression of GFRalpha2 in gonadotropinomas might play a role in pituitary tumorigenesis. PMID- 24402130 TI - Community-weighted mean functional effect traits determine larval amphibian responses to litter mixtures. AB - Plant species composition is changing across many landscapes, but it is unclear how these changes affect habitat quality for animals. We used functional diversity and community-weighted mean (CWM) trait values for four plant traits (litter N, P, lignin and soluble phenolics) to explore how changes in plant species composition may affect larval amphibians in a simplified aquatic ecosystem. We predicted that increased functional diversity would improve amphibian performance (survivorship, developmental rate, and size). We also predicted that increases in CWM N and P would improve amphibian performance, while increases in CWM lignin and soluble phenolics would have negative effects on amphibian performance. We did not detect an effect of functional diversity; instead, CWM litter N and soluble phenolics were useful predictors of amphibian performance. We demonstrate that quantifying the CWM of ecologically relevant traits represents a powerful approach for predicting how changes in plant species composition can affect aquatic communities. PMID- 24402131 TI - Native insect herbivory limits population growth rate of a non-native thistle. AB - The influence of native fauna on non-native plant population growth, size, and distribution is not well documented. Previous studies have shown that native insects associated with tall thistle (Cirsium altissimum) also feed on the leaves, stems, and flower heads of the Eurasian congener C. vulgare, thus limiting individual plant performance. In this study, we tested the effects of insect herbivores on the population growth rate of C. vulgare. We experimentally initiated invasions by adding seeds at four unoccupied grassland sites in eastern Nebraska, USA, and recorded plant establishment, survival, and reproduction. Cumulative foliage and floral herbivory reduced C. vulgare seedling density, and prevented almost any reproduction by C. vulgare in half the sites. The matrix model we constructed showed that this herbivory resulted in a reduction of the asymptotic population growth rate (lambda), from an 88% annual increase to a 54% annual decline. These results provide strong support for the hypothesis that indigenous herbivores limit population invasion of this non-native plant species into otherwise suitable grassland habitat. PMID- 24402132 TI - Coupling G2/M arrest to the Wnt/beta-catenin pathway restrains pancreatic adenocarcinoma. AB - beta-catenin plays a pivotal role in organogenesis and oncogenesis. Alterations in beta-catenin expression are common in pancreatic cancer, which is an extremely aggressive malignancy with a notably poor prognosis. In this report, we analyzed the apoptotic activity of withanolide-D (witha-D), a steroidal lactone that was purified from an Indian medicinal plant, Withania somnifera, and its underlying mechanism of action. Witha-D induced apoptosis in pancreatic ductal adenocarcinoma cells by prompting cell-cycle arrest at the G2/M phase. This lactone abrogated beta-catenin signaling in these cells regardless of disease grade, mutational status, and gemcitabine sensitivity. Witha-D also upregulated E cadherin in most cells, thereby supporting the inversion of the epithelial mesenchymal transition. Furthermore, the Akt/Gsk3beta kinase cascade was identified as a critical mediator of G2/M regulation and beta-catenin signaling. Witha-D deactivated Akt, which failed to promote Gsk3beta deactivation phosphorylation. Consequently, activated Gsk3beta facilitated beta-catenin destruction in pancreatic carcinoma cells. The knockdown of Chk1 and Chk2 further activated Akt and reversed the molecular signal. Taken together, the results of the current study represent the first evidence of beta-catenin signal crosstalk during the G2/M phase by functionally inactivating Akt via witha-D treatment in pancreatic cancer cells. In conclusion, this finding suggests the potential identification of a new lead molecule in the treatment of pancreatic adenocarcinoma. PMID- 24402133 TI - Serotonin-1A receptor stimulation mediates effects of a metabotropic glutamate 2/3 receptor antagonist, 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9 yl)propanoic acid (LY341495), and an N-methyl-D-aspartate receptor antagonist, ketamine, in the novelty-suppressed feeding test. AB - RATIONALE: alpha-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor stimulation has been proposed to be a common neural mechanism of metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists and an N-methyl-D aspartate receptor antagonist, ketamine, exerting antidepressant effects in animal models. AMPA receptor stimulation has also been shown to mediate an increase in the extracellular level of serotonin (5-HT) in the medial prefrontal cortex by an mGlu2/3 receptor antagonist in rats. However, involvement of the serotonergic system in the actions of mGlu2/3 receptor antagonists and ketamine is not well understood. OBJECTIVES: We investigated involvement of the serotonergic system in the effects of an mGlu2/3 receptor antagonist, 2S-2-amino 2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (LY341495), and ketamine in a novelty-suppressed feeding (NSF) test in mice. RESULTS: The intraperitoneal administration of LY341495 or ketamine at 30 min prior to the test significantly shortened latency to feed, which was attenuated by an AMPA receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydr-obenzo[f]quinoxaline-7 sulfonamide (NBQX). The effects of LY341495 and ketamine were no longer observed in mice pretreated with a tryptophan hydroxylase inhibitor, para chlorophenylalanine (PCPA). Moreover, the effects of LY341495 and ketamine were blocked by a 5-HT1A receptor antagonist, N-{2-[4-(2-methoxyphenyl)-1 piperazinyl]ethyl}-N-(2-pyridynyl) cyclohexane-carboxamide (WAY100635), but not by a 5-HT2A/2C receptor antagonist, ritanserin. Likewise, an AMPA receptor potentiator, 2,3-dihydro-1,4-benzodioxin-7-yl-(1-piperidyl)methanone (CX546), shortened latency to feed in the NSF test, which was prevented by depletion of 5 HT and blockade of 5-HT1A receptor. CONCLUSIONS: These results suggest that AMPA receptor-dependent 5-HT release and subsequent 5-HT1A receptor stimulation may be involved in the actions of an mGlu2/3 receptor antagonist and ketamine in the NSF test. PMID- 24402134 TI - The effects of the beta-lactam antibiotic, ceftriaxone, on forepaw stepping and L DOPA-induced dyskinesia in a rodent model of Parkinson's disease. AB - RATIONALE: Glutamate receptor antagonists can improve the symptoms of Parkinson's disease (PD) and reduce L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in both animal models and humans, but usually produce intolerable side effects. Recent evidence suggests that upregulation of the major glutamate transporter, GLT-1, by the beta-lactam antibiotic, ceftriaxone, can increase the removal of synaptic glutamate without producing noticeable side effects, and may provide an effective alternative to receptor antagonists for several neurodegenerative diseases. OBJECTIVES: We examined whether repeated i.p. injections of ceftriaxone would, like glutamate antagonists, reduce the deficits in contralateral forepaw stepping produced by unilateral injections of 6-OHDA into the medial forebrain bundle of rats and reduce LID (as measured by abnormal involuntary movements). METHODS AND RESULTS: In Experiment 1, daily injections of 100 mg/kg ceftriaxone improved contralateral forepaw stepping by 44%, and these therapeutic effects were still apparent 29 days following the cessation of treatment. In Experiment 2, daily injections of 50 mg/kg ceftriaxone were as effective as daily injections of 10 mg/kg L-DOPA in increasing contralateral forepaw stepping by 40%. These therapeutic effects of ceftriaxone were decreased by an injection of 10 mg/kg of the selective GLT-1 antagonist, dihydrokainate (DHK), and were still evident 69 days after the cessation of ceftriaxone injections. Furthermore, ceftriaxone did not produce dyskinesia by itself and reduced the development, but not the expression, of LID. CONCLUSIONS: These data suggest that ceftriaxone, by producing a long-term increase in GLT-1 function and increasing the removal of synaptic glutamate, may offer several advantages over L DOPA as therapy for PD. PMID- 24402135 TI - Effect of streptozotocin-induced diabetes on performance on a progressive ratio schedule. AB - RATIONALE: It has been suggested that streptozotocin (STZ)-induced diabetes causes a motivational deficit in rodents. However, some of the evidence adduced in support of this suggestion may be interpreted in terms of a motor impairment rather than a motivational deficit. OBJECTIVE: This experiment examined the effect of STZ-induced diabetes on performance on a progressive ratio schedule. The data were analysed using a new model derived from Killeen's (Behav Brain Sci 17:105-172, 1994) Mathematical Principles of Reinforcement model which enables the effects of interventions on motivation or incentive value to be separated from effects on motor function. METHOD: Animals were trained under a progressive ratio schedule using food-pellet reinforcement. Then they received a single intraperitoneal injection of 50 mg/kg of STZ or the vehicle. Training continued for 30 sessions after treatment. Running and overall response rates in successive ratios were analysed using the new model, and estimates of the model's parameters were compared between groups. RESULTS: The parameter expressing incentive value was reduced in the group treated with STZ, whereas the parameters expressing motor capacity and post-reinforcement pausing were not affected by the treatment. Blood glucose concentration was significantly elevated in the STZ-treated group compared to the vehicle-treated group. CONCLUSIONS: The results are consistent with the suggestion that STZ-induced diabetes is associated with a reduction of the incentive value of food. PMID- 24402137 TI - Alpha-synuclein deletion decreases motor impulsivity but does not affect risky decision making in a mouse Gambling Task. AB - RATIONALE: There is evidence to support the role of alpha-synuclein in motor impulsivity, but the extrapolation of this finding to other types of impulsivity remains to be elucidated. OBJECTIVE: This study aims to investigate the role of alpha-synuclein in choice impulsivity/risky decision-making by means of a mouse version of the Iowa Gambling Task (mIGT). METHODS: Two strains of mice that differ in the expression of the alpha-synuclein gene, the C57BL/6JOlaHsd (HA) and C57BL/6J (CR), were tested in the mIGT. HA mice differ from their CR ancestors in possessing a chromosomal deletion resulting in the loss of two genes: snca, encoding alpha-synuclein and mmrn1, encoding multimerin-1. Mice were trained in the mIGT until a stable pattern of responding was achieved and then the acute effects of ethanol and cocaine in choice preference were investigated. RESULTS: No differences between the strains were evident in risky decision-making in any of the experiments, but HA mice showed consistently reduced levels of premature responding in comparison with CR mice, confirming the reduced motor impulsivity found in a previous study. Ethanol did not modify the percentage of advantageous choices in either strain, while cocaine increased the risky choice behaviour by increasing the percentage of disadvantageous choices in both strains. CONCLUSIONS: We provide further evidence for the involvement of alpha-synuclein in motor impulsivity and suggest that alpha-synuclein does not play a role in risky decision-making as evaluated in the mIGT. PMID- 24402138 TI - Does a history of suicide attempt predict higher antipsychotic dosage in schizophrenia? AB - RATIONALE: Antipsychotic dosage is generally adjusted by physicians depending on the stability of the patient and the response to that particular drug. Our hypothesis is that patients with previous suicide attempt are prescribed higher doses of antipsychotics. OBJECTIVE: We examined the dosage and patterns of antipsychotic use in regard to past suicidal behaviour. METHODS: For this study, 304 subjects with schizophrenia spectrum disorders between the ages of 18 and 75 were recruited. A cross-sectional assessment was used for this study, in which data were collected from each patient through an interview and self-report questionnaires. The percentages of the Compendium of Pharmaceuticals and Specialties (CPS) maximum recommended daily dose were applied to standardize antipsychotic dosages across different treatments. We compared the standardized dosage of antipsychotics in schizophrenics with previous suicide attempts and those who have never attempted suicide. RESULTS: Applying the ANCOVA, our preliminary results show no significant difference (P = 0.467) in antipsychotic dosage in the attempters and non-attempters. The prescribed clozapine dosage fails to show a significant relationship with suicidal history (P >0.05). CONCLUSIONS: In summary, our analysis does not show antipsychotic dosage adjustment based on past suicide attempt, after controlling for the current suicidal ideation and hopelessness. PMID- 24402139 TI - The relationship between the nicotine metabolite ratio and three self-report measures of nicotine dependence across sex and race. AB - RATIONALE: Variability in the rate of nicotine metabolism, measured by the nicotine metabolite ratio (NMR), is associated with smoking behavior. However, data linking the NMR with nicotine dependence measured by the Fagerstrom test for nicotine dependence (FTND) are mixed. Few past studies have examined alternative measures of nicotine dependence and how this relationship may vary by sex and race. OBJECTIVE: Using data from smokers undergoing eligibility evaluation for a smoking cessation clinical trial (n = 833), this study examined variability in the relationship between NMR and nicotine dependence across sex and race and using three measures of nicotine dependence: FTND, time-to-first-cigarette (TTFC), and the heaviness of smoking index (HSI). RESULTS: Controlling for sex and race, nicotine metabolism was associated with nicotine dependence only when using the HSI (p < 0.05). Male normal metabolizers of nicotine were more likely to have high nicotine dependence based on the FTND and HSI (p < 0.05), but NMR was not related to measures of nicotine dependence in women. For African Americans, the NMR was associated with nicotine dependence only for the TTFC (p < 0.05), but NMR was not associated with nicotine dependence among Caucasians. Post hoc analyses indicated that the NMR was associated with cigarettes per day, overall, and among men and Caucasians (p < 0.05). CONCLUSIONS: While there was some variation in the relationship between nicotine metabolism and nicotine dependence across measures and sex and race, the results indicate that this relationship may be more attributable to the association between NMR and cigarettes per day. PMID- 24402140 TI - The role of ovarian hormone-derived neurosteroids on the regulation of GABAA receptors in affective disorders. AB - RATIONALE: Neuroactive derivatives of steroid hormones, neurosteroids, can act on GABAA receptors (GABAARs) to potentiate the effects of GABA on these receptors. Neurosteroids become elevated to physiologically relevant levels under conditions characterized by increased steroid hormones. There is considerable evidence for plasticity of GABAARs associated with altered levels of neurosteroids which may counteract the fluctuations in the levels of these allosteric modulators. OBJECTIVES: The objective of this review is to summarize the current literature on GABAAR plasticity under conditions characterized by alterations in neurosteroid levels, such as over the estrous cycle, during puberty, and throughout pregnancy and the postpartum period. RESULTS: The expression of specific GABAAR subunits is altered over the estrous cycle, at puberty, and throughout pregnancy and the postpartum period. Inability to regulate delta subunit-containing GABAARs throughout pregnancy and the postpartum period is associated with depression-like behavior restricted to the postpartum period. CONCLUSIONS: GABAAR plasticity associated with alterations in neurosteroid levels represents a homeostatic compensatory mechanism to maintain an ideal level of inhibition to offset the potentiating effects of neurosteroids on GABAergic inhibition. Failure to properly regulate GABAARs under conditions of altered neurosteroid levels may increase vulnerability to mood disorders, such as premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), and postpartum depression. PMID- 24402142 TI - Construction and characterisation of a complete reverse genetics system of dengue virus type 3. AB - Dengue virulence and fitness are important factors that determine disease outcome. However, dengue virus (DENV) molecular biology and pathogenesis are not completely elucidated. New insights on those mechanisms have been facilitated by the development of reverse genetic systems in the past decades. Unfortunately, instability of flavivirus genomes cloned in Escherichia coli has been a major problem in these systems. Here, we describe the development of a complete reverse genetics system, based on the construction of an infectious clone and replicon for a low passage DENV-3 genotype III of a clinical isolate. Both constructs were assembled into a newly designed yeast-E. coli shuttle vector by homologous recombination technique and propagated in yeast to prevent any possible genome instability in E. coli. RNA transcripts derived from the infectious clone are infectious upon transfection into BHK-21 cells even after repeated passages of the plasmid in yeast. Transcript-derived DENV-3 exhibited growth kinetics, focus formation size comparable to original DENV-3 in mosquito C6/36 cell culture. In vitro characterisation of DENV-3 replicon confirmed its identity and ability to replicate transiently in BHK-21 cells. The reverse genetics system reported here is a valuable tool that will facilitate further molecular studies in DENV replication, virus attenuation and pathogenesis. PMID- 24402141 TI - Neonatal phencyclidine administration and post-weaning social isolation as a dual hit model of 'schizophrenia-like' behaviour in the rat. AB - RATIONALE: Schizophrenia is a debilitating disorder comprising positive, negative and cognitive deficits with a poorly defined neurobiological aetiology; therefore, animal models with greater translational reliability are essential to develop improved therapies. OBJECTIVES: This study combines two developmental challenges in rats, neonatal phencyclidine (PCP) injection and subsequent rearing in social isolation from weaning, to attempt to produce more robust behavioural deficits with greater translational relevance to schizophrenia than either challenge alone. METHODS: Forty-two male Lister-hooded rat pups received the N methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP, 10 mg/kg, s.c.), or vehicle on post-natal day (PND) 7, 9 and 11 and were weaned on PND 23 into group housing (saline-treated n = 11 or PCP-treated n = 10) or isolation (saline n = 10 or PCP n = 11). Six weeks post-weaning, novelty- and PCP-induced (3.2 mg/kg) locomotor activity, novel object discrimination, prepulse inhibition of acoustic startle and contextual memory in a conditioned emotion response (CER) were recorded. RESULTS: Isolation rearing alone significantly elevated baseline locomotor activity and induced visual recognition memory impairment in novel object discrimination. Neonatal PCP treatment did not induce locomotor sensitisation to a subsequent acute PCP injection, but it impaired prepulse inhibition when combined with isolation rearing. CER freezing behaviour was significantly reduced by isolation rearing but an even greater effect occurred when combined with neonatal PCP treatment. CONCLUSIONS: Neonatal PCP and isolation rearing both produce behavioural deficits in adult rats, but combined treatment caused a wider range of more severe cognitive impairments, providing a more comprehensive preclinical model to determine the neurobiological aetiology of schizophrenia than either treatment alone. PMID- 24402143 TI - Rapid detection of multidrug-resistant Mycobacterium tuberculosis using the malachite green decolourisation assay. AB - Early detection of drug resistance in Mycobacterium tuberculosis isolates allows for earlier and more effective treatment of patients. The aim of this study was to investigate the performance of the malachite green decolourisation assay (MGDA) in detecting isoniazid (INH) and rifampicin (RIF) resistance in M. tuberculosis clinical isolates. Fifty M. tuberculosis isolates, including 19 multidrug-resistant, eight INH-resistant and 23 INH and RIF-susceptible samples, were tested. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and agreement of the assay for INH were 92.5%, 91.3%, 92.5%, 91.3% and 92%, respectively. Similarly, the sensitivity, specificity, PPV, NPV and agreement of the assay for RIF were 94.7%, 100%, 100%, 96.8% and 98%, respectively. There was a major discrepancy in the tests of two isolates, as they were sensitive to INH by the MGDA test, but resistant by the reference method. There was a minor discrepancy in the tests of two additional isolates, as they were sensitive to INH by the reference method, but resistant by the MGDA test. The drug susceptibility test results were obtained within eight nine days. In conclusion, the MGDA test is a reliable and accurate method for the rapid detection of INH and RIF resistance compared with the reference method and the MGDA test additionally requires less time to obtain results. PMID- 24402144 TI - A comparison of larval, ovitrap and MosquiTRAP surveillance for Aedes (Stegomyia) aegypti. AB - In Brazil, the entomological surveillance of Aedes (Stegomyia) aegypti is performed by government-mandated larval surveys. In this study, the sensitivities of an adult sticky trap and traditional surveillance methodologies were compared. The study was performed over a 12-week period in a residential neighbourhood of the municipality of Pedro Leopoldo, state of Minas Gerais, Brazil. An ovitrap and a MosquiTRAP were placed at opposite ends of each neighbourhood block (60 traps in total) and inspections were performed weekly. The study revealed significant correlations of moderate strength between the larval survey, ovitrap and MosquiTRAP measurements. A positive relationship was observed between temperature, adult capture measurements and egg collections, whereas precipitation and frequency of rainy days exhibited a negative relationship. PMID- 24402145 TI - Cell vacuolation induced by Haemophilus influenzae supernatants in HEp-2 cells. AB - Haemophilus influenzae belongs to respiratory tract microbiota. We observed vacuoles formation in previous studies with H. influenzae culture supernatants, so in this work we characterised that cytotoxic effect. We observed an abundant production of acidic cytoplasmic vacuoles due to the presence of a "vacuolating factor" in H. influenzae supernatants which was characterised as thermolabile. Greatest vacuolating activity was observed when utilizing the fraction > 50 kDa. The presence of a large number of vacuoles in HEp-2 cells was verified by transmission electron microscopy and some vacuoles were identified with a double membrane and/or being surrounded by ribosomes. These results suggest similar behaviour to that of vacuolating effects described by autotransporter proteins an undescribed cytotoxic effect induced by H. influenzae. PMID- 24402146 TI - A rapid diagnostic test for Schistosomiasis mansoni. AB - This article presents an improvement to the Kato-Katz (KK) method, making it faster and more efficient for the visualisation of fertile eggs in stool samples. This modified KK method uses sodium acetate formalin as a fixative and reveals the intensity of infection in less than 1 h, reducing the diagnostic time without increasing the cost. This modified method may contribute to future epidemiological studies in both hospitals and the field due to its rapid and precise diagnostic, which allow for immediate treatment. PMID- 24402148 TI - Chagas disease: control, elimination and eradication. Is it possible? AB - From an epidemiological point of view, Chagas disease and its reservoirs and vectors can present the following characteristics: (i) enzooty, maintained by wild animals and vectors, with broad occurrence from southern United States of America (USA) to southern Argentina and Chile (42oN 49oS), (ii) anthropozoonosis, when man invades the wild ecotope and becomes infected with Trypanosoma cruzi from wild animals or vectors or when the vectors and wild animals, especially marsupials, invade the human domicile and infect man, (iii) zoonosis-amphixenosis and exchanged infection between animals and humans by domestic vectors in endemic areas and (iv) zooanthroponosis, infection that is transmitted from man to animals, by means of domestic vectors, which is the rarest situation in areas endemic for Chagas disease. The characteristics of Chagas disease as an enzooty of wild animals and as an anthropozoonosis are seen most frequently in the Brazilian Amazon and in the Pan-Amazon region as a whole, where there are 33 species of six genera of wild animals: Marsupialia, Chiroptera, Rodentia, Edentata (Xenarthra), Carnivora and Primata and 27 species of triatomines, most of which infected with T. cruzi . These conditions place the resident populations of this area or its visitors - tourists, hunters, fishermen and especially the people whose livelihood involves plant extraction - at risk of being affected by Chagas disease. On the other hand, there has been an exponential increase in the acute cases of Chagas disease in that region through oral transmission of T. cruzi , causing outbreaks of the disease. In four seroepidemiological surveys that were carried out in areas of the microregion of the Negro River, state of Amazonas, in 1991, 1993, 1997 and 2010, we found large numbers of people who were serologically positive for T. cruzi infection. The majority of them and/or their relatives worked in piassava extraction and had come into contact with and were stung by wild triatomines in that area. Finally, a characteristic that is greatly in evidence currently is the migration of people with Chagas disease from endemic areas of Latin America to non-endemic countries. This has created a new dilemma for these countries: the risk of transmission through blood transfusion and the onus of controlling donors and treating migrants with the disease. As an enzooty of wild animals and vectors, and as an anthropozoonosis, Chagas disease cannot be eradicated, but it must be controlled by transmission elimination to man. PMID- 24402149 TI - Evidence of an increased incidence of day 3 parasitaemia in Suriname: an indicator of the emerging resistance of Plasmodium falciparum to artemether. AB - The emerging resistance to artemisinin derivatives that has been reported in South-East Asia led us to assess the efficacy of artemether-lumefantrine as the first line therapy for uncomplicated Plasmodium falciparum infections in Suriname. This drug assessment was performed according to the recommendations of the World Health Organization in 2011. The decreasing number of malaria cases in Suriname, which are currently limited to migrating populations and gold miners, precludes any conclusions on artemether efficacy because adequate numbers of patients with 28-day follow-up data are difficult to obtain. Therefore, a comparison of day 3 parasitaemia in a 2011 study and in a 2005/2006 study was used to detect the emergence of resistance to artemether. The prevalence of day 3 parasitaemia was assessed in a study in 2011 and was compared to that in a study in 2005/2006. The same protocol was used in both studies and artemether lumefantrine was the study drug. Of 48 evaluable patients in 2011, 15 (31%) still had parasitaemia on day 3 compared to one (2%) out of 45 evaluable patients in 2005/2006. Overall, 11 evaluable patients in the 2011 study who were followed up until day 28 had negative slides and similar findings were obtained in all 38 evaluable patients in the 2005/2006 study. The significantly increased incidence of parasite persistence on day 3 may be an indication of emerging resistance to artemether. PMID- 24402147 TI - Genetics of chloroquine-resistant malaria: a haplotypic view. AB - The development and rapid spread of chloroquine resistance (CQR) in Plasmodium falciparum have triggered the identification of several genetic target(s) in the P. falciparum genome. In particular, mutations in the Pfcrt gene, specifically, K76T and mutations in three other amino acids in the region adjoining K76 (residues 72, 74, 75 and 76), are considered to be highly related to CQR. These various mutations form several different haplotypes and Pfcrt gene polymorphisms and the global distribution of the different CQR- Pfcrt haplotypes in endemic and non-endemic regions of P. falciparum malaria have been the subject of extensive study. Despite the fact that the Pfcrt gene is considered to be the primary CQR gene in P. falciparum , several studies have suggested that this may not be the case. Furthermore, there is a poor correlation between the evolutionary implications of the Pfcrt haplotypes and the inferred migration of CQR P. falciparum based on CQR epidemiological surveillance data. The present paper aims to clarify the existing knowledge on the genetic basis of the different CQR- Pfcrt haplotypes that are prevalent in worldwide populations based on the published literature and to analyse the data to generate hypotheses on the genetics and evolution of CQR malaria. PMID- 24402150 TI - Aspidosperma (Apocynaceae) plant cytotoxicity and activity towards malaria parasites. Part I: Aspidosperma nitidum (Benth) used as a remedy to treat fever and malaria in the Amazon. AB - Infusions of Aspidosperma nitidum (Apocynaceae) wood bark are used to treat fever and malaria in the Amazon Region. Several species of this family are known to possess indole alkaloids and other classes of secondary metabolites, whereas terpenoids, an inositol and the indole alkaloids harmane-3 acid and braznitidumine have been described in A. nitidum . In the present study, extracts from the wood bark, leaves and branches of this species were prepared for assays against malaria parasites and cytotoxicity testing using human hepatoma and normal monkey kidney cells. The wood bark extracts were active against Plasmodium falciparum and showed a low cytotoxicity in vitro, whereas the leaf and branch extracts and the pure alkaloid braznitidumine were inactive. A crude methanol extract was subjected to acid-base fractionation aimed at obtaining alkaloid-rich fractions, which were active at low concentrations against P. falciparum and in mice infected with and sensitive Plasmodium berghei parasites. Our data validate the antimalarial usefulness of A. nitidum wood bark, a remedy that can most likely help to control malaria. However, the molecules responsible for this antimalarial activity have not yet been identified. Considering their high selectivity index, the alkaloid-rich fractions from the plant bark might be useful in the development of new antimalarials. PMID- 24402151 TI - Predicting the geographic distribution of Lutzomyia longipalpis (Diptera: Psychodidae) and visceral leishmaniasis in the state of Mato Grosso do Sul, Brazil. AB - To understand the geographic distribution of visceral leishmaniasis (VL) in the state of Mato Grosso do Sul (MS), Brazil, both the climatic niches of Lutzomyia longipalpis and VL cases were analysed. Distributional data were obtained from 55 of the 79 counties of MS between 2003-2012. Ecological niche models (ENM) of Lu. longipalpis and VL cases were produced using the maximum entropy algorithm based on eight climatic variables. Lu. longipalpis showed a wide distribution in MS. The highest climatic suitability for Lu. longipalpis was observed in southern MS. Temperature seasonality and annual mean precipitation were the variables that most influenced these models. Two areas of high climatic suitability for the occurrence of VL cases were predicted: one near Aquidauana and another encompassing several municipalities in the southeast region of MS. As expected, a large overlap between the models for Lu. longipalpis and VL cases was detected. Northern and northwestern areas of MS were suitable for the occurrence of cases, but did not show high climatic suitability for Lu. longipalpis. ENM of vectors and human cases provided a greater understanding of the geographic distribution of VL in MS, which can be applied to the development of future surveillance strategies. PMID- 24402152 TI - Large-scale patterns in morphological diversity and species assemblages in Neotropical Triatominae (Heteroptera: Reduviidae). AB - We analysed the spatial variation in morphological diversity (MDiv) and species richness (SR) for 91 species of Neotropical Triatominae to determine the ecological relationships between SR and MDiv and to explore the roles that climate, productivity, environmental heterogeneity and the presence of biomes and rivers may play in the structuring of species assemblages. For each 110 km x 110 km-cell on a grid map of America, we determined the number of species (SR) and estimated the mean Gower index (MDiv) based on 12 morphological attributes. We performed bootstrapping analyses of species assemblages to identify whether those assemblages were more similar or dissimilar in their morphology than expected by chance. We applied a multi-model selection procedure and spatial explicit analyses to account for the association of diversity-environment relationships. MDiv and SR both showed a latitudinal gradient, although each peaked at different locations and were thus not strictly spatially congruent. SR decreased with temperature variability and MDiv increased with mean temperature, suggesting a predominant role for ambient energy in determining Triatominae diversity. Species that were more similar than expected by chance co-occurred near the limits of the Triatominae distribution in association with changes in environmental variables. Environmental filtering may underlie the structuring of species assemblages near their distributional limits. PMID- 24402153 TI - Morbidity of Chagas heart disease in the microregion of Rio Negro, Amazonian Brazil: a case-control study. AB - A case-control study on the morbidity of Chagas heart disease was carried out in the municipality of Barcelos in the microregion of the Rio Negro, state of Amazonas. One hundred and six individuals, who were serologically positive for Trypanosoma cruzi infection, as confirmed by at least two techniques with different principles, were matched according to age and sex with an equal number of seronegative individuals. The cases and controls were evaluated using an epidemiological questionnaire and clinical, electrocardiograph and echocardiograph examinations. In the seroepidemiological evaluation, 62% of the interviewees recognised triatomines and most of them confirmed that they had seen these insects in the piassava plantations of the riverside communities of the Negro River tributaries. Of the seropositive patients, 25.8% affirmed that they had been stung by the triatomines and 11.7% denied having been stung. The principal clinical manifestations of the seropositive individuals were palpitations, chest pain and dyspnoea upon effort. Cardiac auscultation revealed extrasystoles, bradycardia and systolic murmurs. The electrocardiographic alterations were ventricular extrasystoles, left and right bundle branch block, atrioventricular block and primary T wave alterations. The echocardiogram was altered in 22.6% of the seropositive individuals and in 8.5% of the seronegative individuals. PMID- 24402154 TI - Comparison of automatic traps to capture mosquitoes (Diptera: Culicidae) in rural areas in the tropical Atlantic rainforest. AB - In several countries, surveillance of insect vectors is accomplished with automatic traps. This study addressed the performance of Mosquito Magnet(r) Independence (MMI) in comparison with those of CDC with CO2 and lactic acid (CDC A) and CDC light trap (CDC-LT). The collection sites were in a rural region located in a fragment of secondary tropical Atlantic rainforest, southeastern Brazil. Limatus durhami and Limatus flavisetosus were the dominant species in the MMI, whereas Ochlerotatus scapularis was most abundant in CDC-A. Culex ribeirensis and Culex sacchettae were dominant species in the CDC-LT. Comparisons among traps were based on diversity indices. Results from the diversity analyses showed that the MMI captured a higher abundance of mosquitoes and that the species richness estimated with it was higher than with CDC-LT. Contrasting, difference between MMI and CDC-A was not statistically significant. Consequently, the latter trap seems to be both an alternative for the MMI and complementary to it for ecological studies and entomological surveillance. PMID- 24402155 TI - Analysing deltamethrin susceptibility and pyrethroid esterase activity variations in sylvatic and domestic Triatoma infestans at the embryonic stage. AB - The aim of the present work was to study the deltamethrin susceptibility of eggs from Triatoma infestans populations and the contribution of pyrethroid esterases to deltamethrin degradation. Insects were collected from sylvatic areas, including Veinte de Octubre and Kirus-Mayu (Bolivia) and from domiciliary areas, including El Palmar (Bolivia) and La Pista (Argentina). Deltamethrin susceptibility was determined by dose-response bioassays. Serial dilutions of deltamethrin (0.0005-1 mg/mL) were topically applied to 12-day-old eggs. Samples from El Palmar had the highest lethal dose ratio (LDR) value (44.90) compared to the susceptible reference strain (NFS), whereas the Veinte de Octubre samples had the lowest value (0.50). Pyrethroid esterases were evaluated using 7-coumaryl permethrate (7-CP) on individually homogenised eggs from each population and from NFS. The El Palmar and La Pista samples contained 40.11 and 36.64 pmol/min/mg protein, respectively, and these values were statistically similar to NFS (34.92 pmol/min/mg protein) and different from Kirus-Mayu and Veinte de Octubre (27.49 and 22.69 pmol/min/mg protein, respectively). The toxicological data indicate that the domestic populations were resistant to deltamethrin, but no statistical contribution of 7-CP esterases was observed. The sylvatic populations had similar LDR values to NFS, but lower 7-CP esterase activities. Moreover, this is the first study of the pyrethroid esterases on T. infestans eggs employing a specific substrate (7-CP). PMID- 24402156 TI - A conventional polymerase chain reaction-based method for the diagnosis of human schistosomiasis in stool samples from individuals in a low-endemicity area. AB - The aim of this study was to evaluate the efficacy of a polymerase chain reaction (PCR)-based method to detect Schistosoma mansoni DNA in stool samples from individuals living in a low-endemicity area in Brazil. Of the 125 initial stool samples, 80 were ELISA reactive and eggs were identified in 19 of the samples by parasitological examination. For the PCR evaluations, 56 stool samples were selected and divided into five groups. Groups I-IV were scored negative for S. mansoni eggs by parasitological examination. Groups I and II were ELISA reactive, whereas Groups III and IV were ELISA nonreactive. Groups II and III were positive for other intestinal parasites. PCR testing scored eight samples as positive from these four groups. Group V represented the S. mansoni -positive group and it included ELISA-reactive samples that were scored positive for S. mansoni by one or more parasitological examinations (6/19 were positive by Kato-Katz method, 9/17 by saline gradient and 10/13 by Helmintex(r)). PCR scored 13 of these 19 samples as positive for S. mansoni . We conclude that while none of these methods yielded 100% sensitivity, a combination of techniques should be effective for improving the detection of S. mansoni infection in low-endemicity areas. PMID- 24402157 TI - First published record of urban malaria in Puerto Gaitan, Meta, Colombia. AB - Patterns of malaria cases were compared between the department of Meta and the municipality of Puerto Gaitan, Colombia, to examine temporal change in malaria from 2005-2010. During this time frame in Meta the mean ratio was 2.53; in contrast, in Puerto Gaitan it was 1.41, meaning that a surprisingly high proportion of Plasmodium falciparum cases were reported from this municipality. A detailed analysis of data from Puerto Gaitan for 2009 and 2010 detected a significant difference (chi2, p < 0.001) in the distribution of plasmodia, with Plasmodium vivax more prevalent in 2009 and P. falciparum in 2010. Males had the highest number of cases but there was no difference in the distribution of cases between sexes and years. In both years, for both sexes, people 16-40 accounted for the majority of cases (58.9% in 2009; 60.4% in 2010). There were significant differences in the distribution of both P. vivax (chi2, p < 0.01) and P. falciparum cases (chi2, p < 0.05) by geographic setting (urban vs. non-urban) between years. Urban cases of both P. vivax and P. falciparum are recorded in this study for the first time in Puerto Gaitan, possibly the result of area wide displacement and migration due to armed conflict. PMID- 24402158 TI - Serial measurement of the circulating levels of tumour necrosis factor and its soluble receptors 1 and 2 for monitoring leprosy patients during multidrug treatment. AB - Leprosy is an infectious and contagious spectral disease accompanied by a series of immunological events triggered by the host response to the aetiologic agent, Mycobacterium leprae . The induction and maintenance of the immune/inflammatory response in leprosy are linked to multiple cell interactions and soluble factors, primarily through the action of cytokines. The purpose of the present study was to evaluate the serum levels of tumour necrosis factor (TNF)-alpha and its soluble receptors (sTNF-R1 and sTNF-R2) in leprosy patients at different stages of multidrug treatment (MDT) in comparison with non-infected individuals and to determine their role as putative biomarkers of the severity of leprosy or the treatment response. ELISA was used to measure the levels of these molecules in 30 healthy controls and 37 leprosy patients at the time of diagnosis and during and after MDT. Our results showed increases in the serum levels of TNF-alpha and sTNF R2 in infected individuals in comparison with controls. The levels of TNF-alpha, but not sTNF-R2, decreased with treatment. The current results corroborate previous reports of elevated serum levels of TNF-alpha in leprosy and suggest a role for sTNF-R2 in the control of this cytokine during MDT. PMID- 24402159 TI - Anthropophilic biting behaviour of Anopheles (Kerteszia) neivai Howard, Dyar & Knab associated with Fishermen's activities in a malaria-endemic area in the Colombian Pacific. AB - On the southwest Pacific Coast of Colombia, a field study was initiated to determine the human-vector association between Anopheles (Kerteszia) neivai and fishermen, including their nearby houses. Mosquitoes were collected over 24-h periods from mangrove swamps, marshlands and fishing vessels in three locations, as well as in and around the houses of fishermen. A total of 6,382 mosquitoes were collected. An. neivai was most abundant in mangroves and fishing canoes (90.8%), while Anopheles albimanus was found indoors (82%) and outdoors (73%). One An. neivai and one An. albimanus collected during fishing activities in canoes were positive for Plasmodium vivax , whereas one female An. neivai collected in a mangrove was positive for P. vivax . In the mangroves and fishing canoes, An. neivai demonstrated biting activity throughout the day, peaking between 06:00 pm-07:00 pm and there were two minor peaks at dusk and dawn. These peaks coincided with fishing activities in the marshlands and mangroves, a situation that places the fishermen at risk of contracting malaria when they are performing their daily activities. It is recommended that protective measures be implemented to reduce the risk that fishermen will contract malaria. PMID- 24402160 TI - The first record of Lutzomyia longipalpis in the Argentine northwest. AB - In 2004, the urban presence of Lutzomyia longipalpis was recorded for the first time in Formosa province. In 2006, the first autochthonous case of human urban visceral leishmaniasis (VL) was recorded in Misiones in the presence of the vector, along with some canine VL cases. After this first case, the vector began to spread primarily in northeast Argentina. Between 2008-2011, three human VL cases were reported in Salta province, but the presence of Lu. longipalpis was not recorded. Captures of Phlebotominae were made in Tartagal, Salta, in 2013, and the presence of Lu. longipalpis was first recorded in northwest Argentina at that time. Systematic sampling is recommended to observe the distribution and dispersion patterns of Lu. longipalpis and consider the risk of VL transmission in the region. PMID- 24402161 TI - Inhibitor of apoptosis proteins as therapeutic targets in multiple myeloma. AB - The inhibitor of apoptosis (IAP) proteins have a critical role in the control of apoptotic machinery, and has been explored as a therapeutic target. Here, we have examined the functional importance of IAPs in multiple myeloma (MM) by using a Smac (second mitochondria-derived activator of caspases)-mimetic LCL161. We observed that LCL161 was able to potently induce apoptosis in some MM cell lines but not in others. Examining the levels of X-linked inhibitor of apoptosis protein (XIAP), cellular inhibitor of apoptosis protein 1 (cIAP1) and cellular inhibitor of apoptosis protein 2 (cIAP2) post LCL161 treatment indicated clear downregulation of both XIAP activity and cIAP1 levels in both the sensitive and less sensitive (resistant) cell lines. cIAP2, however, was not downregulated in the cell line resistant to the drug. Small interfering RNA-mediated silencing of cIAP2 significantly enhanced the effect of LCL161, indicating the importance of downregulation of all IAPs simultaneously for induction of apoptosis in MM cells. LCL161 induced marked up regulation of the Jak2/Stat3 pathway in the resistant MM cell lines. Combining LCL161 with a Jak2-specific inhibitor resulted in synergistic cell death in MM cell lines and patient cells. In addition, combining LCL161 with death-inducing ligands clearly showed that LCL161 sensitized MM cells to both Fas-ligand and TRAIL. PMID- 24402162 TI - CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. AB - Calreticulin (CALR) mutations were recently described in JAK2 and MPL unmutated primary myelofibrosis (PMF) and essential thrombocythemia. In the current study, we compared the clinical, cytogenetic and molecular features of patients with PMF with or without CALR, JAK2 or MPL mutations. Among 254 study patients, 147 (58%) harbored JAK2, 63 (25%) CALR and 21 (8.3%) MPL mutations; 22 (8.7%) patients were negative for all three mutations, whereas one patient expressed both JAK2 and CALR mutations. Study patients were also screened for ASXL1 (31%), EZH2 (6%), IDH (4%), SRSF2 (12%), SF3B1 (7%) and U2AF1 (16%) mutations. In univariate analysis, CALR mutations were associated with younger age (P<0.0001), higher platelet count (P<0.0001) and lower DIPSS-plus score (P=0.02). CALR-mutated patients were also less likely to be anemic, require transfusions or display leukocytosis. Spliceosome mutations were infrequent (P=0.0001) in CALR-mutated patients, but no other molecular or cytogenetic associations were evident. In multivariable analysis, CALR mutations had a favorable impact on survival that was independent of both DIPSS-plus risk and ASXL1 mutation status (P=0.001; HR 3.4 for triple negative and 2.2 for JAK2-mutated). Triple-negative patients also displayed inferior LFS (P=0.003). The current study identifies 'CALR(-)ASXL1(+)' and 'triple-negative' as high-risk molecular signatures in PMF. PMID- 24402163 TI - Both leukaemic and normal peripheral B lymphoid cells are highly sensitive to the selective pharmacological inhibition of prosurvival Bcl-2 with ABT-199. AB - Overexpression of the prosurvival protein Bcl-2 marks many B-lymphoid malignancies and contributes to resistance to many commonly used chemotherapeutic agents. The first effective BH3 mimetic inhibitors of Bcl-2, ABT-737 and navitoclax, also target Bcl-xL, causing dose-limiting thrombocytopenia. This prompted the development of the Bcl-2-selective antagonist, ABT-199. Here we show that in lymphoid cells, ABT-199 specifically causes Bax/Bak-mediated apoptosis that is triggered principally by the initiator BH3-only protein Bim. As expected, malignant cells isolated from patients with chronic lymphocytic leukaemia are highly sensitive to ABT-199. However, we found that normal, untransformed mature B cells are also highly sensitive to ABT-199, both in vitro and in vivo. By contrast, the B-cell precursors are largely spared, as are cells of myeloid origin. These results pinpoint the probable impact of the pharmacological inhibition of Bcl-2 by ABT-199 on the normal mature haemopoietic cell lineages in patients, and have implications for monitoring during ABT-199 therapy as well as for the clinical utility of this very promising targeted agent. PMID- 24402164 TI - High number of additional genetic lesions in acute myeloid leukemia with t(8;21)/RUNX1-RUNX1T1: frequency and impact on clinical outcome. AB - t(8;21)/RUNX1-RUNX1T1-positive acute myeloid leukemia (AML) is prognostically favorable; however, outcome is heterogeneous. We analyzed 139 patients with t(8;21)/RUNX1-RUNX1T1-positive AML (de novo: n=117; therapy-related: n=22) to determine frequency and prognostic impact of additional genetic abnormalities. All patients were investigated for mutations (mut) in ASXL1, FLT3, KIT, NPM1, MLL, IDH1, IDH2, KRAS, NRAS, CBL and JAK2. Sixty-nine of 139 cases (49.6%) had 1 mutation in addition to RUNX1-RUNX1T1, and 23/139 (16.5%) had ?2 additional mutations. Most common were KITmut (23/139; 16.5%), NRASmut (18/139; 12.9%) and ASXL1mut (16/139; 11.5%). FLT3-ITD, FLT3-TKDmut, CBLmut, KRASmut, IDH2mut and JAK2mut were found in 2.9-5.0%. Additional chromosomal abnormalities (ACAs) were found in 97/139 (69.8%). Two-year overall survival (OS) was 73.4% in 111 intensively treated patients. KITD816mut negatively impacted on OS in de novo AML (2-year OS: 59.1% vs 82.0%, P=0.03), ASXL1mut on EFS (de novo AML: 20% vs 59.1%, P=0.011; total cohort: 28.6% vs 56.7%, P=0.021). Sex chromosome loss was favorable (2-year EFS: 66.9% vs 43.0%, P=0.031), whereas +8 was adverse on EFS (2 year EFS: 26.7% vs 55.9%, P=0.02). In conclusion, t(8;21)/RUNX1-RUNX1T1-positive AML shows a high frequency of additional genetic alterations. Investigation for KITD816 and ASXL1mut combined with investigation of ACAs is recommended in t(8;21)/RUNX1-RUNX1T1-positive AML because of the prognostic significance of these parameters. PMID- 24402165 TI - Ultrasound predictors of malignancy in indeterminate thyroid nodules. AB - BACKGROUND: Asymptomatic thyroid nodules are an increasingly common clinical problem. Lesions greater than a centimetre require cytological assessment. Indeterminate lesions often need surgical excision to establish a definitive diagnosis and plan further management. If a definitive diagnosis could be accurately predicted pre-operatively, the most appropriate surgical procedure could be performed at the initial operation. AIM: The aim of this study was to identify whether specific thyroid ultrasound features could predict malignancy in indeterminate thyroid nodules. METHODS: A retrospective review of all patients undergoing surgery for an indeterminate thyroid lesion between 2006 and 2012 was performed. Demographic features, surgical intervention and final histological findings were determined. Pre-operative ultrasound findings and final histology were correlated and the ultrasonic markers predictive of malignancy were determined. RESULTS: A total of 40 patients were identified as having undergone surgical intervention for indeterminate thyroid nodules. The majority of patients were diagnosed with a follicular adenoma (n = 22; 55 %). Papillary thyroid carcinoma was identified in three patients (7.5 %) and follicular carcinoma in a further 3 (7.5 %). Ultrasound features associated with malignancy included poorly defined nodule borders and increased vascularity. The presence of malignancy was not related to nodule size, echogenicity or the presence of calcifications. CONCLUSIONS: The majority of indeterminate thyroid lesions are benign on final histological assessment. High nodule vascularity associated with ill-defined borders is associated with malignancy. Further research is warranted to identify predictors of malignancy in indeterminate nodules in order to avoid unnecessary or repeated procedures. PMID- 24402166 TI - Breast clinic referrals: can mastalgia be managed in primary care? AB - BACKGROUND: Centralisation of breast cancer services in Ireland has resulted in a significant increase in the number of patients attending symptomatic breast units (SBU). A considerable proportion of patients referred to SBU present with non suspicious symptoms and fall into a "low-risk" category for breast cancer. It has been proposed that consideration be given to a primary care-delivered service for these patients. AIM: To evaluate SBU attendances and correlate with diagnosis to identify a cohort of patients who may be suitable for management in the primary care setting. METHODS: Data were collected from a prospectively maintained database on patients attending SBU at two tertiary referral centres (Beaumont Hospital and University College Hospital Galway) from January 2011 to 2012. Reasons for attendance, outcome of triple-assessment and incidence of malignancy were analysed. RESULTS: 14,325 patients underwent triple assessment at the SBU in this time period. 5,841 patients were referred with mastalgia, of whom 3,331 (57 %) reported mastalgia as the only symptom. The incidence of breast cancer in patients presenting with mastalgia alone was 1.2 %. All patients diagnosed with breast cancer in this cohort were over 35 years of age. CONCLUSION: The incidence of breast cancer in patients referred to SBU with mastalgia as an isolated symptom is extremely low. Patients under 35 years of age, with mastalgia as an isolated symptom do not require breast imaging and have a sufficiently low risk of breast cancer that they may be suitable for management in the primary care setting. PMID- 24402168 TI - Delineating cooperative responses of processive motors in living cells. AB - Characterizing the collective functions of cytoskeletal motors is critical to understanding mechanisms that regulate the internal organization of eukaryotic cells as well as the roles various transport defects play in human diseases. Though in vitro assays using synthetic motor complexes have generated important insights, dissecting collective motor functions within living cells still remains challenging. Here, we show that the protein heterodimerization switches FKBP rapalog-FRB can be harnessed in engineered COS-7 cells to compare the collective responses of kinesin-1 and myosinVa motors to changes in motor number and cargo size. The dependence of cargo velocities, travel distances, and position noise on these parameters suggests that multiple myosinVa motors can cooperate more productively than collections of kinesins in COS-7 cells. In contrast to observations with kinesin-1 motors, the velocities and run lengths of peroxisomes driven by multiple myosinVa motors are found to increase with increasing motor density, but are relatively insensitive to the higher loads associated with transporting large peroxisomes in the viscoelastic environment of the COS-7 cell cytoplasm. Moreover, these distinctions appear to be derived from the different sensitivities of kinesin-1 and myosinVa velocities and detachment rates to forces at the single-motor level. The collective behaviors of certain processive motors, like myosinVa, may therefore be more readily tunable and have more substantial roles in intracellular transport regulatory mechanisms compared with those of other cytoskeletal motors. PMID- 24402167 TI - The interaural time difference pathway: a comparison of spectral bandwidth and correlation sensitivity at three anatomical levels. AB - Temporal differences between the two ears are critical for spatial hearing. They can be described along axes of interaural time difference (ITD) and interaural correlation, and their processing starts in the brainstem with the convergence of monaural pathways which are tuned in frequency and which carry temporal information. In previous studies, we examined the bandwidth (BW) of frequency tuning at two stages: the auditory nerve (AN) and inferior colliculus (IC), and showed that BW depends on characteristic frequency (CF) but that there is no difference in the mean BW of these two structures when measured in a binaural, temporal framework. This suggested that there is little frequency convergence in the ITD pathway between AN and IC and that frequency selectivity determined by the cochlear filter is preserved up to the IC. Unexpectedly, we found that AN and IC neurons can be similar in CF and BW, yet responses to changes in interaural correlation in the IC were different than expected from coincidence patterns ("pseudo-binaural" responses) in the AN. To better understand this, we here examine the responses of bushy cells, which provide monaural inputs to binaural neurons. Using broadband noise, we measured BW and correlation sensitivity in the cat trapezoid body (TB), which contains the axons of bushy cells. This allowed us to compare these two metrics at three stages in the ITD pathway. We found that BWs in the TB are similar to those in the AN and IC. However, TB neurons were found to be more sensitive to changes in stimulus correlation than AN or IC neurons. This is consistent with findings that show that TB fibers are more temporally precise than AN fibers, but is surprising because it suggests that the temporal information available monaurally is not fully exploited binaurally. PMID- 24402169 TI - Sympatric incipient speciation of spiny mice Acomys at "Evolution Canyon," Israel. AB - Does the paucity of empirical evidence of sympatric speciation in nature reflect reality, despite theoretical support? Or is it due to inappropriate searches in nature with overly restrictive assumptions and an incorrect null hypothesis? Spiny mice, Acomys, described here at Evolution Canyon (EC) incipiently and sympatrically speciate owing to microclimatic interslope divergence. The opposite slopes at EC vary dramatically, physically and biotically, representing the dry and hot south-facing slope savannoid-African continent ["African" slope (AS)], abutting with the north-facing slope forested south-European continent ["European" slope (ES)]. African-originated spiny mice, of the Acomys cahirinus complex, colonized Israel 30,000 y ago based on fossils. Genotypically, we showed significantly higher genetic diversity of mtDNA and amplified fragment length polymorphism of Acomys on the AS compared with the ES. This is also true regionally across Israel. In complete mtDNA, 25% of the haplotypes at EC were slope-biased. Phenotypically, the opposite slope's populations also showed adaptive morphology, physiology, and behavior divergence paralleling regional populations across Israel. Preliminary tests indicate slope-specific mate choices. Colonization of Acomys at the EC first occurred on the AS and then moved to the ES. Strong slope-specific natural selection (both positive and negative) overrules low interslope gene flow. Both habitat slope selection and mate choices suggest ongoing incipient sympatric speciation. We conclude that Acomys at the EC is ecologically and genetically adaptively, incipiently, sympatrically speciating on the ES owing to adaptive microclimatic natural selection. PMID- 24402170 TI - Transparent p-type epitaxial thin films of nickel oxide. AB - Transparent p-type nickel oxide (NiO) thin films have been epitaxially grown on (0001) Al2O3 substrates by a chemical solution method of polymer-assisted deposition for the first time. The films have a high optical transparency of above 95% in the wavelength range of 350-900 nm. PMID- 24402171 TI - Detecting and visualizing outliers in provider profiling via funnel plots and mixed effect models. AB - In this work we propose the use of a graphical diagnostic tool (the funnel plot) to detect outliers among hospitals that treat patients affected by Acute Myocardial Infarction (AMI). We consider an application to data on AMI hospitalizations recorded in the administrative databases of our regional district. The outcome of interest is the in-hospital mortality, a variable indicating if the patient has been discharged dead or alive. We then compare the results obtained by graphical diagnostic tools with those arising from fitting parametric mixed effects models to the same data. PMID- 24402172 TI - 2.7 MUm emission of high thermally and chemically durable glasses based on AlF3. AB - AlF3-based glasses (AlF3-YF3-CaF2-BaF2-SrF2-MgF2) with enhanced thermal and chemical stability were synthesized and compared with the well-known fluorozirconate glass (ZBLAN). The 2.7 MUm mid-infrared emission in the AlF3 based glasses was also investigated through the absorption and emission spectra. Both the temperature of glass transition and the characteristic temperatures (DeltaT, Hr, k(gl)) of the fluoroaluminate glasses were much larger than those of the ZBLAN glasses. The corrosion phenomenon can be observed by naked-eye, and the transmittance dropped dramatically (0% at 3 MUm) when the ZBLAN glass was placed into distilled water. However, the AlF3-based glass was relatively stable. The fluoroaluminate glasses possessed large branching ratio (20%) along with the emission cross section (9.4*10(-21) cm(-2)) of the Er(3+):(4)I(11/2)->(4)I(13/2) transition. Meanwhile, the enhanced 2.7 MUm emission in highly Er(3+)-doped AYF glass was obtained. Therefore, these results showed that this kind of fluoride glass has a promising application for solid state lasers at 3 MUm. PMID- 24402173 TI - Analysis of lymph node dissection in patients with >=7-cm renal tumors. AB - PURPOSE: To analyze the role of lymph node dissection (LND) in patients with large renal tumors. METHODS: We performed a retrospective study of patients with renal cell carcinoma >=7 cm in size undergoing surgery between 1990 and 2012. Primary outcome measures were recurrence-free and overall survival of patients who did and did not undergo LND. Cox proportional hazards regression models were created to account for known risk factors for recurrence and survival. Secondary outcomes were recurrence-free and overall survival by lymph node status, lymph node template and number of lymph nodes removed. RESULTS: Of 524 patients, 164 had disease recurrence and 197 died. Median follow-up was 5 and 5.5 years for patients who did not die or have a recurrence, respectively. A total of 334 (64 %) patients underwent LND, and node-positive disease was identified in 26 (8 %). For patients who did and did not undergo LND, 5-year recurrence-free survival was 64 and 77 %, respectively. Five-year overall survival was 75 and 78 %, respectively. LND was not a predictor of recurrence or survival in multivariate analysis. Node-positive disease was associated with recurrence (p < 0.0005) and mortality (p = 0.032), although node-positive patients had a 5-year overall survival of 65 %. CONCLUSIONS: We did not find a difference in recurrence-free or overall survival in patients with >=7-cm tumors whether or not they underwent LND. Node-positive disease was associated with worse outcomes, suggesting that LND provides important staging information that can be important in the design of adjuvant clinical trials. PMID- 24402174 TI - Astaxanthin: sources, extraction, stability, biological activities and its commercial applications--a review. AB - There is currently much interest in biological active compounds derived from natural resources, especially compounds that can efficiently act on molecular targets, which are involved in various diseases. Astaxanthin (3,3'-dihydroxy beta, beta'-carotene-4,4'-dione) is a xanthophyll carotenoid, contained in Haematococcus pluvialis, Chlorella zofingiensis, Chlorococcum, and Phaffia rhodozyma. It accumulates up to 3.8% on the dry weight basis in H. pluvialis. Our recent published data on astaxanthin extraction, analysis, stability studies, and its biological activities results were added to this review paper. Based on our results and current literature, astaxanthin showed potential biological activity in in vitro and in vivo models. These studies emphasize the influence of astaxanthin and its beneficial effects on the metabolism in animals and humans. Bioavailability of astaxanthin in animals was enhanced after feeding Haematococcus biomass as a source of astaxanthin. Astaxanthin, used as a nutritional supplement, antioxidant and anticancer agent, prevents diabetes, cardiovascular diseases, and neurodegenerative disorders, and also stimulates immunization. Astaxanthin products are used for commercial applications in the dosage forms as tablets, capsules, syrups, oils, soft gels, creams, biomass and granulated powders. Astaxanthin patent applications are available in food, feed and nutraceutical applications. The current review provides up-to-date information on astaxanthin sources, extraction, analysis, stability, biological activities, health benefits and special attention paid to its commercial applications. PMID- 24402175 TI - Biochemical and genetic engineering of diatoms for polyunsaturated fatty acid biosynthesis. AB - The role of diatoms as a source of bioactive compounds has been recently explored. Diatom cells store a high amount of fatty acids, especially certain polyunsaturated fatty acids (PUFAs). However, many aspects of diatom metabolism and the production of PUFAs remain unclear. This review describes a number of technical strategies, such as modulation of environmental factors (temperature, light, chemical composition of culture medium) and culture methods, to influence the content of PUFAs in diatoms. Genetic engineering, a newly emerging field, also plays an important role in controlling the synthesis of fatty acids in marine microalgae. Several key points in the biosynthetic pathway of PUFAs in diatoms as well as recent progresses are also a critical part and are summarized here. PMID- 24402176 TI - Induced marine fungus Chondrostereum sp. as a means of producing new sesquiterpenoids chondrosterins I and J by using glycerol as the carbon source. AB - Chondrostereum sp., a marine fungus isolated from a soft coral Sarcophyton tortuosum, can yield hirsutane framework sesquiterpenoids. However, the metabolites profiles vary dramatically with the composition change of the culture media. This fungus was cultured in a liquid medium containing glycerol as the carbon source, and two new metabolites, chondrosterins I and J (1 and 2), were obtained. Their structures were elucidated primarily based on MS, NMR and X-ray single-crystal diffraction data. By comparison with the known hirsutane sesquiterpenoids, chondrosterins I and J have unique structural features, including a methyl was migrated from C-2 to C-6, and the methyl at C-3 was carboxylated. Compound 2 exhibited potent cytotoxic activities against the cancer cell lines CNE-1 and CNE-2 with the IC50 values of 1.32 and 0.56 MUM. PMID- 24402177 TI - Stereochemistry of complex marine natural products by quantum mechanical calculations of NMR chemical shifts: solvent and conformational effects on okadaic acid. AB - Marine organisms are an increasingly important source of novel metabolites, some of which have already inspired or become new drugs. In addition, many of these molecules show a high degree of novelty from a structural and/or pharmacological point of view. Structure determination is generally achieved by the use of a variety of spectroscopic methods, among which NMR (nuclear magnetic resonance) plays a major role and determination of the stereochemical relationships within every new molecule is generally the most challenging part in structural determination. In this communication, we have chosen okadaic acid as a model compound to perform a computational chemistry study to predict 1H and 13C NMR chemical shifts. The effect of two different solvents and conformation on the ability of DFT (density functional theory) calculations to predict the correct stereoisomer has been studied. PMID- 24402180 TI - Complex cystic lesions in the liver causing abdominal pain. PMID- 24402179 TI - Dutch-Flemish translation of 17 item banks from the patient-reported outcomes measurement information system (PROMIS). AB - BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS((r))) is a new, state-of-the-art assessment system for measuring patient reported health and well-being of adults and children that has the potential to be more valid, reliable and responsive than existing PROMs. The PROMIS items can be administered in short forms or, more efficiently, through computerized adaptive testing. This paper describes the translation of 563 items from 17 PROMIS item banks (domains) for adults from the English source into Dutch Flemish. METHODS: The translation was performed by FACITtrans using standardized methodology and approved by the PROMIS Statistical Center. The translation included four forward translations, two back-translations, three to five independent reviews (at least two Dutch, one Flemish) and pre-testing in 70 adults (age range 20-77) from the Netherlands and Flanders. RESULTS: A small number of items required separate translations for Dutch and Flemish: physical function (five items), pain behaviour (two items), pain interference (one item), social isolation (one item) and global health (one item). Challenges faced in the translation process included: scarcity or overabundance of possible translations, unclear item descriptions, constructs broader/smaller in the target language, difficulties in rank ordering items, differences in unit of measurement, irrelevant items or differences in performance of activities. By addressing these challenges, acceptable translations were obtained for all items. CONCLUSION: The methodology used and experience gained in this study can be used as an example for researchers in other countries interested in translating PROMIS. The Dutch Flemish PROMIS items are linguistically equivalent. Short forms will soon be available for use and entire item banks are ready for cross-cultural validation in the Netherlands and Flanders. PMID- 24402182 TI - Have drivers at alcohol outlets changed their behavior after the new traffic law? AB - OBJECTIVE: In an attempt to reduce high levels of traffic crashes, a new legislation was approved in Brazil in 2008. This study aimed to assess behavioral change among drivers who had drunk at alcohol outlets (AO) after implementation of the law. METHOD: A three-stage probability sampling survey was conducted in Porto Alegre, state of Rio Grande do Sul, Brazil. Individuals seen leaving AOs after drinking were approached (n=3,018). Selected drivers (n=683) answered a structured interview, were breathalyzed, and had saliva specimens collected for drug screening. RESULTS: Overall, 60.3% (SE 4.5) of drivers reported they did not change their behavior. Among those who reported behavioral changes, most reported drinking less as their main strategy toward safer driving behavior. Variables independently associated with behavior change included having drunk at a high outlet density area (odds ratio [OR] 1.7 [1.1-2.8]) and having a favorable opinion about the law (OR 4.3 [2.1-8.9]). CONCLUSIONS: Our findings suggest that awareness of the law has not been enough to promote behavioral change. As most drivers had a favorable opinion of the law and this variable was found to be the strongest predictor of behavior change, efforts to better integrate education and enforcement seem to be pivotal and might be well received by the population. PMID- 24402183 TI - A review on the evidence of transgenerational transmission of posttraumatic stress disorder vulnerability. AB - OBJECTIVE: To understand the risks of posttraumatic stress disorder (PTSD) development in the next generation of PTSD patients, we conducted a review on the biological, but not genetic, evidence of transgenerational transmission of PTSD vulnerability. METHODS: Pertinent articles published from 1985 to September 2011 were searched using online academic search engines, including MEDLINE, EMBASE, ScienceDirect, OVID, PsycLIT, and SCOPUS, and a non-systematic review was conducted. RESULTS: There is paradoxical evidence that hypothalamic-pituitary adrenal axis changes in PTSD patients may also be evident in their offspring. This effect and biological vulnerability to PTSD may be transmitted across generations through maternal epigenetic programming during pregnancy. The samples of most studies, which were not large enough and represented the outcome of few research groups, consisted of a specific type of patients with a particular trauma. CONCLUSIONS: There is still a need to conduct studies in other geographical areas with different genetic background and larger samples considering different types of trauma other than those specified in the current literature, so as to strengthen the evidence of transgenerational transmission of PTSD vulnerability. PMID- 24402184 TI - Beyond sipuleucel-T: immune approaches to treating prostate cancer. AB - OPINION STATEMENT: At present, sipuleucel-T represents the only approved immunotherapy for prostate cancer. Sipuleucel-T is an autologous cellular therapy, which primes autologous antigen-presenting cells against the prostatic acid phosphatase (PAP) antigen. For patients with metastatic castrate-resistant prostate cancer (CRPC) who are asymptomatic or minimally symptomatic, sipuleucel T monotherapy is one of the standard of care treatment options pre- or postdocetaxel. With the approval of new treatments, including abiraterone and enzatutamide, sequencing and combination of these treatments with sipuleucel-T represent unanswered questions facing the field. Whereas steroids that are coadministered with abiraterone and chemotherapy have long been thought to be immunosuppressive, early results show that concurrent abiraterone and prednisone does not significantly impact the ability to develop immune responses to this treatment. Additional clinical data are needed to elucidate optimal sequencing of therapeutic agents in CRPC. Several novel immunotherapies are currently in development, and enrollment in clinical trials should be considered. These include PROSTVAC-VF, a viral vaccine that encodes PSA and T-cell costimulatory molecules, which is currently undergoing phase III clinical trials. DNA plasmid based vaccines targeting different antigens, including PAP, also are under investigation. Immune checkpoint blockade with ipilimumab, a monoclonal antibody against CTLA-4, which is approved for metastatic melanoma, also is being evaluated. Whereas this treatment failed to show significant improvement in overall survival in CRPC patients treated with docetaxel, results from a phase III trial in the predocetaxel setting are pending. Conventional therapies for prostate cancer, such as radiation and hormonal therapy, may have immunomodulatory effects. Future areas for research include the sequencing and combination of immunotherapies as well as other conventional therapies. PMID- 24402185 TI - A collagen-based scaffold delivering exogenous microrna-29B to modulate extracellular matrix remodeling. AB - Directing appropriate extracellular matrix remodeling is a key aim of regenerative medicine strategies. Thus, antifibrotic interfering RNA (RNAi) therapy with exogenous microRNA (miR)-29B was proposed as a method to modulate extracellular matrix remodeling following cutaneous injury. It was hypothesized that delivery of miR-29B from a collagen scaffold will efficiently modulate the extracellular matrix remodeling response and reduce maladaptive remodeling such as aggressive deposition of collagen type I after injury. The release of RNA from the scaffold was assessed and its ability to silence collagen type I and collagen type III expression was evaluated in vitro. When primary fibroblasts were cultured with scaffolds doped with miR-29B, reduced levels of collagen type I and collagen type III mRNA expression were observed for up to 2 weeks of culture. When the scaffolds were applied to full thickness wounds in vivo, reduced wound contraction, improved collagen type III/I ratios and a significantly higher matrix metalloproteinase (MMP)-8: tissue inhibitor of metalloproteinase (TIMP)-1 ratio were detected when the scaffolds were functionalized with miR-29B. Furthermore, these effects were significantly influenced by the dose of miR-29B in the collagen scaffold (0.5 versus 5 MUg). This study shows a potential of combining exogenous miRs with collagen scaffolds to improve extracellular matrix remodeling following injury. PMID- 24402186 TI - The inflammatory cellular constituents of foetal and infant leptomeninges: a survey of hospital-based autopsies without trauma. AB - OBJECTIVES: Notwithstanding the lack of definitive evidence from studies conducted to date, inflammatory infiltrates and iron deposition in the leptomeninges are routinely used as forensic markers of traumatic brain injury. We investigated the presence of these forensic markers of trauma in neonates and infants, with the objective of determining their suitability for use in forensic cases. METHODS: Leptomeninges derived from non-traumatic deaths were studied. Thirty-three cases were divided into groups 1 and 2, according to set age groups. Inflammatory cells and iron in these groups were quantified. RESULTS: CD45, CD68 and CD163 positive inflammatory cells were identified in the leptomeninges of sections of the cerebellum, brain stem and cortex of all 33 cases of non traumatic infant deaths surveyed in this study. There were no significant differences between the two groups. Iron was found in the leptomeninges in several cases, even those without recent haemorrhage. Overall within the two subgroups, the numbers of inflammatory cells and iron containing cells were not significantly different. CONCLUSION: These findings demonstrate that inflammatory cells and iron in the leptomeninges can be found in natural and non-traumatic conditions. Further, two cases with no reported neuropathology demonstrated the presence of inflammatory cells and iron. Thus, cautious interpretation of the presence of inflammatory cells and iron containing cells in forensic paediatric cases is recommended. PMID- 24402187 TI - Nanoscopic polypyrrole AFM-SECM probes enabling force measurements under potential control. AB - Conductive polymers, and in particular polypyrrole, are frequently used as biomimetic interfaces facilitating growth and/or differentiation of cells and tissues. Hence, studying forces and local interactions between such polymer interfaces and cells at the nanoscale is of particular interest. Frequently, such force interactions are not directly accessible with high spatial resolution. Consequently, we have developed nanoscopic polypyrrole electrodes, which are integrated in AFM-SECM probes. Bifunctional AFM-SECM probes were modified via ion beam-induced deposition resulting in pyramidal conductive Pt-C composite electrodes. These nanoscopic electrodes then enabled localized polypyrrole deposition, thus resulting in polymer-modified AFM probes with a well-defined geometry. Furthermore, such probes may be reversibly switched from an insulating to a conductive state. In addition, the hydrophilicity of such polymer tips is dependent on the dopant, and hence, on the oxidation state. Force studies applying different tip potentials were performed at plasma-treated glass surfaces providing localized information on the associated force interactions, which are dependent on the applied potential and the dopant. PMID- 24402188 TI - Synthesis of squaraine dyes under mild conditions: applications for labelling and sensing of biomolecules. AB - We report the synthesis of squaraine dyes under mild conditions by carbodiimide activation of squaric acid or semi-squaraine dyes. Despite low yields when the reaction was carried out in solution, these conditions were successfully applied to efficient peptide labelling on resin and nucleic acid sensing in solution. PMID- 24402189 TI - Efficient photocatalytic hydrogen generation from water by a cationic cobalt(II) porphyrin. AB - Efficient photocatalytic hydrogen evolution is obtained from 1 M phosphate buffer at pH 7 in the presence of a Ru(bpy)3(2+) sensitizer, an ascorbic acid sacrificial donor, and a water-soluble Co(II) porphyrin catalyst. Spectroscopic investigation of the system by stationary and time-resolved techniques enables a complete characterization of the photoinduced dynamics. PMID- 24402190 TI - Truth and consequences: it's not a game anymore. PMID- 24402191 TI - The anthropomorphic mouse. PMID- 24402192 TI - TWIST1 and SNAI1 as markers of poor prognosis in human colorectal cancer are associated with the expression of ALDH1 and TGF-beta1. AB - Epithelial-mesenchymal transition (EMT) is an important factor in cancer invasiveness and metastatic progression. During EMT, cancer cells acquire stem cell properties. The role of EMT and stemness in colon cancer has not been fully understood. We aimed to demonstrate the clinical significance of EMT and the stem cell phenotype in colorectal cancer. Two hundred and thirty-one surgically resected colon cancer cases were included in the present study. mRNAs of E cadherin, TWIST1 and SNAI1 were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) (n=109). Immunohistochemical staining was performed for six markers (ALDH1, TGF-beta1, E-cadherin, beta-catenin, TWSIT1 and SNAI1) (n=231). We assessed clinicopathological characteristics according to the expression of the stem cell phenotype and EMT markers. Based on the results of qRT-PCR, TWIST1 and SNAI1 significantly influenced node metastasis (P=0.04 and P=0.02, respectively). High TWIST1 and SNAI1 mRNA expression was associated with poor overall survival according to the univariate analysis (P<0.01 and P=0.01, respectively) and the multivariate analysis (P=0.04 and P=0.04, respectively). ALDH1 expression as detected by immunohistochemical staining was associated with high nodal stage, advanced clinical stage, lymphatic invasion and poor survival (P=0.01, P=0.04, P<0.05 and P<0.01, respectively) and with the expression of TGF beta1 and beta-catenin. In conclusion, in human colorectal cancer, the EMT markers TWIST1 and SNAI1 are suggested as important markers of poor prognosis. Their expression is associated with the expression of putative stem cell marker ALDH1, and ALDH1 is associated with the expression of TGF-beta1. PMID- 24402193 TI - Circadian variation in the effect of intravenous thrombolysis after non-lacunar stroke. AB - The onset of non-lacunar stroke symptoms has a circadian variation, with a higher risk in the early morning hours and lower risk during the nighttime period, but this circadian distribution has not been clearly established on the effect of intravenous (IV) thrombolysis. The aim of the present study was to assess whether the time interval based on time of Alteplase IV infusion may influence the effect of treatment in patients with non-lacunar stroke. We conducted an analysis on prospectively collected data of 476 non-lacunar stroke patients treated with IV thrombolysis. To identify a possible circadian variation in the effect of Alteplase IV infusion, we used the following outcome measures: major neurological improvement (NIH stroke scale [NIHSS] score decrease of <=8 points from baseline or NIHSS score of 0 at 24 h), and hemorrhagic transformation according to European Cooperative Acute Stroke Study trial definition within 24 h. Multivariate analysis showed that ORs for major neurological improvement were lower in patients who started IV thrombolysis in the 6 AM-noon interval (OR 0.35, 95% CI 0.16-0.74, p = 0.006) and noon-6 PM interval (OR 0.40, 95% CI 0.20-0.81, p = 0.010), whereas ORs for hemorrhagic transformation were lower in patients who started IV thrombolysis in the noon-6 PM interval (OR 0.29, 95% CI 0.12-0.67, p = 0.004) and in the 6 PM-midnight interval (OR 0.26, 95% CI 0.11-0.62, p = 0.002), compared with midnight-6 AM interval. The effect of Alteplase IV infusion could show a circadian variation in patients with non-lacunar stroke. After comparison with the midnight-6 AM interval, thrombolysis could be more safe from noon to midnight, and less effective from 6 AM to 6 PM. PMID- 24402194 TI - Efficacy and safety of rivaroxaban versus low-molecular-weight heparin therapy in patients with lower limb fractures. AB - Thromboprophylaxis with rivaroxaban has proved effective and safe in patients undergoing hip and knee replacement surgery. As it is unclear whether it is also effective and safe in fracture patients, the aim of the present study was to evaluate the efficacy and safety of rivaroxaban in patients with lower limb fractures. We performed a retrospective cohort study of 2,050 consecutive patients treated for lower limb fractures at our trauma center, comparing rates of venous thromboembolism (VTE), bleeding and surgical complications, and the length of hospital stay for 608 patients who received rivaroxaban and 717 who received a low-molecular-weight heparin (LMWH). Rates of symptomatic VTE were 4.9 and 8.6% in the rivaroxaban and LMWH groups, respectively (p = 0.008), and distal VTE rates were 1.8 and 5.7%, respectively (p = 0.036). The incidence of major bleeding events in the rivaroxaban group was also lower than in the LMWH group (0.2 vs 0.6%), but the difference between the groups was not statistically significant. The mean length of hospital stay was significantly shorter in the rivaroxaban group (12.2 vs 13.1 days, respectively; p = 0.016). This retrospective cohort study is the first report documenting the efficacy and safety of rivaroxaban in patients with lower extremity fractures. In comparison with LMWH, rivaroxaban reduced the incidence of VTE by 45% without increasing the risk of bleeding. However, prospective, randomized controlled trials comparing rivaroxaban and LMWH are needed to confirm our findings. PMID- 24402195 TI - Transforming growth factor (TGF)-beta levels and unprovoked recurrent venous thromboembolism. AB - Prediction of recurrence in patients with unprovoked venous thromboembolism (VTE) remains a challenge. Studies of atherosclerosis suggest a protective role of transforming growth factor (TGF)-beta. However, the role of TGF-beta has not been studied in VTE. The aim of this study was to investigate TGF-beta as a predictive marker of recurrent VTE in patients with a first episode of unprovoked VTE. Patients in the Malmo Thrombophilia Study (MATS) were followed after the discontinuation of anticoagulant treatment until the diagnosis of recurrent VTE or the end of the study in December 2008 (mean +/- SD 38.5 months +/- 27). Among patients with a first episode of unprovoked VTE, we identified 42 patients with recurrent VTE during the follow-up period. Two age- and sex-matched control subjects without recurrent VTE were selected for each patient (n = 84). Plasma levels of the three isoforms of TGF-beta (TGF-beta1, TGF-beta2 and TGF-beta3) were quantified simultaneously by TGF-beta 3-plex immunoassay. Compared to controls, plasma levels of TGF-beta1 and TGF-beta2 were significantly lower in patients with recurrent VTE (p < 0.05), whereas no difference was found for TGF beta3. In a multivariate Cox regression analyses, adjusted for inherited thrombophilia, age, sex and BMI, low levels of TGF-beta1 [hazard ratio (HR) = 2.2, 95% confidence interval (CI) 1.1-4.3; p = 0.02] and TGF-beta2 (HR = 2.4, 95% CI 1.2-4.7; p = 0.01) were independently associated with a higher risk of recurrent VTE. We propose TGF-beta1 and TGF-beta2 as potential predictive markers for recurrence in patients with unprovoked VTE. PMID- 24402196 TI - Transition metal complexes and radical anion salts of 1,10-phenanthroline derivatives annulated with a 1,2,5-tiadiazole and 1,2,5-tiadiazole 1,1-dioxide moiety: multidimensional crystal structures and various magnetic properties. AB - Advances in the molecular variety and the elucidation of the physical properties of 1,10-phenanthroline annulated with 1,2,5-thiadiazole and 1,2,5-thiadiazole 1,1 dioxide moieties have been achieved, and are described herein. A 1,2,5 thiadiazole compound, [1,2,5]thiadiazolo[3,4-f][1,10]phenanthroline (tdap), was used as a ligand to create multidimensional network structures based on S***S and S***N intermolecular interactions. A 1,2,5-thiadiazole 1,1-dioxide compound, [1,2,5] thiadiazolo[3,4-f][1,10]phenanthroline, 1,1-dioxide (tdapO2), was designed to create a stable radical anion, as well as good network structures. Single crystal X-ray structure analyses revealed that transition metal complexes of tdap, and radical anion salts of tdapO2 formed multidimensional network structures, as expected. Two kinds of tdap iron complexes, namely [Fe(tdap)2(NCS)2] and [Fe(tdap)2(NCS)2]*MeCN exhibited spin crossover transitions, and their transition temperatures showed a difference of 150 K, despite their similar molecular structures. Magnetic measurements for the tdapO2 radical anion salts revealed that the magnetic coupling constants between neighboring radical species vary from strongly antiferromagnetic (J=-320 K) to ferromagnetic (J=24 K), reflecting the differences in their pi overlap motifs. PMID- 24402197 TI - Toxicity assessments of chalcone and some synthetic chalcone analogues in a zebrafish model. AB - The aim of this study was to investigate the in vivo toxicities of some novel synthetic chalcones. Chalcone and four chalcone analogues 1a-d were evaluated using zebrafish embryos following antibody staining to visualize their morphological changes and muscle fiber alignment. Results showed that embryos treated with 3'-hydroxychalcone (compound 1b) displayed a high percentage of muscle defects (96.6%), especially myofibril misalignment. Ultrastructural analysis revealed that compound 1b-treated embryos displayed many muscle defect phenotypes, including breakage and collapse of myofibrils, reduced cell numbers, and disorganized thick (myosin) and thin (actin) filaments. Taken together, our results provide in vivo evidence of the myotoxic effects of the synthesized chalcone analogues on developing zebrafish embryos. PMID- 24402198 TI - N-substituted 5-amino-6-methylpyrazine-2,3-dicarbonitriles: microwave-assisted synthesis and biological properties. AB - In this work a series of 15 N-benzylamine substituted 5-amino-6-methyl-pyrazine 2,3-dicarbonitriles was prepared by the aminodehalogenation reactions using microwave assisted synthesis with experimentally set and proven conditions. This approach for the aminodehalogenation reaction was chosen due to its higher yields and shorter reaction times. The products of this reaction were characterized by IR, NMR and other analytical data. The compounds were evaluated for their antibacterial, antifungal and herbicidal activity. Compounds 3 (R=3,4-Cl), 9 (R=2 Cl) and 11 (R=4-CF3) showed good antimycobacterial activity against Mycobacterium tuberculosis (MIC=6.25 ug/mL). It was found that the lipophilicity is important for antimycobacterial activity and the best substitution on the benzyl moiety of the compounds is a halogen or trifluoromethyl group according to Craig's plot. The activities against bacteria or fungi were insignificant. The presented compounds also inhibited photosynthetic electron transport in spinach chloroplasts and the IC50 values of the active compounds varied in the range from 16.4 to 487.0 umol/L. The most active substances were 2 (R=3-CF3), 3 (R=3,4-Cl) and 11 (R=4-CF3). A linear dependence between lipophilicity and herbicidal activity was observed. PMID- 24402199 TI - A STD-NMR study of the interaction of the Anabaena ferredoxin-NADP+ reductase with the coenzyme. AB - Ferredoxin-NADP+ reductase (FNR) catalyzes the electron transfer from ferredoxin to NADP+ via its flavin FAD cofactor. To get further insights in the architecture of the transient complexes produced during the hydride transfer event between the enzyme and the NADP+ coenzyme we have applied NMR spectroscopy using Saturation Transfer Difference (STD) techniques to analyze the interaction between FNRox and the oxidized state of its NADP+ coenzyme. We have found that STD NMR, together with the use of selected mutations on FNR and of the non-FNR reacting coenzyme analogue NAD+, are appropriate tools to provide further information about the the interaction epitope. PMID- 24402200 TI - Study on the mechanism of intestinal absorption of epimedins a, B and C in the Caco-2 cell model. AB - Epimedium spp. is commonly used in Traditional Chinese Medicine. Epimedins A, B, and C are three major bioactive flavonoids found in Epimedium spp. that share similar chemical structures. In this study, the intestinal absorption mechanism of these three compounds was investigated using the Caco-2 cell monolayer model in both the apical-to-basolateral (A-B) and the basolateral-to-apical (B-A) direction. The absorption permeability (PAB) of epimedins A, B, and C were extremely low and increased as the concentration of the epimedins increased from 5 to 20 MUM, but, at 40 MUM, the PAB values were reduced. Meanwhile, the amount of transported compounds increased in a time-dependent manner. The PAB of epimedins A and C were significantly increased and efflux ratios decreased in the presence of verapamil (an inhibitor of P-glycoprotein) and dipyridamole (an inhibitor of breast cancer resistance protein) while, in the presence of MK571 (an inhibitor of multidrug resistance proteins), the absorption of epimedins A and C did not change significantly, indicating that P-gp and BCRP might be involved in the transport of epimedins A and C. The PAB of epimedin B significantly increased while its secretory permeability (PBA) significantly decreased in the presence of dipyridamole, indicating that BCRP might be involved in the transport of epimedin B. No obvious changes in the transport of epimedin B were observed in the presence of verapamil and MK571. In summary, our results clearly demonstrate, for the first time, that poor bioavailability of these three prenylated flavonoids is the result of poor intrinsic permeability and efflux by apical efflux transporters. PMID- 24402201 TI - Magnetically separable and recyclable Fe3O4-supported Ag nanocatalysts for reduction of nitro compounds and selective hydration of nitriles to amides in water. AB - As hybrid nanostructures have become more important in many fields of chemistry, Ag nanoparticles (NPs) are being increasingly immobilized onto Fe3O4 microspheres in situ. Structural characterization reveals that the Ag NPs are uniformly immobilized in the Fe3O4 microsphere-based supports. Moreover, Ag NPs are more stable in the hybrid structure than in the naked state and show high catalytic activity for the reduction of nitro compounds and hydration of nitriles to amides in water. The Fe3O4 microspheres were recycled several times using an external magnet. PMID- 24402202 TI - Trifolium pratense L. as a potential natural antioxidant. AB - The essential oils of three different growth stages of Trifolium pratense L. (TP1, TP2 and TP3) were investigated by gas chromatography-mass spectrometry and tested for their antioxidant and antimicrobial activities. The highest content of volatile compounds was found in the essential oil sample TP1, where terpenes such as beta-myrcene (4.55%), p-cymene (3.59%), limonene (0.86%), tetrahydroionone (1.56%) were highlighted due to their biological activity. The antioxidant activity was determined by following the scavenging capacity of the essential oils for the free radicals DPPH., NO. and O2.-, as well as effects of the investigated oils on lipid peroxidation (LP). In all three cases, the sample TP1 showed the best radical-capturing capacity for DPPH. (27.61+/-0.12 ug/mL), NO. (16.03+/-0.11 ug/mL), O2.- (16.62+/-0.29 ug/mL) and also had the best lipid peroxidation effects in the Fe2+/ascorbate induction system (9.35+/-0.11 ug/mL). Antimicrobial activity was evaluated against the following bacteria cultures: Escherichia coli (ATCC10526), Salmonella typhimurium (ATCC 14028), Staphylococcus aureus (ATCC 11632) and Bacillus cereus (ATCC 10876). None of the examined essential oil samples showed inhibitory effects on the tested bacterial strains. PMID- 24402203 TI - Novelty detection is enhanced when attention is otherwise engaged: an event related potential study. AB - Novel stimuli are detected and evaluated quickly, suggesting that processing them is a priority for the brain. In the present study, the effects of attention on this early visual novelty processing were investigated in two experiments using the event-related potential (ERP) technique. In the first experiment, participants performed two tasks that varied in the amount of attention available for novel stimuli. In the Visual Oddball task, participants responded to an infrequent target presented among standard and novel stimuli. In the Working Memory task, participants saw the same stimuli, but they could ignore them. Instead, participants had to keep six letters in working memory and report one of these letters at the end of the trial; attention was thus maximally allocated away from the visual oddball stimuli. In line with attention being fully occupied in the Working Memory task, the P3a to the visual oddball stimuli was smaller in the Working Memory than in the Visual Oddball task. In contrast, the anterior N2 component to task-irrelevant stimuli was enhanced in the Working Memory task. These findings suggest that the initial detection of novel stimuli is enhanced (large anterior N2) when few attentional resources are available, which is inconsistent with earlier findings that if anything, the N2 is enhanced by attention. In a second experiment, a condition was added in which working memory load was low, but visual oddball stimuli were task-irrelevant. Results from this experiment showed that while the reduction in P3a amplitude was due to task irrelevance, the enhanced anterior N2 was linked to a high working memory load. This suggests that novelty detection is enhanced when attention is otherwise engaged. PMID- 24402204 TI - Bi(x)La(1-x)VO4 solid solutions: tuning of electronic properties via stoichiometry modifications. AB - BixLa1-xVO4 solid solutions were obtained in the form of fine powder via a microwave-assisted hydrothermal route. The presence of a solid solution in the studied system was confirmed using X-ray diffraction (XRD) and optical spectroscopy techniques. Pure BiVO4 and LaVO4 were obtained in the monoclinic form, whereas solid solutions in the tetragonal, zircon-type structure. The optical band gap dependence on the composition of the solid solution is parabolic, thus there is a possibility to tune this parameter in a wide concentration range, from 2.4 to 4.0 eV. An absorption coefficient maximum is also concentration-dependent, possibly, due to the structural disorder of the samples. Solid solutions with Bi(3+) concentration between 11.94 and 32.57 at.% exhibit intense, green luminescence. This indicates the presence of Bi-originated electronic states within the band gap. The value of the conduction band edge potential, measured by both electrochemical impedance spectroscopy and work function measurements, is concentration-independent. Moreover, solid solutions exhibit a photoelectrochemical photocurrent switching effect, thus they may be promising materials for molecular electronics and as dioxygen activators. PMID- 24402205 TI - Evolutionary significance of the role of family units in a broader social system. AB - Indirect benefits to individual fitness in social species can be influenced by a variety of behavioral factors. Behaviors which support the fitness of kin provide indirect benefits in the form of evolutionary success of relatives. Further, individuals may obtain additional indirect benefits via participation in a well organized social environment. Building on previous models of selfishly-motivated self-organizing societies, we explore the evolutionary trade-off between inclusion and maintenance of family groups and the ability of a population to sustain a well-organized social structure. Our results demonstrate that the interactions between Hamiltonian and organizationally-based indirect benefits to individual fitness interact to favor certain types of social affiliation traits. Conversely, we show how particular types of social affiliation dynamics may provide selective pressures to limit the size of behaviorally-defined familial groups. We present the first studies of the evolution of social complexity differentiating affiliation behavior between kin and non-kin. PMID- 24402207 TI - Outcome predictors of smoking cessation treatment provided by an addiction care unit between 2007 and 2010. AB - OBJECTIVE: To analyze the predictors of smoking cessation treatment outcomes in a sample with a high rate of medical and psychiatric disorders and addictions. METHODS: Analysis of predictors of success of a 6-week treatment provided by an addiction care unit (CAPS-AD) to 367 smokers in Brazil from 2007 to 2010. Forty variables were collected at baseline. Success was defined as abstinence from smoking for a period of at least 14 consecutive days, including the last day of treatment. Twenty variables were selected for the logistic regression model. RESULTS: The only condition correlated with successful treatment after logistic regression was smoking one's first cigarette 5 minutes or more after waking (beta = 1.85, 95% confidence interval [95%CI] = 1.11-3.10, p = 0.018). Subjects with hypertension and alcohol use disorders and those who were undergoing psychiatric treatment showed success rates comparable to or greater than the average success rate of the sample (34.2-44.4%). CONCLUSIONS: These findings support the importance of the variable time to first cigarette in treatment outcomes for a sample with a high rate of clinical and psychiatric disorders. Good success rates were observed for pharmacological treatment, which was combined with group therapy based on cognitive-behavioral concepts and integrated into ongoing treatment of other addictions and psychiatric disorders. PMID- 24402208 TI - Anxiety disorders in young people: a population-based study. AB - OBJECTIVE: To assess the prevalence of anxiety disorders and associated factors in young adults. METHODS: Cross-sectional population-based study of individuals between the ages of 18 and 24 years randomly selected from 89 census-based sectors to ensure an adequate sample size. Household selection within the sectors was performed according to a systematic sampling process. Anxiety disorders were assessed using the Mini International Neuropsychiatric Interview (MINI). The final sample comprised 1,560 young adults. RESULTS: Of the participants who were diagnosed with anxiety disorders, 12.3% had agoraphobia, 9.7% had generalised anxiety disorder, 4.0% had social phobia, 3.3% had obsessive-compulsive disorder, 2.5% had panic disorder, and 2.1% had post-traumatic stress disorder; only 23.8% had received any previous treatment. Anxiety disorders were associated with sex, socioeconomic status, psychiatric problems in parents, alcohol abuse, and tobacco use. CONCLUSIONS: The identification of factors associated with anxiety disorders in young people enables us to develop intervention strategies. Anxiety disorders are not only highly prevalent but are also associated with significant functional impairment, significant reductions in quality of life, lower productivity, and higher rates of comorbidities. PMID- 24402209 TI - Depression during gestation in adolescent mothers interferes with neonatal neurobehavior. AB - OBJECTIVE: To compare the neurobehavior of neonates born to adolescent mothers with and without depression during gestation. METHODS: This prospective cross sectional study included healthy term neonates born to adolescent mothers with untreated depression during gestation, without exposure to legal or illicit drugs, and compared them with infants born to adolescent mothers without psychiatric disorders. Maternal psychiatric diagnoses were assessed by the Composite International Diagnostic Interview (CIDI 2.1) and neonatal neurobehavior by the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS) at 24 to 72 hours of life. Neurobehavioral outcomes were analyzed by ANOVA adjusted for confounders. RESULTS: 37 infants born to mothers with depression during gestation were compared to 332 infants born to mothers without psychiatric disorders. Infants of mothers with depression had smaller head circumferences. Significant interactions of maternal depression and male gender, gestational age > 40 weeks, regional anesthesia during delivery, vaginal delivery, and infant head circumference >= 34 cm were found. Worse performance was noted in the following neonatal neurobehavioral parameters: arousal, excitability, lethargy, hypotonicity, and signs of stress and abstinence. CONCLUSION: Infants born to adolescent mothers with depression exhibit some behavioral changes in the first days of life. These changes are associated with infant sex, gestational age, type of anesthesia, mode of delivery, and head circumference. PMID- 24402210 TI - The time has come to stop rotations for the identification of structures in the Hamilton Depression Scale (HAM-D17). AB - OBJECTIVE: To use principal component analysis (PCA) to test the hypothesis that the items of the Hamilton Depression Scale (HAM-D17) have been selected to reflect depression disability, whereas some of the items are specific for sub typing depression into typical vs. atypical depression. METHOD: Our previous study using exploratory factor analysis on HAM-D17 has been re-analyzed with PCA and the results have been compared to a dataset from another randomized prospective study. RESULTS: PCA showed that the first principal component was a general factor covering depression disability with factor loadings very similar to those obtained in the STAR*D study. The second principal component was a bi directional factor contrasting typical vs. atypical depression symptoms. Varimax rotation gave no new insight into the factor structure of HAM-D17. CONCLUSION: With scales like the HAM-D17, it is very important to make a proper clinical interpretation of the PCA before attempting any form of exploratory factor analysis. For the HAM-D17, our results indicate that profile scores are needed because the total score of all 17 items in the HAM-D17 does not give sufficient information. PMID- 24402211 TI - Quality of life in adolescents with obsessive-compulsive disorder. AB - OBJECTIVE: To compare adolescents with and without obsessive-compulsive disorder (OCD) with regard to quality of life and to investigate the association between quality of life and clinical characteristics. METHODS: Participants were recruited from an epidemiological study conducted at high schools in the city of Porto Alegre, southern Brazil. The sample comprised 75 adolescents with OCD and 150 without the disorder, aged between 14 and 18 years. Participants were assessed using the following instruments: Schedule for Affective Disorders and Schizophrenia for School Aged Children - Present and Lifetime Version (K-SADS PL), Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), World Health Organization Quality of Life Assessment - Abbreviated Version (WHOQOL-BREF), Beck Anxiety Inventory (BAI), and Beck Depressive Inventory - II (BDI-II). RESULTS: The two groups showed significant differences in relation to depression symptoms, anxiety symptoms, and quality of life (all domains), with a poorer performance among adolescents with OCD when compared to those without the disorder. Stepwise regression analysis revealed a significant association between BDI-II scores and quality of life, in all domains. CONCLUSIONS: Our findings suggest that adolescents with OCD, especially those with depression symptoms, have a poorer quality of life when compared with adolescents without OCD. PMID- 24402212 TI - Expression of matrix metalloproteinases in patients with bipolar disorder. AB - OBJECTIVE: High cardiovascular mortality rates have been reported in patients with bipolar disorder (BD). Studies indicate that matrix metalloproteinases (MMPs) are implicated in cardiovascular diseases. We evaluated the expression pattern of MMP-2 and MMP-9 in blood from patients with BD during acute mania and after euthymia, in comparison with healthy controls. METHODS: Twenty patients and 20 controls were recruited and matched for sex and age. MMP messenger RNA (mRNA) levels were measured using real-time quantitative polymerase chain reaction (PCR). Body mass index (BMI) was calculated for all subjects. RESULTS: There were no significant differences in MMP-2 and MMP-9 mRNA expression between patients and controls. mRNA levels were not significantly different during mania and euthymia. However, MMP-2 mRNA levels were negatively associated with BMI in BD patients and positively associated with BMI in controls. There was no difference in the pattern of MMP-9 expression between patients and controls. CONCLUSIONS: Our results suggest a different pattern of association between MMP-2 and BMI in BD patients as compared with controls. Despite some study limitations, we believe that the role of MMPs in BD should be further investigated to elucidate its relationship with cardiovascular risk. PMID- 24402213 TI - Acute and chronic administration of cannabidiol increases mitochondrial complex and creatine kinase activity in the rat brain. AB - OBJECTIVE: To investigate the effects of cannabidiol (CBD) on mitochondrial complex and creatine kinase (CK) activity in the rat brain using spectrophotometry. METHOD: Male adult Wistar rats were given intraperitoneal injections of vehicle or CBD (15, 30, or 60 mg/kg) in an acute (single dose) or chronic (once daily for 14 consecutive days) regimen. The activities of mitochondrial complexes and CK were measured in the hippocampus, striatum, and prefrontal cortex. RESULTS: Both acute and chronic injection of CBD increased the activity of the mitochondrial complexes (I, II, II-III, and IV) and CK in the rat brain. CONCLUSIONS: Considering that metabolism impairment is certainly involved in the pathophysiology of mood disorders, the modulation of energy metabolism (e.g., by increased mitochondrial complex and CK activity) by CBD could be an important mechanism implicated in the action of CBD. PMID- 24402214 TI - Amitriptyline, clomipramine, and maprotiline attenuate the inflammatory response by inhibiting neutrophil migration and mast cell degranulation. AB - OBJECTIVE: Despite the recognized anti-inflammatory potential of heterocyclic antidepressants, the mechanisms concerning their modulating effects are not completely known. Thus, we evaluated the anti-inflammatory effect of amitriptyline, clomipramine, and maprotiline and the possible modulating properties of these drugs on neutrophil migration and mast cell degranulation. METHODS: The hind paw edema and air-pouch models of inflammation were used. Male Wistar rats were treated with saline, amitriptyline, clomipramine or maprotiline (10, 30, or 90 mg/kg, per os [p.o.]) 1 h before the injection of carrageenan (300 MUg/0.1 mL/paw) or dextran (500 MUg/0.1 mL/paw). Then, edema formation was measured hourly. Neutrophil migration to carrageenan (500 MUg/pouch) and N-formyl methionyl-leucyl-phenylalanine (fMLP) (10-6 M/mL/pouch) was also investigated in 6-day-old air-pouch cavities. Compound 48/80-induced mast cell degranulation was assessed in the mesenteric tissues of antidepressant-treated rats. RESULTS: All tested antidepressants prevented both carrageenan- and dextran-induced edema. The anti-inflammatory effect of these drugs partially depends on the modulation of neutrophil migration, since they significantly counteracted the chemotactic response of both carrageenan and fMLP (p < 0.01). Furthermore, amitriptyline, clomipramine and maprotiline inhibited compound 48/80-induced mast cell degranulation (p < 0.001). CONCLUSIONS: These results suggest an important anti inflammatory role of heterocyclic antidepressants, which is dependent on the modulation of neutrophil migration and mast cell stabilization. PMID- 24402215 TI - Pharmacotherapy of bipolar disorder in children and adolescents: an update. AB - OBJECTIVE: To review the options for acute and maintenance pharmacological treatment of bipolar disorder in children and adolescents, including the treatment of bipolar depression and comorbid attention deficit/hyperactivity disorder (ADHD). METHODS: Narrative review of randomized clinical trials and open label studies published from 2000 to 2012. The PubMed and PsycINFO websites were queried. Case series were included when a higher level of evidence was not available. RESULTS: Published data from randomized controlled trials (RCTs) in acute mania/hypomania with significant responses are available for lithium, topiramate, risperidone, olanzapine, and aripiprazole. Open trials of lithium and lamotrigine show that these drugs may be effective in the treatment of depressive episodes. No trials of selective serotonin reuptake inhibitors (SSRIs) have been conducted. In the treatment of comorbid ADHD, there are encouraging findings with mixed amphetamine salts and atomoxetine; conflicting results are observed with methylphenidate. CONCLUSIONS: Published RCTs of traditional mood stabilizers are scarce, but the best available evidence (results from meta-analytic regression) suggests that second-generation antipsychotics (SGAs) as a group are more effective in reducing manic symptoms. Risperidone was the only one included in head-to-head comparisons (vs. lithium and divalproex), showing superiority in terms of efficacy, but with more metabolic side effects, which were also more common in most of the SGAs. There are few studies addressing the treatment of ADHD and depression. Brazilian guidelines for the treatment of pediatric bipolar disorder should also include some SGAs (especially risperidone and aripiprazole) as first-line treatment, and these drugs should be provided by the public health services. PMID- 24402216 TI - Brazilian Medical Association guidelines for the diagnosis and differential diagnosis of panic disorder. AB - OBJECTIVE: To present the most relevant findings regarding the Brazilian Medical Association guidelines for the diagnosis and differential diagnosis of panic disorder. METHODS: We used the methodology proposed by the Brazilian Medical Association for the Diretrizes Project. The MEDLINE (PubMed), Scopus, Web of Science, and LILACS online databases were queried for articles published from 1980 to 2012. Searchable questions were structured using the PICO format (acronym for "patient" [or population], "intervention" [or exposure], "comparison" [or control], and "outcome"). RESULTS: We present data on clinical manifestations and implications of panic disorder and its association with depression, drug abuse, dependence and anxiety disorders. In addition, discussions were held on the main psychiatric and clinical differential diagnoses. CONCLUSIONS: The guidelines are proposed to serve as a reference for the general practitioner and specialist to assist in and facilitate the diagnosis of panic disorder. PMID- 24402217 TI - Psychometric properties of the Beck Depression Inventory-II: a comprehensive review. AB - OBJECTIVE: To review the psychometric properties of the Beck Depression Inventory II (BDI-II) as a self-report measure of depression in a variety of settings and populations. METHODS: Relevant studies of the BDI-II were retrieved through a search of electronic databases, a hand search, and contact with authors. Retained studies (k = 118) were allocated into three groups: non-clinical, psychiatric/institutionalized, and medical samples. RESULTS: The internal consistency was described as around 0.9 and the retest reliability ranged from 0.73 to 0.96. The correlation between BDI-II and the Beck Depression Inventory (BDI-I) was high and substantial overlap with measures of depression and anxiety was reported. The criterion-based validity showed good sensitivity and specificity for detecting depression in comparison to the adopted gold standard. However, the cutoff score to screen for depression varied according to the type of sample. Factor analysis showed a robust dimension of general depression composed by two constructs: cognitive-affective and somatic-vegetative. CONCLUSIONS: The BDI-II is a relevant psychometric instrument, showing high reliability, capacity to discriminate between depressed and non-depressed subjects, and improved concurrent, content, and structural validity. Based on available psychometric evidence, the BDI-II can be viewed as a cost-effective questionnaire for measuring the severity of depression, with broad applicability for research and clinical practice worldwide. PMID- 24402218 TI - Is disorganized schizophrenia a predictor of treatment resistance? Evidence from an observational study. AB - OBJECTIVE: To investigate whether inpatients with disorganized schizophrenia are more resistant to treatment. METHOD: Eighty-five inpatients were assessed at admission and at discharge for schizophrenia subtype, symptom severity, and treatment resistance criteria. RESULTS: Disorganized patients were significantly more treatment-resistant than paranoid patients (60%, p = 0.001), and presented worse scores on the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale (CGI-S), and the Global Assessment of Functioning Scale (GAF) (p < 0.001). Although the difference was not significant, 80% of treatment resistant patients with disorganized schizophrenia responded to clozapine. CONCLUSION: Patients with the disorganized subtype of schizophrenia should benefit from clozapine as a second-line agent. PMID- 24402219 TI - Deficits in recognition, identification, and discrimination of facial emotions in patients with bipolar disorder. AB - OBJECTIVE: To analyze the recognition, identification, and discrimination of facial emotions in a sample of outpatients with bipolar disorder (BD). METHODS: Forty-four outpatients with diagnosis of BD and 48 matched control subjects were selected. Both groups were assessed with tests for recognition (Emotion Recognition-40 - ER40), identification (Facial Emotion Identification Test - FEIT), and discrimination (Facial Emotion Discrimination Test - FEDT) of facial emotions, as well as a theory of mind (ToM) verbal test (Hinting Task). Differences between groups were analyzed, controlling the influence of mild depressive and manic symptoms. RESULTS: Patients with BD scored significantly lower than controls on recognition (ER40), identification (FEIT), and discrimination (FEDT) of emotions. Regarding the verbal measure of ToM, a lower score was also observed in patients compared to controls. Patients with mild syndromal depressive symptoms obtained outcomes similar to patients in euthymia. A significant correlation between FEDT scores and global functioning (measured by the Functioning Assessment Short Test, FAST) was found. CONCLUSIONS: These results suggest that, even in euthymia, patients with BD experience deficits in recognition, identification, and discrimination of facial emotions, with potential functional implications. PMID- 24402220 TI - Applicability of the single-case methodology in a patient with dementia with Lewy bodies. PMID- 24402221 TI - Verbal fluency in older adults with low educational level: what is the role of executive functions and processing speed? PMID- 24402222 TI - Varenicline: the risks of over-the-counter sales in Brazil. PMID- 24402223 TI - Homicide, fragile X syndrome, and mental retardation. PMID- 24402224 TI - Skin pigmentation provides evidence of convergent melanism in extinct marine reptiles. AB - Throughout the animal kingdom, adaptive colouration serves critical functions ranging from inconspicuous camouflage to ostentatious sexual display, and can provide important information about the environment and biology of a particular organism. The most ubiquitous and abundant pigment, melanin, also has a diverse range of non-visual roles, including thermoregulation in ectotherms. However, little is known about the functional evolution of this important biochrome through deep time, owing to our limited ability to unambiguously identify traces of it in the fossil record. Here we present direct chemical evidence of pigmentation in fossilized skin, from three distantly related marine reptiles: a leatherback turtle, a mosasaur and an ichthyosaur. We demonstrate that dark traces of soft tissue in these fossils are dominated by molecularly preserved eumelanin, in intimate association with fossilized melanosomes. In addition, we suggest that contrary to the countershading of many pelagic animals, at least some ichthyosaurs were uniformly dark-coloured in life. Our analyses expand current knowledge of pigmentation in fossil integument beyond that of feathers, allowing for the reconstruction of colour over much greater ranges of extinct taxa and anatomy. In turn, our results provide evidence of convergent melanism in three disparate lineages of secondarily aquatic tetrapods. Based on extant marine analogues, we propose that the benefits of thermoregulation and/or crypsis are likely to have contributed to this melanisation, with the former having implications for the ability of each group to exploit cold environments. PMID- 24402225 TI - Mycorrhiza-mediated competition between plants and decomposers drives soil carbon storage. AB - Soil contains more carbon than the atmosphere and vegetation combined. Understanding the mechanisms controlling the accumulation and stability of soil carbon is critical to predicting the Earth's future climate. Recent studies suggest that decomposition of soil organic matter is often limited by nitrogen availability to microbes and that plants, via their fungal symbionts, compete directly with free-living decomposers for nitrogen. Ectomycorrhizal and ericoid mycorrhizal (EEM) fungi produce nitrogen-degrading enzymes, allowing them greater access to organic nitrogen sources than arbuscular mycorrhizal (AM) fungi. This leads to the theoretical prediction that soil carbon storage is greater in ecosystems dominated by EEM fungi than in those dominated by AM fungi. Using global data sets, we show that soil in ecosystems dominated by EEM-associated plants contains 70% more carbon per unit nitrogen than soil in ecosystems dominated by AM-associated plants. The effect of mycorrhizal type on soil carbon is independent of, and of far larger consequence than, the effects of net primary production, temperature, precipitation and soil clay content. Hence the effect of mycorrhizal type on soil carbon content holds at the global scale. This finding links the functional traits of mycorrhizal fungi to carbon storage at ecosystem to-global scales, suggesting that plant-decomposer competition for nutrients exerts a fundamental control over the terrestrial carbon cycle. PMID- 24402226 TI - Ecology: Good dirt with good friends. PMID- 24402227 TI - UvrD facilitates DNA repair by pulling RNA polymerase backwards. AB - UvrD helicase is required for nucleotide excision repair, although its role in this process is not well defined. Here we show that Escherichia coli UvrD binds RNA polymerase during transcription elongation and, using its helicase/translocase activity, forces RNA polymerase to slide backward along DNA. By inducing backtracking, UvrD exposes DNA lesions shielded by blocked RNA polymerase, allowing nucleotide excision repair enzymes to gain access to sites of damage. Our results establish UvrD as a bona fide transcription elongation factor that contributes to genomic integrity by resolving conflicts between transcription and DNA repair complexes. Furthermore, we show that the elongation factor NusA cooperates with UvrD in coupling transcription to DNA repair by promoting backtracking and recruiting nucleotide excision repair enzymes to exposed lesions. Because backtracking is a shared feature of all cellular RNA polymerases, we propose that this mechanism enables RNA polymerases to function as global DNA damage scanners in bacteria and eukaryotes. PMID- 24402229 TI - Molecular biology: The tug of DNA repair. PMID- 24402228 TI - Genetics of single-cell protein abundance variation in large yeast populations. AB - Variation among individuals arises in part from differences in DNA sequences, but the genetic basis for variation in most traits, including common diseases, remains only partly understood. Many DNA variants influence phenotypes by altering the expression level of one or several genes. The effects of such variants can be detected as expression quantitative trait loci (eQTL). Traditional eQTL mapping requires large-scale genotype and gene expression data for each individual in the study sample, which limits sample sizes to hundreds of individuals in both humans and model organisms and reduces statistical power. Consequently, many eQTL are probably missed, especially those with smaller effects. Furthermore, most studies use messenger RNA rather than protein abundance as the measure of gene expression. Studies that have used mass spectrometry proteomics reported unexpected differences between eQTL and protein QTL (pQTL) for the same genes, but these studies have been even more limited in scope. Here we introduce a powerful method for identifying genetic loci that influence protein expression in the yeast Saccharomyces cerevisiae. We measure single-cell protein abundance through the use of green fluorescent protein tags in very large populations of genetically variable cells, and use pooled sequencing to compare allele frequencies across the genome in thousands of individuals with high versus low protein abundance. We applied this method to 160 genes and detected many more loci per gene than previous studies. We also observed closer correspondence between loci that influence protein abundance and loci that influence mRNA abundance of a given gene. Most loci that we detected were clustered in 'hotspots' that influence multiple proteins, and some hotspots were found to influence more than half of the proteins that we examined. The variants that underlie these hotspots have profound effects on the gene regulatory network and provide insights into genetic variation in cell physiology between yeast strains. PMID- 24402230 TI - MicroRNA-195-5p is a potential diagnostic and therapeutic target for breast cancer. AB - MicroRNAs (miRNAs) are a class of highly conserved, small endogenous single strand non-coding RNAs. They are aberrantly expressed in the circulation and tissue of patients with cancer. Therefore, it has been suggested that they may act as key regulators of carcinogenesis. The aim of the present study was to examine the expression level of miR-195-5p in human breast cancer and its potential role in carcinogenesis. The expression level of miR-195-5p was measured in 40 breast cancer specimens and adjacent normal breast tissues by quantitative polymerase chain reaction (qPCR). Next, to explore the potential function of miR 195-5p, we used MDA-MB-231 human breast cancer cells and carried out MTT, colony formation, Transwell chamber migration and cell cycle assays. The dual-luciferase reporter assay was also performed to determine putative targets of miR-195-5p, which were validated using qPCR and western blot assays. We found that miR-195-5p expression was significantly decreased in the 40 breast cancer specimens when compared with that in the adjacent normal breast tissues (P<0.05). Overexpression of miR-195-5p inhibited cell proliferation, reduced cell colony formation, suppressed cell migration and caused an accumulation of cells in the G1 phase of the cell cycle. In the 3'-untranslated region (3'-UTR) of cyclin E1 (CCNE1), we found two putative target sites which may bind miR-195-5p, suggesting that CCNE1 is a direct target of miR-195-5p. Furthermore, through qPCR and western blot assays we showed that overexpression of miR-195-5p reduced CCNE1 mRNA and protein levels, respectively. Our study suggests that miR-195-5p may act as a tumor suppressor in breast cancer. Therefore, targeting of this miRNA may provide a novel strategy for the diagnosis and treatment of patients with this lethal disease. PMID- 24402231 TI - Ocular complications after kidney transplantation: a case report and review of literature. AB - Membranoproliferative glomerulonephritis type II (MPGN II), also known as a dense deposit disease, is a chronic progressive kidney disease that often progresses to end-stage renal disease within 10 years. Most patients also have multiple subretinal white spots or drusen-like deposits that are histopathologically identical to the glomerular basement membrane deposits. The purpose is to determine ocular findings in a patient with MPGN II before and after renal transplantation and to correlate them with clinical characteristics related to transplantation and review of literature. We present a case of a 45-year-old female with MPGN II who developed bilateral serous retinal detachment and retinal hemorrhages in the left eye, which appeared 6 months after a renal transplant. Ocular complications in our case, with the exception on the retina, were present at the cornea and iris. Changes to the eyes were independent of the renal disease, because there was no recurrence of MPGN II on the renal graft. PMID- 24402232 TI - Improved perioperative outcomes with minimally invasive distal pancreatectomy: results from a population-based analysis. AB - IMPORTANCE: Interest in minimally invasive distal pancreatectomy (MIDP) has grown in recent years, but currently available data are limited. Greater insight into application patterns and outcomes may be gained from a national database inquiry. OBJECTIVES: To study trends in the use of MIDP and compare the short-term outcomes of MIDP with those of open distal pancreatectomy. DESIGN, SETTING, AND PARTICIPANTS: Population-based retrospective cohort study evaluating perioperative outcomes and hospital charge measures for distal pancreatectomy, comparing the surgical approaches and adjusting for patient- and hospital-level factors, among patients undergoing elective distal pancreatectomy from 1998 to 2009 in the Nationwide Inpatient Sample in a 20% stratified sample of all US hospitals. MAIN OUTCOMES AND MEASURES: In-hospital mortality, rates of perioperative complications and splenectomy, total charges, and length of stay. RESULTS: A total of 8957 distal pancreatectomies were included in this analysis, of which 382 (4.3%) were MIDPs. On a national level, this projected to 42,320 open distal pancreatectomies and 1908 MIDPs. The proportion of distal pancreatectomies performed via minimally invasive approaches tripled between 1998 and 2009, from 2.4% to 7.3%. The groups were comparable for sex and comorbidity profiles, while patients who underwent MIDP were 1.5 years older. On multivariate analysis, MIDP was associated with lower rates of overall predischarge complications, including lower incidences of postoperative infections and bleeding complications, as well as a shorter length of stay by 1.22 days. There were no differences in rates of in-hospital mortality, concomitant splenectomy, or total charges. CONCLUSIONS AND RELEVANCE: This population-based study of MIDP reveals that the application of this approach has tripled in practice and provides strong evidence that MIDP has evolved into a safe option in the treatment of benign and malignant pancreatic diseases. PMID- 24402233 TI - [Trends of work force participation of patients with rheumatic diseases : results from German social insurance data and the national database of the German collaborative arthritis centers]. AB - Positive therapeutic effects on the work force participation derived from international clinical trials may not be directly transferable to the community based care in Germany. Therefore recent changes of data regarding sick leave (SL), work disability pension (WDP) and employment from the social insurance and from the national database of the German collaborative arthritis centers were analyzed covering a time period of at least 10 years. Health insurance data showed a steeper decline in the average duration of SL caused by rheumatoid arthritis (RA), ankylosing spondylitis (AS) and systemic lupus erythematosus (SLE) compared with all other diseases. In RA patients from the collaborative arthritis centers the mean duration of SL was much more reduced than the average duration of SL for members of the compulsory health insurance. The proportion of gainfully employed RA patients in collaborative arthritis centers has particularly increased in women. According to data from the pension insurance fund less incident cases of WDP due to RA, AS, and SLE have been observed than WDP caused by all other diseases. Thus different nationwide data show positive changes of the work force participation of individuals suffering from inflammatory rheumatic diseases in Germany. PMID- 24402234 TI - Methylglyoxal (MG) and cerebro-renal interaction: does long-term orally administered MG cause cognitive impairment in normal Sprague-Dawley rats? AB - Methylglyoxal (MG), one of the uremic toxins, is a highly reactive alpha dicarbonyl compound. Recent clinical studies have demonstrated the close associations of cognitive impairment (CI) with plasma MG levels and presence of kidney dysfunction. Therefore, the present study aims to examine whether MG is a direct causative substance for CI development. Eight-week-old male Sprague-Dawley (SD) rats were divided into two groups: control (n = 9) and MG group (n = 10; 0.5% MG in drinking water), and fed a normal diet for 12 months. Cognitive function was evaluated by two behavioral tests (object exploration test and radial-arm maze test) in early (4-6 months of age) and late phase (7-12 months of age). Serum MG was significantly elevated in the MG group (495.8 +/- 38.1 vs. 244.8 +/- 28.2 nM; p < 0.001) at the end of study. The groups did not differ in cognitive function during the course of study. No time-course differences were found in oxidative stress markers between the two groups, while, antioxidants such as glutathione peroxidase and superoxide dismutase activities were significantly increased in the MG group compared to the control. Long-term MG administration to rats with normal kidney function did not cause CI. A counter balanced activation of the systemic anti-oxidant system may offset the toxicity of MG in this model. Pathogenetic significance of MG for CI requires further investigation. PMID- 24402236 TI - Converting oxazoles into imidazoles: new opportunities for diversity-oriented synthesis. AB - We report the optimization of a neglected reaction for the rapid and direct conversion of oxazoles into N-substituted imidazoles. The utility of this microwave-promoted reaction for diversity-oriented synthesis is demonstrated in the preparation of >40 N-substituted imidazoles, including alpha-imidazolyl esters. PMID- 24402237 TI - An air-supported liquid crystal system for real-time reporting of host-guest inclusion events. AB - A new method for reporting host-guest inclusion phenomena using an air-supported liquid crystal (LC) system based on cyclodextrins (CDs) was developed. In this work inclusion complexation of beta-CD with sodium dodecyl sulfate (SDS) or with methylene blue (MB) using SDS as the probe was visualized using the LC, according to the principle that the orientation of LCs was coupled to the organization of SDS molecules. PMID- 24402235 TI - The E. coli CNF1 as a pioneering therapy for the central nervous system diseases. AB - The Cytotoxic Necrotizing Factor 1 (CNF1), a protein toxin from pathogenic E. coli, modulates the Rho GTPases, thus, directing the organization of the actin cytoskeleton. In the nervous system, the Rho GTPases play a key role in several processes, controlling the morphogenesis of dendritic spines and synaptic plasticity in brain tissues. This review is focused on the peculiar property of CNF1 to enhance brain plasticity in in vivo animal models of central nervous system (CNS) diseases, and on its possible application in therapy. PMID- 24402238 TI - Substrate-induced band gap renormalization in semiconducting carbon nanotubes. AB - The quasiparticle band gaps of semiconducting carbon nanotubes (CNTs) supported on a weakly-interacting hexagonal boron nitride (h-BN) substrate are computed using density functional theory and the GW Approximation. We find that the direct band gaps of the (7,0), (8,0) and (10,0) carbon nanotubes are renormalized to smaller values in the presence of the dielectric h-BN substrate. The decrease in the band gap is the result of a polarization-induced screening effect, which alters the correlation energy of the frontier CNT orbitals and stabilizes valence band maximum and conduction band minimum. The value of the band gap renormalization is on the order of 0.25 to 0.5 eV in each case. Accounting for polarization-induced band gap changes is crucial in comparing computed values with experiment, since nanotubes are almost always grown on substrates. PMID- 24402240 TI - Sequential swallowing of liquid in elderly adults: cup or straw? AB - This article describes the study of the characteristics of sequential swallowing of 100 ml of liquid (dyed water) in two swallowing trials, directly from a cup and through a straw, in healthy elderly individuals. The aim of the study was to determine whether differences in the swallowing pattern are influenced by the type of utensil used. The subjects were subjected to clinical assessment and fiberoptic endoscopic evaluation of swallowing. The research found that intake from the cup showed a significantly lower median as regards time to drink the total volume. The final intake volume was significantly larger from the cup. A statistically significant difference was found in the oral spillage of liquid, which was notably higher in the cup trial. Despite the presence of residue in the valleculae and pyriform sinuses, in neither trial was there penetration or aspiration of liquid. The straw has a favorable influence on the quality of the sequential swallowing of liquid in regard to bolus containment within the oral cavity, which was better with that utensil. The cup provides a higher final volume in a shorter time for intake but there is more fluid spillage. PMID- 24402239 TI - Changes in swallowing physiology and patient perception of swallowing function following chemoradiation for head and neck cancer. AB - Patients treated with chemoradiation for head and neck cancer often report difficulty with swallowing and are frequently diagnosed with dysphagia. The extent to which patient awareness of dysphagia corresponds to observed physiologic changes in swallowing is unclear. The purpose of this study was to determine how both patient awareness of swallowing function and swallowing physiology individually change following chemoradiation and then to clarify the relationship between them. Twenty-one patients with head and neck cancer treated with chemoradiation were assessed before and after treatment and matched with twenty-one control subjects. The modified barium swallow test was utilized to examine swallowing physiology. Each subject was also given a series of items regarding awareness of specific dysphagia symptoms. Results showed decreased swallow efficiencies, higher percentages of residue, and more occurrences of penetration and aspiration following chemoradiation. Patients also had significantly higher ratings for 4 of the 12 items ("dry mouth," "food sticking in my mouth," "need water to help food go down," and "change in sense of taste"). Only one strong and significant correlation was found between ratings for "I have difficulty swallowing" and swallow efficiency values. Based on these findings, it appears that patients sense a general difficulty with swallowing but have less awareness of specific symptoms of dysphagia. PMID- 24402241 TI - Long open amphotericin channels revealed in cholesterol-containing phospholipid membranes are blocked by thiazole derivative. AB - The action of antifungal drug, amphotericin B (AmB), on solvent-containing planar lipid bilayers made of sterols (cholesterol, ergosterol) and synthetic C14-C18 tail phospholipids (PCs) or egg PC has been investigated in a voltage-clamp mode. Within the range of PCs tested, a similar increase was achieved in the lifetime of one-sided AmB channels in cholesterol- and ergosterol-containing membranes with the C16 tail PC, DPhPC at sterol/DPhPC molar ratio <=1. The AmB channel lifetimes decreased only at sterol/DPhPC molar ratio >1 that occurred with sterol/PC molar ratio of target cell membranes at a pathological state. These data obtained on bilayer membranes two times thicker than one-sided AmB channel length are consistent with the accepted AmB pore-forming mechanism, which is associated with membrane thinning around AmB-sterol complex in the lipid rafts. Our results show that AmB can create cytotoxic (long open) channels in cholesterol membrane with C14-C16 tail PCs and nontoxic (short open) channels with C17-C18 tail PCs as the lifetime of one-sided AmB channel depends on ~2-5 A difference in the thickness of sterol-containing C16 and C18 tail PC membranes. The reduction in toxic AmB channels efficacy can be required at the drug administration because C16 tails in native membrane PCs occur almost as often as C18 tails. The comparative analysis of AmB channel blocking by tetraethylammonium chloride, tetramethylammonium chloride and thiazole derivative of vitamin B1, 3 decyloxycarbonylmethyl-4-methyl-5-(2-hydroxyethyl) thiazole chloride (DMHT), has proved that DMHT is a comparable substitute for both tetraalkylammonia that exhibits a much higher affinity. PMID- 24402242 TI - Distance measurements and conformational analysis of sn-2-arachidonoylglycerol membrane sample by 2H-31P REDOR NMR. AB - The purpose of these studies is to determine the intermolecular distances that define the location, orientation, and conformation of 2-AG in palmitoyl-oleoyl phosphatidylcholine (POPC) lipid bilayers using rotational-echo double-resonance (REDOR) NMR. All five protons on the glycerol backbone of 2-AG were replaced with 2H and the distance between the deuterons and naturally occurring 31P on the POPC lipid headgroup determined with REDOR. To determine the distance from each deuteron to the phosphorus, the POPC headgroup was arranged in a hexagonal array. The 2-AG intercalates between the lipid molecules and the 2H labels, resulting in an average distance of z directly above or below the center of the parallelogram of the four phosphorus atoms P1, P2, P3, and P4. For different z values, the 2H 31P inter-nuclear distances were 7.6-9.1 A (2H-31P1 and 2H-31P31) and 4.4-6.7 A (2H-31P2 and 2H-31P4). Each result involved the calculations and summation of 893,101 terms. Based on the curve-fitting parameters, the calculations with z = 0 fits the data the best, which means these methylene 2H atoms are at the same level as the phosphate group of the POPC lipid bilayer. Molecular dynamic simulation data suggested that the 2H atoms at the glycerol backbone of 2-AG are involved in an extended H-bonding network with the phosphorus atoms after 10-ns simulation. PMID- 24402243 TI - Reply to response to 'What do aquaporin knockout studies tell us about fluid transport in epithelia?' Maclaren OJ, Sneyd J, Crampin EJ (2013) J Membr Biol 246:297-305. PMID- 24402244 TI - Photocleavage control of nucleated DNA nanosystems--the influence of surface strand sterics. AB - We use sterically inaccessible 'seed' strands, released from a surface into solution by photocleavage to initiate a nucleated DNA polymerization reaction. We demonstrate control of the quantity of 'seed' release and that hairpin steric protection of the 'seed' leads to less 'leaky' surfaces. This polymerization is a model system for surface-photocleavage initiation of sub-stoichiometric reaction cascades; these cascades should find use as a component of labs-on-chips capable of bioanalytical and DNA-computing tasks. PMID- 24402245 TI - Explaining racial disparities in outcomes after cardiac surgery: the role of hospital quality. AB - IMPORTANCE: Racial disparities in mortality rates after coronary artery bypass graft (CABG) surgery are well established. We have yet to fully understand how care at high-mortality, low-quality hospitals contributes to racial disparities in surgical outcomes. OBJECTIVE: To determine the effects of hospital quality on racial disparities in mortality rates after CABG surgery. DESIGN, SETTING, AND PARTICIPANTS: The national Medicare database (2007-2008) was used to identify 173,925 patients undergoing CABG surgery in US hospitals. MAIN OUTCOMES AND MEASURES: Our primary measure of quality was the risk-adjusted mortality rate for each hospital. Logistic regression was used to determine the relationship between race and mortality rates, accounting for patient characteristics, socioeconomic status, and hospital quality. RESULTS: Nonwhite patients had 33% higher risk adjusted mortality rates after CABG surgery than white patients (odds ratio [OR], 1.33; 95% CI, 1.23-1.45). In hospitals treating the highest proportion of nonwhite patients (>17.7%), the mortality was 4.8% in nonwhite and 3.8% in white patients. When assessed independently, differences in hospital quality explained 35% of the observed disparity in mortality rates (OR, 1.22; 95% CI, 1.12-1.34). We were able to explain 53% of the observed disparity after adjusting for differences in socioeconomic status and hospital quality. However, even after these factors were taken into account, nonwhite patients had a 16% higher mortality (OR, 1.16; 95% CI, 1.05-1.27). CONCLUSIONS AND RELEVANCE: Hospital quality contributes significantly to racial disparities in outcomes after CABG surgery. However, a significant fraction of this racial disparity remains unexplained. Efforts to decrease racial disparities in health care should focus on underperforming centers of care treating disproportionately high numbers of nonwhite patients. PMID- 24402246 TI - Adolescent alcohol use: risks and consequences. AB - AIMS: The aim of the study was to summarize results of recent epidemiological research on adolescent alcohol use and its consequences, to outline the risk factors for drinking in adolescents and to consider effective treatment and preventative interventions. METHODS: A literature review of relevant studies on adolescent alcohol use. RESULTS: Alcohol use and other risk-taking behaviours such as smoking, substance use and risky sexual behaviour emerge in adolescence and tend to cluster together. Heavy alcohol consumption in late adolescence appears to persist into adulthood and is associated with alcohol problems, including dependence, premature death and diminished work capacity. Early identification of adolescent risk factors may be helpful in preventing and/or attenuating risk. CONCLUSION: There is a need for high-quality long-term prospective cohort studies to investigate the long-term consequences of adolescent drinking and further work is needed to identify the most effective intervention strategies. PMID- 24402248 TI - This was no Antarctic pleasure cruise. PMID- 24402259 TI - Leaked files slam stem-cell therapy. PMID- 24402247 TI - Can cannabis be considered a substitute medication for alcohol? AB - AIMS: Substituting cannabis for alcohol may reduce drinking and related problems among alcohol-dependent individuals. Some even recommend prescribing medical cannabis to individuals attempting to reduce drinking. The primary aim of this review is to assess whether cannabis satisfies the seven previously published criteria for substitute medications for alcohol [e.g. 'reduces alcohol-related harms'; 'is safer in overdose than alcohol'; 'should offer significant health economic benefits'; see Chick and Nutt ((2012) Substitution therapy for alcoholism: time for a reappraisal? J Psychopharmacol 26:205-12)]. METHODS: Literature review. RESULTS: All criteria appear either satisfied or partially satisfied, though studies relying on medical cannabis patients may be limited by selection bias and/or retrospective designs. Individual-level factors, such as severity of alcohol problems, may also moderate substitution. CONCLUSIONS: There is no clear pattern of outcomes related to cannabis substitution. Most importantly, the recommendation to prescribe alcohol-dependent individuals cannabis to help reduce drinking is premature. Future studies should use longitudinal data to better understand the consequences of cannabis substitution. PMID- 24402260 TI - Particle-physics papers set free. PMID- 24402261 TI - Projects set to tackle neglected diseases. PMID- 24402262 TI - Many eyes on Earth. PMID- 24402263 TI - China tops Europe in R&D intensity. PMID- 24402264 TI - Computer science: The learning machines. PMID- 24402265 TI - Workplace violence: Caught on campus. PMID- 24402270 TI - Publishing: Halt self-citation in impact measures. PMID- 24402271 TI - Taxonomy: Call for ecosystem modelling data. PMID- 24402272 TI - Environment: Himalayas already have hazard network. PMID- 24402273 TI - Pollinator declines: Avoid pitfalls of consensus methods. PMID- 24402274 TI - Electrochemistry: Metal-free energy storage. PMID- 24402276 TI - Therapeutics: Detective work on drug dosage. PMID- 24402277 TI - HIV: Ringside views. PMID- 24402280 TI - A metal-free organic-inorganic aqueous flow battery. AB - As the fraction of electricity generation from intermittent renewable sources- such as solar or wind--grows, the ability to store large amounts of electrical energy is of increasing importance. Solid-electrode batteries maintain discharge at peak power for far too short a time to fully regulate wind or solar power output. In contrast, flow batteries can independently scale the power (electrode area) and energy (arbitrarily large storage volume) components of the system by maintaining all of the electro-active species in fluid form. Wide-scale utilization of flow batteries is, however, limited by the abundance and cost of these materials, particularly those using redox-active metals and precious-metal electrocatalysts. Here we describe a class of energy storage materials that exploits the favourable chemical and electrochemical properties of a family of molecules known as quinones. The example we demonstrate is a metal-free flow battery based on the redox chemistry of 9,10-anthraquinone-2,7-disulphonic acid (AQDS). AQDS undergoes extremely rapid and reversible two-electron two-proton reduction on a glassy carbon electrode in sulphuric acid. An aqueous flow battery with inexpensive carbon electrodes, combining the quinone/hydroquinone couple with the Br2/Br(-) redox couple, yields a peak galvanic power density exceeding 0.6 W cm(-2) at 1.3 A cm(-2). Cycling of this quinone-bromide flow battery showed >99 per cent storage capacity retention per cycle. The organic anthraquinone species can be synthesized from inexpensive commodity chemicals. This organic approach permits tuning of important properties such as the reduction potential and solubility by adding functional groups: for example, we demonstrate that the addition of two hydroxy groups to AQDS increases the open circuit potential of the cell by 11% and we describe a pathway for further increases in cell voltage. The use of pi-aromatic redox-active organic molecules instead of redox-active metals represents a new and promising direction for realizing massive electrical energy storage at greatly reduced cost. PMID- 24402283 TI - Synthesis of gamma-labeled nucleoside 5'-triphosphates using click chemistry. AB - Real-time enzymatic studies are gaining importance as their chemical and technical instrumentation improves. Here we report the efficient synthesis of gamma-alkyne modified triphosphate amidates that are converted into a variety of gamma-fluorophore labeled triphosphates by Cu(I) catalyzed alkyne/azide click reactions. The synthesized triphosphates are incorporated into DNA by DNA polymerases. PMID- 24402281 TI - Structural basis for hijacking CBF-beta and CUL5 E3 ligase complex by HIV-1 Vif. AB - The human immunodeficiency virus (HIV)-1 protein Vif has a central role in the neutralization of host innate defences by hijacking cellular proteasomal degradation pathways to subvert the antiviral activity of host restriction factors; however, the underlying mechanism by which Vif achieves this remains unclear. Here we report a crystal structure of the Vif-CBF-beta-CUL5-ELOB-ELOC complex. The structure reveals that Vif, by means of two domains, organizes formation of the pentameric complex by interacting with CBF-beta, CUL5 and ELOC. The larger domain (alpha/beta domain) of Vif binds to the same side of CBF-beta as RUNX1, indicating that Vif and RUNX1 are exclusive for CBF-beta binding. Interactions of the smaller domain (alpha-domain) of Vif with ELOC and CUL5 are cooperative and mimic those of SOCS2 with the latter two proteins. A unique zinc finger motif of Vif, which is located between the two Vif domains, makes no contacts with the other proteins but stabilizes the conformation of the alpha domain, which may be important for Vif-CUL5 interaction. Together, our data reveal the structural basis for Vif hijacking of the CBF-beta and CUL5 E3 ligase complex, laying a foundation for rational design of novel anti-HIV drugs. PMID- 24402284 TI - Annexin A2 participates in human skin keloid formation by inhibiting fibroblast proliferation. AB - Abnormal scarring results from the expression and composition of extracellular matrix molecules. The transcription and translation of collagens I and III, fibronectin, laminin, periostin, and tenascin are all increased in raised dermal scar tissue. However, human keloid development is not fully defined. In this study, we identified proteins expressed differentially between normal skin and keloid scar tissues and examined their function in keloid formation using fibroblasts. Skin specimens from normal volunteers and patients with keloids were obtained by skin biopsy. Whole proteins were isolated by two-dimensional electrophoresis, and differentially expressed proteins were identified by matrix assisted laser desorption/ionization-time of flight/time of flight mass spectrometry. Protein function was determined by proliferation assay using annexin A2-overexpressing keloid fibroblasts. The expression of 11 protein spots was altered by at least 1.5-fold in patients with keloids than in normal volunteers. Of these proteins, annexin A2, a pre-serum amyloid P component, serum albumin precursor, and tryptase-I, were down-regulated in keloid tissue compared to normal skin. Collagen alpha 1(V) chain precursor, collagen alpha 1(I) chain precursor, ferritin light subunit, alpha 1(III) collagen, 6 phosphogluconolactonase, and calponin 2 were up-regulated. Diminished expression of annexin A2 was confirmed by immunoblotting and immunohistochemistry. Treatment with the recombinant human epidermal growth factor increased proliferation of keloid fibroblasts, which was more inhibited in annexin A2-overexpressing fibroblasts than in non-transfected control cells. These results imply that annexin A2 may participate in keloid formation by inhibiting keloid fibroblast proliferation. Therefore, it is concluded that annexin A2 may be a valuable therapeutic target for keloid lesions. PMID- 24402285 TI - Clinical efficacy and safety of 4-hexyl-1,3-phenylenediol for improving skin hyperpigmentation. AB - Hyperpigmentation disorders are of social and cosmetic concerns to many individuals due to their prevalent locations on highly visible parts of the body. Topical formulation containing hydroquinone is the most widely used remedy for the treatment of hyperpigmentation disorders. However, reports of side effects in long-term usage have raised concerns for its use in cosmetic products. Thus, it is highly desirable to develop a safe and effective alternative to treat hyperpigmentation disorders. The objective of the current study is to investigate the de-pigmenting efficacy of 4-hexyl-1,3-phenylenediol in various in vitro models and in a randomized controlled clinical study. We showed that 4-hexyl-1,3 phenylenediol significantly reduced melanogenesis in primary human melanocytes, murine melanoma cells, and pigmented human epidermal equivalents. It was determined that the reduction in melanogenesis is mediated through inhibition of tyrosinase enzyme activity and protein expression. Further investigation revealed that the inhibition of melanogenesis is reversible and is not associated with cellular toxicity in melanocytes. In addition, significant improvements in key clinical parameters such as overall skin lightening, appearance of spots on the cheeks, overall contrast between spots and surrounding skin, and overall pigmentation size were detected in a double-blinded, randomized controlled clinical study. In conclusion, our findings clearly demonstrated the potency of 4 hexyl-1,3-phenylenediol in modulating skin pigmentation, and it is safe and well tolerated after 12-week topical application. PMID- 24402286 TI - Frosch' surface microscopy score for the assessment of steroid-induced atrophy. PMID- 24402287 TI - [Not Available]. PMID- 24402288 TI - [Not Available]. PMID- 24402289 TI - [Not Available]. PMID- 24402291 TI - [Not Available]. PMID- 24402290 TI - [Not Available]. PMID- 24402292 TI - [Not Available]. PMID- 24402279 TI - Elephant shark genome provides unique insights into gnathostome evolution. AB - The emergence of jawed vertebrates (gnathostomes) from jawless vertebrates was accompanied by major morphological and physiological innovations, such as hinged jaws, paired fins and immunoglobulin-based adaptive immunity. Gnathostomes subsequently diverged into two groups, the cartilaginous fishes and the bony vertebrates. Here we report the whole-genome analysis of a cartilaginous fish, the elephant shark (Callorhinchus milii). We find that the C. milii genome is the slowest evolving of all known vertebrates, including the 'living fossil' coelacanth, and features extensive synteny conservation with tetrapod genomes, making it a good model for comparative analyses of gnathostome genomes. Our functional studies suggest that the lack of genes encoding secreted calcium binding phosphoproteins in cartilaginous fishes explains the absence of bone in their endoskeleton. Furthermore, the adaptive immune system of cartilaginous fishes is unusual: it lacks the canonical CD4 co-receptor and most transcription factors, cytokines and cytokine receptors related to the CD4 lineage, despite the presence of polymorphic major histocompatibility complex class II molecules. It thus presents a new model for understanding the origin of adaptive immunity. PMID- 24402294 TI - [Not Available]. PMID- 24402293 TI - [Not Available]. PMID- 24402295 TI - [Not Available]. PMID- 24402296 TI - Importance of biomarkers in risk stratification of pulmonary thromboembolism patients. AB - INTRODUCTION: Patients with pulmonary thromboembolism (PTE) are classified into 3 groups according to the clinical risk factors associated with mortality. High risk patients and some of the intermediate-risk patients should be treated immediately to decrease the high mortality risk. Although clinical risk level of PTE can be determined by using echocardiography to evaluate right ventricle overload and pulmonary artery pressure findings, it may not be available in all emergency settings. AIM: The purpose of the study was to define the laboratory biomarkers, which can be used in place of echocardiography for PTE risk stratification. METHODS: Patients (n = 98) were divided into 3 groups as high risk (n = 13), intermediate-risk (n = 50), and low-risk (n = 35) groups, according to clinical risk factors at the first referral to hospital. Hepatic, cardiac, and renal markers were evaluated and compared among 3 groups. RESULTS: Among biomarkers examined, lactate dehydrogenase, urea, creatinine, uric acid, troponin I, N-terminal-pro-B-type natriuretic peptide, creatine kinase-MB, D dimer, and erythrocyte sedimentation rate (ESR) levels were found different between groups. All of these biomarkers except for ESR had positive correlation, whereas ESR had negative correlation with the mortality risk. An analysis of covariance for the age difference among patient groups showed that all the biomarkers other than urea and D-dimer levels remained significantly different among risk groups. CONCLUSIONS: At emergency conditions in which echocardiography assessment is not available, PTE patients who have increased levels of certain hepatic, cardiac, and renal biomarkers should cautiously be evaluated for having an increased risk for mortality. Increased levels of these biomarkers may guide the consideration for thrombolytic treatment. PMID- 24402297 TI - Effect of prostaglandin I2 analogs on macrophage inflammatory protein 1alpha in human monocytes via I prostanoid receptor and cyclic adenosine monophosphate. AB - AIMS: Inflammation plays critical roles in atherosclerosis. Chemokines are responsible for leukocyte trafficking and involve in inflammatory diseases. Macrophage inflammatory protein 1alpha (MIP-1alpha) has been implicated in atherosclerotic lesion formation. Prostaglandin I2 (PGI2) analog, used in pulmonary hypertension, has been reported to have anti-inflammatory functions. However, little is known about its role in the MIP-1alpha production in human monocytes. METHODS: We investigated the effects of 3 conventional (iloprost, beraprost, and treprostinil) and 1 new (ONO-1301) PGI2 analogs, on the expression of MIP-1alpha expression in human monocytes. Human primary monocytes from control subjects and THP-1 cell line were treated with PGI2 analogs, with or without lipopolysaccharide (LPS) stimulation. Supernatants were harvested to measure MIP 1alpha levels by enzyme-linked immunosorbent assay. To explore which receptors involved the effects of PGI2 analogs on the expression of MIP-1alpha expression, I prostanoid (IP) and E prostanoid, peroxisome proliferator-activated receptor (PPAR)-alpha, and PPAR-r receptor antagonists were used to pretreat THP-1 cells. Forskolin, a cyclic adenosine monophosphate (cAMP) activator, was also used to further confirm the cAMP involvement on the effect of PGI2 analogs in MIP-1alpha production. RESULTS: Three PGI2 analogs could suppress LPS-induced MIP-1alpha production in THP-1 cells and human primary monocytes. ONO-1301 had a similar effect. CAY 10449, an IP receptor antagonist, could reverse the suppressive effects on MIP-1alpha production of iloprost. Forskolin, a cAMP activator, also suppressed MIP-1alpha production in THP-1 cells. CONCLUSIONS: Prostaglandin I2 analogs suppressed LPS-induced MIP-1alpha production in human monocytes via the IP receptor and cAMP pathway. The PGI2 analog may be potential in the treatment for atherosclerosis. PMID- 24402298 TI - Triglyceride-to-high-density-lipoprotein-cholesterol ratio is an index of heart disease mortality and of incidence of type 2 diabetes mellitus in men. AB - BACKGROUND: High triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) impart risk for heart disease. This study examines the relationships of TG/HDL-C ratio to mortality from all causes, coronary heart disease (CHD), or cardiovascular disease (CVD). SUBJECTS AND METHODS: Survival analysis was done in 39,447 men grouped by TG/HDL-C ratio cut point of 3.5 and for metabolic syndrome. National Death Index International Classification of Diseases (ICD-9 and ICD-10) codes were used for CVD and CHD deaths occurring from 1970 to 2008. Incidence of type 2 diabetes mellitus (DM) according to ratio was estimated in 22,215 men. Triglyceride/HDL-C ratio and cross-product of TG and fasting blood glucose (TyG index) were used in analysis. RESULTS: Men were followed up for 581,194 person years. Triglyceride/HDL-C ratio predicted CHD, CVD, and all-cause mortality after adjustment for established risk factors and non-HDL-C. Mortality rates were higher in individuals with a high ratio than in those with a low ratio. Fifty five percent of men had metabolic syndrome that was also predictive of CHD, CVD, and all-cause mortality. Annual incidence of DM was 2 times higher in men with high TG/HDL-C ratio than in those with a low ratio. Individuals with high TG/HDL C ratio had a higher incidence of DM than those with a low ratio. The TyG index was not equally predictive of causes of mortality to TG/HDL-C, but both were equally predictive of diabetes incidence. CONCLUSIONS: Triglyceride/HDL-C ratio predicts CHD and CVD mortality as well as or better than do metabolic syndrome in men. Also, a high ratio predisposes to DM. The TyG index does not predict CHD, CVD, or all-cause mortality equally well, but like TG/HDL-C ratio, it predicts DM incidence. PMID- 24402299 TI - Triglyceride glucose index and common carotid wall shear stress. AB - OBJECTIVES: Alterations in wall shear stress contribute to both clinical and subclinical atherosclerosis. Several conditions such as hypertension, diabetes, and obesity can impair shear stress, but the role of insulin resistance has never been investigated. The present study was designed to investigate whether insulin resistance assessed by TyG Index associates with wall shear stress in the common carotid artery. METHODS: One hundred six individuals were enrolled. Blood pressure, lipids, glucose, and cigarette smoking were evaluated. TyG Index was calculated as log[fasting triglycerides * fasting glucose / 2]. Subjects underwent blood viscosity measurement and echo-Doppler evaluation of carotid arteries to calculate wall shear stress. The association between TyG Index and carotid wall shear stress was assessed by simple and multiple regression analyses. RESULTS: TyG Index was significantly and inversely associated with carotid wall shear stress both in simple (r = -0.44, P < 0.001) and multiple regression analyses accounting for age, sex, and major cardiovascular risk factors. The association was further confirmed after exclusion of subjects with diabetes, dyslipidemia, fasting blood glucose greater than 100 mg/dL, and triglycerides greater than 150 mg/dL. CONCLUSIONS: The present findings suggest that increasing insulin resistance, as assessed by TyG Index, associates with atherosclerosis-prone shear stress reduction in the common carotid artery. PMID- 24402300 TI - Characterization of culturable heterotrophic bacteria in hydrocarbon-contaminated soil from an alpine former military site. AB - We characterized the culturable, heterotrophic bacterial community in soil collected from a former alpine military site contaminated with petroleum hydrocarbons. The physiologically active eubacterial community, as revealed by fluorescence-in situ-hybridization, accounted for 14.9 % of the total (DAPI stained) bacterial community. 4.0 and 1.2 % of the DAPI-stained cells could be attributed to culturable, heterotrophic bacteria able to grow at 20 and 10 degrees C, respectively. The majority of culturable bacterial isolates (23/28 strains) belonged to the Proteobacteria with a predominance of Alphaproteobacteria. The remaining isolates were affiliated with the Firmicutes, Actinobacteria and Bacteroidetes. Five strains could be identified as representatives of novel species. Characterization of the 28 strains demonstrated their adaptation to the temperature and nutrient conditions prevailing in the studied soil. One-third of the strains was able to grow at subzero temperatures ( 5 degrees C). Studies on the effect of temperature on growth and lipase production with two selected strains demonstrated their low-temperature adaptation. PMID- 24402301 TI - Arterial stiffness as a risk factor for coronary artery disease. AB - Hypertension is a major modifiable risk factor, and clinical trials have demonstrated that successful reduction of elevated blood pressure to target levels translates into decreased risk for the development of coronary artery disease, stroke, heart failure, and renal failure. The arterial system had previously been regarded as a passive conduit for the transportation of arterial blood to peripheral tissues. The physiologic role the arterial system was greatly expanded by the recognition of the central role of the endothelial function in a variety of physiologic processes. The role of arterial function and structure in cardiovascular physiology was expanded with the development of a variety of parameters that evaluate arterial stiffness. Markers of arterial stiffness have been correlated with cardiovascular outcomes, and have been classified as an emerging risk factor that provides prognostic information beyond standard stratification strategies involving hypertension, diabetes, obesity, dyslipidemia and smoking. Multiple epidemiologic studies have correlated markers of arterial stiffness such as pulse-wave velocity, augmentation index and pulse pressure with risk for the development of fatal and nonfatal cardiovascular events. Additionally, measurements of arterial stiffness had clarified the results of clinical trials that demonstrated differing impacts on clinical outcomes, despite similar reductions in blood pressure, as measured by brachial and sphygmomanometry. PMID- 24402302 TI - Deterioration of an Etruscan tomb by bacteria from the order Rhizobiales. AB - The Etruscan civilisation originated in the Villanovan Iron Age in the ninth century BC and was absorbed by Rome in the first century BC. Etruscan tombs, many of which are subterranean, are one of the best representations of this culture. The principal importance of these tombs, however, lies in the wall paintings and in the tradition of rich burial, which was unique in the Mediterranean Basin, with the exception of Egypt. Relatively little information is available concerning the biodeterioration of Etruscan tombs, which is caused by a colonisation that covers the paintings with white, circular to irregular aggregates of bacteria or biofilms that tend to connect each other. Thus, these colonisations sometimes cover extensive surfaces. Here we show that the colonisation of paintings in Tomba del Colle is primarily due to bacteria of the order Rhizobiales (Alphaproteobacteria), which were likely influenced by the neighbouring rhizosphere community and the availability of nutrients from root exudates. PMID- 24402303 TI - Analysis of SEMA3B methylation and expression patterns in gastric cancer tissue and cell lines. AB - The family of semaphorins has been demonstrated to possess tumor suppressor activity, in which semaphorin 3B (SEMA3B) is differentially expressed in several types of tumors. The relationship between SEMA3B expression and its clinical significance in gastric cancer (GC) is currently unclear. In the present study, the expression and methylation status of the SEMA3B gene were detected by quantitative PCR and bisulfite sequencing PCR (BSP). Data indicated that the levels of SEMA3B mRNA decreased in gastric tumor tissues and the methylation status of SEMA3B in the tumor group was higher than the paired normal tissues. By BSP, the SEMA3B gene showed high methylated status which was detected in all 4 cell lines (AGS, BGC-823, MGC-803 and SGC-7901). Treatment of the cells with 5 Aza-2'-deoxycytidine revealed clearly elevated mRNA levels of SEMA3B. These results were further confirmed by western blot analysis of Sema3b protein expression. At the same time, increased expression of p53 mRNA in BGC-823, MGC 803 was detected and indicated that p53 may be involved in the regulation of SEMA3B expression in specific genetic background. Downregulation of SEMA3B was negatively correlated with tumor size and N staging in GC (p<0.05). In conclusion, CpG methylation of SEMA3B epigenetically regulates SEMA3B expression during development of GC. Furthermore, 5-Aza-2'-deoxycytidine could reverse the hypermethylation status of SEMA3B, which may benefit future studies exploring the application of demethylating agents in clinical usage of GC. PMID- 24402304 TI - ABSL-4 aerobiology biosafety and technology at the NIH/NIAID integrated research facility at Fort Detrick. AB - The overall threat of a viral pathogen to human populations is largely determined by the modus operandi and velocity of the pathogen that is transmitted among humans. Microorganisms that can spread by aerosol are considered a more challenging enemy than those that require direct body-to-body contact for transmission, due to the potential for infection of numerous people rather than a single individual. Additionally, disease containment is much more difficult to achieve for aerosolized viral pathogens than for pathogens that spread solely via direct person-to-person contact. Thus, aerobiology has become an increasingly necessary component for studying viral pathogens that are naturally or intentionally transmitted by aerosol. The goal of studying aerosol viral pathogens is to improve public health preparedness and medical countermeasure development. Here, we provide a brief overview of the animal biosafety level 4 Aerobiology Core at the NIH/NIAID Integrated Research Facility at Fort Detrick, Maryland, USA. PMID- 24402305 TI - Were the English sweating sickness and the Picardy sweat caused by hantaviruses? AB - The English sweating sickness caused five devastating epidemics between 1485 and 1551, England was hit hardest, but on one occasion also mainland Europe, with mortality rates between 30% and 50%. The Picardy sweat emerged about 150 years after the English sweat disappeared, in 1718, in France. It caused 196 localized outbreaks and apparently in its turn disappeared in 1861. Both diseases have been the subject of numerous attempts to define their origin, but so far all efforts were in vain. Although both diseases occurred in different time frames and were geographically not overlapping, a common denominator could be what we know today as hantavirus infections. This review aims to shed light on the characteristics of both diseases from contemporary as well as current knowledge and suggests hantavirus infection as the most likely cause for the English sweating sickness as well as for the Picardy sweat. PMID- 24402306 TI - Proteomic analyses of human cytomegalovirus strain AD169 derivatives reveal highly conserved patterns of viral and cellular proteins in infected fibroblasts. AB - Human cytomegalovirus (HCMV) particle morphogenesis in infected cells is an orchestrated process that eventually results in the release of enveloped virions. Proteomic analysis has been employed to reveal the complexity in the protein composition of these extracellular particles. Only limited information is however available regarding the proteome of infected cells preceding the release of HCMV virions. We used quantitative mass spectrometry to address the pattern of viral and cellular proteins in cells, infected with derivatives of the AD169 laboratory strain. Our analyses revealed a remarkable conservation in the patterns of viral and of abundant cellular proteins in cells, infected for 2 hours, 2 days, or 4 days. Most viral proteins increased in abundance as the infection progressed over time. Of the proteins that were reliably detectable by mass spectrometry, only IE1 (pUL123), pTRS1, and pIRS1 were downregulated at 4 days after infection. In addition, little variation of viral proteins in the virions of the different viruses was detectable, independent of the expression of the major tegument protein pp65. Taken together these data suggest that there is little variation in the expression program of viral and cellular proteins in cells infected with related HCMVs, resulting in a conserved pattern of viral proteins ultimately associated with extracellular virions. PMID- 24402307 TI - Trends in atmospheric concentrations of weed pollen in the context of recent climate warming in Poznan (Western Poland). AB - A significant increase in summer temperatures has been observed for the period 1996-2011 in Poznan, Poland. The phenological response of four weed taxa, widely represented by anemophilous species (Artemisia spp., Rumex spp. and Poaceae and Urticaceae species) to this recent climate warming has been analysed in Poznan by examining the variations in the course of airborne pollen seasons. Pollen data were collected by 7-day Hirst-type volumetric trap. Trends in pollen seasons were determined using Mann-Kendall test and Sen's slope estimator, whereas the relationships between meteorological and aerobiological data were established by Spearman's rank correlation coefficient. Significant trends in pollen data were detected. The duration of pollen seasons of all analysed taxa increased (from +2.0 days/year for Urticaceae to +3.8 days/year for Rumex), which can be attributed to a delay in pollen season end dates rather than earlier start dates. In addition, the intensity of Artemisia pollen seasons significantly decreased and correlates with mean July-September daily minimum temperatures (r = -0.644, p < 0.01). In contrast, no significant correlations were found between temperature and characteristics of Rumex pollen seasons. The results of this study show that observed shifts in weed pollen seasons in Poznan, i.e. longer duration and later end dates, might be caused by the recorded increase in summer temperature. This influence was the strongest in relation to Artemisia, which is the taxon that flowers latest in the year. The general lack of significant correlations between Rumex and Urticaceae pollen seasons and spring and/or summer temperature suggests that other factors, e.g. land use practices, could also be partially responsible for the observed shifts in pollen seasons. PMID- 24402309 TI - Involvement of histamine 4 receptor in the pathogenesis and progression of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is one of the major autoimmune diseases with a global prevalence. Despite significant research into this disease, no drugs with acceptable safety profiles are yet available for its treatment. We investigated the possible anti-arthritic effects of the 4-methylhistamine (4-MeH) histamine 4 receptor (H4R) agonist and the JNJ77777120 (JNJ) H4R antagonist to explore the role of H4R in a mouse model of collagen antibody-induced arthritis (CAIA). Arthritis was induced via intravenous (tail vein) injection of Balb/c mice with a 5-clone cocktail of mAbs against collagen type II, followed by LPS, and the effects of treatment with 4-MeH or JNJ (30 mg kg(-1), i.p, twice daily) for 7 days (prophylactic or therapeutic regimens) were assessed. The results revealed increased paw edema, arthritic scores, joint histological inflammatory damage and matrix metalloproteinase-3 levels and high levels of Th1 pro-inflammatory cytokine mRNA and serum proteins in CAIA mice or following H4R activation via 4 MeH. Additionally, 4-MeH efficiently increased expression levels of NF-kappaB p65. JNJ-treated mice showed a substantial reduction in all the previously mentioned effects, with a similar trend being observed under prophylactic and therapeutic treatment regimens. The results of the present work indicate that JNJ exhibits significant anti-inflammatory and anti-arthritic activities, demonstrating the clear involvement of H4R antagonism in the pathogenesis and progression of RA. PMID- 24402308 TI - The open conformation of WASP regulates its nuclear localization and gene transcription in myeloid cells. AB - Mutations in the gene encoding the Wiskott-Aldrich syndrome protein (WASP) are responsible for Wiskott-Aldrich syndrome and WASP is a major actin regulator in the cytoplasm. Although rare gain-of-function mutations in the WASP gene are known to result in X-linked neutropenia (XLN), the molecular pathogenesis of XLN is not fully understood. In this study, we showed that all reported constitutively activating mutants (L270P, S272P and I294T) of WASP were hyperphosphorylated by Src family tyrosine kinases and demonstrated higher actin polymerization activities compared with wild-type (WT) WASP. Further analysis showed a tendency of activating WASP mutants to localize in the nucleus compared with WT or the Y291F mutant of WASP. In addition, we found that WASP could form a complex with nuclear RNA-binding protein, 54 kDa (p54nrb) and RNA polymerase II (RNAP II). ChIP assays revealed that WASP associated with DNA, although the affinity was relatively weaker than RNAP II. To determine whether gene transcription was affected by WASP mutation in myeloid cells, we performed microarray analysis and found different expression profiles between WT and L270P WASP-transfected K562 cells. Among the genes affected, granulocyte colony stimulating factor receptor, Runx1, and protein tyrosine phosphatase receptor c were included. ChIP on chip analysis of genomic DNA showed WT and L270P WASP had a highly similar DNA-binding pattern but differed in binding affinity at the same locus. Therefore, our results suggest that the open conformation of WASP regulates its nuclear localization and plays requisite roles in regulating gene transcription that would contribute to the outcome in the nucleus of myeloid cells. PMID- 24402310 TI - Transendothelial migration of effector T cells across inflamed endothelial barriers does not require heparan sulfate proteoglycans. AB - Leukocyte diapedesis is a chemotactic multistep process that requires optimal chemoattractant presentation by the endothelial barrier. Recent studies have described a critical role for heparan sulfate glycosaminoglycans (HSGAGs) in the presentation and functions of chemokines essential for lymphocyte interactions with the lymph node vasculature. We wished to test whether HS expression by a prototypic endothelial cell type, i.e. human umbilical vein endothelial cells (HUVECs), is critical for their ability to support neutrophil and lymphocyte adhesion and transendothelial migration (TEM) under shear flow. We found that HUVECs deposit HS GAGs mainly at their basolateral compartments in both their resting and inflamed states. We next inactivated the key enzyme involved in HS biosynthesis, exostosin-1 (Ext1). Silencing Ext1 resulted in a complete loss of HS biosynthesis; nonetheless, TNF-alpha and IL-1beta stimulation of key adhesion molecules and inflammatory chemokines necessary for neutrophil or lymphocyte adhesion and TEM remained intact. Ext1 silencing reduced neutrophil arrest and markedly impaired TEM, consistent with a role of basolateral HS GAGs in directing neutrophil crossing of inflamed endothelial barriers. Strikingly, however, the TEM of effector T cells across identically Ext1-silenced HUVECs remained normal. Importantly, the biosynthesis of the main promigratory chemokines for effector T cells and neutrophils, respectively, CCL2 and CXCL1, and their vesicle distributions were also Ext1 independent. These results suggest that transmigrating neutrophils must respond to chemokines transiently presented by apical and basolateral endothelial HS GAGs. In contrast, effector T cells can integrate chemotactic TEM signals directly from intra-endothelial chemokine stores rather than from externally deposited chemokines. PMID- 24402312 TI - Rhodium-catalyzed three-component reaction of 3-diazooxindoles with indoles and isatin-derived ketimines: a facile and versatile approach to functionalized 3,3',3''-trisindoles. AB - A simple, facile and efficient Rh2(OAc)4-catalyzed three-component reaction of 3 diazooxindoles with indoles and isatin-derived N-Boc ketimines towards a variety of functionalized 3,3',3''-trisindoles in high yields with moderate to excellent diastereoselectivities has been developed. This methodology provides an ideal approach for the direct introduction of indole and oxindole into an isatin moiety at the 3-position. PMID- 24402311 TI - IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation. AB - IDO2 is implicated in tryptophan catabolism and immunity but its physiological functions are not well established. Here we report the characterization of mice genetically deficient in IDO2, which develop normally but exhibit defects in IDO mediated T-cell regulation and inflammatory responses. Construction of this strain was prompted in part by our discovery that IDO2 function is attenuated in macrophages from Ido1 (-/-) mice due to altered message splicing, generating a functional mosaic with implications for interpreting findings in Ido1 (-/-) mice. No apparent defects were observed in Ido2 (-/-) mice in embryonic development or hematopoietic differentiation, with wild-type profiles documented for kynurenine in blood serum and for immune cells in spleen, lymph nodes, peritoneum, thymus and bone marrow of naive mice. In contrast, upon immune stimulation we determined that IDO1-dependent T regulatory cell generation was defective in Ido2 (-/-) mice, supporting Ido1-Ido2 genetic interaction and establishing a functional role for Ido2 in immune modulation. Pathophysiologically, both Ido1 (-/-) and Ido2 (-/ ) mice displayed reduced skin contact hypersensitivity responses, but mechanistic distinctions were apparent, with only Ido2 deficiency associated with a suppression of immune regulatory cytokines that included GM-CSF, G-CSF, IFN gamma, TNF-alpha, IL-6 and MCP-1/CCL2. Different contributions to inflammation were likewise indicated by the finding that Ido2 (-/-) mice did not phenocopy Ido1 (-/-) mice in the reduced susceptibility of the latter to inflammatory skin cancer. Taken together, our results offer an initial glimpse into immune modulation by IDO2, revealing its genetic interaction with IDO1 and distinguishing its non-redundant contributions to inflammation. PMID- 24402313 TI - Immobilisation of photoswitchable diarylcyclohexenes synthesised via cobalt mediated Diels-Alder reaction. AB - Functionalised photoswitches--photochromic dithienylcyclohexenes--were prepared in two steps by a cobalt-mediated Diels-Alder reaction of internal alkynes with the isoprenylpinacolboronic ester. The three-component one-pot reaction sequence provides the photochromic dithienylcyclohexenes in up to 67% overall yield. PMID- 24402314 TI - Fifty-three years' experience with randomized clinical trials of emergency portacaval shunt for bleeding esophageal varices in Cirrhosis: 1958-2011. AB - IMPORTANCE: Emergency treatment of bleeding esophageal varices (BEV) consists mainly of endoscopic and pharmacologic measures, with transjugular intrahepatic portal-systemic shunt (TIPS) performed when bleeding is not controlled. Surgical shunt has been relegated to salvage. At the University of California, San Diego, Medical Center, our group has conducted 10 studies of emergency portacaval shunt (EPCS) during 46 years. OBJECTIVE: To describe 2 randomized clinical trials (RCTs) conducted from 1988 to 2011 in unselected consecutive patients who received emergency treatment for BEV. DESIGN, SETTING, AND PARTICIPANTS: In RCT No. 1, a total of 211 unselected consecutive patients with cirrhosis and acute BEV were randomized to emergency endoscopic sclerotherapy (EEST) (n=106) or EPCS (n=105). In RCT No. 2, a total of 154 unselected consecutive patients with cirrhosis and acute BEV were randomized to TIPS (n=78) or EPCS (n=76). Diagnostic workup was completed within 6 hours of initial contact, and primary treatment was initiated within 8 to 12 hours. Regular follow-up for up to 10 years was accomplished in 100% of the patients. INTERVENTIONS: In RCT No. 1, EEST or EPCS; in RCT No. 2, TIPS or EPCS. MAIN OUTCOMES AND MEASURES: The 2 groups were compared with regard to survival, control of bleeding, portal-systemic encephalopathy, and direct cost of care. RESULTS Distribution in Child risk classes was almost identical. One-third of patients were in Child class C. Permanent control of bleeding was achieved by EEST in only 20% of the patients and by TIPS in only 22%. In contrast, EPCS permanently controlled bleeding in 97% and 100% of the patients in RCT No. 2 and RCT No. 1, respectively (P<.001). Survival was significantly greater following EPCS than after EEST and TIPS (P<.001). Median survival was more than 10 years following EPCS compared with 1.99 years after TIPS. Occlusion of TIPS was demonstrated in 84% of the patients, 63% of whom underwent TIPS revision, which failed in 80% of the cases. Recurrent portal-systemic encephalopathy developed in 35% of the patients who underwent EEST and 61% of those who received TIPS. In contrast, portal-systemic encephalopathy occurred in 15% of the patients who received EPCS in RCT No. 1 and 21% of those in RCT No. 2. Direct costs of care were 5 to 7 times greater in the EEST ($168100) and TIPS ($264800) groups than in the EPCS ($39000) group (P<.001). CONCLUSIONS AND RELEVANCE: Emergency portacaval shunt permanently stopped variceal bleeding, almost never became occluded, accomplished 5 times the long-term survival than EEST or TIPS, and was much less costly than EEST or TIPS. The widespread practice of using EPCS mainly as salvage for failure of endoscopic therapy or TIPS is not supported by the definitive results of these long-term RCTs in unselected patients with cirrhosis. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00690027 and NCT00734227. PMID- 24402315 TI - Mad1 kinetochore recruitment by Mps1-mediated phosphorylation of Bub1 signals the spindle checkpoint. AB - The spindle checkpoint is a conserved signaling pathway that ensures genomic integrity by preventing cell division when chromosomes are not correctly attached to the spindle. Checkpoint activation depends on the hierarchical recruitment of checkpoint proteins to generate a catalytic platform at the kinetochore. Although Mad1 kinetochore localization is the key regulatory downstream event in this cascade, its receptor and mechanism of recruitment have not been conclusively identified. Here, we demonstrate that Mad1 kinetochore association in budding yeast is mediated by phosphorylation of a region within the Bub1 checkpoint protein by the conserved protein kinase Mps1. Tethering this region of Bub1 to kinetochores bypasses the checkpoint requirement for Mps1-mediated kinetochore recruitment of upstream checkpoint proteins. The Mad1 interaction with Bub1 and kinetochores can be reconstituted in the presence of Mps1 and Mad2. Together, this work reveals a critical mechanism that determines kinetochore activation of the spindle checkpoint. PMID- 24402317 TI - Context dependency of Set1/COMPASS-mediated histone H3 Lys4 trimethylation. AB - The stimulation of trimethylation of histone H3 Lys4 (H3K4) by H2B monoubiquitination (H2Bub) has been widely studied, with multiple mechanisms having been proposed for this form of histone cross-talk. Cps35/Swd2 within COMPASS (complex of proteins associated with Set1) is considered to bridge these different processes. However, a truncated form of Set1 (762-Set1) is reported to function in H3K4 trimethylation (H3K4me3) without interacting with Cps35/Swd2, and such cross-talk is attributed to the n-SET domain of Set1 and its interaction with the Cps40/Spp1 subunit of COMPASS. Here, we used biochemical, structural, in vivo, and chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq) approaches to demonstrate that Cps40/Spp1 and the n-SET domain of Set1 are required for the stability of Set1 and not the cross-talk. Furthermore, the apparent wild-type levels of H3K4me3 in the 762-Set1 strain are due to the rogue methylase activity of this mutant, resulting in the mislocalization of H3K4me3 from the promoter proximal regions to the gene bodies and intergenic regions. We also performed detailed screens and identified yeast strains lacking H2Bub but containing intact H2Bub enzymes that have normal levels of H3K4me3, suggesting that monoubiquitination may not directly stimulate COMPASS but rather works in the context of the PAF and Rad6/Bre1 complexes. Our study demonstrates that the monoubiquitination machinery and Cps35/Swd2 function to focus COMPASS's H3K4me3 activity at promoter-proximal regions in a context-dependent manner. PMID- 24402316 TI - A conserved role for Snail as a potentiator of active transcription. AB - The transcription factors of the Snail family are key regulators of epithelial mesenchymal transitions, cell morphogenesis, and tumor metastasis. Since its discovery in Drosophila ~25 years ago, Snail has been extensively studied for its role as a transcriptional repressor. Here we demonstrate that Drosophila Snail can positively modulate transcriptional activation. By combining information on in vivo occupancy with expression profiling of hand-selected, staged snail mutant embryos, we identified 106 genes that are potentially directly regulated by Snail during mesoderm development. In addition to the expected Snail-repressed genes, almost 50% of Snail targets showed an unanticipated activation. The majority of "Snail-activated" genes have enhancer elements cobound by Twist and are expressed in the mesoderm at the stages of Snail occupancy. Snail can potentiate Twist mediated enhancer activation in vitro and is essential for enhancer activity in vivo. Using a machine learning approach, we show that differentially enriched motifs are sufficient to predict Snail's regulatory response. In silico mutagenesis revealed a likely causative motif, which we demonstrate is essential for enhancer activation. Taken together, these data indicate that Snail can potentiate enhancer activation by collaborating with different activators, providing a new mechanism by which Snail regulates development. PMID- 24402318 TI - Common variants of apolipoprotein E and cholesteryl ester transport protein genes in male patients with coronary heart disease and variable body mass index. AB - Plasma lipids are major risk factors for coronary heart disease (CHD). Cholesteryl ester transfer protein (CETP) and apolipoprotein (apo) E genes are involved in lipoprotein metabolism, thus affecting plasma lipid and lipoproteins levels. Furthermore, such polymorphisms have been associated with susceptibility to CHD and obesity. We evaluated the influence of the gene polymorphisms of CETP TaqIB (B1, B2) and I405V (V, I) and apo E (?2,?3,?4) on lipid levels, according to body mass index (BMI) in Greek men with CHD. The TaqIB (B1, B2) polymorphism affected plasma low-density lipoprotein cholesterol levels in overweight men with CHD, whereas the I405V (V, I) polymorphism affected triglyceride concentrations in normal weight men. No correlation was found between BMI and apo E polymorphisms. Large prospective studies are required to investigate the relationships of CETP and apo E polymorphisms with lipids, BMI, and CHD susceptibility. PMID- 24402319 TI - Does bilirubin level have an effect on serum lipid parameters and atherogenic plaque formation? PMID- 24402321 TI - Renal denervation: transition from pathophysiology to clinical practice. AB - Resistant hypertension, defined as failure to reach blood pressure (BP) goals despite treatment with >=3 antihypertensive agents, one of which is a diuretic, bears a significant risk of cardiovascular complications. Strong evidence exists, implicating the overactivation of the sympathetic nervous system (SNS) in the pathogenesis of resistant hypertension through complex neurohormonal interactions. Renal denervation is a novel attractive option to achieve adequate blockade of the sympathetic system, with subsequent BP reductions in patients with resistant hypertension. Data have shown promising results regarding the efficacy of the procedure, maintaining a favorable safety profile. As such, the paradigm of resistant hypertension has expanded in other conditions involving a hyperadrenergic state such as the metabolic syndrome, heart failure, arrhythmias, sleep apnea, and renal failure. This review focuses on the pathophysiological rationale of modifying SNS tone and the evidence of the benefits of such intervention beyond BP control. PMID- 24402320 TI - Endocan--a novel inflammatory indicator in newly diagnosed patients with hypertension: a pilot study. AB - Endothelial dysfunction is regarded as the initial lesion in the development of atherosclerosis. Endocan, previously called endothelial cell-specific molecule 1 (ESM-1), is a new candidate immunoinflammatory marker that may be associated with cardiometabolic risk factors. Therefore, we assessed serum levels of endocan in newly diagnosed patients with untreated essential hypertension (HT). A total of 18 patients with HT and 23 normotensive control participants were included in the study. Serum endocan levels, carotid intima-media thickness (cIMT), and high sensitivity C-reactive protein (hsCRP) were measured. Serum endocan levels were significantly higher in the HT group (P < .001). In patients with HT, serum endocan levels correlated positively with cIMT and hsCRP (r = .551, P < .001 and r = .644, P < .001, respectively). Our findings suggest that circulating endocan levels represent a new marker in patients with essential HT. Endocan may be a surrogate endothelial dysfunction marker and may have a functional role in endothelium-dependent pathological disorders. PMID- 24402322 TI - Negative associations between arterial stiffness parameter evaluated by cardio ankle vascular index and serum low-density lipoprotein cholesterol concentration in early-stage atherosclerosis. AB - The cardio-ankle vascular index (CAVI), calculated values from cardio-ankle pulse wave velocity and blood pressure, corresponds predominantly to the stiffness of the aorta and peripheral arteries of the lower limbs. However, the reported associations between CAVI and serum low-density lipoprotein cholesterol (LDL-C) levels remain inconsistent. A cross-sectional study of 1878 consecutive patients (mean age: 59.2 years) who underwent general health checkup showed a negative association between CAVI and serum LDL-C or non-high-density lipoprotein cholesterol (non-HDL-C) concentrations with age-adjusted correlation and multiple regression analysis. Using the similar analyses divided by the status of risk factors and degree of maximum carotid intima-media thickness (maxIMT), negative correlations between CAVI and LDL-C or non-HDL-C levels were observed only in nonrisk groups including nondiabetics patients or patients with maxIMT <1.0 mm, in those with expected low extent of advanced atherosclerotic lesions. In contrast, such a correlation was not found in each comparable risk-loaded group. PMID- 24402324 TI - Broadband terahertz generation from metamaterials. AB - The terahertz spectral regime, ranging from about 0.1-15 THz, is one of the least explored yet most technologically transformative spectral regions. One current challenge is to develop efficient and compact terahertz emitters/detectors with a broadband and gapless spectrum that can be tailored for various pump photon energies. Here we demonstrate efficient single-cycle broadband THz generation, ranging from about 0.1-4 THz, from a thin layer of split-ring resonators with few tens of nanometers thickness by pumping at the telecommunications wavelength of 1.5 MUm (200 THz). The terahertz emission arises from exciting the magnetic dipole resonance of the split-ring resonators and quickly decreases under off resonance pumping. This, together with pump polarization dependence and power scaling of the terahertz emission, identifies the role of optically induced nonlinear currents in split-ring resonators. We also reveal a giant sheet nonlinear susceptibility ~10(-16) m(2) V(-1) that far exceeds thin films and bulk non-centrosymmetric materials. PMID- 24402323 TI - Prediction of the response to docetaxel-based chemotherapy for locoregionally advanced nasopharyngeal carcinoma: the role of double-phase (99m)Tc-MIBI SPECT/CT. AB - To evaluate the role of double-phase (99m)Technetium labeled sestamibi ((99m)Tc MIBI) single-photon emission computed tomography/compute tomography (SPECT/CT) in predicting the response to neoadjuvant chemotherapy with docetaxel-based regimen in patients with nasopharyngeal carcinoma. Thirty-nine pathologically proven nasopharyngeal carcinoma patients participated in this prospective study. Before treatment, early and delayed SPECT/CT images were obtained 5 min and 2 h after an intravenous injection of 25-30 mCi (99m)Tc-MIBI. All patients received neoadjuvant chemotherapy consisting of docetaxel, cisplatin plus 5-fluorouracil for two cycles. The relationships between the efficacy of neoadjuvant chemotherapy and early uptake ratio (EUR), delayed uptake ratio (DUR) and washout rate (WR) of (99m)Tc-MIBI were evaluated. The EUR of (99m)Tc-MIBI (2.8 +/- 0.97) in the lesions which were sensitive to chemotherapy was significantly higher (p < 0.001) compared with that (1.69 +/- 0.46) in the insensitive lesions. The difference of the DUR between the sensitive (1.65 +/- 0.58) and the insensitive (1.06 +/- 0.62) was also statistically significant (p = 0.011). However, the WR of (99m)Tc-MIBI was not significantly different between the two groups. When a EUR of 1.97 and a DUR of 1.06 were used as the cutoff value, the sensitivity, specificity, positive and negative predictive values were 76.1, 87.5, 97.2 and 38.8 % for EUR, 91.3, 67.5, 90 and 66.6 % for DUR, respectively. These results suggest that the early and delayed uptake ratios of (99m)Tc-MIBI calculated with SPECT/CT may have predictive value for identifying the response to neoadjuvant chemotherapy with docetaxel-based regimen in NPC patients. PMID- 24402325 TI - Selective monomethylation of primary amines with simple electrophiles. AB - Direct monomethylation of primary amines with methyl triflate was achieved with high selectivity (up to 96%). The key point of this single methyl transfer stems from the use of HFIP as the solvent that interferes with amines and avoids overmethylation. PMID- 24402326 TI - Cardiovascular risk in children and adolescents with type 2 diabetes mellitus. AB - The epidemic of childhood obesity worldwide has led to increased incidence of the metabolic syndrome and type 2 diabetes in the pediatric and adolescent population. As such, there is increasing concern that this large population of children is at risk for the long-term complications of diabetes, specifically cardiovascular disease. With cardiovascular disease remaining the leading cause of death in adults, this presents a significant public health concern as these children age. In this article, we discuss cardiovascular disease and risk in children and adolescents with type 2 diabetes, including the epidemiology of type 2 diabetes, atherosclerotic cardiovascular disease, obesity, hypertension, and left ventricular function. PMID- 24402328 TI - Eradication of cervical cancer: the beginning of the end. PMID- 24402327 TI - Impact of breastfeeding on maternal metabolism: implications for women with gestational diabetes. AB - Lactating compared with nonlactating women display more favorable metabolic parameters, including less atherogenic blood lipids, lower fasting and postprandial blood glucose as well as insulin, and greater insulin sensitivity in the first 4 months postpartum. However, direct evidence demonstrating that these metabolic changes persist from delivery to postweaning is much less available. Studies have reported that longer lactation duration may reduce long-term risk of cardiometabolic disease, including type 2 diabetes, but findings from most studies are limited by self-report of disease outcomes, absence of longitudinal biochemical data, or no assessment of maternal lifestyle behaviors. Studies of women with a history gestational diabetes mellitus (GDM) also reported associations between lactation duration and lower the incidence of type 2 diabetes and the metabolic syndrome. The mechanisms are not understood, but hormonal regulation of pancreatic beta-cell proliferation and function or other metabolic pathways may mediate the lactation association with cardiometabolic disease in women. PMID- 24402329 TI - Exploration of selective recognition of iodide with dipodal sensor: 2,2'-[ethane 1,2-diylbis(iminoethane-1,1-diyl)]diphenol. AB - A dipodal fluorescent receptor, 2,2'-[ethane-1,2-diylbis(iminoethane-1,1 diyl)]diphenol (), with amine and hydroxyl moieties as binding sites has been synthesised and characterized with spectroscopic methods and single crystal X-ray techniques. The recognition of the anions with receptor was studied using UV-Vis and fluorescence spectroscopy. The (1)H-NMR spectroscopic and DFT studies revealed the distinct recognition of I(-) ions over the other surveyed anions. PMID- 24402330 TI - Engineering acidic Streptomyces rubiginosus D-xylose isomerase by rational enzyme design. AB - To maximize bioethanol production from lignocellulosic biomass, all sugars must be utilized. Yeast fermentation can be improved by introducing the d-xylose isomerase enzyme to convert the pentose sugar d-xylose, which cannot be fermented by Saccharomyces cerevisiae, into the fermentable ketose d-xylulose. The low activity of d-xylose isomerase, especially at the low pH required for optimal fermentation, limits its use. A rational enzyme engineering approach was undertaken, and seven amino acid positions were replaced to improve the activity of Streptomyces rubiginosus d-xylose isomerase towards its physiological substrate at pH values below 6. The active-site design was guided by mechanistic insights and the knowledge of amino acid protonation states at low pH obtained from previous joint X-ray/neutron crystallographic experiments. Tagging the enzyme with 6 or 12 histidine residues at the N-terminus resulted in a significant increase in the active-site affinity towards substrate at pH 5.8. Substituting an asparagine at position 215, which hydrogen bonded to the metal bound Glu181 and Asp245, with an aspartate gave a variant with almost an order of magnitude lower KM than measured for the native enzyme, with a 4-fold increase in activity. Other studied variants showed similar (Asp57Asn, Glu186Gln/Asn215Asp), lower (Asp57His, Asn247Asp, Lys289His, Lys289Glu) or no (Gln256Asp, Asp287Asn, DeltaAsp287) activity in acidic conditions relative to the native enzyme. PMID- 24402332 TI - Engineering lipase A from mesophilic Bacillus subtilis for activity at low temperatures. AB - Loops or unordered regions of a protein are structurally dynamic and are strongly implicated in activity, stability and proteolytic susceptibility of proteins. Diminished activity of proteins at lower temperatures is considered to be due to compromised dynamics of the protein at lower temperatures. To evolve an active mesophilic lipase (Bacillus subtilis) at low temperatures, we subjected all the loop residues (n = 88) to site saturation mutagenesis (SSM). Based on a three level screening protocol, we identified 14 substitutions, among 16,000 mutant population, which contributed to a substantial increase in activity at 5 degrees C. Based on the preliminary activity of recombinants at several temperatures, 5 substitutions among the 14 were found to be beneficial. A recombinant of these five mutations, named as 5CR, exhibited 7-fold higher catalytic efficiency than wild-type (WT) lipase at 10 degrees C. All the mutants, individually and in a recombinant (5CR), were characterized by substrate-binding parameters, melting temperatures and secondary structure. 5CR was similar to WT in substrate preferences and showed a significant improvement in activity at both lower and higher temperatures compared with the WT. To establish the contribution of mutations on the dynamics of the protein, we performed 100-ns molecular dynamics (MD) simulations on the WT and mutant lipase at 10 and 37 degrees C. The root mean square fluctuations (RMSFs) indeed showed that the mutations enhance the protein dynamics locally in the loop region having a catalytic residue, which may help in improved activities at lower temperatures. PMID- 24402331 TI - Computationally designed libraries for rapid enzyme stabilization. AB - The ability to engineer enzymes and other proteins to any desired stability would have wide-ranging applications. Here, we demonstrate that computational design of a library with chemically diverse stabilizing mutations allows the engineering of drastically stabilized and fully functional variants of the mesostable enzyme limonene epoxide hydrolase. First, point mutations were selected if they significantly improved the predicted free energy of protein folding. Disulfide bonds were designed using sampling of backbone conformational space, which tripled the number of experimentally stabilizing disulfide bridges. Next, orthogonal in silico screening steps were used to remove chemically unreasonable mutations and mutations that are predicted to increase protein flexibility. The resulting library of 64 variants was experimentally screened, which revealed 21 (pairs of) stabilizing mutations located both in relatively rigid and in flexible areas of the enzyme. Finally, combining 10-12 of these confirmed mutations resulted in multi-site mutants with an increase in apparent melting temperature from 50 to 85 degrees C, enhanced catalytic activity, preserved regioselectivity and a >250-fold longer half-life. The developed Framework for Rapid Enzyme Stabilization by Computational libraries (FRESCO) requires far less screening than conventional directed evolution. PMID- 24402333 TI - A general strategy for antibody library screening via conversion of transient target binding into permanent reporter deposition. AB - We report here a generally applicable method for the selective covalent attachment of a reporter molecule to a replicating entity that allows one to obtain specific binders from a single round of library screening. We show that selective biotinylation of phage particles displaying a binder to any given target can be achieved by application of a coupled enzyme reaction on the surface of the target-binding phage particles that includes a peroxidase, an oxidase and a catalase. Due to the covalent linkage of biotin together with the tight and stable interaction of biotin with streptavidin, very stringent wash conditions for removal of nonspecific binders can be applied. The method termed (3)CARD (triple catalytic reporter deposition) was successfully applied to single-round screening of a phage display library of camelid single-domain antibodies against three different target proteins. PMID- 24402334 TI - Coping with crack consumption. PMID- 24402335 TI - Seroprevalence of hepatitis C and factors associated with this in crack users. AB - OBJECTIVE: to investigate the seroprevalence of hepatitis C in crack users in Piaui. METHOD: seroepidemiological survey, undertaken in the Psycho-Social Care Centers for Drugs and Alcohol (CAPS AD) in Piaui in the period December 2011 to May 2012. A questionnaire was administered and blood samples were collected for serological research. Fisher's exact test and the Mann-Whitney test were used, with a level of significance of (p<0.05). RESULTS: the prevalence of Anti-HCV was 05 (1.4%) and 04 (1.1%) for the RNA-HCV. There was a statistically significant association between hepatitis C (serological marker RNA-HCV) and age, being resident at home, length of use of crack, interruption of the use of crack, and the habit of sharing the crack pipes. CONCLUSION: the findings support the need to implement health policies aimed at crack users, due to the accelerated process of physical and psychological deterioration to which these are subject. PMID- 24402336 TI - Comparison of hand hygiene antimicrobial efficacy: Melaleuca alternifolia essential oil versus triclosan. AB - OBJECTIVE: this study aimed to evaluate the efficacy of hand hygiene performed with two different soap formulations: 0.3% Melaleuca alternifolia essential oil versus 0.5% triclosan, and to compare them with two reference hygiene procedures: the official methodology procedure (soft soap) versus the draft version of the procedure (soft soap + propan-2-ol). METHOD: using the European EN 1499 method, logarithmic reduction factors were determined for the number of colony forming units of Escherichia coli K12 before and after hand hygiene of 15 volunteer subjects, and compared using the one-tailed Wilcoxon test. RESULTS: referring to the soft soap, there was no difference between the performance of soap with 0.3% M. alternifolia and soap containing 0.5% triclosan. The soft soap + propan-2-ol proved to be more effective than the other hand hygiene procedures. CONCLUSION: studies to verify the therapeutic efficacy of essential oil in hand hygiene can improve adherence to this practice. PMID- 24402337 TI - Nursing care in childcare services: Acantose nigricans as a marker for metabolic risk. AB - OBJECTIVE: to analyze the association between the presence of Acantose nigricans and metabolic changes in overweight adolescents, so as to ascertain the relevance of the identification of this marker in the nursing consultation. METHOD: a cross sectional study undertaken between April 2009 and April 2010 with 118 adolescents who were service users of the Center for Child Obesity in Campina Grande in the Brazilian State of Paraiba (PB). The presence of Acantose nigricans, and the subjects' anthropometric measurements, were investigated. The following exams were made: insulin, triglycerides, HDL-Cholesterol, Glucose and the homeostatic model of assessment (HOMA-IR). RESULTS: there was association between the presence of Acantose nigricans and participants with insulin resistance (p=0.008), metabolic syndrome (p=0.031), elevated triglycerides (p=0.045) and altered HDL (p=0.002). CONCLUSIONS: the suggestion is supported that the detection/identification of Acantose nigricans may be used in the nursing consultation as a tool for identifying overweight adolescents with greater risk of metabolic changes. PMID- 24402338 TI - The cost of waste of consumable materials in a surgical center. AB - OBJECTIVES: to identify the types, quantities and cost of the consumable materials sent, used, returned unopened and wasted in surgical operations; to classify the incidences of waste as avoidable or unavoidable losses, and to calculate the rate of waste of the consumable materials in the peri-operative period in the Surgical Center of a Sao Paulo university hospital. METHOD: a descriptive-exploratory case study with a quantitative approach. The convenience sample corresponded to 105 types of consumable materials sent for the 275 operations observed between February and May 2011. RESULTS: the items wasted most were surgical sutures, surgical cotton sutures, and gauze compresses. The total cost of the waste was R$ 709.84. The mean percentage of waste in the sample was 9.34%, of which 1.23% was avoidable and 8.14% unavoidable. CONCLUSION: the study evidenced that the effective management of material resources reduces the costs of the processes, and reduces waste. PMID- 24402339 TI - Nasal colonization with Staphylococcus aureus in individuals with HIV/ AIDS attended in a Brazilian teaching hospital. AB - OBJECTIVE: to evaluate the prevalence of nasal colonization with Staphylococcus aureus in individuals with HIV/AIDS under inpatient treatment in a teaching hospital in the state of Sao Paulo (Brazil). METHOD: a cross-sectional study undertaken in two units specialized in attending people living with HIV/AIDS, in the period August 2011 - July 2012. Socio-demographic and clinical data was collected through individual interviews and from the medical records; samples of nasal secretion were collected with Stuart swabs on the first day of inpatient treatment. Ethical aspects were respected. RESULT: of the 229 individuals with HIV/AIDS hospitalized in this period, 169 participated in the study, with Staphylococcus aureus being identified in the culture tests of 46 (27.2%) of the individuals, resistance to oxacillin being evidenced in 10 (21.8%) participants. CONCLUSION: the results of the research indicate that the prevalence of colonization with Staphylococcus aureus in individuals with HIV/AIDS in the specialized units was considered relevant, possibly contributing to future investigations and, moreover, to the implementation of measures to prevent and control this pathogen in this population. PMID- 24402340 TI - Body composition of chronic renal patients: anthropometry and bioimpedance vector analysis. AB - OBJECTIVE: to compare the body composition of patients undergoing hemodialysis with that of healthy individuals using different methods. METHOD: cross-sectional study assessing male individuals using anthropometric markers, electrical bioimpedance and vector analysis. RESULTS: the healthy individuals presented larger triceps skinfold and arm circumference (p<0.001). The bioimpedance variables also presented significant higher values in this group. Significant difference was found in the confidence interval of the vector analysis performed for both the patients and healthy individuals (p<0.0001). The tolerance intervals showed that 55.20% of the patients were dehydrated, 10.30% presented visible edema, and 34.50% were within normal levels of hydration. Bioimpedance and vector analysis revealed that 52% of the patients presented decreased cell mass while 14.00% presented increased cell mass. CONCLUSIONS: the differences in the body composition of patients and healthy individuals were revealed through bioimpedance and vector analysis but not through their measures of arm circumference and arm muscle area. PMID- 24402341 TI - Assessment of evaluation of transference support and training impact on the work of nurses. AB - OBJECTIVES: to assess the impact of the Training Course on Prevention and Treatment of PU, in width and depth; to observe and analyze the variables of transference support of training, offered by the organization and to verify the existence of the relationship between transference support and training impact. METHODS: this was a quantitative study, in which data were collected through the application of Likert-type instruments, conducted with 75 nurses participating in a training at a hospital organization in Sao Paulo city. Data were analyzed statistically. RESULTS: there was a positive impact in width and depth, and the variables of transference support were strongly related to the impact, and situational factors of support were the main predictors of impact. CONCLUSION: the results pointed toward pathways to redirect the practice of instructional actions in the work environment of individuals in the study scenario and in similar situations that occur in organizations. PMID- 24402342 TI - Workloads, strain processes and sickness absenteeism in nursing. AB - OBJECTIVE: to analyze the workloads, strain processes and sickness absenteeism among nursing workers from a teaching hospital in the Brazilian Central-West. METHOD: a descriptive and cross-sectional study was developed with a quantitative approach, based on the theoretical framework of the social determination of the health-disease process. Data were collected between January and December 2009, based on records of complaints related to occupational exposure among nursing professionals, filed in the software Monitoring System of Nursing Workers' Health. For the sake of statistical analysis, relative and absolute frequencies of the variables and the risk coefficient were considered. RESULTS: 144 notifications of occupational exposure were registered across the analysis period, which represented 25% of the total nursing population at the hospital. The physiological and psychic workloads were the most representative, corresponding to 37% and 36%, respectively. These notifications culminated in 1567 days of absenteeism for disease treatment. CONCLUSIONS: the findings evidence the impact of occupational illnesses on the absenteeism of nursing workers, and can be used to demonstrate the importance of institutional investments in occupational health surveillance. PMID- 24402343 TI - Work ability in nursing: relationship with psychological demands and control over the work. AB - OBJECTIVE: to evaluate the association between psychological demands, control over the work and the reduction of work ability of nursing professionals. METHOD: this cross-sectional study involved 498 nursing professionals of a university hospital in the State of Rio Grande do Sul, Brazil. Data collection was carried out in 2009 using the Brazilian versions of the Work Ability Index and Job Stress Scale, with logistic regression models used for the data analysis. RESULTS: the prevalence of 43.3% for reduced work ability and 29.7% for high-strain in the job (high psychological demand and low control) were observed. The chances for professionals presenting reduced work ability under high-strain were higher and significant when compared to those classified as being under low-strain, even after adjusting for potential confounders, except for age and gender. CONCLUSION: a high prevalence of reduced work ability was observed. This evidence indicates the need for investigation and detailed analysis of the psychosocial aspects of the professionals with regard to the health/disease process of nursing professionals. PMID- 24402344 TI - Job satisfaction among health care workers: the role of gender and age. AB - OBJECTIVE: to analyze the influence of gender and age on the quality of the professional lives of health care professionals at a university hospital. METHOD: a total of 546 professionals completed a general questionnaire that measured sociodemographic variables and evaluated job satisfaction using a scale adopted from the NTP 394 Job Satisfaction scale and translated into Spanish. RESULTS: overall, 77.2% of the professionals surveyed were satisfied with the work they perform. With regards to gender, we found overwhelming evidence of the feminization of practically all health care professions included in the study, with higher levels of job satisfaction among women than men. Regarding age, 20-30 year-olds and professionals over 61 years old showed higher satisfaction levels than did middle-aged professionals. Higher levels of dissatisfaction were reported by professionals between 41 and 50 years old. CONCLUSIONS: we were able to detect the influence of gender and age on the level of job satisfaction, finding significant associations between job satisfaction and both of these variables. Generally, women expressed more satisfaction than men, and elderly professionals showed higher satisfaction compared to younger professionals. Management policies should focus on taking action to correct the conditions that produce dissatisfaction among certain groups of employees. PMID- 24402345 TI - Comparison between ability and performance: a study on the functionality of dependent elderly individuals. AB - OBJECTIVE: to compare the ability and performance of Basic Activities of Daily Living of dependent elderly individuals cared for in a geriatric healthcare center. METHOD: cross-sectional, observational study with quantitative approach. The Functional Independence Measure (FIM) was applied in 109 elderly individuals cared for in a geriatric healthcare center. Of these, 60 individuals were classified as dependent in the case of basic activities of daily living described according to the International Classification of Functionality, Disability and Health (ICF). The process of triangulation reinforced reliability of data, which included information provided by patients and caregivers and that contained in medical files and objective assessment. RESULTS: the average age was 81.0+/-7.1 with a predominance of women. The difference between ability and performance was statistically significant (p<0.05) in most daily tasks. CONCLUSION: the contribution of this study in using ICF was semi-quantitatively interpreting its qualifiers, which enabled more objective comparisons and inferences, and revealed a clear distance between the performance and ability of these individuals in most of the assessed activities. PMID- 24402346 TI - Relationship between subjective social status and perceived health among Latin American immigrant women. AB - OBJECTIVE: to explore the relationship between socioeconomic status and subjective social status and explain how subjective social status predicts health in immigrant women. METHODS: cross-sectional study based on data from 371 Latin American women (16-65 years old) from a total of 7,056 registered immigrants accessed through community partners between 2009-2010. Socioeconomic status was measured through education, income and occupation; subjective social status was measured using the MacArthur Scale, and perceived health, using a Likert scale. RESULTS: a weak correlation between socioeconomic and subjective social status was found. In the bivariate analysis, a significantly higher prevalence of negative perceived health in women with no education, low income, undocumented employment was observed. In the multivariate analysis, higher odds of prevalence of negative perceptions of health in the lower levels of the MacArthur scale were observed. No significant differences with the rest of the variables were found. CONCLUSIONS: the study suggests that subjective social status was a better predictor of health status than the socioeconomic status measurements. Therefore, the use of this measurement may be relevant to the study of health inequalities, particularly in socially disadvantaged groups such as immigrants. PMID- 24402347 TI - The hospitalized preterm newborn: the significance of parents' participation in the Neonatal Unit. AB - OBJECTIVE: to identify and analyze the significance of participation for parents in a Neonatal Unit (NU) of a maternity hospital in San Luis Potosi, Mexico. METHOD: a qualitative study with 20 parents of both sexes, between 18 and 39 years of age, with a preterm hospitalized child. A content analysis using a thematic approach was used for information processing. RESULTS: the significance of: a) the NICU as a place of suffering and waiting, b) dealing with the child's admittance, c) being excluded from the hospitalized child's care and d) being aware of inadequacies in the child's care. CONCLUSION: parents deal with their suffering and experience barriers that impede their participation; they respond to the medical hierarchy that limits participation, even when it goes against their natural role as parents. The caregiving philosophy needs to be transformed so that parents are considered people with the right to participate and to be competent in caring for their child. PMID- 24402348 TI - 500-year climate cycles stacking of recent centennial warming documented in an East Asian pollen record. AB - Here we presented a high-resolution 5350-year pollen record from a maar annually laminated lake in East Asia (EA). Pollen record reflected the dynamics of vertical vegetation zones and temperature change. Spectral analysis on pollen percentages/concentrations of Pinus and Quercus, and a temperature proxy, revealed ~500-year quasi-periodic cold-warm fluctuations during the past 5350 years. This ~500-year cyclic climate change occurred in EA during the mid-late Holocene and even the last 150 years dominated by anthropogenic forcing. It was almost in phase with a ~500-year periodic change in solar activity and Greenland temperature change, suggesting that ~500-year small variations in solar output played a prominent role in the mid-late Holocene climate dynamics in EA, linked to high latitude climate system. Its last warm phase might terminate in the next several decades to enter another ~250-year cool phase, and thus this future centennial cyclic temperature minimum could partially slow down man-made global warming. PMID- 24402349 TI - Prevention and treatment of venous thromboembolism--International Consensus Statement. AB - The aim of this document is to provide a clear and concise account of the evidence regarding efficacy or harm for various methods available to prevent and manage venous thromboembolism (VTE). PMID- 24402350 TI - Correlation of daytime sleepiness with urine metabolites in patients with obstructive sleep apnea. AB - PURPOSE: The apnea-hypopnea index (AHI) is closely related with the severity of daytime sleepiness, but excessive daytime sleepiness (EDS) is not presented on all patients with obstructive sleep apnea (OSA). It is unclear why daytime sleepiness is not always present in OSA patients even if their sleep is disrupted from the perspective of polysomnographic findings. This study aimed to analyze the correlation between sleepiness and urine metabolites of neurotransmitters involved in the arousal system. METHODS: On the basis of AHI in polysomnography, 49 consecutive OSA patients were included. According to their Epworth sleepiness scale (ESS), 23 non-sleepy patients (ESS <11) and 26 sleepy patients (ESS >=11) were included. Urine samples were collected before and after polysomnography and analyzed by gas chromatography-mass spectrometry with selective ion monitoring. Six metabolites of dopamine, norepinephrine and serotonin were analyzed. RESULTS: The dopamine metabolites, homovanillic acid (r = 0.366, P = 0.017) and 3,4 dihydroxyphenylacetic acid (DOPAC; r = 0.584, P < 0.0001), were significantly correlated with ESS after adjusting for age, sex, body mass index, AHI, sleep efficiency and total sleep time. A two-by-two table analysis revealed that the overnight increase in the urine DOPAC was more frequent in sleepy patients while its decrease was more frequent in non-sleepy patients (odds ratio = 3.54, P = 0.032). CONCLUSION: Urine dopamine metabolites may identify sleepy patients with OSA. In particular, the overnight change of urine DOPAC may indicate OSA patients with EDS. PMID- 24402352 TI - Hydrogen evolution from a copper(I) oxide photocathode coated with an amorphous molybdenum sulphide catalyst. AB - Concerns over climate change resulting from accumulation of anthropogenic carbon dioxide in the atmosphere and the uncertainty in the amount of recoverable fossil fuel reserves are driving forces for the development of renewable, carbon-neutral energy technologies. A promising clean solution is photoelectrochemical water splitting to produce hydrogen using abundant solar energy. Here we present a simple and scalable technique for the deposition of amorphous molybdenum sulphide films as hydrogen evolution catalyst onto protected copper(I) oxide films. The efficient extraction of excited electrons by the conformal catalyst film leads to photocurrents of up to -5.7 mA cm(-2) at 0 V versus the reversible hydrogen electrode (pH 1.0) under simulated AM 1.5 solar illumination. Furthermore, the photocathode exhibits enhanced stability under acidic environments, whereas photocathodes with platinum nanoparticles as catalyst deactivate more rapidly under identical conditions. The work demonstrates the potential of earth-abundant light-harvesting material and catalysts for solar hydrogen production. PMID- 24402351 TI - Autophagy and hippocampal neuronal injury. AB - BACKGROUND: Autophagy is a specific universal biological phenomenon in eukaryotic cells, which is characterized by cytoplasmic vacuoles in the process of degrading cellular contents in lysosomes. The hippocampus plays an important role in higher nervous activities such as emotional integration, cognition, and memory. As an area closely related to learning and memory functions of the brain, the hippocampus is particularly sensitive to injuries caused by various reasons. PURPOSE: Autophagy has certain links with a variety of causes of hippocampal neuronal injury. This short review discusses and summarizes this correlation with a focus on the possible role of autophagy and mechanisms in it. CONCLUSION: The current correlation between autophagy and hippocampal neuronal injury has not been completely determined by the general public alike. Further studies are needed to determine special effects of autophagy on hippocampal neuronal injury, which might accelerate the development of therapeutic interventions in hippocampal neuronal injury in many neurological disorders. PMID- 24402353 TI - A highly sensitive immunoassay using antibody-conjugated spherical mesoporous silica with immobilized enzymes. AB - A highly sensitive immunoassay was developed by using antibody-conjugated spherical mesoporous silica with immobilized enzymes. The higher ratio of enzyme/antibody than conventional ELISA improved both the sensitivity and dynamic range. Especially, the use of spherical mesoporous silica could achieve a limit of detection (LOD) with a sensitivity that is 20 times more than that of ELISA using amorphous silica. PMID- 24402355 TI - The value of histology in predicting the effectiveness of vulvar vestibulectomy in provoked vestibulodynia. AB - OBJECTIVE: This study aimed to determine whether histology can predict response to vestibulectomy in the management of provoked vestibulodynia. MATERIALS AND METHODS: Inflammatory cell, mast cell, and nerve fiber counts were determined in prospectively collected vulvar vestibulectomy specimens from 30 women treated surgically for provoked vestibulodynia. RESULTS: Twenty-three subjects (77%) had a complete early response to surgery. At 3 years of follow-up, this had increased to 28 (93%), with a 29th showing some improvement. No subject had gotten worse after surgery or in the 3 years of follow-up. When comparing patients with an early complete response with those patients who still had symptoms, no difference in lymphocyte counts (27.6 vs. 37.8 per mm), mast cell counts (110.4 vs. 97.8 per mm), or stromal nerve fiber counts (16.4 vs. 16.4 per mm) was found. CONCLUSIONS: Vestibulectomy is a very effective treatment option in women with provoked vestibulodynia who have had failed conservative treatment. Histology is unable to predict which patients will respond to surgery. PMID- 24402356 TI - Hormonal therapy for aggressive angiomyxoma: a case report and proposed management algorithm. AB - OBJECTIVE: This study aimed to report the results of hormonal therapy in the management of a patient with recurrent aggressive angiomyxoma (AAM) and to propose a management strategy for AAM based on (1) the estrogen receptor (ER) and progestin receptor contents of the tumor (2) the extent of disease based on magnetic resonance imaging findings and (3) the patient's menopausal status. MATERIALS AND METHODS: The chart of a patient with multiple pelvic recurrences of AAM managed surgically during a 16-year period followed by hormonal therapy was reviewed, and a literature search of pelvic, vaginal, and vulva AAM was performed. RESULTS: The patient presented in this report experienced 7 recurrences of AAM managed surgically during a 16-year period. She then was placed on leuprolide acetate for 3 monthly cycles, but the tumor recurred 6 months after the leuprolide acetate was discontinued. The patient was placed back on monthly leuprolide acetate for 5 years and has remained free of disease for more than 2 years after discontinuing the leuprolide acetate. A literature review suggest a role for hormonal therapy in the management of AAM based on the presence of ER/progestin receptor, the extent of the disease, and the menopausal status of the patient. Gonadotropin-releasing hormone analogs have been successfully used in premenopausal women as neoadjuvant therapy before surgery for previously untreated or recurrent disease, as adjuvant therapy after the initial surgical resection or after the resection of recurrent disease, and as the definitive treatment of AAM. Aromatase inhibitors may play a role in the treatment of ER-positive AAM occurring in postmenopausal women. CONCLUSIONS: Aggressive angiomyxoma can be an extremely hormonally sensitive tumor. Hormonal therapy may have a significant role in the treatment of patients with extensive or recurrent AAM that is ER positive. The selection of hormonal agents used for treating AAM can be based on the patient's menopausal status. PMID- 24402357 TI - Botryomycosis of the vulva: a case report. AB - OBJECTIVE: Vulvar ulcers may be caused by various etiologies including infection, trauma, dermatosis, and cancer. We report a case of a vulvar ulcer caused by botryomycosis. CASE: An 85-year-old woman presented with vulvar itching, pain, bleeding, and ulcerations suspicious for cancer. Biopsies of the ulcers returned without dysplasia or malignancy. She was referred to the tertiary care vulvar vaginal disease clinic. Dermatopathologic reevaluation of pathologic slides diagnosed lichen sclerosus and botryomycosis. The patient was treated with ciprofloxacin for 7 weeks with complete resolution of vulvar ulcerations. CONCLUSION: Botryomycosis should be included in the differential diagnosis of infectious etiology of vulvar ulcers. PMID- 24402358 TI - Fungal endophytes of aquatic macrophytes: diverse host-generalists characterized by tissue preferences and geographic structure. AB - Most studies of endophytic symbionts have focused on terrestrial plants, neglecting the ecologically and economically important plants present in aquatic ecosystems. We evaluated the diversity, composition, host and tissue affiliations, and geographic structure of fungal endophytes associated with common aquatic plants in lentic waters in northern Arizona, USA. Endophytes were isolated in culture from roots and photosynthetic tissues during two growing seasons. A total of 226 isolates representing 60 putative species was recovered from 9,600 plant tissue segments. Although isolation frequency was low, endophytes were phylogenetically diverse and species-rich. Comparisons among the most thoroughly sampled species and reservoirs revealed that isolation frequency and diversity did not differ significantly between collection periods, among species, among reservoirs, or as a function of depth. However, community structure differed significantly among reservoirs and tissue types. Phylogenetic analyses of a focal genus (Penicillium) corroborated estimates of species boundaries and informed community analyses, highlighting clade- and genotype level affiliations of aquatic endophytes with both sediment- and waterborne fungi, and endophytes of proximate terrestrial plants. Together these analyses provide a first quantitative examination of endophytic associations in roots and foliage of aquatic plants and can be used to optimize survey strategies for efficiently capturing fungal biodiversity at local and regional scales. PMID- 24402359 TI - Identification of bacterial strains isolated from the Mediterranean Sea exhibiting different abilities of biofilm formation. AB - The Mediterranean Sea has rarely been investigated for the characterization of marine bacteria as compared to other marine environments such as the Atlantic or Pacific Ocean. Bacteria recovered from inert surfaces are poorly studied in these environments, when it has been shown that the community structure of attached bacteria can be dissimilar from that of planktonic bacteria present in the water column. The objectives of this study were to identify and characterize marine bacteria isolated from biofilms developed on inert surfaces immersed in the Mediterranean Sea and to evaluate their capacity to form a biofilm in vitro. Here, 13 marine bacterial strains have been isolated from different supports immersed in seawater in the Bay of Toulon (France). Phylogenetic analysis and different biological and physico-chemical properties have been investigated. Among the 13 strains recovered, 8 different genera and 12 different species were identified including 2 isolates of a novel bacterial species that we named Persicivirga mediterranea and whose genus had never been isolated from the Mediterranean Sea. Shewanella sp. and Pseudoalteromonas sp. were the most preponderant genera recovered in our conditions. The phenotypical characterization revealed that one isolate belonging to the Polaribacter genus differed from all the other ones by its hydrophobic properties and poor ability to form biofilms in vitro. Identifying and characterizing species isolated from seawater including from Mediterranean ecosystems could be helpful for example, to understand some aspects of bacterial biodiversity and to further study the mechanisms of biofilm (and biofouling) development in conditions approaching those of the marine environment. PMID- 24402360 TI - 16S rDNA pyrosequencing analysis of bacterial community in heavy metals polluted soils. AB - Soil contamination with heavy metals is a widespread problem, especially prominent on grounds lying in the vicinity of mines, smelters, and other industrial facilities. Many such areas are located in Southern Poland; they are polluted mainly with Pb, Zn, Cd, or Cu, and locally also with Cr. As for now, little is known about most bacterial species thriving in such soils and even less about a core bacterial community--a set of taxa common to polluted soils. Therefore, we wanted to answer the question if such a set could be found in samples differing physicochemically and phytosociologically. To answer the question, we analyzed bacterial communities in three soil samples contaminated with Pb and Zn and two contaminated with Cr and lower levels of Pb and Zn. The communities were assessed with 16S rRNA gene fragments pyrosequencing. It was found that the samples differed significantly and Zn decreased both diversity and species richness at species and family levels, while plant species richness did not correlate with bacterial diversity. In spite of the differences between the samples, they shared many operational taxonomic units (OTUs) and it was possible to delineate the core microbiome of our sample set. The core set of OTUs comprised members of such taxa as Sphingomonas, Candidatus Solibacter, or Flexibacter showing that particular genera might be shared among sites ~40 km distant. PMID- 24402361 TI - Molecular characterization of skin microbiota between cancer cachexia patients and healthy volunteers. AB - Systemic inflammation contributes to both the development of cancer and of cachexia. The microenvironment of bacterial habitats might be changed during the progression of cancer cachexia. The aim of this study was to quantitatively and qualitatively compare the composition of the skin microbiota between cancer cachexia patients and healthy volunteers. Cutaneous bacteria were swabbed at the axillary fossa of 70 cancer cachexia patients and 34 healthy individuals from China. Nested-PCR-denaturing gradient gel electrophoresis (PCR-DGGE) with primers specifically targeting V3 region and quantitative PCR (qPCR) for total bacteria, Corynebacterium spp., Staphylococcus spp., and Staphylococcus epidermidis were performed on all samples. Barcoded 454 pyrosequencing of the V3-V4 regions was performed on 30 randomly selected samples. By comparing diversity and richness indices, we found that the skin microbiome of cachectic cancer patients is less diverse than that of healthy participants, though these differences were not significant. The main microbes that reside on human skin were divided into four phyla: Firmicutes, Actinobacteria, Proteobacteria, and Bacteroidetes. Staphylococcus spp. and Corynebacterium spp. were the dominant bacteria at the genus level. Significantly fewer Corynebacterium spp. had been observed in cachexia patients compared to healthy subjects. These results suggest that the presence of cancer and cachexia alters human skin bacterial communities. Understanding the changes in microbiota during cancer cachexia may lead to new insights into the syndrome. PMID- 24402362 TI - Molecular techniques revealed highly diverse microbial communities in natural marine biofilms on polystyrene dishes for invertebrate larval settlement. AB - Biofilm microbial communities play an important role in the larval settlement response of marine invertebrates. However, the underlying mechanism has yet to be resolved, mainly because of the uncertainties in characterizing members in the communities using traditional 16S rRNA gene-based molecular methods and in identifying the chemical signals involved. In this study, pyrosequencing was used to characterize the bacterial communities in intertidal and subtidal marine biofilms developed during two seasons. We revealed highly diverse biofilm bacterial communities that varied with season and tidal level. Over 3,000 operational taxonomic units with estimates of up to 8,000 species were recovered in a biofilm sample, which is by far the highest number recorded in subtropical marine biofilms. Nineteen phyla were found, of which Cyanobacteria and Proteobacteria were the most dominant one in the intertidal and subtidal biofilms, respectively. Apart from these, Actinobacteria, Bacteroidetes, and Planctomycetes were the major groups recovered in both intertidal and subtidal biofilms, although their relative abundance varied among samples. Full-length 16S rRNA gene clone libraries were constructed for the four biofilm samples and showed similar bacterial compositions at the phylum level to those revealed by pyrosequencing. Laboratory assays confirmed that cyrids of the barnacle Balanus amphitrite preferred to settle on the intertidal rather than subtidal biofilms. This preference was independent of the biofilm bacterial density or biomass but was probably related to the biofilm community structure, particularly, the Proteobacterial and Cyanobacterial groups. PMID- 24402363 TI - An affinity-effect relationship for microbial communities in plant-soil feedback loops. AB - Feedback loops involving soil microorganisms can regulate plant populations. Here, we hypothesize that microorganisms are most likely to play a role in plant soil feedback loops when they possess an affinity for a particular plant and the capacity to consistently affect the growth of that plant for good or ill. We characterized microbial communities using whole-community DNA fingerprinting from multiple "home-and-away" experiments involving giant ragweed (Ambrosia trifida L.) and common sunflower (Helianthus annuus L.), and we looked for affinity effect relationships in these microbial communities. Using canonical ordination and partial least squares regression, we developed indices expressing each microorganism's affinity for ragweed or sunflower and its putative effect on plant biomass, and we used linear regression to analyze the relationship between microbial affinity and effect. Significant linear affinity-effect relationships were found in 75 % of cases. Affinity-effect relationships were stronger for ragweed than for sunflower, and ragweed affinity-effect relationships showed consistent potential for negative feedback loops. The ragweed feedback relationships indicated the potential involvement of multiple microbial taxa, resulting in strong, consistent affinity-effect relationships in spite of large scale microbial variability between trials. In contrast, sunflower plant-soil feedback may involve just a few key players, making it more sensitive to underlying microbial variation. We propose that affinity-effect relationship can be used to determine key microbial players in plant-soil feedback against a low "signal-to-noise" background of complex microbial datasets. PMID- 24402364 TI - Role of prokaryotic biomasses and activities in carbon and phosphorus cycles at a coastal, thermohaline front and in offshore waters (Gulf of Manfredonia, Southern Adriatic Sea). AB - The Western areas of the Adriatic Sea are subjected to inputs of inorganic nutrients and organic matter that can modify the trophic status of the waters and consequently, the microbiological processes involved in the carbon and phosphorus biogeochemical cycles, particularly in shallow coastal environments. To explore this topic, a survey was carried out during the spring of 2003 in a particular hydrodynamic area of the Gulf of Manfredonia, where the potential (P) and real (R) rates of four different microbial exoenzymatic activities (EEA) (alpha [alphaG] and beta glucosidases [betaG], leucine aminopeptidase [LAP], and alkaline phosphatase [AP]) as well as the P and R rates of prokaryotic heterotrophic production (PHP), AP as well as the P and R rates of PHP, primary production (PPnet), the prokaryotic and phototrophic stocks and basic hydrological parameters were examined. Three different water masses were found, with a thermohaline front (THF) being detected between the warmer and less saline coastal waters and colder and saltier offshore Adriatic waters. Under the general oligotrophic conditions of the entire Gulf, a decreasing gradient from the coastal toward the offshore areas was detected, with PHP, PPnet, stocks and EEA (alphaG, betaG, AP) being directly correlated with the temperature and inversely correlated with the salinity, whereas opposite relationships were observed for LAP activity. No enhancement of microbiological activities or stocks was observed at the THF. The use of P or R rates of microbiological activities, which decrease particularly for EEA, could result in discrepancies in interpreting the efficiency of several metabolic processes. PMID- 24402365 TI - Root-associated fungi of Rosa rugosa grown on the frontal dunes of the Baltic Sea Coast in Lithuania. AB - The aim of the present study was to assess fungal communities associated with fine living roots of Rosa rugosa Thunb grown on the frontal dunes of Curonian Spit at the Baltic Sea coast in Lithuania. The roots of R. rugosa were sampled at five sites (Nida, Preila, Pervalka, Juodkrante and Smiltyne) situated at a distance ca. 5-15 km from each other. Direct amplification, cloning and sequencing of fungal ITS rRNA from the fine roots resulted in 134 high-quality sequences, representing 31 fungal taxa among which saprotrophs and endophytes Mycena sp. (14.2 %), Tumularia sp. (14.2 %), Penicillium spinulosum (11.9 %) and Cadophora malorum (9.0 %) were most common. Arbuscular mycorrhizal fungi including Entrophospora baltica (0.7 %) and Rhizophagus irregularis (0.7 %) and potentially root pathogenic fungi--Ceratobasidium sp. (4.5 %), Fusarium oxysporum (3.0 %), Fusarium culmorum (0.7 %) and Ilyonectria crassa (0.7 %)--were also detected at low proportions. In conclusion, the results demonstrated that the fine roots of R. rugosa are inhabited by various groups of fungi. Although saprotrophs and endophytes were dominant, the detection of arbuscular mycorrhizal fungi indicated that these may be important for mineral nutrition of R. rugosa established on dry and poor fertility coastal dunes. PMID- 24402366 TI - Detection of thermoactinomyces species in selected agricultural substrates from Queensland. AB - Selected overheated substrates commercially available for public use in sub tropical Queensland, Australia were screened for the presence of Thermoactinomyces species using an air sampler. All substrates with the exception of tea tree mulch were found to contain Thermoactinomyces species. Subsequent 16S rDNA oligonucleotide sequencing of the selected eight isolates indicated that some of these species were closely related to previously reported allergenic Thermoactinomyces vulgaris and Laceyella sacchari. In view of this, the isolates were tested to determine their adhesion ability and cytotoxicity to human lung cells (calu-3 cells). The results indicated that all eight isolates were highly adherent and showed cytotoxicity to this cell line. These findings might indicate that the presence of such species in overheated agricultural materials may constitute a public health risk if storage and handling conditions are not optimal and do not meet criteria defined for sub-tropical climates. PMID- 24402367 TI - 16S rRNA gene pyrosequencing reveals shift in patient faecal microbiota during high-dose chemotherapy as conditioning regimen for bone marrow transplantation. AB - Gastrointestinal disturbances are a side-effect frequently associated with haematological malignancies due to the intensive cytotoxic treatment given in connection with bone marrow transplantation (BMT). However, intestinal microbiota changes during chemotherapy remain poorly described, probably due to the use of culture-based and low-resolution molecular methods in previous studies. The objective of our study was to apply a next generation DNA sequencing technology to analyse chemotherapy-induced changes in faecal microbiota. We included eight patients with non-Hodgkin's lymphoma undergoing one course of BMT conditioning chemotherapy. We collected a prechemotherapy faecal sample, the day before chemotherapy was initiated, and a postchemotherapy sample, collected 1 week after the initiation of chemotherapy. Total DNA was extracted from faecal samples, denaturing high-performance liquid chromatography based on amplification of the V6 to V8 region of the 16S ribosomal RNA (rRNA) gene, and 454-pyrosequencing of the 16 S rRNA gene, using PCR primers targeting the V5 and V6 hypervariable 16S rRNA gene regions were performed. Raw sequence data were screened, trimmed, and filtered using the QIIME pipeline. We observed a steep reduction in alpha diversity and significant differences in the composition of the intestinal microbiota in response to chemotherapy. Chemotherapy was associated with a drastic drop in Faecalibacterium and accompanied by an increase of Escherichia. The chemotherapy-induced shift in the intestinal microbiota could induce severe side effects in immunocompromised cancer patients. Our study is a first step in identifying patients at risk for gastrointestinal disturbances and to promote strategies to prevent this drastic shift in intestinal microbiota. PMID- 24402368 TI - Ecological diversification of Vibrio fischeri serially passaged for 500 generations in novel squid host Euprymna tasmanica. AB - Vibrio fischeri isolated from Euprymna scolopes (Cephalopoda: Sepiolidae) was used to create 24 lines that were serially passaged through the non-native host Euprymna tasmanica for 500 generations. These derived lines were characterized for biofilm formation, swarming motility, carbon source utilization, and in vitro bioluminescence. Phenotypic assays were compared between "ES" (E. scolopes) and "ET" (E. tasmanica) V. fischeri wild isolates to determine if convergent evolution was apparent between E. tasmanica evolved lines and ET V. fischeri. Ecological diversification was observed in utilization of most carbon sources examined. Convergent evolution was evident in motility, biofilm formation, and select carbon sources displaying hyperpolymorphic usage in V. fischeri. Convergence in bioluminescence (a 2.5-fold increase in brightness) was collectively evident in the derived lines relative to the ancestor. However, dramatic changes in other properties--time points and cell densities of first light emission and maximal light output and emergence of a lag phase in growth curves of derived lines--suggest that increased light intensity per se was not the only important factor. Convergent evolution implies that gnotobiotic squid light organs subject colonizing V. fischeri to similar selection pressures. Adaptation to novel hosts appears to involve flexible microbial metabolism, establishment of biofilm and swarmer V. fischeri ecotypes, and complex changes in bioluminescence. Our data demonstrate that numerous alternate fitness optima or peaks are available to V. fischeri in host adaptive landscapes, where novel host squids serve as habitat islands. Thus, V. fischeri founder flushes occur during the initiation of light organ colonization that ultimately trigger founder effect diversification. PMID- 24402370 TI - Persistence and recycling of bioinsecticidal Bacillus thuringiensis subsp. israelensis spores in contrasting environments: evidence from field monitoring and laboratory experiments. AB - Sprays of commercial preparations of the bacterium Bacillus thuringiensis subsp. israelensis are widely used for the control of mosquito larvae. Despite an abundant literature on B. thuringiensis subsp. israelensis field efficiency on mosquito control, few studies have evaluated the fate of spores in the environment after treatments. In the present article, two complementary experiments were conducted to study the effect of different parameters on B. thuringiensis subsp. israelensis persistence and recycling, in field conditions and in the laboratory. First, we monitored B. thuringiensis subsp. israelensis persistence in the field in two contrasting regions in France: the Rhone-Alpes region, where mosquito breeding sites are temporary ponds under forest cover with large amounts of decaying leaf matter on the ground and the Mediterranean region characterized by open breeding sites such as brackish marshes. Viable B. thuringiensis subsp. israelensis spores can persist for months after a treatment, and their quantity is explained both by the vegetation type and by the number of local treatments. We found no evidence of B. thuringiensis subsp. israelensis recycling in the field. Then, we tested the effect of water level, substrate type, salinity and presence of mosquito larvae on the persistence/recycling of B. thuringiensis subsp. israelensis spores in controlled laboratory conditions (microcosms). We found no effect of change in water level or salinity on B. thuringiensis subsp. israelensis persistence over time (75 days). B. thuringiensis subsp. israelensis spores tended to persist longer in substrates containing organic matter compared to sand-only substrates. B. thuringiensis subsp. israelensis recycling only occurred in presence of mosquito larvae but was unrelated to the presence of organic matter. PMID- 24402371 TI - Versatile ruthenium(II)-catalyzed C-H cyanations of benzamides. AB - Direct cyanations of arenes and heteroarenes bearing only weakly coordinating amides were accomplished using a robust ruthenium(II) catalyst. The user-friendly C(sp(2))-H activation occurred with the assistance of carboxylate with high site selectivity, excellent functional group tolerance and ample scope. PMID- 24402369 TI - Factors affecting the strength of Cardinium-induced cytoplasmic incompatibility in the parasitic wasp Encarsia pergandiella (Hymenoptera: Aphelinidae). AB - Bacteria that cause cytoplasmic incompatibility (CI) are among the most common maternally transmitted parasites of insects. In CI, uninfected females produce few or no offspring when they mate with infected males and, as a result, are often at a reproductive disadvantage relative to infected females. Two different bacteria are known to cause CI, Wolbachia and Cardinium. CI Cardinium was discovered more recently and has been little studied. Here, factors that could influence the reduction in reproductive output in a CI cross, or CI "strength," were explored in the parasitic wasp Encarsia pergandiella. Cardinium in this wasp exhibits variable CI strength. Experiments tested the effect of male age, male size, male host species, Cardinium density, and male development time on CI strength. We found a striking effect of male development time, with males that took longer to develop exhibiting stronger CI when mated to uninfected females. Male age had little effect; although in one experiment, the oldest males exhibited stronger CI. Male size, host species, and bacterial density had no effect on the strength of CI. Identifying the factors that control CI are crucial for understanding the dynamics of infection, as well as the success of strategies that aim to use CI microbes to control insect pests and disease vectors. PMID- 24402372 TI - Near-infrared diffuse optical monitoring of cerebral blood flow and oxygenation for the prediction of vasovagal syncope. AB - Significant drops in arterial blood pressure and cerebral hemodynamics have been previously observed during vasovagal syncope (VVS). Continuous and simultaneous monitoring of these physiological variables during VVS is rare, but critical for determining which variable is the most sensitive parameter to predict VVS. The present study used a novel custom-designed diffuse correlation spectroscopy flow oximeter and a finger plethysmograph to simultaneously monitor relative changes of cerebral blood flow (rCBF), cerebral oxygenation (i.e., oxygenated/deoxygenated/total hemoglobin concentration: r[HbO2]/r[Hb]/rTHC), and mean arterial pressure (rMAP) during 70 deg head-up tilt (HUT) in 14 healthy adults. Six subjects developed presyncope during HUT. Two-stage physiological responses during HUT were observed in the presyncopal group: slow and small changes in measured variables (i.e., Stage I), followed by rapid and dramatic decreases in rMAP, rCBF, r[HbO2], and rTHC (i.e., Stage II). Compared to other physiological variables, rCBF reached its breakpoint between the two stages earliest and had the largest decrease (76+/-8%) during presyncope. Our results suggest that rCBF has the best sensitivity for the assessment of VVS. Most importantly, a threshold of ~50% rCBF decline completely separated the subjects from those without presyncope, suggesting its potential for predicting VVS. PMID- 24402374 TI - miR-511 induces the apoptosis of radioresistant lung adenocarcinoma cells by triggering BAX. AB - Radioresistance is one of the main reasons for the failure of radiotherapy in lung cancer. The present study was conducted to identify the role of miR-511 in suppressing the growth of radioresistant lung adenocarcinoma cells. First, a radioresistant A549/R cell line was generated after prolonged exposure to X-rays for 68 Gy (2 Gy/day, 5 days/week) and the radioresistance was confirmed by wound healing assay. Next, oncogenic TRIB2 was found to be upregulated in the radioresistant A549/R cells when compared to that of the control A549 cells as determined by western blot analysis. As the upstream miRNA, quantitative PCR showed that miR-511 expression was decreased in the radioresistant A549/R cells. Overexpression of miR-511 in miR-511-transfected A549/R cells inhibited cell growth and increased the number of apoptotic cells when compared with the control treatment. Flow cytometric analysis further demonstrated that the growth suppressive effect of miR-511 on A549/R cells was mediated by regulation of the cell cycle, most likely due to a block in the G1-S transition. Finally, our results showed that the expression of BAX was lower in the radioresistant A549/R cells when compared with that in the control A549 cells. After downregulation of TRIB2 by miR-511 treatment, BAX expression was obviously increased in the miR-511 transfected apoptotic A549/R cells when compared to that in the NC-treated or control cultures. In summary, our results revealed that miR-511 regulates the growth of radioresistant A549/R cells by increasing BAX expression through TRIB2, which suggests that miR-511 may be a potential therapeutic molecule for the treatment of radioresistant lung adenocarcinoma. PMID- 24402375 TI - The nature and extent of mutational pleiotropy in gene expression of male Drosophila serrata. AB - The nature and extent of mutational pleiotropy remain largely unknown, despite the central role that pleiotropy plays in many areas of biology, including human disease, agricultural production, and evolution. Here, we investigate the variation in 11,604 gene expression traits among 41 mutation accumulation (MA) lines of Drosophila serrata. We first confirmed that these expression phenotypes were heritable, detecting genetic variation in 96% of them in an outbred, natural population of D. serrata. Among the MA lines, 3385 (29%) of expression traits were variable, with a mean mutational heritability of 0.0005. In most traits, variation was generated by mutations of relatively small phenotypic effect; putative mutations with effects of greater than one phenotypic standard deviation were observed for only 8% of traits. With most (71%) traits unaffected by any mutation, our data provide no support for universal pleiotropy. We further characterized mutational pleiotropy in the 3385 variable traits, using sets of 5, randomly assigned, traits. Covariance among traits chosen at random with respect to their biological function is expected only if pleiotropy is extensive. Taking an analytical approach in which the variance unique to each trait in the random 5 trait sets was partitioned from variance shared among traits, we detected significant (at 5% false discovery rate) mutational covariance in 21% of sets. This frequency of statistically supported covariance implied that at least some mutations must pleiotropically affect a substantial number of traits (>70; 0.6% of all measured traits). PMID- 24402376 TI - Spectroelectrochemistry of Fe(III)- and Co(III)-mimochrome VI artificial enzymes immobilized on mesoporous ITO electrodes. AB - UV-visible absorption spectroelectrochemistry elucidated the different redox behaviours of Fe(III)- and Co(III)-mimochrome VI artificial enzymes, adsorbed on mesoporous conductive films of ITO. The reduction of the ferric complex was rapid and reversible, while the cobaltic complex exhibited irreversible processes probably related to multiple coordination states. PMID- 24402377 TI - p63 and Ki-67 immunostainings in laryngeal squamous cell carcinoma are related to survival. AB - To examine the prognostic significance of the immunohistochemical expression of p63 and Ki-67 oncoproteins in patients with laryngeal squamous cell carcinoma, a retrospective evaluation was carried out on a cohort of 108 patients with primary laryngeal squamous cell carcinoma (LSCC) treated by primary surgery. For the immunohistochemical evaluation, tissue section obtained by formalin-fixed and paraffin-embedded tissue blocks from resection of each patient was used. Clinicopathologic data were associated with the immunostaining results. The association among the considered variables was assessed by Fisher's exact test, Mann-Whitney test, non-parametric chi(2) test, and Spearman's rho rank test was used to assess the relations among them. Differences in p63 and Ki-67 immunoreactivity among the different groups were compared via Kruskal-Wallis test and post hoc tests were performed using Mann-Whitney test with Bonferroni correction. The overall survival rate was estimated via Kaplan-Meier method, and the cumulative incidence functions for different groups were compared using log rank statistics. Cox proportional hazard model was employed in a multivariate analysis to assess the effect of prognostic factors in the overall survival rate. Furthermore, taking into account death due to other causes, we estimated LSCC related survival and disease-free survival rates using competing risk analysis. The results of immunohistochemical examination showed a statistically significant relationship between the up-regulation of P63 and Ki-67, an increase in histological grading, and primary tumours associated with lymph node metastases. p63 and Ki-67 up-regulation was related to a shorter disease-free survival and a significant association was found between p63 and Ki-67 percentage of positive cells and patient survival. Finally, we noticed a significant relation between p63 and Ki-67 (rho = 0.87). On the other hand, no statistically significant associations were found between p63 and Ki-67 down-regulation and clinicopathologic data. Our findings suggest that abnormal p63 and Ki-67 immunoreactivity may be involved in the early phases of laryngeal tumorigenesis and may become a significant prognostic predictor for both overall and disease free survivals. These biomarkers could thus help in the selection of high-risk patients with LSCC who may benefit from more aggressive therapy or chemoprevention. PMID- 24402378 TI - Inventory of economic evaluation of head and neck oncology from the German perspective. AB - New treatment strategies for head and neck neoplasms include induction chemotherapy and biomarker treatment. Moreover, different therapeutic modalities, especially robotic surgery, induction chemotherapy, biotherapy and altered fractionation schedules of chemo-(radio)therapy are newly combined to optimize treatment benefit and minimize treatment-associated morbidity. Often, overall survival does not change significantly between the competing treatment schedules. Therefore, the evaluation of the patient's treatment-related quality of life (QoL) and organ function becomes more and more important. Finally, the sponsor's financial resources are restricted, which makes it necessary to evaluate therapies for pricing and effectiveness. In head and neck cancer in Europe, analyses of the current situation are lacking. Selective literature research for publications on economic cost-effectiveness analyses was performed. An overview of the current situation with a special focus on Europe is provided. Cost effectiveness values and QoL assessments should be respected in former prospective study construction to gain systematic information on this topic. PMID- 24402379 TI - The attention deficit hyperactivity disorder phenotype as a summation of deficits in executive functioning and reward sensitivity: does this explain its relationship with oppositional defiant disorder? AB - OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) commonly coexist but the relationship between them has not been well explained. We present a view of the ADHD phenotype as a summation of deficits in executive functioning and reward sensitivity and apply this to explain its co-occurrence with ODD. MODEL: ADHD relates to difficulty in sustaining concentration for completing tasks. This is associated with lack of reward due to lack of achievement. The unfavorable balance of effort to reward in ADHD is exacerbated in ODD, a condition in which lack of reward is responsible for an adverse effect on mood resulting in a negative attitude and oppositional behavior. We have called this model the "Mental effort-reward imbalances model". CONCLUSION: This model predicts that oppositional symptoms would be highly prevalent in ADHD, to the extent that ODD would be a frequent co-morbidity. PMID- 24402380 TI - Micellar self-assemblies of gadolinium(III)/europium(III) amphiphilic complexes as model contrast agents for bimodal imaging. AB - The synthesis and characterization of two novel DTPA bisamide derivatives DTPA BC12PheA and DTPA-BC14PheA functionalized with p-dodecylaniline and p tetradecylaniline are described. The ligands were coordinated to Gd(iii) and Eu(iii), resulting in highly paramagnetic and luminescent complexes, respectively. Mixed micelles consisting of Gd/Eu-DTPA-BC12PheA and DTPA-BC14PheA with a homogeneous size distribution (33-40 nm) were prepared by the assembly of the amphiphilic complexes with phospholipid DPPC and a surfactant Tween 80(r). Taking into account the sensitivity difference between magnetic resonance and optical imaging techniques, the ratios of Gd and Eu complexes (Gd/Eu) 1 : 1, 2 : 1, 3 : 1, 20 : 1 and 50 : 1 were combined in one single micelle and their optical and relaxometric properties were characterized in detail. Upon excitation at 290 nm, the micelles display characteristic red emission bands due to the (5)D0 >(7)FJ (J = 0-4) transitions of Eu(iii). The number of water molecules in the first coordination sphere of Eu(iii) (qEu = 0.1-0.2) was calculated from the lifetime measurements performed in H2O and D2O solutions. Micelles composed of exclusively europium complexes display quantum yields in the range of 1.0%, decreasing with the europium concentration when going from 1 : 1 to 50 : 1 Gd/Eu contents. The ligand-to-lanthanide sensitization efficiency for micelles consisting of Eu-DTPA-BC12PheA and Eu-DTPA-BC14PheA equals 3.8% and 4.1%, respectively. The relaxivity r1 per Gd(iii) ion at 40 MHz and 310 K reaches a maximum value of 14.2 s(-1) mM(-1) for the Gd-DTPA-BC12PheA assemblies and 16.0 s(-1) mM(-1) for the micellar Gd-DTPA-BC14PheA assemblies compared to a value of 3.5 s(-1) mM(-1) for Gd-DTPA (Magnevist(r)). Theoretical fitting of the (1)H NMRD profiles results in tauR values of 4.2 to 6.6 ns. The optimal concentration ratio of Gd/Eu compounds in the micelles in order to provide the required bimodal performance has been determined to be 20 : 1. In the search for other bimodal systems, this discovery can be used as a guideline concerning the load of paramagnetic agents with respect to luminescent probes. PMID- 24402381 TI - Prevalence and risk factors of food insecurity among a cohort of older Australians. AB - OBJECTIVE: With ongoing national concern about food security, the aim of the study was to estimate the prevalence of food insecurity and to identify associated characteristics in a cohort of older Australians. DESIGN, SETTING AND PARTICIPANTS: The Blue Mountains Eye Study is a cohort study of community living participants aged 49 + years. The 12-item food security survey was completed by 3068 participants in the cross sectional study which comprised 2335 survivors from baseline and the recruitment of an additional 1174 eligible residents. MAIN OUTCOME MEASURES: Prevalence of self reported food insecurity was calculated and multivariate logistic regression provided odds ratios with 95% confidence intervals to determine risk factors. RESULTS: Overall prevalence of food insecurity was 13%. Women (15.7%) compared with men (9.4%) and younger participants, aged <70 years (15.7%) than older participants, >=70 years (8.4%), were significantly more likely to report being food insecure. Characteristics for reporting food insecurity included participants living in rented accommodation (OR 4.10, 95% CI: 2.83, 5.89) and those living on a pension only (OR 1.90, 95%CI: 1.30, 2.78). CONCLUSIONS: A relatively high level of food insecurity among this representative population of older Australians should be an issue of concern for policy makers and health and welfare service providers. Addressing food insecurity should be a priority of integrated national food and nutrition policies and this should in turn inform health and welfare service provision to this vulnerable population. PMID- 24402382 TI - Examining change in social support and fruit and vegetable consumption in African American adults. AB - OBJECTIVE: To examine (a) inter-individual variation in African Americans' fruit and vegetable social support, behavior, and consumption trajectories by estimating latent growth curves (LGCs) and (b) the associations between these trajectories over time. DESIGN: As part of a larger intervention study, data were collected from mid-life and older African Americans yearly for three years. The study incorporated a quasi-experimental design with random selection of participants, stratifying for age and gender. SETTING: Six churches in North Florida. PARTICIPANTS: Two hundred and thirty one (73% women; median age range of 57-63) older African Americans. MEASUREMENTS: A structured questionnaire elicited personal data as well as information on dietary social support, eating-related behaviors, and fruit and vegetable dietary intake. RESULTS: Age was positively associated with initial social support but negatively associated with the rate of change in social support. More important, the rate of change in dietary social support predicted eating-related behavior trajectories, which influenced the rate of change in fruit and vegetable consumption over time after controlling for the intervention. CONCLUSION: These findings illustrate the mediating role of eating related behaviors and the inter-locking nature of social support, behavior and consumption trajectories. This research has implications for future research as well as community interventions and programs. PMID- 24402383 TI - A path model of sarcopenia on bone mass loss in elderly subjects. AB - OBJECTIVE: Aging is associated with decreases in muscle mass, strength, power (sarcopenia) and bone mineral density (BMD). The aims of this study were to investigate in elderly the role of sarcopenia on BMD loss by a path model, including adiposity, inflammation, and malnutrition associations. METHODS: Body composition and BMD were measured by dual X-ray absorptiometry in 159 elderly subjects (52 male/107 female; mean age 80.3 yrs). Muscle strength was determined with dynamometer. Serum albumin and PCR were also assessed. Structural equations examined the effect of sarcopenia (measured by Relative Skeletal Muscle Mass, Total Muscle Mass, Handgrip, Muscle Quality Score) on osteoporosis (measured by Vertebral and Femoral T-scores) in a latent variable model including adiposity (measured by Total Fat Mass, BMI, Ginoid/Android Fat), inflammation (PCR), and malnutrition (serum albumin). RESULTS: The sarcopenia assumed a role of moderator in the adiposity-osteoporosis relationship. Specifically, increasing the sarcopenia, the relationship adiposity-osteoporosis (beta: -0.58) decrease in intensity. Adiposity also influences sarcopenia (beta: -0.18). Malnutrition affects the inflammatory and the adiposity states (beta: +0.61, and beta: -0.30, respectively), while not influencing the sarcopenia. Thus, adiposity has a role as a mediator of the effect of malnutrition on both sarcopenia and osteoporosis. Malnutrition decreases adiposity; decreasing adiposity, in turn, increase the sarcopenia and osteoporosis. CONCLUSIONS: This study suggests such as in a group of elderly sarcopenia affects the link between adiposity and BMD, but not have a pure independent effect on osteoporosis. PMID- 24402384 TI - Metabolic syndrome is associated with increased prevalence of advanced colorectal polyps. AB - OBJECTIVES: To examine the association between metabolic syndrome (MetS) and/or its components and colorectal neoplasms in adult population undergoing screening colonoscopy. DESIGN: Cross-sectional study. SETTING: Institute of Gastroenterology, Kaplan Medical Center, Rehovot, Israel. PARTICIPANTS: Two hundred ninety nine consecutive outpatients undergoing screening colonoscopy. MEASUREMENTS: MetS was determined according to the Adult Treatment Panel III of the National Cholesterol Education Program (ATP III) criteria. Blood test results and other clinical data were retrieved from the electronic medical records. RESULTS: In 94 patients (31.8%) polyps were detected. Thirty two (34%) of the polyps were advanced. Eighty one percent of patients with an advanced polyp met the criteria for MetS. About the same MetS prevalence (84%) was found in men, but not in women. An advanced polyp was detected in 14% of patients with MetS, compared to 5% of patients without MetS. Odds ratio for having an advanced polyp in a patient with MetS compared to a patient without MetS was 10.64. CONCLUSION: MetS was found to be a risk factor for advanced polyps. This association is suggestive of the need that patients with MetS should be urged to have a screening colonoscopy. PMID- 24402385 TI - Low muscle mass in older men: the role of lifestyle, diet and cardiovascular risk factors. AB - OBJECTIVE: To explore associations between low muscle mass and a wide range of lifestyle, dietary and cardiovascular risk factors in older men including metabolic risk factors, markers of inflammation, endothelial dysfunction and coagulation. DESIGN: Cross-sectional study. SETTING: British Regional Heart Study. PARTICIPANTS: 4252 men aged 60-79 years. MEASUREMENTS: PARTICIPANTS attended a physical examination in 1998-2000, and completed a general questionnaire and a food frequency questionnaire. Low muscle mass was assessed by two measures: midarm muscle circumference (MAMC) and fat-free mass index (FFMI). Associations between risk factors and low muscle mass were analysed using logistic regression. RESULTS: Physical inactivity, insulin resistance, C-reactive protein, von Willebrand factor and fibrinogen were associated with significantly increased odds of low MAMC and FFMI after adjustment for body mass index, lifestyle characteristics and morbidity. Those with higher percent energy intake from carbohydrates showed decreased odds of low MAMC (OR: 0.73, 95% CI: 0.55 0.96) and FFMI (OR: 0.76, 95% CI: 0.58-0.99). Other dietary variables, smoking, alcohol intake, D-dimer, interleukin 6 and homocysteine showed no important associations with MAMC and FFMI. CONCLUSION: Increasing physical activity, consuming a diet with a high proportion of energy from carbohydrates, and taking steps to prevent insulin resistance and reduce inflammation and endothelial dysfunction may help to reduce the risk of low muscle mass in older men. PMID- 24402386 TI - Dentition status, malnutrition and mortality among older service housing residents. AB - BACKGROUND: Oral health status and oral health problems can affect eating habits and thus consequently the nutritional status of frail older people. OBJECTIVES: To assess older service house residents' dentition and its associations with nutritional status and eating habits, and as well as to explore the prognostic value of dentition status for mortality. DESIGN: A cross-sectional study with a three-year follow-up. METHODS: In 2007, we assessed the nutritional status of all residents in service houses in the two cities of Helsinki and Espoo in Finland (N=2188). Altogether 1475 subjects (67%) participated in the study; dentition status data were available for 1369 of them. Using a personal interview and assessment, trained nurses familiar to the resident collected the subjects' demographic data, medical history, functional and cognitive status, information on dentition status, oral symptoms, eating habits and diets. We assessed nutritional status with the Mini Nutritional Assessment (MNA), and retrieved information on mortality from central registers on 6 July 2010. RESULTS: Edentulousness was common; more than half of the residents (52%) had lost all their teeth: 7% (n=94) were totally edentulous without prosthesis (Group 1), 45% (n=614) had removable dentures (Group 2), and 48% (n = 661) of the residents, had some natural teeth left (Group 3). Dentition status was associated with age, gender, education and disability. According to the MNA, 13% were malnourished, 65% were at risk for malnutrition, and 22% were well nourished. Edentulousness without prosthesis was associated with malnutrition, oral symptoms and infrequent use of oral care services. In Group 1, 52% were deceased during follow-up period. The respective figures for Groups 2 and 3 were 48% and 40% (p=0.004). However, in Cox regression analysis adjusted for age, gender, comorbidity and MNA score, dentition status no longer predicted mortality. CONCLUSION: Edentulousness is still common among older service housing residents. Edentulousness without prosthesis was associated with poor nutritional status, oral symptoms and infrequent use of dental services. These findings suggest the need for co operation between nursing staff and oral care services. PMID- 24402387 TI - Validation of the nutrition screening tool 'Seniors in the Community: Risk Evaluation for Eating and Nutrition, version II' among octogenarians. AB - OBJECTIVE: To determine the validity of the nutrition screening tool 'Seniors in the Community: Risk Evaluation for Eating and Nutrition, version II' (SCREEN II) among a purposive sample of octogenarians. DESIGN: Cross-sectional validation study. SETTING: Bay of Plenty, New Zealand. PARTICIPANTS: Forty-five community living residents aged 85-86 years. Equal proportions of participants were recruited at low, medium and high nutrition risk based on their SCREEN II score 12 months prior. MEASUREMENTS: Nutrition risk was assessed using SCREEN II. Demographic and health data were established. Using established criterion a dietitian's nutrition risk rating assessment ranked participants from low risk (score of 1) to high risk (score of 10). The assessment included a medical history, anthropometric measures and dietary intake. Dietary intake was established from three 24 hour multiple pass recalls (MPR). A Spearman's correlation determined the association between the SCREEN II score and the dietitian's risk score. Receiver operating characteristic (ROC) curves were completed to determine the sensitivity and specificity of the cut-off point for high nutrition risk. RESULTS: The SCREEN II score was significantly correlated with the dietitian's risk rating (rs = -0.76 (p<0.01). A newly defined cut-off point <49 was established for high nutrition risk derived from ROC curves and AUC (0.87, p < 0.01); sensitivity 90% and specificity 86%. CONCLUSION: SCREEN II is a simple, easy to use, 14 item questionnaire and appears to be a valid tool for detection of nutrition risk people aged 85-86 years. PMID- 24402388 TI - Medication management capacity in relation to cognition and self-management skills in older people on polypharmacy. AB - OBJECTIVE: To determine the medication management capacity of independently living older people (>=75 years) on polypharmacy (>= 5 medications) in relation to their cognitive- and self-management skills. DESIGN: Cross-sectional study. SETTING: Two homecare organizations in the Netherlands. PARTICIPANTS: Homecare clients aged 75 and older on polypharmacy (N=95). MEASUREMENTS: The primary outcome measure was medication management capacity, quantified as the number of 'yes' answers (range = 0-17) on the Medication Management Capacity (MMC) questionnaire. Other measures included self-management ability (assessed with the SMAS30) and cognitive skills (assessed with the clock drawing test). RESULTS: Overall, 48.4% (n= 46) of the participants were able to manage their medication by themselves at home. About 40% of the participants were unable to state the names of their medications, even with the aid of a medication list, and about 25% reported having problems with opening medication packages. Correlations were found between self-management ability (Rs = 0.473; p < 0.001), cognitive skills (Rs = 0.372; p < 0.001), and age (Rs = 0.216; p < 0.005) and Medication Management Capacity score. Self-management ability and medication management support were significantly associated with medication management capacity. CONCLUSION: A considerable proportion of independently living older people who receive home care and regularly use five or more medications lack the knowledge and skills needed to independently manage their own medications. Cognition and self management ability were related to medication management capacity. Self management ability and medication management support were predictors of medication management capacity. PMID- 24402389 TI - Utility of 123I-FP-CIT SPECT for dementia diagnoses and therapeutic strategies in elderly patients. AB - OBJECTIVES: Evaluation of the influence of single photon emission computed tomography (SPECT) of the dopamine transporter (123I-FP-CIT) on diagnosis and treatment strategies in elderly patients with mild dementia. DESIGN: Retrospective study. SETTING: Geriatrics memory clinic. PARTICIPANTS: Consecutive ambulatory patients who had 123I-FP-CIT SPECT for a suspicion of DLB. MEASUREMENTS: Clinical diagnoses before SPECT were compared with imaging results. RESULTS: 46 patients were included. Pre imaging clinical hypotheses were probable DLB in 14, possible DLB in 21 and alternate diagnoses in 11. Rates of abnormal imaging in these groups were respectively 71%, 43% and 18%. Overall, diagnoses were revised in 37% of the cases. Four patients with probable DLB had normal imaging. Their number of core criteria did not differ from the remainder (2.75 +/ 0.5 vs. 2.1 +/- 0.6), but hallucinations in 2 patients were not well formed and detailed as usual in DLB. Among 38 patients free of antipsychotics, rates of abnormal scans were 36% in patients with questionable parkinsonism, 57% in definite parkinsonism, 67% in patients with no parkinsonism. Among 9 patients on Levodopa, 6 had normal scans and Levodopa was stopped. CONCLUSION: We show a significant impact of 123I-FP-CIT SPECT on diagnoses, even in cases of definite parkinsonism or probable DLB. In the latter, scarcity of hallucinations, especially if there are not well formed and detailed, should prompt 123I-FP-CIT SPECT. PMID- 24402390 TI - Effects of individual dietary counseling as part of a comprehensive geriatric assessment (CGA) on nutritional status: a population-based intervention study. AB - BACKGROUND: Nutritional risk is relatively common in community-dwelling older people. OBJECTIVE: To objective of this study was to evaluate the effects of individual dietary counseling as part of a Comprehensive Geriatric Assessment on nutritional status among community-dwelling people aged 75 years or older. METHODS: Data were obtained from a subpopulation of participants in the population-based Geriatric Multidisciplinary Strategy for the Good Care of the Elderly (GeMS) intervention study in 2004 to 2007. In the present study, the population consist 173 persons at risk of malnutrition in the year 2005 in an intervention (n=84) and control group (n=89). Nutritional status, body weight, body mass index, serum albumin were performed at the beginning of the study and at a two-year follow-up. The nutritional screening was performed using the Mini Nutritional Assessment (MNA) test. RESULTS: A increase in MNA scores (1.8 95% confidence interval [CI]: 0.7 to 2.0) and in serum albumin (0.8 g/L, 95% CI: 0.2 to 0.9 g/L) were a significant difference between the groups. CONCLUSIONS: Nutritional intervention, even dietary counseling without nutritional supplements, may improve nutritional status. PMID- 24402391 TI - The impact of sarcopenia on a physical activity intervention: the Lifestyle Interventions and Independence for Elders Pilot Study (LIFE-P). AB - OBJECTIVE: To determine if sarcopenia modulates the response to a physical activity intervention in functionally limited older adults. DESIGN: Secondary analysis of a randomized controlled trial. SETTING: Three academic centers. PARTICIPANTS: Elders aged 70 to 89 years at risk for mobility disability who underwent dual-energy x-ray absorptiometry (DXA) for body composition at enrollment and follow-up at twelve months (N = 177). INTERVENTION: Subjects participated in a physical activity program (PA) featuring aerobic, strength, balance, and flexibility training, or a successful aging (SA) educational program about healthy aging. MEASUREMENTS: Sarcopenia as determined by measuring appendicular lean mass and adjusting for height and total body fat mass (residuals method), Short Physical Performance Battery score (SPPB), and gait speed determined on 400 meter course. RESULTS: At twelve months, sarcopenic and non-sarcopenic subjects in PA tended to have higher mean SPPB scores (8.7+/-0.5 and 8.7+/-0.2 points) compared to sarcopenic and non-sarcopenic subjects in SA (8.3+/-0.5 and 8.4+/-0.2 points, p = 0.24 and 0.10), although the differences were not statistically significant. At twelve months, faster mean gait speeds were observed in PA: 0.93+/-0.4 and 0.95+/-0.03 meters/second in sarcopenic and non-sarcopenic PA subjects, and 0.89+/-0.4 and 0.91+/-0.03 meters/second in sarcopenic and non-sarcopenic SA subjects (p = 0.98 and 0.26), although not statistically significant. There was no difference between the sarcopenic and non sarcopenic groups in intervention adherence or number of adverse events. CONCLUSION: These data suggest that older adults with sarcopenia, who represent a vulnerable segment of the elder population, are capable of improvements in physical performance after a physical activity intervention. PMID- 24402392 TI - Is obesity a marker of robustness in vulnerable hospitalized aged populations? Prospective, multicenter cohort study of 1 306 acutely ill patients. AB - BACKGROUND: The "obesity paradox" is poorly understood in vulnerable older hospitalized populations. OBJECTIVES: To prospectively analyze the impact of body mass index (BMI) and comorbidities on early (6-week), one- and two-year mortality. DESIGN: Prospective multicenter study with a two-year follow-up of old patients participating in the SAFES cohort study. SETTINGS: Nine university hospitals in France. PARTICIPANTS: Patients aged 75 or older hospitalized in medical divisions through the emergency department. MEASUREMENT: Inpatients' characteristics were obtained through a comprehensive geriatric assessment of inpatients, conducted in the first week of hospitalization. All-cause mortalities at 6-week, one- and two-year were determined using bivariable and multivariable Cox proportional hazard model. RESULTS: The SAFES cohort included 1,306 patients, aged 85+/-6 years, with a majority of women (65%). One- and two-year mortality were inversely associated with BMI >=30 kg/m2 while early mortality was not, and positively associated with age, burden of comorbidities, walking disorders, level of dependency and presence of a dementia syndrome. Survival rates between patients in low (< 18.0 kg/m2) and intermediate (18-24.9 and 25-29.9 kg/m2) BMI categories were not significant. CONCLUSION: While our findings seem to confirm the reality of the "obesity paradox" in vulnerable older hospitalized population, the exact understanding of underlying mechanisms and even the truthfulness of this paradoxical relationship are still fraught with considerable methodological, epidemiological and metabolic challenges. PMID- 24402393 TI - Influence of the geriatric oncology consultation on the final therapeutic decision in elderly subjects with cancer: analysis of 191 patients. AB - OBJECTIVES: Evaluate the impact of the Geriatric Oncology Consultation on the final therapeutic management of cancer in elderly patients aged 70 and older. DESIGN: Retrospective study. SETTING: The Pilot Coordination Unit in Geriatric Oncology of Cote d'Or, Burgundy, France. PARTICIPANTS: From January 2010 to December 2010, 191 patients with cancer aged 70 and older. MEASUREMENTS: The concordance between the treatments proposed following the Tumor Board, those proposed following the Geriatric Evaluation (GE) and those actually given to the patients was evaluated using the Kappa agreement test. RESULTS: One hundred and ninety-one patients were included. Mean age was 81.5. The most frequent cancer locations were breast (31.9%), colon-rectum (14.1%) and lung (10.5%). Concordance between the cancer treatments proposed by the Tumor Board and those suggested after the GE was excellent except for chemotherapy and targeted therapy, which were recommended less frequently by the geriatrician (Kappa = 0.67), and support care, which was more often proposed after the GE (Kappa = 0.61). However, concordance between treatments proposed by the geriatrician and treatment actually given was not so good for chemotherapy (Kappa = 0.58), and surgery (Kappa = 0.61), since both were often replaced by a less aggressive treatment. CONCLUSION: Concordance between the therapies proposed during the Tumor Board or after the Geriatric Oncology Consultation and the treatment actually given was satisfactory. However, the role of the oncologist remains determinant in the final choice, especially for chemotherapy. PMID- 24402394 TI - Risk of in-hospital mortality following emergency department admission: results from the geriatric EDEN cohort study. AB - OBJECTIVE: To determine whether being admitted to emergency department (ED) for social disorders may predict a higher risk of in-hospital mortality among older inpatients. DESIGN: Prospective cohort study (mean follow-up: 9.1+/-10.0 days). SETTING: Angers University Hospital, France. PARTICIPANTS: Four hundred twenty two inpatients (mean age 84.9+/-5.6years, 64.2% women). METHODS: At their admission to ED, inpatients aged 75 years and over received an assessment composed of 6 items: age, gender, number of drugs daily taken, history of falls during the past 6 months, usual place of life, and use of formal and/or informal home and social services. The reasons for admission to ED as well the diagnosis at the time of hospital discharge were separated into social and health disorders. The length of hospital stay was calculated in number of days using the hospital registry. Inpatients were separated into 2 groups based on the occurrence or not of death during the hospital stay. RESULTS: Older inpatients who died at hospital were more frequently institutionalized (P=0.034) and admitted to ED for social disorders (P=0.002) than those who did not. Multiple Cox regression model revealed that living in institution and social disorders as a reason for admission to ED were significantly associated with the occurrence of death at hospital (P=0.008 and P=0.036). Kaplan-Meier distributions of in hospital mortality showed that home-living inpatients admitted to ED for social disorders died more and faster during hospitalization than those admitted for health disorders (P=0.016). CONCLUSION: Being admitted to ED for social disorders and living in institution predicted a higher risk of in-hospital mortality. PMID- 24402395 TI - Characteristics of polymedicated (>= 4) elderly: a survey in a community-dwelling population aged 60 years and over. AB - BACKGROUND: Polypharmacy is an important concern for patient safety and has been associated with increased adverse drug reactions, hospitalization and mortality in the elderly. OBJECTIVE: In light of the above, the present study aimed to assess the major characteristics associated with polypharmacy (>= 4 drugs) in a larger population of apparently healthy older subjects over 60 years. STUDY DESIGN: Cross-sectional study. SETTING: The preventive medical center (CMP) in Nancy. PARTICIPANTS: 2,545 volunteers (1,175 women, 1,370 men) aged 60 years and older (66 +/- 4.8 years) were included from the Senior health examination study. MEASUREMENTS: All subjects underwent clinical, biological examinations. Sociodemographic data, practice of regular physical activity and drug intake data were collected. A self-administered questionnaire of health status, psychological status and questions regarding falls were collected. RESULTS: The prevalence of polypharmacy in this study was 29.9%. The number of drugs in polymedicated people was 5.67 +/- 1.82 versus 1.32 +/- 1.11 in non polymedicated people; p<=0.01. Multivariate analyses identified 6 independent variables associated with polypharmacy: age over 65 years (OR = 1.58 95% CI: [1.05 - 2.38]; p = 0.03), poor self-perceived health status (2.79 [1.80 - 4.31]; p <= 0,01), history of falls (1.66 [1.02 - 2.71]; p = 0.04), lack of a physical activity (1.50 [1.001 - 2.26]; p = 0.049), metabolic syndrome (3.17 [1.95 - 5.15]; p <= 0,01), low or medium education level (2.20 [1.24 - 4.30]; p = 0.02). CONCLUSION: Among community dwelling people aged 60 years and over, in addition to the presence of several diseases and advanced age, the psychological and socio-educative factors may influence drug intake and polypharmacy in the elderly. Physicians should be take into account these considerations before issuing any prescriptions and review all medications used at every visit to avoid unnecessary addictions or dangerous drug drug interactions. PMID- 24402396 TI - Frailty: the quest for new domains, clinical definitions and subtypes. Is this justified on new evidence emerging? PMID- 24402397 TI - Cognitive frailty: rational and definition from an (I.a.N.a./i.a.g.g.) international consensus group. PMID- 24402398 TI - The role of 'modified Mediterranean diet' and quantum therapy in Alzheimer's disease primary prevention. PMID- 24402399 TI - Aging society and gerontechnology: a solution for an independent living? AB - Recent studies report that the majority of older adults wish to live in their own homes, for as long as possible. This creates a growing interest in technologies to enable older people to remain living independently at home. The purpose of this article is to provide a narrative review of current technology appropriate for older adults' home use. The key research questions were as follow: 1- What is the evidence demonstrating that gerontechnologies are effective in enabling independent living? 2- What are devices designed specifically for frail elderly persons ? Several publications were identified about devices targeting social isolation (videophonic communication, affective orthotic devices or companion type robots, personal emergency response systems [security]), autonomy loss (technologies for maintenance of autonomy in the activities of daily living) and cognitive disorders (cognitive orthotics, wandering management systems, telemonitoring). Very few articles dealt specifically with the frail older person. In particular, there was extremely limited evidence on use and efficacy of these devices within this population. There is a need to obtain a consensus on definition of the technologies, and also to revisit work strategies and develop innovative business models. To meet this goal, we need to create a network of technological companies, aging services organizations, end-users, academics, and government representatives to explore the real needs of the frail older population and to develop and validate new devices promoting aging at home. PMID- 24402400 TI - High-performance transparent and stretchable all-solid supercapacitors based on highly aligned carbon nanotube sheets. AB - By using highly aligned carbon nanotube (CNT) sheets of excellent optical transmittance and mechanical stretchability as both the current collector and active electrode, high-performance transparent and stretchable all-solid supercapacitors with a good stability were developed. A transmittance up to 75% at the wavelength of 550 nm was achieved for a supercapacitor made from a cross over assembly of two single-layer CNT sheets. The transparent supercapacitor has a specific capacitance of 7.3 F g(-1) and can be biaxially stretched up to 30% strain without any obvious change in electrochemical performance even over hundreds stretching cycles. PMID- 24402401 TI - The impact of glucose disorders on cognition and brain volumes in the elderly: the Sydney Memory and Ageing Study. AB - Type 2 diabetes predicts accelerated cognitive decline and brain atrophy. We hypothesized that impaired fasting glucose (IFG) and incident glucose disorders have detrimental effects on global cognition and brain volume. We further hypothesized that metabolic and inflammatory derangements accompanying hyperglycaemia contribute to change in brain structure and function. This was a longitudinal study of a community-dwelling elderly cohort with neuropsychological testing (n = 880) and brain volumes by magnetic resonance imaging (n = 312) measured at baseline and 2 years. Primary outcomes were global cognition and total brain volume. Secondary outcomes were cognitive domains (processing speed, memory, language, visuospatial and executive function) and brain volumes (hippocampal, parahippocampal, precuneus and frontal lobe). Participants were categorised as normal, impaired fasting glucose at both assessments (stable IFG), baseline diabetes or incident glucose disorders (incident diabetes or IFG at 2 years). Measures included inflammatory cytokines and oxidative metabolites. Covariates were age, sex, education, non-English speaking background, smoking, blood pressure, lipid-lowering or antihypertensive medications, mood score, apolipoprotein E genotype and baseline cognition or brain volume. Participants with incident glucose disorders had greater decline in global cognition and visuospatial function compared to normal, similar to that observed in baseline diabetes. Homocysteine was independently associated with the observed effect of diabetes on executive function. Apolipoprotein E genotype did not influence the observed effects of diabetes on cognition. Incident glucose disorders and diabetes were also associated with greater 2-year decline in total brain volume, compared to normal (40.0 +/- 4.2 vs. 46.7 +/- 5.7 mm(3) vs. 18.1 +/- 6.2, respectively, p < 0.005). Stable IFG did not show greater decline in global cognition or brain volumes compared to normal. Incident glucose disorders, like diabetes, are associated with accelerated decline in global cognition and brain volumes in non-demented elderly, whereas stable IFG is not. Preventing deterioration in glucose metabolism in the elderly may help preserve brain structure and function. PMID- 24402402 TI - Dysnatremia on intensive care unit admission is a stronger risk factor when associated with organ dysfunction. AB - AIM: Dysnatremia present at the time of intensive care unit (ICU) admission is associated with mortality. In this study, we investigated the epidemiology of dysnatremia present on ICU admission and the impact of organ dysfunction on the association between dysnatremia and mortality. We hypothesized that dysnatremia comorbid with organ dysfunction is associated with higher risk of mortality. METHODS: This retrospective study was conducted on all patients admitted to the International Hospital General ICU in Istanbul over a period of 6 years (2006 2011). Patients were classified, according to the most abnormal serum sodium values measured within 24 hours after ICU admission, into 7 groups as follows: normonatremia (135<=Na<=145 mmol/L), borderline hyponatremia (130<=Na<135 mmol/L), mild hyponatremia (125<=Na<130 mmol/L), severe hyponatremia (Na <125 mmol/L), borderline hypernatremia (145155 mmol/L). RESULTS: The total admitting patient were 1657. A total of 1060 patients' data were analyzed in this study. Sodium levels were normal in 637 (60.1%), hyponatremic in 367 (34.6%) and hypernatremic in 56 (5.3%) patients. Multivariate analysis showed that only SAPS II was associated with increased mortality (OR, 1.05 [95% confidence interval, 1.02-1.09]). The odds ratio (95% CI) of dysnatremia (Na <125 mmol/L and >150 mmol/L) for mortality was 4.37 (2.29-8.36) in patients with organ dysfunction (number of dysfunctional organs >=1) (P<0.001). CONCLUSION: Below 125 and above 150 mmol/L sodium levels at ICU admission are risk factors for higher mortality rates in patients with comorbid organ dysfunction. The effect of dysnatremia on mortality is observed when organ dysfunction is present. PMID- 24402403 TI - Eusociality in history. AB - For more than 100,000 years, H. sapiens lived as foragers, in small family groups with low reproductive variance. A minority of men were able to father children by two or three women; and a majority of men and women were able to breed. But after the origin of farming around 10,000 years ago, reproductive variance increased. In civilizations which began in Mesopotamia, Egypt, India, and China, and then moved on to Greece and Rome, kings collected thousands of women, whose children were supported and guarded by thousands of eunuchs. Just a few hundred years ago, that trend reversed. Obligate sterility ended, and reproductive variance declined. For H. sapiens, as for other organisms, eusociality seems to be an effect of ecological constraints. Civilizations rose up in lake and river valleys, hemmed in by mountains and deserts. Egalitarianism became an option after empty habitats opened up. PMID- 24402404 TI - New daily persistent headache and potential new therapeutic agents. AB - New daily persistent headache is a form of a chronic daily headache with a unique temporal profile. Patients can recall the exact day when their headache started. It can be one of the most refractory types of headache to treat. Recent publications have highlighted different subtypes and heterogeneity in presentation. Referring to it as a syndrome versus a distinct disorder has also been suggested. Several different classes of medications have been used for the treatment, with mixed results. The underlying pathophysiology of new daily persistent headache is unclear, but tumor necrosis factor may play a role. The clinical features, differential diagnosis and potential new therapeutic agents will be discussed. PMID- 24402405 TI - Migraine and patent foramen ovale. AB - Migraine is a widespread disorder with a large impact on society. Patent foramen ovale (PFO) is a common occurrence, affecting about 25 % of the population. Observational studies report PFO to be more prevalent in patients with migraine with aura, and patients with migraine with aura have a higher incidence of PFO. The only population-based study does not support this link. It is possible that an association exists between large-sized PFO and migraine. This association may explain how migraine with aura can be triggered. Numerous studies have reported improved migraine with PFO closure, but the only prospective placebo-controlled trial aimed at closure of PFO in patients with migraine with aura did not support this. At this time, evidence does not support the routine detection and closure of PFO in patients with migraine. PMID- 24402406 TI - Evaluating implementation of a rapid response team: considering alternative outcome measures. AB - OBJECTIVE: Determine the prolonged effect of rapid response team (RRT) implementation on failure to rescue (FTR). DESIGN: Longitudinal study of institutional performance with control charts and Bayesian change point (BCP) analysis. SETTING: Two academic hospitals in Midwest, USA. PARTICIPANTS: All inpatients discharged between 1 September 2005 and 31 December 2010. INTERVENTION: Implementation of an RRT serving the Mayo Clinic Rochester system was phased in for all inpatient services beginning in September 2006 and was completed in February 2008. MAIN OUTCOME MEASURE: Modified version of the AHRQ FTR measure, which identifies hospital mortalities among medical and surgical patients with specified in-hospital complications. RESULTS: A decrease in FTR, as well as an increase in the unplanned ICU transfer rate, occurred in the second year post-RRT implementation coinciding with an increase in RRT calls per month. No significant decreases were observed pre- and post-implementation for cardiopulmonary resuscitation events or overall mortality. A significant decrease in mortality among non-ICU discharges was identified by control charts, although this finding was not detected by BCP or pre- vs. post-analyses. CONCLUSIONS: Reduction in the FTR rate was associated with a substantial increase in the number of RRT calls. Effects of RRT may not be seen until RRT calls reach a sufficient threshold. FTR rate may be better at capturing the effect of RRT implementation than the rate of cardiac arrests. These results support prior reports that short-term studies may underestimate the impact of RRT systems, and support the need for ongoing monitoring and assessment of outcomes to facilitate best resource utilization. PMID- 24402409 TI - The unimolecular chemistry of [Zn(amino acid)2-H]+ in the gas phase: H2 elimination when the amino acid is a secondary amine. AB - The unimolecular chemistry of the [Zn(Pro-H)(Pro)](+) complex following collisional or infrared multiple photon activation was studied, and interestingly was found to lose H2 as one of the main dissociation pathways. Furthermore a second dehydrogenation step, forming [Zn(Pro-H)(Pro)-2H2](+), was also observed. When proline was substituted for sarcosine, also a secondary amine, a single dehydrogenation was observed. In contrast, [Zn(Gly-H)(Gly)](+) and [Zn(Ala H)(Ala)](+) were found to lose H2O as their primary fragmentation route with no dehydrogenation observed. Tandem mass spectrometry, deuterium substitution, and infrared spectroscopy were used to determine the origin of the H atoms in the losses of H2, as well as for other fragmentation routes, including the loss of H2O. The hydrogen atoms for H2 loss from [Zn(Pro-H)(Pro)](+) was found to originate on the amine group and primarily from C5 on the non-deprotonated proline, with a smaller contribution from the C2 hydrogen. Both hydrogens for H2O loss were determined to be from labile hydrogens. Potential energy surfaces were computed for the H2 loss and H2O loss routes for both [Zn(Pro-H)(Pro)](+) and [Zn(Gly-H)(Gly)](+) and were compared. For [Zn(Pro-H)(Pro)](+), H2 loss was found to be the pathway with the lower energy requirement than for H2O loss, and the opposite was found for [Zn(Gly-H)(Gly)](+). The greater basicities of proline and sarcosine are most likely responsible for stabilizing the 3 coordinate Zn(2+) transition states en route to H2 loss, compared to those complexes formed with the much less basic glycine or alanine. PMID- 24402410 TI - Rotating-shift nurses after a day off: peripheral clock gene expression, urinary melatonin, and serum 17-beta-estradiol levels. AB - OBJECTIVE: Impairment of clock gene expression and changes in melatonin and 17 beta-estradiol levels may constitute biological alterations underlying the increased risk of breast cancer among shift workers. The aim of this study was to compare levels of selected core clock gene expression, 6-sulfatoxymelatonin (aMT6s), and 17-beta-estradiol between rotational shift work (SW) and daytime (DT) workers after a day off. METHODS: The cross-sectional study comprised 60 nurses with >=2 years of SW and 56 permanent DT nurses. Transcript levels of circadian genes BMAL1, CLOCK, NPAS2, CRY1, CRY2, PER1, PER2, PER3, and REVERBalpha were determined by quantitative real-time polymerase chain reaction (PCR) in lymphocytes. All participants were tested in the early follicular phase of the menstrual cycle. Samples were collected at the beginning of the morning shift after a regular night's sleep on a day off. Chronotype and sociodemographic characteristics were also evaluated. RESULTS: We found a significantly higher expression of BMAL1, CLOCK, NPAS2, PER1, PER2, and REVERBalpha and a lower expression of PER3, CRY1 and CRY2 among SW compared to DT nurses. SW participants did not demonstrate a significant difference in aMT6s levels, but they did show significantly higher 17-beta-estradiol levels compared to DT nurses. Multiple linear regression analysis confirmed the role of SW on expression of BMAL1 (beta 0.21, P=0.040), CLOCK (beta 0.35, P=0.008), NPAS2 (beta 0.30, P=0.012), PER1 (beta 0.33, P=0.008), PER2 (beta 0.19, P=0.047), PER3 (beta -0.27, P=0.012), CRY1 (beta -0.33, P=0.002), CRY2 (beta -0.31, P=0.005), REVERBalpha (beta 0.19, P=0.045), and on 17-beta-estradiol levels (beta 0.32, P=0.003). The analysis also confirmed the role of chronotype as an independent factor for PER1 (beta 0.48, P=0.001) and PER2 (beta -0.22, P=0.022) expression, and 17-beta-estradiol levels (beta 0.26, P=0.011). CONCLUSIONS: Rotating SW nurses show alterations in peripheral clock gene expression and 17-beta-estradiol levels at the beginning of the morning shift after a day off. PMID- 24402411 TI - Fosaprepitant-induced phlebitis: a focus on patients receiving doxorubicin/cyclophosphamide therapy. AB - PURPOSE: The purpose of this study was to investigate the incidence of fosaprepitant-associated infusion site adverse events (ISAEs) among a cohort of breast cancer patients receiving doxorubicin/cyclophosphamide (AC) chemotherapy. METHODS: A retrospective review of electronic medical record (EMR) data was performed for all patients who were initiated on AC from January 2011 to April 2012. Data collected included baseline demographics, antiemetic regimen, documentation of ISAEs, and type of intravenous (IV) access. Descriptive statistics (mean and standard deviation or percentages) were summarized overall, by type of IV access and initial antiemetic given. RESULTS: Among the 148 patients included in this analysis, 98 initially received fosaprepitant and 44 received aprepitant. The incidence of ISAEs associated with fosaprepitant administration was 34.7 % (n=34), while the incidence of aprepitant-associated ISAEs was 2.3 % (n=1). All ISAEs were associated with peripheral IV access. The most commonly reported ISAEs were infusion site pain (n=26), erythema (n=22), swelling (n=12), superficial thrombosis (n=8), infusion site hives (n=5), and phlebitis/thrombophlebitis (n=5). Twenty-six patients experienced more than one type of ISAE. CONCLUSIONS: The incidence and severity of ISAEs associated with fosaprepitant administration among a group of patients receiving AC chemotherapy are significant and appreciably higher than what has been previously reported. PMID- 24402412 TI - Incidence of infusion-site reactions associated with peripheral intravenous administration of fosaprepitant. AB - PURPOSE: Fosaprepitant is known to cause infusion-site reactions. However, there is limited data regarding these reactions including the effect of peripheral intravenous administration or other potential factors on their incidence. This single-institution retrospective study was undertaken to investigate the incidence of infusion-site reactions with single-dose intravenous (IV) fosaprepitant when given through a peripheral line prior to administration of chemotherapy. Risk factors for the development of infusion-site reactions with fosaprepitant were also explored. METHODS: Medical records of patients with cancer receiving IV fosaprepitant through a peripheral line were reviewed. The primary objective of this study was to estimate the incidence of infusion-site reactions at our institution. Data collection included demographics, fosaprepitant infusion information, and grading of reactions. RESULTS: We found a 15 % incidence of infusion-site reactions among all peripherally administered doses of fosaprepitant. The 50 reactions occurred in 43 unique patients representing an incidence per patient of 28.7 % (43/150; 95 % confidence interval (CI) 21.6-36.6). Factors found to be associated with infusion-site reactions included age [odds ratio (OR) 0.97 (95 % CI 0.94-0.99)], location of IV line [OR forearm vs. hand 0.41 (95 % CI 0.20-0.85); OR antecubital fossa vs. hand 0.31 (95 % CI 0.11-0.87)], and simultaneous maintenance IV fluid rate >=100 mL/h during fosaprepitant infusion [OR 0.19 (95 % CI 0.08-0.44)]. CONCLUSIONS: The incidence of infusion-site reactions with peripherally administered fosaprepitant as seen in this study is higher than that reported in the package insert. Risk factors for developing infusion-site reactions in our patient population include age, location of IV line, and simultaneous maintenance IV fluid rate of <100 mL/h. PMID- 24402413 TI - Author's response to 'procalcitonin in febrile neutropenia--timing is important'. PMID- 24402416 TI - Establishing a core microbiome in acetate-fed microbial fuel cells. AB - Establishing a core microbiome is the first step in understanding and subsequently optimizing microbial interactions in anodic biofilms of microbial fuel cells (MFCs) for increased power, efficiency, and decreased start-up times. In the present study, we used 454 pyrosequencing to demonstrate that a core anodic community would consistently emerge over a period of 4 years given similar conditions. The development and variation across reactor designs of these communities was also explored. The core members present in all high-power generating biofilms were Geobacter, Aminiphilus, Sedimentibacter, Acetoanaerobium, and Spirochaeta, accounting for 72 +/- 9 % of all genera. Aminiphilus spp., member of the Synergistetes phylum was present at higher abundances than previously reported in any other ecological studies. Results suggest a stable core microbiome in acetate-fed MFCs on both phylogenetic and functional levels. PMID- 24402414 TI - Factors related to clinically relevant fatigue in disease-free stomach cancer survivors and expectation-outcome consistency. AB - BACKGROUND: Although early detection and improved treatment have increased the number of long-term survivors, little is known about the prevalence and associations of clinically relevant fatigue (CRF) in disease-free stomach cancer survivors. Because no effective CRF management strategy yet exists, understanding CRF risk factors is important for developing treatment approaches. METHODS: Stomach cancer survivors (N = 374) completed a mailed survey that included the Brief Fatigue Inventory, Beck Depression Inventory, and the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire and its gastric module QLQ-STO22. We assessed sociodemographic, clinical, and symptom characteristics using multivariate logistic regression models to identify CRF-associated factors. RESULTS: Approximately half of disease-free stomach cancer survivors reported CRF, which was associated with female gender, low economic status, rural residence, current smoker, early tumor progress, current depression, and poor performance. Significant relationships of CRF with current depression and poor performance status remained robust after adjusting for potential confounders. Most functional and symptom scores of fatigued survivors deteriorated more than in non-fatigued survivors. Additionally, congruence between tumor progress and surgery type might influence CRF severity. CONCLUSION: In disease-free stomach cancer survivors, CRF is a common problem that is strongly associated with quality of life and other symptoms. Current depression, poor performance, and perceived understanding regarding postoperative condition are important CRF risk factors. Thus, CRF management in this population should focus on identifying these factors. PMID- 24402415 TI - A simple cost-effective methodology for large-scale purification of recombinant non-animal collagens. AB - Recently, a different class of collagen-like molecules has been identified in numerous bacteria. Initial studies have shown that these collagens are readily produced in Escherichia coli and they have been isolated and purified by various small-scale chromatography approaches. These collagens are non-cytotoxic, are non immunogenic, and can be produced in much higher yields than mammalian collagens, making them potential new collagens for biomedical materials. One of the major drawbacks with large-scale fermentation of collagens has been appropriate scalable down-stream processing technologies. Like other collagens, the triple helical domains of bacterial collagens are particularly resistant to proteolysis. The present study describes the development and optimization of a simple, scalable procedure using a combination of acid precipitation of the E. coli host proteins, followed by proteolysis of residual host proteins to produce purified collagens in large scale without the use of chromatographic methods. PMID- 24402417 TI - Triploid planarian reproduces truly bisexually with euploid gametes produced through a different meiotic system between sex. AB - Although polyploids are common among plants and some animals, polyploidization often causes reproductive failure. Triploids, in particular, are characterized by the problems of chromosomal pairing and segregation during meiosis, which may cause aneuploid gametes and results in sterility. Thus, they are generally considered to reproduce only asexually. In the case of the Platyhelminthes Dugesia ryukyuensis, populations with triploid karyotypes are normally found in nature as both fissiparous and oviparous triploids. Fissiparous triploids can also be experimentally sexualized if they are fed sexual planarians, developing both gonads and other reproductive organs. Fully sexualized worms begin reproducing by copulation rather than fission. In this study, we examined the genotypes of the offspring obtained by breeding sexualized triploids and found that the offspring inherited genes from both parents, i.e., they reproduced truly bisexually. Furthermore, meiotic chromosome behavior in triploid sexualized planarians differed significantly between male and female germ lines, in that female germ line cells remained triploid until prophase I, whereas male germ line cells appeared to become diploid before entry into meiosis. Oocytes at the late diplotene stage contained not only paired bivalents but also unpaired univalents that were suggested to produce diploid eggs if they remained in subsequent processes. Triploid planarians may therefore form euploid gametes by different meiotic systems in female and male germ lines and thus are be able to reproduce sexually in contrast to many other triploid organisms. PMID- 24402418 TI - A nonlinear optoelectronic filter for electronic signal processing. AB - The conversion of electrical signals into modulated optical waves and back into electrical signals provides the capacity for low-loss radio-frequency (RF) signal transfer over optical fiber. Here, we show that the unique properties of this microwave-photonic link also enable the manipulation of RF signals beyond what is possible in conventional systems. We achieve these capabilities by realizing a novel nonlinear filter, which acts to suppress a stronger RF signal in the presence of a weaker signal independent of their separation in frequency. Using this filter, we demonstrate a relative suppression of 56 dB for a stronger signal having a 1-GHz center frequency, uncovering the presence of otherwise undetectable weaker signals located as close as 3.5 Hz away. The capabilities of the optoelectronic filter break the conventional limits of signal detection, opening up new possibilities for radar and communication systems, and for the field of precision frequency metrology. PMID- 24402419 TI - Preparation of gamma-Fe2O3@C@MoO3 core/shell nanocomposites as magnetically recyclable catalysts for efficient and selective epoxidation of olefins. AB - Magnetic gamma-Fe2O3@C@MoO3 core-shell structures were fabricated via a general approach and characterized by several techniques such as XRD, XPS, ICP-AES, Raman etc. The catalytic performance of them has been demonstrated in heterogeneously catalyzed oxidation of cyclooctene with tert-butyl hydroperoxide (tBuOOH) as an oxidant, and high conversion (100%) and selectivity (over 99%) were achieved with relatively low catalyst dosage under mild conditions. It should be emphasized that the hybrid catalyst could be easily separated by an external magnet and reused up to 9 times with no significant loss of activity and selectivity. The reaction mechanism over MoO3 is also discussed on the basis of the FTIR and XPS measurements. It is suggested that the high catalytic activity is related to the formation of the transition state, a Mo-alkyl peroxide and olefin complex, which is beneficial for an efficient oxygen atom transfer by converting the intermolecular process directly into an intramolecular process. PMID- 24402420 TI - AETIQ: a novel synthetic compound with anti-inflammatory properties in activated microglia. AB - Neuroinflammation is believed to be involved in the pathogenesis of neurodegenerative diseases. Our novel synthetic compound 2-acetyl-1-ethyl-7 hydroxy-6-methoxy-1, 2, 3, 4-tetrahydroisoquinoline (AETIQ) was tested for its anti-inflammatory properties in activated microglial BV-2 cells. AETIQ attenuated nitric oxide (NO) and reactive oxygen species generation. It also downregulated the production of the proinflammatory enzymes inducible NO synthase, cyclooxygenase-2, and matrix metalloproteinase-3 at both mRNA and protein levels. Furthermore, AETIQ suppressed generation of the proinflammatory cytokines IL 1beta and TNF-alpha as determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and ELISA assays. AETIQ attenuated NFkappaB signaling by downregulating NFkappaB nuclear translocation. The compound was stable against the liver enzymes in the microsomal and S9 fractions, indicative of good bioavailability. These results suggested that AETIQ might be utilized towards development of a therapy for neuroinflammation-related diseases. PMID- 24402421 TI - Insulin resistance is associated with increased concentrations of NT-proBNP in rheumatoid arthritis: IL-6 as a potential mediator. AB - We examined the hypothesis that insulin resistance (IR) decreases circulating concentrations of N-terminal (NT)-probrain natriuretic peptide (BNP). Obesity, despite being a risk factor for heart failure (HF), is paradoxically associated with lower concentrations of BNP, a marker of myocardial stress. Low BNP in obesity is postulated to be due to IR; however, it has been difficult to define the role of IR independent of obesity. IR in rheumatoid arthritis (RA) is increased, independent of obesity, thus allowing potential mechanistic insights into the relationship between IR and BNP. We measured demographic factors, traditional cardiovascular risk factors, body mass index (BMI), markers of inflammation (interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor alpha (TNFalpha)), NT-proBNP, and IR by the homeostatic model assessment (HOMA) in 140 patients with RA and 82 control subjects. Patients with heart failure and coronary artery disease were excluded. We used multiple linear regression models to examine the relationship between HOMA and NT-proBNP in RA and controls and in RA alone, the additional effect of inflammation. As previously reported, NT-proBNP concentrations were higher in RA (median 80.49 pg/mL, IQR (23.67-167.08 pg/mL)) than controls (17.84 pg/mL (3.28-36.28 pg/mL)) (P < 0.001), and the prevalence of IR, defined by HOMA > 2.114, was higher among RA than controls (53 % vs. 15%, P > 0.001). HOMA was positively correlated with NT-proBNP (rho = 0.226, P = 0.007) in RA, but not in controls (rho = -0.154, P = 0.168). In a multivariable model adjusted for age, race, and sex, we found that increasing HOMA was statistically associated with increasing NT-proBNP concentrations in RA (P = 0.001), but not controls (P = 0.543) (P for interaction = 0.036). In RA subjects, when IL-6 was further included in the model, IL-6 (P = 0.0014), but not HOMA (P = 0.43), remained significantly associated with NT proBNP, suggesting that IL-6 may be mechanistically involved in the relationship between IR and NT-proBNP in RA. We conclude that in patients with RA, insulin resistance is associated with higher, rather than the expected lower, concentrations of NT-proBNP and that this may be related to increased IL-6. PMID- 24402423 TI - Validated or not validated? That is the question. PMID- 24402424 TI - Anxiety fuels growing trends in double mastectomy. PMID- 24402422 TI - Identification and validation of an anthracycline/cyclophosphamide-based chemotherapy response assay in breast cancer. AB - BACKGROUND: There is no method routinely used to predict response to anthracycline and cyclophosphamide-based chemotherapy in the clinic; therefore patients often receive treatment for breast cancer with no benefit. Loss of the Fanconi anemia/BRCA (FA/BRCA) DNA damage response (DDR) pathway occurs in approximately 25% of breast cancer patients through several mechanisms and results in sensitization to DNA-damaging agents. The aim of this study was to develop an assay to detect DDR-deficient tumors associated with loss of the FA/BRCA pathway, for the purpose of treatment selection. METHODS: DNA microarray data from 21 FA patients and 11 control subjects were analyzed to identify genetic processes associated with a deficiency in DDR. Unsupervised hierarchical clustering was then performed using 60 BRCA1/2 mutant and 47 sporadic tumor samples, and a molecular subgroup was identified that was defined by the molecular processes represented within FA patients. A 44-gene microarray-based assay (the DDR deficiency assay) was developed to prospectively identify this subgroup from formalin-fixed, paraffin-embedded samples. All statistical tests were two-sided. RESULTS: In a publicly available independent cohort of 203 patients, the assay predicted complete pathologic response vs residual disease after neoadjuvant DNA-damaging chemotherapy (5-fluorouracil, anthracycline, and cyclophosphamide) with an odds ratio of 3.96 (95% confidence interval [Cl] =1.67 to 9.41; P = .002). In a new independent cohort of 191 breast cancer patients treated with adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, a positive assay result predicted 5-year relapse-free survival with a hazard ratio of 0.37 (95% Cl = 0.15 to 0.88; P = .03) compared with the assay negative population. CONCLUSIONS: A formalin-fixed, paraffin-embedded tissue-based assay has been developed and independently validated as a predictor of response and prognosis after anthracycline/cyclophosphamide-based chemotherapy in the neoadjuvant and adjuvant settings. These findings warrant further validation in a prospective clinical study. PMID- 24402425 TI - Evidence accumulating that depression may hinder survival. PMID- 24402426 TI - Downfall of iniparib: a PARP inhibitor that doesn't inhibit PARP after all. PMID- 24402429 TI - Cancer survivorship gains importance. PMID- 24402431 TI - Use of Evidence-Based Practices and Resources Among Comprehensive Cancer Control Programs. AB - CONTEXT: While efforts to promote use of evidence-based practices (EBPs) for cancer control have increased, questions remain whether this will result in widespread adoption of EBPs (eg, Guide to Community Preventive Services interventions) by comprehensive cancer control (CCC) programs. OBJECTIVE: To examine use of EBPs among CCC programs to develop cancer control plans and select interventions. DESIGN: Conducted Web-based surveys of and telephone interviews with CCC program staff between March and July 2012. SETTING: CCC programs funded by the Centers for Disease Control and Prevention's National Comprehensive Cancer Control Program (NCCCP). PARTICIPANTS: Sixty-one CCC program directors. MAIN OUTCOME MEASURES: 1) Use of and knowledge/attitudes about EBPs and related resources and 2) EBP-related technical assistance needs. RESULTS: Seventy-five percent of eligible program directors reported use of EBPs to a moderate or great extent to address program objectives. Benefits of using EBPS included their effectiveness has been proven, they are an efficient use of resources, and they lend credibility to an intervention. Challenges to using EBPs included resource limitations, lack of culturally appropriate interventions, and limited skills adapting EBPs for local use. Most respondents had heard of and used Web sites for The Guide to Community Preventive Services (95% and 91%, respectively) and Cancer Control P.L.A.N.E.T. (98% and 75%, respectively). Training needs included how to adapt an EBP and its materials for cultural appropriateness (state 78%, tribe 86%, territory 80%) and how to maintain the fidelity of an EBP (state 75%, tribe 86%, territory 60%). CONCLUSIONS: While awareness, knowledge, and use of EBPs and related resources are high, respondents identified numerous challenges and training needs. The findings from this study may be used to enhance technical assistance provided to NCCCP grantees related to selecting and implementing EBPs. PMID- 24402432 TI - Describing the continuum of collaboration among local health departments with hospitals around the community health assessments. AB - BACKGROUND: Hospitals and local health departments (LHDs) are under policy requirements from the Affordable Care Act and accreditation standards through the Public Health Accreditation Board. Tax exempt hospitals must perform a community health needs assessment (CHNA), similar to the community health assessment (CHA) required for LHDs. These efforts have led to a renewed interest in hospitals and LHDs working together to achieve common goals. PURPOSE: The purpose of this study is to gain a better understanding of levels of joint action leading toward collaboration between LHDs and hospitals and describe collaboration around CHAs. METHODS: Local health departments were selected on the basis of reporting collaboration (n = 26) or unsure about collaboration (n = 29) with local hospitals. Local health departments were surveyed regarding their relationship with local hospitals. For LHDs currently collaborating with a hospital, a collaboration continuum scale was calculated. Appropriate nonparametric tests, chi-squares, and Spearman's rank correlations were conducted to determine differences between groups. RESULTS: A total of 44 LHDs responded to the survey (80.0%). Currently collaborating LHDs were more likely to be interested in accreditation and to refer to their CHA 5 or more times a year compared to the unsure LHDs. In the analysis, a collaboration continuum was created and is positively correlated with aspects of the CHA and CHA process. CONCLUSIONS: This study is the first attempt to quantify the level of collaboration between LHDs and hospitals around CHAs. Better understanding of the levels of joint action required may assist LHDs in making informed decisions regarding deployment of resources on the path to accreditation. PMID- 24402433 TI - A systematic approach to evaluating public health training: the obesity prevention in public health course. AB - OBJECTIVE: Public health practitioners require new knowledge and skills to address the multilevel factors contributing to obesity. This article presents the systematic approach the Center of Excellence for Training and Research Translation (Center TRT) used both to assess practitioners' competencies to lead public health obesity prevention initiatives and to evaluate its annual, competency-based obesity prevention course. DESIGN: In 2006, Center TRT identified priority public health competencies for obesity prevention and then planned 7 annual courses to address the priority competencies progressively over time. Each year, a longitudinal evaluation based on Kirkpatrick's training evaluation framework was administered to course participants (n = 243) to assess perceptions of the course (daily), changes in self-reported competency (immediately pre- and postcourse), and course impact on practice over time (at 6 months). RESULTS: Participants rated the course highly for quality and relevance. Although many participants reported low levels of confidence prior to the course, following the course, at least 70% reported feeling confident to perform almost all competencies. At 6-month follow-up, the majority of participants reported completing at least 1 activity identified during course action planning. CONCLUSIONS: We identified practitioners' high-priority competency needs and then designed 7 annual courses to progressively address those needs and new needs as they arose. This approach resulted in trainings valued by practitioners and effective in increasing their sense of competence to lead public health obesity prevention initiatives. The course's continuing impact was evidenced by participants' high level of completion of their action plans at 6-month follow up. Competency-based training is important to develop a skilled public health workforce. PMID- 24402434 TI - Immunization information systems: a decade of progress in law and policy. AB - This article reports on a study of laws, regulations, and policies governing Immunization Information Systems (IIS, also known as "immunization registries") in states and selected urban areas of the United States. The study included a search of relevant statutes, administrative codes and published attorney general opinions/findings, an online questionnaire completed by immunization program managers and/or their staff, and follow-up telephone interviews.The legal/regulatory framework for IIS has changed considerably since 2000, largely in ways that improve IIS' ability to perform their public health functions while continuing to maintain strict confidentiality and privacy controls. Nevertheless, the exchange of immunization data and other health information between care providers and public health and between entities in different jurisdictions remains difficult due in part to ongoing regulatory diversity.To continue to be leaders in health information exchange and facilitate immunization of children and adults, IIS will need to address the challenges presented by the interplay of federal and state legislation, regulations, and policies and continue to move toward standardized data collection and sharing necessary for interoperable systems. PMID- 24402435 TI - PGC-1alpha integrates glucose metabolism and angiogenesis in multiple myeloma cells by regulating VEGF and GLUT-4. AB - Human peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC 1alpha) is a key coactivator in the regulation of gene transcriptional activity in normal tissues. However, it is not clear whether it is involved in the angiogenesis and metabolism of multiple myeloma (MM). The aim of the present study was to investigate the role of PGC-1alpha in MM. Small interfering RNA (siRNA) was used to inhibit PGC-1alpha expression in RPMI-8226 cells. An endothelial cell migration assay was performed using transwell chambers and the expression of PGC-1alpha, estrogen-related receptor-alpha (ERR-alpha), vascular endothelial growth factor (VEGF) and glucose transporter-4 (GLUT-4) was tested by reverse transcription-polymerase chain reaction (RT-PCR). The protein expression of PGC-1alpha, ERR-alpha and GLUT-4 was assayed by western blot analysis. Lastly, RPMI-8226 cell proliferation was evaluated using CCK-8 assay. VEGF and GLUT-4 mRNA levels were decreased in cells treated with siRNA targeting PGC-1alpha, as was the level of GLUT-4 protein. Endothelial cell migration was significantly reduced when these cells were cultured with culture medium from RPMI-8226 cells treated with siPGC-1alpha. The proliferation rates at 24 and 48 h were suppressed by PGC-1alpha inhibition. Our results showed that inhibition of PGC-1alpha suppresses cell proliferation probably by downregulation of VEGF and GLUT-4. The present study suggests that PGC-1alpha integrates angiogenesis and glucose metabolism in myeloma through regulation of VEGF and GLUT-4. PMID- 24402436 TI - Fossil records of subsection Pinus (genus Pinus, Pinaceae) from the Cenozoic in Japan. AB - Extant pines of subsection Pinus (section Pinus, genus Pinus, Pinaceae) are predominantly distributed in Eastern Asia. However, the extent of diversification in the section has yet to be fully clarified. We reviewed fossil records of subsection Pinus from Japan and collected permineralized materials, in which anatomical details are preserved for better understanding of the diversification. Our results suggest that this subsection appeared in Japan no earlier than the Middle Eocene, with extant species (i.e., Pinus densiflora and Pinus thunbergii) appearing around the beginning of the Pleistocene. Pinus fujiii (Early Miocene to Early Pleistocene) is inferred to have a close affinity to P. thunbergii based on the medial arrangement of its leaf resin canals. Additionally, P. fujiii has a similar cone morphology to those of extant species living in China, bridging the morphological gap between P. thunbergii and Chinese relatives of P. thunbergii as inferred by molecular phylogenetic analyses. Our results also suggest that taxonomic revisions of Pinus miocenica and Pinus oligolepis are required among the Japanese fossil species reported to date. PMID- 24402437 TI - Features of the piezo-phototronic effect on optoelectronic devices based on wurtzite semiconductor nanowires. AB - The piezo-phototronic effect, a three way coupling effect of piezoelectric, semiconductor and photonic properties in non-central symmetric semiconductor materials, utilizing the piezo-potential as a "gate" voltage to tune the charge transport/generation/recombination and modulate the performance of optoelectronic devices, has formed a new field and attracted lots of interest recently. The mechanism was verified in various optoelectronic devices such as light emitting diodes (LEDs), photodetectors and solar cells etc. The fast development and dramatic increasing interest in the piezo-phototronic field not only demonstrate the way the piezo-phototronic effects work, but also indicate the strong need for further research in the physical mechanism and potential applications. Furthermore, it is important to distinguish the contribution of the piezo phototronic effect from other factors induced by external strain such as piezoresistance, band shifting or contact area change, which also affect the carrier behaviour and device performance. In this perspective, we review our recent progress on piezo-phototronics and especially focus on pointing out the features of piezo-phototronic effect in four aspects: I-V characteristics; c-axis orientation; influence of illumination; and modulation of carrier behaviour. Finally we proposed several criteria for describing the contribution made by the piezo-phototronic effect to the performance of optoelectronic devices. This systematic analysis and comparison will not only help give an in-depth understanding of the piezo-phototronic effect, but also work as guide for the design of devices in related areas. PMID- 24402438 TI - Muscle synergies may improve optimization prediction of knee contact forces during walking. AB - The ability to predict patient-specific joint contact and muscle forces accurately could improve the treatment of walking-related disorders. Muscle synergy analysis, which decomposes a large number of muscle electromyographic (EMG) signals into a small number of synergy control signals, could reduce the dimensionality and thus redundancy of the muscle and contact force prediction process. This study investigated whether use of subject-specific synergy controls can improve optimization prediction of knee contact forces during walking. To generate the predictions, we performed mixed dynamic muscle force optimizations (i.e., inverse skeletal dynamics with forward muscle activation and contraction dynamics) using data collected from a subject implanted with a force-measuring knee replacement. Twelve optimization problems (three cases with four subcases each) that minimized the sum of squares of muscle excitations were formulated to investigate how synergy controls affect knee contact force predictions. The three cases were: (1) Calibrate+Match where muscle model parameter values were calibrated and experimental knee contact forces were simultaneously matched, (2) Precalibrate+Predict where experimental knee contact forces were predicted using precalibrated muscle model parameters values from the first case, and (3) Calibrate+Predict where muscle model parameter values were calibrated and experimental knee contact forces were simultaneously predicted, all while matching inverse dynamic loads at the hip, knee, and ankle. The four subcases used either 44 independent controls or five synergy controls with and without EMG shape tracking. For the Calibrate+Match case, all four subcases closely reproduced the measured medial and lateral knee contact forces (R2 >= 0.94, root mean-square (RMS) error < 66 N), indicating sufficient model fidelity for contact force prediction. For the Precalibrate+Predict and Calibrate+Predict cases, synergy controls yielded better contact force predictions (0.61 < R2 < 0.90, 83 N < RMS error < 161 N) than did independent controls (-0.15 < R2 < 0.79, 124 N < RMS error < 343 N) for corresponding subcases. For independent controls, contact force predictions improved when precalibrated model parameter values or EMG shape tracking was used. For synergy controls, contact force predictions were relatively insensitive to how model parameter values were calibrated, while EMG shape tracking made lateral (but not medial) contact force predictions worse. For the subject and optimization cost function analyzed in this study, use of subject specific synergy controls improved the accuracy of knee contact force predictions, especially for lateral contact force when EMG shape tracking was omitted, and reduced prediction sensitivity to uncertainties in muscle model parameter values. PMID- 24402440 TI - Mental health service use types among Asian Americans with a psychiatric disorder: considerations of culture and need. AB - Despite levels of need that are comparable with other groups, relatively few Asian Americans receive mental health care. While studies have described the tendency for Asian Americans to delay care until mental health symptoms are severe, relatively little research has examined how the severity of symptoms impact mental health service use. This study uses publicly available data from the National Latino and Asian American Study (NLAAS) and focuses solely on Asian American respondents with a psychiatric disorder (n = 230). Unexpectedly, few Asian Americans with a psychiatric disorder received care in a medical setting. The perception of mental health needs increased the likelihood of using mental health specialist care. Social and systemic barriers together hinder mental health service use. Implications for addressing Asian American mental health service use within a changing health care environment are discussed. PMID- 24402439 TI - Perceived barriers to weight maintenance among university students in Kuwait: the role of gender and obesity. AB - OBJECTIVE: To investigate the barriers to weight maintenance among university students in Kuwait by gender and obesity. METHODS: A sample of 530 students was selected at convenience from four universities in Kuwait (2 public and 2 private). The age of students ranged from 19 to 26 years. A self-reported pretested questionnaire was used to obtain the barriers, which were divided into barriers to healthy eating and barriers to physical activity. Weight and height were based on self-reporting, and the students were grouped into non-obese and obese according to the WHO classification. The response options to barriers were: very important, somewhat important and not important. RESULTS: The main barriers to healthy eating for both genders were: "Do not have skills to plan, shop for, prepare or cook healthy foods" and "Not having time to prepare or eat healthy food". In general, there were no significant differences between men and women in barriers to healthy eating. There were highly significant differences between men and women regarding barriers to physical activity (P values ranged from <0.001 to <0.016). "Not having time to be physically active" and "The climate is not suitable for practising exercise" were the main barriers reported. Obese men were more likely to face barriers to healthy eating than non-obese men. There were no significant differences between obese and non-obese women regarding barriers to healthy eating and physical activity. CONCLUSION: The findings of this study can be utilized in intervention activities to promote a healthy lifestyle and to combat obesity in Kuwait, and maybe in other Arab countries. PMID- 24402441 TI - Physiological capacity and physical testing in male elite team handball. AB - AIM: The aim of the present study was to examine the physical demands placed on male elite team handball players in relation to playing position. METHODS: Male elite team handball field players were evaluated during match-play over a six season time span using physiological measurements and by subsequent physical testing. RESULTS: Mean heart rate and relative workload during match-play (N.=41) were 163 +/- 5 beats.min-1 (group means+/-SD) and 70.9 +/- 6.0% of VO(2-max), respectively. Relative workload was lower (P<0.01) in the second half vs. the first (66.3 +/- 5.9% vs. 75.4 +/- 5.6% of VO(2-max)). Post-match blood lactate concentration was 4.8 +/- 1.9 mM (range: 2.8-10.8 mM). Mean fluid loss was 0.81 +/- 0.41 l pr. match. Mean VO(2max) was 5.18 +/- 0.66 l O2.min-1 corresponding to 57.0 +/- 4.1 mL O2.min-1.kg-1. Mean total running distance in the Yo-Yo intermittent recovery test (level 2) was 895 +/- 184 m (range: 520-1360 m), which was greater in wing players (975 +/- 123 m) than backcourt players (897 +/- 108 m) and pivots (827 +/- 264 m) (P<0.05). Fastest 30-m sprint time was 4.09 +/- 0.12 s (range: 3.87-4.28 s). The repeated sprint test (7 x 30 m) yielded a mean fatigue index of -8.1 +/- 2.7 %. Maximal jumping height in "Jump and Reach" testing was 0.71 +/- 0.08 m (range: 0.61-0.86 m). Maximal ball throwing speed was observed using the set shot with 3-step run-up (92.8 +/- 5.3 km.h-1, range: 75.8 108.2 km.h-1). CONCLUSION: Modern male elite team handball imposes moderate-to high demands on the aerobic energy system and high demands on the anaerobic energy systems during certain periods of the match. Indications of temporary fatigue and a subsequent decline in performance were observed, since the relative workload decreased both in the first and in the second half of the match. Physiological profiles and physical test results differed between playing positions, with wing players covering a greater total distance in the Yo-Yo test and showing superior jumping performance and repeated sprint running capacity than backcourt players and pivots. PMID- 24402443 TI - Transition from a spectrum filter to a polarizer in a metallic nano-slit array. AB - The transition from a spectrum filter (resonant transmission) to a polarizer (broadband transmission) for TM polarized light is observed in a metallic nano slit array as period is decreased. A theoretical model is developed and shows that the spectrum filter behavior is caused by the coupled slit/grating resonance. With decreasing period, the slit resonance is decoupled from the grating resonance, which then dominates the transmission spectrum and broadens the transmission peak. With further reducing period, the slit resonance diminishes and the peak spectrum transforms to a broadband transmission. This effect is the basis for the operation of wire grid polarizers. The transition is explained by the change of the impedance to the incoming wave. PMID- 24402442 TI - Structural analysis of human 2'-O-ribose methyltransferases involved in mRNA cap structure formation. AB - The 5' cap of human messenger RNA contains 2'-O-methylation of the first and often second transcribed nucleotide that is important for its processing, translation and stability. Human enzymes that methylate these nucleotides, termed CMTr1 and CMTr2, respectively, have recently been identified. However, the structures of these enzymes and their mechanisms of action remain unknown. In the present study, we solve the crystal structures of the active CMTr1 catalytic domain in complex with a methyl group donor and a capped oligoribonucleotide, thereby revealing the mechanism of specific recognition of capped RNA. This mechanism differs significantly from viral enzymes, thus providing a framework for their specific targeting. Based on the crystal structure of CMTr1, a comparative model of the CMTr2 catalytic domain is generated. This model, together with mutational analysis, leads to the identification of residues involved in RNA and methyl group donor binding. PMID- 24402444 TI - Paediatric acquired pathological vertebral collapse. AB - Vertebral collapse is a significant event in the paediatric patient with a real potential for associated deformity and morbidity. While in adults the causes tend towards the malignant, particularly metastatic and metabolic disease, the paediatric population demonstrates a different range of diagnoses. This article reviews the typical imaging findings of the more common underlying acquired pathological causes of vertebral collapse in children, including Langerhans cell histiocytosis, chronic recurrent multifocal osteomyelitis, osteogenesis imperfecta. Other causes include pyogenic osteomyelitis and tuberculosis and neoplastic lesions, either primary, metastatic or of haematological origin. PMID- 24402445 TI - Phosphaturic mesenchymal tumor: two contrasting cases. PMID- 24402446 TI - Surgery in lumbar degenerative spondylolisthesis: indications, outcomes and complications. A systematic review. AB - PURPOSE: This systematic review summarises the literature on patient selection, decision-making, effectiveness and outcomes in the surgical treatment of lumbar degenerative spondylolisthesis (LDS). INTRODUCTION: In daily practice, decision making in the treatment of LDS is challenging. There is little consensus on either the precise indications or prognostic factors for any specific therapy (operative or non-operative). METHODS: We searched for LDS trials published between 01.01.1990 and 16.11.2011 in Medline, Embase, Cochrane Library and Cinahl. Two independent reviewers selected studies according to the inclusion criteria. Data were then extracted by two of the authors. Quality assessment was performed using the Downs and Black list for the clinical trials/studies and AMSTAR for the reviews. RESULTS: DATA SYNTHESIS: 21 papers met the inclusion criteria (2 studies comprising both a RCT and a concurrent observational analysis, 1 RCT, 6 prospective studies, 8 retrospective studies, 3 reviews, 1 review guideline). The quality of the clinical studies was on average "fair" [mean score 15.6 points (range 10-19) out of 24 points (Downs and Black)]. The quality of the reviews ranged from 1 to 7 out of 11 points with an average of 5 points (AMSTAR). The study outcomes could not be subject to meta-analysis due to heterogeneity of study design and variable measure used. CONCLUSIONS: Despite there being many articles describing and/or comparing different surgical options for LDS, there was insufficient evidence to draw conclusions concerning clear indications for specific types of surgical treatment, predictors of outcome or complication rates. There remains a need to establish a decision-making tool to facilitate daily clinical practice and to assure appropriate treatment for patients with LDS. PMID- 24402447 TI - Prefailure and failure mechanics of the porcine ascending thoracic aorta: experiments and a multiscale model. AB - Ascending thoracic aortic aneurysms (ATAA) have a high propensity for dissection, which occurs when the hemodynamic load exceeds the mechanical strength of the aortic media. Despite our recognition of this essential fact, the complex architecture of the media has made a predictive model of medial failure-even in the relatively simple case of the healthy vessel-difficult to achieve. As a first step towards a general model of ATAA failure, we characterized the mechanical behavior of healthy ascending thoracic aorta (ATA) media using uniaxial stretch to-failure in both circumferential (n = 11) and axial (n = 11) orientations and equibiaxial extensions (n = 9). Both experiments demonstrated anisotropy, with higher tensile strength in the circumferential direction (2510 +/- 439.3 kPa) compared to the axial direction (750 +/- 102.6 kPa) for the uniaxial tests, and a ratio of 1.44 between the peak circumferential and axial loads in equibiaxial extension. Uniaxial tests for both orientations showed macroscopic tissue failure at a stretch of 1.9. A multiscale computational model, consisting of a realistically aligned interconnected fiber network in parallel with a neo-Hookean solid, was used to describe the data; failure was modeled at the fiber level, with an individual fiber failing when stretched beyond a critical threshold. The best-fit model results were within the 95% confidence intervals for uniaxial and biaxial experiments, including both prefailure and failure, and were consistent with properties of the components of the ATA media. PMID- 24402448 TI - An examination of the differences between two methods of estimating energy expenditure in resistance training activities. AB - To date, few studies have looked at the energy expenditure (EE) of individual resistance training (RT) exercises. The purpose of this study was to evaluate the EE of 4 modes of RT (push-ups, curl-ups, pull-ups, and lunges) using 2 different calculation methods for estimating EE. Twelve healthy men with a minimum of 1 year of RT experience were randomly assigned to an RT circuit. Each circuit contained the 4 RT exercises in a specified order. The participants completed 3 trials of their assigned circuit during one visit to the laboratory. Oxygen consumption was measured continuously throughout the trial using indirect calorimetry. Two different calculation methods were applied to estimate EE. Using the traditional method (TEC), we estimated EE by calculating the average oxygen consumption recorded during each activity. Using the second, nontraditional method (NEC), we estimated EE by calculating the average oxygen consumption recorded during the recovery period. Independent T-tests were used to evaluate mean EE differences between the 2 methods. Estimates of EE obtained from the NEC were significantly higher for all the 4 activities (p < 0.001). Using the NEC, 3 of the 4 activities were classified as vigorous intensity (push-ups: 6.91 metabolic equivalents (METs); lunges: 7.52 METs; and pull-ups: 8.03 METs), whereas none were classified as vigorous using the TEC. Findings suggest that the methods we use to calculate the EE of anaerobic activities significantly affect EE estimates. Using the TEC may underestimate actual EE of anaerobic activities. PMID- 24402449 TI - Lean mass asymmetry influences force and power asymmetry during jumping in collegiate athletes. AB - The purpose of this investigation was to (a) examine how asymmetry in lower extremity lean mass influenced force and power asymmetry during jumping, (b) determine how power and force asymmetry affected jump height, and (c) report normative values in collegiate athletes. Force and power were assessed from each limb using bilateral force plates during a countermovement jump in 167 division 1 athletes (mass = 85.7 +/- 20.3 kg, age = 20.0 +/- 1.2 years; 103 men and 64 women). Lean mass of the pelvis, thigh, and shank was assessed using dual-energy x-ray absorptiometry. Percent asymmetry was calculated for lean mass at each region (pelvis, thigh, and shank) as well as force and power. Forward stepwise regressions were performed to determine the influence of lean mass asymmetry on force and power asymmetry. Thigh and shank lean mass asymmetry explained 20% of the variance in force asymmetry (R = 0.20, p < 0.001), whereas lean mass asymmetry of the pelvis, thigh, and shank explained 25% of the variance in power asymmetry (R = 0.25, p < 0.001). Jump height was compared across level of force and power asymmetry (p > 0.05) and greater than 10% asymmetry in power tended to decrease the performance (effect size >1.0). Ninety-five percent of this population (2.5th to 97.5th percentile) displayed force asymmetry between -11.8 and 16.8% and a power asymmetry between -9.9 and 11.5%. A small percentage (<4%) of these athletes displayed more than 15% asymmetry between limbs. These results demonstrate that lean mass asymmetry in the lower extremity is at least partially responsible for asymmetries in force and power. However, a large percentage remains unexplained by lean mass asymmetry. PMID- 24402450 TI - Inspiratory muscle fatigue affects latissimus dorsi but not pectoralis major activity during arms only front crawl sprinting. AB - The purpose of this study was to determine whether inspiratory muscle fatigue (IMF) affects the muscle activity of the latissimus dorsi and pectoralis major during maximal arms only front crawl swimming. Eight collegiate swimmers were recruited to perform 2 maximal 20-second arms only front crawl sprints in a swimming flume. Both sprints were performed on the same day, and IMF was induced 30 minutes after the first (control) sprint. Maximal inspiratory and expiratory mouth pressures (PImax and PEmax, respectively) were measured before and after each sprint. The median frequency (MDF) of the electromyographic signal burst was recorded from the latissimus dorsi and pectoralis major during each 20-second sprint along with stroke rate and breathing frequency. Median frequency was assessed in absolute units (Hz) and then referenced to the start of the control sprint for normalization. After IMF inducement, stroke rate increased from 56 +/- 4 to 59 +/- 5 cycles per minute, and latissimus dorsi MDF fell from 67 +/- 11 Hz at the start of the sprint to 61 +/- 9 Hz at the end. No change was observed in the MDF of the latissimus dorsi during the control sprint. Conversely, the MDF of the pectoralis major shifted to lower frequencies during both sprints but was unaffected by IMF. As the latter induced fatigue in the latissimus dorsi, which was not otherwise apparent during maximal arms only control sprinting, the presence of IMF affects the activity of the latissimus dorsi during front crawl sprinting. PMID- 24402451 TI - Long-term training-induced changes in sprinting speed and sprint momentum in elite rugby union players. AB - Speed and sprint momentum are considered to be important physical qualities for rugby. The purpose of the study was to understand the development of these qualities in senior and junior international rugby players. In part 1 of the study, a group of senior (n = 38) and junior (n = 31) players were tested for speed over 40 m. Initial sprint velocity (ISV), maximal sprint velocity (MSV), initial sprint momentum (ISM), and maximal sprint momentum (MSM) were calculated using 10-m splits. In part 2 of the study, a group of junior (n = 12) and senior (n = 15) players were tracked over a 2-year period for body mass, ISV, MSV, ISM, and MSM. In part 1, senior backs and forwards were not found to have significantly greater ISV and MSV than junior players but were found to have greater ISM and MSM. Forwards were found to have significantly greater ISM and MSM than backs but significantly lower ISV and MSV than backs. In part 2, no significant differences were found over the 2 years between senior and junior players, but greater effect sizes for juniors were generally found when compared with seniors for improvements in ISV (d = 0.73 vs. 0.79), MSV (d = 1.09 vs. 0.68), ISM (d = 0.96 vs. 0.54), and MSM (d = 1.15 vs. 0.50). Sprint momentum is a key discriminator between senior and junior players, and large changes can be made by junior players as they transition into senior rugby. Speed appears to peak for players in their early 20s but sprint momentum appears to be more trainable. PMID- 24402452 TI - National collegiate athletic association strength and conditioning coaches' knowledge and practices regarding prevention and recognition of exertional heat stroke. AB - The purpose of this study was to assess and determine content knowledge of National Collegiate Athletic Association Strength and Conditioning Coaches (SCCs) regarding prevention and recognition of exertional heat stroke (EHS) and to determine whether the type of professional certification is an indicator of enhanced content knowledge. A questionnaire was e-mailed to 1305 SCCs and was used to assess SCC's EHS knowledge in the areas of extrinsic risk factors (ERF), intrinsic risk factors (IRF), recognition of EHS (R), and general training safety knowledge (TSK). The 319 SCC participants who responded were separated into 4 groups based on certification: Certified Strength and Conditioning Specialists (CSCS) (116), Strength and Conditioning Coach Certification (SCCC) (46), combined CSCS/SCCC (62), or no certification (NC) (95). Only 2.2% of the total coaches surveyed scored >=90% on the total score, whereas 47% earned a score <=59%. When comparing across certifications, NC scored significantly lower (p <= 0.05) on total score, and the IRF and TSK constructs than CSCS, SCCC, and CSCS/SCCC. CSCS/SCCC coaches performed significantly better on the total score than SCCC (p = 0.047), whereas a trend toward a higher score (p = 0.085) was seen in CSCS compared with SCCC. CSCS coaches and the combined CSCS/SCCC certifications scored significantly higher (p < 0.000) than NC in the ERF and R constructs. In conclusion, SCCs seemed to lack essential knowledge to prevent or recognize EHS in each of the factors assessed. It is recommended that consideration be given to include EHS prevention and recognition competencies as part of the professional preparation and certification requirements for SCCs. PMID- 24402453 TI - An unprecedented high nuclearity catecholato-based Ti(IV)-architecture bearing labile pyridine ligands. AB - We describe the synthesis and characterisation of a robust S4-symmetry titanium based architecture bearing catecholato and pyridine ligands. This neutral complex formulated as [Ti10O12(cat)8(py)8] displays a tetrahedral inorganic core decorated by catecholato ligands with unusual coordination modes. In solution, the pyridine ligands are labile as shown in DOSY studies at variable temperature. The light absorption property in the visible domain (lambdamax = 411 nm, epsilon = 10 800) was also characterised for the complex. PMID- 24402455 TI - Optimization of PACS data persistency using indexed hierarchical data. AB - We present a new approach for the development of a data persistency layer for a Digital Imaging and Communications in Medicine (DICOM)-compliant Picture Archiving and Communications Systems employing a hierarchical database. Our approach makes use of the HDF5 hierarchical data storage standard for scientific data and overcomes limitations of hierarchical databases employing inverted indexing for secondary key management and for efficient and flexible access to data through secondary keys. This inverted indexing is achieved through a general purpose document indexing tool called Lucene. This approach was implemented and tested using real-world data against a traditional solution employing a relational database, in various store, search, and retrieval experiments performed repeatedly with different sizes of DICOM datasets. Results show that our approach outperforms the traditional solution on most of the situations, being more than 600 % faster in some cases. PMID- 24402456 TI - SimITK: visual programming of the ITK image-processing library within Simulink. AB - The Insight Segmentation and Registration Toolkit (ITK) is a software library used for image analysis, visualization, and image-guided surgery applications. ITK is a collection of C++ classes that poses the challenge of a steep learning curve should the user not have appropriate C++ programming experience. To remove the programming complexities and facilitate rapid prototyping, an implementation of ITK within a higher-level visual programming environment is presented: SimITK. ITK functionalities are automatically wrapped into "blocks" within Simulink, the visual programming environment of MATLAB, where these blocks can be connected to form workflows: visual schematics that closely represent the structure of a C++ program. The heavily templated C++ nature of ITK does not facilitate direct interaction between Simulink and ITK; an intermediary is required to convert respective data types and allow intercommunication. As such, a SimITK "Virtual Block" has been developed that serves as a wrapper around an ITK class which is capable of resolving the ITK data types to native Simulink data types. Part of the challenge surrounding this implementation involves automatically capturing and storing the pertinent class information that need to be refined from an initial state prior to being reflected within the final block representation. The primary result from the SimITK wrapping procedure is multiple Simulink block libraries. From these libraries, blocks are selected and interconnected to demonstrate two examples: a 3D segmentation workflow and a 3D multimodal registration workflow. Compared to their pure-code equivalents, the workflows highlight ITK usability through an alternative visual interpretation of the code that abstracts away potentially confusing technicalities. PMID- 24402458 TI - Application of biofilm bioreactors in white biotechnology. AB - The production of valuable compounds in industrial biotechnology is commonly done by cultivation of suspended cells or use of (immobilized) enzymes rather than using microorganisms in an immobilized state. Within the field of wastewater as well as odor treatment the application of immobilized cells is a proven technique. The cells are entrapped in a matrix of extracellular polymeric compounds produced by themselves. The surface-associated agglomerate of encapsulated cells is termed biofilm. In comparison to common immobilization techniques, toxic effects of compounds used for cell entrapment may be neglected. Although the economic impact of biofilm processes used for the production of valuable compounds is negligible, many prospective approaches were examined in the laboratory and on a pilot scale. This review gives an overview of biofilm reactors applied to the production of valuable compounds. Moreover, the characteristics of the utilized materials are discussed with respect to support of surface-attached microbial growth. PMID- 24402457 TI - Incidence and risk factors for injuries to the recurrent laryngeal nerve during neck surgery in the moderate-volume setting. AB - PURPOSE: Total lobectomy is currently recommended also in benign thyroid disease in order to reduce the risk of goitre recurrence, an approach claimed not to increase post-operative morbidity. The aim of the study was to analyse risk factors for recurrent laryngeal nerve (RLN) palsy during neck surgery, with particular interest in complications after total lobectomy and subtotal resection, respectively. METHODS: All consecutive patients operated for thyroid and parathyroid diseases at one institution between 1984 and 2011 were prospectively recorded, and 1,322 patients were included. Patients with permanent post-operative RLN palsy were re-examined in 2011. RESULTS: The risk of permanent RLN palsy after parathyroid surgery was 0.3 %. Patients operated for thyroid cancer had a 5.9 % risk of permanent nerve injury, higher than that of patients with benign thyroid disease (1.4 %; P = 0.029). Independent risk factors for RLN paralysis after benign thyroid surgery were intrathoracic goitre (odds ratio (OR), 3.57; 95 % confidence interval, 1.70-7.48), ipsilateral redo-surgery (OR, 3.64; 1.00-13.28) and total lobectomy (OR, 2.41; 1.05-5.55). At long-time follow up (median, 10 years), 7 of 12 patients with permanent RLN palsy still suffered moderate or severe symptoms. CONCLUSIONS: RLN paralysis is an infrequent complication after neck surgery, but with major negative impact on patients' well being when permanent. Hemithyroidectomy/total thyroidectomy is increasingly preferred over subtotal resection in multinodular goitre. This is supported by an increased risk of RLN injury during redo-surgery for recurrency but should be carefully weighed against individual risk factors for nerve palsy, including surgical experience and volume. PMID- 24402460 TI - Optical rotation calculations on large molecules using the approximate coupled cluster model CC2 and the resolution-of-the-identity approximation. AB - We investigate the performance of the approximate coupled cluster singles- and doubles model CC2 in the prediction of optical rotations of organic molecules. For this purpose we employ a combination of two test sets from the literature which include small and medium-sized rigid organic molecules and a series of helicenes. CC2 calculations on molecules as large as 11-helicene became possible through a recent implementation of frequency-dependent second-order properties for CC2 which makes use of the resolution-of-the-identity approximation for the electron repulsion integrals. The results are assessed with respect to the accuracy of the absolute values of the optical rotation and the prediction of the correct sign, which is crucial for the determination of absolute configurations. The performance of CC2 is compared with that of density functional theory at the B3LYP and CAM-B3LYP levels. Furthermore we investigated the influence of the molecular geometry and the one-electron basis set and tested to which extent spin component scaling changes the results. PMID- 24402459 TI - A thalamo-cortical neural mass model for the simulation of brain rhythms during sleep. AB - Cortico-thalamic interactions are known to play a pivotal role in many brain phenomena, including sleep, attention, memory consolidation and rhythm generation. Hence, simple mathematical models that can simulate the dialogue between the cortex and the thalamus, at a mesoscopic level, have a great cognitive value. In the present work we describe a neural mass model of a cortico thalamic module, based on neurophysiological mechanisms. The model includes two thalamic populations (a thalamo-cortical relay cell population, TCR, and its related thalamic reticular nucleus, TRN), and a cortical column consisting of four connected populations (pyramidal neurons, excitatory interneurons, inhibitory interneurons with slow and fast kinetics). Moreover, thalamic neurons exhibit two firing modes: bursting and tonic. Finally, cortical synapses among pyramidal neurons incorporate a disfacilitation mechanism following prolonged activity. Simulations show that the model is able to mimic the different patterns of rhythmic activity in cortical and thalamic neurons (beta and alpha waves, spindles, delta waves, K-complexes, slow sleep waves) and their progressive changes from wakefulness to deep sleep, by just acting on modulatory inputs. Moreover, simulations performed by providing short sensory inputs to the TCR show that brain rhythms during sleep preserve the cortex from external perturbations, still allowing a high cortical activity necessary to drive synaptic plasticity and memory consolidation. In perspective, the present model may be used within larger cortico-thalamic networks, to gain a deeper understanding of mechanisms beneath synaptic changes during sleep, to investigate the specific role of brain rhythms, and to explore cortical synchronization achieved via thalamic influences. PMID- 24402461 TI - Use of novel oral anticoagulants in patients with heart failure. AB - OPINION STATEMENT: Pathophysiologically, there is a prothrombotic state evident in heart failure (HF). This is particularly evident within atria in patients whose course of the disease is complicated by concomitant atrial fibrillation (AF). A predisposition for thrombogenesis exists in patients with dilated dysfunctional cardiac chambers, such as those seen in patients with large myocardial infarction, left ventricular (LV) aneurysm or dilated cardiomyopathy. Based on subgroup analyses of recent phase 3 randomized trials, the novel oral anticoagulants are equally effective and safe in AF patients with HF or without HF. This appears to be true regarding both HF with systolic LV dysfunction and with preserved LVEF. However, patients with HF with preserved LVEF with more strict definition (ie, LVEF >= 55 %) have not been analyzed specifically. There is no information from clinical trial regarding possible utility of the novel oral anticoagulants in HF patients in sinus rhythm. Further research is required to cover gaps in knowledge on utility of these medications in a substantial proportion of HF patients not included in major clinical trials on novel oral anticoagulants. PMID- 24402462 TI - Evaluation of tadalafil nanosuspensions and their PEG solid dispersion matrices for enhancing its dissolution properties. AB - The aim of this work was to prepare and evaluate Tadalafil nanosuspensions and their PEG 4000 solid dispersion matrices to enhance its dissolution rate. Nanosuspensions were prepared by precipitation/ultrasonication technique at 5 degrees C where different stabilizers were screened for stabilization. Nanosuspensions were characterized in terms of particle size and charge. Screening process limited suitable stabilizers into structurally related surfactants composed of a mixture of Tween80 and Span80 at 1:1 ratio (in percent, weight/volume) in adjusted alkaline pH (named TDTSp-OH). The surfactant mixture aided the production of nanosuspensions with an average particle size of 193 +/- 8 nm and with short-term stability sufficient for further processing. Solid dispersion matrices made of dried Tadalafil nanosuspensions or dried Tadalafil raw powder suspensions and PEG 4000 as a carrier were prepared by direct compression. Drying was performed via dry heat or via freeze dry. Drug release studies showed that, in general, tablet formulations made of freeze-dried product exhibited faster initial release rates than the corresponding tablets made of oven-dried products which could be attributed to possible larger crystal growth and larger crushing strengths of oven-dried formulations. At best, 60% of drug was released from solid dispersion matrices, while more than 90% of drug was released from TDTSp-OH nanosuspension within the first 5 min. In conclusion, Tadalafil nanosuspensions obtained using a mixed surfactant system provided rapid dissolution rates of Tadalafil that can theoretically enhance its bioavailability. PMID- 24402463 TI - An Integrated, Acceptance-Based Behavioral Approach for Depression With Social Anxiety: Preliminary Results. AB - Depression and social anxiety disorder (SAD) are highly comorbid, resulting in greater severity and functional impairment compared with each disorder alone. Although recently transdiagnostic treatments have been developed, no known treatments have addressed this comorbidity pattern specifically. Preliminary support exists for acceptance-based approaches for depression and SAD separately, and they may be more efficacious for comorbid depression and anxiety compared with traditional cognitive-behavioral approaches. The aim of the current study was to develop and pilot test an integrated acceptance-based behavioral treatment for depression and comorbid SAD. Participants included 38 patients seeking pharmacotherapy at an outpatient psychiatry practice, who received 16 individual sessions of the therapy. Results showed significant improvement in symptoms, functioning, and processes from pre- to post-treatment, as well as high satisfaction with the treatment. These results support the preliminary acceptability, feasibility, and effectiveness of this treatment in a typical outpatient psychiatry practice, and suggest that further research on this treatment in larger randomized trials is warranted. PMID- 24402464 TI - Feasibility and Acceptability of a Mobile Intervention to Improve Treatment Adherence in Bipolar Disorder: A Pilot Study. AB - We evaluated the feasibility and acceptability of a 2-week-long ecological momentary intervention (EMI), delivered via personal digital assistants (PDAs), to improve treatment adherence in bipolar disorder. EMIs use mobile technology to deliver treatment as clients engage in their typical daily routines, in their usual settings. Overall, participants (N = 14) stated that EMI sessions were helpful, user-friendly, and engaging, and reported satisfaction with the timing and burden of sessions, as well as the method of delivery. All participants completed the study, and all PDAs were returned undamaged. On average, participants completed 92% of EMI sessions. Although this study was not designed to assess efficacy, depression scores decreased significantly over the study period and data suggest relatively high rates of treatment adherence; missed medication was reported 3% of the time and three participants reported missing a total of six mental health appointments. Negative feedback largely involved technical and logistical issues, many of which are easily addressable. These preliminary findings add to the growing body of literature indicating that mobile technology-assisted interventions are feasible to implement and acceptable to patients with serious mental illnesses. PMID- 24402465 TI - Lung cancer incidence trends among men and women--United States, 2005-2009. AB - Lung cancer is the leading cause of cancer death and the second most commonly diagnosed cancer (excluding skin cancer) among men and women in the United States. Although lung cancer can be caused by environmental exposures, most efforts to prevent lung cancer emphasize tobacco control because 80%-90% of lung cancers are attributed to cigarette smoking and secondhand smoke. One sentinel health consequence of tobacco use is lung cancer, and one way to measure the impact of tobacco control is by examining trends in lung cancer incidence rates, particularly among younger adults. Changes in lung cancer rates among younger adults likely reflect recent changes in risk exposure. To assess lung cancer incidence and trends among men and women by age group, CDC used data from the National Program of Cancer Registries (NPCR) and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program for the period 2005 2009, the most recent data available. During the study period, lung cancer incidence decreased among men in all age groups except <35 years and decreased among women aged 35-44 years and 54-64 years. Lung cancer incidence decreased more rapidly among men than among women and more rapidly among adults aged 35-44 years than among other age groups. To further reduce lung cancer incidence in the United States, proven population-based tobacco prevention and control strategies should receive sustained attention and support. PMID- 24402466 TI - Recreational water-associated disease outbreaks--United States, 2009-2010. AB - Recreational water-associated disease outbreaks result from exposure to infectious pathogens or chemical agents in treated recreational water venues (e.g., pools and hot tubs or spas) or untreated recreational water venues (e.g., lakes and oceans). For 2009-2010, the most recent years for which finalized data are available, public health officials from 28 states and Puerto Rico electronically reported 81 recreational water-associated disease outbreaks to CDC's Waterborne Disease and Outbreak Surveillance System (WBDOSS) via the National Outbreak Reporting System (NORS). This report summarizes the characteristics of those outbreaks. Among the 57 outbreaks associated with treated recreational water, 24 (42%) were caused by Cryptosporidium. Among the 24 outbreaks associated with untreated recreational water, 11 (46%) were confirmed or suspected to have been caused by cyanobacterial toxins. In total, the 81 outbreaks resulted in at least 1,326 cases of illness and 62 hospitalizations; no deaths were reported. Laboratory and environmental data, in addition to epidemiologic data, can be used to direct and optimize the prevention and control of recreational water-associated disease outbreaks. PMID- 24402467 TI - Algal bloom-associated disease outbreaks among users of freshwater lakes--United States, 2009-2010. AB - Harmful algal blooms (HABs) are excessive accumulations of microscopic photosynthesizing aquatic organisms (phytoplankton) that produce biotoxins or otherwise adversely affect humans, animals, and ecosystems. HABs occur sporadically and often produce a visible algal scum on the water. This report summarizes human health data and water sampling results voluntarily reported to CDC's Waterborne Disease and Outbreak Surveillance System (WBDOSS) via the National Outbreak Reporting System (NORS) and the Harmful Algal Bloom-Related Illness Surveillance System (HABISS)* for the years 2009-2010. For 2009-2010, 11 waterborne disease outbreaks associated with algal blooms were reported; these HABs all occurred in freshwater lakes. The outbreaks occurred in three states and affected at least 61 persons. Health effects included dermatologic, gastrointestinal, respiratory, and neurologic signs and symptoms. These 11 HAB associated outbreaks represented 46% of the 24 outbreaks associated with untreated recreational water reported for 2009-2010, and 79% of the 14 freshwater HAB-associated outbreaks that have been reported to CDC since 1978. Clinicians should be aware of the potential for HAB-associated illness among patients with a history of exposure to freshwater. PMID- 24402468 TI - Vital signs: communication between health professionals and their patients about alcohol use--44 states and the District of Columbia, 2011. AB - INTRODUCTION: Excessive alcohol use accounted for an estimated 88,000 deaths in the United States each year during 2006-2010, and $224 billion in economic costs in 2006. Since 2004, the U.S. Preventive Services Task Force (USPSTF) has recommended alcohol misuse screening and behavioral counseling (also known as alcohol screening and brief intervention [ASBI]) for adults to address excessive alcohol use; however, little is known about the prevalence of its implementation. ASBI will also be covered by many health insurance plans because of the Affordable Care Act. METHODS: CDC analyzed Behavioral Risk Factor Surveillance System (BRFSS) data from a question added to surveys in 44 states and the District of Columbia (DC) from August 1 to December 31, 2011, about patient reported communication with a health professional about alcohol. Elements of ASBI are traditionally delivered via conversation. Weighted state-level prevalence estimates of this communication were generated for 166,753 U.S. adults aged >=18 years by selected demographic characteristics and drinking behaviors. RESULTS: The prevalence of ever discussing alcohol use with a health professional was 15.7% among U.S. adults overall, 17.4% among current drinkers, and 25.4% among binge drinkers. It was most prevalent among those aged 18-24 years (27.9%). However, only 13.4% of binge drinkers reported discussing alcohol use with a health professional in the past year, and only 34.9% of those who reported binge drinking >=10 times in the past month had ever discussed alcohol with a health professional. State-level estimates of communication about alcohol ranged from 8.7% in Kansas to 25.5% in DC. CONCLUSIONS: Only one of six U.S. adults, including binge drinkers, reported ever discussing alcohol consumption with a health professional, despite public health efforts to increase ASBI implementation. IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Increased implementation of ASBI, including systems-level changes such as integration into electronic health records processes, might reduce excessive alcohol consumption and the harms related to it. Routine surveillance of ASBI by states and communities might support monitoring and increasing its implementation. PMID- 24402469 TI - Non-classicality of the molecular vibrations assisting exciton energy transfer at room temperature. AB - Advancing the debate on quantum effects in light-initiated reactions in biology requires clear identification of non-classical features that these processes can exhibit and utilize. Here we show that in prototype dimers present in a variety of photosynthetic antennae, efficient vibration-assisted energy transfer in the sub-picosecond timescale and at room temperature can manifest and benefit from non-classical fluctuations of collective pigment motions. Non-classicality of initially thermalized vibrations is induced via coherent exciton-vibration interactions and is unambiguously indicated by negativities in the phase-space quasi-probability distribution of the effective collective mode coupled to the electronic dynamics. These quantum effects can be prompted upon incoherent input of excitation. Our results therefore suggest that investigation of the non classical properties of vibrational motions assisting excitation and charge transport, photoreception and chemical sensing processes could be a touchstone for revealing a role for non-trivial quantum phenomena in biology. PMID- 24402470 TI - Background free imaging of single mRNAs in live cells using split fluorescent proteins. AB - We describe a technique for imaging single mRNAs in living cells based on fluorescent protein (FP) complementation. We employ the high affinity interaction between the bacterial phage MS2/PP7 coat proteins and their respective RNA binding motifs as an RNA scaffold to bring two halves of a split-FP together to image single reporter mRNAs without background fluorescence. PMID- 24402471 TI - A biophysical model of adaptive noise filtering in the shark brain. AB - Sharks detect their prey using an extremely sensitive electrosensory system that is capable of distinguishing weak external stimuli from a relatively strong background noise generated by the animal itself. Experiments indicate that part of the shark's hindbrain, the dorsal octavolateralis nucleus (DON), is responsible for extracting the external stimulus using an adaptive filter mechanism to suppress signals correlated with the shark's breathing motion. The DON's principal neuron integrates input from afferents as well as many thousands of parallel fibres transmitting, inter alia, breathing-correlated motor command signals. There are a number of models in the literature, studying how this adaptive filtering mechanisms occurs, but most of them are based on a spike-train model approach.This paper presents a biophysically based computational simulation which demonstrates a mechanism for adaptive noise filtering in the DON. A spatial model of the neuron uses the Hodgkin-Huxley equations to simulate the propagation of action potentials along the dendrites. Synaptic inputs are modelled by applied currents at various positions along the dendrites, whose input conductances are varied according to a simple learning rule.Simulation results show that the model is able to demonstrate adaptive filtering in agreement with previous experimental and modelling studies. Furthermore, the spatial nature of the model does not greatly affect its learning properties, and in its present form is effectively equivalent to an isopotential model which does not incorporate a spatial element. PMID- 24402472 TI - Editorial: special issue on stochastic modelling of reaction-diffusion processes in biology. PMID- 24402473 TI - Primary total hip arthroplasty with a proximally HA-coated titanium femoral component: results at 10-15-year follow-up. AB - INTRODUCTION: Registries in both the United Kingdom and Sweden suggest that the popularity of uncemented femoral components is increasing. As this trend progresses, long-term survival data for such components are becoming increasingly more important. We present the results of a cohort of patients treated with the Omnifit (Stryker, Mahwah, NJ) femoral component with the follow-up of 10-15 years. METHODS: A prospective study was performed in our unit between 1996 and 2001. Patients were reviewed pre-operatively and then at 6, 12, 26 and 52 weeks post-operatively and annually thereafter. They were assessed clinically and radiographically, and the Merle d'Aubigne Postel (MDP) hip score was calculated at each visit. A visual analogue scale (VAS) score and satisfaction score were also recorded to assess patient satisfaction with their procedure. Specific enquiry was made regarding anterior thigh pain. Statistical calculations were performed using the Student's t test. Kaplan-Meier survival analysis was performed. RESULTS: One hundred and four patients (113 hips) were included (48 males, 56 females). Bilateral procedures were performed in nine patients. Mean age was 60.4 years (33-72 years). Mean follow-up was 12.9 years (10-15 years). Mean pre-operative MDP score was 8.8 (3-16) and VAS score 7.8 (1-10) with ten representing the most severe symptoms. At final follow-up, the average MDP and VAS scores were 16.9 (13-18) and 2.1 (0-6), respectively. High levels of satisfaction were reported by 96.1% of patients. Two dislocations and two cases of anterior thigh pain occurred. Four patients required revision surgery. Survival of the femoral component with revision for any reason as the end point was 96%. CONCLUSION: This prosthesis provides symptom relief, return to function and high levels of patient satisfaction in the long term. Survival of this component is comparable to the best results for primary total hip arthroplasty with any means of fixation. PMID- 24402478 TI - Advances and innovations in vascular neurosurgery: Foreword: Part I. PMID- 24402474 TI - Revisiting morphine-augmented hepatobiliary imaging for diagnosing acute cholecystitis: the potential pitfall of high false positive rate. AB - PURPOSE: The aim of this retrospective study was to investigate the efficacy of morphine-augmented hepatobiliary imaging (MAHBI) for diagnosing acute cholecystitis (AC). METHODS: Sixty-eight patients (Male:Female = 36:32, age = 54 +/- 17 years) referred for diagnosis of AC by 30-min post-morphine MAHBI after the standard 1-h imaging were recruited. Non-visualization of gallbladder on 30 min post-morphine images by visual analysis was considered positive. Final diagnosis of pathological examination for all patients was used as the gold standard. RESULTS: There was significant correlation of AC and MAHBI (p < 0.05). There were 45 true positive (TP), 19 false positive (FP), 4 true negative (TN), and no false negative (FN) cases using gallbladder visualization by 30-min post morphine as the criteria, with a high false positive rate of 83%. The sensitivity, specificity, accuracy, positive and negative predictive values of MAHBI in detecting AC were 100%, 17%, 72%, 70%, and 100%, respectively. CONCLUSIONS: MAHBI is sensitive but may not specific for diagnosing AC due to the potential pitfall of high false positive rate. Correlation with other clinical findings is recommended for optimal patient management. PMID- 24402479 TI - Advances and innovations in revascularization of extracranial vertebral artery. AB - Revascularization of the extracranial vertebral artery has evolved significantly since the adoption of endovascular techniques. The current neurosurgical armamentarium includes microsurgical and endovascular approaches. The indications for each treatment modality, however, still need to be further delineated. In contrast to carotid artery endarterectomy and carotid artery angioplasty/stenting, there is limited comparative evidence on the efficacy of medical, open, and endovascular treatment of atherosclerotic disease of the extracranial vertebral artery. More recently, drug-eluting stents have gained momentum after high rates of in-stent restenosis have been reported with bare metal stents placed in the vertebral artery. In this article, we discuss the indications, clinical assessment, and surgical nuances of microsurgical and endovascular revascularization for atherosclerotic disease of the extracranial vertebral artery. Despite a general tendency to consider endovascular treatment in the majority of patients, ultimately, open and endovascular revascularization of extracranial vertebral artery should be regarded as complementary therapies and both treatment options need to be discussed in selected patients. PMID- 24402480 TI - Advances and surgical considerations in the treatment of moyamoya disease. AB - Moyamoya is a rare disorder that involves steno-occlusive arterial changes of the anterior circulation, along with proliferative development of basal arterial collaterals. It is either idiopathic (called moyamoya disease) or the result of a specific underlying condition such as atherosclerosis, radiation therapy, or sickle cell disease (called moyamoya syndrome or phenomenon). In recent years, numerous insights into and advances in the understanding, evaluation, and management of moyamoya patients have occurred. This article briefly reviews the spectrum of moyamoya conditions and then provides a synopsis of numerous recent investigations that shed light on various aspects of the disease, including its clinical characteristics, natural history, underlying pathology, imaging, surgical techniques, and long-term patient outcome. PMID- 24402481 TI - Endovascular advances for intracranial occlusive disease. AB - Stroke is the fourth leading cause of death in the United States. Intracranial atherosclerotic disease accounts for 8%-10% of ischemic stroke in the United States. So far, surgical bypass has not proved to be superior to medical therapy. As both medical and endovascular therapies for intracranial atherosclerosis evolve, so too do the guidelines for treatment. Initial reports on the results of stent placement for symptomatic high-grade intracranial atherosclerotic disease were encouraging; however, recent trials suggest that initial medical management may be preferable. Currently, intracranial angioplasty and stenting for symptomatic intracranial atherosclerosis is now more controversial. Further trials are necessary to help determine which patients are ideal for endovascular therapies. PMID- 24402482 TI - The role of endovascular therapy in the treatment of acute ischemic stroke. AB - Of the approximately 795,000 strokes in the United States annually, 87% are ischemic and result in significant morbidity and mortality. Improvements in acute ischemic stroke (AIS) outcomes have been achieved with intravenous thrombolytics (IVT) and intra-arterial thrombolytics vs supportive medical therapy. Given its ease of administration, noninvasiveness, and most validated efficacy, IVT is the standard of care in AIS patients without contraindications to systemic fibrinolysis. However, patients with large-vessel occlusions respond poorly to IVT. Recent trials designed to select this population for randomization to IVT vs IVT with adjunctive endovascular therapy have not shown improvement in clinical outcomes with endovascular therapy. This could be due to the lack of utilization of modern thrombectomy devices such as Penumbra aspiration devices, Solitaire stent-trievers, or Trevo stent-trievers, which have shown the best recanalization results. Continued improvement in the techniques with using these devices as well as randomized controlled trials using them is warranted. This article defines the goals of AIS revascularization, presents the evolution of treatment from the initial use of IVT to modern thrombectomy devices, and discusses current treatment and ongoing AIS trials. PMID- 24402483 TI - Spontaneous intracerebral and intraventricular hemorrhage: advances in minimally invasive surgery and thrombolytic evacuation, and lessons learned in recent trials. AB - Optimal management of spontaneous intracerebral hemorrhage (ICH) remains one of the highly debated areas in the field of neurosurgery. Earlier studies comparing open surgical intervention with best medical management failed to show a clear benefit. More recent experience with minimally invasive techniques has shown greater promise. Well-designed phase II trials have confirmed the safety and preliminary treatment effect of thrombolytic aspiration and clearance of spontaneous ICH and associated intraventricular obstructive hemorrhage. Those trials are reviewed, including respective protocols and technical nuances, and lessons learned regarding patient selection, the concept of hemorrhage stabilization, optimization of the surgical procedure, and thrombolytic dosing decisions. These concepts have been incorporated in the design of ongoing definite phase III randomized trials (MISTIE and CLEAR) funded by the National Institutes of Health. These are presented including the role of surgical leadership in the training and monitoring of the surgical task and quality assurance. The impact of these techniques on neurosurgical practice is discussed. PMID- 24402484 TI - Craniectomy in acute ischemic stroke. AB - Anterior and posterior circulation acute ischemic stroke carries significant morbidity and mortality as a result of malignant cerebral edema. Decompressive craniectomy has evolved as a viable neurosurgical intervention in the armamentarium of treatment options for this life-threatening edema. In this review, we highlight the history of craniectomy for stroke and discuss recent data relevant to its efficacy in modern neurosurgical practice. PMID- 24402485 TI - Balloons in endovascular neurosurgery: history and current applications. AB - The use of balloons in the field of neurosurgery is currently an essential part of our clinical practice. The field has evolved over the last 40 years since Serbinenko used balloons to test the feasibility of occluding cervical vessels for intracranial pathologies. Since that time, indications have expanded to include sacrificing cervical and intracranial vessels with detachable balloons, supporting the coil mass in wide-necked aneurysms (balloon remodeling technique), and performing intracranial and cervical angioplasty for atherosclerotic disease, as well as an adjunct to treat arteriovenous malformations. With the rapid expansion of endovascular technologies, it appears that the indications and uses for balloons will continue to expand. In this article, we review the history of balloons, the initial applications, the types of balloons available, and the current applications available for endovascular neurosurgeons. PMID- 24402486 TI - Advances in endovascular approaches to cerebral aneurysms. AB - Recent advancements in all phases of endovascular aneurysm treatment, including medical therapy, diagnostics, devices, and implants, abound. Advancements in endovascular technologies and techniques have enabled treatment of a wide variety of intracranial aneurysms. In this article, technical advances in endovascular treatment of cerebral aneurysms are discussed, with an effort to incorporate a clinically relevant perspective. Advancements in diagnostic tools, medical therapy, and implants are reviewed and discussed. PMID- 24402487 TI - Cerebrovascular neurosurgery in evolution: the endovascular paradigm. AB - Endovascular technique represents an important, minimally invasive approach to treating cerebrovascular disease. In this article, we discuss the origins of endovascular neurosurgery as a discipline in the context of important technical milestones, evidence-based medicine, and future cerebrovascular neurosurgical training. Cerebrovascular neurosurgery has seen a steady, convergent evolution toward the surgeon capable of seamless incorporation of open and endovascular approaches to any complex vascular disease affecting the central nervous system. Neurosurgery must assume the leadership role in the multidisciplinary neurovascular team. PMID- 24402488 TI - Genealogy of training in vascular neurosurgery. AB - Remarkable advances and changes in the landscape of neurovascular disease have occurred recently. Concurrently, a paradigm shift in training and resident education is underway. This crossroad of unique opportunities and pressures necessitates creative change in the training of future vascular neurosurgeons to allow incorporation of surgical advances, new technology, and supplementary treatment modalities in a setting of reduced work hours and increased public scrutiny. This article discusses the changing landscape in neurovascular disease treatment, followed by the recent changes in resident training, and concludes with our view of the future of training in vascular neurosurgery. PMID- 24402489 TI - Advances and innovations in vascular neurosurgery: Foreword: Part II. PMID- 24402490 TI - Advances in surgical approaches to dural fistulas. AB - Dural arteriovenous fistulas are abnormal connections of dural arteries to dural veins or venous sinuses originating from within the dural leaflets. They are usually located near or within the wall of a dural venous sinus that is frequently obstructed or stenosed. The dural fistula sac is contained within the dural leaflets, and drainage can be via a dural sinus or retrograde through cortical veins (leptomeningeal drainage). Dural arteriovenous fistulas can occur at any dural sinus but are found most frequently at the cavernous or transverse sinus. Leptomeningeal venous drainage can lead to venous hypertension and intracranial hemorrhage. The various treatment options include transarterial and transvenous embolization, stereotactic radiosurgery, and open surgery. Although many of the advances in dural arteriovenous fistula treatment have occurred in the endovascular arena, open microsurgical advances in the past decade have primarily been in the tools available to the surgeon. Improvements in microsurgical and skull base approaches have allowed surgeons to approach and obliterate fistulas with little or no retraction of the brain. Image-guided systems have also allowed better localization and more efficient approaches. A better understanding of the need to simply obliterate the venous drainage at the site of the fistula has eliminated the riskier resections of the past. Finally, the use of intraoperative angiography or indocyanine green videoangiography confirms the complete disconnection of fistula while the patient is still on the operating room table, preventing reoperation for residual fistulas. PMID- 24402491 TI - Endovascular treatment of intracranial dural arteriovenous fistulas. AB - Endovascular treatment options for dural arteriovenous fistulas (DAVFs) have vastly expanded and become progressively safer in the last several years. Angiographic imaging systems have improved, catheter technology has advanced, and liquid embolic and coil options have increased. As a likely result, an increasing proportion of DAVFs are treated via an endovascular approach. In addition to allowing physicians to appreciate and treat lesions better, varied approaches have been developed. The "plug and push" technique and the new availability of dimethyl sulfoxide--compatible dual lumen balloons have allowed safer and more thorough transarterial treatments. Transvenous treatment has proved to be a valuable technique for some lesions. Hybrid approaches with surgical assisted access to vascular structures have been successfully used to treat more challenging fistulas. PMID- 24402492 TI - Toward a new renaissance in the treatment of neurovascular diseases and stroke. PMID- 24402493 TI - Advances in radiosurgery for arteriovenous malformations of the brain. AB - Arteriovenous malformations of the brain are a considerable source of morbidity and mortality for patients who harbor them. Although our understanding of this disease has improved, it remains in evolution. Advances in our ability to treat these malformations and the modes by which we address them have also improved substantially. However, the variety of patient clinical and disease scenarios often leads us into challenging and complex management algorithms as we balance the risks of treatment against the natural history of the disease. The goal of this article is to provide a focused review of the natural history of cerebral arteriovenous malformations, to examine the role of stereotactic radiosurgery, to discuss the role of endovascular therapy as it relates to stereotactic radiosurgery, and to look toward future advances. PMID- 24402494 TI - Advances and innovations in brain arteriovenous malformation surgery. AB - Arteriovenous malformations (AVMs) of the brain are very complex and intriguing pathologies. Since their initial description by Luschka and Virchow in the middle of the 19th century, multiple advances and innovations have revolutionized their management and surgical treatment. Here, we review the historical landmarks in the surgical treatment of AVMs and then illustrate the most recent and futuristic technologies aiming to improve outcomes in AVM surgeries. In particular, we examine potential advances in patient selection, imaging, surgical technique, neuroanesthesia, and postoperative neuro-rehabilitation and quantitative assessments. Finally, we illustrate how concurrent advances in radiosurgery and endovascular techniques might present new opportunities to treat AVMs more safely from a surgical perspective. PMID- 24402495 TI - Advances in open microsurgery for cerebral aneurysms. AB - BACKGROUND: Endovascular techniques introduced strong extrinsic forces that provoked reactive changes in aneurysm surgery. Microsurgery has become less invasive, more appealing to patients, lower risk, and efficacious for complex aneurysms, particularly those unfavorable for or failing endovascular therapy. OBJECTIVE: To review specific advances in open microsurgery for aneurysms. METHODS: A university-based, single-surgeon practice was examined for the use of minimally invasive craniotomies, surgical management of recurrence after coiling, the use of intracranial-intracranial bypass techniques, and cerebrovascular volume-outcome relationships. RESULTS: The mini-pterional, lateral supraorbital, and orbital-pterional craniotomies are minimally invasive alternatives to standard craniotomies. Mini-pterional and lateral supraorbital craniotomies were used in one-fourth of unruptured patients, increasing from 22% to 28%, whereas 15% of patients underwent orbital-pterional craniotomies and trended upward from 11% to 20%. Seventy-four patients were treated for coil recurrences (2.3% of all aneurysms) with direct clip occlusion (77%), clip occlusion after coil extraction (7%), or parent artery occlusion with bypass (16%). Intracranial-intracranial bypass (in situ bypass, reimplantation, reanastomosis, and intracranial grafts) transformed the management of giant aneurysms and made the surgical treatment of posterior inferior cerebellar artery aneurysms competitive with endovascular therapy. Centralization maximized the volume-outcome relationships observed with clipping. CONCLUSION: Aneurysm microsurgery has embraced minimalism, tailoring the exposure to the patient's anatomy with the smallest possible craniotomy that provides adequate exposure. The development of intracranial-intracranial bypasses is an important advancement that makes microsurgery a competitive option for complex and recurrent aneurysms. Trends toward centralizing aneurysm surgery in tertiary centers optimize results achievable with open microsurgery. PMID- 24402496 TI - Endovascular advances for brain arteriovenous malformations. AB - Arteriovenous malformations (AVMs) of the brain represent unique challenges for treating physicians. Although these lesions have traditionally been treated with surgical resection alone, advancements in endovascular and radiosurgical therapies have greatly expanded the treatment options for patients harboring brain AVMs. Perhaps no subspecialty within neurosurgery has seen as many advancements over a relatively short period of time as the endovascular field. A number of these endovascular innovations have been designed primarily for cerebral AVMs, and even those advancements that are not particular to AVMs have resulted in substantial changes to the way cerebral AVMs are treated. These advancements have enabled the embolization of cerebral AVMs to be performed either as a stand-alone treatment, or in conjunction with surgery or radiosurgery. Perhaps nothing has impacted the treatment of brain AVMs as substantially as the development of liquid embolics, most notably Onyx and n butyl cyanoacrylate. However, of near-equal impact has been the innovations seen in the catheters that help deliver the liquid embolics to the AVMs. These developments include flow-directed catheters, balloon-tipped catheters, detachable-tipped catheters, and distal access catheters. This article aims to review some of the more substantial advancements in the endovascular treatment of brain AVMs and to discuss the literature surrounding the expanding indications for endovascular treatment of these lesions. PMID- 24402497 TI - Surgical advances for extracranial carotid stenosis. AB - Carotid endarterectomy is a commonly performed operation to prevent stroke in patients who have asymptomatic or symptomatic internal carotid artery atherosclerotic stenosis. Carotid angioplasty and stenting has also been advocated for treatment of these patients. In this article, we address a number of questions for which a review of available data will advance our understanding of the role of carotid endarterectomy in stroke prevention. These include the following: Are carotid endarterectomy and carotid angioplasty and stenting equivalent procedures for the treatment of carotid artery disease? Which patients should be deemed at high risk for carotid endarterectomy? Should carotid endarterectomy be an urgent procedure in symptomatic patients with severe internal carotid artery stenosis? Finally, what is the role of carotid endarterectomy in asymptomatic patients? We also review the senior author's personal experience with >2000 consecutive carotid endarterectomies, with special attention to his present approach to this operation. We believe that carotid endarterectomy, in experienced hands, is a minimally invasive operation that remains the procedure of choice for most patients with carotid artery disease who will benefit from invasive treatment. PMID- 24402498 TI - Endovascular advances for extracranial carotid stenosis. AB - Carotid artery stenting has become a viable alternative to carotid endarterectomy in the management of carotid stenosis. Over the past 20 years, many trials have attempted to compare both treatment modalities and establish the indications for each one, depending on clinical and anatomic features presented by patients. Concurrently, carotid stenting techniques and devices have evolved and made endovascular management of carotid stenosis safe and effective. Among the most important innovations are devices for distal and proximal embolic protection and new stent designs. This paper reviews these advances in the endovascular management of carotid artery stenosis within the context of the historical background. PMID- 24402499 TI - Re: Mitochondria and tumor progression in ulcerative colitis. PMID- 24402500 TI - Response. PMID- 24402501 TI - Identification of a novel plasmid-associated spectinomycin adenyltransferase gene spd in methicillin-resistant Staphylococcus aureus ST398 isolated from animal and human sources. AB - OBJECTIVES: Previously described methicillin-resistant Staphylococcus aureus (MRSA) ST398 strains revealed a high frequency of phenotypic resistance to spectinomycin. However, only a few were found to carry the spc resistance determinant. The aim of this study was to identify the genetic mechanism of spectinomycin resistance among spc-negative MRSA ST398 strains. METHODS: Nine spectinomycin-resistant, but spc-negative, MRSA ST398 strains were analysed. The strains were screened for carriage of the spw gene and tested for the presence of transferrable spectinomycin resistance. Plasmid DNA was isolated from all strains and used in transformation assays. The plasmid identified as mediating resistance to spectinomycin was fully sequenced. The function of the novel spectinomycin resistance gene was confirmed by restriction digest inactivation and its distribution was determined using a PCR assay. RESULTS: A single MRSA ST398 strain was spw positive. The remaining strains carried a plasmid that mediated resistance to spectinomycin. Sequence analysis of a single plasmid, termed pDJ91S, revealed that it was 3928 bp in size and contained three open reading frames: a novel spectinomycin resistance gene, designated spd, as well as a repN gene and a rec gene. The XmnI digest inactivation of the spd gene resulted in a 4 fold decrease in spectinomycin MIC. The spd gene was detected in seven other spectinomycin-resistant MRSA ST398 strains that carried a plasmid comparable in size to pDJ91S. CONCLUSIONS: A novel gene, designated spd, that confers resistance to spectinomycin has been identified on a small plasmid in MRSA ST398. PMID- 24402503 TI - Polymyxin B and haemofiltration in an adolescent with leukaemia. PMID- 24402502 TI - Prevalence of day-care centre children (France) with faecal CTX-M-producing Escherichia coli comprising O25b:H4 and O16:H5 ST131 strains. AB - OBJECTIVES: Determining the prevalence of children in day-care centres (DCCs) carrying faecal extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and molecularly characterizing those belonging to the Escherichia coli species. METHODS: Stools were collected from children's diapers (January-April 2012) in randomly chosen DCCs and plated onto ChromID ESBL. Colonies growing on this medium were identified by the Vitek 2 system and tested for antibiotic susceptibility and for ESBL production by the double-disc synergy test. ESBL genotypes were determined as well as phylogenetic groups, ERIC-2 (enterobacterial repetitive intergenic consensus) PCR profiles and sequence types (STs) for the E. coli isolates. Serotypes, virotypes, fimH alleles, ESBL-carrying plasmids and PFGE patterns were determined for the ST131 E. coli isolates. RESULTS: Among 419 children from 25 participating DCCs, 1 was colonized by CTX-M 15-producing Klebsiella pneumoniae and 27 (6.4%) by E. coli, which all produced CTX-M enzymes [CTX-M-15 (37%), CTX-M-1 (26%), CTX-M-14 (22%), CTX-M-27 (11%) and CTX-M-22 (4%)]. The 27 E. coli isolates, 55.5% belonging to group B2, displayed 20 ERIC-2 PCR profiles and 16 STs. The ST131 E. coli isolates were dominant (44%), displayed serotypes O25b:H4 and O16:H5, fimH alleles 30 and 41 and virotypes A and C. According to the PFGE patterns, one strain of E. coli ST131 producing a CTX-M-15 enzyme carried by an IncF F2:A1:B- plasmid had spread within one DCC. CONCLUSIONS: This study shows a notable prevalence (6.4%) of DCC children with faecal CTX-M-producing E. coli isolates comprising a high proportion of E. coli ST131 isolates, suggesting that these children might be a reservoir of this clone. PMID- 24402505 TI - Enhancement of L-ornithine production by disruption of three genes encoding putative oxidoreductases in Corynebacterium glutamicum. AB - Recently, Corynebacterium glutamicum has been shown to exhibit gluconate bypass activity, with two key enzymes, glucose dehydrogenase (GDH) and gluconate kinase, that provides an alternate route to 6-phosphogluconate formation. In this study, gene disruption analysis was used to examine possible metabolic functions of three proteins encoded by open reading frames having significant sequence similarity to GDH of Bacillus subtilis. Chromosomal in-frame deletion of three genes (NCgl0281, NCgl2582, and NCgl2053) encoding putative NADP+-dependent oxidoreductases led to the absence of GDH activity and correlated with increased specific glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities. This finding suggested that enhanced carbon flux from glucose was directed toward the oxidative pentose phosphate (PP) pathway, when the mutant was cultivated with 6 % glucose. Consequently, the mutant showed 72.4 % increased intracellular NADPH and 66.3 % increased extracellular L-ornithine production. The enhanced activities of the oxidative PP pathway in the mutant explain both the increased intracellular NADPH and the high extracellular concentration of L ornithine. Thus, the observed metabolic changes in this work corroborate the importance of NADPH in L-ornithine production from C. glutamicum. PMID- 24402508 TI - Two- and one-step cooperative spin transitions in Hofmann-like clathrates with enhanced loading capacity. AB - Structural, magnetic, calorimetric and Mossbauer studies of the cooperative spin crossover naphthalene and nitrobenzene clathrates of the novel Fe(II) Hofmann like porous metal-organic framework {Fe(bpb)[Pt(CN)4]}.2Guest are described (bpb = bis(4-pyridyl)butadiyne). PMID- 24402507 TI - Modeling tumor microenvironments in vitro. AB - Tumor progression depends critically upon the interactions between the tumor cells and their microenvironment. The tumor microenvironment is heterogeneous and dynamic; it consists of extracellular matrix, stromal cells, immune cells, progenitor cells, and blood and lymphatic vessels. The emerging fields of tissue engineering and microtechnologies have opened up new possibilities for engineering physiologically relevant and spatially well-defined microenvironments. These in vitro models allow specific manipulation of biophysical and biochemical parameters, such as chemical gradients, biomatrix stiffness, metabolic stress, and fluid flows; thus providing a means to study their roles in certain aspects of tumor progression such as cell proliferation, invasion, and crosstalk with other cell types. Challenges and perspectives for deconvolving the complexity of tumor microenvironments will be discussed. Emphasis will be given to in vitro models of tumor cell migration and invasion. PMID- 24402509 TI - Strontium-substituted, luminescent and mesoporous hydroxyapatite microspheres for sustained drug release. AB - The multifunctional strontium (Sr)-substituted hydroxyapatite microsphere was prepared via hydrothermal method, in which the luminescent and controlled drug release functions can be realized. The structure and morphology of the as prepared microspheres were studied by using XRD, FTIR, SEM, TEM, HR-TEM, BET method. The optical properties was investigated by using photoluminescence (PL) and XPS measurement. Then, the as-prepared multifunctional microspheres were performed as a drug delivery carrier using vancomycin as a model drug. The experimental results show that the composition, morphology, luminescent properties and drug storage/release behaviour were obviously influenced by the amount of Sr. The microspheres with Sr(2+)/(Ca(2+) + Sr(2+)) = 0.3 of Sr substitution showed the maximum specific surface area, best pore structure and strongest PL intensity. All the samples presented remarkable sustained drug release kinetics. In addition, the PL intensity of SrHA in the drug delivery system increased with the cumulative release time (amount) of vancomycin, which would make the drug release might be possibly tracked by the change of the luminescent intensity. Our study indicated a potential prospect that the fabricated multifunctional SrHA mesoporous microspheres might be applied in the field of bone regeneration and drug delivery. PMID- 24402510 TI - [Stress and job satisfaction in the discipline of inpatient anesthesiology : results of a web-based survey]. AB - BACKGROUND: How do physicians in the specialty of anesthesiology perceive the working conditions regarding stress and job satisfaction? The health system in Germany has been confronted with a rapidly changing framework over the last 20 years: For example, an increased influence of economic patterns on the workflow and the medical decision of physicians has been established forcing them to always take the economic aspects into account. Moreover, a new generation (generation Y) of physicians with other requirements of the work place, meaning mainly a demand for a better work-life balance, has gained a foothold in hospitals. These changes make it very important to investigate the status quo of current working conditions. AIM: Working conditions in hospitals in the specialty of anesthesiology is the main issue investigated in this study. METHODS: For this study 1,321 completed online-questionnaires from physicians in hospitals with the specialty of anesthesiology were analyzed. The questionnaire was based on the stress theory, the effort-reward-imbalance model (ERI) and the job-demand-control model (JDC).The items used in the questionnaire were taken from the ERI questionnaire and the short questionnaire on work analysis (KFZA). By calculating a certain ratio of several items (according to the stress theory), the prevalence of distress could be measured. In addition the overall job satisfaction in the field of anesthesiology was measured and analyzed. RESULTS: In this study 47.0 % (95 %-CI: 44.3-49.7 %) of all respondents showed signs of distress. Simultaneously, 61.8 % (95 %-CI: 59.2-64.5 %) were very satisfied with the job situation. Regarding gender, female physicians perceived a lower control of the work situation whereas male physicians perceived a much higher decision level. This led to a higher prevalence of distress in the group of female physicians regarding the JDC model (odds ratio, OR: 1.54, 95 %-CI: 1.19-2.01). Regarding age, the prevalence of distress increased from 36.5 % in the respondents under 35 years old to 50.7 % in those 35-59 years old (OR: 1.79, 95 %-CI: 1.38-2.32). Looking at the different functional positions in the hospital, senior doctors showed a much higher prevalence of distress (52.8 %) than junior doctors (OR: 1.57, 95 %-CI: 1.21-2.05). Analyzing job satisfaction with respect to the functional position, the highest significant proportion was shown by senior doctors (65.8 %). CONSEQUENCES: This study revealed a high prevalence of unfavorable working conditions for anesthetists in hospitals. Taking the forthcoming shortage of qualified physicians in German hospitals into account, these results have to be considered as a cause for concern. Constant unfavorable working conditions have a negative effect on the mental and physical health of employees. Sooner or later a migration of qualified physicians abroad could be the consequence. To prevent a future shortage of qualified physicians and to make the hospital work place more appealing, working conditions have to be adapted to current needs and expectations of employees. The focus should be put on balanced working conditions according to stress models shown in this study. PMID- 24402511 TI - [Rare complication after endoscopic discectomy]. AB - Surgical treatment of the lumbar spine is a standard procedure in orthopedic and neurosurgery. After endoscopic discectomy an otherwise healthy patient developed massive dyspnea in combination with severe abdominal pain. Sonography revealed a large volume of free fluid in the abdominal cavity which proved to be surgical irrigation solution after computed tomography (CT) guided puncture. After insertion of a drainage channel fluid could be removed and the patient was transferred to a peripheral ward after a 24 h monitoring period. This review reports on the complications and anesthetic characteristics of percutaneous spinal interventions and presents differential diagnoses of postoperative dyspnea. PMID- 24402512 TI - [Perioperative antibiotic prophylaxis]. AB - In times of growing bacterial resistance against antimicrobiotic drugs the broad prescription of antibiotics in human medicine must be carefully considered. The perioperative antibiotic treatment is in the center of that conflict. On the one hand an efficient pathogen reduction for the preemptive treatment of infectious complications is desired but on the other hand it is suspected that this promotes the selection of multiresistant pathogens which could lead to an increase of more complicated nosocomial infections. The aim of this article is a critical appraisal of this subject on the basis of the 2012 guidelines of the German working group of Hygiene in Hospital and Practice (AWMF) and the 2010 recommendations of the Paul-Ehrlich-Gesellschaft. PMID- 24402513 TI - Editor's Spotlight/Take 5: Magnetic resonance imaging of the hip: poor cost utility for treatment of adult patients with hip pain. PMID- 24402514 TI - CORR Insights((r)): Patients with hip osteoarthritis have a phenotype with high bone mass and low lean body mass. PMID- 24402515 TI - Letter to the editor: Art in science: orthopaedics through philatelic material. PMID- 24402516 TI - New insight into the potential energy landscape and relaxation pathways of photoexcited aniline from CASSCF and XMCQDPT2 electronic structure calculations. AB - There have been a number of recent experimental investigations of the nonadiabatic relaxation dynamics of aniline following excitation to the first three singlet excited states, 1(1)pipi*, 1(1)pi3s/pisigma* and 2(1)pipi*. Motivated by differences between the interpretations of experimental observations, we have employed CASSCF and XMCQDPT2 calculations to explore the potential energy landscape and relaxation pathways of photoexcited aniline. We find a new prefulvene-like MECI connecting the 1(1)pipi* state with the GS in which the carbon-atom carrying the amino group is distorted out-of-plane. This suggests that excitation above the 1(1)pi3s/pisigma* vertical excitation energy could be followed by electronic relaxation from the 1(1)pipi* state to the ground electronic state through this MECI. We find a MECI connecting the 1(1)pi3s/pisigma* and 1(1)pipi* states close to the local minimum on 1(1)pi3s/pisigma* which suggests that photoexcitation to the 1(1)pi3s/pisigma* state could be followed by relaxation to the 1(1)pipi* state and to the dissociative component of the 1(1)pi3s/pisigma* state. We also find evidence for a new pathway from the 2(1)pipi* state to the ground electronic state that is likely to pass through a three-state conical intersection involving the 2(1)pipi*, 1(1)pi3s/pisigma* and 1(1)pipi* states. PMID- 24402517 TI - Prenatal iron deficiency and monoamine oxidase A (MAOA) polymorphisms: combined risk for later cognitive performance in rhesus monkeys. AB - Monoamine oxidase A (MAOA) gene polymorphisms resulting in high and low transcription rates are associated with individual differences in reward efficacy and response inhibition. Iron deficiency (ID) is the most frequent single nutrient deficiency worldwide, and prenatal ID has recently been shown to carry a risk for lower mental development scores in infants. In this study, a potential interaction of MAOA genotype and prenatal ID was studied in young male rhesus monkeys. Cognitive tasks, including problem solving, responsiveness to reward and attention, were used to characterize the potential interaction of these two fetal risks. ID was induced by feeding rhesus monkey dams an iron-deficient (10 ppm, ID) or an iron-sufficient (100 ppm, IS) diet during gestation (n = 10/group). Subgroups of the ID and IS diet offspring had low-MAOA or high-MAOA transcription rate polymorphisms. ID combined with low-MAOA genotype showed distinctive effects on reward preference and problem solving while ID in hi-MAOA juveniles modified response inhibition. Given the incidence of ID and MAOA polymorphisms in humans, this interaction could be a significant determinant of cognitive performance. PMID- 24402518 TI - A case-control study on the effect of metabolic gene polymorphisms, nutrition, and their interaction on the risk of non-alcoholic fatty liver disease. AB - The oxidative stress is a key issue in the etiology of non-alcoholic fatty liver disease (NAFLD). The aim of our study was to evaluate the effect of metabolic gene polymorphisms involved in the oxidative stress (GSTT1, GSTM1, SULT1A1, CYP2E1, and 1A1), lifestyle and nutrition aspects, and their interaction, on the risk of NAFLD. We enrolled 294 cases and 359 controls, and collected demographics, anthropometric, lifestyle, and nutrition data. A subgroup of NAFLD provided additional data on nutrients and on physical activity engagement. Each patient provided a blood sample for DNA extraction and genotyping. Clinical and laboratory data were collected from cases. Multivariable analysis shows a significant protective effect of age, gender, and moderate drinking habits on the risk of NAFLD, while an increased risk for greater consumption of fruit and grilled meat or fish. Significant interactions were reported between alcohol consumption, fruit intake, grilled meat and fish, and selected genetic variants. From the subgroup analysis, a moderate/high consumption of fat and/or grilled meat/fish, and a high consumption of white meat increase the risk of NAFLD. Engaging any physical activity at least 1 time/week halves the risk of NAFLD. Besides confirming the beneficial effect of moderate alcohol intake and regular physical activity, and the increased risk associated with high fruit and fat intake, for the first time, we report a detrimental effect of grilled food on NAFLD risk. An effect modification by selected gene variants increases the risk in combination with fruit and grilled food intake. PMID- 24402519 TI - Genome-wide identification of long noncoding natural antisense transcripts and their responses to light in Arabidopsis. AB - Recent research on long noncoding RNAs (lncRNAs) has expanded our understanding of gene transcription regulation and the generation of cellular complexity. Depending on their genomic origins, lncRNAs can be transcribed from intergenic or intragenic regions or from introns of protein-coding genes. We have recently reported more than 6000 intergenic lncRNAs in Arabidopsis. Here, we systematically identified long noncoding natural antisense transcripts (lncNATs), defined as lncRNAs transcribed from the opposite DNA strand of coding or noncoding genes. We found a total of 37,238 sense-antisense transcript pairs and 70% of annotated mRNAs to be associated with antisense transcripts in Arabidopsis. These lncNATs could be reproducibly detected by different technical platforms, including strand-specific tiling arrays, Agilent custom expression arrays, strand-specific RNA-seq, and qRT-PCR experiments. Moreover, we investigated the expression profiles of sense-antisense pairs in response to light and observed spatial and developmental-specific light effects on 626 concordant and 766 discordant NAT pairs. Genes for a large number of the light responsive NAT pairs are associated with histone modification peaks, and histone acetylation is dynamically correlated with light-responsive expression changes of NATs. PMID- 24402522 TI - Manipulating surface reactions in lithium-sulphur batteries using hybrid anode structures. AB - Lithium-sulphur batteries have high theoretical energy density and potentially low cost, but significant challenges such as severe capacity degradation prevent its widespread adoption. Here we report a new design of lithium-sulphur battery using electrically connected graphite and lithium metal as a hybrid anode to control undesirable surface reactions on lithium. Lithiated graphite placed in front of the lithium metal functions as an artificial, self-regulated solid electrolyte interface layer to actively control the electrochemical reactions and minimize the deleterious side reactions, leading to significant performance improvements. Lithium-sulphur cells incorporating this hybrid anodes deliver capacities of >800 mAh g(-1) for 400 cycles at a high rate of 1,737 mA g(-1), with only 11% capacity fade and a Coulombic efficiency >99%. This simple hybrid concept may also provide scientific strategies for protecting metal anodes in other energy-storage devices. PMID- 24402524 TI - ACG presidential introduction. PMID- 24402520 TI - Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment. AB - Differential methylation between the two alleles of a gene has been observed in imprinted regions, where the methylation of one allele occurs on a parent-of origin basis, the inactive X-chromosome in females, and at those loci whose methylation is driven by genetic variants. We have extensively characterized imprinted methylation in a substantial range of normal human tissues, reciprocal genome-wide uniparental disomies, and hydatidiform moles, using a combination of whole-genome bisulfite sequencing and high-density methylation microarrays. This approach allowed us to define methylation profiles at known imprinted domains at base-pair resolution, as well as to identify 21 novel loci harboring parent-of origin methylation, 15 of which are restricted to the placenta. We observe that the extent of imprinted differentially methylated regions (DMRs) is extremely similar between tissues, with the exception of the placenta. This extra-embryonic tissue often adopts a different methylation profile compared to somatic tissues. Further, we profiled all imprinted DMRs in sperm and embryonic stem cells derived from parthenogenetically activated oocytes, individual blastomeres, and blastocysts, in order to identify primary DMRs and reveal the extent of reprogramming during preimplantation development. Intriguingly, we find that in contrast to ubiquitous imprints, the majority of placenta-specific imprinted DMRs are unmethylated in sperm and all human embryonic stem cells. Therefore, placental-specific imprinting provides evidence for an inheritable epigenetic state that is independent of DNA methylation and the existence of a novel imprinting mechanism at these loci. PMID- 24402525 TI - ACG presidential address: Strength, courage, and wisdom. PMID- 24402521 TI - H2A.B facilitates transcription elongation at methylated CpG loci. AB - H2A.B is a unique histone H2A variant that only exists in mammals. Here we found that H2A.B is ubiquitously expressed in major organs. Genome-wide analysis of H2A.B in mouse ES cells shows that H2A.B is associated with methylated DNA in gene body regions. Moreover, H2A.B-enriched gene loci are actively transcribed. One typical example is that H2A.B is enriched in a set of differentially methylated regions at imprinted loci and facilitates transcription elongation. These results suggest that H2A.B positively regulates transcription elongation by overcoming DNA methylation in the transcribed region. It provides a novel mechanism by which transcription is regulated at DNA hypermethylated regions. PMID- 24402526 TI - New anticoagulants and antiplatelet agents: a primer for the clinical gastroenterologist. AB - The discovery of the first oral anticoagulant, warfarin, was a milestone in anticoagulation. Warfarin's well-known limitations, however, have led to the recent development of more effective anticoagulants. The rapidly growing list of these drugs, however, presents a challenge to endoscopists who must treat patients on these sundry medications. This review is intended to summarize the pharmacological highlights of new anticoagulants, with particular attention to suggested "best-practice" recommendations for the withholding of these drugs before endoscopic procedures. PMID- 24402527 TI - Images of the month: A case of strongyloidiasis presenting as a colonic mass. PMID- 24402528 TI - Video of the month: Multimodality endoscopic retrograde cholangiopancreatography in Billroth II anatomy. PMID- 24402531 TI - The etiology of intrahepatic cholestasis of pregnancy: towards solving a monkey puzzle. AB - Clinical and epidemiological findings implicate genetic predisposition and the effects of elevated steroids in pregnancy in the pathogenesis of intrahepatic cholestasis of pregnancy. To date, a number of studies have identified polymorphisms encoding biliary canalicular transporters, including those encoded by ABCB4 and ABCB11, which are associated with intrahepatic cholestasis of pregnancy. Questions remain regarding divergent findings between populations and the relative contributions of these polymorphisms. In a large study of Western European women with intrahepatic cholestasis of pregnancy, Dixon et al. (this issue) provide further insights into the genetics of this cholestatic syndrome, which contribute to ongoing evaluation of cholestasis generally. PMID- 24402534 TI - Pancreatic cysts: more answers, more questions. AB - Management of incidental pancreatic cysts has been a conundrum for the clinician owing to uncertain implications for the presence of cancer or progression to pancreatic malignancy. Asymptomatic pancreatic cysts are being detected in increasing numbers, especially in elderly patients getting radiologic imaging studies for evaluation of other non-pancreatic symptoms and signs. As a result, various radiologic, endoscopic, and pathologic criteria have been developed to help stratify the risk of malignancy in these patients and optimize strategies for patient care including surveillance or resection. In this issue, Wu and co workers (Am J Gastroenterol, this issue) present their study assessing the prediction of malignancy in cystic neoplasms of the pancreas. PMID- 24402535 TI - Why is spleen stiffness better at predicting large esophageal varices and variceal bleeders? PMID- 24402536 TI - Response to Chin et al. PMID- 24402537 TI - Polyethylene glycol in constipation-predominant irritable bowel syndrome. PMID- 24402538 TI - Response to Drs Shearer and Ford. PMID- 24402539 TI - The acid pocket: rediscovery of an old concept. PMID- 24402540 TI - Response to Drs Trang and Graham. PMID- 24402541 TI - Risk factors of community-acquired enteric infection. PMID- 24402542 TI - Response to Fujita et al. PMID- 24402543 TI - The impact of preoperative anti-TNF in surgical and infectious complications of abdominal procedures for Crohn's disease: controversy still persists. PMID- 24402544 TI - Response to Kotze et al. PMID- 24402545 TI - Robust detection of liver steatosis and staging of NAFLD by an improved ELISA for serum cytokeratin-18 fragments. PMID- 24402546 TI - Psychological status of liver cirrhosis patients might impact disease self management learning. PMID- 24402550 TI - Proof-of-principle experiment of reference-frame-independent quantum key distribution with phase coding. AB - We have demonstrated a proof-of-principle experiment of reference-frame independent phase coding quantum key distribution (RFI-QKD) over an 80-km optical fiber. After considering the finite-key bound, we still achieve a distance of 50 km. In this scenario, the phases of the basis states are related by a slowly time varying transformation. Furthermore, we developed and realized a new decoy state method for RFI-QKD systems with weak coherent sources to counteract the photon number-splitting attack. With the help of a reference-frame-independent protocol and a Michelson interferometer with Faraday rotator mirrors, our system is rendered immune to the slow phase changes of the interferometer and the polarization disturbances of the channel, making the procedure very robust. PMID- 24402549 TI - Differential expression and regulation of prohibitin during curcumin-induced apoptosis of immortalized human epidermal HaCaT cells. AB - Prohibitin (PHB), also known as inhibin, is important in cell proliferation, differentiation and apoptosis. This protein localizes to the inner membrane of mitochondria, where it acts as a chaperone protein, and is also found in the nucleus, where it negatively regulates transcription. The tumor-suppressive role of PHB in cell proliferation appears to be contradictory. In this study, we investigated the existence, localization and alterations in the expression of PHB in the whole cell and nuclear matrix and analyzed its co-localization with the expression products of related genes. The western blot analysis results revealed that PHB exists in the composition of nuclear matrix proteins and that the expression level of PHB is significantly increased in the whole cell and markedly decreased in the nuclear matrix after curcumin (1,7-bis(4-hydroxy-3 methoxyphenyl)-1,6-heptadiene-3,5-dione) treatment. The laser confocal scanning microscope results demonstrated the co-localization of PHB with p53, c-Myc, Bax, and Fas in HaCaT cells, and this co-localization region was transferred as a result of curcumin treatment. In addition, the results of the GST pull-down assay demonstrated the direct interaction of PHB with p53, c-Myc and Bax but not Fas in vitro. Results of the present study confirmed that the expression and distribution of PHB, which is a nuclear matrix protein, affect the apoptosis of HaCaT cells and its co-localization with specific gene products connected with cell apoptosis. PMID- 24402551 TI - The anterior interhemispheric approach: a safe and effective approach to anterior skull base lesions. AB - BACKGROUND: Many approaches to the anterior skull base have been reported. Frequently used are the pterional, the unilateral or bilateral frontobasal, the supraorbital and the frontolateral approach. Recently, endoscopic transnasal approaches have become more popular. The benefits of each approach has to be weighted against its complications and limitations. The aim of this study was to investigate if the anterior interhemispheric approach (AIA) could be a safe and effective alternative approach to tumorous and non-tumorous lesions of the anterior skull base. METHODS: We screened the operative records of all patients with an anterior skull base lesion undergoing transcranial surgery. We have used the AIA in 61 patients. These were exclusively patients with either olfactory groove meningioma (OGM) (n = 43), ethmoidal dural arteriovenous fistula (dAVF) ( n = 6) or frontobasal fractures of the anterior midline with cerebrospinal fluid (CSF) leakage ( n = 12). Patient records were evaluated concerning accessibility of the lesion, realization of surgical aims (complete tumor removal, dAVF obliteration, closure of the dural tear), and approach related complications. RESULTS: The use of the AIA exclusively in OGMs, ethmoidal dAVFs and midline frontobasal fractures indicated that we considered lateralized frontobasal lesions not suitable to be treated successfully. If restricted to these three pathologies, the AIA is highly effective and safe. The surgical aim (complete tumor removal, complete dAVF occlusion, no rhinorrhea) was achieved in all patients. The complication rate was 11.5 % (wound infection (n = 2; 3.2 %), contusion of the genu of the corpus callosum, subdural hygroma, epileptic seizure, anosmia and asymptomatic bleed into the tumor cavity (n = 1 each). Only the contusion of the corpus callosum was directly related to the approach (1.6 %). Olfaction, if present before surgery, was preserved in all patients, except one (1.6 %). CONCLUSIONS: The AIA is an effective and a safe approach to tumorous, vascular and traumatic pathologies of the midline anterior skull base. This approach should be part of the armamentarium of skull base surgeons. PMID- 24402552 TI - Microsurgical reconstruction of the cauda equina after traumatic transecting injury. AB - INTRODUCTION: The microsurgical reconstruction of the cauda equina nerve roots (MRCER) after traumatic injury is a highly controversial procedure with very few reports in the literature. METHODS: We report on four patients who had a penetrating traumatic injury in the lumbosacral area and underwent primary MRCER at our institution during the last decade. RESULTS: All four patients presented complete distal sensory and motor palsy affecting the lower lumbosacral roots. Primary microsuture was feasible in three patients harboring stab wounds, whereas autologous nerve graft interposition was necessary in the patient who had a gunshot wound. At the 5-year follow-up, we observed a marked improvement in motor function in two patients, but no sensory recovery. PMID- 24402553 TI - Letter to the editor: Duddy et al. repair of a large thoracolumbar myelomeningocele with associated lumbar kyphosis. October 2013, Volume 155, Issue 10, pp 1965-1968. PMID- 24402554 TI - Cytokine levels (IL-4, IL-6, IL-8 and TGFbeta) as potential biomarkers of systemic inflammatory response in trauma patients. AB - PURPOSE: Much research is now being conducted in order to understand the role of cytokines in the development of the inflammatory response following trauma. The purpose of this study was to evaluate whether serum levels of certain cytokines, measured immediately after initial injury, can be used as potential biomarkers for predicting the development and the degree of severity of the systemic inflammatory response (SIRS) in patients with moderate and severe trauma. METHODS: We conducted a prospective study with 71 individuals of whom 13 (18.3 %) were healthy controls and 58 (81.7 %) were traumatized orthopaedic patients who were categorized into two groups: 31 (43.6 %) with moderate injuries and 27 (38.1 %) patients with severe orthopaedic trauma. Thirty cc of heparinized blood were drawn from each individual within a few hours after the injury. Serum levels of pro-inflammatory, regulatory and anti-inflammatory cytokines were measured in each individual participant. RESULTS: High levels of pro-inflammatory cytokines IL-1beta,-6,-8,-12, tumour necrosis factor alpha and interferon gamma were found in all injured patients compared to healthy controls. Only IL-6 and IL-8 were significantly higher in the injured patients. Levels of the regulatory cytokines, transformed growth factor beta (TGF-beta) and IL-10 were higher in the injured patients, but significant only for TGF-beta. Levels of IL-4 were significantly lower in the injured groups as compared to the controls. CONCLUSIONS: Secretion of large amounts of pro-inflammatory cytokines and decreased level of anti inflammatory cytokines during the acute phase of trauma may lead to the development of systemic inflammatory response syndrome (SIRS) in unstable polytraumatized patients. SIRS may result in life threatening conditions as acute respiratory distress syndrome (ARDS) and multiple organ failure (MOF). High levels of IL-6, IL-8, TGFbeta and low levels of IL-4 were found to be reliable markers for the existence of immune reactivity in trauma patients. More research is needed to study pattern of cytokine levels along the acute period of injury, after surgical interventions and during recovery. PMID- 24402555 TI - Common causes of failed unicompartmental knee arthroplasty: a single-centre analysis of four hundred and seventy one cases. AB - PURPOSE: We performed this retrospective study to determine the main causes for early and late failures of unicompartmental knee arthroplasty (UKA). METHODS: Between January 2000 and March 2012, all patients treated for a failed medial UKA in the authors' institution were retrospectively reviewed. A total of 471 patients were identified, and causes of failure were analysed based on the medical records and radiographs at the time of revision. RESULTS: The cohort included 161 males and 310 females, with a mean age of 67.7 years (range, 42-91 years; SD = 10.1) at the time of revision. The mean time from index arthroplasty to revision surgery was 6.1 years (range, 0.1-27.9 years; SD = 5.6). A total of 254 cases (53.9 %) failed within five years after primary implantation, and 108 cases (22.9 %) failed after ten years. The major reason for failure was the development of other compartment arthritis (39.5 %), followed by aseptic loosening (25.4 %). CONCLUSIONS: Of importance, the mean time to failure after UKA was 6.1 years, with more than 50 % of failures occurring within the first five years postoperatively. PMID- 24402556 TI - A new angle stable nailing concept for the treatment of distal tibia fractures. AB - PURPOSE: Surgical treatment of distal tibial fractures demands a stable fracture fixation while minimizing the irritation to the soft tissues by approach and implant. Biomechanical studies have demonstrated superior performance for angular stable locked nails over standard locked nails in distal tibial fractures. The experimental Retrograde Tibial Nail (RTN) is a minimally invasive local intramedullary osteosynthesis, which has been under design by our group. We conducted a biomechanical comparison in composite tibiae of the Retrograde Tibial Nail against the Expert Tibial Nail (Synthes(r)). Our hypothesis was that the RTN would provide equivalent biomechanical stability with respect to extra-axial compression, torsion and load to failure testing, in an extra-articular distal tibia fracture model. METHODS: Biomechanical composite bone testing was conducted in 14 biomechanical composite tibiae in an AO 43 A3 fracture model. In both groups, triple angle stable interlocking was performed in the distal fragment. RESULTS: Results show a statistically non-significant higher stability of the ETN during the axial loading tests. Torsional stability testing resulted in a statistically superior performance for the RTN (p = 0.018). Destructive extra axial compression resulted in failure of six ETN constructs, while all RTN specimens survived the maximal load. CONCLUSIONS: The experimental Retrograde Tibial Nail provides the key features for the treatment of distal tibial fractures. It combines a minimally invasive local intramedullary osteosynthesis with the ability to securely fix the fracture by multiple angle stable locking options. PMID- 24402557 TI - Predictive factors for failure after total knee replacement revision. AB - PURPOSE: We used the Optetrak Condylar Constrained (CCK) implant, a modular and constrained knee implant as replacement for a failed primary arthroplasty, to assess the survivorship, the complications, the clinical, radiological, and functional situation, and the quality of life of those patients in whom a CCK had been implanted in recent years in order to find predictive pre-operative conditions of survival and clinical outcomes. METHODS: We performed a retrospective study of 125 CCK implanted between 1999 and 2005. The mean follow up was nine years (range, seven to 13). Mean age was 73.6 years. A total of 78% of the revised TKA were cemented and 66% were CR. We assessed the pre-operative, the operative and the postoperative conditions studying the medical files of all the patients. In order to study the functional and clinical situation we used the Hospital for Special Surgery (HSS) score and the Knee Society score (KSS), both clinical and functional. We analysed all the X-rays using the Knee Society Roentgenographic evaluation. The quality of life was studied using the Oxford knee score (OKS). RESULTS: The mean results of the KSS clinical and the KSS functional were 68.24 and 63.85, respectively. There were not any conditions associated with poor results of the knees (p > 0.05). The global survival at 24 months was 92.7%, at 60 months 87.8% and at 96 months it was 87.8%. There were some conditions associated with poor survival of the knees, e.g. patients were younger than 70 years old, rheumatic diseases, kidney faliure, tibial tuberosity osteotomy, PS primary arthroplasty, revision before five years and septic loosening. CONCLUSIONS: Based on these results there are some pre-operative factors that change the survival of the total knee replacement revision. PMID- 24402558 TI - Task and crisis analysis during surgical training. AB - PURPOSE: To design a surgical training environment based on task and crisis analysis of the surgical workflow. METHOD: The environment consists of: (1) real surgical instruments that are augmented with realistic haptic feedback and VR capabilities, (2) human sensory channels such as tactile, auditory and visual in real time, and (3) the ability to facilitate deliberate exposure to adverse events enabling mediation of error recovery strategies. VALIDATION: Five surgeons were immersed in our medical simulation environment through task and crisis scenarios of a typical vertebroplasty workflow. RESULTS: Based on a five-point Likert-scale survey, the face validity of our simulation environment was confirmed by investigating surgeon behavior and workflow response. CONCLUSIONS: The result of the conducted user-study corroborates our unique medical simulation concept of combining VR and human multisensory responses into surgical workflow. PMID- 24402559 TI - Effects of vorapaxar on platelet reactivity and biomarker expression in non-ST elevation acute coronary syndromes. The TRACER Pharmacodynamic Substudy. AB - Vorapaxar is an antagonist of the protease activated receptor-1 (PAR-1), the principal platelet thrombin receptor. The Thrombin Receptor Antagonist for Clinical Event Reduction (TRACER) trial evaluated vorapaxar compared to placebo in non-ST-elevation (NSTE)-acute coronary syndrome (ACS) patients. It was the study's objective to assess the pharmacodynamic effects of vorapaxar versus placebo that included aspirin or a thienopyridine or, frequently, a combination of both agents in NSTE-ACS patients. In a substudy involving 249 patients, platelet aggregation was assessed by light transmittance aggregometry (LTA) in 85 subjects (41 placebo, 44 vorapaxar) using the agonists thrombin receptor activating peptide (TRAP, 15 MUM), adenosine diphosphate (ADP, 20 MUM), and the combination of collagen-related peptide (2.5 MUg/ml) + ADP (5 MUM) + TRAP (15 MUM) (CAT). VerifyNow(r) IIb/IIIa and vasodilator-stimulated phosphoprotein (VASP) phosphorylation assays were performed, and platelet PAR-1 expression, plasma platelet/endothelial and inflammatory biomarkers were determined before and during treatment. LTA responses to TRAP and CAT and VerifyNow results were markedly inhibited by vorapaxar. Maximal LTA response to TRAP (median, interquartile range) 2 hours post loading dose: placebo 68% (53-75%) and vorapaxar 3% (2-6%), p<0.0001. ADP inhibition was greater in the vorapaxar group at 4 hours and one month (p<0.01). In contrast to the placebo group, PAR-1 receptor number in the vorapaxar group at one month was significantly lower than the baseline (179 vs 225; p=0.004). There were significant changes in selected biomarker levels between the two treatment groups. In conclusion, vorapaxar caused a potent inhibition of PAR-1-mediated platelet aggregation. Further studies are needed to explore vorapaxar effect on P2Y12 inhibition, PAR-1 expression and biomarkers and its contribution to clinical outcomes. PMID- 24402560 TI - High-resolution 3D whole-heart coronary MRA: a study on the combination of data acquisition in multiple breath-holds and 1D residual respiratory motion compensation. AB - OBJECT: To study a scan protocol for coronary magnetic resonance angiography based on multiple breath-holds featuring 1D motion compensation and to compare the resulting image quality to a navigator-gated free-breathing acquisition. Image reconstruction was performed using L1 regularized iterative SENSE. MATERIALS AND METHODS: The effects of respiratory motion on the Cartesian sampling scheme were minimized by performing data acquisition in multiple breath holds. During the scan, repetitive readouts through a k-space center were used to detect and correct the respiratory displacement of the heart by exploiting the self-navigation principle in image reconstruction. In vivo experiments were performed in nine healthy volunteers and the resulting image quality was compared to a navigator-gated reference in terms of vessel length and sharpness. RESULTS: Acquisition in breath-hold is an effective method to reduce the scan time by more than 30% compared to the navigator-gated reference. Although an equivalent mean image quality with respect to the reference was achieved with the proposed method, the 1D motion compensation did not work equally well in all cases. CONCLUSION: In general, the image quality scaled with the robustness of the motion compensation. Nevertheless, the featured setup provides a positive basis for future extension with more advanced motion compensation methods. PMID- 24402562 TI - Insights into regional adaptations in the growing pulmonary artery using a meso scale structural model: effects of ascending aorta impingement. AB - As the next step in our investigations into the structural adaptations of the main pulmonary artery (PA) during postnatal growth, we utilized the extensive experimental measurements of the growing ovine PA from our previous study (Fata et al., 2013, "Estimated in vivo Postnatal Surface Growth Patterns of the Ovine Main Pulmonary Artery and Ascending Aorta," J. Biomech. Eng., 135(7), pp. 71010 71012). to develop a structural constitutive model for the PA wall tissue. Novel to the present approach was the treatment of the elastin network as a distributed fiber network rather than a continuum phase. We then utilized this model to delineate structure-function differences in the PA wall at the juvenile and adult stages. Overall, the predicted elastin moduli exhibited minor differences remained largely unchanged with age and region (in the range of 150 to 200 kPa). Similarly, the predicted collagen moduli ranged from ~1,600 to 2700 kPa in the four regions studied in the juvenile state. Interestingly, we found for the medial region that the elastin and collagen fiber splay underwent opposite changes (collagen standard deviation juvenile = 17 deg to adult = 28 deg, elastin standard deviation juvenile = 35 deg to adult = 27 deg), along with a trend towards more rapid collagen fiber strain recruitment with age, along with a drop in collagen fiber moduli, which went from 2700 kPa for the juvenile stage to 746 kPa in the adult. These changes were likely due to the previously observed impingement of the relatively stiff ascending aorta on the growing PA medial region. Intuitively, the effects of the local impingement would be to lower the local wall stress, consistent with the observed parallel decrease in collagen modulus. These results suggest that during the postnatal somatic growth period local stresses can substantially modulate regional tissue microstructure and mechanical behaviors in the PA. We further underscore that our previous studies indicated an increase in effective PA wall stress with postnatal maturation. When taken together with the fact that the observed changes in mechanical behavior and structure in the growing PA wall were modest in the other three regions studied, our collective results suggest that the majority of the growing PA wall is subjected to increasing stress levels with age without undergoing major structural adaptations. This observation is contrary to the accepted theory of maintenance of homeostatic stress levels in the regulation of vascular function, and suggests alternative mechanisms might regulate postnatal somatic growth. Understanding the underlying mechanisms will help to improve our understanding of congenital defects of the PA and lay the basis for functional duplication in their repair and replacement. PMID- 24402563 TI - Gene expression in vessel-associated cells upon xylem embolism repair in Vitis vinifera L. petioles. AB - In this work, the involvement of vessel-associated cells in embolism recovery was investigated by studying leaf petiole hydraulics and expression profiles of aquaporins and genes related to sugar metabolism. Two different stress treatments were imposed onto grapevines to induce xylem embolism: one involved a pressure collar applied to the stems, while the other consisted of water deprivation (drought). Embolism formation and repair were monitored during stress application and release (recovery). At the same time, stomatal conductance (g(s)), leaf water potential (Psi(leaf)) and leaf abscisic acid (ABA) concentration were measured. For each treatment, gene transcript levels were assessed on vessel-associated cells (isolated from leaf petioles by laser microdissection technique) and whole petioles. Both treatments induced severe xylem embolism formation and drops in g s and Psi (leaf) at a lesser degree and with faster recovery in the case of application of the pressure collar. Leaf ABA concentration only increased upon drought and subsequent recovery. Transcripts linked to sugar mobilisation (encoding a beta-amylase and a glucose-6-P transporter) were over-expressed upon stress or recovery, both in vessel-associated cells and whole petioles. However, two aquaporin genes (VvPIP2;1 and VvPIP2;4N) were activated upon stress or recovery only in vessel-associated cells, suggesting a specific effect on embolism refilling. Furthermore, the latter gene was only activated upon drought and subsequent recovery, suggesting that either severe water stress or ABA is required for its regulation. PMID- 24402565 TI - Understanding improved electrochemical properties of NiO-doped NiF2-C composite conversion materials by X-ray absorption spectroscopy and pair distribution function analysis. AB - The conversion reactions of pure NiF2 and the NiO-doped NiF2-C composite (NiO NiF2-C) were investigated using X-ray absorption spectroscopy (XAS) and pair distribution function (PDF) analysis. The enhanced electronic conductivity of NiO NiF2-C is associated with a significant improvement in the reversibility of the conversion reaction compared to pure NiF2. Different evolutions of the size distributions of the Ni nanoparticles formed during discharge were observed. While a bimodal nanoparticle size distribution was maintained for NiO-NiF2-C following the 1st and 2nd discharge, for pure NiF2 only smaller nanoparticles (~14 A) remained following the 2nd discharge. We postulate that the solid electrolyte interphase formed upon the 1st discharge at large overpotential retards the growth of metallic Ni leading to formation of smaller Ni particles during the 2nd discharge. In contrast, the NiO doping and the carbon layer covering the NiO-NiF2-C possibly facilitate the conversion process on the surface preserving the reaction kinetics upon the 2nd discharge. Based on the electronic conductivity and surface properties, the resulting size of the Ni nanoparticles is associated with the conversion kinetics and consequently the cyclability. PMID- 24402566 TI - Simultaneous identification of growth law and estimation of its rate parameter for biological growth data: a new approach. AB - Scientific formalizations of the notion of growth and measurement of the rate of growth in living organisms are age-old problems. The most frequently used metric, "Average Relative Growth Rate" is invariant under the choice of the underlying growth model. Theoretically, the estimated rate parameter and relative growth rate remain constant for all mutually exclusive and exhaustive time intervals if the underlying law is exponential but not for other common growth laws (e.g., logistic, Gompertz, power, general logistic). We propose a new growth metric specific to a particular growth law and show that it is capable of identifying the underlying growth model. The metric remains constant over different time intervals if the underlying law is true, while the extent of its variation reflects the departure of the assumed model from the true one. We propose a new estimator of the relative growth rate, which is more sensitive to the true underlying model than the existing one. The advantage of using this is that it can detect crucial intervals where the growth process is erratic and unusual. It may help experimental scientists to study more closely the effect of the parameters responsible for the growth of the organism/population under study. PMID- 24402564 TI - RNA interference: concept to reality in crop improvement. AB - The phenomenon of RNA interference (RNAi) is involved in sequence-specific gene regulation driven by the introduction of dsRNA resulting in inhibition of translation or transcriptional repression. Since the discovery of RNAi and its regulatory potentials, it has become evident that RNAi has immense potential in opening a new vista for crop improvement. RNAi technology is precise, efficient, stable and better than antisense technology. It has been employed successfully to alter the gene expression in plants for better quality traits. The impact of RNAi to improve the crop plants has proved to be a novel approach in combating the biotic and abiotic stresses and the nutritional improvement in terms of bio fortification and bio-elimination. It has been employed successfully to bring about modifications of several desired traits in different plants. These modifications include nutritional improvements, reduced content of food allergens and toxic compounds, enhanced defence against biotic and abiotic stresses, alteration in morphology, crafting male sterility, enhanced secondary metabolite synthesis and seedless plant varieties. However, crop plants developed by RNAi strategy may create biosafety risks. So, there is a need for risk assessment of GM crops in order to make RNAi a better tool to develop crops with biosafety measures. This article is an attempt to review the RNAi, its biochemistry, and the achievements attributed to the application of RNAi in crop improvement. PMID- 24402567 TI - Molecular cloning and heterologous expression in Pichia pastoris of X-prolyl dipeptidyl aminopeptidase from basidiomycete Ustilago maydis. AB - Dipeptidyl aminopeptidases are enzymes involved in the posttranslational control of bioactive peptides. Here we identified the gene dapUm in Ustilago maydis by homology with other fungal dipeptidyl aminopeptidases. Analysis of the dapUm deduced amino acid sequence indicated that it encodes for membrane-type serine protease with a characteristic prolyl oligopeptidase catalytic motif triad: Ser, Asp, His. In order to overexpress the DapUm, the gene encoding for it was cloned and transformed into Pichia. Using this system, we observed a ~ 125-kDa recombinant protein with an optimal enzymatic activity at pH 6.0 and at 40 degrees C for the Ala-Pro-p-nitroanilide substrate and an experimental pH of 6.9. U. maydis DapUm was specifically inhibited by phenylmethylsulfonyl fluoride and Pefabloc, confirming the presence of a serine residue in the active site. To our knowledge, this study is the first report on the cloning and expression of a DPP IV dipeptidyl aminopeptidase from a basidiomycete organism. Moreover, the use of recombinant DapUm will allow us to further study and characterize this enzyme, in addition to testing chemical compounds for pharmaceutical purposes. PMID- 24402568 TI - Seedling development and evaluation of genetic stability of cryopreserved Dendrobium hybrid mature seeds. AB - Vitrification, a simple, fast, and recommended cryopreservation method for orchid germplasm conservation, was evaluated for Dendrobium hybrid "Dong Yai" mature seeds. The genetic stability of regenerated seedlings was also evaluated using flow cytometry. Mature seeds from this hybrid were submitted to plant vitrification solution (PVS2) for 0, 0.5, 1, 2, 3, 4, 5, or 6 h at 0 degrees C. Subsequently, they were plunged into liquid nitrogen (LN) at -196 degrees C for 1 h and recovered in half-strength Murashige and Skoog culture medium (1/2 MS), and seed germination was evaluated after 30 days. Seeds directly submitted to LN did not germinate after cryopreservation. Seeds treated with PVS2 between 1 and 3 h presented the best germination (between 51 and 58%), although longer exposure to PVS2 returned moderated germination (39%). Germinated seeds were further subcultured in P-723 culture medium and developed whole seedlings in vitro after 180 days, with no abnormal characteristics, diseases, or nutritional deficiencies. Seedlings were successfully acclimatized under greenhouse conditions with over 80% survival. Flow cytometry analysis revealed no chromosomal changes on vitrified seedlings, as well as seedlings germinated from the control treatment (direct exposure to LN). These findings indicate that vitrification is a feasible and safe germplasm cryopreservation method for commercial Dendrobium orchid hybrid conservation. PMID- 24402569 TI - High efficiency preparation and characterization of intact poly(vinyl alcohol) dehydrogenase from Sphingopyxis sp.113P3 in Escherichia coli by inclusion bodies renaturation. AB - Poly(vinyl alcohol) dehydrogenase (PVADH, EC 1.1.99.23) is an enzyme which has potential application in textile industry to degrade the poly(vinyl alcohol) (PVA) in waste water. Previously, a 1,965-bp fragment encoding a PVADH from Sphingopyxis sp. 113P3 was synthesized based on the replacement of the rare codons in Escherichia coli (E. coli). In this work, the deduced mature PVADH (mPVADH) gene of 1,887 bp was amplified by polymerase chain reaction (PCR) and inserted into the site between NcoI and HindIII in pET-32a(+). The constructed recombinant plasmid was transformed into E. coli Rosetta (DE3). In shake flask, the fusion protein of thioredoxin (Trx)-mPVADH was expressed precisely; however, Trx-mPVADH was found to accumulate mainly as inclusion bodies. After isolating, dissolving in buffer containing urea, purification, dialysis renaturation, and digesting with recombinant enterokinase/His (rEK/His), the bioactive mPVADH fragments were obtained with protein concentration of 0.56 g/L and enzymatic activity of 194 U/mL. The K m and V max values for PVA 1799 were 2.33 mg/mL and 15.7 nmol/(min.mg protein), respectively. (1)H-NMR and infrared (IR) spectrum demonstrated that its biological function was oxidizing hydroxyl groups of PVA 1799 to form diketone, and PVA 1799 could be degraded completely by successive treatment with mPVADH and oxidized PVA hydrolase (OPH). PMID- 24402570 TI - [Assessment of the benefit of medical devices in surgical practice. Problems and possible solutions]. AB - The market approval of medical devices in Germany does not yet require a benefit assessment. Thus, there is a lack of high quality studies that clearly prove the benefit of medical innovations. In the past, the Federal Joint Committee in Germany (G-BA) did not have the opportunity to adequately address this issue of lacking evidence. A law for the improvement of the care structure in the statutory health insurance offers the possibility for the G-BA to obtain evidence for the benefit of medical practice. With an integrated regulation for testing of medical devices the manufacturers have the option to apply for an assessment of new and established treatment methods and to provide scientific evidence for the benefit of medical devices as a requirement for inclusion in the catalogue of services of the statutory health insurance. However, this expanded scope of action is also a challenge for clinicians. The already existing problem of integrating multicenter clinical trials in the surgical routine will remain. The Surgical Study Network Germany (CHIR-Net) offers an ideal way to cope with the increased requirements on studies in the field of medical devices through established partnerships with methodological institutions and practitioners in clinical settings. PMID- 24402571 TI - Sex differences in translocator protein 18 kDa (TSPO) in the heart: implications for imaging myocardial inflammation. AB - Myocarditis is more severe in men than in women and difficult to diagnose due to a lack of imaging modalities that directly detect myocardial inflammation. Translocator protein 18 kDa (TSPO) is used extensively to image brain inflammation due to its presence in CD11b(+) brain microglia. In this study, we examined expression of TSPO and CD11b in mice with coxsackievirus B3 (CVB3) myocarditis and biopsy sections from myocarditis patients in order to determine if it could be used to image myocarditis. We found that male mice with CVB3 myocarditis upregulated more genes associated with TSPO activation than female mice. TSPO expression was increased in the heart of male mice and men with myocarditis compared with female subjects due to testosterone, where it was expressed predominantly in CD11b(+) immune cells. We show that TSPO ligands detect myocardial inflammation using microSPECT, with increased uptake of [(125)I]-IodoDPA-713 in male mice with CVB3 myocarditis compared with undiseased controls. PMID- 24402572 TI - EMP1, a member of a new family of antiproliferative genes in breast carcinoma. AB - This study aimed to analyze the expression, clinical significance of epithelial membrane protein 1 (EMP1) in breast carcinoma and the biological effect in its cell line by EMP1 overexpression. Immunohistochemistry and western blot were used to analyze EMP1 protein expression in 67 cases of breast cancer and 35 cases of normal tissues to study the relationship between EMP1 expression and clinical factors. Quantitative real-time RT-PCR and western blot were used to detect the mRNA level and protein of EMP1. MTT assay, migration and invasion assays were also conducted as to the influence of the upregulated expression of EMP1 that might be found on MCF-7 cell biological effect. The relative amount of EMP1 protein in breast cancer tissue was found to be significantly lower than in normal tissues (P < 0.05). The level of EMP1 protein expression was correlated with T stages, lymph node metastasis, clinic stage, and histological grade (P < 0.05). Meanwhile, loss of EMP1 expression correlated significantly with poor overall survival time by Kaplan-Meier analysis (P < 0.05). The result shown that MCF-7 cell transfected EMP1 had a lower survival fraction, higher cell apoptosis, significant decrease in migration and invasion, higher caspase-9, and lower VEGFC protein expression compared with MCF-7 cell untransfected EMP1 (P < 0.05). EMP1 expression decreased in breast cancer and correlated significantly with lymph node metastasis, clinic stage, histological grade, and poor overall survival, T stages, suggesting that EMP1 may play important roles as a negative regulator to breast cancer MCF-7 cell by regulating the expression of caspase 9 and VEGFC protein. PMID- 24402573 TI - Single nucleotide polymorphisms (SNPs) of ERCC2, hOGG1, and XRCC1 DNA repair genes and the risk of triple-negative breast cancer in Polish women. AB - Triple-negative breast cancer (TNBC) refers to about 15-20% of all breast cancer cases. It is characterized by worse clinical outcome, poor prognosis, and absence of prognostic indicators. Several polymorphisms in the nucleotide excision repair (NER) and base excision repair (BER) gene have been extensively studied in association with various human cancers. The aim of this study was to evaluate the role of the hOGG1-Ser326Cys (rs13181), XRCC1-Arg194Trp (rs1799782), and ERCC2 Lys751Gln (rs13181) gene polymorphisms with clinical parameters and the risk for development of triple-negative breast cancer. Our research included 70 patients with TNBC and 70 healthy controls. Gene polymorphisms were genotyped by the PCR RFLP (restriction fragment length polymorphism) method. The genotype distributions were contrasted by the chi-square test, and the significance of the polymorphism was assessed by multiple logistic regression producing odds ratios (ORs) and 95% confidence intervals (CIs). In the present work, a relationship was identified between ERCC2-Lys751Gln polymorphism and the incidence of triple negative breast cancer. An association was observed between triple-negative breast carcinoma occurrence and the presence of Gln/Gln genotype (OR = 5.71 (2.12 5.43), p = 0.0007). A tendency for an increased risk of TNBC was detected with the occurrence of 751Gln allele of ERCC2 polymorphism. No significant associations between Ser326Cys and Arg194Trp genotype and TNBC were observed. We suggest that the Lys751Gln polymorphism of the ERCC2 gene may be risk factors for triple-negative breast cancer development in Polish women. PMID- 24402574 TI - Expression profile of apoptosis-related genes potentially explains early recurrence after definitive chemoradiation in esophageal squamous cell carcinoma. AB - Definitive chemoradiation is a curative treatment option for patients with locoregional esophageal squamous cell carcinoma (ESCC) who are not suitable for surgical resection, but many tend to develop local recurrence. The purpose of the study was to investigate factors affecting local recurrence of the tumor. Seventy two patients with stage II-III thoracic ESCC who received definitive concurrent chemoradiation (CRT) and completely responded to the treatment were enrolled into this study. The case patients were 49 patients who recurred locally within 24 months after definitive CRT and 23 patients who did not have a local recurrence within 24 months were considered as controls. We investigated whether dysregulation of apoptosis-related genes was associated with early tumor recurrence. Quantitative real-time polymerase chain reaction showed upregulation of BCLAF1 and downregulation of BAG4, CARD6, IGF1R, and TNF in the tissues of case patients, as compared with controls. Among the patients with recurrent ESCC, those with tumors which exhibited more than twofold upregulated BCLAF1 and more than twofold downregulated BAG4 and TNF had a decreased time interval to local recurrence. Three gene pairs of the downregulated genes showed a significant correlation with local recurrence: BAG4 and CARD6, BAG4 and TNF, CARD6, and TNF. The patients with T3-4 disease and those with tumor >3 cm in length had a trend toward early local recurrence, though the associations were not reached statistical significance. Upregulation of BCLAF1 and downregulation of BAG4 and TNF was independently associated with early local recurrence in multivariate analysis (P < 0.05). This study supports the involvement of apoptosis-related genes in early tumor recurrence after definitive chemoradiation in patients with stage II-III thoracic ESCC. PMID- 24402575 TI - Sprouty4 interferes with cell proliferation and migration of breast cancer derived cell lines. AB - Sprouty proteins are modulators of mitogen-induced signal transduction processes and therefore can influence the process of cancerogenesis. In particular, Sprouty2 has been shown to have an important role in cancer development of many tumor entities including breast cancer. In this report, we investigated the role of Sprouty4 in breast cancer-derived cell lines. We have found that ectopic Sprouty4 expression inhibits cell proliferation of breast cancer cell lines independently of their endogenous expression levels. Corroborating Sprouty4 downregulation causes accelerated growth. Furthermore, we demonstrate that an increase in Sprouty4 content interferes with serum-induced activation of mitogen activated protein kinase pathway. Additionally, Sprouty4 expression negatively influences cell migration. These data suggest that Sprouty4 is a possible candidate for a tumor suppressor in breast cancer. PMID- 24402576 TI - Glutamatergic autoencephalitides: an emerging field. AB - Autoimmune responses targeting synaptic proteins are associated with a wide range of neurologic symptoms. Among these disorders are those associated with antibodies to ionotropic glutamate receptors, including the NMDAR (N-methyl-D aspartate receptor) and AMPAR (alpha-amino-3-hydrozy-5-methyl-4 isoxazolepropionic acid receptor). Patients with anti-NMDAR encephalitis present with psychiatric symptoms, seizures, movement disorders, impaired consciousness, and autonomic derangements; half of patients have an associated ovarian teratoma, and most patients respond to immunosuppressive therapies. Patients' antibodies bind to the amino terminal domain of the NMDAR, and result in loss of NMDARs from synapses with subsequent NMDAR hypofunction. Anti-NMDAR antibodies have now been reported in other neuropsychiatric conditions, including psychosis, dementia, and HSV encephalitis. The pathophysiologic relevance of anti-NMDAR antibodies in these disorders is not yet clear, but their presence may indicate a role for immunotherapy in some patients. Although considerable work remains to be done, our understanding of disorders associated with anti-glutamate receptor antibodies has grown exponentially since they were first described just over 7 years ago, revolutionizing neurology. These antibodies, by interfering with synaptic function, readily link basic science and clinical medicine, and have revealed the impact of sudden but sustained loss of specific neurotransmitter receptors in humans. Improved understanding of their pathophysiology will lead to better treatments for these diseases while providing novel insights regarding the roles of glutamate receptors in learning, memory, and neuropsychiatric disease. PMID- 24402578 TI - An object-based image analysis of pinyon and juniper woodlands treated to reduce fuels. AB - Mechanical and prescribed fire treatments are commonly used to reduce fuel loads and maintain or restore sagebrush steppe rangelands across the Great Basin where pinyon (Pinus) and juniper (Juniperus) trees are encroaching and infilling. Geospatial technologies, particularly remote sensing, could potentially be used in these ecosystems to (1) evaluate the longevity of fuel reduction treatments, (2) provide data for planning and designing future fuel-reduction treatments, and (3) assess the spatial distribution of horizontal fuel structure following fuel reduction treatments. High-spatial resolution color-infrared imagery (0.06-m pixels) was acquired for pinyon and juniper woodland plots where fuels were reduced by either prescribed fire, tree cutting, or mastication at five sites in Oregon, California, Nevada, and Utah. Imagery was taken with a Vexcel UltraCam X digital camera in June 2009. Within each treatment plot, ground cover was measured as part of the Sagebrush Steppe Treatment Evaluation Project. Trimble eCognition Developer was used to classify land cover classes using object-based image analysis (OBIA) techniques. Differences between cover estimates using OBIA and ground-measurements were not consistently higher or lower for any land cover class and when evaluated for individual sites, were within +/-5 % of each other. The overall accuracy and the K hat statistic for classified thematic maps for each treatment were: prescribed burn 85 % and 0.81; cut and fell 82 % and 0.77, and mastication 84 % and 0.80. Although cover assessments from OBIA differed somewhat from ground measurements, they are sufficiently accurate to evaluate treatment success and for supporting a broad range of management concerns. PMID- 24402577 TI - The antimalarial drug quinine interferes with serotonin biosynthesis and action. AB - The major antimalarial drug quinine perturbs uptake of the essential amino acid tryptophan, and patients with low plasma tryptophan are predisposed to adverse quinine reactions; symptoms of which are similar to indications of tryptophan depletion. As tryptophan is a precursor of the neurotransmitter serotonin (5-HT), here we test the hypothesis that quinine disrupts serotonin function. Quinine inhibited serotonin-induced proliferation of yeast as well as human (SHSY5Y) cells. One possible cause of this effect is through inhibition of 5-HT receptor activation by quinine, as we observed here. Furthermore, cells exhibited marked decreases in serotonin production during incubation with quinine. By assaying activity and kinetics of the rate-limiting enzyme for serotonin biosynthesis, tryptophan hydroxylase (TPH2), we showed that quinine competitively inhibits TPH2 in the presence of the substrate tryptophan. The study shows that quinine disrupts both serotonin biosynthesis and function, giving important new insight to the action of quinine on mammalian cells. PMID- 24402579 TI - The prevalence of depression in rheumatoid arthritis: a systematic review and meta-analysis: reply. PMID- 24402581 TI - Follicular helper T cells in autoimmune diseases. PMID- 24402580 TI - Rheumatoid arthritis pathophysiology: update on emerging cytokine and cytokine associated cell targets. AB - Biologic therapies that target pathogenic cytokines such as TNF, IL-1beta or IL-6 have greatly improved the treatment of RA. Unfortunately, not all RA patients respond to current biologic therapies and responses are not always maintained, suggesting that there are alternative drivers of RA pathogenesis that might serve as promising therapeutic targets. Discovery of the new Th17 subset of Th cells, and their role in autoimmune disease development, has implicated the proinflammatory IL-12 and IL-17 families of cytokines in RA disease pathogenesis. Members of these cytokine families are elevated in the blood and joints of RA patients and have been shown to remain elevated in patients who do not respond to current biologics. In addition, these cytokines have been shown to play roles in joint destruction and erosion. A new subclass of biologics that target the IL-12 and/or IL-17 signalling pathways are under development. Here we review evidence for a role of Th17 cells as well as IL-12 and IL-17 cytokines in RA pathogenesis as the rationale for a subsequent discussion of the ongoing and completed clinical trials of newly emerging biologic therapies directed at IL-12 or IL-17 pathway inhibition. PMID- 24402582 TI - The prevalence of depression in rheumatoid arthritis: a systematic review and meta-analysis. PMID- 24402583 TI - Combination of AG490, a Jak2 inhibitor, and methylsulfonylmethane synergistically suppresses bladder tumor growth via the Jak2/STAT3 pathway. AB - Human urinary bladder cancer is the fifth most common cancer, with a worldwide estimate of about two million patients. Recurrence after complete transurethral prostatic resection is the most important problem in therapy. Combination therapy is a new approach in the treatment of cancers that do not respond to current therapies. These therapies have many advantages over conventional therapies, such as fewer side-effects and greater efficiency. Research efforts using natural compounds for the elimination or growth suppression of the cancer arise from studies on methylsulfonylmethane (MSM). MSM is a natural sulfur compound with no side-effects. AG490 is a tyrosine kinase inhibitor that has been extensively used for inhibiting Jak2 in vitro and in vivo. In our study, the combinatorial effect of these two agents on human bladder cancer cell lines and xenografts was analyzed. We observed that the combination of AG490 and MSM inhibited cancer cell viability and cell migration in vitro. This combination inhibited VEGF mRNA expression in bladder cancer cell lines. In vivo experiments showed that oral administration of AG490 and MSM combination significantly inhibited the growth of tumor xenografts in mice. Our study clearly demonstrates that the predominant effect of this combination is the reduction of signaling molecules including STAT3, STAT5b, IGF-1R, VEGF and VEGF-R2 which are involved in the growth, progression and metastasis of human bladder cancer. The anti-metastatic ability of this drug combination is confirmed using metastatic animal models. Therefore, this combination could have the effect of genesistasis and powerful anticancer effects against bladder cancer. PMID- 24402585 TI - Amniotic fluid embolism. AB - Amniotic fluid embolism remains one of the most devastating conditions in obstetric practice with an incidence of approximately 1 in 40,000 deliveries and a reported mortality rate ranging from 20% to 60%. The pathophysiology appears to involve an abnormal maternal response to fetal tissue exposure associated with breaches of the maternal-fetal physiologic barrier during parturition. This response and its subsequent injury appear to involve activation of proinflammatory mediators similar to that seen with the classic systemic inflammatory response syndrome. Progress in our understanding of this syndrome continues to be hampered by a lack of universally acknowledged diagnostic criteria, the clinical similarities of this condition to other types of acute critical maternal illness, and the presence of a broad spectrum of disease severity. Clinical series based on population or administrative databases that do not include individual chart review by individuals with expertise in critical care obstetrics are likely to both overestimate the incidence and underestimate the mortality of this condition by the inclusion of women who did not have amniotic fluid embolism. Data regarding the presence of risk factors for amniotic fluid embolism are inconsistent and contradictory; at present, no putative risk factor has been identified that would justify modification of standard obstetric practice to reduce the risk of this condition. Maternal treatment is primarily supportive, whereas prompt delivery of the mother who has sustained cardiopulmonary arrest is critical for improved newborn outcome. PMID- 24402586 TI - Cost differences among robotic, vaginal, and abdominal hysterectomy. AB - OBJECTIVE: To compare the costs of vaginal and abdominal hysterectomy with robotically assisted hysterectomy. METHODS: We identified all cases of robotically assisted hysterectomy, with or without bilateral salpingo oophorectomy, treated at the Mayo Clinic (Rochester, Minnesota) from January 1, 2007, through December 31, 2009. Cases were propensity score-matched (one-to-one) to cases of vaginal and abdominal hysterectomy, selected randomly from January 1, 2004, through December 31, 2006 (before acquisition of the robotic surgical system). All billed costs were abstracted through the sixth postoperative week from the Olmsted County Healthcare Expenditure and Utilization Database and compared between cohorts with a generalized linear modeling framework. Predicted costs were estimated with the recycled predictions method. Costs of operative complications also were estimated. RESULTS: The total number of abdominal hysterectomies collected for comparison was 234 and the total number of vaginal hysterectomies was 212. Predicted mean cost of robotically assisted hysterectomy was $2,253 more than that of vaginal hysterectomy ($13,619 compared with $11,366; P<.001), although costs of complications were not significantly different. The predicted mean costs of robotically assisted compared with abdominal hysterectomy were similar ($14,679 compared with $15,588; P=.35). The costs of complications were not significantly different. CONCLUSIONS: Overall, vaginal hysterectomy was less costly than robotically assisted hysterectomy. Abdominal hysterectomy and robotically assisted hysterectomy had similar costs. LEVEL OF EVIDENCE: II. PMID- 24402584 TI - Caenorhabditis elegans SWI/SNF subunits control sequential developmental stages in the somatic gonad. AB - The Caenorhabditis elegans somatic gonadal precursors (SGPs) are multipotent progenitors that give rise to all somatic tissues of the adult reproductive system. The hunchback and Ikaros-like gene ehn-3 is expressed specifically in SGPs and is required for their development into differentiated tissues of the somatic gonad. To find novel genes involved in SGP development, we used a weak allele of ehn-3 as the basis for a reverse genetic screen. Feeding RNAi was used to screen ~2400 clones consisting of transcription factors, signaling components, and chromatin factors. The screen identified five members of the C. elegans SWI/SNF chromatin remodeling complex as genetic enhancers of ehn-3. We characterized alleles of 10 SWI/SNF genes and found that SWI/SNF subunits are required for viability and gonadogenesis. Two conserved SWI/SNF complexes, PBAF and BAF, are defined by their unique array of accessory subunits around a common enzymatic core that includes a catalytic Swi2/Snf2-type ATPase. Tissue-specific RNAi experiments suggest that C. elegans PBAF and BAF complexes control different processes during somatic gonadal development: PBRM-1, a signature subunit of PBAF, is important for normal SGP development, whereas LET-526, the distinguishing subunit of BAF, is required for development of a differentiated cell type, the distal tip cell (DTC). We found that the SWSN-4 ATPase subunit is required for SGP and DTC development. Finally, we provide evidence that C. elegans PBAF subunits and hnd-1/dHand are important for the cell fate decision between SGPs and their differentiated sisters, the head mesodermal cells. PMID- 24402587 TI - Same-day synthetic osmotic dilators compared with overnight laminaria before abortion at 14-18 weeks of gestation: a randomized controlled trial. AB - OBJECTIVE: To increase access to early second-trimester surgical abortion by determining noninferiority of same-day synthetic osmotic dilators compared with overnight Laminaria for cervical preparation before early second-trimester dilation and evacuation. METHODS: We enrolled women between 14 and 18 weeks of gestation and randomized them to same-day synthetic osmotic dilators or overnight Laminaria. Study participants and clinicians were blinded to group assignment. The primary outcome was procedure duration. The trial was powered to assess noninferiority of synthetic osmotic dilators to exclude a mean difference of 5 minutes or longer. RESULTS: We enrolled 72 patients: 36 were randomized to same day synthetic osmotic dilators and 36 to overnight Laminaria. Mean procedure duration was 8.1 and 5.9 minutes, respectively, with a mean difference of 2.1 minutes (97.5% confidence interval -0.3 to 4.5). Same-day synthetic osmotic dilators resulted in less initial cervical dilation than overnight Laminaria (mean circumference 48 compared with 60 mm Pratt, P<.001) and required more mechanical dilation (69% compared with 27%, P=.001). There was no difference in complications, all of which were minor, or in the median procedural difficulty score rated by physicians. Most patients in both groups would choose a same-day procedure if necessary in the future. CONCLUSION: Despite less initial cervical dilation and a greater need for mechanical dilation, same-day synthetic osmotic dilators are not inferior to overnight Laminaria with respect to procedure duration. Same-day osmotic dilation is preferred by patients and may be a reasonable alternative to overnight Laminaria for cervical preparation before early second-trimester dilation and evacuation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00775983. LEVEL OF EVIDENCE: I. PMID- 24402588 TI - Maternal hypertension, medication use, and hypospadias in the National Birth Defects Prevention Study. AB - OBJECTIVE: To investigate whether antihypertensive classes and specific medications in early pregnancy increase the risk of severe hypospadias and to assess prior associations detected for late-treated and untreated hypertension in the National Birth Defects Prevention Study. METHODS: Using telephone interviews from mothers of 2,131 children with severe hypospadias and 5,129 nonmalformed male control children for 1997-2009 births in a population-based case-control study, we estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) with multivariable logistic regression. We adjusted P values to account for multiple testing. RESULTS: Forty-eight (2.3%) case and 70 (1.4%) control mothers reported early pregnancy antihypertensive treatment, 45 (2.1%) case and 31 (0.6%) control mothers reported late treatment, and 315 (14.8%) case and 394 (7.7%) control mothers reported untreated hypertension. Selective beta-blockers, centrally acting agents, renin-angiotensin system-acting agents, diuretics, and specific medications, methyldopa and atenolol, were not associated with hypospadias. Nonselective beta-blockers (adjusted OR 3.22, 95% CI 1.47-7.05) were associated with hypospadias; however, P values adjusted for multiple testing were not statistically significant. We confirmed prior findings for associations between hypospadias and untreated hypertension (adjusted OR 2.09, 95% CI 1.76 2.48) and late initiation of treatment (adjusted OR 3.98, 95% CI 2.41-6.55). The increased risks would translate to severe hypospadias prevalences of 11.5, 17.7, and 21.9 per 10,000 births for women with untreated hypertension, nonselective beta-blocker use, and late initiation of treatment, respectively. CONCLUSION: Our study suggests a relationship between hypospadias and the severity of hypertension. LEVEL OF EVIDENCE: II. PMID- 24402589 TI - Safety of trial of labor after cesarean delivery in grandmultiparous women. AB - OBJECTIVE: To evaluate the risk of uterine rupture and other major labor complications in a trial of labor after cesarean delivery (TOLAC) in grandmultiparous women. METHODS: A retrospective descriptive study of 64,345 births in three hospitals between the years 1999 and 2009. The study group included 1,922 deliveries of women in their sixth or higher birth with one previous cesarean delivery. RESULTS: The risk for uterine rupture was 0.3% (six cases) (95% confidence interval [CI] 0.11-0.68); of these, two cases ended in hysterectomy. There were another four hysterectomies not attributable to uterine rupture (a total risk of 0.3%). Neither induction nor augmentation of labor increased the risk for uterine rupture. Trial of labor after cesarean delivery in the first labor after prior cesarean delivery conferred a higher risk for hysterectomy (1% compared with 0.1%; P=.019). In the presence of shoulder dystocia (n=20), the risk of uterine rupture was 10% (two cases) compared with 0.2% when shoulder dystocia did not occur (P=.002; odds ratio 52.7, 95% CI 9 306). CONCLUSION: Grandmultiparous women with one previous cesarean delivery can be offered TOLAC. Labor induction is not contraindicated in such women. LEVEL OF EVIDENCE: III. PMID- 24402590 TI - Abortion and mental health: findings from The National Comorbidity Survey Replication. AB - OBJECTIVE: To examine whether a first abortion increases risk of mental health disorders compared with a first childbirth with and without considering prepregnancy mental health and adverse exposures, childhood economic status, miscarriage history, age at first abortion or childbirth, and race or ethnicity. METHODS: A cohort study compared rates of mental disorders (anxiety, mood, impulse-control, substance use, eating disorders, and suicidal ideation) among 259 women postabortion and 677 women postchildbirth aged 18-42 years at the time of interview from The National Comorbidity Survey-Replication. RESULTS: The percentage of women with no, one, two, and three or more mental health disorders before their first abortion was 37.8%, 19.7%, 15.2%, and 27.3% and before their first childbirth was 57.9%, 19.6%, 9.2%, and 13.3%, respectively, indicating that women in the abortion group had more prior mental health disorders than women in the childbirth group (P<.001). Although in unadjusted Cox proportional hazard models, abortion compared with childbirth was associated with statistically significant higher hazards of postpregnancy mental health disorders, associations were reduced and became nonstatistically significant for five disorders after adjusting for the aforementioned factors. Hazard ratios and associated 95% confidence intervals dropped from 1.52 (1.08-2.15) to 1.12 (0.87-1.46) for anxiety disorders; from 1.56 (1.23-1.98) to 1.18 (0.88-1.56) for mood disorders; from 1.62 (1.02-2.57) to 1.10 (0.75-1.62) for impulse-control disorders; from 2.53 (1.09-5.86) to 1.82 (0.63-5.25) for eating disorders; and from 1.62 (1.09 2.40) to 1.25 (0.88-1.78) for suicidal ideation. Only the relationship between abortion and substance use disorders remained statistically significant, although the hazard ratio dropped from 3.05 (1.94-4.79) to 2.30 (1.35-3.92). CONCLUSIONS: After accounting for confounding factors, abortion was not a statistically significant predictor of subsequent anxiety, mood, impulse-control, and eating disorders or suicidal ideation. LEVEL OF EVEDIENCE: II. PMID- 24402592 TI - Surgical proctoring for gynecologic surgery. AB - Surgical proctoring allows a hospital's credentialing committee to objectively monitor, regulate, or oversee surgical privileging for its medical staff to ensure the safety and quality of care for its patients. The surgical proctor does not participate directly in patient care and does not establish a patient physician relationship before the procedure and therefore is under no obligation to intervene if an intraoperative complication occurs or substandard care is witnessed. Good Samaritan legislation enacted in every state should provide immunity for the proctoring physician if intervention is necessary. Teleproctoring may become the most cost-effective method for institutions that are unable to identify a local proctor for surgical privileging. PMID- 24402591 TI - Factors associated with vulvodynia incidence. AB - OBJECTIVE: To assess incidence rates of and risk factors for vulvodynia. METHODS: We conducted a longitudinal population-based study of women in southeast Michigan (Woman-to-Woman Health Study) using a validated survey-based screening test for vulvodynia that was repeated at 6-month intervals over 30 months. Unadjusted incidence rates were determined using Poisson models. Demographic and symptom related risk factors for incidence were assessed using discrete time survival analysis. RESULTS: Women who screened negative for vulvodynia at baseline and were followed through at least one additional survey (n=1,786) were assessed for onset of vulvodynia. The incidence rate was 4.2 cases per 100 person-years, and rates per 100 person-years were greater in women who were younger (7.6 cases per 100 person-years at age 20 years, compared with 3.3 cases per 100 person-years at age 60 years), Hispanic (9.5 cases per 100 person-years), married, or living as married (4.9 cases per 100 person-years); had reported symptoms of vulvar pain but did not meet vulvodynia criteria on the initial survey (11.5 cases per 100 person-years); or had reported past symptoms suggesting a history of vulvodynia (7.5 cases per 100 person-years). Increased risk of new-onset vulvodynia also included baseline sleep disturbance, chronic pain in general, specific comorbid pain disorders, and specific comorbid psychological disorders. CONCLUSIONS: The incidence rates of vulvodynia differ by age, ethnicity, and marital status. Onset is more likely among women with previous symptoms of vulvodynia or those with intermediate symptoms not meeting criteria for vulvodynia and among those with pre-existing sleep, psychological, and comorbid pain disorders. This suggests vulvodynia is an episodic condition with a potentially identifiable prodromal phase. LEVEL OF EVIDENCE: II. PMID- 24402593 TI - The numbers game: evaluation of statistics by obstetrics & gynecology. AB - Statistical analysis has become integral to the planning, conduct, and reporting of modern medical research. Attention to the statistical aspects of manuscripts submitted to Obstetrics & Gynecology goes back approximately 40 years and the process used in their evaluation has evolved over that time. For the past 20 years, submissions with any type of statistics and being seriously considered for acceptance have routinely been reviewed by a Statistical Editor who judges the work on a number of statistical and design characteristics. Findings of the statistical design review (which has been done by one Statistical Editor over the entire 20-year period) are integrated into the editorial decision about acceptance. The statistical review generally leads to rejection of approximately 16-25% of manuscripts and in a larger proportion, it identifies less serious problems, the correction of which improves the final product. PMID- 24402594 TI - Bowel preparation before vaginal prolapse surgery: a randomized controlled trial. AB - OBJECTIVE: To compare surgeons' intraoperative surgeon acceptability or assessment of the operative field regarding bowel contents and patients' satisfaction with or without a mechanical bowel preparation before reconstructive vaginal prolapse surgery. METHODS: In this single-blind, randomized trial, women scheduled to undergo vaginal prolapse surgery with a planned apical suspension and posterior colporrhaphy were allocated using block randomization to an intervention or control group. Surgeons were blinded to patient allocation. One day before surgery, mechanical bowel preparation instructions consisted of a clear liquid diet and two self-administered saline enemas; the participants in the control group sustained a regular diet and nothing by mouth after midnight. The primary outcome was surgeons' intraoperative assessment of the surgical field regarding bowel content as measured on a 4-point Likert scale (1, excellent; 4, poor). Secondary outcomes included participant satisfaction and bowel symptoms. The primary outcome was determined by intention-to-treat analysis and other analyses were per protocol. RESULTS: Of the 150 women randomized (75 women to intervention and control group), 145 completed the study. No differences existed in the demographic, clinical, and intraoperative characteristics between groups (P>.05). Surgeons' intraoperative assessment rating was 85% "excellent or good" with bowel preparation compared with 90% for participants in the control group (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.21-1.61; P=.30). The bowel preparation group was less likely to report "complete" satisfaction compared with the participants in the control group (OR 0.11, 95% CI 0.04-0.35; P<.001). Abdominal fullness and cramping, fatigue, anal irritation, and hunger pains were greater in the bowel preparation group (all P<.01). CONCLUSION: Before reconstructive vaginal surgery, mechanical bowel preparation conferred no benefit regarding surgeons' intraoperative assessment of the operative field, reflected decreased patient satisfaction, and had increased abdominal symptoms. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01431040. LEVEL OF EVIDENCE: I. PMID- 24402595 TI - Absorbable mesh augmentation compared with no mesh for anterior prolapse: a randomized controlled trial. AB - OBJECTIVE: To compare anatomical and patient-reported outcomes at 12 months postoperatively for women who had anterior compartment pelvic organ prolapse (POP) surgery using a repair augmented with porcine small intestine submucosa mesh (Mesh Group) compared with those who had a native tissue repair (No Mesh Group). METHODS: This was a randomized controlled trial with 12 months follow-up. The surgical procedure was identical in both groups except for the placement of intervening mesh. The primary outcome was anatomical "cure" (Ba of -1 or less on Pelvic Organ Prolapse Quantification [POP-Q]). Secondary outcomes included POP-Q stage, patient-reported outcomes, and patient satisfaction. The study was powered to detect a 40% difference at 80% power (alpha=0.05). RESULTS: Fifty-seven women were randomized (28 to Mesh Group, 29 to No Mesh Group). Forty-five (79%) underwent concomitant surgery. At the 12-month follow-up, 56% (15/27) in the Mesh Group and 61% (17/28) in the No Mesh Group were considered cured (relative risk 0.90, 95% confidence interval 0.52-1.54). There were no significant differences between groups in recurrent or persistent prolapse (7% in each group) nor in patient-reported outcomes at 12 months. Pelvic girdle pain occurred in 4 of 27 in the Mesh Group and 3 of 28 in the No Mesh Group. CONCLUSION: No significant differences were observed in anatomical or patient-reported outcomes outcome parameters at 12 months after correction of symptomatic anterior POP by mesh or no mesh repair. In our study, porcine small intestine submucosa mesh did not confer additional benefit over a native tissue repair. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT0095544. LEVEL OF EVEDIENCE: I. PMID- 24402596 TI - Maternal hemodynamics by thoracic impedance cardiography for normal pregnancy and the postpartum period. AB - OBJECTIVE: To establish normative impedance cardiography values for the second half of pregnancy and up to 48 hours postpartum after either vaginal or cesarean delivery. METHODS: A single-center prospective observational institutional review board-approved study of normotensive women (n=168) using thoracic impedance cardiography performed at specific times during gestation. Antepartum testing was performed at three time periods: 20-27 weeks, 28-33 weeks, and 34-40 weeks of gestation. Postpartum testing was undertaken after the immediate puerperium at 6 23 hours and 24-48 hours after vaginal or cesarean delivery. Data analysis was performed using STATA software; data are expressed as mean+/-standard deviation. RESULTS: All seven of the patient groups studied were comparable with regard to demographic features; 80% of the study participants were African American. Group means obtained between 20 and 40 weeks of gestation and postpartum after vaginal and cesarean delivery fell within the "normal range" of the hemodynamic graph that was developed to associate mean arterial pressure and systemic vascular resistance. The thoracic fluid content group means in both vaginal and cesarean delivery groups were higher than the antepartum patient groups. The thoracic fluid content mean after cesarean delivery at 48 hours is significantly higher than the mean value recorded between 20 and 27 weeks of gestation (P<.05). The systemic vascular resistance systemic vascular resistance means in each of the postpartum groups were significantly higher than the late second-trimester group means recorded at 20-27 weeks of gestation (P<.05). CONCLUSION: The normative values reported in this investigation can be used to interpret and assess similarly tested patients with hypertensive or otherwise complicated pregnancy. LEVEL OF EVIDENCE: III. PMID- 24402597 TI - Low-dose levonorgestrel and ethinyl estradiol patch and pill: a randomized controlled trial. AB - OBJECTIVE: To compare a new low-dose levonorgestrel and ethinyl estradiol contraceptive patch (Patch) with a combination oral contraceptive (Pill; 100 micrograms levonorgestrel, 20 micrograms ethinyl estradiol) regarding efficacy, safety, compliance, and unscheduled uterine bleeding. METHODS: Women (17-40 years; body mass index 16-60) were randomized in a 3:1 ratio to one of two groups: Patch only (13 cycles) or Pill (six cycles) followed by Patch (seven cycles). Investigators evaluated adverse events during cycles 2, 4, 6, 9, and 13. Participants recorded drug administration and uterine bleeding on daily diary cards. Compliance was assessed by measuring levonorgestrel and ethinyl estradiol plasma levels. Pearl Index (pregnancies per 100 woman-years) was calculated to evaluate efficacy. RESULTS: Participants (N=1,504) were randomized to Patch (n=1,129) or Pill (n=375). Approximately 30% were obese, more than 40% were racial or ethnic minorities, and more than 55% were new users of hormonal contraceptives. Laboratory-verified noncompliance (undetectable plasma drug levels) was 11% of Patch and 12.6% of Pill users at cycle 6. Pearl Indices (95% confidence intervals) for the intention-to-treat population (cycles 1-6) were 4.45 (2.34-6.57) for Patch and 4.02 (0.50-7.53) for Pill; excluding laboratory verified noncompliant participants, Pearl Indices were 2.82 (0.98-4.67) for Patch and 3.80 (0.08-7.52) for Pill (differences not statistically significant). Incidence of unscheduled bleeding and incidence and severity of adverse events were similar for both contraceptives (no statistically significant difference). CONCLUSIONS: Efficacy and safety of the new contraceptive Patch are comparable to those of a Pill. Laboratory-verified noncompliance and bleeding profile are similar between the two treatments. The Patch was well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01181479. LEVEL OF EVIDENCE: I. PMID- 24402598 TI - A model for predicting the risk of de novo stress urinary incontinence in women undergoing pelvic organ prolapse surgery. AB - OBJECTIVE: To construct and validate a prediction model for estimating the risk of de novo stress urinary incontinence (SUI) after vaginal pelvic organ prolapse (POP) surgery and compare it with predictions using preoperative urinary stress testing and expert surgeons' predictions. MATERIALS AND METHODS: Using the data set (n=457) from the Outcomes Following Vaginal Prolapse Repair and Midurethral Sling trial, a model using 12 clinical preoperative predictors of de novo SUI was constructed. De novo SUI was determined by Pelvic Floor Distress Inventory responses through 12 months postoperatively. After fitting the multivariable logistic regression model using the best predictors, the model was internally validated with 1,000 bootstrap samples to obtain bias-corrected accuracy using a concordance index. The model's predictions were also externally validated by comparing findings against actual outcomes using Colpopexy and Urinary Reduction Efforts trial patients (n=316). The final model's performance was compared with experts using a test data set of 32 randomly chosen Outcomes Following Vaginal Prolapse Repair and Midurethral Sling trial patients through comparison of the model's area under the curve against: 1) 22 experts' predictions; and 2) preoperative prolapse reduction stress testing. RESULTS: A model containing seven predictors discriminated between de novo SUI status (concordance index 0.73, 95% confidence interval [CI] 0.65-0.80) in Outcomes Following Vaginal Prolapse Repair and Midurethral Sling participants and outperformed expert clinicians (area under the curve 0.72 compared with 0.62, P<.001) and preoperative urinary stress testing (area under the curve 0.72 compared with 0.54, P<.001). The concordance index for Colpopexy and Urinary Reduction Efforts trial participants was 0.62 (95% CI 0.56-0.69). CONCLUSION: This individualized prediction model for de novo SUI after vaginal POP surgery is valid and outperforms preoperative stress testing, prediction by experts, and preoperative reduction cough stress testing. An online calculator is provided for clinical use. LEVEL OF EVIDENCE: III. PMID- 24402600 TI - Association between obstetrician forceps volume and maternal and neonatal outcomes. AB - OBJECTIVE: To estimate the association between obstetric forceps volume and severe perineal lacerations or adverse neonatal outcomes. METHODS: This is a retrospective cohort of forceps deliveries performed at a tertiary care hospital. Obstetricians were grouped by quartile of forceps volume over the study time period. Severe (third- or fourth-degree) perineal lacerations and adverse neonatal outcomes were compared across quartiles. Individual patient characteristics were controlled for using multilevel multivariable analysis. This study had 90% power to detect a twofold difference in severe perineal lacerations between the first and fourth quartiles. Additional analyses were performed using physician years in practice or year of residency of the involved resident physicians. RESULTS: One hundred eighteen attending physicians (2,369 forceps deliveries) were included. The median (interquartile range) annual number of forceps per quartile was 1.3 (1.0-1.8), 3.8 (3.0-4.3), 6.3 (5.5-6.8), and 11.5 (9.8-17.3). The frequency of severe perineal lacerations from lowest to highest quartile was 29.9%, 27.5%, 33.3%, and 36.9% (P=.013). After adjusting for confounders, the relationship between volume quartile and severe perineal lacerations became nonsignificant. Although not powered to this outcome, the frequency of composite adverse neonatal outcome was not associated with volume quartile in either bivariate or multivariable analysis. Similarly, neither physician years of practice nor resident year was associated with severe perineal laceration. However, more experience as a resident was associated with a reduced odds of composite adverse neonatal outcomes. CONCLUSIONS: After controlling for patient factors, neither attending forceps volume nor physician years in practice was associated with severe perineal lacerations or composite neonatal injury. LEVEL OF EVIDENCE: II. PMID- 24402599 TI - Placental findings in singleton stillbirths. AB - OBJECTIVE: To compare placental lesions for stillbirth cases and live birth controls in a population-based study. METHODS: Pathologic examinations were performed on placentas from singleton pregnancies using a standard protocol. Data were analyzed overall and within gestational age groups at delivery. RESULTS: Placentas from 518 stillbirths and 1,200 live births were studied. Single umbilical artery was present in 7.7% of stillbirths and 1.7% of live births, velamentous cord insertion was present in 5% of stillbirths and 1.1% of live births, diffuse terminal villous immaturity was present in 10.3% of stillbirths and 2.3% of live births, inflammation (eg, acute chorioamnionitis of placental membranes) was present in 30.4% of stillbirths and 12% of live births, vascular degenerative changes in chorionic plate were present in 55.7% of stillbirths and 0.5% of live births, retroplacental hematoma was present in 23.8% of stillbirths and 4.2% of live births, intraparenchymal thrombi was present in 19.7% of stillbirths and 13.3% of live births, parenchymal infarction was present in 10.9% of stillbirths and 4.4% of live births, fibrin deposition was present in 9.2% of stillbirths and 1.5% of live births, fetal vascular thrombi was present in 23% of stillbirths and 7% of live births, avascular villi was present in 7.6% of stillbirths and 2.0% of live births, and hydrops was present in 6.4% of stillbirths and 1.0% of live births. Among stillbirths, inflammation and retroplacental hematoma were more common in placentas from early deliveries, whereas thrombotic lesions were more common in later gestation. Inflammatory lesions were especially common in early live births. CONCLUSIONS: Placental lesions were highly associated with stillbirth compared with live births. All lesions associated with stillbirth were found in live births but often with variations by gestational age at delivery. Knowledge of lesion prevalence within gestational age groups in both stillbirths and live birth controls contributes to an understanding of the association between placental abnormality and stillbirth. LEVEL OF EVIDENCE: II. PMID- 24402601 TI - Number of embryos transferred after in vitro fertilization and good perinatal outcome. AB - OBJECTIVE: To assess the association between number of embryos transferred and a measure of assisted reproductive technology success that emphasizes good perinatal outcome. METHODS: We analyzed assisted reproductive technology cycles initiated in 2011 that progressed to fresh embryo transfer among women using autologous oocytes and reported to the U.S. National Assisted Reproductive Technology Surveillance System (n=82,508). Percentages of good perinatal outcome (live birth of a term [at or after 37 weeks of gestation], normal birth weight [2,500 g or greater] singleton) were stratified by prognosis (favorable, average, less favorable), age, embryo stage (day 3, day 5), and number of embryos transferred. Differences in the percentages by number of embryos transferred were evaluated using Fisher's exact test with Bonferroni correction. RESULTS: Among patients younger than 35 years with a favorable prognosis, chances of a good perinatal outcome were higher with transferring a single (compared with double) day 5 (43% compared with 27%) or day 3 embryo (36% compared with 30%). Likewise, a higher chance of a good perinatal outcome was observed with transferring a single day 5 embryo in patients 35-37 years old with a favorable prognosis (39% compared with 28%) or patients younger than 35 years old with an average prognosis (35% compared with 26%). A higher chance of good perinatal outcome was associated with transferring two (compared with one) day 3 embryos among patients aged 40 years or younger with an average prognosis or patients younger than 35 years old with a less favorable prognosis. CONCLUSION: The association between number of embryos transferred and the birth of a term, normal birth weight singleton is described. Among patients younger than 35 years of age undergoing in vitro fertilization with a favorable prognosis, the highest chance of good perinatal outcome is associated with a single embryo transfer. LEVEL OF EVIDENCE: II. PMID- 24402602 TI - The journal of last resort. PMID- 24402603 TI - What is new in multiple gestations? Best articles from the past year. AB - This month, we focus on current research on multiple gestations. Dr. Jackson discusses four recent publications, and each is concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts. PMID- 24402604 TI - "Doctor, it hurts...". PMID- 24402605 TI - The postresection alpha-fetoprotein in cirrhotic patients with hepatocellular carcinoma. An independent predictor of outcome. AB - BACKGROUND: The postresection alpha-fetoprotein (AFP) in cirrhotic patients with hepatocellular carcinoma (HCC) may predict overall survival (OS) and recurrence beyond Milan criteria (MC) among the subgroup of initially transplantable patients. METHODS: All patients with cirrhosis resected for HCC between January 1990 and December 2010 in a single institution and presenting a serum AFP value > 15 ng/ml at diagnosis were included. The postresection AFP was analyzed as a dichotomized variable: normalization (norm + group) or not (norm - group) within the 90-day postresection period. RESULTS: Among 271 resected patients, 141 patients (52%) had a level of serum AFP >= 15 ng/ml at diagnosis. Five-year OS and median survival were 42% and 52 months in group norm + versus 20% and 23 months in the group norm - (P = 0.009). On multivariate analysis, the absence of AFP normalization was an independent factor of poor OS as well as microvascular invasion, and satellites nodules. Among theoretically transplantable patients, independent predictors of recurrence beyond MC were the absence of AFP normalization (risk ratio (RR) 5.02 [1.53-16.34]) and microvascular invasion (RR 4.76 [1.42-15.34]). CONCLUSION: The postresection AFP has an independent prognostic value. Transplantable patients resected for HCC without 90-day AFP normalization should be discussed for early liver transplantation. PMID- 24402606 TI - Does preoperative cross-sectional imaging accurately predict main duct involvement in intraductal papillary mucinous neoplasm? AB - Main pancreatic duct (MPD) involvement is a well-demonstrated risk factor for malignancy in intraductal papillary mucinous neoplasm (IPMN). Preoperative radiographic determination of IPMN type is heavily relied upon in oncologic risk stratification. We hypothesized that radiographic assessment of MPD involvement in IPMN is an accurate predictor of pathological MPD involvement. Data regarding all patients undergoing resection for IPMN at a single academic institution between 1992 and 2012 were gathered prospectively. Retrospective analysis of imaging and pathologic data was undertaken. Preoperative classification of IPMN type was based on cross-sectional imaging (MRI/magnetic resonance cholangiopancreatography (MRCP) and/or CT). Three hundred sixty-two patients underwent resection for IPMN. Of these, 334 had complete data for analysis. Of 164 suspected branch duct (BD) IPMN, 34 (20.7%) demonstrated MPD involvement on final pathology. Of 170 patients with suspicion of MPD involvement, 50 (29.4%) demonstrated no MPD involvement. Of 34 patients with suspected BD-IPMN who were found to have MPD involvement on pathology, 10 (29.4%) had invasive carcinoma. Alternatively, 2/50 (4%) of the patients with suspected MPD involvement who ultimately had isolated BD-IPMN demonstrated invasive carcinoma. Preoperative radiographic IPMN type did not correlate with final pathology in 25% of the patients. In addition, risk of invasive carcinoma correlates with pathologic presence of MPD involvement. PMID- 24402607 TI - Image findings in celiac artery stenosis due to median arcuate ligament compression: a crucial diagnosis when planning for pancreaticoduodenectomy. AB - Celiac axis stenosis caused by extrinsic compression by the median arcuate ligament (MAL) is present in up to 5% of patients undergoing pancreaticoduodenectomy. Failure to identify and manage MAL compression can lead to potentially devastating postoperative consequences that include frank liver necrosis and death. We report an incidental discovery of celiac axis stenosis by MAL in a patient prepared for pancreaticoduodenectomy. Image findings and operative management are discussed. PMID- 24402608 TI - In vitro and in vivo characterisation of the profibrinolytic effect of an inhibitory anti-rat TAFI nanobody. AB - One of the main disadvantages of current t-PA thrombolytic treatment is the increased bleeding risk. Upon activation, thrombin activatable fibrinolysis inhibitor (TAFI) is a very powerful antifibrinolytic enzyme. Therefore, co administration of a TAFI inhibitor during thrombolysis could reduce the required t-PA dose without compromising the thrombolytic efficacy. In this study we generated and characterised a nanobody that is inhibitory towards rat TAFI and evaluated its profibrinolytic property in vitro and in vivo. Nanobody VHH-rTAFI i81 inhibits (at a 16-fold molar ratio nanobody over TAFI) the thrombin/thrombomodulin (T/TM)-mediated activation of rat TAFI (rTAFI) by 83 +/- 1.8% with an IC50 of 0.46 (molar ratio nanobody over TAFI). The affinity (KA) of VHH-rTAFI-i81 for rTAFI, as determined by surface plasmon resonance (Biacore(r)), is 2.5 +/- 0.2 x 10(10) M(-1) and illustrates a very strong binding. In an in vitro clot lysis assay, administration of VHH-rTAFI-i81 strongly enhances the degree of lysis and reduces time to reach full lysis of t-PA-mediated clot lysis. Epitope mapping discloses that Lys392 is of primary importance for the nanobody/rTAFI interaction besides minor contributions of Tyr175 and Glu183. In vivo application of VHH-rTAFI-i81 in a tissue factor-induced mouse thromboembolism model significantly decreases fibrin deposition in the lungs in the absence of exogenous administered t-PA. Nanobody VHH-rTAFI-i81 is a very potent inhibitor of T/TM-mediated TAFI activation. Co-administration of this nanobody and t-PA enhances the fibrinolytic efficacy. In an in vivo mouse thromboembolism model, VHH-rTAFI-i81 reduces fibrin deposition in the lungs. PMID- 24402609 TI - Circular permutation of E. coli EPSP synthase: increased inhibitor resistance, improved catalytic activity, and an indicator for protein fragment complementation. AB - We performed the first circular permutation analysis for E. coli 5 enolpyruvylshikimate-3-phosphate synthase, and identified one circular permutant with notably increased resistance to its specific inhibitor and several others with moderately improved catalytic activity. Valid circular permutation sites can be used as effective split sites of protein fragment complementation. PMID- 24402611 TI - CRMP2: functional roles in neural development and therapeutic potential in neurological diseases. AB - Cytoskeletal restructuring is essential for nearly all cellular processes in the developing brain. After cell fate determination, newborn cortical neurons must migrate to their final positions while establishing proper axon-dendrite polarity. Significant progress has recently been made towards understanding the cellular and molecular mechanisms underlying neuronal polarization in vivo. Collapsin response mediator protein 2 (CRMP2) has long been identified as a microtubule-binding protein that regulates neuronal polarity in vitro. Recent studies provide new insights into the roles of CRMP2 in neuronal migration and subsequent neuronal differentiation. Both the expression and activity of CRMP2 are tightly regulated during cortex development. CRMP2 is suggested to be important in the multipolar-bipolar transition in radial migration. The increasing number of known interaction partners indicates that CRMP2 has functions beyond cytoskeletal regulation, including axonal transport, vesicle trafficking, and neurotransmitter release. This review discusses the current knowledge about CRMP2 in the context of neuronal development and highlights a recent emerging theme regarding its potential therapeutic applications. PMID- 24402612 TI - How Plastic Is the Brain after a Stroke? AB - Stroke is a common problem, and with an aging population, it is likely to become more so. Outcomes from stroke are wide ranging from death to complete recovery, but the majority result in severe motor impairments that affect quality of life and become a burden on health care systems, family, and friends. Therapeutically, removal of thromboses can greatly improve outcomes, but for many stroke sufferers, the only currently available therapy is rehabilitative training in which spared brain areas and fiber tracts are strengthened and trained to take over new functions. Experimental data in animals show that this is in part based on changes in the connectivity of the brain and spinal cord and on the growth of new nerve fiber branches, a process called structural plasticity. So, just how plastic is the brain after a stroke? In this review, we explore the factors that affect plasticity after strokes, such as age and the overall size and location of the lesion. We discuss the peri-infarct area as extensive research has shown that processes occurring there are likely to be involved mechanistically in plastic changes in cortical circuitry. Finally, we review promising interventions being tested preclinically and discuss those that have been translated into clinical research. PMID- 24402613 TI - Nogo-A: Multiple Roles in CNS Development, Maintenance, and Disease. AB - Initially discovered as a potent neurite outgrowth inhibitor in the central nervous system (CNS), Nogo-A has emerged as a multifunctional protein. Involvement of this protein has been demonstrated in numerous developmental processes, ranging from cell migration, axon guidance and fasciculation, dendritic branching and CNS plasticity to oligodendrocyte differentiation and myelination. Although initially necessary and beneficial for shaping and later maintaining CNS structure and functionality, the growth restricting properties of Nogo-A can have negative effects on nervous system injury or disease. Hence, correlating with its various neurobiological roles, Nogo-A was implicated in a range of CNS disturbances, including trauma such as spinal cord injury or stroke, neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis or multiple sclerosis, or in schizophrenia. In this review, we summarize the current state of knowledge for Nogo-A's involvement in these nervous system diseases and perturbations and discuss the possible underlying mechanisms. Furthermore, we provide a comprehensive overview on molecular signaling pathways as well as structural properties identified for Nogo-A and point to open questions in the field. PMID- 24402614 TI - Dystrophic calcification and accentuated localized Argyria after fractionated carbon dioxide laser therapy of hypertrophic scars. AB - IMPORTANCE: Fractionated, ultrapulsed carbon dioxide (CO2) laser therapy is a powerful tool for the treatment of scars. Common adverse effects of this therapeutic modality have been previously documented. We describe 2 unreported adverse effects of ultrapulsed CO2 laser treatment of mature scars in a patient previously treated with silver-impregnated dressings. OBSERVATIONS: A teenage survivor of toxic epidermal necrolysis presented with faint but diffuse dyschromia clinically and histologically consistent with localized argyria secondary to silver-impregnated dressings used years earlier. The patient was subsequently treated with fractionated CO2 for her scarring, but her hyperpigmentation worsened with each treatment. A subsequent biopsy specimen revealed a zone of dystrophic calcification with adjacent pseudo-ochronotic fibers that were not appreciated on biopsy specimens taken before CO2 laser treatment, suggesting unique complications not previously reported. CONCLUSIONS AND RELEVANCE: We present 2 unique complications secondary to ultrapulsed, fractionated CO2 laser treatment in a patient previously treated with silver impregnated dressings: (1) the appearance of pseudo-ochronotic fibers in areas of worsening pigmentation and (2) evidence of dystrophic calcification limited to columns of fractionated laser ablation. Therefore, a history of argyria or treatment with silver-impregnated dressings should be considered before treatment with fractionated CO2 lasers. PMID- 24402615 TI - Understanding the fast thermal isomerisation of azophenols in glassy and liquid crystalline polymers. AB - The good solubility of azophenols in low molar mass liquid crystals together with the ability of their related polymers to form homogeneous nematic and glassy thin films make such azoderivatives valuable chromophores to get a great variety of photoactivatable systems with fast switching speeds under ambient conditions. In fact, the final applicability of these systems is mainly determined by the thermal cis-to-trans isomerisation rate of the photoactive azophenol used, in other words, by the intimate mechanism the reaction goes through. The kinetico mechanistic study reported herein shows that the rate of the thermal back reaction for azophenols is very sensitive to the local environment where the azo chromophore is located, mainly to its capability to establish hydrogen bonding with its surroundings. With a proper design, azophenol-based polymers can exhibit thermal isomerisation rates as fast as those of the monomers in solution even without the presence of any solvent. PMID- 24402616 TI - Effect of vitreomacular adhesion on antivascular endothelial growth factor therapy for macular edema secondary to branch retinal vein occlusion. AB - PURPOSE: To investigate the association between vitreomacular adhesion (VMA) and the visual and anatomic outcomes of antivascular endothelial growth factor therapy for macular edema due to branch retinal vein occlusion (BRVO). METHODS: This study included 107 eyes of 107 patients with BRVO who underwent intravitreal injection of 1.25 mg bevacizumab. The presence of VMA was determined with spectral-domain optical coherence tomography (SD-OCT). All eyes underwent best corrected visual acuity (BCVA) and central retinal thickness (CRT) measurements using SD-OCT immediately before the injection and at 3, 6, 9, and 12 months after the injection. The main outcome measures were changes in BCVA and CRT from baseline. RESULTS: The VMA(+) and VMA(-) groups consisted of 47 and 60 eyes, respectively, and patients' age differed significantly between the groups (P < 0.001). In both groups, BCVA and CRT improved after the injection. The VMA(+) group showed better improvement in BCVA than did the VMA(-) group (P = 0.0150), and the presence of VMA was associated with a greater decrease in CRT after adjusting for age (P = 0.0019). CONCLUSIONS: Presence of VMA may be associated with superior visual and anatomic outcome for intravitreal bevacizumab in the treatment of macular edema due to BRVO. PMID- 24402617 TI - Mycobacterium massiliense induces inflammatory responses in macrophages through Toll-like receptor 2 and c-Jun N-terminal kinase. AB - Mycobacterium massiliense (Mmass) is an emerging, rapidly growing mycobacterium (RGM) that belongs to the M. abscessus (Mabc) group, albeit clearly differentiated from Mabc. Compared with M. tuberculosis, a well-characterized human pathogen, the host innate immune response against Mmass infection is largely unknown. In this study, we show that Mmass robustly activates mRNA and protein expression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 in murine bone marrow-derived macrophages (BMDMs). Toll-like receptor (TLR)-2 and myeloid differentiation primary response gene 88 (MyD88), but neither TLR4 nor Dectin-1, are involved in Mmass-induced TNF-alpha or IL-6 production in BMDMs. Mmass infection also activates the mitogen-activated protein kinase (MAPKs; c-Jun N-terminal kinase (JNK), ERK1/2 and p38 MAPK) pathway. Mmass-induced TNF-alpha and IL-6 production was dependent on JNK activation, while they were unaffected by either the ERK1/2 or p38 pathway in BMDMs. Additionally, intracellular reactive oxygen species (ROS), NADPH oxidase-2, and nuclear factor-kappaB are required for Mmass-induced proinflammatory cytokine generation in macrophages. Furthermore, the S morphotype of Mmass showed lower overall induction of pro inflammatory (TNF-alpha, IL-6, and IL-1beta) and anti-inflammatory (IL-10) cytokines than the R morphotype, suggesting fewer immunogenic characteristics for this clinical strain. Together, these results suggest that Mmass-induced activation of host proinflammatory cytokines is mediated through TLR2-dependent JNK and ROS signaling pathways. PMID- 24402618 TI - First report of the Hyper-IgM syndrome Registry of the Latin American Society for Immunodeficiencies: novel mutations, unique infections, and outcomes. AB - Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). Of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the CD40L gene (CD40LG). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by Mycoplasma pneumoniae, Serratia marcescens or Aspergillus sp. and diarrhea caused by Microsporidium sp. or Isospora belli. Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas. PMID- 24402619 TI - Cartilage-hair hypoplasia: follow-up of immunodeficiency in two patients. AB - PURPOSE: To study the changes in the immunological status in 2 children with cartilage hair hypoplasia (CHH). METHODS: A 4-6 year immunological follow-up from infancy. RESULTS: In infancy the children presented a combined T cell and B cell immunodeficiency which partly resolved in time. Mitogen-induced T cell proliferation values fluctuated but lymphopenia has remained constant. Both patients had no recent thymic emigrants (TREC). Both children have suffered from a prolonged viral infection. Hypogammaglobulinemia normalized during the first years of life but both children have a specific antibody deficiency (SAD). CONCLUSIONS: The changes in the immunological status in CHH patients emphasize the importance of a regular follow-up. SAD should be searched for in CHH. The absence of TRECs supports combined immunodeficiency and possible need of hematopoietic stem cell transplantation. PMID- 24402620 TI - Bone density and fractures in autosomal dominant hyper IgE syndrome. AB - PURPOSE: Autosomal Dominant Hyper IgE Recurrent Infection Syndrome (AD-HIES) is caused by mutations in STAT3 and characterized by eczema, recurrent bacterial infections, and skeletal and connective tissue abnormalities. To further understand the minimal trauma fractures of AD-HIES, we examined bone mineral density (BMD) and laboratory markers of bone turnover. METHODS: Patients with AD HIES enrolled in a prospective natural history study were examined with dual x ray absorptiometry (DEXA) scans and laboratory studies of bone metabolism. The number of fractures was recorded as well as clinical features of AD-HIES including scoliosis and retained primary teeth. Patients on medications with skeletal effects, including bisphosphonates, were examined separately. RESULTS: Twenty-three AD-HIES children (6-18 years) and 33 AD-HIES adults (21-50 years) not receiving bone-active drugs were studied. Fourteen of the 23 children (61%) had histories of minimal trauma fractures, as did 26 of the 33 adults (79%). Osteopenia or osteoporosis was found in 79% of children and adults. Only radial BMD correlated with the qualitative occurrence of fractures but it did not correlate with the numbers of fractures. Markers of bone metabolism did not correlate with minimal trauma fractures or BMD. Patients on bone-active medications had improved BMD, but still sustained fractures. CONCLUSIONS: Minimal trauma fractures and decreased BMD are common in AD-HIES. Low radial BMD is associated with fractures, but hip and spine BMD are not. Treatment with bisphosphonates increased BMD but its role in fracture prevention remains undefined. PMID- 24402622 TI - News from the CIS Executive Committee. PMID- 24402621 TI - Caucasian origin of disease associated HLA haplotypes in chinese blood donors with IgA deficiency. AB - PURPOSE: Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Caucasians with a prevalence of 1:600. However, the prevalence of IgAD is markedly lower in East Asian countries but no genetic studies have been performed on IgAD individuals in the Mongoloid population. METHODS: We investigated the prevalence of IgAD in a large number of Chinese blood donors (n = 39,015) in Shanghai, China. We measured immunoglobulin class, IgG subclass and anti-IgA serum levels among the IgAD donors. These donors were subsequently tissue typed and the allele frequency was compared with the Shanghai bone marrow donor HLA registry. RESULTS: Seventeen IgAD Chinese blood donors were identified, giving a prevalence of 1: 2,295. Two previously identified IgAD blood donor samples were added in the subsequent tests. Most IgAD donors had serum IgG levels above the normal range with no major IgG subclass deficiency and one donor was weakly positive for anti-IgA. Two-thirds of the Chinese IgAD donors carried Caucasian IgAD associated risk haplotypes, including DRB1*0301-DQB1*0201, DRB1*0701-DQB1*0202 and DRB1*0102-DQB1*0501, giving a significantly higher frequency of these haplotypes as compared to the Shanghai bone marrow donor HLA registry. CONCLUSIONS: The prevalence of IgAD in Chinese in this study is markedly lower than in Caucasians. This is the first study to investigate the genetics of IgAD in the Mongoloid population and two-thirds of the Chinese IgAD donors showed a mixture of Caucasian IgAD risk haplotypes. The low prevalence of IgAD could potentially be due to the low frequency of the disease associated risk haplotypes in China. PMID- 24402623 TI - [Stocking process for consumables and investement goods in the Italian public health service (part II)]. AB - The necessity for fairness and transparency during the processes of supply of consumables and capital goods within the Italian Health Service together with that of containing costs in line with budget reductions, are points outlined in the 2006 public and European Union allocation codes and related procedures. These include methods to guarantee open, limited negotiation both without or after the official announcement for competitive bidding has been made, plus mediation and framework agreement. The publicizing of announcements of bidding to potential Health Service suppliers, criteria for applicant selection and selection of personnel to comprise the panels who effectively make the choice of suppliers, are all phases that are carefully regulated at a legal level. Even small expenditures (down to 20,000) are covered by these regulations. An overview of specific responsibilities, the institution of boards of physicians and the application of sanctions ends the present review. PMID- 24402624 TI - What can we learn from a statistically inconclusive trial? Consensus conference on the EVOLVE study results. AB - The link between serum parathyroid hormone (iPTH) and cardiovascular (CVS) mortality has not been fully elucidated. The EVOLVE Study was designed to test whether a drug such as cinacalcet, aimed at lowering iPTH, could reduce the astonishingly high cardiovascular risk in patients on maintenance dialysis (CKD 5D). Accordingly, the primary outcome of the study was the combined endpoint of time to death or hospitalization due to CVS factors or from any cause. Time to bone fracture and parathyroidectomy were regarded as secondary endpoints. At study completion, the Intention-To-Treat analysis documented a non- significant 7% (Hazard Ratio: 0.93; 95% Confidence interval: 0.85-1.02; P = 0.11) reduction of the primary composite endpoint. However, the intention to treat analysis does not take into account adherence to drug regimens or control for factors that may potentially jeopardize the conduction of the study. In particular, in spite of a careful pre-planned study sample calculation, the final power of the EVOLVE study was 54% instead of the assumed 90%, greatly reducing the reliability of study results. Furthermore, the pre-planned multivariable adjustment of the primary endpoint suggests a nominally significant reduction of the risk of the primary composite endpoint when age is entered into the statistical model. The sensitivity analysis further corroborates this result. The Lag Time Censoring Analysis (LTCA) evidenced a nominally significant 15% risk reduction of the composite endpoint among patients allocated to cinacalcet if the patients follow up was terminated 6 months after the study drug discontinuation, as pre-planned in the protocol. It is interesting that the LTCA suggests that the effect of cinacalcet weakened over time and became insignificant after about 1 year from drug discontinuation. Although authors could not detect any effect of cinacalcet on bone fracture associated with cinacalcet use, the secondary analyses of the EVOLVE trial suggest a nominally significant 60-70% risk reduction of parathyroidectomy and a reassuring safety profile of prolonged exposure to cinacalcet. In summary, the EVOLVE study adds to the list of inconclusive randomized clinical trials in Nephrology. However, the preplanned exploratory and sensitivity analyses suggest that when imbalances of patients characteristics at study entry (i.e. age) or study drug discontinuation are considered, a 'nominally' significant risk reduction in CVS and parathyroidectomy associated with cinacalcet treatment is noted. PMID- 24402625 TI - [Enzyme replacement therapy in patients with Fabry disease: state of the art and review of the literature]. AB - Anderson-Fabry disease is a hereditary X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha galactosidase A. It results in the accumulation of the glycosphingolypid globotrioasoyl ceramide (Gb3 in different cells and organs, resulting in a multi-system pathology including end organ failure. Patients with Fabry disease present clinically with cardiac, renal and neurological involvement; both life expectancy and quality of life are severely compromised. The current causal treatment for Fabry disease is enzyme replacement therapy (ERT), available since 2001. The two recombinant preparations available for ERT are agalsidase alfa (Replagal) and agalsidase beta (Fabrazyme). They have both been showed to have positive effect on kidney and heart, on the symptoms of pain and quality of life. Few data to date are available on comparison of the two preparations of ERT. This article reviews evidence of the literature and shows our personal experience about the safety and efficacy of ERT. PMID- 24402626 TI - AKI with serious state of acidosis in diabetic patients treated with metformin. AB - Metformin is a drug increasingly used in the treatment of diabetic patients. In addition to its hypoglycemic effect, it reduces vascular risk and does not determine an increase in body weight. Compared to the older molecule, phenformin, metformin possesses a lower risk of induction of severe lactic acidosis in the general diabetic population. On the other hand, metformin must be used with caution in patients with kidney damage. In patients with a glomerular filtration rate (GFR) below 30 ml/min, the use of metformin is also associated with a high risk of lactic acidosis. The assessment of glomerular filtration rate using MDRD or CKD-EPI formulas allows the clinician to identify patients potentially at risk. All subjects with normal renal function treated with metformin for years are at risk of suddenly developing lactic acidosis during episodes of acute worsening renal function. We report a case of lactic acidosis in association with acute kidney injury (AKI). PMID- 24402627 TI - [Liposomial iron: a new proposal for the treatment of anaemia in chronic kidney disease]. AB - Iron supplementation is essential for the treatment of anemia in the chronic kidney disease (CKD) population. Liposomial iron is a preparation of ferric pyrophosphate carried within a phospholipidic membrane. Compared to other oral formulations, it is well absorbed from the gut and demonstrates high bioavailability together with a lower incidence of side effects. The aim of our study was to evaluate the effectiveness of treatment with liposomial iron compared to intravenous iron in a CKD population with anemia and iron deficiency. Our study is a single-center, prospective, randomized, fourth-phase study. Enrollment for the study began in October 2011 and CKD 3, 4 and 5 patients were randomized to receive either intravenous iron or liposomial iron in a 1:2 ratio. The primary outcome was set as the increase of hemoglobin from baseline. The secondary outcomes were the reduction of erythropoietin dosage by at least 25% in patients treated with erythropoiesis-stimulating agents and an increase in serum ferritin of 100 ng/ml from baseline values. In the preliminary study, 21 patients were analyzed, 14 of whom were treated with oral liposomial iron and 7 with intravenous iron. The observed increase of hemoglobin at 8 weeks compared to baseline was similar in both groups but was significant in the liposomial group only. PMID- 24402628 TI - [Gas analysis in bicarbonate dialysis]. AB - The acid-base abnormalities in uremic patients on hemodialysis are well known. There is less awareness of the fact that during bicarbonate dialysis patients are simultaneously exposed to the four fundamental acid-base disorders. Attempts at compensation involving the respiratory system persist in the hours following hemodialysis. Furthermore, several landmark publications in addition to more recent papers clearly show that bicarbonate HD is only able to compensate for uremic acidosis through the elimination of surplus CO2 from dialysate via the lungs. The artificial kidney and lungs of the patient work together to ensure the efficiency of hemodialysis. Dialysate is a more acidic solution than the patient's blood and contains, in addition to oxygen and bicarbonate, at least twice the CO2 concentration of blood. The high dialysance of CO2 allows for its rapid diffusion from the dialysate to the blood compartment and can be a clinically relevant issue in patients with co-morbidities, especially respiratory disease. In such circumstances, hemodialysis may cause iatrogenic respiratory acidosis which, if not recognized, can require ventilatory assistance and advanced life support. Checking for such problems in a real life setting, such as an outpatient hemodialysis unit, is an important part of the nephrologists day-to day work. PMID- 24402629 TI - [Pathophysiology and diagnosis of cardio-renal syndrome: actual picture and future prospectives]. AB - The cardiorenal syndrome (CRS) indicates how close the relationship is between heart and kidney during failure of these organs. At present, the classification of the syndrome includes five types of CRS: types I and II which are strictly related to initial heart failure (both acute and chronic), types III and IV which include initial kidney failure, and type V which includes several systemic diseases. Many pathophysiological pathways have been described illustrating how heart and kidney disease are involved in clinical conditions. The diagnosis of CRS is based on both blood tests and ultrasound imaging. Several biomarkers indicating levels of heart and kidney function have emerged over the last few decades which can be used to predict kidney failure in patients with acute or chronic heart disease. Kidney injury biomarkers have also to be tested, especially those indicating glomerular and tubular damage. Renal ultrasound and trans-thoracic echocardiography can provide further information on heart and kidney failure in patients with cardio-renal syndrome at any stage. PMID- 24402630 TI - [Lights and shadows in the care of an adult patient in cardiology intensive care unit in treatment with venovenouse hemofiltration]. AB - In order to switch the focus from a patients treatment to the care of the patient, it is important to understand and fully consider the full impact on the patient of both the heart disease itself and the various treatment options available. The literature includes many studies of treatment options but little to inform us of the care necessary to support the adult patient who must undergo venovenous ultrafiltration on ICU. Although still requiring investigation, reviews of the literature suggest that a care-oriented approach aiming to reduce both acute and chronic stress through involvement of the patients social contacts, exerts a protective effect and improves the patient's outcome. Suggestions for future research are included. PMID- 24402632 TI - Genetic diversity of group A rotavirus in swine in Canada. AB - Group A rotaviruses (RVA) in pigs have been poorly investigated in Canada. In a continued effort to fill this gap, ten finisher swine farms in Quebec, Canada, were sampled over a nine-month period. The presence of RVA was detected in healthy pigs on all farms investigated during the entire sampling period. The genotypes detected included G2, G5, G9 and G11; P[6], P[7], P[13], P[27] and P[34]; and I5 and I14. The predominant types were G2, P[13] and I5, which is different from previous global reports. Various fomites were consistently contaminated by RVA, suggesting that a resident viral flora remains in the farm environment and may play a role in the infection of incoming pigs. The results also suggest temporal or geographical specificities regarding strain distribution on pig farms. PMID- 24402633 TI - Molecular and biological characterization of a recombinant isolate of potato virus Y from Mexico. AB - An isolate of potato virus Y (PVY), PVY-M3, was subjected to biological characterization on potato indicators and to whole-genome sequencing. PVY-M3 induced a local and systemic hypersensitive resistance (HR) response in potato cultivar Maris Bard expressing the Nz gene while inducing no HR in potato cultivars Desiree and King Edward, carrying Ny and Nc genes, respectively. These HR responses, combined with a lack of vein necrosis in tobacco, clearly defined PVY-M3 as an isolate of the PVY(Z) strain. Recombination analysis demonstrated that PVY-M3 had a typical European PVY(NTN) genome with three recombinant junctions, and PVY(N) and PVY(O) were identified as parents. PMID- 24402634 TI - Simultaneous discrimination and detection of influenza A(H1N1)pdm09 and seasonal influenza A viruses using a rapid immunogold biosensor. AB - A rapid immunogold biosensor for the simultaneous discrimination of influenza A(H1N1)pdm09 and seasonal influenza A viruses was developed successfully. Monoclonal antibodies (mAbs) that were specific for the hemagglutinin protein of the A(H1N1)pdm09 virus were produced, and the best mAb pairs were selected. Using an mAb that was specific for the influenza A nucleoprotein, a rapid immunogold biosensor for the discrimination and detection of A(H1N1)pdm09/seasonal influenza viruses was developed. When tested with 72 virus isolates, the system achieved 100 % detection of the A(H1N1)pdm09 virus without cross-reactivity against seasonal influenza A (H1, H3 subtypes) and B viruses, parainfluenza viruses, respiratory syncytial viruses, and adenoviruses. The detection limits for A(H1N1)pdm09 and seasonal strains were 5 * 10(2)-7.5 * 10(3) and 1 * 10(3)-7.5 * 10(5) TCID50/mL, respectively. When tested with 49 clinical specimens, the specificity was high (100 %). The sensitivity for the detection of A(H1N1)pdm09 and seasonal strains was 90 % and 100 %, respectively, which correlated with the results of real-time reverse transcription polymerase chain reaction as a reference method. The ability of the system to detect and discriminate the A(H1N1)pdm09 strain from the seasonal strains suggests that this method may be beneficial for investigation of outbreaks and diagnostic applications. Furthermore, this method might be a useful platform for developing a rapid diagnostic system for the simultaneous discrimination of other influenza virus subtypes during future outbreaks. PMID- 24402635 TI - Expression of concern. AB - The Editor in Chief would like to alert readers to the following three articles published in Biological Trace Element Research. PMID- 24402636 TI - Effect of zinc supplementation on inflammatory markers and adipokines in young obese women. AB - Obesity is a chronic inflammatory state characterized by altered adipokine production and increased levels of inflammatory cytokines. The study explored the effect of zinc supplementation on inflammatory markers and adipocyte hormones in young obese women. Twenty five non-obese women and forty obese women (body mass index >=25 kg/m(2)) aged 19-28 years were recruited for this study. Twenty obese women of the study group took 30 mg/day of supplemental zinc as zinc gluconate for 8 weeks and 20 obese women of control group took placebo. Usual dietary zinc intake was estimated from 3-day diet records. Serum zinc and urinary zinc concentration were measured by Atomic Absorption Spectrophotometry. Inflammatory markers such as high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-alpha), and interleukin (IL)-6 and adipocyte hormones such as lepin and adiponectin were measured by enzyme immunoassay. Inflammatory markers and leptin were significantly higher, but adiponectin was significantly lower in obese women than non-obese women. Zinc supplementation increased serum zinc by 15% and urinary zinc by 56% (P < 0.05). The levels of hs-CRP (P = 0.03) and IL-6 (P = 0.006) significantly decreased with zinc supplementation, but not in placebo group. Serum leptin and plasma adiponectin concentration did not differ with either zinc supplementation or placebo. The levels of IL-6 and leptin were inversely associated with dietary zinc intake. These results suggest that zinc may have a favorable effect on obesity-related inflammation in young adults. PMID- 24402638 TI - Intratumoral heterogeneity of the distribution of kinetic parameters in breast cancer: comparison based on the molecular subtypes of invasive breast cancer. AB - PURPOSE: To evaluate the distribution pattern of kinetic parameters in breast cancers with various molecular subtypes. MATERIALS AND METHODS: This study was approved by institutional review board and was compliant with HIPAA. We classified 192 invasive breast cancers of 186 patients into four molecular subtypes using hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) results and evaluated the distribution pattern of kinetic parameters (percent volume of kinetic types relative to the tumor volume) in the molecular subtypes. RESULTS: In the delayed phase, all three types of kinetic parameter (persistent, plateau, and washout pattern) were observed in each molecular subtype without any dominant type of kinetic parameter. The percentages of washout pattern in the HR+ and HER2- type and triple negative (TN) cancers tended to be lower than those in the other molecular subtype cancers. CONCLUSION: Each molecular subtype of invasive breast cancer showed a heterogeneous kinetic pattern in dynamic-contrast magnetic resonance imaging (MRI). The HR+/HER2- cancers and the TN cancers had relatively lower percentages of washout pattern. When a manual assessment of the kinetic parameters is performed, close attention should be paid in order to identify the malignant washout kinetic pattern, particularly in HR+/HER2- cancer and TN cancer. PMID- 24402637 TI - Clopidogrel metaboliser status based on point-of-care CYP2C19 genetic testing in patients with coronary artery disease. AB - We compared results obtained with the Nanosphere Verigene(r) System, a novel point-of-care (POC) genetic test capable of analysing 11 CYP2C19 variants within 3 hours, to an established, validated genotyping method (AffymetrixTM DMET+; reference assay) for identifying extensive and reduced metabolisers of clopidogrel. Based on genotyping, patients (N=82) with stable coronary artery disease on clopidogrel 75 mg daily were defined as extensive metabolisers (*1/*1, *1/*17, *17/*17), reduced metabolisers (*1/*2, *1/*8, *2/*2, *2/*3), or of indeterminate metaboliser status (*2/*17). Pharmacokinetic exposure to clopidogrel's active metabolite and pharmacodynamic measures with P2Y12 reaction units (PRU) (VerifyNow(r)P2Y12 assay) and VASP PRI (PRI) were also assessed. There was a 99.9% overall concordance of marker-level data between the Nanosphere Verigene and DMET+ systems in identifying the CYP2C19 variants and 100% agreement in classifying the patients as extensive (n=59) or reduced metabolisers (n=15). Extensive metabolisers had significantly higher active metabolite exposure than reduced metabolisers (LS means 12.6 ng*h/ml vs 7.7 ng*h/ml; p<0.001). Extensive metabolisers also had lower PRU (LS means 158 vs 212; p=0.003) and VASP PRI (LS means 48% vs 63%, p=0.01) compared to reduced metabolisers. Rates of high on treatment platelet reactivity were higher in reduced metabolisers compared to extensive metabolisers (VASP PRI >= 50%: 79% vs 47%; PRU >235: 33% vs 16%). The Nanosphere Verigene CBS system identified 11 CYP2C19 alleles in less than 3 hours with a high degree of accuracy when compared to a conventional method, and was further validated against pharmacokinetic and pharmacodynamic phenotypes. PMID- 24402639 TI - A novel diagnostic method targeting genomic instability in intracystic tumors of the breast. AB - BACKGROUND: Even after needle biopsy, the preoperative differential diagnoses of intracystic tumors of the breast are challenging because of their nonspecific radiological characteristics and subtle cytological and histological appearance. The aim of this study is to investigate a novel diagnostic method, targeting genomic instability (GIN) in intracystic tumors of the breast, using tumor DNA from samples obtained by fine-needle aspiration biopsy (FNAB). METHODS: Thirteen consecutive intracystic tumors of the breast, including five cancers and eight benign tumors, were studied. Three FNAB passages per tumor were used for array comparative genomic hybridization (aCGH) analysis to quantify GIN in each tumor. Tumor DNA from the main tumor, taken from formalin-fixed, paraffin-embedded (FFPE) blocks corresponding to FNAB samples, was also analyzed to compare cytogenetic profiles between these sample types. RESULTS: After three FNAB passages, an average of 7.09 MUg (0.24-25.0 MUg) of DNA was obtained. The quality of the DNA and the aCGH data was excellent, as judged by the mean derivative log ratio spread (DLRSpread) of 0.22 (0.15-0.29). The cytogenetic profiles of paired FNAB and main tumor FFPE samples were highly similar, with an average concordance rate of 97.7 % (81.2-100 %). aCGH analysis from FNAB samples showed significantly more GIN in cancers than in benign tumors, with mean frequencies of aberrant chromosomal regions of 17.5 and 0.34 %, respectively (Wilcoxon's rank sum test, P = 0.0016). CONCLUSIONS: Our novel diagnostic method, which targets GIN, can clearly distinguish cancers from benign tumors of breast intracystic lesions with minimal invasion, thereby avoiding the need for surgical excisional biopsy. PMID- 24402640 TI - Microfluidic acoustophoretic force based low-concentration oil separation and detection from the environment. AB - Detecting and quantifying extremely low concentrations of oil from the environment have broad applications in oil spill monitoring in ocean and coastal areas as well as in oil leakage monitoring on land. Currently available methods for low-concentration oil detection are bulky or costly with limited sensitivities. Thus they are difficult to be used as portable and field deployable detectors in the case of oil spills or for monitoring the long-term effects of dispersed oil on marine and coastal ecosystems. Here, we present a low concentration oil droplet trapping and detection microfluidic system based on the acoustophoresis phenomenon where oil droplets in water having a negative acoustic contrast factor move towards acoustic pressure anti-nodes. By trapping oil droplets from water samples flowing through a microfluidic channel, even very low concentrations of oil droplets can be concentrated to a detectable level for further analyses, which is a significant improvement over currently available oil detection systems. Oil droplets in water were successfully trapped and accumulated in a circular acoustophoretic trapping chamber of the microfluidic device and detected using a custom-built compact fluorescent detector based on the natural fluorescence of the trapped crude oil droplets. After the on-line detection, crude oil droplets released from the trapping chamber were successfully separated into a collection outlet by acoustophoretic force for further off-chip analyses. The developed microfluidic system provides a new way of trapping, detecting, and separating low-concentration crude oil from environmental water samples and holds promise as a low-cost field-deployable oil detector with extremely high sensitivity. The microfluidic system and operation principle are expected to be utilized in a wide range of applications where separating, concentrating, and detecting small particles having a negative acoustic contrast factor are required. PMID- 24402641 TI - Evaluation of a computer program for non-invasive determination of pulmonary shunt and ventilation-perfusion mismatch. AB - We describe a three-compartment model (shunt and two perfused compartments) to analyse the relationship between inspired oxygen (FIO2) and arterial oxygen saturation (SaO2) in terms of pulmonary shunt and ventilation-perfusion ratio (VA/Q). The program was tested using 24 exact datasets, each with six pairs of FIO2 and SaO2 data points with known VA/Q and shunt, generated by a complex calculator of gas exchange. Additional datasets were created by adding noise and rounding the exact sets, and by reducing the number of data points per dataset. The importance of the oxyhaemoglobin dissociation curve and the arterio-venous difference in oxygen content (avDO2) were also tested. Analysis using the three compartment model was more accurate than the two compartment model and less affected by data degradation. The absolute error in shunt estimation was never more than 2.2 % for the exact and rounded datasets, but the error in VA/Q estimation was -29 to 19 % of the true value (10th-90th centiles). The characteristics of the well-ventilated compartment were not determined accurately. At extremes of cardiac output, an assumed value of avDO2 resulted in significant errors. It is probably advantageous to correct for foetal haemoglobin in neonatal datasets. Analysis of FIO2 versus SaO2 datasets using a three compartment model provides accurate estimates of shunt and VA/Q when arterio venous difference in oxygen content is known. The estimates may have value as objective measures of gas exchange, and as a visual guide for oxygen therapy. PMID- 24402642 TI - Risk factors for rebleeding and prognostic factors for postoperative survival in patients with balloon-occluded retrograde transvenous obliteration of acute gastric variceal rupture. AB - PURPOSE: Balloon-occluded retrograde transvenous obliteration (B-RTO) has shown great potential in controlling acute gastric variceal hemorrhage, although rebleeding related to the procedure may occur in a small percentage of patients. The purpose of this study was to identify risk factors of perioperative rebleeding and prognostic factors of postoperative survival in B-RTO performed for acute episodes of gastric variceal hemorrhage. METHODS: We retrospectively analyzed 39 consecutive patients who underwent B-RTO for gastric variceal rupture at our hospital between June 2003 and May 2011. Uni- and multi-variate analyses were performed to assess risk factors for perioperative rebleeding and prognostic factors for postoperative survival. RESULTS: Surgical success and complete eradication of varices were achieved in 36 cases (92.3 %) and 35 cases (89.7 %), respectively. Six patients experienced rebleeding either intraoperatively (n = 3) or within 1 h after B-RTO (n = 3). Child-Pugh class C was identified as a risk factor for rebleeding on univariate (P = 0.018) and multivariate analyses (odds ratio, 6.003; P = 0.014). With a median follow-up of 23 months (range 0-106.6 months), overall survival rates at 1, 3, and 5 years were 91.7, 74.7, and 67.2 %, respectively. Multivariate analyses revealed Child-Pugh class C as a prognostic factor for survival (relative risk, 4.014; P = 0.023). CONCLUSION: Although B-RTO is generally effective in the treatment of acute gastric variceal rupture, patients classified as Child-Pugh class C have a higher risk of perioperative rebleeding and shorter survival. PMID- 24402643 TI - Mechanical thrombectomy with stent retrievers in acute ischemic stroke. AB - Mechanical thrombectomy (MTE) in patients with acute ischemic infarct caused by large-vessel occlusion is becoming used with increasing frequency in many stroke centers. With the introduction of stent retrievers, recanalization rates >80 % are reached by most operators. However, although the technical success rate of MTE has been increased, clinical results have not improved to the same degree. In this review, the indications for MTE, the technique, and the technical and clinical outcomes are discussed. Complications and predictors for good clinical outcome are described based on recent data from the literature. PMID- 24402644 TI - Evaluation of Delcath Systems' Generation 2 (GEN 2) melphalan hemofiltration system in a porcine model of percutaneous hepatic perfusion. AB - PURPOSE: A new melphalan hemoperfusion filter (GEN 2) was evaluated in a simulated-use porcine model of percutaneous hepatic perfusion (PHP). The current study evaluated melphalan filtration efficiency, the transfilter pressure gradient, and the removal of specific blood products. MATERIALS AND METHODS: A porcine PHP procedure using the GEN 2 filter was performed under Good Laboratory Practice conditions to model the 60-min clinical PHP procedure. RESULTS: The mean filter efficiency for removing melphalan in six filters was 99.0 +/- 0.4 %. The transfilter pressure gradient across the filter averaged 20.9 mmHg for the 60-min procedure. Many blood components, including albumin and platelets, decreased on average from 3.55 to 2.02 g/dL and from 342 to 177 * 10.e3/MUL, respectively, during the procedure. CONCLUSION: The increased melphalan extraction efficiency of the new filter is expected to decrease systemic melphalan exposure. In addition, the low transfilter pressure gradient resulted in low resistance to blood flow in the GEN 2 filter, and the changes to blood components are expected to be clinically manageable. PMID- 24402645 TI - Percutaneous image-guided cryoablation in inoperable extra-abdominal desmoid tumors: a study of tolerability and efficacy. AB - OBJECTIVE: To determine the tolerability, effectiveness and outcomes of percutaneous image-guided cryoablation on inoperable extra-abdominal desmoid tumors. METHODS: Between 2011 and 2012, 13 patients (mean age 39.3 years, range 15-74) with inoperable extra-abdominal desmoid tumors were consecutively treated with cryoablation (17 tumors treated in 17 procedures), including two patients with Gardner syndrome and nine recurrences after surgery. Disease-free survival (DFS) and local control based on RECIST criteria were calculated on prospective clinical and imaging follow-up until 2013. RESULTS: Cryoablation was performed under ultrasound (n = 8), computed tomography (n = 1), or combined (n = 8) guidance, and under general (n = 15) or local (n = 2) anesthesia. A major complication was observed in one session (5.8%). Mean follow-up was 11.3 months (6-27 months). Among all the patients treated, eight patients (47%) presented residual tumors on the first magnetic resonance follow-up, which were asymptomatic. The DFS rate was stable at 82.3% (95% confidence interval 0.55 0.94) at 6, 12, and 24 months. The local tumor progression rate was 0% at 6, 12, and 24 months. Two patients (12%) presented an in situ recurrence. CONCLUSIONS: Despite high rates of partial ablation, percutaneous image-guided cryoablation appears to be safe and effective for local control for patients with inoperable extra-abdominal desmoid tumors. PMID- 24402646 TI - A swan song for CCSVI. PMID- 24402647 TI - Epigallocatechin-3-gallate inhibits cell growth, induces apoptosis and causes S phase arrest in hepatocellular carcinoma by suppressing the AKT pathway. AB - Epigallocatechin-3-gallate (EGCG) has been shown to inhibit the growth and induce apoptosis of certain cancer cells. The aim of this study was to determine the role of EGCG in hepatocellular carcinoma (HCC) and the underlying mechanism(s) thereof. MTT assay was used to determine the cell growth inhibition by EGCG. Apoptosis induced by EGCG was investigated by both AO/EB staining and flow cytometry. The cell cycle distribution was analyzed by flow cytometry. The mRNA levels of the AKT pathway were analyzed by quantitative PCR. The expression of AKT and its phosphorylation at Ser473 were detected by western blotting. The IC50 of EGCG at 48 h for HepG2, SMMC7721 and SK-hep1 cells were 74.7, 59.6 and 61.3 ug/ml, respectively. Significantly higher proportion of SMMC7721 cells entered the S phase upon treatment with EGCG for 48 h compared with control cells. EGCG decreased the mRNA levels of PI3K, AKT and NF-kappaB. The protein levels of AKT decreased and its phosphorylation at Ser473 was downregulated with EGCG treatment. EGCG inhibited growth by affecting the cell cycle and induced apoptosis in different HCC cells by downregulating PI3K/AKT activity. The results suggest the potential of EGCG as an anticancer agent in the prevention or treatment of HCC. PMID- 24402648 TI - Decellularized allogeneic and xenogeneic tissue as a bioscaffold for regenerative medicine: factors that influence the host response. AB - Biologic scaffold materials composed of mammalian extracellular matrix (ECM) are prepared by decellularization of source tissues harvested from either humans (allogeneic) or a variety of other (xenogeneic) species. These matrix scaffold materials are commonly regulated and used as surgical mesh materials for applications such as ventral hernia repair, musculotendinous tissue reconstruction, dura mater replacement, reconstructive breast surgery, pelvic floor reconstruction, and the treatment of cutaneous ulcers, among others. The clinical results for these applications vary widely for reasons which include characteristics of the source tissue, methods and efficacy of tissue decellularization, and methods of processing/manufacturing. However, the primary determinant of success or failure in the clinical setting is the response of the host to these implanted biologic scaffold materials. It is logical to question why any non-self biologic material, particularly a xenogeneic material, would not elicit an early and aggressive adverse immune response. The present manuscript briefly describes the known mechanisms by which these biologic scaffold materials can facilitate a constructive remodeling response, the known causative factors of an adverse response, and provides a general discussion of the role of the macrophage in determining outcome. PMID- 24402649 TI - The role of social and intergenerational equity in making changes in human well being sustainable. AB - A sustainable world is one in which human needs are met equitably and without sacrificing the ability of future generations to meet their needs. Human well being is described by four primary elements-basic human needs, economic needs, environmental needs, and subjective well-being. These elements can interact in a myriad of ways to influence overall well-being. What makes changes in human well being sustainable for a population or a nation? Two major interactional concepts can push changes in human well-being toward a sustainable state in space and time social equity and intergenerational equity. The concept of social equity distributes well-being over space, ensuring the fair treatment of all members of society promoting spatial sustainability of a well-being decision. The concept of intergenerational equity distributes well-being through time, ensuring the well being of present and future generations of a population or nation, promoting temporal sustainability of a well-being decision. The roles of social and intergenerational equity in terms of their influence on human well-being are examined with a focus on more sustainable decision-making. PMID- 24402650 TI - Genetics of atopic dermatitis: beyond filaggrin-the role of thymic stromal lymphopoietin in disease persistence. PMID- 24402651 TI - Embracing the future and learning from the past. PMID- 24402652 TI - The essential role of the rehabilitation nurse in facilitating care transitions: a white paper by the association of rehabilitation nurses. PMID- 24402653 TI - Effects of acute psychosocial stress on neural activity to emotional and neutral faces in a face recognition memory paradigm. AB - Previous studies have shown that acute psychosocial stress impairs recognition of declarative memory and that emotional material is especially sensitive to this effect. Animal studies suggest a central role of the amygdala which modulates memory processes in hippocampus, prefrontal cortex and other brain areas. We used functional magnetic resonance imaging (fMRI) to investigate neural correlates of stress-induced modulation of emotional recognition memory in humans. Twenty-seven healthy, right-handed, non-smoker male volunteers performed an emotional face recognition task. During encoding, participants were presented with 50 fearful and 50 neutral faces. One hour later, they underwent either a stress (Trier Social Stress Test) or a control procedure outside the scanner which was followed immediately by the recognition session inside the scanner, where participants had to discriminate between 100 old and 50 new faces. Stress increased salivary cortisol, blood pressure and pulse, and decreased the mood of participants but did not impact recognition memory. BOLD data during recognition revealed a stress condition by emotion interaction in the left inferior frontal gyrus and right hippocampus which was due to a stress-induced increase of neural activity to fearful and a decrease to neutral faces. Functional connectivity analyses revealed a stress-induced increase in coupling between the right amygdala and the right fusiform gyrus, when processing fearful as compared to neutral faces. Our results provide evidence that acute psychosocial stress affects medial temporal and frontal brain areas differentially for neutral and emotional items, with a stress-induced privileged processing of emotional stimuli. PMID- 24402655 TI - [Assessment of correct positioning and complications after insertion of central venous catheters using chest radiography]. AB - The central venous catheter (CVC) is a very common procedure in the daily medical practice. In fact the CVCs are used to administer liquids and chemotherapeutics, the parenteral nutrition management, the measurement of the central venous pressure, the administration of hemodialysis. The international guidelines recommends always verifying the correct positioning of the tip of the CVC and to identify possible complications before his use. In the clinical practice the radiography of the chest represents the technique used more diffusedly for the control of the positioning and the possible precocious complications of the temporary and permanent CVCs positioned in the central veins. The integrated use of conventional radiology, above all digital of last generation, spiral computed tomography and ultrasounds allows to nearly have in every situation the answers for a correct diagnosis. The nephrologist, necessarily brought to deal with CVC, cannot refuse from a knowledge of such tools. PMID- 24402654 TI - Recent advances in clinical practice challenges and opportunities in the management of obesity. AB - Despite advances in understanding the roles of adiposity, food intake, GI and adipocyte-related hormones, inflammatory mediators, the gut-brain axis and the hypothalamic nervous system in the pathophysiology of obesity, the effects of different therapeutic interventions on those pathophysiological mechanisms are controversial. There are still no low-cost, safe, effective treatments for obesity and its complications. Currently, bariatric surgical approaches targeting the GI tract are more effective than non-surgical approaches in inducing weight reduction and resolving obesity-related comorbidities. However, current guidelines emphasise non-surgical approaches through lifestyle modification and medications to achieve slow weight loss, which is not usually sustained and may be associated with medication-related side effects. This review analyses current central, peripheral or hormonal targets to treat obesity and addresses challenges and opportunities to develop novel approaches for obesity. PMID- 24402656 TI - [The role of bioelectrical impedance in peritoneal dialysis]. AB - Dialysis must control the bodys fluid content accurately in order to maintain optimal health. Determination of body hydration and nutritional status are significant problems in dialysis patients. In practice, clinical evaluation is usually used to estimate the ultrafiltration target, since accurate knowledge of dry weight is lacking. PD over-hydration is more common than in HD. The only commonly used, practical and objective measurements we have to guide fluid removal are very inaccurate. Several methods have been proposed for non-clinical dry weight assessment; unfortunately these methods suffer from several shortcomings, such as poor specificity (natriuretic peptides), operator dependence (inferior vena cava diameter measurements) and poor correlation with extra cellular volume (continuous blood volume measurement). Recent study has validated bioimpedance (BIA) as an objective measure of fluid and nutritional status in dialysis patients. There are a number of different methods suitable for routine use available to the clinician. This review analyze the role of the different BIA techniques in peritoneal dialysis. PMID- 24402657 TI - [Nephrologist's behaviours and perceptions on sideropenic anemia's diagnosis and treatment for conservative phase nephropatic patient intolerant or not responding to oral iron therapy]. AB - INTRODUCTION. The objective of this survey was to describe the nephrologists attitude on the diagnosis and treatment of patients with non-dialysis Chronic Kidney Disease (CKD stages 3, 4 and 5), with iron deficiency anemia and no response/intolerance to oral iron therapy. Furthermore, this survey describes the nephrologists view about the impact of lack of anemia correction on patient health, as well as the influence of organization and management of nephrological centers on IV iron management. MATERIALS AND METHODS. 60 nephrologists were interviewed via web by using an interactive simulation that investigates nephrologists clinical and therapeutic approach on 3 different types of patients; subsequently, a questionnaire was administered with in-deeper questions. RESULTS. Regarding the first virtual patient, 64% of nephrologists still choose oral iron, while IV iron was chosen by 16% of them. 36% opted for ESA. For the other two virtual patients the most selected treatments were combinations of oral iron + ESA (42% and 36%) or IV iron + ESA (21% and 38%), respectively. According to what was perceived by nephrologists, issues related to IV iron are: patient discomfort due to frequent hospital transfers for IV administration (50%), inadequate center organization (48%), fear of damaging the venous tree (40%). CONCLUSIONS. Half of the nephrologists stated they are unsatisfied with available iron therapies. Difficult therapy management and restrictions of health structure were identified as barriers to the prescription of IV iron therapy. A smaller number of administrations and less free-iron toxicity are expected from nephrologists from the new iron preparations for the management of iron deficiency in patients not responding/intolerant to oral iron therapy. PMID- 24402658 TI - [Transplant cross-over, an attractive option]. AB - Kidney transplant from living donors is an excellent option for patients with end stage renal disease: around the world approximately 10-20% of patients on waiting lists have intended living donors incompatible by blood type or for the presence of donor-specific antibodies. Current strategies to overcome these barriers are desensitization protocols and the recent option of the kidney exchange programs. In this work we describe the types of donor exchange programs, from the two-way Kidney Paired Donation, where two incompatible donor-recipient couples exchange donors, to complex chains of transplants where the altruistic donation of a kidney (Living Non-direct Donor, or non-specific donation) is associated to a Kidney Paired Exchange Program (Domino Kidney Paired Donation, NEAD chains). The thesis also discusses some related ethical topics that have become international matters of debate, as well as some important cultural and social arguments for and against the application of kidney exchanges in Italy. PMID- 24402659 TI - [What future for today young nephrologists?]. AB - In this article, the Italian Society of Nephrology discusses the risks for the Medical Specialty in Nephrology and the possible lack of job opportunities by young nephrologists, that arises from the actions taken in the last years by National and Regional Italian Governments. The article reports the main legislative rules required to access the work system both in public and private hospital. Finally, we examined the different criteria and the standards requested for Regional Accreditation by Italian National Health System, and to obtain reimbursement by private and public providers. These requirements might be useful to guarantee both the specificity of nephrology specialty in the assistance to patients affected by kidney diseases, and a stable and qualified job for young nephrologists. PMID- 24402660 TI - [Clinical and histological findings in Fabry nephropathy]. AB - Fabry disease is a complex pathology, requiring a multidisciplinar approach both in the diagnostic workout and in the management of therapy. Clinical criteria able to predict its morbidity have not yet been found. The wide variability of clinical signs and symptoms requires an individual approach based on the single patient, in order to achieve an optimal management. Enzyme replacement therapy (ERT) has been introduced in the clinical setting for over ten years, but its ability to change the course of the disease has not yet been clearly proved. Recently the hypothesis that ERT may be ineffective in patients with severe organ involvement has emerged. The clinical course of Fabry disease is usually slower in eterozygous women than emizygous men, but can be frequently associated to severe organ failure and premature death in both cases. In this review we discuss the histological aspects of Fabry nephropathy in relation to diagnosis, prognosis, therapy and its effectiveness. PMID- 24402661 TI - [Biological and bio-similar pharmaceuticals: understanding the problem]. AB - The patent expiration of many biotechnology drugs has effectively opened to the pharmaceutical industry the possibility of producing biosimilar, allowing an expansion of the market and a reduction in costs and, therefore, allowing to extend the therapeutic benefits of biotechnological medicines to more patients. This is a new complex theme and many are the discussions promoted in the recent past years around this topic (what type of erythropoietin prescribe and when). The need to understand the argument emerges from the ongoing debate among doctors, researchers, regulators and manufacturers about the relationship between biotechnology patent medicines and Biosimilar. In this field is also necessary understand the provisions of the various Italian regions. In this article I have tried to avoid any statement which could be biased and I only reported data from official documents (AIFA, EMA,C.C. etc.), trying to "understand" the problem and trying to motivate the choice of nephrologist; at the end, the prescription is anyway under the responsibility of the nephrologist. PMID- 24402662 TI - [The use of tolvaptan in a case of severe hyponatriemia in SIADH during meningitis]. AB - Vaptans, vasopressin V2 receptor antagonists, are new drugs indicated in the treatment of Inappropriate ADH Secretion Syndrome (SIADH). We report a case of SIADH in a patient affected by AIDS. During a hospitalization for an ongoing CMV meningitis she developed a severe hyponatremia (114 mEq/L), which was initially treated with restriction of free water. When the diagnosis of SIADH was done (plasma Osmolarity 240 mOsm/kg, urinary sodium >30 mEq/24 h, normal volemia, lack of hypocorticosurrenalism and hypothyroidism), tolvaptan was given at the dose of 15 mg/day. Important fluctuations of plasma Na were observed thereafter (119-143 mEq/L). The progressive reduction of the drug (to 2 mg/die) allowed a stable correction of natremia. Unconsciousness determined the impossibility of the patient to freely access to water, thus explaining the fluctuations of natremia and the difficult management of the drug. Only a posology reduction to doses lower than those available for sale allowed a stable correction of natremia. PMID- 24402663 TI - [A case of encapsulating peritoneal sclerosis after fifteen years of peritoneal dialysis with a favorable outcome]. AB - Encapsulating peritoneal sclerosis (EPS) represents a critical complication of peritoneal dialysis (PD). EPS is characterized by abdominal discomfort, often leading to fatal outcomes with limited pharmaceutical and surgical options. Herein is described a case of EPS with a favorable outcome in an African male treated with PD for 15 years. Repeated courses of prednisone and tamoxifen significantly attenuated the abdominal symptoms and the peritoneal membrane thickening. This case suggests a time dependent effect of medical treatment encouraging clinical efforts to maintain a mild immunosuppressant regimen and tamoxifen in the presence of EPS also on the long run. Future and ad hoc studies should test this hypothesis. PMID- 24402664 TI - [Renal involvement in Erdheim-Chester disease]. AB - The Erdheim-Chester disease is a rare form of Langherans cells. Since 1987 it is distinguished from other istiocytosis previously identified. The diagnosis of the disease relies on defined radiological (bone imaging) and pathological (histiocytic infiltration) criteria. Bone disease is crucial but systemic manifestations are reported more frequently at onset. Renal involvement is always asymptomatic at onset of disease or in the follow-up. In this review we analyze the reports of the literature; we highlight 3 pathological mechanisms of renal involvement: renal and retroperitoneal infiltration, urinary tract obstruction, renal arteries stenosis. No treatment to date has demonstrated an improvement in survival of patients with EC. Renal involvement is therefore symptomatic (ureteral stenting, percutaneous nephrostomy) or is adopted a wait-and-see attitude. PMID- 24402665 TI - [Hemodialysis improves the subendocardial viability ratio]. AB - The subendocardial viability ratio (SEVR), a parameter introduced by Buckberg, represents a non-invasive measure of myocardial perfusion related to left ventricular work. AIM. The aim of this study was to verify if dialysis may determine modifications of SEVR and how these modifications are modulated in the 2-day interdialytic period. METHODS.We studied 54 subjects of mean age 6314 years and receiving dialysis for 3215 months. Exclusion criteria were diabetes, resistant hypertension and peripheral vascular diseases and intradialytic hypotension evidenced during the study dialysis session. Pulse wave velocity and SEVR assessments were performed during the third dialysis session of the week, before (pre-HD) and after (post-HD) dialysis, in 2-day interdialytic period after and at the beginning of the following dialysis session. RESULTS.Dialysis reduces PWV, in particular the tertile with the lowest PWV presents the highest percentage reduction (-26%) compared with the second and the third tertiles. In the same way, dialysis leads to an increase of SEVR and patients in the tertile with the highest SEVR values maintain high SEVR values during dialysis and in the interdialytic period. Patients with severe vascular calcifications present higher PWV value and lower SEVR value. CONCLUSIONS.The results of present study demonstrate that ultrafiltration improves PWV (with a mean reduction of 16%) and SEVR (increase of 13%) and that the severity of vascular calcifications influences the effect of ultrafiltration on these two parameters. More studies are certainly necessary to verify our findings. Considered the higher mortality of patients with higher SEVR, it would be important to understand if new dialytic strategies are needed in patients with higher PVW and lower SEVR values. PMID- 24402667 TI - [Phosphate control in end stage renal disease: barriers and opportunities. Malnutrition: yes or not?]. AB - The fear of malnutrition, caused by the low-protein diet, conditions in an inappropriate use of a useful nutrition therapy in Chronic Kidney Disease. Often malnutrition is due to reduced intake of energy, because a low (or very low) protein proper diet with adequate amount of calories (30-35 cal/kg bw/day). We analyze the positive aspects of the low-protein diet for optimal control of hypertension, hyperphosphatemia, anemia, and proteinuria that is the goal of pharmacological management Chronic Kidney Disease patients. PMID- 24402666 TI - [Role of inflammation on renal anaemia]. AB - It is well-known the central role of inflammation in the inhibition of erythropoiesis and iron availability in chronic kidney disease (CKD) patients with erythropoietin (EPO)-resistant anaemia. This inflammatory action is mediated by suppressive cytokines (i.e. IL-6, TNF-, INF-) inhibiting differentiation and proliferation activities of erythroid cells in the EPO-indipendent phase of erythropoiesis and stimulating hepcidin production for iron retention in reticulo endothelial system and enterocytes. EPO resistance is associated with adverse outcomes, such as cardiovascular disease, faster progression to end stage renal disease and mortality. Treatment of the causes of EPO hyporesponsiveness including chronic inflammation results in an improvement of anaemia and a reduction in EPO requirements. PMID- 24402668 TI - [The Italian Registry of Vascular Access]. AB - The Vascular Access Study Group of Italian Society of Nephrology has designed a National Register in order to create an archive that collects the data on vascular accesses more detailed than the mere indication of arteriovenous fistula with native vessels, prosthetic fistula and central venous catheter. The obstacles to such a project are represented by the absence of "uniformity" in the name of the arterovenous fistula, the difficulty in increasing the daily work of dialysis centers with another registry and finally by privacy concerns. In order to standardize the vascular accesses name the Study Group proposal is to eliminate any denomination and adopt a code-descriptive system, indicating the seat of the anastomosis (1/3 distal, middle and proximal forearm, arm or lower limb), the limb (if dominant or non-dominant), the vessels involved, the type of anastomosis and the number of interventions that the pt has undergone including the last one. In this way, uniformity and universality are guaranteed. Every aspect scribed will be a cell of a data base and can used to statistical analysis. The study group has set up a software (Gev@) in order to facilitate data storage. The software is based on a form compiled at the end of each surgical procedure. The form will then be archived in digital format thereby generating automatically the data base. The advantage of this system, is represented by the possibility of turning a routine medical procedure, namely the recording of a surgical procedure, in a data base exportable for the creation of the register. As regards the issue of privacy will be obtained the patient's consent to the processing of data and the register will be stored and managed according to the regulations in terms of privacy. In the coming months, after a time of testing, the software will be available to each italian dialisys center. PMID- 24402669 TI - Proteomics of larval hemolymph in Bombyx mori reveals various nutrient-storage and immunity-related proteins. AB - The silkworm, Bombyx mori, is an important economic insect for its production of silk. The larvae of many lepidopteran insects are major agricultural pests and often silkworm is explored as a model organism for other lepidopteran pest species. The hemolymph of caterpillars contains a lot of nutrient and immune components. In this study, we applied liquid chromatography-tandem mass spectrometry to gain a better understanding of the larval hemolymph proteomics in B. mori. We identified 752 proteins in hemolymph collected from day-4 fourth instar and day-7 fifth instar. Nearly half the identified proteins (49%) were predicted to function as binding proteins and 46% were predicted to have catalytic activities. Apolipophorins, storage proteins, and 30K proteins constituted the most abundant groups of nutrient-storage proteins. Of them, 30K proteins showed large differences between fourth instar larvae and fifth instar larvae. Besides nutrient-storage proteins, protease inhibitors are also expressed very highly in hemolymph. The analysis also revealed lots of immunity-related proteins, including recognition, signaling, effectors and other proteins, comprising multiple immunity pathways in hemolymph. Our data provide an exhaustive research of nutrient-storage proteins and immunity-related proteins in larval hemolymph, and will pave the way for future physiological and pathological studies of caterpillars. PMID- 24402670 TI - [Intramedullary nailing vs. locking plate osteosynthesis in proximal humeral fractures: Long-term outcome]. AB - BACKGROUND: For the treatment of proximal humeral fractures two major therapeutic principles can be employed: intramedullary nailing (PHN) or locking plate osteosynthesis. The aim of this study was to evaluate and compare clinical and radiological long-term outcome of proximal humeral fracture stabilization using PHN or angular stable plating. MATERIALS AND METHODS: In a retrospective study between March 2009 and March 2010, we analyzed 72 out of 118 patients with unified proximal humeral fracture who had been treated at least 3 years previously using PHN (44 patients) or angular stable plating (28 patients) in a level 1 trauma center. Functional and radiological outcomes were assessed at least 3 years after trauma using the Constant and Murley score and SF-36 score. RESULTS: According to the Neer classification, there were 31 3-part fractures (PHN: 23; plate: 8) and 41 4-part fractures (PHN: 21; plate: 20), respectively. No clinical symptoms after 3 years were observed in 42 patients, whereas in 30 patients clinical symptoms were evaluated related to pain and/or loss of function. Functional outcome using the Constant and Murley score demonstrated a total score of 73 points (ipsilateral side) vs. 88 points (contralateral side) in all evaluated patients, on average. CONCLUSION: Both PHN and angular stable plating are adequate treatment options for proximal humeral fractures. Both systems require precise preoperative planning and advanced surgical experience. No significant differences in long-term clinical and radiological outcome between implants regarding fracture classification, age of patient, and choice of implant were found. PMID- 24402671 TI - Novel catalyst system for hydrostannation of alkynes. AB - A catalyst system was developed for the highly regio- and stereoselective hydrostannation of a range of alkynes with tributylstannane under mild conditions. The active catalytic species was generated from a stable diruthenium complex by illuminating household fluorescent light (30 W) at room temperature. PMID- 24402672 TI - Flat-topped and condylomatous papules in a lung transplant patient. PMID- 24402673 TI - Differential ion mobility separations in up to 100% helium using microchips. AB - The performance of differential IMS (FAIMS) analyzers is much enhanced by gases comprising He, especially He/N2 mixtures. However, electrical breakdown has limited the He fraction to ~50%-75%, depending on the field strength. By the Paschen law, the threshold field for breakdown increases at shorter distances. This allows FAIMS using chips with microscopic channels to utilize much stronger field intensities (E) than "full-size" analyzers with wider gaps. Here we show that those chips can employ higher He fractions up to 100%. Use of He-rich gases improves the resolution and resolution/sensitivity balance substantially, although less than for full-size analyzers. The optimum He fraction is ~80%, in line with first-principles theory. Hence, one can now measure the dependences of ion mobility on E in pure He, where ion-molecule cross section calculations are much more tractable than in other gases that form deeper and more complex interaction potentials. This capability may facilitate quantitative modeling of high-field ion mobility behavior and, thus, FAIMS separation properties, which would enable a priori extraction of structural information about the ions. PMID- 24402674 TI - Mechanical loading by fluid shear stress of myotube glycocalyx stimulates growth factor expression and nitric oxide production. AB - Skeletal muscle fibers have the ability to increase their size in response to a mechanical overload. Finite element modeling data suggest that mechanically loaded muscles in vivo may experience not only tensile strain but also shear stress. However, whether shear stress affects biological pathways involved in muscle fiber size adaptation in response to mechanical loading is unknown. Therefore, our aim was twofold: (1) to determine whether shear stress affects growth factor expression and nitric oxide (NO) production by myotubes, and (2) to explore the mechanism by which shear stress may affect myotubes in vitro. C2C12 myotubes were subjected to a laminar pulsating fluid flow (PFF; mean shear stress 0.4, 0.7 or 1.4 Pa, 1 Hz) or subjected to uni-axial cyclic strain (CS; 15 % strain, 1 Hz) for 1 h. NO production during 1-h PFF or CS treatment was quantified using Griess reagent. The glycocalyx was degraded using hyaluronidase, and stretch-activated ion channels (SACs) were blocked using GdCl3. Gene expression was analyzed immediately after 1-h PFF (1.4 Pa, 1 Hz) and at 6 h post PFF treatment. PFF increased IGF-I Ea, MGF, VEGF, IL-6, and COX-2 mRNA, but decreased myostatin mRNA expression. Shear stress enhanced NO production in a dose-dependent manner, while CS induced no quantifiable increase in NO production. Glycocalyx degradation and blocking of SACs ablated the shear stress stimulated NO production. In conclusion, shear stress activates signaling pathways involved in muscle fiber size adaptation in myotubes, likely via membrane-bound mechanoreceptors. These results suggest that shear stress exerted on myofiber extracellular matrix plays an important role in mechanotransduction in muscle. PMID- 24402675 TI - The neurobiology of speech perception decline in aging. AB - Speech perception difficulties are common among elderlies; yet the underlying neural mechanisms are still poorly understood. New empirical evidence suggesting that brain senescence may be an important contributor to these difficulties has challenged the traditional view that peripheral hearing loss was the main factor in the etiology of these difficulties. Here, we investigated the relationship between structural and functional brain senescence and speech perception skills in aging. Following audiometric evaluations, participants underwent MRI while performing a speech perception task at different intelligibility levels. As expected, with age speech perception declined, even after controlling for hearing sensitivity using an audiological measure (pure tone averages), and a bioacoustical measure (DPOAEs recordings). Our results reveal that the core speech network, centered on the supratemporal cortex and ventral motor areas bilaterally, decreased in spatial extent in older adults. Importantly, our results also show that speech skills in aging are affected by changes in cortical thickness and in brain functioning. Age-independent intelligibility effects were found in several motor and premotor areas, including the left ventral premotor cortex and the right supplementary motor area (SMA). Age-dependent intelligibility effects were also found, mainly in sensorimotor cortical areas, and in the left dorsal anterior insula. In this region, changes in BOLD signal modulated the relationship between age and speech perception skills suggesting a role for this region in maintaining speech perception in older ages. These results provide important new insights into the neurobiology of speech perception in aging. PMID- 24402676 TI - Effects of congruent and incongruent visual cues on speech perception and brain activity in cochlear implant users. AB - While deafness-induced plasticity has been investigated in the visual and auditory domains, not much is known about language processing in audiovisual multimodal environments for patients with restored hearing via cochlear implant (CI) devices. Here, we examined the effect of agreeing or conflicting visual inputs on auditory processing in deaf patients equipped with degraded artificial hearing. Ten post-lingually deafened CI users with good performance, along with matched control subjects, underwent H 2 (15) O-positron emission tomography scans while carrying out a behavioral task requiring the extraction of speech information from unimodal auditory stimuli, bimodal audiovisual congruent stimuli, and incongruent stimuli. Regardless of congruency, the control subjects demonstrated activation of the auditory and visual sensory cortices, as well as the superior temporal sulcus, the classical multisensory integration area, indicating a bottom-up multisensory processing strategy. Compared to CI users, the control subjects exhibited activation of the right ventral premotor supramarginal pathway. In contrast, CI users activated primarily the visual cortices more in the congruent audiovisual condition than in the null condition. In addition, compared to controls, CI users displayed an activation focus in the right amygdala for congruent audiovisual stimuli. The most notable difference between the two groups was an activation focus in the left inferior frontal gyrus in CI users confronted with incongruent audiovisual stimuli, suggesting top-down cognitive modulation for audiovisual conflict. Correlation analysis revealed that good speech performance was positively correlated with right amygdala activity for the congruent condition, but negatively correlated with bilateral visual cortices regardless of congruency. Taken together these results suggest that for multimodal inputs, cochlear implant users are more vision-reliant when processing congruent stimuli and are disturbed more by visual distractors when confronted with incongruent audiovisual stimuli. To cope with this multimodal conflict, CI users activate the left inferior frontal gyrus to adopt a top-down cognitive modulation pathway, whereas normal hearing individuals primarily adopt a bottom up strategy. PMID- 24402677 TI - Highly sensitive hydrazine chemical sensor based on ZnO nanorods field-effect transistor. AB - A highly sensitive hydrazine chemical sensor has been fabricated based on a field effect transistor (FET) by growing vertically-aligned ZnO nanorods directly on silver electrodes. The FET sensor showed a high sensitivity and a low limit of detection (LOD) of 59.175 MUA cm(-2)MUM(-1) and ~3.86 nM, respectively. This demonstrates a cost effective and low power consuming FET strategy for the detection of hydrazine. PMID- 24402678 TI - A 5-day: the favourable way? PMID- 24402679 TI - Estimation of Excited State Dipolemoments from Solvatochromic Shifts-Effect of pH. AB - Multicomponent, highly efficient, catalytic synthesis of some polysubstituted imidazole under solvent-free condition is reported. Characterization of polysubstituted imidazole have been carried out by X-ray diffraction (XRD) and spectral techniques. Electronic spectral studies reveal that their solvatochromic behavior depends not only on the polarity of the medium but also on the hydrogen bonding properties of the solvents. Specific hydrogen bonding interaction in polar solvents modulated the order of the two close lying lowest singlet states. The solvent effect on both the absorption and emission spectral results have been analyzed by multiple parametric regression analysis. Solvatochromic effects on the emission spectral position indicate the charge transfer (CT) character of the emitting singlet states both in a polar and a non polar environment. The fluorescence decays for the imidazole fit satisfactorily to a single exponential kinetics. The prototropic studies of N,N-dimethyl-4-(1,4,5-triphenyl-1H-imidazol 2-yl)naphthalen-1-amine (DTINA) reveal that two monocations [imidazole nitrogen protanated (MC1) and dimethylamino nitrogen protanated (MC2)] and a dication [both imidazole nitrogen and dimethylamino nitrogen protanated (DC)] are formed by protonation in both ground and excited states. These observations are in consistent with quantum chemical calculations. PMID- 24402680 TI - Adult proximal humerus locking plate for fixation of paediatric subtrochanteric fractures. AB - PURPOSE: The current study was done to evaluate the outcome of paediatric subtrochanteric fractures managed by adult proximal humerus locking plate (PHLP). METHODS: This prospective study included eight children (three females and five males) with femoral subtrochanteric fractures who met the inclusion criteria and underwent open reduction and internal fixation of the fracture with ipsilateral long adult PHLP. The mean age of the patients at the time of surgery was 13 years (range 10-16 years), and the mean follow-up was 32 months (range 18-48 months). Outcome at final follow-up was assessed using the Harris hip score. RESULTS: At the time of final follow-up, all fractures united at an average of 8.75 weeks (range 6-14 weeks). The average final Harris hip score was 80.25 (range 67-90). The only complain was prominent hardware in the proximal thigh, near the trochanteric ridge, which was present in two of our patients, and one of them opted for implant removal at 10 months. CONCLUSION: Internal fixation of paediatric subtrochanteric fractures using the proximal humeral locking plate of the ipsilateral side appears to be a good treatment option for the age group of 10-16 years, though comparative studies with a larger sample size are required to further support this observation. PMID- 24402681 TI - Mania and depression in the perinatal period among women with a history of major depressive disorders. AB - Women with a history of major depressive disorder (MDD) have increased risks for postpartum depression, but less is known about postpartum mania in this population. The objectives of this study were to prospectively determine the frequency with which mania occurs in the postpartum among women who have a history of MDD and to explore temporal relationships between onset of mania/hypomania and depression. We administered the Structured Clinical Interview for DSM IV disorders (SCID) to pregnant women with a self-reported history of MDD to confirm diagnosis and exclude women with any history of mania/hypomania. Participants completed the Edinburgh Postnatal Depression Scale and Altman Self Rating Mania Scale (ASRM) once during the pregnancy (~26 weeks) and 1 week, 1 month, and 3 months postpartum. Among women (n = 107) with a SCID-confirmed diagnosis of MDD, 34.6 % (n = 37) experienced mania/hypomania (defined by an ASRM score of >=6) at >=1 time point during the postpartum, and for just over half (20/37, 54 %), onset was during the postpartum. The highest frequency of mania/hypomania (26.4 %, n = 26) was at 1 week postpartum. Women who experienced mania/hypomania at 1 week postpartum had significantly more symptoms of mania/hypomania later in the postpartum. A substantive proportion of women with a history of MDD may experience first onset of mania/hypomania symptoms in the early postpartum, others may experience first onset during pregnancy. Taken with other recent data, these findings suggest a possible rationale for screening women with a history of MDD for mania/hypomania during the early postpartum period, but issues with screening instruments are discussed. PMID- 24402682 TI - ROS-mediated JNK/p38-MAPK activation regulates Bax translocation in Sorafenib induced apoptosis of EBV-transformed B cells. AB - Sorafenib (SRF) is a multi-kinase inhibitor that has been shown to have antitumor activity against several types of cancers, but the effect of SRF on EBV transformed B cells is unknown. We report that SRF can induce the apoptosis of EBV-transformed B cells through JNK/p38-MAPK activation. SRF triggered the generation of reactive oxygen species (ROS), translocation of Bax into the mitochondria, disruption of mitochondrial membrane potential, activation of caspase-9, caspase-3 and PARP, and subsequent apoptosis. Moreover, we found that SRF exposure activated the phosphorylation of JNK and p38-MAPK and suppressed the phosphorylation of PI3K-p85 and Akt. N-acetyl-l-cysteine (NAC) inhibited the activation of JNK and p38-MAPK. SP600125 and SB203580 blocked apoptosis and mitochondrial membrane disruption but did not affect ROS production after SRF treatment. These findings provide novel insights into the molecular mechanisms driving SRF-mediated cell death and suggest that SRF could be a potential therapeutic drug for the treatment of EBV-related malignant diseases. PMID- 24402683 TI - Unraveling the crystal structure of lanthanide-murexide complexes: use of an ancient complexometry indicator as a near-infrared-emitting single-ion magnet. AB - Herein, we provide some structural evidence of the complexation color-change of murexide solutions in presence of lanthanide, which has been used for decades in complexometric studies. For Ln = Sm to Lu and Y, the compounds crystallize as monomeric [Ln(Murex)3]?11 H2O with an N3O6 tricapped square-antiprism environment, which are stable up to 250 degrees C. Single-ion magnet (SIM) behavior is then observed on the Yb(III) derivative in an original nine coordinated environment. In-field slow relaxation (Delta = (15.6+/-1) K; tau0 = 2.73*10(-6) s) is observed with a very narrow distribution of the relaxation time (alphamax = 0.09). Magnetic and photophysical properties can be correlated. On one hand the analysis of NIR emission spectrum permits to have access to crystal field parameters and to compare them with those extracted from dc measurements. On the other hand, magnetic measurements permit to identify the nature of the MJ states involved in the (2)F5/2 -> (2)F7/2 luminescence spectrum. The gap between the low-lying states is in agreement with the energy barrier obtained from magnetic slow-relaxation measurement. PMID- 24402685 TI - Empirical corroboration of an earlier theoretical resolution to the UV paradox of insect polarized skylight orientation. AB - It is surprising that many insect species use only the ultraviolet (UV) component of the polarized skylight for orientation and navigation purposes, while both the intensity and the degree of polarization of light from the clear sky are lower in the UV than at longer (blue, green, red) wavelengths. Why have these insects chosen the UV part of the polarized skylight? This strange phenomenon is called the "UV-sky-pol paradox". Although earlier several speculations tried to resolve this paradox, they did this without any quantitative data. A theoretical and computational model has convincingly explained why it is advantageous for certain animals to detect celestial polarization in the UV. We performed a sky polarimetric approach and built a polarized skylight sensor that models the processing of polarization signals by insect photoreceptors. Using this model sensor, we carried out measurements under clear and cloudy sky conditions. Our results showed that light from the cloudy sky has maximal degree of polarization in the UV. Furthermore, under both clear and cloudy skies the angle of polarization of skylight can be detected with a higher accuracy. By this, we corroborated empirically the soundness of the earlier computational resolution of the UV-sky-pol paradox. PMID- 24402684 TI - Characterization of a standardized glucagon challenge test as a pharmacodynamic tool in pharmacological research. AB - The aim of this study was to characterize a glucagon challenge test as a tool in diabetes research by assessing the inter- and intra-individual variability, and investigating the activity of the autonomic nervous system (ANS) during the challenge, as this might have an indirect impact on glucose homeostasis. The study was performed in 24 healthy volunteers separated in 2 groups. The first group of 12 volunteers underwent a 5-h glucagon challenge during a pancreatic clamp procedure with infusion of [6,6-2H2]-glucose infusion in combination with heart rate variability measurements. In the second group, 12 other healthy volunteers underwent two 6-h glucagon challenges separated by 6 weeks, and fat biopsies were taken for analysis of glucagon receptor expression. Serum glucose rose rapidly after glucagon infusion, and reached a plateau at 90 min. The time profiles suggested rapid development of tolerance for glucagon-induced hyperglycemia. During the glucagon challenge intra- and inter-individual variabilities for hepatic glucose production, the rate of disappearance of glucose, and plasma glucose were approximately 10-15% for all variables. Hyperglucagonemia did not affect heart rate variability. Human adipose tissue had a low, but variable, expression of glucagon receptor mRNA. This standardized glucagon challenge test has a good reproducibility with only limited variability over 6 weeks. It is a robust tool to explore in detail the contribution of glucagon in normal and altered glucose homeostasis and can also be used to evaluate the effects of drugs antagonizing glucagon action in humans without confounding changes in ANS tone. PMID- 24402686 TI - Sensing the intruder: a quantitative threshold for recognition cues perception in honeybees. AB - The ability to discriminate among nestmates and non-nestmate is essential to defend social insect colonies from intruders. Over the years, nestmate recognition has been extensively studied in the honeybee Apis mellifera; nevertheless, the quantitative perceptual aspects at the basis of the recognition system represent an unexplored subject in this species. To test the existence of a cuticular hydrocarbons' quantitative perception threshold for nestmate recognition cues, we conducted behavioural assays by presenting different amounts of a foreign forager's chemical profile to honeybees at the entrance of their colonies. We found an increase in the explorative and aggressive responses as the amount of cues increased based on a threshold mechanism, highlighting the importance of the quantitative perceptual features for the recognition processes in A. mellifera. PMID- 24402687 TI - Djungarian hamsters (Phodopus sungorus) are not susceptible to stimulating effects of 6-methoxy-2-benzoxazolinone on reproductive organs. AB - The secondary plant metabolite 6-methoxy-2-benzoxazolinone (6-MBOA) is abundant in vegetative parts of monocotyledons emerging in spring. This grazing protective has been shown to promote gonadal growth and, thus enable precise alignment of reproductive activity with favorable environmental conditions in a variety of seasonally breeding rodent species. Feeding and breeding ecology make the Djungarian hamster (Phodopus sungorus) a potential candidate using 6-MBOA as an acute environmental cue to optimize reproductive timing when photorefractoriness induces reproductive recrudescence. Therefore, four different experiments were designed to examine whether the hamsters' reproductive organs are responsive to oral 6-MBOA administration under different photoperiodic conditions. Only under a long photoperiod, we found a slight increase in uterine weights. In a short photoperiod, 6-MBOA-treated hamsters showed a slight body weight gain without a change in uterine weights. However, these marginal effects are likely not to be of ecophysiological significance for reproductive timing. The results are in agreement with the common view that the annual changes in photoperiod length are not only the predominant environmental cue for Djungarian hamsters, but are also sufficient to synchronize reproductive efforts with favorable breeding conditions in highly predictable climates like the continental Asian steppes. PMID- 24402688 TI - Platelet NOX, a novel target for anti-thrombotic treatment. AB - There is a growing body of evidence to suggest that reactive oxidant species (ROS) including O2-, OH- or H2O2 act as second messengers to activate platelets via 1) calcium mobilisation, 2) nitric oxide (NO) inactivation, and 3) interaction with arachidonic to give formation of isoprostanes. Among the enzymes generating ROS formation NOX2, the catalytic core of NADPH oxidase (NOX), plays a prominent role as shown by the almost absent ROS production by platelets taken from patients with hereditary deficiency of NOX2. Experimental and clinical studies provided evidence that NOX2 is implicated in platelet activation. Thus, impaired platelet activation has been detected in patients with NOX2 hereditary deficiency. Similarly, normal platelets added with NOX2 specific inhibitors disclosed impaired platelet activation along with ROS down-regulation. Accordingly, animals prone to atherosclerosis treated with apocynin, a NOX inhibitor, showed reduced platelet adhesion and atherosclerotic plaque. Furthermore, a significant association between NOX2 up-regulation and platelet activation has been detected in patients at athero-thrombotic risk, but a cause effect relationship needs to be established. These findings may represent a rationale to plan interventional trials with NOX inhibitors to establish if blocking NOX2 or other NOX isoforms may represent a novel anti-platelet approach. PMID- 24402690 TI - HIV-related stigma among African-American youth in the Northeast and Southeast US. AB - HIV-related stigma inhibits optimal HIV prevention and treatment among African Americans. Regional differences in HIV/AIDS prevalence may be related to stigma among young African-Americans. Baseline data (N = 1,606) from an HIV prevention intervention were used to investigate regional differences in HIV-related stigma and knowledge among African-American adolescents in four midsized cities in the Northeastern and Southeastern US. Analyses indicated greater HIV-related stigma among adolescents from the Southeast relative to adolescents from the Northeast (F = 22.23; p < 0.0001). Linear regression indicated a negative relationship between HIV stigma and HIV knowledge (b = -0.65; p < 0.0001). Addressing HIV/AIDS in high prevalence locales should include efforts to reduce HIV-related stigma. PMID- 24402689 TI - Do HIV-positive women receive depression treatment that meets best practice guidelines? AB - This study addressed whether psychopharmacologic and psychotherapeutic treatment of depressed HIV+ women met standards defined in the best practice literature, and tested hypothesized predictors of standard-concordant care. 1,352 HIV positive women in the multi-center Women's Interagency HIV Study were queried about depressive symptoms and mental health service utilization using standards published by the American Psychiatric Association and the Agency for Healthcare Research and Quality to define adequate depression treatment. We identified those who: (1) reported clinically significant depressive symptoms (CSDS) using Centers for Epidemiological Studies-Depression Scale scores of >=16; or (2) had lifetime diagnoses of major depressive disorder (MDD) assessed by World Mental Health Composite International Diagnostic Interviews plus concurrent elevated depressive symptoms in the past 12 months. Adequate treatment prevalence was 46.2 % (n = 84) for MDD and 37.9 % (n = 211) for CSDS. Multivariable logistic regression analysis found that adequate treatment was more likely among women who saw the same primary care provider consistently, who had poorer self-rated role functioning, who paid out-of-pocket for healthcare, and who were not African American or Hispanic/Latina. This suggests that adequate depression treatment may be increased by promoting healthcare provider continuity, outreaching individuals with lower levels of reported role impairment, and addressing the specific needs and concerns of African American and Hispanic/Latina women. PMID- 24402691 TI - Sexual risk behaviors among adolescents in Port-au-Prince, Haiti. AB - Engagement in sexual activity among Haitian youth is increasing. The present cross-sectional study examined the independent correlates of sexual risk behaviors among 200 (108 male/92 female) 13-18 year-old adolescents in Port-au Prince, Haiti using face-to-face interviews. The majority (60.0 %) had engaged in sexual intercourse. Multivariate modeling found males to be 3.52 times more likely to have had sex, 5.42 times more likely to report sexual debut before age 14, 9.75 times more likely to have >1 sexual partner, and 3.33 times more likely to not have used a condom during last sex. Adolescents living with parents, grandparents, aunts or uncles were less likely to report having unprotected sex compared with those without adult family members in the home (AOR range 0.26 0.51). The high prevalence of risky sex among males and the protective influence of stable family cohesiveness have important implications for HIV prevention efforts. PMID- 24402692 TI - Correlation of Twist upregulation and senescence bypass during the progression and metastasis of cervical cancer. AB - Cervical carcinoma is associated with high propensity for local invasion and lymph node metastasis. However, the molecular alterations that drive progression and metastasis of cervical cancer remain unclear. Cellular senescence has been proposed as the mechanism that protects an organism against cancer progression and metastasis. In addition, Twist, a basic helix-loop-helix transcription factor, has been suggested as an oncogene because it is overexpressed in many types of human cancer. This gene also exhibits a positive function in regulating invasion and metastasis. In this study, Twist was strongly and positively expressed in normal tissue, squamous cell carcinoma (SCC) IA-IIA, and SCC IIB IIIB (4.3%, 44%, and 88.9%, respectively). The strong positive expressions of the senescence marker CBX3 were 39.1%, 32%, and 15.6%, respectively. The strong positive expressions of Twist in the SCC groups with or without lymph node metastasis were 80.8% and 50%. For CBX3, such expressions were 7.7% and 29.5%, respectively. Results also showed that the expression of Twist was inversely correlated with that of CBX3. Moreover, the knockdown of Twist with target siRNA in SiHa triggered the induction of the chromatin marker of the cellular senescence CBX3 and senescence-associated beta-galactosidase activity. Our results suggested that the expression of Twist increased during the progression and metastasis of cervical cancer. Furthermore, Twist-induced senescence bypass is important in this process. PMID- 24402693 TI - Hyperthermia on skin immune system and its application in the treatment of human papillomavirus-infected skin diseases. AB - Hyperthermia is a condition characterized by increased body temperature as a consequence of failed thermoregulation. Hyperthermia occurs when a body produces or absorbs more heat than it dissipates. Hyperthermia also elicits various effects on the physiology of living cells. For instance, fever-range temperature (39 degrees C to 40 degrees C) can modulate the activities of immune cells, including antigen-presenting cells, Tcells, and natural killer cells. Heat shock temperature (41 degrees C to 43 degrees C) can increase the immunogenicity of tumor cells. Cytotoxic temperature (> 43 degrees C) can create an antigen source to induce an anti-tumor immune response. The immunomodulatory effect of hyperthermia has promoted an interest in hyperthermia-aided immunotherapy, particularly against tumors. Hyperthermia has also been used to treat deep fungal, bacterial, and viral skin infections. We conducted a series of open or controlled trials to treat skin human papillomavirus infection by inducing local hyperthermia. More than half of the patients were significantly cured compared with those in the control trial. A series of challenging clinical cases, such as large lesions in pregnant patients or patients with diabetes mellitus, were also successfully and safely managed using the proposed method. However, further studies should be conducted to clarify the underlying mechanisms and promote the clinical applications of hyperthermia. PMID- 24402694 TI - Dynamic covalent side-chain cross-links via intermolecular oxime or hydrazone formation from bifunctional peptides and simple organic linkers. AB - Peptide cyclization via chemoselective reactions between side chains has proven a useful strategy to control folded structure. We report here a method for the synthesis of side-chain to side-chain cyclic peptides based on the intermolecular reaction between a linear peptide functionalized with two aminooxy or hydrazide side chains and an organic dialdehyde linker. A family of oxime-based and hydrazone-based cyclic products is prepared in a modular and convergent fashion by combination of unprotected linear peptide precursors and various small molecule linkers in neutral aqueous buffer. The side-chain to side-chain linkages that result can alter peptide folding behavior. The dynamic covalent nature of the Schiff bases in the cyclic products can be utilized to create mixtures where product composition changes in response to experimental conditions. Thus, a linear peptide precursor can select one organic linker from a mixture, and a cyclic product can dynamically exchange the small molecule component of the macrocycle. PMID- 24402696 TI - Tetracyanoquinodimethane reduction by complexed guanidinyl-functionalized aromatic compounds. AB - In this work, we report on the reduction of tetracyanoquinodimethane (TCNQ) with dicationic complexes of guanidinyl-functionalized aromatic (GFA) electron donors. In contrast to reduction with free GFAs, milder reduction conditions were achieved, and this led to semiconducting materials with extended TCNQ pi stacking. The charge on the TCNQ units was estimated from the structural data obtained by single-crystal X-ray diffraction analysis and from IR spectroscopic data. The electrical conductivity was studied and the activation energy of the semiconducting materials was estimated from the temperature dependence of the conductivity. PMID- 24402697 TI - VR-MDS: multidimensional scaling for classification tasks of virtual and real stimuli. AB - Evaluating the perceptual similarity between virtual and real sensory stimuli has been a serious problem for virtual reality interface researchers for a long time. One of the most commonly used evaluation methods is a classification task where assessors classify randomly presented stimuli into multiple candidate types. The results of this method are summarized using two types of confusion matrices, which have different stimulus sets. The present study developed a method that computes the locations of simulated and real stimuli in a perceptual space on the basis of the two confusion matrices. The spatial distribution of the stimuli allows us to visually interpret the perceptual relationships between stimuli and their perceptual dimensionality. This method is recommended when the guidance index based on the answer ratios of the confusion matrices is fairly high. PMID- 24402695 TI - Vitamin D and cancer: the promise not yet fulfilled. AB - The negative association of the latitude where people live and the incidence of non cutaneous cancer in that population in North America have been demonstrated in many studies for many types of cancer. Since the intensity of UVB exposure decreases with increasing latitude, and UVB exposure provides the mechanism for vitamin D production in the skin, the hypothesis that increased vitamin D provides protection against the development of cancer has been proposed. This hypothesis has been tested in a substantial number of prospective and case control studies and in a few randomized clinical trials (RTC) assessing whether either vitamin D intake or serum levels of 25 hydroxyvitamin D (25OHD) correlate (inversely) with cancer development. Most of the studies have focused on colorectal, breast, and prostate cancer. The results have been mixed. The most compelling data for a beneficial relationship between vitamin D intake or serum 25OHD levels and cancer have been obtained for colorectal cancer. The bulk of the evidence also favors a beneficial relationship for breast cancer, but the benefit of vitamin D for prostate and skin cancer in clinical populations has been difficult to demonstrate. RTCs in general have been flawed in execution or too small to provide compelling evidence one way or the other. In contrast, animal studies have been quite consistent in their demonstration that vitamin D and/or its active metabolite 1,25 dihydroxyvitamin D (1,25(OH)2D) can prevent the development and/or treat a variety of cancers in a variety of animal models. Furthermore, 1,25(OH)2D has been shown to impact a number of cellular mechanisms that would be expected to underlie its anticancer effects. Thus, there is a dilemma-animal and cellular studies strongly support a role for vitamin D in the prevention and treatment of cancer, but the clinical studies for most cancers have not yet delivered compelling evidence that the promise from preclinical studies has been fulfilled in the clinic. PMID- 24402698 TI - Visual selective attention is equally functional for individuals with low and high working memory capacity: evidence from accuracy and eye movements. AB - Selective attention and working memory capacity (WMC) are related constructs, but debate about the manner in which they are related remains active. One elegant explanation of variance in WMC is that the efficiency of filtering irrelevant information is the crucial determining factor, rather than differences in capacity per se. We examined this hypothesis by relating WMC (as measured by complex span tasks) to accuracy and eye movements during visual change detection tasks with different degrees of attentional filtering and allocation requirements. Our results did not indicate strong filtering differences between high- and low-WMC groups, and where differences were observed, they were counter to those predicted by the strongest attentional filtering hypothesis. Bayes factors indicated evidence favoring positive or null relationships between WMC and correct responses to unemphasized information, as well as between WMC and the time spent looking at unemphasized information. These findings are consistent with the hypothesis that individual differences in storage capacity, not only filtering efficiency, underlie individual differences in working memory. PMID- 24402699 TI - Automatic spatial association for luminance. AB - In the present study, we investigated whether luminance and the side of response execution are associated, showing a SNARC-like effect (faster responses with the left hand for dark stimuli, and vice versa for light stimuli). A total of 30 participants were tested in two experiments. In Experiment 1, the association between space and the luminance of chromatic stimuli was directly tested (brightness discrimination). In Experiment 2, the same spatial association was tested indirectly (hue discrimination). The results showed that participants responded faster with their left hand to hues with lower luminance, and with their right hand to hues with higher luminance, in either the direct or the indirect task. The consistency of this association in both tasks demonstrates the automaticity of the SNARC-like effect for luminance. PMID- 24402700 TI - Changes at our journal. PMID- 24402701 TI - Mother Nature's surprises. PMID- 24402702 TI - Filariasis presenting as massive diffuse cervical swelling in child. PMID- 24402703 TI - Schistosomiasis elimination strategies and potential role of a vaccine in achieving global health goals. AB - In March 2013, the National Institute of Allergy and Infectious Diseases and the Bill and Melinda Gates Foundation co-sponsored a meeting entitled "Schistosomiasis Elimination Strategy and Potential Role of a Vaccine in Achieving Global Health Goals" to discuss the potential role of schistosomiasis vaccines and other tools in the context of schistosomiasis control and elimination strategies. It was concluded that although schistosomiasis elimination in some focal areas may be achievable through current mass drug administration programs, global control and elimination will face several significant scientific and operational challenges, and will require an integrated approach with other, additional interventions. These challenges include vector (snail) control; environmental modification; water, sanitation, and hygiene; and other future innovative tools such as vaccines. Defining a clear product development plan that reflects a vaccine strategy as complementary to the existing control programs to combat different forms of schistosomiasis will be important to develop a vaccine effectively. PMID- 24402705 TI - 2013 ASTMH award, fellowship and medal recipients. PMID- 24402706 TI - Valve-in-valve implantation with a 23-mm balloon-expandable transcatheter heart valve for the treatment of a 19-mm stentless bioprosthesis severe aortic regurgitation using a strategy of "extreme" underfilling. AB - We report a case of valve-in-valve (ViV) implantation by transfemoral approach with a 23-mm balloon-expandable prosthesis inside a stentless 19-mm acutely degenerated bioprosthesis, using a strategy of "extreme" underfilling. A 74-year old patient presented to our institution in cardiogenic shock. An initial transesophageal echocardiography (TEE) showed severe central aortic regurgitation (AR) due to a torn leaflet. She was deemed inoperable and considered for urgent transcatheter aortic valve replacement. Given the fairly small true internal diameter, a strategy of 3-cc underfilling of a 23-mm transcatheter heart valve (THV) was planned. However, the final implantation was performed with 5-cc underfilling due to the incapacity to deliver the entire amount of fluid contained in the inflation syringe. TEE guidance confirmed the successful positioning and deployment of the prosthesis, with no AR and a mean gradient of 25 mm Hg. While implantation of a smaller prosthesis (20 mm) was debated during the Heart Team discussion, the risk of valve embolization due to inadequate anchoring inside the stentless prosthesis led to the selection of a 23-mm THV. At 6-month follow-up, the patient was in NYHA class I, with no AR and a mean gradient of 28 mm Hg. We report for the first time the use of in vivo THV with 5 cc underfilling with no acute or short-term structural failure, and the first ViV implantation by transfemoral approach with a 23-mm balloon-expandable prosthesis inside a stentless 19-mm bioprosthesis. The current report presents the challenges related to ViV implantation inside a small stentless bioprosthesis and offers practical ways to overcome them. (c) 2014 Wiley Periodicals, Inc. PMID- 24402707 TI - Promoter methylation-associated silencing of p27kip1 gene with metastasis in esophageal squamous cell carcinoma. AB - The aim of the present study was to determine the frequency of p27kip1 promoter methylation in esophageal squamous cell carcinoma (ESCC). The methylation status of the p27kip1 promoter was analyzed by methylation-specific polymerase chain reaction (MSP) in 50 ESCC and matched non-tumor tissues. Cell lines were treated with the demethylation agent 5-aza-2'-deoxycytidine (5-Aza-CdR) and p27kip1 mRNA expression was detected by quantitative polymerase chain reaction. p27kip1 methylation was found in 36% (18/50) of ESCC patients, but only in 12% (6/50) of the corresponding non-tumor tissues (P=0.005). There were statistically significant associations between the presence of methylation and tumor metastasis (P=0.002). The p27kip1 mRNA was lower in ESCC compared with non-tumor tissues (mean +/- standard deviation, -0.886+/-3.298 vs. 0.988+/-0.257; P=0.0033). Furthermore, a significant association was identified between the methylation status of the p27kip1 promoter and p27kip1 mRNA expression in the tissue (P<0.01). Thus, demethylation by 5-Aza-CdR was capable of inducing p27kip1 mRNA expression in esophageal cancer cell lines. The high promoter methylation of p27kip1 is a common phenomenon in ESCC, which may be an important mechanism of silencing p27kip1 mRNA expression. PMID- 24402708 TI - Taking the lymphatic route: dendritic cell migration to draining lymph nodes. AB - In contrast to leukocyte migration through blood vessels, trafficking via lymphatic vessels (LVs) is much less well characterized. An important cell type migrating via this route is antigen-presenting dendritic cells (DCs), which are key for the induction of protective immunity as well as for the maintenance of immunological tolerance. In this review, we will summarize and discuss current knowledge of the cellular and molecular events that control DC migration from the skin towards, into, and within LVs, followed by DC arrival and migration in draining lymph nodes. Finally, we will discuss potential strategies to therapeutically target this migratory step to modulate immune responses. PMID- 24402709 TI - Immunopathology of lupus nephritis. AB - When patients with systemic lupus erythematosus (SLE) present with urinary abnormalities, a renal biopsy is usually needed to rule out or confirm lupus nephritis. Renal biopsy is also needed to define the type of renal manifestation as different entities are associated with different outcomes; hence, renal biopsy results shape lupus management. But why does lupus nephritis come in different shapes? Why do patients with SLE often show change over time in class of lupus nephritis or have mixed forms? How does autoimmunity in SLE evolve? Why does loss of tolerance against nuclear antigens preferentially affect the kidney? Why are immune complex deposits in different glomerular compartments associated with different outcomes? What determines crescent formation in lupus? In this review, we discuss these questions by linking the latest information on lupus pathogenesis into the context of the different classes of lupus nephritis. This should help the basic scientist, the pathologist, and the clinician to gain a more conceptual view on the immunopathology of lupus nephritis. PMID- 24402710 TI - Immunopathogenesis of idiopathic nephrotic syndrome with relapse. AB - Idiopathic change nephrotic syndrome (INS), the most frequent glomerular disease in children and young adults, is characterized by heavy proteinuria and a relapsing remitting course. Although the mechanisms underlying the pathophysiology of proteinuria remain unclear, clinical and experimental observations suggest that lymphocyte and podocyte disturbances are two sides of the disease. The current hypothesis suggests that immune cells release a putative factor, which alters podocyte function resulting in nephrotic proteinuria. Besides T-cell abnormalities, recent evidence of B-cell depletion efficacy in sustained remissions added a new challenge in understanding the immunological mechanisms of INS. In this review, we discuss recent insights related to podocyte disorders occurring in INS and their relevance in human diseases. PMID- 24402712 TI - When, how, and where can oral cholera vaccines be used to interrupt cholera outbreaks? AB - Cholera continues to be a major global health problem, at times causing major and prolonged outbreaks in both endemic and nonendemic settings in developing countries. While improved water quality, sanitation, and hygiene (WASH) will provide the ultimate solution to prevention of this disease burden, this is a far off goal for most developing countries. Oral cholera vaccines cholera vaccines (OCVs) have been demonstrated to be effective in the control of cholera outbreaks, and constitute useful tools to be used in conjunction with efforts to improve WASH. Two killed OCVs are prequalified by WHO for purchase by UN agencies for international use. Recently, WHO has launched a global stockpile stockpile of killed OCVs for use to control outbreaks. Rational deployment of OCV from this stockpile will require consideration of costs, feasibility, disease epidemiology epidemiology , and the protective characteristics of the vaccine deployed, as well as effective and rapid coordination of processes and logistics logistics used to make decisions on deployment and delivery of the vaccine to the population in need. Despite not having data on all the questions of relevance as to how to use OCVs to control cholera outbreaks in different settings, there is clearly more than enough evidence to initiate their use, as answers to remaining questions and refinement of policies will mainly come with experience. PMID- 24402711 TI - The effects of dobutamine stress on cardiac mechanical synchrony determined by phase analysis of gated SPECT myocardial perfusion imaging in a canine model. AB - BACKGROUND: Precise identification of left ventricular (LV) systolic mechanical dyssynchrony may be useful in optimizing the response to cardiac resynchronization therapy in heart failure (HF) patients. However, LV dyssynchrony is mostly measured at rest; patients often suffer from the HF symptoms during exercise. OBJECTIVES: Our objective was to examine the impacts of stress on LV synchronism with phase analysis of gated SPECT myocardial perfusion imaging (GMPS) within a normal animal cohort. METHODS: Stress was induced with different levels of dobutamine infusion in six healthy canine subjects. Hemodynamic properties were assessed by LV pressure measurements. Also, LV mechanical synchronism (coordination of LV septal and lateral wall at the time of contraction) was determined by phase analysis of GMPS using commercially available QGS software and in-house MHI4MPI software, with the thickening- and displacement-based method. Synchrony indexes in MHI4MPI included the septal-to lateral delay and homogeneity index, derived from each of the two methods. Also, bandwidth, SD, and entropy (synchrony indexes) of the QGS software were assessed. RESULTS: LVEF increased from 36.7% +/- 8.7% at rest to 53.67% +/- 12.34% at 20 MUg . kg(-1) . minute(-1) (P < .001). Also, cardiac output increased from 3.67 +/ 1.0 L . minute(-1) at rest to 8.4 +/- 2.6 L . minute(-1) at 10 MUg . kg(-1) . minute(-1) (P < .001). The same trend was observed for dP/dt max which increased from 1,247 +/- 382.7 at rest to 5,062 +/- 1,800 mm Hg . s(-1) at 10 MUg . kg(-1) . minute(-1) (P < .01). Entropy decreased from 55.2% +/- 8% at baseline to 43.5% +/- 8.5% at 5 and 43.0% +/- 3.7% at 10 MUg . kg(-1) . minute(-1) dobutamine (P < .01). Thickening homogeneity index showed a difference from 91.7% +/- 5.53% at rest to 98.2% +/- 0.75% at 20 MUg . kg(-1) . minute(-1) (P < .05). CONCLUSIONS: Dobutamine stimulation could amplify the ventricular synchronism, and the thickening-based approach is more accurate than wall displacement for assessment of mechanical dyssynchrony in GMPS. PMID- 24402713 TI - Experimental perspective on fallback foods and dietary adaptations in early hominins. AB - The robust jaws and large, thick-enameled molars of the Plio-Pleistocene hominins Australopithecus and Paranthropus have long been interpreted as adaptations for hard-object feeding. Recent studies of dental microwear indicate that only Paranthropus robustus regularly ate hard items, suggesting that the dentognathic anatomy of other australopiths reflects rare, seasonal exploitation of hard fallback foods. Here, we show that hard-object feeding cannot explain the extreme morphology of Paranthropus boisei. Rather, analysis of long-term dietary plasticity in an animal model suggests year-round reliance on tough foods requiring prolonged postcanine processing in P. boisei. Increased consumption of such items may have marked the earlier transition from Ardipithecus to Australopithecus, with routine hard-object feeding in P. robustus representing a novel behaviour. PMID- 24402714 TI - Hunter-gatherers have less famine than agriculturalists. AB - The idea that hunter-gatherer societies experience more frequent famine than societies with other modes of subsistence is pervasive in the literature on human evolution. This idea underpins, for example, the 'thrifty genotype hypothesis'. This hypothesis proposes that our hunter-gatherer ancestors were adapted to frequent famines, and that these once adaptive 'thrifty genotypes' are now responsible for the current obesity epidemic. The suggestion that hunter gatherers are more prone to famine also underlies the widespread assumption that these societies live in marginal habitats. Despite the ubiquity of references to 'feast and famine' in the literature describing our hunter-gatherer ancestors, it has rarely been tested whether hunter-gatherers suffer from more famine than other societies. Here, we analyse famine frequency and severity in a large cross cultural database, in order to explore relationships between subsistence and famine risk. This is the first study to report that, if we control for habitat quality, hunter-gatherers actually had significantly less--not more--famine than other subsistence modes. This finding challenges some of the assumptions underlying for models of the evolution of the human diet, as well as our understanding of the recent epidemic of obesity and type 2 diabetes mellitus. PMID- 24402715 TI - The corn snake yolk sac becomes a solid tissue filled with blood vessels and yolk rich endodermal cells. AB - The amniote egg was a key innovation in vertebrate evolution because it supports an independent existence in terrestrial environments. The egg is provisioned with yolk, and development depends on the yolk sac for the mobilization of nutrients. We have examined the yolk sac of the corn snake Pantherophis guttatus by the dissection of living eggs. In contrast to the familiar fluid-filled sac of birds, the corn snake yolk sac invades the yolk mass to become a solid tissue. There is extensive proliferation of yolk-filled endodermal cells, which associate with a meshwork of blood vessels. These novel attributes of the yolk sac of corn snakes compared with birds suggest new pathways for the evolution of the amniote egg. PMID- 24402716 TI - Humans rely on the same rules to assess emotional valence and intensity in conspecific and dog vocalizations. AB - Humans excel at assessing conspecific emotional valence and intensity, based solely on non-verbal vocal bursts that are also common in other mammals. It is not known, however, whether human listeners rely on similar acoustic cues to assess emotional content in conspecific and heterospecific vocalizations, and which acoustical parameters affect their performance. Here, for the first time, we directly compared the emotional valence and intensity perception of dog and human non-verbal vocalizations. We revealed similar relationships between acoustic features and emotional valence and intensity ratings of human and dog vocalizations: those with shorter call lengths were rated as more positive, whereas those with a higher pitch were rated as more intense. Our findings demonstrate that humans rate conspecific emotional vocalizations along basic acoustic rules, and that they apply similar rules when processing dog vocal expressions. This suggests that humans may utilize similar mental mechanisms for recognizing human and heterospecific vocal emotions. PMID- 24402717 TI - Are thyroid hormones mediators of incubation temperature-induced phenotypes in birds? AB - Incubation temperature influences a suite of traits in avian offspring. However, the mechanisms underlying expression of these phenotypes are unknown. Given the importance of thyroid hormones in orchestrating developmental processes, we hypothesized that they may act as an upstream mechanism mediating the effects of temperature on hatchling phenotypic traits such as growth and thermoregulation. We found that plasma T3, but not T4 concentrations, differed among newly hatched wood ducks (Aix sponsa) from different embryonic incubation temperatures. T4 at hatching correlated with time spent hatching, and T3 correlated with hatchling body condition, tarsus length, time spent hatching and incubation period. In addition, the T3 : T4 ratio differed among incubation temperatures at hatch. Our findings are consistent with the hypothesis that incubation temperature modulates plasma thyroid hormones which in turn influences multiple aspects of duckling phenotype. PMID- 24402718 TI - Ecological networks: delving into the architecture of biodiversity. AB - In recent years, the analysis of interaction networks has grown popular as a framework to explore ecological processes and the relationships between community structure and its functioning. The field has rapidly grown from its infancy to a vibrant youth, as reflected in the variety and quality of the discussions held at the first international symposium on Ecological Networks in Coimbra-Portugal (23 25 October 2013). The meeting gathered 170 scientists from 22 countries, who presented data from a broad geographical range, and covering all stages of network analyses, from sampling strategies to effective ways of communicating results, presenting new analytical tools, incorporation of temporal and spatial dynamics, new applications and visualization tools.(1) During the meeting it became evident that while many of the caveats diagnosed in early network studies are successfully being tackled, new challenges arise, attesting to the health of the discipline. PMID- 24402719 TI - Modern Multi-line Slot Machine Games: The Effect of Lines Wagered on Winners, Losers, Bonuses, and Losses Disguised as Wins. AB - We simulated the commercially available multi-line slot machine game "Money Storm," including its bonus wins. Our results show that after a specified amount of time (such as 1 or 50 h), when players played a single line, there were marked differences between one player and the next-a few won a lot, others lost far more than average. When playing 20 lines there were fewer big winners and fewer players quickly losing a large percentage of their money. We simulated a Gambler's Ruin scenario whereby players arrived with $100 and made $1 wagers until broke. Again we saw a reduction in the variability among player as the number of lines wagered increased, fewer players lost their entire bankroll quickly, and fewer players had big wins. The bonus wins in Money Storm contribute approximately 24% to the payback of the game, and our simulations of bonus wins shows that with 20 lines wagered the players spend approximately 11% of their time in bonus wins. With one line wagered, there are no losses disguised as wins while with 20 lines wagered the majority of hits are losses disguised as wins. Players using multi-line machines can thus tune the characteristics of the machine gambling experience to match their preferred pattern, though most seem in practice to bet on the most possible lines. Our results serve to inform researchers, counsellors, gamblers and others about how slot machines are designed, and the effect that wagering on multiple lines has on short-term and long-term play, bonus wins, and losses disguised as wins. PMID- 24402720 TI - Gambler Risk Perception: A Mental Model and Grounded Theory Analysis. AB - Few studies have investigated how gamblers perceive risk or the role of risk perception in disordered gambling. The purpose of the current study therefore was to obtain data on lay gamblers' beliefs on these variables and their effects on decision-making, behaviour, and disordered gambling aetiology. Fifteen regular lay gamblers (non-problem/low risk, moderate risk and problem gamblers) completed a semi-structured interview following mental models and grounded theory methodologies. Gambler interview data was compared to an expert 'map' of risk perception, to identify comparative gaps or differences associated with harmful or safe gambling. Systematic overlapping processes of data gathering and analysis were used to iteratively extend, saturate, test for exception, and verify concepts and themes emerging from the data. The preliminary findings suggested that gambler accounts supported the presence of expert conceptual constructs, and to some degree the role of risk perception in protecting against or increasing vulnerability to harm and disordered gambling. Gambler accounts of causality, meaning, motivation, and strategy were highly idiosyncratic, and often contained content inconsistent with measures of disordered gambling. Disordered gambling appears heavily influenced by relative underestimation of risk and overvaluation of gambling, based on explicit and implicit analysis, and deliberate, innate, contextual, and learned processing evaluations and biases. PMID- 24402722 TI - Effects of laparoscopic adjustable gastric banding on weight loss, metabolism, and obesity-related comorbidities: 5-year results in China. AB - BACKGROUND: Despite some reports about the long-term metabolic outcomes after laparoscopic adjustable gastric banding (LAGB) in the Western populations, there are few reports on the Asian population whose body size and fat distribution are different. Therefore, this study was conducted to evaluate the medium-term effects of LAGB on weight loss and metabolic outcomes of obese patients with different body mass index (BMI) in China. METHODS: A retrospective study was performed to review the 5-year follow-up data of 56 patients (18 males, 38 females) who received LAGB from November 2003 to May 2013 at the Shanghai Changhai Hospital. The patients were evaluated at years 1, 3, and 5 after operation in the outpatient clinic, and the weight loss, metabolic parameters, and remission of comorbidities were measured. RESULTS: The 56 patients preoperatively had BMI of 37.4 +/- 6.0 kg/m2, with BMI < 35 kg/m2 in 19 patients (BMI <35 kg/m2 group), and BMI >= 35 kg/m2 in 37 patients (BMI >= 35 kg/m2 group). The percentages of excess weight loss (%EWL) of the BMI < 35 kg/m2 group at years 1, 3, and 5 were 65.2, 65.6, and 65.7%, respectively, indicating the majority of metabolic parameters were significantly improved (P < 0.05). However, in the BMI >= 35 kg/m2 group, the %EWL were 37.9, 34.8, and 26.5%, respectively, except at year 1 when the metabolic parameters improved significantly (P < 0.05), those at year 3 and year 5 did not significantly improve compared with the preoperative levels. Similar results were observed in the improvement of comorbidities. CONCLUSIONS: Relatively low medium-term weight loss, metabolic improvement, and resolution or remission of obesity-related comorbidities and high reoperation rate were observed in our population of patients with BMI >= 35 kg/m2 who underwent LAGB. PMID- 24402721 TI - Whole-body magnetic resonance imaging (WB-MRI) as surveillance for subsequent malignancies in survivors of hereditary retinoblastoma: a pilot study. AB - BACKGROUND: Individuals with hereditary retinoblastoma (RB) are at very high risk of developing subsequent malignant neoplasms (SMNs) of which osteosarcoma (OS) is one of the most common. We hypothesized that annual surveillance using whole-body magnetic resonance imaging (WB-MRI) in asymptomatic survivors of hereditary RB would detect SMN of the bone and soft tissues at an early stage. PROCEDURE: Retrospective review of the results of a WB-MRI screening program in hereditary RB survivors from February 2008 to August 2012. The primary outcome was to determine the sensitivity and specificity of WB-MRI in detecting SMNs. RESULTS: Twenty-five patients had at least one WB-MRI performed (range: 1-5). First WB-MRI was performed at a median age of 16 years (range: 8-25 years). WB-MRI detected new osseous abnormalities suspicious for malignancy in five patients: two were diagnosed with localized high-grade OS of the extremity and three were found to have benign osseous abnormalities after dedicated imaging (n = 5/5) and/or biopsy (n = 3/5). One patient was diagnosed with secondary OS 3 months after a normal screening WB-MRI exam. Among a total of 41 WB-MRI screening tests performed in survivors of hereditary RB, the sensitivity of detecting SMN was 66.7% and the specificity was 92.1%. CONCLUSIONS: Preliminary results suggest that annual WB MRI surveillance detects SMN in survivors of hereditary RB, but with modest sensitivity. Further study is needed to assess the performance of annual surveillance WB-MRIs and whether this modality decreases SMN-related mortality in RB survivors. PMID- 24402723 TI - [No exchange of information without technology : modern infrastructure in radiology]. AB - Modern radiology cannot accomplish the daily numbers of examinations without supportive technology. Even though technology seems to be becoming increasingly more indispensable, business continuity should be ensured at any time and if necessary even with a limited technical infrastructure by business continuity management. An efficient information security management system forms the basis. The early radiology information systems were islands of information processing. A modern radiology department must be able to be modularly integrated into an informational network of a bigger organization. The secondary use of stored data for clinical decision-making support poses new challenges for the integrity of the data or systems because medical knowledge is displayed and provided in a context of treatment. In terms of imaging the creation and distribution radiology services work in a fully digital manner which is often different for radiology reports. Legally secure electronic diagnostic reports require a complex technical infrastructure; therefore, diagnostic findings still need to be filed as a paper document. The internal exchange and an improved dose management can be simplified by systems which continuously and automatically record the doses and thus provide the possibility of permanent analysis and reporting. Communication between patient and radiologist will gain ongoing importance. Intelligent use of technology will convey this to the radiologist and it will facilitate the understanding of the information by the patient. PMID- 24402725 TI - [Change in the editor of Der Radiologe]. PMID- 24402724 TI - [Current reporting in radiology : what will happen tomorrow?]. AB - CLINICAL/METHODICAL ISSUE: Reporting in radiology faces considerable changes in the near future that will be influenced by a broader understanding of the task and increasing technological possibilities. STANDARD RADIOLOGICAL METHODS: Until now a radiological report could be regarded as a text phrased by a radiologist after viewing imaging data. METHODICAL INNOVATIONS: New solutions will be accessed by advances in visualization of large datasets, in extracting, analyzing, and communicating metadata as well as by improved integration and interpretation of clinical information. PERFORMANCE: Virtual reality, texture analysis, growing networks, semantic annotation, data mining and context based presentation have the potential to extensively change the everyday working routine. ACHIEVEMENTS: Although many of these developments are still in a laboratory phase, the impact on the process of reporting can already be predicted. PRACTICAL RECOMMENDATIONS: As the leading community in information analysis and technology, radiology as a subject should strive to lead and shape these impending changes. PMID- 24402726 TI - Social isolation and perceived barriers to establishing social networks among Latina immigrants. AB - Research has identified numerous mechanisms through which perceived social isolation and lack of social support negatively impact health. Little research attention has been dedicated to factors that influence the development of social networks, which have the potential to decrease perceptions of social isolation and provide social support. There is mixed evidence concerning the availability of supportive social networks for Latinos in the US. This study explores trauma exposed Latina immigrants' experiences of social isolation in the US and its perceived causes. Twenty-eight Latina immigrant women participated in an interview about traumatic experiences. Informal help seeking and the availability of friendships in the US were also queried. Frequent comparisons between experiences in their home countries and in the US shaped the emerging themes of social isolation and lack of social support. Women reported feeling lonely, isolated, closed-in, and less free in the US due to family separation and various obstacles to developing and maintaining relationships. Socioeconomic, environmental, and psychosocial barriers were offered as explanations for their limited social networks in the US. Understanding experiences of social isolation as well as barriers to forging social networks can help inform the development of social support interventions that can contribute to improved health among Latinos. PMID- 24402727 TI - The application of community psychology practice competencies to reduce health disparities. AB - This article demonstrates the application of community psychology practice competencies to health disparities reduction. It begins with a discussion of changes and evolution of the maternal child health field over nearly three decades, then describes implications for community psychology practice and the application of practice competencies. PMID- 24402728 TI - Aggressive behavior of cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia. AB - OBJECTIVES/HYPOTHESIS: Immunosuppression in organ transplant recipients increases the incidence and aggressiveness of cutaneous squamous cell carcinoma. However, there are little clinical data on cutaneous squamous cell carcinoma in patients with immunosuppression due to chronic lymphocytic leukemia. In this study we evaluated the clinical features, patterns of recurrence, and outcomes of cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia. STUDY DESIGN: Retrospective cohort study. METHODS: A review was performed of 42 consecutive patients with cutaneous squamous cell carcinoma and chronic lymphocytic leukemia presenting to our institution between July 2000 and July 2010. Baseline characteristics, treatment details, and outcomes were analyzed. RESULTS: Thirty-four patients presented with primary cutaneous squamous cell carcinoma (33 node negative, 1 node positive), and eight patients presented with nodal disease without a simultaneous index primary. The 2-year cumulative incidence of local recurrence for primary cutaneous squamous cell carcinoma was 15%. Nodal recurrence occurred in 36% of node-negative patients. The 3-year overall and cause-specific survival rate for all patients was 37% and 65%, respectively. In patients managed curatively for nodal disease at presentation or relapse (n = 17), the 3-year overall and cause-specific survival rate was 21% and 53%, respectively. CONCLUSIONS: Patients with cutaneous squamous cell carcinoma and chronic lymphocytic leukemia experience higher rates of skin cancer recurrence and death than expected in an immunocompetent population. Novel strategies are needed to improve outcomes. PMID- 24402729 TI - Polytwistane. AB - Twistane, C10H16, is a classic D2-symmetric chiral hydrocarbon that has been studied for decades due to its fascinating stereochemical and thermodynamic properties. Here we propose and analyze in detail the contiguous linear extension of twistane with ethano (ethane-1,2-diyl) bridges to create a new chiral, C2 symmetric hydrocarbon nanotube called polytwistane. Polytwistane, (CH)n, has the same molecular formula as polyacetylene but is composed purely of C(sp(3))-H units, all of which are chemically equivalent. The polytwistane nanotube has the smallest inner diameter (2.6 A) of hydrocarbons considered to date. A rigorous topological analysis of idealized polytwistane and a C236H242 prototype optimized by B3LYP density functional theory reveals that the polymer has a nonrepeating, alternating sigma-helix, with an irrational periodicity parameter and an instantaneous rise (or lead) angle near 15 degrees . A theoretical analysis utilizing homodesmotic equations and explicit computations as high as CCSD(T)/cc pVQZ yields the enthalpies of formation Delta(f)H(0) degrees (twistane) = -1.7 kcal mol(-1) and Delta(f)H(0) degrees (polytwistane) = +1.28 kcal (mol CH)(-1), demonstrating that the hypothetical formation of polytwistane from acetylene is highly exothermic. Hence, polytwistane is synthetically viable both on thermodynamic grounds and also because no obvious pathways exist for its rearrangement to lower-lying isomers. The present analysis should facilitate the preparation and characterization of this new chiral hydrocarbon nanotube. PMID- 24402730 TI - Benign mast cell hyperplasia and atypical mast cell infiltrates in penile lichen planus in adult men. AB - Introduction. Lichen planus (LP) is a chronic cytokine-mediated disease of possible auto-immune etiology. 25% of men have anogenital manifestations. Erosive penile LP causes a scarring phimosis of the foreskin in uncircumcised men. Mast cells as potent immune modulators have been implicated in a number of autoimmune and chronic inflammatory diseases, but have not been investigated in LP. Material and Methods. Formalin-fixed tissues of 117 circumcision specimens of adult men affected by LP were evaluated for the extent of mast cell and lymphocyte infiltrates, characterized immunohistochemically with antibodies to CD 3, 4, 8, 20, 21, 25, 30, 117c and human mast cell tryptase. Specimens with dense mast cell infiltrates were analyzed for point mutations of the c-kit gene (D816V). Results. Unaffected skin and modified mucosa of foreskins contained ?5 mast cells/mm2. The inflammatory infiltrate of LP-lesions displayed ?15 mast cells/mm2 in 33/117 foreskins, 16-40 mast cells/mm2 in 22/117 and ?40 mast cells/mm2 (average 70, range 40-100) in 62/117 foreskins. Lesional mast cells of 29/117 (24%) foreskins showed aberrant CD25-expression and/or spindled morphology, with 11/29 men having erosive LP, 13/29 a lymphocytic vasculitis and 1/28 a systemic mastocytosis. Neither CD30-expression nor c-kit mutations were identified. Atypical mast cell infiltrates in LP correlated with high disease activity, erosive LP and presence of lymphocytic vasculitis Conclusions. Increased mast cells in penile LP, mostly representing a benign hyperplasia/activation syndrome, suggests them as targets for innovative therapy options for symptomatic LP-patients not responding to corticosteroid therapy. Presently, the biological implications of atypical mast cell infiltrates in penile LP are unknown. PMID- 24402732 TI - A novel balloon assisted two-stents telescoping technique for repositioning an embolized stent in the pulmonary conduit. AB - A 9-year-old male, with history of pulmonary atresia and ventricular septal defect, status post complete repair with a 16 mm pulmonary homograft in the right ventricular outflow tract (RVOT) underwent 3110 Palmaz stent placement for conduit stenosis. Following deployment the stent embolized proximally into the right ventricle (RV). We undertook the choice of repositioning the embolized stent into the conduit with a transcatheter approach. Using a second venous access, the embolized stent was carefully maneuvered into the proximal part of conduit with an inflated Tyshak balloon catheter. A second Palmaz 4010 stent was deployed in the distal conduit telescoping through the embolized stent. The Tyshak balloon catheter was kept inflated in the RV to stabilize the embolized stent in the proximal conduit until it was successfully latched up against the conduit with the deployment of the overlapping second stent. One year later, he underwent Melody valve implantation in the pre-stented conduit relieving conduit insufficiency. This novel balloon assisted two-stents telescoping technique is a feasible transcatheter option to secure an embolized stent from the RV to the RVOT. PMID- 24402733 TI - Chemo-enzymatic three-fragment assembly of semisynthetic proteins. AB - Here, we report the development of a method for three-fragment assemblies of semisynthetic proteins by combining sortase-mediated ligation with site-specific bioconjugation catalyzed by the 4'-phosphopantetheine transferase Sfp. This method enables the introduction of synthetic peptides into central regions of proteins without the need to purify intermediates. The assembled proteins are linked at the N-terminal junction with a 4'-phosphopantetheine moiety and with a peptide bond at the C-terminal ligation site. We have demonstrated the applicability of this method by assembling a semisynthetic model protein derived from fluorescence resonance energy transfer-based reporters from three fragments in a one-pot reaction. PMID- 24402735 TI - Tuning the guest-binding ability of a helically folded capsule by in situ modification of the aromatic oligoamide backbone. AB - Starting from a previously described aromatic oligoamide helically folded capsule that binds tartaric acid with high affinity and diastereoselectivity, we demonstrate the feasibility of the direct in situ modification of the helix backbone, which results in a conformational change that reduces its affinity for guests by two orders of magnitude. Specifically, ring contraction of the central pyridazine unit into a pyrrole in the full helical sequence was investigated by using electrochemical and chemical processes. The sequence containing the pyrrole was synthesized independently in a convergent manner to ascertain its structure. The conformation of the pyrrolic folded capsule was elucidated in the solid state by X-ray crystallography and in solution by using (1)H and (13)C NMR spectroscopy. Solution studies revealed an unanticipated solvent-dependent equilibrium between the anti-anti and syn-syn conformations of the pyrrole ring with respect to its two adjacent pyridine units. Titrations of the pyrrole containing sequence monitored by (1)H NMR spectroscopy confirmed the expected drop in affinity for tartaric acid and malic acid that arises from the conformation change in the backbone that follows the replacement of the pyridazine by a pyrrole. The reduction of the pyridazine to a pyrrole was characterized by cyclic voltammetry both on the entire sequence and on a shorter precursor. The lower cathodic potential of the precursor made its preparative scale electroreduction possible. Direct in situ modification of the pyridazine within the entire capsule sequence was achieved chemically by using zinc in acetic acid. PMID- 24402731 TI - Knowledge is power: how conceptual knowledge transforms visual cognition. AB - In this review, we synthesize the existing literature demonstrating the dynamic interplay between conceptual knowledge and visual perceptual processing. We consider two theoretical frameworks that demonstrate interactions between processes and brain areas traditionally considered perceptual or conceptual. Specifically, we discuss categorical perception, in which visual objects are represented according to category membership, and highlight studies showing that category knowledge can penetrate early stages of visual analysis. We next discuss the embodied account of conceptual knowledge, which holds that concepts are instantiated in the same neural regions required for specific types of perception and action, and discuss the limitations of this framework. We additionally consider studies showing that gaining abstract semantic knowledge about objects and faces leads to behavioral and electrophysiological changes that are indicative of more efficient stimulus processing. Finally, we consider the role that perceiver goals and motivation may play in shaping the interaction between conceptual and perceptual processing. We hope to demonstrate how pervasive such interactions between motivation, conceptual knowledge, and perceptual processing are in our understanding of the visual environment, and to demonstrate the need for future research aimed at understanding how such interactions arise in the brain. PMID- 24402736 TI - Understanding the genetic basis of parathyroid carcinoma. AB - Parathyroid carcinoma has always been difficult to diagnose pathologically. In fact, most parathyroid tumors which are classified as carcinoma do not recur after excision, and most parathyroid tumors which actually metastasize or recur repeatedly in the neck are not recognized as malignant at first presentation. In 2002, germline HRPT2 (also known as CDC73) mutation was reported as the cause of hyperparathyroidism-jaw tumor (HPT-JT) syndrome, an autosomal dominant hereditary tumor syndrome associated with a lifetime risk of parathyroid carcinoma approaching 15 %. Subsequently, bi-allelic inactivation or mutation of HRPT2 has been reported in the majority of parathyroid carcinomas that actually behave in a malignant manner but very rarely in sporadic benign parathyroid disease. Furthermore, germline testing for HRPT2 mutation in patients presenting with parathyroid carcinoma often identifies occult HPT-JT syndrome even in the absence of a family history or other syndromic manifestations. HRPT2 mutation testing is not readily available, and loss of expression of parafibromin (the protein encoded by HRPT2) as determined by immunohistochemistry has been used as a surrogate marker of HRPT2 mutation. Immunohistochemistry for parafibromin can be technically difficult and has been deployed by different investigators with variable enthusiasm and success. However, proponents have found immunohistochemistry for parafibromin useful to definitively confirm a pathological diagnosis of parathyroid carcinoma, predict a worse outcome in definite parathyroid carcinomas, triage formal genetic testing for HPT-JT syndrome, and predict the outcome of histologically atypical parathyroid adenomas. PMID- 24402738 TI - A stable porous anionic metal-organic framework for luminescence sensing of ln(3+) ions and detection of nitrobenzene. AB - A hexagonal channel-based porous anionic metal-organic framework was successfully constructed. IFMC-3 is stable in air and acidic/basic aqueous solutions at room temperature, and constitutes a selective luminescent sensing material for Ln(3+) ions and a recyclable probe for the sensitive detection of nitrobenzene. PMID- 24402737 TI - Functional cardiac paraganglioma associated with a rare SDHC mutation. AB - Paragangliomas are catecholamine-secreting tumors external to the adrenal glands, most commonly arising in the head and neck, followed by the abdominal and thoracic cavities. The heart is a rare location for paragangliomas to originate from, with fewer than 50 cases as described in the literature. Functional paragangliomas of the right atrium are even more unusual, with only five cases reported to date. The investigations and therapies of a 41-year-old male presenting with a clinically functional cardiac paraganglioma are discussed. We performed a detailed pathology review of the primary cardiac tumor and a lung nodule to examine morphologic changes, along with an immunohistochemical profile (chromogranin A, tyrosine hydroxylase, MIB-1, and succinate dehydrogenase subunit B (SDHB)) of both tumors. Genetic testing of germline mutations in SDH genes was also completed. Both the 9.5-cm cardiac mass and 0.5-cm lung nodule were positive for chromogranin A and tyrosine hydroxylase and showed a global loss of SDHB expression. The MIB-1 labeling index of the smaller lesion and the bulk of the larger lesion was <5 %, but there were cellular foci of the larger lesion that had a labeling index of 10%. Genetic testing yielded an intronic frameshift mutation in the SDHC gene, c.IVS 5 + 1, G > A. We report the first case of a functional cardiac paraganglioma associated with an intronic frameshift SDHC gene mutation. PMID- 24402739 TI - Pneumocystis jirovecii pneumonia in two patients with systemic lupus erythematosus after rituximab therapy. AB - New cases of Pneumocystis jirovecii pneumonia (PJP) have recently been reported in patients with systemic lupus erythematosus (SLE) after rituximab therapy. Several factors may contribute to susceptibility to P. jirovecii infection in this type of patients, including the immunological characteristics of the disease, the mechanisms of rituximab action, environmental factors, and the biological characteristics of the fungus. We report two patients with SLE who developed PJP after rituximab therapy. PMID- 24402740 TI - Comparing Inspiratory Resistive Muscle Training with Incentive Spirometry on Rehabilitation of COPD Patients. AB - PURPOSE: To examine the effect of incentive spirometry in pulmonary rehabilitation of chronic obstructive pulmonary disease (COPD) patients and compare its efficacy with inspiratory resistive muscle training (IMT) technique. DESIGN: Randomized controlled trial. METHODS: Thirty patients with COPD, from a general hospital in Mashhad, Iran, were randomly assigned to two study groups. All subjects trained daily in two 15-minute sessions, 4 days a week, for 4 weeks. Respiratory function tests were compared before interventions and at the end of weeks 2 and 4. FINDINGS: Both techniques improved the mean values of all respiratory function tests (p<=.01). The IMT technique was more effective to improve MVV and PImax (p<=.05). PEFR was better improved in the incentive spirometry group (p<=.05). There was no significant difference for other spirometric parameters between two groups. CONCLUSIONS: Incentive spirometry can be considered as an effective component for pulmonary rehabilitation in COPD patients. PMID- 24402741 TI - Early rapidly developing constrictive pericarditis after aortic valve surgery. PMID- 24402742 TI - Phosphatation of zeolite H-ZSM-5: a combined microscopy and spectroscopy study. AB - A variety of phosphated zeolite H-ZSM-5 samples are investigated by using a combination of Fourier transfer infrared (FTIR) spectroscopy, single pulse (27)Al, (29)Si, (31)P, (1)H-(31)P cross polarization (CP), (27)Al-(31)P CP, and (27)Al 3Q magic angle spinning nuclear magnetic resonance (MAS NMR) spectroscopy, scanning transmission X-ray microscopy (STXM) and N2 physisorption. This approach leads to insights into the physicochemical processes that take place during phosphatation. Direct phosphatation of H-ZSM-5 promotes zeolite aggregation, as phosphorus does not penetrate deep into the zeolite material and is mostly found on and close to the outer surface of the zeolite, acting as a glue. Phosphatation of pre-steamed H-ZSM-5 gives rise to the formation of a crystalline tridymite AlPO4 phase, which is found in the mesopores of dealuminated H-ZSM-5. Framework aluminum species interacting with phosphorus are not affected by hydrothermal treatment. Dealuminated H-ZSM-5, containing AlPO4 , retains relatively more framework Al atoms and acid sites during hydrothermal treatment than directly phosphated H-ZSM-5. PMID- 24402743 TI - Occlusion therapy in amblyopia: an experience from Hong Kong. AB - OBJECTIVES. To review the results of patching for amblyopia management in Hong Kong. DESIGN. Retrospective case series. SETTING. Regional hospital, Hong Kong. PATIENTS. Records of all patients attending Paediatric Ophthalmology Clinic at United Christian Hospital, Hong Kong from 1 January 2009 to 31 March 2009 were retrospectively reviewed. Records of all children who underwent patching for amblyopia in the study period were evaluated. RESULTS. The mean age of 50 children (50 eyes) was 4 (standard deviation, 1; range, 2-7) years and mean pretreatment visual acuity was 0.35 (0.15; 0.02-0.63) [~20/60]. The values for mean, standard deviation, and range of treatment duration were 27, 16, 4-67 months respectively, and corresponding values for prescribed patching per day were 4, 1, 2-8 hours. The mean, standard deviation, and range of visual acuity at final post-treatment assessment were 0.66, 0.16, 0.1-1.0 (~20/30), respectively. The overall success rate (ie final visual acuity >0.7 or 20/30) was 62%. Children with moderate amblyopia (20/40-20/80) and severe amblyopia (20/100-20/400) had success rates of 74% and 55%, respectively. The mean visual acuity improvements for moderate and severely amblyopic children were 2.3 lines and 5.8 lines, respectively. The mean, standard deviation, and range of patching prescriptions for moderate and severely amblyopic children were 5, 1, 2-7 hours and 5, 1, 3-6 hours, respectively. Recurrence ensued in 7% of the children with moderate amblyopia and 46% of those with severe amblyopia. Reported compliance was good (>75% of the time) in 68% of the children. CONCLUSION. Occlusion therapy is the mainstay of treatment in Hong Kong. The overall success rate was comparable to that achieved in the Amblyopia Treatment Study. Recurrence was more common in patients with severe amblyopia, for whom maintenance therapy may reduce the risk of recurrence. The duration of treatment was much longer in our locality than in western countries. Reported compliance was suspicious possibly due to traditional cultural contexts. It is important to emphasise compliance to all parents. PMID- 24402744 TI - Crosstalk between the mesothelium and lymphomatous cells: insight into the mechanisms involved in the progression of body cavity lymphomas. AB - The peculiar localization of body cavity lymphomas implies a specific contribution of the intracavitary microenvironment to the pathogenesis of these tumors. In this study, primary effusion lymphoma (PEL) was used as a model of body cavity lymphoma to investigate the role of mesothelial cells, which line the serous cavities, in lymphoma progression. The crosstalk between mesothelial and lymphomatous cells was studied in cocultures of primary human mesothelial cells (HMC) with PEL cells and a xenograft mouse model of peritoneal PEL. PEL cells were found to induce type 2 epithelial-mesenchymal transition (EMT) in HMC, which converted into a myofibroblastic phenotype characterized by loss of epithelial markers (pan cytokeratin and E-cadherin), expression of EMT-associated transcriptional repressors (Snail1, Slug, Zeb1, Sip1), and acquisition of alpha smooth muscle actin (alpha-SMA), a mesenchymal protein. A progressive thickening of serosal membranes was observed in vivo, accompanied by loss of cytokeratin staining and appearance of alpha-SMA-expressing cells, confirming that fibrosis occurred during intracavitary PEL development. On the other hand, HMC were found to modulate PEL cell turnover in vitro, increasing their resistance to apoptosis and proliferation. This supportive activity on PEL cells was retained after transdifferentiation, and was impaired by interferon-alpha2 b treatment. On the whole, our results indicate that PEL cells induce type 2 EMT in HMC, which support PEL cell growth and survival, providing a milieu favorable to lymphoma progression. Our findings provide new clues into the mechanisms involved in lymphoma progression and may indicate new targets for effective treatment of malignant effusions growing in body cavities. PMID- 24402745 TI - An unexpected fluctuating reactivity for odd and even carbon numbers in the TiO2 based photocatalytic decarboxylation of C2-C6 dicarboxylic acids. AB - The degradation behaviours of five straight-chain dicarboxylic acids (from ethanedioic acid to hexanedioic acid) were compared in aqueous TiO2-based photocatalysis. When all other conditions were identical, the degradation rates were found to fluctuate regularly with the parity of the number of carbon atoms. Dicarboxylic acids with an even number of carbon atoms (e-DAs) always degraded more slowly than those acids with an odd number of carbon atoms (o-DAs). This unusual fluctuation in the reactivity for the degradation of dicarboxylic acids by TiO2-based photocatalysis is very closely related to the different pre coordination modes of the acids with the photocatalyst. Attenuated total reflection FTIR (ATR-FTIR) of e-DAs labelled with (13)C showed that both carboxyl groups of the acid coordinate to TiO2 through bidentate chelating forms. In contrast, only one carboxyl group of the o-DAs coordinated to TiO2 in a bidentate chelating manner, whereas the other formed a monodentate binding linkage. The bidentate chelating form with bilateral symmetric coordination did not favour degradation. Isotope-labelling experiments were performed with (18)O2 to observe the different ways in which incorporated oxygen entered the initial decarboxylated products of e- and o-DAs. For the degradation of butanedioic acid, (45.9+/-0.5) % of the oxygen in the formed propanedioic acid came from H2O, whereas for pentanedioic acid, (97.4+/-0.2) % of the oxygen in the formed butanedioic acid came from H2O. Our results demonstrate that in TiO2-based photocatalysis, the reactivity of active species, such as .OH/h(vb)(+), is far from non-selective and that the attacks of these active species on organic substrates are significantly affected by the coordination patterns of the substrates on the TiO2 surface. PMID- 24402746 TI - Predictors of olfactory dysfunction in rhinosinusitis using the brief smell identification test. AB - OBJECTIVES/HYPOTHESIS: Associations between olfactory function to quality-of-life (QOL) and disease severity in patients with rhinosinusitis is poorly understood. We sought to evaluate and compare olfactory function between subgroups of patients with rhinosinusitis using the Brief Smell Identification Test (B-SIT). STUDY DESIGN: Cross-sectional evaluation of a multicenter cohort. METHODS: Patients with recurrent acute sinusitis and chronic rhinosinusitis with and without nasal polyposis were prospectively enrolled from three academic tertiary care sites. Each subject completed the B-SIT, in addition to measures of disease specific QOL. Patient demographics, comorbidities, and clinical measures of disease severity were compared between patients with normal (BSIT>=9) and abnormal (BSIT<9) olfaction scores. Regression modeling was used to identify potential risk factors associated with olfactory impairment. RESULTS: Patients with rhinosinusitis (n=445) were found to suffer olfactory dysfunction as measured by the B-SIT (28.3%). Subgroups of rhinosinusitis differed in the degree of olfactory dysfunction reported. Worse disease severity, measured by computed tomography and nasal endoscopy, correlated to worse olfaction. Olfactory scores did not consistently correlate with the Rhinosinusitis Disability Index or Sinonasal Outcome Test scores. Regression models demonstrated nasal polyposis was the strongest predictor of olfactory dysfunction. Recalcitrant disease and aspirin intolerance were strongly predictive of worse olfactory function. CONCLUSIONS: Olfactory dysfunction is a complex, multifactorial process found to be differentially expressed within subgroups of rhinosinusitis. Olfaction was associated with disease severity as measured by imaging and endoscopy, with only weak associations to disease-specific QOL measures. LEVEL OF EVIDENCE: 2b. PMID- 24402747 TI - Joachim Oelhaf and the first public autopsy in Gdansk in 1613. AB - The first both in Gdansk and in Central Europe alleged public autopsy was performed by Joachim Oelhaf in February 1613. It was an evidence for Gdansk status as one of the leading anatomical centres in Europe. The aim of the article is to present the history of teaching medicine in Gdansk in early modern era and the eminent anatomists working in Academic Gymnasium of Gdansk. The preserved report of the autopsy of a new-born child with congenital defects is analysed as one of the very first texts in pathological anatomy. The described by Oelhaf case is identified as limb-body wall complex. PMID- 24402748 TI - The mandible and its foramen: anatomy, anthropology, embryology and resulting clinical implications. AB - The aim of this paper is to summarise the knowledge about the anatomy, embryology and anthropology of the mandible and the mandibular foramen and also to highlight the most important clinical implications of the current studies regarding anaesthesia performed in the region of the mandible. An electronic journal search was undertaken to identify all the relevant studies published in English. The search included MEDLINE and EMBASE databases and years from 1950 to 2012. The subject search used a combination of controlled vocabulary and free text based on the search strategy for MEDLINE using key words: 'mandible', 'mandibular', 'foramen', 'anatomy', 'embryology', 'anthropology', and 'mental'. The reference lists of all the relevant studies and existing reviews were screened for additional relevant publications. Basing on relevant manuscripts, this short review about the anatomy, embryology and anthropology of the mandible and the mandibular foramen was written. PMID- 24402749 TI - Configurations of the circle of Willis: a computed tomography angiography based study on a Polish population. AB - The aim of the study was to investigate the distribution of the circle of Willis variants in Polish population by means of computed tomography angiography (CTA). The results were then analysed and compared with another study that used similar methods but that was carried out on an ethnically distinct population. Patients presenting with intracranial pathology were excluded from the initial study population. In total, 250 CTA belonging to 129 female and 121 male patients were reviewed. A modified classification system of the circle was proposed, which took into consideration the anterior and the posterior aspects of the circle individually. The typical variant of Willis's circle occurred in 16.80% of cases. The anterior and the posterior portions of the circle were normal in 47.20% and 26.80% of the patients respectively. As for the anterior part, lack of the anterior communicating artery was the most frequent abnormality (22.80%). Bilateral absence of posterior communicating arteries was the most common anomaly in the posterior part of the circle (29.20%). This type of anomaly was also the most common, when taking into consideration the entire circle (12.00%). There were statistically significant differences between the age groups and genders when considering the occurrence of an incomplete circle. Overall, a substantial proportion of patients manifested clinically important variants that were incapable of providing collateral circulation. Comparison with other imaging based and cadaveric studies revealed noticeable differences, that may have resulted from the variable technical features of other studies or other factors such as the ethnical origins of the studied populations. PMID- 24402750 TI - Effect of light-dark changes on the locomotor activity in open field in adult rats and opossums. AB - There have been no reports on how the light-dark changes determine the locomotor activity of animals in the group of high reactivity (HR) and low reactivity (LR). In the present study we have compared selected parameters of the locomotor activity of the HR and the LR groups of the laboratory opossums and Wistar rats during consecutive, light and dark phases in the open field test. Sixty male Wistar adult rats, at an average weight of 350 g each, and 24 adult Monodelphis opossums of both sexes at an average weight of 120 g each were used. The animals' activity for 2 h daily between the hours of 17:30 and 19:30, in line with the natural light-dark cycle were recorded and then analysed using VideoTrack ver.2.0 (Vievpoint France). According to our results, we noted that a change of the experimental conditions from light to dark involves an increase in the locomotor activity in rats and opossums of the HR group, while there is no effect on the activity of the rats and opossums in the LR group. Locomotor activity in the HR rats, both in the light and dark conditions is characterised by a consistent pattern of change - higher activity in the first stage of the recording and a slowdown (habituation) in the second phase of the observation. The locomotor activity of the opossum, during both light and dark conditions, was observed to be at a consistently high level compared to the rats. PMID- 24402751 TI - Association between frontal sinus development and persistent metopic suture. AB - BACKGROUND: Frontal sinuses are 2 irregular cavities, placed between 2 lamina of frontal bone. Expansion continues during childhood and reaches full size after puberty. Persistent metopic suture is one of the factors that are related to abnormal frontal sinus development. In this study, we want to discuss about the coexistence of persistent metopic suture and abnormal frontal sinus development using radiological techniques. MATERIALS AND METHODS: In this retrospectively planned study, images of 631 patients were examined, 217 (34.4%) of them were men and 414 (65.6%) of them were women. Brain computed tomography and magnetic resonance images were retrieved from the electronic archive for analysis. RESULTS: In this study, frontal sinus development is categorised as right side atrophy, left side atrophy, bilateral atrophy and bilaterally developed sinuses. The presence of metopic suture was accepted as persistent metopic suture. Frontal sinus atrophy was found in 22.7% and persistent metopic sutures were found in 9.7% of overall. CONCLUSIONS: In this study, no significant results were detected that were relatedto the frontal sinus agenesis or dismorphism associated with persistent metopicsuture. We conclude that, although publications propounding metopism thatleads to abnormal frontal sinus development are present in the literature, noreasonable explanation has been mentioned in these articles; and we believe thatthese findings are all incidental. PMID- 24402752 TI - Variations in the topography of the infraorbital canal/groove complex: a proposal for classification and its potential usefulness in orbital floor surgery. AB - BACKGROUND: The aim of the study was to precisely describe and classify the infraorbital canal/groove (IOC/G) complex in dry human skulls and to evaluate the presence of asymmetry in the IOC/G complex. MATERIALS AND METHODS: Seventy orbits of 35 human skulls were investigated.The following distances were measured: the distance between the posterior and anterior margin of the infraorbital groove (S C); the posterior margin of the infraorbital canal and the infraorbital foramen (C-IOF); and the total length of the infraorbital canal-groove complex (S-C-IOF). The symmetry of the contralateral measurements was analysed. RESULTS: Three types of the IOC/G complex were distinguished: types I, II, III, whose respective incidences were 11.4%, 68.6%, 20.0%. The mean length of the infraorbital groove plus canal complex on the right and left with standard deviation were 27.78+/ 3.69 mm and 28.06+/-3.37 mm, respectively. CONCLUSIONS: The results presented in this study may be particularly helpful for surgery in patients with blow-out fractures and different endoscopic and reconstructive procedures in the region of the inferior orbital wall. The type III IOC/G complex, according to our classification, seems the most likely to be exposed to trauma during surgical manipulations. PMID- 24402753 TI - Radiological evaluation of the styloid process length in the normal population. AB - BACKGROUND: The aim of this study was to evaluate the styloid process (SP) length in the normal population using multidetector computed tomography (MDCT). MATERIALS AND METHODS: In this study, 160 patients who underwent paranasal MDCT between January 2012 and December 2012 were retrospectively evaluated. The patients were divided into groups according to their age and gender: Group 1 age 31-40 years old, 111 subjects; Group 2 age 41-50 years old, 49 subjects; Group A 98 males; Group B 62 females. The mean SP length was calculated from the mean of 2 measurements. SPs were assessed for their average lengths in different gender and age groups. Student's t-test was used for the comparison of the mean SP lengths between the groups. Differences were considered to be statistically significant at p<0.05. RESULTS: The mean SP length on both sides varied from 18 to 51 mm (28.4+/-5.5) in all the patients. The mean SP length was 27.2+/-5.2 mm in females and 29.2+/-5.6 mm in males. There was a statistically significant difference between the mean SP lengths in terms of gender (p<0.028). The mean SP length was 28.5+/-5.7 mm in Group 1 and 28.2+/-5.1 mm in Group 2. There was no statistically significant difference between the mean SP lengths in terms of age (p>0.718). CONCLUSIONS: In conclusion, there is still no consensus on the normal values of SP length. Normal values should be determined according to the geographical regions and ethnic groups for the diagnosis of Eagle's syndrome. PMID- 24402754 TI - Cholinergic innervation of human mesenteric lymphatic vessels. AB - BACKGROUND: The cholinergic neurotransmission within the human mesenteric lymphatic vessels has been poorly studied. Therefore, our aim is to analyse the cholinergic nerve fibres of lymphatic vessels using the traditional enzymatic techniques of staining, plus the biochemical modifications of acetylcholinesterase (AChE) activity. MATERIALS AND METHODS: Specimens obtained from human mesenteric lymphatic vessels were subjected to the following experimental procedures: 1) drawing, cutting and staining of tissues; 2) staining of total nerve fibres; 3) enzymatic staining of cholinergic nerve fibres; 4) homogenisation of tissues; 5) biochemical amount of proteins; 6) biochemical amount of AChE activity; 6) quantitative analysis of images; 7) statistical analysis of data. RESULTS: The mesenteric lymphatic vessels show many AChE positive nerve fibres around their wall with an almost plexiform distribution. The incubation time was performed at 1 h (partial activity) and 6 h (total activity). Moreover, biochemical dosage of the same enzymatic activity confirms the results obtained with morphological methods. CONCLUSIONS: The homogenates of the studied tissues contain strong AChE activity. In our study, the lymphatic vessels appeared to contain few cholinergic nerve fibres. Therefore, it is expected that perivascular nerve stimulation stimulates cholinergic nerves innervating the mesenteric arteries to release the neurotransmitter AChE, which activates muscarinic or nicotinic receptors to modulate adrenergic neurotransmission. These results strongly suggest, that perivascular cholinergic nerves have little or no effect on the adrenergic nerve function in mesenteric arteries. The cholinergic nerves innervating mesenteric arteries do not mediate direct vascular responses. PMID- 24402755 TI - Co-localisation of cocaine- and amphetamine-regulated transcript peptide and vasoactive intestinal polypeptide in the myenteric plexus of the porcine transverse colon. AB - Cocaine- and amphetamine-regulated transcript peptide (CART) is a substance,which can play the role of neuromediator and/or neuromodulator in nerve structures within the gastrointestinal tract. However knowledge concerning its functions and co-localisation with other neuronal factors is rather scarce. During the present investigation the co-localisation of CART and vasoactive intestinal polypeptide (VIP) in the neurons of meyenteric plexus within the porcine transverse colon was studied using double immunofluorescence technique and semiquantitative arbitrary scale of the frequency of presence CART+/VIP+, CART+/VIP- and CART-/VIP+ neuronal cells. The most often (+++) CART-/VIP+ neurons were encountered, neurons simultaneously immunoreactive to CART and VIP were observed somewhat rarer (++) and only single (+) CART+/VIP- perikarya were visible. The present study reports for the first time on the co-localisation of CART and VIP in myenteric neurons of the porcine transverse colon. PMID- 24402756 TI - Thyroid hormone dysfunctions affect the structure of rat thoracic aorta: a histological and morphometric study. AB - BACKGROUND: There are limited data about the influence of hypothyroidism and hyperthyroidism on the connective tissue component and smooth muscle cells of the thoracic aorta. The aim was to study the histological changes of the wall of the thoracic aorta in the hypothyroid and hyperthyroid rats. Morphometric measurements were also done. MATERIALS AND METHODS: Thirty adult rats were used. They were divided into control, hyperthyroid, and hypothyroid groups. Each group consisted of 10 rats. The animals were sacrificed at the end of 8 weeks and the descending aorta was excised. Sections were stained with haematoxylin and eosin, orcein and Masson's trichrome stains. Themorphometric measurement included: number of smooth muscle cell nuclei, number of the elastic lamellae, thickness of the tunica media, elastic fibre optic density, and relative collagen area. RESULTS: Atheromatous plagues had been observed in the hyperthyroid group. Thinning and rupture of the elastic lamellae had been observed in the hypothyroid group; these were accompanied with intimal ulceration and aortic dissection. The average number of smooth muscle cell nuclei in the hyperthyroid group had doubled and tripled compared to their fellows in the control and hypothyroid groups, respectively. The thickness of the tunica media increased in the hyperthyroid and hypothyroid groups by 75% and 35%. In addition, the relative collagen area increased in the previously mentioned groups by 142% and 120%, respectively. On the other hand, the mean elastic fibre optic density decreased in both groups by 30%. CONCLUSIONS: Structure wall affections of the intima and media of the descending aorta were associated with the thyroid hormone dysfunctions. These changes were more severe in the hypothyroid group. PMID- 24402758 TI - Morphology and clinical implication of the extra-head of biceps brachii muscle. AB - The biceps brachii muscle is present in the anterior aspect of the arm. Its morphological variations have great clinical significance for surgeons, orthopaedic surgeons, anaesthetists, neurologists and anatomists. This study aimed to describe the incidence and morphology of the extra-heads of the biceps brachii muscle. Hundred upper limbs of 50 adult human cadavers (30 men and 20 women) were used in this study after the approval of the medical ethical committee. These cadavers were obtained from the Anatomy Department, Faculty of Medicine, King Abdul-Aziz University. The incidence of anatomical variations of biceps muscle was equal in both male and female cadavers (10%) with predominance of the left side (7%). The 3-headed biceps brachii muscle was noticed in 7% (4% male and 3% female), while the 4-headed biceps was seen in 2 (2%) left limbs, 1 male and 1 female. The third head of the biceps muscle arose from the anteromedial aspect of humerus, between the coracobrachialis insertion and the brachialis origin, in 6% and from middle of the medial border of humerus in 3%. While the fourth head originated from the articular capsule of shoulder joint in 1 (1%) limb and from the coracoid process of scapula in the other limb. The biceps common tendon of insertion received the supernumerary heads in 7% of the limbs. However, the extra-head fused with the long head in 2 (2%) limbs and united with the short head in 1 (1%) limb. The mean of the third head length was 118.8+/-10.9 in all limbs, where it was 121.8+/-12.3 in male and 113.5+/-8.1 in female cadavers. The third head length/arm length ratio was 38.4+/-2.6 in all, 38.3+/-3.4 in male and 38.8+/-1.8 in female cadavers. The length of the extra head was extremely significant with those of the corresponding limb in all, male and female cadavers (p<0.0001). Knowledge of the morphological variations of biceps muscle provides better pre-operative evaluation, safe surgical intervention within the arm and better postoperative outcomes. PMID- 24402757 TI - Effect of iodothyronine hormone status on doxorubicin related cardiotoxicity. AB - The anthracycline anticancer agent doxorubicin has been recognised to induce a dose-dependent cardiotoxicity. The chronic form of such complication is characterized by an irreversible cardiac damage and congestive heart failure. Although the pathogenesis of anthracycline cardiotoxicity seems to be multifactorial, the pivotal role has been attributed to reactive oxygen species formation. Because redox equilibrium in cardiomyocytes may be regulated via iodothyronine hormones, the aim of the study was to appraise the effect of hypothyroidism on heart damages induced by doxorubicin. The rats received methimazole in drinking water (0.001 and 0.025%) after doxorubicin administration (2.0, 5.0 and 15 mg/kg). The cardiac morphology and blood biochemical markers of heart damage were assessed. Decreased levels of iodothyronine hormones had not significant impact on cardiac morphological changes and no effect on the level of B-type natriuretic peptide in rats receiving doxorubicin. Lower hormonal levels had sporadic, diverse effect on blood transaminases, lactate dehydrogenase and creatine kinase levels, but any relation to time, doxorubicin doses and hypothyroid status was found. Hypothyreosis leads to increase in fatty acid binding protein in rats receiving higher dose of doxorubicin. Hypothyreosis had no effect on heart stretching and on necrosis at morphological level, but caused biochemical symptoms of cardiomyocyte necrosis in rats receiving doxorubicin. PMID- 24402759 TI - Topography and morphometry of the subarcuate canal. AB - The current study shows in a close-up view anatomical relationship between the subarcuate canal and the osseous labyrinth. For this purpose we used micro computed tomography which allowed performing three-dimensional reconstruction of the subarcuate canal and gave adequate data for estimation its diameter across its course. The diameter of the middle part (the most uniform) of the subarcuate canal varied from 0.28 mm to 0.46 mm. Hence, we calculated the centre of mass for each cross-section of the separated subarcuate canal. This procedure helped us to visualise trajectory of the subarcuate canal and its spatial orientation within the petrous bone. From our data we concluded that subarcuate canals revealed not well defined trajectories and their spatial orientation varied across the studied temporal bones. PMID- 24402760 TI - A rare case of Goldenhar syndrome with radial aplasia. AB - Goldenhar syndrome (GS) is a well-recognised condition characterised by variable degree of uni- or bilateral involvement of craniofacial structures involving first and second branchial arches manifesting ocular and auricular anomalies and also vertebral defect. This syndrome presents at birth and its exact aetiology is still unknown. The affections of the neural crest cells may have some role in the multiple malformations of the GS. We present a teenaged female case who attended the Orthopaedic Outpatient Department to receive handicapped certificate in Bankura Sammilani Medical College and Hospital. She had multiple skeletal abnormalities, which included hemifacial microsomia, vertebral malformations in the form of scoliosis, distorted pelvis, but the most striking feature was the absence of thumb and aplasia of radius of left side. She did not suffer from any ocular or auricular abnormalities, neither from any cardiological, urogenital or gastroenteric ones. Radial defects associated with GS might represent a subset within this spectrum. Our case probably belongs to this subset, therefore is a very rare one. PMID- 24402761 TI - Massive upper gastrointestinal bleeding from an accessory splenic artery mimicking isolated gastric varices. AB - Knowledge of anatomical variations of coeliac trunk and its branches is important for surgeons and interventional radiologists planning surgical and radiological interventions. We describe a case of a 42-year-old male with an accessory splenic artery (ASA) originating from the left gastric artery (LGA) running in the wall of gastric fundus and mimicking isolated gastric varices, which was observed during endoscopy. Bleeding from this artery was massive and was managed with endovascular coil embolisation. Coeliac angiography of the patient with upper gastrointestinal bleeding showed that the coeliac trunk divided into 3 arteries: the LGA, the splenic artery, and the right hepatic artery. Additionally, the variations of ASA and the left hepatic artery arising from LGA, and the left and right inferior phrenic arteries arising from ASA were identified. This case is the first to be presented in the literature with ASA originating from LGA that was situated in the gastric wall where inferior phrenic arteries arose from the ASA. PMID- 24402762 TI - Anatomic variability in the relation between the retromandibular vein and the facial nerve: a case report, literature review and classification. AB - Knowledge of anatomic variations concerning head and neck veins is important to surgeons performing interventions in these regions, as well as to radiologists. The retromandibular vein is used as a guide to expose the facial nerve branches inside the parotid gland, during parotid surgery and open reduction of mandibular condyle fractures. It is also used as a landmark for localisation of the nerve and compartmentalisation of parotid gland lesions preoperatively, during computed tomography, magnetic resonance imaging and sonography. In this paper, the anomalous retromandibular vein's course on the left side of a male cadaver is described. The vein was formed around the nerve, while the maxillary vein travelled medial to the facial nerve branches and superficial to the superficial temporal vein. Interestingly, the facial nerve temporofacial division crossed again the superficial temporal vein upwards, forming a "nerve fork". The incidence of the reported variability of the relationship between the retromandibular vein and the facial nerve are discussed with a detailed literature review. Accordingly, the typical deep position of the retromandibular vein in relation to the facial nerve is estimated to 88.17% to all sides. Furthermore, an updated classification system is proposed, including 4 types and subtypes. PMID- 24402763 TI - Diagnostic performance of plasma biomarkers in patients with acute intestinal ischaemia. AB - BACKGROUND: The aim of this study was to evaluate the use of intestinal fatty acid binding protein (I-FABP) and traditional biomarkers in the early diagnosis of acute intestinal ischaemia of different causes. METHODS: I-FABP, white blood cell (WBC) count, C-reactive protein, base deficit, lactate, lactate dehydrogenase, aspartate aminotransferase, creatine kinase and D-dimer were measured prospectively in consecutive patients suspected of having acute intestinal ischaemia. Biomarker levels were compared in patients with vascular and non-vascular ischaemia. RESULTS: Two hundred and eight patients with a clinical suspicion of acute intestinal ischaemia were enrolled. Vascular intestinal ischaemia was diagnosed in 24 patients (11.5 per cent), non-vascular ischaemia in 62 (29.8 per cent) and non-ischaemic disease in 122 (58.7 per cent). The levels of most biomarkers (except WBC count and creatine kinase) were significantly higher in the vascular ischaemia group than in the other groups (P < 0.010). However, none of the biomarker levels differed between patients with non-vascular intestinal ischaemia and those with non-ischaemic disease. Receiver operating characteristic (ROC) curve analysis suggested that I-FABP was best at diagnosing vascular intestinal ischaemia (area under the curve 0.88). CONCLUSION: Serum biomarkers may be useful in the diagnosis of vascular, but not non vascular, intestinal ischaemia. Among them, I-FABP shows promise for detecting vascular ischaemia. PMID- 24402764 TI - Effective endovascular treatment of calcified femoropopliteal disease with directional atherectomy and distal embolic protection: final results of the DEFINITIVE Ca++ trial. AB - OBJECTIVES: The purpose of the DEFINITIVE Ca(++) study was to evaluate the safety and effectiveness of directional atherectomy and distal embolic protection, used together to treat moderate to severely calcified femoropopliteal lesions. BACKGROUND: Despite advances in endovascular treatment modalities, treatment of calcified lesions remains a challenge. METHODS: A total of 133 subjects with 168 moderate to severely calcified lesions were enrolled. Lesions were treated with directional atherectomy devices, coupled with distal embolic protection. RESULTS: The 30-day freedom from MAE rate was 93.1%. Per angiographic core laboratory assessment, the primary effectiveness endpoint (<=50% residual diameter stenosis) was achieved in 92.0% (lower confidence bound of 87.6%) of lesions. By core lab analysis, these results did not achieve the success criteria (90%) for the primary effectiveness objective. Per site assessment, the objective was met with the endpoint being achieved in 97.0% (lower confidence bound 93.8%). A mean residual diameter stenosis of 33.3% was achieved with the directional atherectomy device. This was further decreased to 24.1% with the use of adjunctive therapy. The proportion of asymptomatic subjects [Rutherford Clinical Category (RCC) = 0] increased from 0% at baseline to 52.3% at the 30-day follow-up visit. In total, 88.5% of subjects experienced an improvement of one or more Rutherford categories. CONCLUSIONS: The results of the DEFINITIVE Ca++ study demonstrate that the SilverHawk and TurboHawk atherectomy devices are safe and effective in the endovascular treatment of moderate to severely calcified lesions in the superficial femoral and/or popliteal arteries when used with the SpiderFX distal embolic protection device. PMID- 24402765 TI - Functional reorganization of brain networks in patients with painful chronic pancreatitis. AB - BACKGROUND: The underlying pain mechanisms of chronic pancreatitis (CP) are incompletely understood, but recent research points to involvement of pathological central nervous system processing involving pain-relevant brain areas. We investigated the organization and connectivity of brain networks involved in nociceptive processing in patients with painful CP. METHODS: Contact heat-evoked potentials (CHEPs) were recorded in 15 patients with CP and in 15 healthy volunteers. The upper abdominal area (sharing spinal innervation with the pancreatic gland) was used as a proxy of 'pancreatic stimulation', while stimulation of a heterologous region remote to the pancreas (right forearm) was used as a control. Subjective pain scores were assessed by visual analogue scale. The brain source organization and connectivity of CHEPs components were analysed. RESULTS: After pancreatic area stimulation, brain source analysis revealed abnormalities in the cingulate/operculo-insular network. A posterior shift of the operculo-insular source (p = 0.004) and an anterior shift of the cingulate source (p < 0.001) were seen in CP patients, along with a decreased strength of the cingulate source (p = 0.01). The operculo-insular shift was positively correlated with the severity of patient clinical pain score (r = 0.61; p = 0.03). No differences in CHEPs characteristics or source localizations were seen following stimulation of the right forearm. CONCLUSIONS: CP patients showed abnormal cerebral processing after stimulation of the upper abdominal area. These changes correlated to the severity of pain the patient was experiencing. Since the upper abdominal area shares spinal innervation with the pancreatic gland, these findings likely reflect maladaptive neuroplastic changes, which are characteristic of CP. PMID- 24402766 TI - Synthesis of heterodinuclear hemisalen complexes on a hexaarylbenzene scaffold and their application for the cross-pinacol coupling reaction. AB - Intermolecular cross-pinacol coupling reaction between aliphatic and aromatic aldehydes by using heterodinuclear hemisalen complexes 1cis with vanadium(V) and titanium(IV) on a hexaarylbenzene scaffold is reported. Our ligand design is based on the individual activation of two aldehydes by vanadium and titanium, which are positioned with a suitable space on the rigid scaffold. Ligands such as 1cis were synthesized by Diels-Alder addition and decarbonylation reaction, followed by condensation of dialdehyde 3cis with various aminophenols. The influence of the substituents on the ligands on the pinacol coupling reaction was investigated. As a result, the reductive coupling reaction between aliphatic and aromatic aldehydes by using a catalytic amount of 1cis in the presence of Me3 SiCl and Zn provided the corresponding cross-coupled 1,2-diol in good yields with high cross-selectivity. PMID- 24402767 TI - beta-Sitosterol attenuates high-fat diet-induced intestinal inflammation in mice by inhibiting the binding of lipopolysaccharide to toll-like receptor 4 in the NF kappaB pathway. AB - SCOPE: beta-Sitosterol, a common phytosterol, has been shown to exhibit anti inflammatory effects. Here, we investigated the effect of beta-sitosterol on high fat diet (HFD) induced colitis in mice and on LPS-stimulated mouse intestinal macrophages. METHODS AND RESULTS: C57BL/6J mice were maintained on an LFD (10 kcal% fat), an HFD (60 kcal% fat), or an HFD with beta-sitosterol (20 mg/kg) administration for 8 weeks. The increased levels of body weight and epididymal fat pad weight as well as the concentrations of circulating proinflammatory cytokines and LPS in HFD mice compared with LFD mice were decreased by oral administration of beta-sitosterol. The HFD-induced colonic inflammation evidenced by the increased expression of proinflammatory cytokines and the activation of nuclear factor kappa B (NF-kappaB) in the colon was also inhibited by beta sitosterol. In LPS-stimulated intestinal macrophages, beta-sitosterol inhibited the production of proinflammatory cytokines and inflammatory enzymes as well as NF-kappaB activation. In addition, beta-sitosterol significantly prevented the binding of LPS to intestinal as well as peritoneal macrophages. Furthermore, beta sitosterol potently inhibited the interaction between LPS and toll-like receptor 4 in intestinal macrophages transfected with control siRNA or MyD88 siRNA. CONCLUSION: These findings indicate that beta-sitosterol ameliorates HFD-induced colitis by inhibiting the binding of LPS to toll-like receptor 4 in the NF-kappaB pathway. PMID- 24402768 TI - Coronary collaterals: an elusive network. PMID- 24402769 TI - Prenatal detection for major congenital heart disease: a key process measure for congenital heart networks. PMID- 24402770 TI - QRISK2 validation by ethnic group. PMID- 24402771 TI - ECG phenomena: alternating QRS morphologies. PMID- 24402772 TI - High sensitivity cardiac troponin T in patients with immunoglobulin light chain amyloidosis. AB - OBJECTIVES: To define whether the high sensitivity cardiac troponin T (hs-cTnT) assay in patients with immunoglobulin light chain amyloidosis (AL) improves risk prediction. BACKGROUND: Cardiac involvement is the major cause of death in patients with AL amyloidosis. Risk stratification is facilitated by cardiac biomarkers such as cardiac troponin T (cTnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP). METHODS: Stored serum from patients with newly diagnosed AL was used to measure hs-cTnT, cTnT, and NT-proBNP. Survival modelling was performed. RESULTS: The direct numeric result from hs-cTnT measurement cannot merely be substituted for a cTnT measurement in the Mayo AL staging system. The performance of the receiver operator curve derived an hs-cTnT cut-point of 54 ng/L which improves on the value of 35 ng/L validated with the prior iteration of the assay. An alternate staging option using hs-cTnT alone-using the two thresholds 14 ng/L and 54 ng/L-performs as well as either the original Mayo AL staging system or other systems incorporating hs-cTnT. On multivariate analysis, an hs-cTnT alone staging system was independent of period of diagnosis, type of therapy, and NT-proBNP value, the last of which dropped out of the model. Alternate models were explored, but none performed better than the original system or the new hs-cTnT system. Thus, hs-cTnT can be used alone for the staging of disease prognosis. CONCLUSIONS: A survival model based on hs-cTnT improves the prognostic staging of patients with AL amyloidosis, relegating NT-proBNP to a measure of cardiac response. PMID- 24402773 TI - Th17 cell expansion in gastric cancer may contribute to cancer development and metastasis. AB - Th0 cells differentiate into Th1 or Th2 depending on multiple transcription factors acting on specific time points to regulate gene expression. Th17 cells, a subset of IL-17-producing T cells distinct from Th1 or Th2 cells has been described as key players in inflammation and autoimmune diseases as well as cancer development. In the present study, 66 patients with gastric cancer were included; the expression level of Th1- and Th17-related IFN-gamma, IL-17, T-bet, RORgammat in gastric cancer tissues and peripheral blood mononuclear cell (PBMC) were detected, analyzed the relationship between Th17 or Th1 infiltration and metastasis and explored the possible mechanism. Our results showed that IL-17 and RORgammat expression were significantly increased in gastric cancer tissues and PBMC, especially, in metastasis patients; plasma IL-17 also increased; furthermore, the mRNA and protein levels of IL-1beta, IL-21 and TGF-beta were up regulated. All the data indicated that Th17 was infiltrated the cancer tissue; IL 1beta, IL-21 and TGF-beta were also involved in gastric cancer development by promoting Th17 cell generation. From the above data, we speculated that Th17 cell expansion in gastric cancer may contribute to cancer development and metastasis. PMID- 24402774 TI - Using the common sense model of self-regulation to understand the relationship between symptom reporting and trait negative affect. AB - BACKGROUND/PURPOSE: Based on the Common Sense Model of Self-Regulation, we examined if the relationship of trait NA to physical symptom reporting was moderated by life events and illness representations. METHODS: This relationship was examined using a cross-sectional dataset of 554 elderly adults. RESULTS: A significant three-way interaction demonstrated that individuals who reported the greatest severity of physical symptoms were higher in trait NA, and reported more life events and a chronic illness history. CONCLUSIONS: The results of this study are consistent with the hypothesis that individual high on trait NA who have a history of a chronic illness have illness representations with both disease specific physical symptoms and symptoms from other causes, such as emotional distress. This may complicate the care of medical conditions for these patients. PMID- 24402775 TI - The role of depression in work-related outcomes of HIV treatment in Uganda. AB - PURPOSE: The primary goal of this analysis was to examine the influence of depression above and beyond the effects of HIV treatment on work activity and function. METHODS: We combined data from three longitudinal studies of patients starting antiretroviral therapy (ART) and/or entering HIV care in Uganda. Assessments were conducted at baseline and months 6 and 12. The nine-item Patient Health Questionnaire (PHQ-9) was used to assess depressive symptoms, as well as Major (scores >9) and Minor (scores 5-9) Depression status; work functioning was assessed using a subscale of the Medical Outcomes Study HIV Health Survey (MOS HIV). Multivariate random-effects logistic regression models for longitudinal data were used to examine the impact of treatment on work status and optimal work functioning, with measures of both baseline and change in physical health functioning, cognitive functioning and depression in the models, controlling for baseline demographics, and CD4 cell count. RESULTS: The sample of 1,731 participants consisted of 1,204 starting ART and 527 not yet eligible for ART. At baseline, 35 % were not working, and 37 % had sub-optimal work functioning. Intention-to-treat analyses revealed that those on ART experienced greater improvement in both work outcomes over 12 months relative to non-ART patients, and that baseline and change in physical health functioning, continuous and categorical depression were all independently associated with improvement in both work outcomes, even after accounting for the direct effect of ART. CONCLUSIONS: Improvement in physical and mental health plays a key role in the positive impact of HIV treatment on work activity and function, suggesting potential economic benefits of integrating depression treatment into HIV care. PMID- 24402777 TI - Introduction to the special section: cross-cultural beliefs, attitudes, and dilemmas about vaccination. PMID- 24402776 TI - Stressful and traumatic life events are associated with burnout-a cross-sectional twin study. AB - BACKGROUND: Most burnout studies focus on symptoms of burnout in relation to work related stress. However, recent studies have found that familial factors and stress in the personal life may also be of importance. Stressful and traumatic life events influence how individuals cope with stress over the life course and may therefore be associated with burnout symptoms. PURPOSE: This study aims to assess the associations between stressful and traumatic life events and burnout symptoms in a population-based sample of twins, adjusting for familial confounding. METHODS: In this cross-sectional questionnaire-based study of 25,378 Swedish twins, odds ratios (OR) with 95% confidence intervals (CI) were calculated using logistic regression analysis. First, the whole sample was analysed. Secondly, a matched co-twin analysis was conducted of the same-sex twin pairs discordant on burnout, in order to adjust for familial factors. RESULTS: A history of traumatic life events was independently associated with burnout symptoms, with a cumulative effect with increasing number of events. ORs adjusted for familial confounding: 1-3 events OR 1.58 (CI = 1.21-2.07) 4 or more events OR 2.00 (CI = 1.45-2.75). Independent associations between the stressful life events: serious family problems OR 1.71 (CI = 1.36-2.15), physical illness OR 1.44 (CI = 1.17-1.77), divorce or separation OR 1.40 (CI = 1.15-1.70), and burnout symptoms were also found. CONCLUSIONS: The results indicate that stressful and traumatic life events are of importance in the burnout process. This finding may have implications in efforts to prevent burnout. PMID- 24402779 TI - An integrated experimental and theoretical approach to the spectroscopy of organic-dye-sensitized TiO2 heterointerfaces: disentangling the effects of aggregation, solvation, and surface protonation. AB - We report a joint experimental and computational study into the spectroscopic properties of a prototypical D5 organic dye, both in solution and adsorbed on a TiO2 surface, with the aim of modeling and quantifying the UV/Vis spectral shifts that occur in the different explored environments. Going from the dye in solution to dye-sensitized TiO2, various factors may shift the position of the UV/Vis absorption maximum, both towards longer and shorter wavelengths. Here we have focused on the effect of dye aggregation on TiO2, surface protonation, and solvent effects. The D5 dye forms stable aggregates on the TiO2 surface that cause spectral blueshifts. We used different sensitization conditions to vary the dye loading and thus the extent of dye aggregation. For each sensitization condition, we explored protonated and native TiO2 films. Computational modeling of different dimeric aggregates with increasing intermolecular interactions and simulation of the associated optical responses also confirm the observed spectral blueshifts. Our results show that both the presence of surface protons and solvent stabilize the excited state of the adsorbed dye molecules, which causes a marked redshift in the absorption maximum and thus moves in the opposite direction to the shift due to the increase in the surface coverage. PMID- 24402778 TI - Expression of FAP, ADAM12, WISP1, and SOX11 is heterogeneous in aggressive fibromatosis and spatially relates to the histologic features of tumor activity. AB - Aggressive fibromatosis (AF) represents a group of tumors with a variable and unpredictable clinical course, characterized by a monoclonal proliferation of myofibroblastic cells. The optimal treatment for AF remains unclear. Identification and validation of genes whose expression patterns are associated with AF may elucidate biological mechanisms in AF, and aid treatment selection. This study was designed to examine the protein expression by immunohistochemistry (IHC) of four genes, ADAM12, FAP, SOX11, and WISP1, that were found in an earlier study to be uniquely overexpressed in AF compared with normal tissues. Digital image analysis was performed to evaluate inter- and intratumor heterogeneity, and correlate protein expression with histologic features, including a histopathologic assessment of tumor activity, defined by nuclear chromatin density ratio (CDR). AF tumors exhibited marked inter- and intratumor histologic heterogeneity. Pathologic assessment of tumor activity and digital assessment of average nuclear size and CDR were all significantly correlated. IHC revealed protein expression of all four genes. IHC staining for ADAM12, FAP, and WISP1 correlated with CDR and was higher, whereas SOX11 staining was lower in tumors with earlier recurrence following excision. All four proteins were expressed, and the regional variation in tumor activity within and among AF cases was demonstrated. A spatial correlation between protein expression and nuclear morphology was observed. IHC also correlated with the probability of recurrence following excision. These proteins may be involved in AF pathogenesis and the corresponding pathways could serve as potential targets of therapy. PMID- 24402780 TI - Signal detection of adverse events with imperfect confirmation rates in vaccine safety studies using self-controlled case series design. AB - The Vaccine Safety Datalink project captures electronic health record data including vaccinations and medically attended adverse events on 8.8 million enrollees annually from participating managed care organizations in the United States. While the automated vaccination data are generally of high quality, a presumptive adverse event based on diagnosis codes in automated health care data may not be true (misclassification). Consequently, analyses using automated health care data can generate false positive results, where an association between the vaccine and outcome is incorrectly identified, as well as false negative findings, where a true association or signal is missed. We developed novel conditional Poisson regression models and fixed effects models that accommodate misclassification of adverse event outcome for self-controlled case series design. We conducted simulation studies to evaluate their performance in signal detection in vaccine safety hypotheses generating (screening) studies. We also reanalyzed four previously identified signals in a recent vaccine safety study using the newly proposed models. Our simulation studies demonstrated that (i) outcome misclassification resulted in both false positive and false negative signals in screening studies; (ii) the newly proposed models reduced both the rates of false positive and false negative signals. In reanalyses of four previously identified signals using the novel statistical models, the incidence rate ratio estimates and statistical significances were similar to those using conventional models and including only medical record review confirmed cases. PMID- 24402781 TI - 2,5-difluorenyl-substituted siloles for the fabrication of high-performance yellow organic light-emitting diodes. AB - 2,3,4,5-Tetraarylsiloles are a class of important luminogenic materials with efficient solid-state emission and excellent electron-transport capacity. However, those exhibiting outstanding electroluminescence properties are still rare. In this work, bulky 9,9-dimethylfluorenyl, 9,9-diphenylfluorenyl, and 9,9' spirobifluorenyl substituents were introduced into the 2,5-positions of silole rings. The resulting 2,5-difluorenyl-substituted siloles are thermally stable and have low-lying LUMO energy levels. Crystallographic analysis revealed that intramolecular pi-pi interactions are prone to form between 9,9'-spirobifluorene units and phenyl rings at the 3,4-positions of the silole ring. In the solution state, these new siloles show weak blue and green emission bands, arising from the fluorenyl groups and silole rings with a certain extension of pi conjugation, respectively. With increasing substituent volume, intramolecular rotation is decreased, and thus the emissions of the present siloles gradually improved and they showed higher fluorescence quantum yields (Phi(F) =2.5-5.4%) than 2,3,4,5 tetraphenylsiloles. They are highly emissive in solid films, with dominant green to yellow emissions and good solid-state Phi(F) values (75-88%). Efficient organic light-emitting diodes were fabricated by adopting them as host emitters and gave high luminance, current efficiency, and power efficiency of up to 44,100 cd m(-2), 18.3 cd A(-1), and 15.7 lm W(-1), respectively. Notably, a maximum external quantum efficiency of 5.5% was achieved in an optimized device. PMID- 24402782 TI - The role of coupling strength and internal delay between compartments in shaping the bursting behavior of cortical neuron. AB - Bursting is a typical firing behavior intrinsically existing in neurons from many brain regions, which has been thought to have functional roles in neuronal reliable signaling and synaptic plasticity. Meanwhile, many factors have been put forward to participate in the modulation of bursting behavior during the past decades. Here, in this research, the modulation of bursting behaviors was numerically investigated in a two-compartment model of cortical pyramidal neuron using the coupling strength and time delay between compartments as control parameters. By means of computer simulations, we showed that, for larger coupling strengths and smaller delays between the two compartments, a wide range of regular bursting can be observed, while too large coupling strengths and time delays would cause the model neuron to be quiescent. In addition, the dynamical firing range of regular spiking can be also obtained, which has two parts: one part corresponds to small coupling strengths irrespective of the values of time delay, while another part corresponds to larger coupling strengths and delays. These results suggested that coupling strength and internal time delay between the inner compartments possess potential roles in modulating the dynamical bursting behavior of neurons. PMID- 24402783 TI - MiR-429 inhibits cells growth and invasion and regulates EMT-related marker genes by targeting Onecut2 in colorectal carcinoma. AB - The 5-year survival rate for colorectal cancer is approximately 55 % because of its invasion and metastasis. The epithelial-mesenchymal transition (EMT) is one of the well-defined processes during the invasion and distant metastasis of primary epithelial tumors. miR-429, a member of the miR-200 family of microRNAs, was previously shown to inhibit the expression of transcriptional repressors ZEB1/delta EF1 and SIP1/ZEB2, and regulate EMT. In this study, we showed that miR 429 was significantly downregulated in colorectal carcinoma (CRC) tissues and cell lines. We found that miR-429 inhibited the proliferation and growth of CRC cells in vitro and in vivo, suggesting that miR-429 could play a role in CRC tumorigenesis. We also showed that downregulation of miR-429 may contribute to carcinogenesis and the initiation of EMT of CRC by targeting Onecut2. Further researches indicated that miR-429 inhibited the cells migration and invasion and reversed TGF-beta-induced EMT changes in SW620 and SW480 cells. miR-429 could reverse the change of EMT-related markers genes induced by TGF-beta1, such as E cadherin, CTNNA1, CTNNB1, TFN, CD44, MMP2, Vimentin, Slug, Snail, and ZEB2 by targeting Onecut2. Taken together, our data showed that transcript factor Onecut2 is involved in the EMT, migration and invasion of CRC cells; miR-429 inhibits the initiation of EMT and regulated expression of EMT-related markers by targeting Onecut2; and miR-429 or Onecut2 is the important therapy target for CRC. PMID- 24402784 TI - Antidepressants for smoking cessation. AB - BACKGROUND: There are at least three reasons to believe antidepressants might help in smoking cessation. Firstly, nicotine withdrawal may produce depressive symptoms or precipitate a major depressive episode and antidepressants may relieve these. Secondly, nicotine may have antidepressant effects that maintain smoking, and antidepressants may substitute for this effect. Finally, some antidepressants may have a specific effect on neural pathways (e.g. inhibiting monoamine oxidase) or receptors (e.g. blockade of nicotinic-cholinergic receptors) underlying nicotine addiction. OBJECTIVES: The aim of this review is to assess the effect and safety of antidepressant medications to aid long-term smoking cessation. The medications include bupropion; doxepin; fluoxetine; imipramine; lazabemide; moclobemide; nortriptyline; paroxetine; S-Adenosyl-L Methionine (SAMe); selegiline; sertraline; St. John's wort; tryptophan; venlafaxine; and zimeledine. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group Specialised Register which includes reports of trials indexed in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and PsycINFO, and other reviews and meeting abstracts, in July 2013. SELECTION CRITERIA: We considered randomized trials comparing antidepressant medications to placebo or an alternative pharmacotherapy for smoking cessation. We also included trials comparing different doses, using pharmacotherapy to prevent relapse or re initiate smoking cessation or to help smokers reduce cigarette consumption. We excluded trials with less than six months follow-up. DATA COLLECTION AND ANALYSIS: We extracted data and assessed risk of bias using standard methodological procedures expected by the Cochrane Collaboration.The main outcome measure was abstinence from smoking after at least six months follow-up in patients smoking at baseline, expressed as a risk ratio (RR). We used the most rigorous definition of abstinence available in each trial, and biochemically validated rates if available. Where appropriate, we performed meta-analysis using a fixed-effect model. MAIN RESULTS: Twenty-four new trials were identified since the 2009 update, bringing the total number of included trials to 90. There were 65 trials of bupropion and ten trials of nortriptyline, with the majority at low or unclear risk of bias. There was high quality evidence that, when used as the sole pharmacotherapy, bupropion significantly increased long-term cessation (44 trials, N = 13,728, risk ratio [RR] 1.62, 95% confidence interval [CI] 1.49 to 1.76). There was moderate quality evidence, limited by a relatively small number of trials and participants, that nortriptyline also significantly increased long term cessation when used as the sole pharmacotherapy (six trials, N = 975, RR 2.03, 95% CI 1.48 to 2.78). There is insufficient evidence that adding bupropion (12 trials, N = 3487, RR 1.9, 95% CI 0.94 to 1.51) or nortriptyline (4 trials, N = 1644, RR 1.21, 95% CI 0.94 to 1.55) to nicotine replacement therapy (NRT) provides an additional long-term benefit. Based on a limited amount of data from direct comparisons, bupropion and nortriptyline appear to be equally effective and of similar efficacy to NRT (bupropion versus nortriptyline 3 trials, N = 417, RR 1.30, 95% CI 0.93 to 1.82; bupropion versus NRT 8 trials, N = 4096, RR 0.96, 95% CI 0.85 to 1.09; no direct comparisons between nortriptyline and NRT). Pooled results from four trials comparing bupropion to varenicline showed significantly lower quitting with bupropion than with varenicline (N = 1810, RR 0.68, 95% CI 0.56 to 0.83). Meta-analyses did not detect a significant increase in the rate of serious adverse events amongst participants taking bupropion, though the confidence interval only narrowly missed statistical significance (33 trials, N = 9631, RR 1.30, 95% CI 1.00 to 1.69). There is a risk of about 1 in 1000 of seizures associated with bupropion use. Bupropion has been associated with suicide risk, but whether this is causal is unclear. Nortriptyline has the potential for serious side-effects, but none have been seen in the few small trials for smoking cessation.There was no evidence of a significant effect for selective serotonin reuptake inhibitors on their own (RR 0.93, 95% CI 0.71 to 1.22, N = 1594; 2 trials fluoxetine, 1 paroxetine, 1 sertraline) or as an adjunct to NRT (3 trials of fluoxetine, N = 466, RR 0.70, 95% CI 0.64 to 1.82). Significant effects were also not detected for monoamine oxidase inhibitors (RR 1.29, 95% CI 0.93 to 1.79, N = 827; 1 trial moclobemide, 5 selegiline), the atypical antidepressant venlafaxine (1 trial, N = 147, RR 1.22, 95% CI 0.64 to 2.32), the herbal therapy St John's wort (hypericum) (2 trials, N = 261, RR 0.81, 95% CI 0.26 to 2.53), or the dietary supplement SAMe (1 trial, N = 120, RR 0.70, 95% CI 0.24 to 2.07). AUTHORS' CONCLUSIONS: The antidepressants bupropion and nortriptyline aid long-term smoking cessation. Adverse events with either medication appear to rarely be serious or lead to stopping medication. Evidence suggests that the mode of action of bupropion and nortriptyline is independent of their antidepressant effect and that they are of similar efficacy to nicotine replacement. Evidence also suggests that bupropion is less effective than varenicline, but further research is needed to confirm this finding. Evidence suggests that neither selective serotonin reuptake inhibitors (e.g. fluoxetine) nor monoamine oxidase inhibitors aid cessation. PMID- 24402790 TI - Comparing activated sludge fungal community population diversity using denaturing gradient gel electrophoresis and terminal restriction fragment length polymorphism. AB - We compared the relative values of denaturing gradient gel electrophoresis (DGGE) and terminal restriction fragment length polymorphism (T-RFLP) for profiling fungal communities in wastewater treatment plants using both ITS and 18S rRNA gene fragments as phylogenetic markers. A similar number of fungal ribotypes was obtained with both methods for the same treatment plant when the ITS primer set was used, while a greater number of ribotypes was obtained with T-RFLP compared to DGGE with the 18S rRNA primer set. Non-metric multi-dimensional scaling of presence/absence data and analysis of similarity showed that both methods could distinguish between the different plant communities at a statistically significant level (p < 0.05), regardless of which phylogenetic marker was used. The data suggest that both methods can be used preferably together to profile activated sludge fungal communities. A comparison of profiles generated with both these phylogenetic markers based on the number of ribotypes/bands, suggests that the 18S rRNA region is more discriminatory than the ITS region. Detected differences in fungal community compositions between plants probably reflect differences in their influent compositions and operational parameters. PMID- 24402793 TI - When would the assessment of fractional flow reserve be nonreproducible? PMID- 24402795 TI - Crystallography and chemistry: an ongoing engagement. PMID- 24402794 TI - Polygynous contexts, family structure, and infant mortality in sub-saharan Africa. AB - Contextual characteristics influence infant mortality above and beyond family level factors. The widespread practice of polygyny is one feature of many sub Saharan African contexts that may be relevant to understanding patterns of infant mortality. Building on evidence that the prevalence of polygyny reflects broader economic, social, and cultural features and that it has implications for how families engage in the practice, we investigate whether and how the prevalence of polygyny (1) spills over to elevate infant mortality for all families, and (2) conditions the survival disadvantage for children living in polygynous families (i.e., compared with monogamous families). We use data from Demographic and Health Surveys to estimate multilevel hazard models that identify associations between infant mortality and region-level prevalence of polygyny for 236,336 children in 260 subnational regions across 29 sub-Saharan African countries. We find little evidence that the prevalence of polygyny influences mortality for infants in nonpolygynous households net of region-level socioeconomic factors and gender inequality. However, the prevalence of polygyny significantly amplifies the survival disadvantage for infants in polygynous families. Our findings demonstrate that considering the broader marital context reveals important insights into the relationship between family structure and child well-being. PMID- 24402798 TI - Infrared detection of Criegee intermediates formed during the ozonolysis of beta pinene and their reactivity towards sulfur dioxide. AB - Recently, direct kinetic experiments have shown that the oxidation of sulfur dioxide to sulfur trioxide by reaction with stabilized Criegee intermediates (CIs) is an important source of sulfuric acid in the atmosphere. So far, only small CIs, generated in photolysis experiments, have been directly detected. Herein, it is shown that large, stabilized CIs can be detected in the gas phase by FTIR spectroscopy during the ozonolysis of beta-pinene. Their transient absorption bands between 930 and 830 cm(-1) appear only in the initial phase of the ozonolysis reaction when the scavenging of stabilized CIs by the reaction products is slow. The large CIs react with sulfur dioxide to give sulfur trioxide and nopinone with a yield exceeding 80%. Reactant consumption and product formation in time-resolved beta-pinene ozonolysis experiments in the presence of sulfur dioxide have been kinetically modeled. The results suggest a fast reaction of sulfur dioxide with CIs arising from beta-pinene ozonolysis. PMID- 24402799 TI - Stereoselective synthesis of silicon-stereogenic aminomethoxysilanes: easy access to highly enantiomerically enriched siloxanes. AB - A route towards the synthesis of N,O-functionalized silicon-stereogenic organosilanes with excellent optical purities has been developed. Investigations into the stereoconvergence and configurational stability of an aminomethoxysilane suggest a kinetically controlled multistep substitution mechanism. Selective exchange of the Si-N bond by a second Si-O bond builds the basis for the controlled formation of chiral siloxane units with different oxygen-containing functional groups. Subsequent reactions of the chiral aminomethoxysilanes with hydroxy groups support a general inversion mechanism at the asymmetrically substituted silicon atom of N,O-functionalized organosilanes. PMID- 24402800 TI - Shape-dependent optoelectronic cell lysis. AB - We show an electrical method to break open living cells amongst a population of different cell types, where cell selection is based upon their shape. We implement the technique on an optoelectronic platform, where light, focused onto a semiconductor surface from a video projector creates a reconfigurable pattern of electrodes. One can choose the area of cells to be lysed in real-time, from single cells to large areas, simply by redrawing the projected pattern. We show that the method, based on the "electrical shadow" that the cell casts, allows the detection of rare cell types in blood (including sleeping sickness parasites), and has the potential to enable single cell studies for advanced molecular diagnostics, as well as wider applications in analytical chemistry. PMID- 24402801 TI - Efficient amide bond formation through a rapid and strong activation of carboxylic acids in a microflow reactor. AB - The development of highly efficient amide bond forming methods which are devoid of side reactions, including epimerization, is important, and such a method is described herein and is based on the concept of rapid and strong activation of carboxylic acids. Various carboxylic acids are rapidly (0.5 s) converted into highly active species, derived from the inexpensive and less-toxic solid triphosgene, and then rapidly (4.3 s) reacted with various amines to afford the desired peptides in high yields (74%-quant.) without significant epimerization (<=3%). Our process can be carried out at ambient temperature, and only CO2 and HCl salts of diisopropylethyl amine are generated. In the long history of peptide synthesis, a significant number of active coupling reagents have been abandoned because the highly active electrophilic species generated are usually susceptible to side reactions such as epimerization. The concept presented herein should renew interest in the use of these reagents. PMID- 24402803 TI - Guidewire withdrawal in ascending aorta increases cerebral microembolism during coronary angiography: a randomized comparison of two guidewire techniques. AB - BACKGROUND: Microemboli are frequently detected entering the middle cerebral arteries during coronary angiography (CA). Recent studies have reported that cerebral microemboli, especially particulate cerebral microemboli, may cause silent ischemic cerebral lesions. AIMS: To investigate whether the occurrence of particulate cerebral microemboli during diagnostic CA is influenced by which guidewire technique is used. METHODS: Patients with stable angina pectoris or non ST elevation acute coronary syndrome, referred for CA, were randomized to initial advancement of catheters with a leading guidewire over the aortic arch or to initial guidewire withdrawal in the descending aorta with advancement of catheters alone. After completed CA (part 1), new catheters and guidewires were advanced with guidewire technique contrary to the one first used (part 2). Patients were continuously monitored with transcranial Doppler (TCD), and cerebral microemboli were automatically counted and differentiated. RESULTS: Statistical analysis was performed on 41 patients. The results in part 1 were confirmed in part 2. The median number (interquartile range) of particulate cerebral microemboli was significantly higher when catheters were advanced with, compared to without, a guidewire over the aortic arch; overall, 6 (IQR, 1-9) vs 1 (IQR, 0-3); P=.01. CONCLUSIONS: Advancement of catheters with a leading guidewire over the aortic arch with subsequent flushing in the ascending aorta consistently generated more particulate cerebral microemboli, implying that the choice of guidewire technique has an impact on the risk for cerebral lesions during CA. PMID- 24402802 TI - Assessment of Appalachian region pediatric hearing healthcare disparities and delays. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study was to examine the timing of diagnostic and therapeutic services in cochlear implant recipients from a rural Appalachian region with healthcare disparity. STUDY DESIGN: Retrospective analysis. METHODS: Cochlear implant recipients from a tertiary referral center born with severe congenital sensorineural hearing loss were examined. Rural status and Appalachian status of their county of origin were recorded. A log-rank test was used to examine differences in the distributions of time to definitive diagnosis of hearing loss, initial amplification fitting, and cochlear implantation in these children. Correlation analysis of the rural status of each county and the timing of services was assessed. RESULTS: A total of 53 children born with congenital hearing loss were included in the study (36 from rural counties and 17 from urban/suburban counties). The distribution of weeks after birth to diagnosis (P=.006), amplification (P=.030), and cochlear implantation (P=.002) was delayed in rural children compared with urban children. An analysis factoring in the effect of implementation of mandatory infant hearing screening in 2000 demonstrated a similar delay in rural children for weeks to diagnosis (P=.028), amplification (P=.087), and cochlear implantation (P<.0001). CONCLUSIONS: Children with severe hearing loss in very rural areas, such as Appalachia, may have significant delays in diagnostic and rehabilitative services. Further investigation is warranted to assess causative factors in delays of cochlear implantation and to develop interventions to promote timely diagnosis and care. LEVEL OF EVIDENCE: 3b. PMID- 24402804 TI - Gradual decline in the age-adjusted in-hospital mortality rate from STEMI-related cardiogenic shock irrespective of cause, race or gender with persistent higher mortality rates in women despite multivariate adjustment. AB - BACKGROUND: Recent improvements in the care of critically ill patients with cardiogenic shock (CS) should be associated with improved outcomes. The goal of this study was to evaluate the trends of age-adjusted mortality rates for all cause and ST-elevation myocardial infarction (STEMI)-related CS in the United States. METHODS: The Nationwide Inpatient Sample (NIS) database was utilized to calculate the age-adjusted mortality rate of all-cause and STEMI-related CS from 1996 to 2006. We used specific ICD- 9 codes for CS and STEMI based on race and gender. RESULTS: We found a gradual decrease in mortality over the 10-year period in patients suffering from all causes or STEMI-related CS irrespective of gender and race with a persistently higher mortality rates in women and African Americans. However, after multivariate adjustment, only female gender remains associated with persistently higher mortality. The age-adjusted mortality rate from STEMI-related CS in women was 2.2% in 1996, with a gradual reduction to the lowest level of 1.7% in 2006 (P<.01). Likewise, the age-adjusted mortality rate from STEMI-related CS in men was 1.7% in 1996, which declined to the lowest level of 1.4% in 2006 (P<.01). CONCLUSION: Regardless of gender and race, age-adjusted in-hospital mortality is gradually declining in patients presenting with all causes or STEMI-related CS. However, as compared to men, women suffer from persistently higher mortality rates in the setting of STEMI-related CS despite multivariate adjustment. PMID- 24402805 TI - Impact of a chronic total occlusion in a non-infarct related artery on clinical outcomes following primary percutaneous intervention in acute ST-elevation myocardial infarction. AB - AIMS: We aimed to assess the impact of a non-infarct related artery (IRA) chronic total occlusion (CTO) on clinical outcomes following primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI) in a real-world cohort of patients. METHODS AND RESULTS: This is a retrospective observational study of 1435 patients treated at a large single tertiary cardiac center providing a high-volume PPCI service. Patients with coexisting CTO (4.7%) were significantly more likely to have presented in cardiogenic shock and less likely to achieve TIMI 2/3 flow in the IRA post procedure resulting in lower ejection fraction and higher peak troponin-T levels. A concurrent CTO in a non IRA was associated with higher in-hospital mortality (16.4% vs 3.1%; P<.001), 30 day mortality (19.4% vs 5.9%; P<.001) and long-term mortality (23.9% vs 12.2%; P=.01). Binary logistic regression analysis showed that the presence of a non-IRA CTO was independently predictive of mortality at 30 days (odds ratio, 3.2; 95% confidence interval, 1.2-8.1) but not for long-term mortality. CONCLUSION: The presence of a coexisting CTO in patients undergoing PPCI for STEMI is associated with adverse clinical outcomes; further work is required to improve prognosis in these patients, which may include early staged revascularization of the non-IRA CTO. PMID- 24402806 TI - SINC or swim (should we intervene in non-culprit vessels during STEMI?). PMID- 24402807 TI - Utility of fluoroscopy in teaching trainees groin puncture technique. AB - OBJECTIVES: To assess trainee physicians' ability to puncture at the femoral head and complication rates when obtaining access to the common femoral artery using fluoroscopy. BACKGROUND: The common femoral artery is the most common artery accessed during cardiac catheterization. Fluoroscopy can be used to visualize the femoral head and estimate the common femoral artery location. Puncture superior or inferior to the femoral head is associated with increased rates of retroperitoneal bleeding or thrombosis, respectively. Adequate training in groin puncture technique is essential in minimizing complications and upholding patient safety. METHODS: Two consecutive samples of patients were retrospectively analyzed - one from Keck Medical Center (Keck) (n = 45), and one from Los Angeles County-University of Southern California (LAC-USC) (n = 100). An attending interventional cardiologist performed all groin punctures at Keck, and a trainee performed groin puncture at LAC-USC after detailed faculty instruction. A single reviewer retrospectively analyzed all angiograms. Puncture was recorded as occurring above, below, or at the femoral head. RESULTS: Percentage of punctures at the femoral head between LAC-USC vs Keck was not significantly different (93.0% vs 95.6%; P=.26). There was no significant difference in percentage of punctures below and above the femoral head between both groups, and no difference in complications. CONCLUSION: Femoral artery puncture at the femoral head is associated with improved outcomes. Our data show no significant difference between attending physicians' and trainees' ability to puncture at the level of the femoral head. Groin puncture using fluoroscopy can be taught to a high proficiency level with appropriate instruction. PMID- 24402808 TI - A critical view of the peripheral atherectomy data in the treatment of infrainguinal arterial disease. AB - BACKGROUND: Revascularization of the peripheral arteries remains technically challenging. By decreasing the volume of the atherosclerotic plaque, debulking procedures may confer superior primary patency after revascularization. AIMS: To assess the impact of atherectomy on primary patency rates at 12 months compared to balloon angioplasty and/or stent placement alone in patients with infrainguinal arterial disease. METHODS: A database search for "directional," "orbital," "rotational," and "laser atherectomy" in peripheral arterial disease (PAD) was performed. Studies were screened according to the STROBE (Strengthening the Reporting of Observational studies in Epidemiology) critical appraisal tool and summarized by population, methodology, and outcomes (primary patency and major adverse events). RESULTS: Only two randomized studies were found. Most of the data were obtained from single-arm studies and registries. The primary patency with directional atherectomy approaches 60% at 12 months as a stand-alone technique, whereas orbital atherectomy in conjunction with balloon angioplasty and stenting achieved primary patency rates of 90%. Laser atherectomy is universally employed with balloon angioplasty and stenting for in-stent restenosis lesions with a primary patency rate of 64%. Although there are data for the safe use of rotational atherectomy, robust data to support its effectiveness are lacking. The combination of drug-coated balloons and atherectomy for the treatment of heavily calcified lesions in patients with critical limb ischemia is under evaluation. CONCLUSION: Despite the successful procedural outcomes reported in clinical registries, the available data do not support the use of atherectomy alone in PAD. Larger randomized controlled studies are warranted to define its role in contemporary endovascular practice. PMID- 24402809 TI - Aneurysmal SAH: current management and complications associated with treatment and disease. AB - The purpose of this article is to give an overview of the management of the most common complications encountered during subarachnoid hemorrhage and endovascular treatment of intracranial aneurysms. We reviewed the literature and identified the complications encountered during endovascular treatment of intracranial aneurysms. We report current management strategies of complications associated with subarachnoid hemorrhage and the interventional procedure. Aneurysmal subarachnoid hemorrhage remains a devastating condition, with high mortality and poor outcome among survivors. The successful treatment of intracranial aneurysms requires a multidisciplinary approach and the treating physicians need to be aware of predisposing factors for complications, their frequency, and also their management. PMID- 24402810 TI - Transcatheter device occlusion of a large pulmonary arteriovenous fistula by exit closure: the road less travelled. AB - Large pulmonary arteriovenous fistula (PAVF) manifests as cyanosis and predisposes to serious complications of right-to-left shunt, and therefore necessitates early treatment. The emergence of antegrade transcatheter closure of feeding arteries as treatment of choice is limited by inherent risk of either recanalization or reappearance of new feeders and potential risk of systemic embolization. Additional closure of the draining vessel by transcatheter device occlusion should overcome the limitations of conventional antegrade technique. We describe two cases of successful transcatheter closure of a large PAVF by antegrade device closure of feeders as well as transseptal retrograde closure of the exiting channel. PMID- 24402811 TI - LAST (local anesthetic systemic toxicity) but not least: systemic lidocaine toxicity during cardiac intervention. AB - Lidocaine is the most common medication used for local anesthesia in cardiac procedures. Sometimes, a higher dose of lidocaine is used to improve the patient's comfort, especially in device implantation or complex interventional procedures requiring several sheath insertions for access. We describe a patient with idiopathic cardiomyopathy who underwent implantable cardioverter defibrillator implantation for primary prevention and developed local anesthetic systemic toxicity (LAST) associated with lidocaine use. Multiple susceptible factors leading to lidocaine toxicity found in this case are common in patients with advanced heart failure. This case emphasizes the importance of dose adjustment of local anesthetic agents in individual patients, especially those with advanced heart failure who undergo cardiovascular procedures. The risk factors, preventive measures, and therapeutic approaches to manage this type of complication are discussed in detail. PMID- 24402812 TI - Snare removal of a deformed coronary stent via radial artery during percutaneous intervention for acute myocardial infarction. AB - A 49-year-old man underwent emergent coronary angiography for acute inferior myocardial infarction (MI). After balloon angioplasty of culprit right coronary artery (RCA) occlusion, a Promus Element stent would not advance to the target lesion. The proximal end of the stent became compressed against the tip of the guiding catheter, such that the stent could neither be advanced nor withdrawn. This case illustrates the technical aspects of snare removal of a severely deformed stent via the radial artery. PMID- 24402813 TI - Multiple and recurrent coronary stent fractures. AB - Coronary stent fracture is an increasingly recognized complication mainly involving drug-eluting stents. Important clinical implications, including in stent restenosis and stent thrombosis, have been associated with this phenomenon. Variable incidence rates and several predisposing factors have been reported, but no general agreement exists on the best treatment strategy. We report a case of recurrent multiple left anterior descending artery sirolimus-eluting stent fractures, with variable clinical presentations ranging from recurrent angina to acute myocardial infarction and ventricular fibrillation cardiac arrest, that were ultimately treated with coronary artery bypass surgery. PMID- 24402814 TI - Synthesis of water-soluble red-emitting thienyl-BODIPYs and bovine serum albumin labeling. AB - The synthesis of three red-emitting and water-soluble thienyl-BODIPYs has been achieved. The trimethyl(propargyl)ammonium group was chosen as a vector for water solubility. One or two cationic arms were introduced either on the 2-position of the thienyl unit or on the 4-position on the boron atom. These dyes have pronounced absorption around 600 nm and intense emission at 650 nm with quantum yield of about 60% in water. Grafting of such BODIPYs via a flexible arm to BSA is very efficient, allowing attachment of 1 to 30 labels in a controlled manner. Very strong fluorescence (quantum yield 56%)without aggregation of the dye at a low loading ratio (1:5 BSA/label) in PBS buffer is measured. PMID- 24402815 TI - Systematic review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia. AB - BACKGROUND: Hypocalcaemia is common after thyroidectomy. Accurate prediction and appropriate management may help reduce morbidity and hospital stay. The aim of this study was to perform a systematic literature review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia. METHODS: A systematic search of PubMed, EMBASE and the Cochrane Library databases was undertaken, and the quality of manuscripts assessed using a modified Newcastle-Ottawa Scale. RESULTS: Some 115 observational studies were included. The median (i.q.r.) incidence of transient and permanent hypocalcaemia was 27 (19-38) and 1 (0-3) per cent respectively. Independent predictors of transient hypocalcaemia included levels of preoperative calcium, perioperative parathyroid hormone (PTH), preoperative 25 hydroxyvitamin D and postoperative magnesium. Clinical predictors included surgery for recurrent goitre and reoperation for bleeding. A calcium level lower than 1.88 mmol/l at 24 h after surgery, identification of fewer than two parathyroid glands (PTGs) at surgery, reoperation for bleeding, Graves' disease and heavier thyroid specimens were identified as independent predictors of permanent hypocalcaemia in multivariable analysis. Factors associated with transient hypocalcaemia in meta-analyses were inadvertent PTG excision (odds ratio (OR) 1.90, 95 per cent confidence interval 1.31 to 2.74), PTG autotransplantation (OR 2.03, 1.44 to 2.86), Graves' disease (OR 1.75, 1.34 to 2.28) and female sex (OR 2.28, 1.53 to 3.40). CONCLUSION: Perioperative PTH, preoperative vitamin D and postoperative changes in calcium are biochemical predictors of post-thyroidectomy hypocalcaemia. Clinical predictors include female sex, Graves' disease, need for parathyroid autotransplantation and inadvertent excision of PTGs. PMID- 24402816 TI - Identifying novel oncogenes: a machine learning approach. AB - Genome sequencing has overflowed the databases with huge amount of SNP data. Although the amount of detected single nucleotide polymorphisms (SNPs) is rising exponentially every day, we still lag behind in characterization techniques. Implementing computational platforms to determine the pathogenecity associated with the SNPs can provide a probable solution to this problem. To improve the prediction quality for SNP characterization methods, we implemented machine learning support vector classification method. Total 557 non-synonymous amino acid variants were collected from CENP family proteins, excluding CENPE. Multivariate simulation of associated changes in biological phenomena's for each SNPs was computed through available SNP analysis platforms. Support vector model was designed using training dataset and the raw classification data was subjected to the classification hyperplane. We observed multiple evidences of cancer associated genetic mutations in CENPI, CENPJ, CENPK, CENPL and CENPX protein. The former four proteins have showed positive hits in cosmic database for mutations in tumour samples, but CENPX has never been reported before for the cancer associated outcomes. Since CENPX has been recently classified and not much functional and pathological insight has been, the results obtained in this study will serve as a starting point for future investigation on cancer research in association to CENPX protein. PMID- 24402817 TI - Study on variability assessment and evolutionary relationships of glutamate racemase in Pseudomonas species. AB - Pseudomonas species is known to cause multiple nosocomial infections in patients and results in high morbidity and mortality rates (10%). The greatest obstacle in treating patients infected with the Pseudomonas species is the widespread emergence of antibiotic resistance. Hence, there is an urgent need to develop new compounds which can be effective against Pseudomonas species and possibly remain tolerant to drug resistance. The enzyme glutamate racemase plays an important role in cell wall synthesis of bacteria and as a rate limiting step, thus it is an excellent target for the designing of new class of antibacterial agents. The objective of this study is to investigate the variations in sequences of glutamate racemase, a potential drug target across the all 31 species of Pseudomonas. Sequence variability and conservation for functional motif identification is helpful for identifying evolutionarily important residues with functional significance; subsequently these results of variable sites were supported by entropy profile obtained from protein variability server using Shannon entropy. Phylogenetic profile among the different Pseudomonas sp. having fully/highly conserved residues was observed, suggesting possible functional similarities between them. The variation analysis in conserved and non-conserved region of the sequence can be used to predict the binding site for target specific drug discovery. PMID- 24402818 TI - In silico prediction of structure and functions for some proteins of male specific region of the human Y chromosome. AB - Male-specific region of the human Y chromosome (MSY) comprises 95% of its length that is functionally active. This portion inherits in block from father to male offspring. Most of the genes in the MSY region are involved in male-specific function, such as sex determination and spermatogenesis; also contains genes probably involved in other cellular functions. However, a detailed characterization of numerous MSY-encoded proteins still remains to be done. In this study, 12 uncharacterized proteins of MSY were analyzed through bioinformatics tools for structural and functional characterization. Within these 12 proteins, a total of 55 domains were found, with DnaJ domain signature corresponding to be the highest (11%) followed by both FAD-dependent pyridine nucleotide reductase signature and fumarate lyase superfamily signature (9%). The 3D structures of our selected proteins were built up using homology modeling and the protein threading approaches. These predicted structures confirmed in detail the stereochemistry; indicating reasonably good quality model. Furthermore the predicted functions and the proteins with whom they interact established their biological role and their mechanism of action at molecular level. The results of these structure-functional annotations provide a comprehensive view of the proteins encoded by MSY, which sheds light on their biological functions and molecular mechanisms. The data presented in this study may assist in future prognosis of several human diseases such as Turner syndrome, gonadal sex reversal, spermatogenic failure, and gonadoblastoma. PMID- 24402819 TI - Underlying mathematics in diversification of human olfactory receptors in different loci. AB - As per conservative estimate, approximately 51-105 Olfactory Receptors (ORs) loci are present in human genome occurring in clusters. These clusters are apparently unevenly spread as mosaics over 21 pairs of human chromosomes. Olfactory Receptor (OR) gene families which are thought to have expanded for the need to provide recognition capability for a huge number of pure and complex odorants, form the largest known multigene family in the human genome. Recent studies have shown that 388 full length and 414 OR pseudo-genes are present in these OR genomic clusters. In this paper, the authors report a classification method for all human ORs based on their sequential quantitative information like presence of poly strings of nucleotides bases, long range correlation and so on. An L-System generated sequence has been taken as an input into a star-model of specific subfamily members and resultant sequence has been mapped to a specific OR based on the classification scheme using fractal parameters like Hurst exponent and fractal dimensions. PMID- 24402820 TI - Computational evaluation of new homologous down regulators of Translationally Controlled Tumor Protein (TCTP) targeted for tumor reversion. AB - The Translationally Controlled Tumor Protein (TCTP) has been investigated for tumor reversion and is a target of cancer therapy. Down regulators which suppress the expression of TCTP can trigger the process of tumor reversion leading to the transformation of tumor cells into revertant cells. The present investigation is a novel protein-protein docking approach to target TCTP by a set of proteins similar to the protein: sorting nexin 6 (SNX6) which is an established down regulator of TCTP. The established down regulator along with its set of most similar proteins were modeled using the PYTHON based software - MODELLER v9.9, followed by structure validation using the Procheck Package. Further TCTP was docked with its established and prospective down regulators using the flexible docking protocol suite HADDOCK. The results were evaluated and ranked according to the RMSD values of the complex and the HADDOCK score, which is a weighted sum of van der Waal's energy, electrostatic energy, restraints violation energy and desolvation energy. Results concluded the protein sorting nexin 6 of Mus musculus to be a better down regulator of TCTP, as compared to the suggested down regulator (Homo sapiens snx6). PMID- 24402821 TI - Studies on interaction of insect repellent compounds with odorant binding receptor proteins by in silico molecular docking approach. AB - The aim of the study was to identify the interactions between insect repellent compounds and target olfactory proteins. Four compounds, camphor (C10H16O), carvacrol (C10H14O), oleic acid (C18H34O2) and firmotox (C22H28O5) were chosen as ligands. Seven olfactory proteins of insects with PDB IDs: 3K1E, 1QWV, 1TUJ, 1OOF, 2ERB, 3R1O and OBP1 were chosen for docking analysis. Patch dock was used and pymol for visualizing the structures. The interactions of these ligands with few odorant binding proteins showed binding energies. The ligand camphor had showed a binding energy of -136 kcal/mol with OBP1 protein. The ligand carvacrol interacted with 1QWV and 1TUJ proteins with a least binding energy of -117.45 kcal/mol and -21.78 kcal/mol respectively. The ligand oleic acid interacted with 1OOF, 2ERB, 3R1O and OBP1 with least binding energies. Ligand firmotox interacted with OBP1 and showed least binding energies. Three ligands (camphor, oleic acid and firmotox) had one, two, three interactions with a single protein OBP1 of Nilaparvatha lugens (Rice pest). From this in silico study we identified the interaction patterns for insect repellent compounds with the target insect odarant proteins. The results of our study revealed that the chosen ligands showed hydrogen bond interactions with the target olfactory receptor proteins. PMID- 24402822 TI - 3D QSAR and pharmacophore study of curcuminoids and curcumin analogs: interaction with thioredoxin reductase. AB - Curcumin is the yellow pigment of Curcuma longa that irreversibly inhibits the activity of thioredoxin reductase (TrxR) and forms adduct. TrxR, a homodimeric enzyme with E and F chains, is responsible for redox control of the cell and defense against oxidative stress. It is also well known that TrxR is over expressed in tumor cells. Hence TrxR is a promising target for curcumin based therapy. Binding site of TrxR for curcumin is at the interface of homodimers. In the present study, naturally occurring curcuminoids and forty four synthetic analogs of curcumin were docked with SP/XP glide suite and E-pharmacophore was simulated. E-pharmacophore of both chains has shown three donor features and one acceptor feature. 3D atom based QSAR models have been proposed for the two series of curcumin analogues of known IC50values. The data obtained indicates that the training set model is quite efficient to predict the test set of data. Obtained models and ADMET prediction could be employed for design and synthesis of more potent inhibitors of TrxR. PMID- 24402823 TI - Uridine monophosphate kinase as potential target for tuberculosis: from target to lead identification. AB - Mycobacterium tuberculosis (Mtb) is a causative agent of tuberculosis (TB) disease, which has affected approximately 2 billion people worldwide. Due to the emergence of resistance towards the existing drugs, discovery of new anti-TB drugs is an important global healthcare challenge. To address this problem, there is an urgent need to identify new drug targets in Mtb. In the present study, the subtractive genomics approach has been employed for the identification of new drug targets against TB. Screening the Mtb proteome using the Database of Essential Genes (DEG) and human proteome resulted in the identification of 60 key proteins which have no eukaryotic counterparts. Critical analysis of these proteins using Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathways database revealed uridine monophosphate kinase (UMPK) enzyme as a potential drug target for developing novel anti-TB drugs. Homology model of Mtb-UMPK was constructed for the first time on the basis of the crystal structure of E. coli UMPK, in order to understand its structure-function relationships, and which would in turn facilitate to perform structure-based inhibitor design. Furthermore, the structural similarity search was carried out using physiological inhibitor UTP of Mtb-UMPK to virtually screen ZINC database. Retrieved hits were further screened by implementing several filters like ADME and toxicity followed by molecular docking. Finally, on the basis of the Glide docking score and the mode of binding, 6 putative leads were identified as inhibitors of this enzyme which can potentially emerge as future drugs for the treatment of TB. PMID- 24402824 TI - Physicochemical properties of the modeled structure of astacin metalloprotease moulting enzyme NAS-36 and mapping the druggable allosteric space of Heamonchus contortus, Brugia malayi and Ceanorhabditis elegans via molecular dynamics simulation. AB - Nematodes represent the second largest phylum in the animal kingdom. It is the most abundant species (500,000) in the planet. It causes chronic, debilitating infections worldwide such as ascariasis, trichuriasis, hookworm, enterobiasis, strongyloidiasis, filariasis and trichinosis, among others. Molecular modeling tools can play an important role in the identification and structural investigation of molecular targets that can act as a vital candidate against filariasis. In this study, sequence analysis of NAS-36 from H. contortus (Heamonchus contortus), B. malayi (Brugia malayi) and C. elegans (Ceanorhabditis elegans) has been performed, in order to identify the conserved residues. Tertiary structure was developed for an insight into the molecular structure of the enzyme. Molecular Dynamics Simulation (MDS) studies have been carried out to analyze the stability and the physical properties of the proposed enzyme models in the H. contortus, B. malayi and C. elegans. Moreover, the drug binding sites have been mapped for inhibiting the function of NAS-36 enzyme. The molecular identity of this protease could eventually demonstrate how ex-sheathment is regulated, as well as provide a potential target of anthelmintics for the prevention of nematode infections. PMID- 24402825 TI - The oral bioavailability of curcumin from micronized powder and liquid micelles is significantly increased in healthy humans and differs between sexes. AB - SCOPE: Curcumin revealed various health-beneficial properties in numerous studies. However its bioavailability is low due to its limited intestinal uptake and rapid metabolism. The aim of our project was to develop novel curcumin formulations with improved oral bioavailability and to study their safety as well as potential sex-differences. METHODS AND RESULTS: In this crossover study, healthy subjects (13 women, 10 men) took, in random order, a single oral dose of 500 mg curcuminoids as native powder, micronized powder, or liquid micelles. Blood and urine samples were collected for 24 h and total curcuminoids and safety parameters were quantified. Based on the area under the plasma concentration-time curve (AUC), the micronized curcumin was 14-, 5-, and 9-fold and micellar curcumin 277-, 114-, and 185-fold better bioavailable than native curcumin in women, men, and all subjects, respectively. Thus, women absorbed curcumin more efficiently than men. All safety parameters remained within the reference ranges following the consumption of all formulations. CONCLUSION: Both, the micronized powder and in particular the liquid micellar formulation of curcumin significantly improved its oral bioavailability without altering safety parameters and may thus be ideally suited to deliver curcumin in human intervention trials. The observed sex differences in curcumin absorption warrant further investigation. PMID- 24402826 TI - Host-guest chemistry of aromatic-amide-linked bis- and tris-calix[4]pyrroles with bis-carboxylates and citrate anion. AB - A small library of polytopic receptors has been synthesized from meso-p- and meso m-aminophenylcalix[4]pyrroles and p- or m-phthaloyl or trimesic chloride. Selected bis-carboxylates and the citrate anion, which either exhibit altered distribution profiles in cancerous tissues in comparison with healthy tissues or are metabolites of carcinogenic substances (for example, trans,trans-muconic acid from benzene exposure in humans) were tested as ligands. Varied affinities and binding modes were observed as a function of the number of calix[4]pyrroles and the topology of amide units present in each of the polytopic receptors. The structures of the 1:1 complexes derived by molecular modeling are in excellent agreement with the results of (1)H NMR complexation studies. PMID- 24402827 TI - The geometric structure of silver-doped silicon clusters. AB - Cationic silver-doped silicon clusters, Si(n)Ag(+) (n=6-15), are studied using infrared multiple photon dissociation in combination with density functional theory computations. Candidate structures are identified using a basin-hopping global optimizations method. Based on the comparison of experimental and calculated IR spectra for the identified low-energy isomers, structures are assigned. It is found that all investigated clusters have exohedral structures, that is, the Ag atom is located at the surface. This is a surprising result because many transition-metal dopant atoms have been shown to induce the formation of endohedral silicon clusters. The silicon framework of Si(n)Ag(+) (n=7-9) has a pentagonal bipyramidal building block, whereas the larger Si(n)Ag(+) (n=10-12, 14, 15) clusters have trigonal prism-based structures. On comparing the structures of Si(n)Ag(+) with those of Si(n)Cu(+) (for n=6-11) it is found that both Cu and Ag adsorb on a surface site of bare Si(n)(+) clusters. However, the Ag dopant atom takes a lower coordinated site and is more weakly bound to the Si(n)(+) framework than the Cu dopant atom. PMID- 24402828 TI - Synthesis and optimization of a bifunctional hyaluronan-based camptothecin prodrug. AB - Aiming to overcome the low solubility and poor targeting ability of camptothecin (CPT), two hyaluronan (HA)-based polymeric prodrugs with different molecular weights (MW) were synthesized and characterized. The structure of HA-CPT was thoroughly verified by ultraviolet (UV), infrared (IR), (1)H nuclear magnetic resonance ((1)H NMR), differential scanning calorimetry (DSC), and high performance liquid chromatography (HPLC). The conjugation of CPT to HA successfully improved the solubility of CPT from 2.08 to 420-620 ug/mL and enhanced tumor targeting, as shown by the in vitro uptake and cytotoxicity results. Moreover, it was found that the high MW conjugate exhibited higher drug loading, higher stability but lower solubility compared with the low MW conjugate. Both HA-CPT conjugates exhibited similar uptake efficiency and antitumor activity. The results demonstrated that HA could act as an effective solubilization carrier and targeting molecule in a HA-based CPT prodrug. PMID- 24402830 TI - A phase II, randomized, multicenter study evaluating the combination of lapatinib and vinorelbine in women with ErbB2 overexpressing metastatic breast cancer. AB - Lapatinib is approved in combination with capecitabine for treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who have progressed on prior trastuzumab in the metastatic setting. Vinorelbine is an important chemotherapy option for MBC. We evaluated efficacy and safety of lapatinib plus vinorelbine, compared with lapatinib plus capecitabine, in women with HER2-positive MBC. In this open-label, multicenter, phase II study, eligible patients (N = 112) were randomized 2:1 to lapatinib plus vinorelbine [(N = 75) 1,250 mg orally once daily (QD) continuously plus 20 mg/m(2)/day intravenously] or lapatinib plus capecitabine [(N = 37) 1,250 mg orally QD continuously plus 2,000 mg/m(2)/day orally, 2 doses]. The primary endpoint was progression-free survival (PFS). Other endpoints included overall survival (OS) and safety. Patients progressing within the study were given the option of crossover to the other treatment arm; time to second progression was an exploratory endpoint. Patient demographics, stratification, and prognostic factors were well balanced between treatments. Median PFS in both arms was 6.2 months [95 % confidence interval (CI) 4.2, 8.8 (lapatinib plus vinorelbine); 4.4, 8.3 (lapatinib plus capecitabine)]. Median OS on lapatinib plus vinorelbine was 24.3 months (95 % CI 16.4, NE) and 19.4 months (95 % CI 16.4, 27.2) on lapatinib plus capecitabine. In total, 42 patients opted to cross over; median PFS was 3.2 months (95 % CI 1.7, 5.1) on lapatinib plus vinorelbine and 4.0 months (95 % CI 2.1, 5.8) on lapatinib plus capecitabine. Lapatinib plus vinorelbine offers an effective treatment option for patients with HER2-overexpressing MBC, having displayed comparable efficacy and tolerability rates to lapatinib plus capecitabine. PMID- 24402831 TI - Mismatches improve the performance of strand-displacement nucleic Acid circuits. AB - Catalytic hairpin assembly (CHA) has previously proven useful as a transduction and amplification method for nucleic acid detection. However, the two hairpin substrates in a CHA circuit can potentially react non-specifically even in the absence of a single-stranded catalyst, and this non-specific background degrades the signal-to-noise ratio. The introduction of mismatched base pairs that impede uncatalyzed strand exchange reactions led to a significant decrease of the background signal, while only partially damping the signal in the presence of a catalyst. Various types and lengths of mismatches were assayed by fluorimetry, and in many instances, our MismatCHA designs yielded 100-fold increased signal-to background ratios compared to a ratio of 4:1 with the perfectly matched substrates. These observations could be of general utility for the design of non enzymatic nucleic acid circuits. PMID- 24402832 TI - Atypical teratoid rhabdoid tumor: improved long-term survival with an intensive multimodal therapy and delayed radiotherapy. The Medical University of Vienna Experience 1992-2012. AB - Atypical teratoid rhabdoid tumors (ATRTs) are recently defined highly aggressive embryonal central nervous system tumors with a poor prognosis and no definitive guidelines for treatment. We report on the importance of an initial correct diagnosis and disease-specific therapy on outcome in 22 consecutive patients and propose a new treatment strategy. From 1992 to 2012, nine patients initially diagnosed correctly as ATRT (cohort A, median age 24 months) were treated according to an intensive multimodal regimen (MUV-ATRT) consisting of three 9 week courses of a dose-dense regimen including doxorubicin, cyclophosphamide, vincristine, ifosfamide, cisplatin, etoposide, and methotrexate augmented with intrathecal therapy, followed by high-dose chemotherapy (HDCT) and completed with local radiotherapy. Thirteen patients were treated differently (cohort B, median age 30 months) most of whom according to protocols in use for their respective diagnoses. As of July 2013, 5-year overall survival (OS) and event-free survival (EFS) for all 22 consecutive patients was 56.3 +/- 11.3% and 52.9 +/- 11.0%, respectively. For MUV-ATRT regimen-treated patients (cohort A) 5-year OS was 100% and EFS was 88.9 +/- 10.5%. For patients treated differently (cohort B) 5-year OS and EFS were 28.8 +/- 13.1%. All nine MUV-ATRT regimen-treated patients are alive for a median of 76 months (range: 16-197), eight in first complete remission. Our results compare favorably to previously published data. The drug combination and sequence used in the proposed MUV-ATRT regimen appear to be efficacious in preventing early relapses also in young children with M1-M3 stage disease allowing postponement of radiotherapy until after HDCT. PMID- 24402833 TI - Highly coke-resistant ni nanoparticle catalysts with minimal sintering in dry reforming of methane. AB - Nickel catalysts are typically used for hydrogen production by reforming reactions. Reforming methane with carbon dioxide, called dry reforming of methane (DRM), is a good way to produce hydrogen or syngas (a mixture of hydrogen and carbon monoxide) from two notable greenhouse gases. However, Ni catalysts used for DRM suffer from severe coke deposition. It has been known that small Ni nanoparticles are advantageous to reduce coke formation, but the high reaction temperature of DRM (800 degrees C) inevitably induces aggregation of the nanoparticles, leading to severe coke formation and degraded activity. Here, we develop highly coke-resistant Ni catalysts by immobilizing premade Ni nanoparticles of 5.2 nm in size onto functionalized silica supports, and then coating the Ni/SiO2 catalyst with silica overlayers. The silica overlayers enable the transfer of reactants and products while preventing aggregation of the Ni nanoparticles. The silica-coated Ni catalysts operate stably for 170 h without any degradation in activity. No carbon deposition was observed by temperature programmed oxidation (TPO), transmission electron microscopy (TEM), X-ray diffraction (XRD), and Raman spectroscopy. The Ni catalysts without silica coating show severe sintering after DRM reaction, and the formation of filamentous carbon was observed. The coke-resistant Ni catalyst is potentially useful in various hydrocarbon transformations. PMID- 24402834 TI - From the Journal archives: Early clinical experience with a new video laryngoscope. PMID- 24402835 TI - Back to the future: medical reversals and perioperative medicine. PMID- 24402836 TI - From the Journal archives: The red blood cell storage lesion: past, present, and future. AB - PURPOSE: This retrospective observational study was performed to determine if the age of transfused units of red blood cells (RBCs) was related to mortality. The study included 31 transfused patients admitted to the intensive care unit during 1992 with severe sepsis (i.e., sepsis associated with organ dysfunction, hypoperfusion, or hypotension). PRINCIPAL FINDINGS: Nineteen of 31 patients (61%) died. On average, non-survivors received older RBC units than survivors. In non survivors, the median age of the units was 24 days (range 7-36 days), whereas the median age in survivors was 21 days (range 5-35 days). Analyzing outcomes according to different age categories revealed that survivors received 85% of units that were less than ten days old, whereas non-survivors received 76% of units that were more than 20 days old. These differences were statistically significant (P < 0.0001). CONCLUSIONS: The authors concluded that the duration of storage of RBCs is directly related to the risk of mortality among transfused patients with severe sepsis. Recognizing the limitations of their small retrospective study that did not adjust for confounders, they also stated that further studies are needed to confirm or refute this association. PMID- 24402837 TI - From the Journal archives: Be alert to the risk of unexpected prolonged postoperative hypoxemia! AB - PURPOSE: In 1978, Drs. R Knill and A. Gelb published the results of a study to measure the effect of subanesthetic levels of halothane on the ability of fit volunteers to respond to sustained hypoxia, and to determine how long potentially hazardous levels of halothane persist after a brief non-complex surgical procedure in healthy patients. The purpose of this commentary is to highlight the historical context of their findings and the impact of their work on our modern day practice of anesthesia. PRINCIPAL FINDINGS: In six fit male volunteers, steady states of halothane reduced the ventilatory response to normocapnic hypoxemia (PETO2 40 mmHg) by ~ 50% at 0.05 MAC and by 70% at 0.10 MAC without affecting resting levels of ventilation. Subjects remained easily rousable and coherent with full memory of events. Symptoms of hypoxemia were markedly reduced or totally absent during hypoxic periods. In five patients recovering from dental procedures (mean duration 59 min), 0.10 MAC halothane levels persisted in the recovery room for approximately one hour. CONCLUSIONS: Patients emerging from a brief (about one hour) halothane anesthetic, although appearing conscious, may have a hazardous degree of depression of the usually protective ventilatory response to hypoxemia for about one hour in the recovery room. Both the symptoms and signs of hypoxemia will be substantially reduced during this emergence phase, enhancing the risk that severe hypoxic episodes may go unrecognized. AUTHORS: Gelb AW, Knill RL. CITATION: Subanaesthetic halothane: Its effect on regulation of ventilation and relevance to the recovery room. Can Anaesth Soc J 1978; 25: 488-94. PMID- 24402838 TI - The off-label utilization of prothrombin complex concentrate with cryoprecipitate as an alternative to plasma transfusion in bleeding patients with acute right ventricular failure. PMID- 24402839 TI - Peripheral arterial calcification: prevalence, mechanism, detection, and clinical implications. AB - Vascular calcification (VC), particularly medial (Monckeberg's medial sclerosis) arterial calcification, is common in patients with diabetes mellitus and chronic kidney disease and is associated with increased cardiovascular morbidity and mortality. Although, the underlying pathophysiological mechanisms and genetic pathways of VC are not fully known, hypocalcemia, hyperphosphatemia, and the suppression of parathyroid hormone activity are central to the development of vessel mineralization and, consequently, bone demineralization. In addition to preventive measures, such as the modification of atherosclerotic cardiovascular risk factors, current treatment strategies include the use of calcium-free phosphate binders, vitamin D analogs, and calcium mimetics that have shown promising results, albeit in small patient cohorts. The impact of intimal and medial VC on the safety and effectiveness of endovascular devices to treat symptomatic peripheral arterial disease (PAD) remains poorly defined. The absence of a generally accepted, validated vascular calcium grading scale hampers clinical progress in assessing the safety and utility of various endovascular devices (e.g., atherectomy) in treating calcified vessels. Accordingly, we propose the peripheral arterial calcium scoring system (PACSS) and a method for its clinical validation. A better understanding of the pathogenesis of vascular calcification and the development of optimal medical and endovascular treatment strategies are crucial as the population ages and presents with more chronic comorbidities. PMID- 24402840 TI - Synthesis and reactivity of mononuclear iron models of [Fe]-hydrogenase that contain an acylmethylpyridinol ligand. AB - [Fe]-hydrogenase has a single iron-containing active site that features an acylmethylpyridinol ligand. This unique ligand environment had yet to be reproduced in synthetic models; however the synthesis and reactivity of a new class of small molecule mimics of [Fe]-hydrogenase in which a mono-iron center is ligated by an acylmethylpyridinol ligand has now been achieved. Key to the preparation of these model compounds is the successful C-O cleavage of an alkyl ether moiety to form the desired pyridinol ligand. Reaction of solvated complex [(2-CH2CO-6-HOC5H3N)Fe(CO)2(CH3CN)2](+)(BF4)(-) with thiols or thiophenols in the presence of NEt3 yielded 5-coordinate iron thiolate complexes. Further derivation produced complexes [(2-CH2CO-6-HOC5H3N)Fe(CO)2(SCH2CH2OH)] and [(2-CH2CO-6 HOC5H3N)Fe(CO)2(CH3COO)], which can be regarded as models of FeGP cofactors of [Fe]-hydrogenase extracted by 2-mercaptoethanol and acetic acid, respectively. When the derivative complexes were treated with HBF4 ?Et2O, the solvated complex was regenerated by protonation of the thiolate ligands. The reactivity of several models with CO, isocyanide, cyanide, and H2 was also investigated. PMID- 24402842 TI - Randomized clinical trial of the effect of perioperative synbiotics versus no synbiotics on bacterial translocation after oesophagectomy. AB - BACKGROUND: The impact of perioperative synbiotics on bacterial translocation and subsequent bacteraemia after oesophagectomy is unclear. This study investigated the effect of perioperative synbiotic administration on the incidence of bacterial translocation to mesenteric lymph nodes (MLNs) and the occurrence of postoperative bacteraemia. METHODS: Patients with oesophageal cancer were randomized to receive perioperative synbiotics or no synbiotics (control group). MLNs were harvested from the jejunal mesentery before dissection (MLN-1) and after the restoration of digestive tract continuity (MLN-2). Blood and faeces samples were taken before and after operation. Microorganisms in each sample were detected using a bacterium-specific ribosomal RNA-targeted reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) method. RESULTS: Some 42 patients were included. There was a significant difference between the two groups in detection levels of microorganisms in the MLN-1 samples. Microorganisms were more frequently detected in MLN-2 samples in the control group than in the synbiotics group (10 of 18 versus 3 of 18; P = 0.035). In addition, bacteraemia detected using RT-qPCR 1 day after surgery was more prevalent in the control group than in the synbiotics group (12 of 21 versus 4 of 21; P = 0.025). Neutrophil counts on postoperative days 1, 2 and 7 after surgery were all significantly higher in the control group than in the synbiotics group. CONCLUSION: Perioperative use of synbiotics reduces the incidence of bacteria in the MLNs and blood. These beneficial effects probably contribute to a reduction in the inflammatory response after oesophagectomy. REGISTRATION NUMBER: ID 000003262 (University Hospital Medical Information Network, http://www.umin.ac.jp). PMID- 24402841 TI - The value and pitfalls of speculation about science and technology in bioethics: the case of cognitive enhancement. AB - In the debate on the ethics of the non-medical use of pharmaceuticals for cognitive performance enhancement in healthy individuals there is a clear division between those who view "cognitive enhancement" as ethically unproblematic and those who see such practices as fraught with ethical problems. Yet another, more subtle issue, relates to the relevance and quality of the contribution of scholarly bioethics to this debate. More specifically, how have various forms of speculation, anticipatory ethics, and methods to predict scientific trends and societal responses augmented or diminished this contribution? In this paper, we use the discussion of the ethics of cognitive enhancement to explore the positive and negative contribution of speculation in bioethics scholarship. First, we review and discuss how speculation has relied on different sets of assumptions regarding the non-medical use of stimulants, namely: (1) terminology and framing; (2) scientific aspects such as efficacy and safety; (3) estimates of prevalence and consequent normalization; and (4) the need for normative reflection and regulatory guidelines. Second, three methodological guideposts are proposed to alleviate some of the pitfalls of speculation: (1) acknowledge assumptions more explicitly and identify the value attributed to assumptions; (2) validate assumptions with interdisciplinary literature; and (3) adopt a broad perspective to promote more comprehensive reflection. We conclude that, through the examination of the controversy about cognitive enhancement, we can employ these methodological guideposts to enhance the value of contributions from bioethics and minimize potential epistemic and practical pitfalls in this case and perhaps in other areas of bioethical debate. PMID- 24402843 TI - Serological cross reactivity to CMV and EBV causes problems in the diagnosis of acute hepatitis E virus infection. AB - Hepatitis E virus (HEV) infection is an important public health concern as a major cause of enterically-transmitted hepatitis worldwide. The detectable window of viraemia is narrow, and HEV IgM and IgG rise simultaneously in acute infection. Furthermore, previous investigators have shown HEV IgM false positive reactions occur against EBV, CMV and potentially hepatitis A. A retrospective analysis of HEV serology testing was performed at a London tertiary referral hospital over a 3-year period. A thousand four hundred and twenty three serum samples were tested for HEV serology, with 33 samples HEV IgM positive and 28 HEV IgM equivocal. One hundred and eleven samples were HEV IgG positive but IgM negative suggesting past infection. No patients with HEV IgM positivity had false positive reactions against hepatitis A. A high degree of EBV and CMV cross reactivity was noted, with 33.3% and 24.2% of HEV IgM positive samples also testing positive for EBV and CMV IgM, respectively. HEV RNA was detected in four HEV IgM positive samples, indicating true positivity, although three demonstrated cross reactivity against EBV. Only 13.3% of samples with positive HEV IgM were HEV PCR positive, highlighting a low positive predictive value of serology testing. Overall a high level of HEV, EBV and CMV IgM cross reactivity was demonstrated, indicating that serology is unreliable in the diagnosis of acute viral hepatitis. It is concluded that that the diagnosis of viral hepatitis should be based on clinical features, raised transaminases, serology, and confirmatory PCR testing. PMID- 24402844 TI - Prevalence of malnutrition and its correlates in older adults living in long stay institutions situated in Beirut, Lebanon. AB - BACKGROUND: Malnutrition represents an important issue in older adults; unfortunately, there is lack of data concerning this topic in Lebanon. This paper aims to provide a description of nutritional status and its correlates in older adults living in long stay institutions situated in Beirut. METHODS: This cross sectional study was conducted in three long stay institutions in Beirut in 2012. The study population was composed of people aged 65 years and above, having a score of Folstein Mini Mental State Examination (MMSE) greater than 14 and without renal failure requiring dialysis. Subjects meeting inclusion criteria filled out a questionnaire consisting of nutritional status scale (Mini Nutritional Assessment: MNA) and several other parts (demographic, self assessment of the state health, smoking and alcohol, physical dependence, quality of life, frailty, depression, social isolation and loneliness). Data were entered and analyzed using the statistical software SPSS (Statistical Package for Social Sciences), version 17.0 (Chicago, IL, USA). RESULTS: Among 111 older adults (55 men and 56 women), 14 (12.6%) were malnourished, 54 (48.7%) were at risk of malnutrition and 43 (38.7%) had an adequate nutritional status. Multivariate analysis showed that physical exercise, depression, frailty and cognitive function were independent correlates of nutritional status of older adults. This model explained 42.2% (adjusted R2 = 0.422) of the older adults nutritional status variability. CONCLUSIONS: We found a moderate percentage of malnutrition in older adults living in long stay institutions situated in Beirut, and the correlates of malnutrition in older adults were low physical exercise, depression, frailty and low cognitive function. PMID- 24402845 TI - Estimating liver cancer deaths in Thailand based on verbal autopsy study. AB - BACKGROUND: Liver cancer mortality is high in Thailand but utility of related vital statistics is limited due to national vital registration (VR) data being under reported for specific causes of deaths. Accurate methodologies and reliable supplementary data are needed to provide worthy national vital statistics. This study aimed to model liver cancer deaths based on verbal autopsy (VA) study in 2005 to provide more accurate estimates of liver cancer deaths than those reported. The results were used to estimate number of liver cancer deaths during 2000-2009. METHODS: A verbal autopsy (VA) was carried out in 2005 based on a sample of 9,644 deaths from nine provinces and it provided reliable information on causes of deaths by gender, age group, location of deaths in or outside hospital, and causes of deaths of the VR database. Logistic regression was used to model liver cancer deaths and other variables. The estimated probabilities from the model were applied to liver cancer deaths in the VR database, 2000-2009. Thus, the more accurately VA-estimated numbers of liver cancer deaths were obtained. RESULTS: The model fits the data quite well with sensitivity 0.64. The confidence intervals from statistical model provide the estimates and their precisions. The VA-estimated numbers of liver cancer deaths were higher than the corresponding VR database with inflation factors 1.56 for males and 1.64 for females. CONCLUSIONS: The statistical methods used in this study can be applied to available mortality data in developing countries where their national vital registration data are of low quality and supplementary reliable data are available. PMID- 24402846 TI - Validation of a musculoskeletal model of lifting and its application for biomechanical evaluation of lifting techniques. AB - BACKGROUND: Lifting methods, including standing stance and techniques have wide effects on spine loading and stability. Previous studies explored lifting techniques in many biomechanical terms and documented changes in muscular and postural response of body as a function of techniques .However, the impact of standing stance and lifting technique on human musculoskeletal had not been investigated concurrently. METHODS: A whole body musculoskeletal model of lifting had been built in order to evaluate standing stance impact on muscle activation patterns and spine loading during each distinctive lifting technique. Verified model had been used in different stances width during squat, stoop and semi-squat lifting for examining the effect of standing stance on each lifting technique. RESULTS: The model muscle's activity was validated by experimental muscle EMGs resulting in Pearson's coefficients of greater than 0.8. Results from analytical analyses show that the effect of stance width on biomechanical parameters consists in the lifting technique, depending on what kind of standing stance was used. CONCLUSIONS: Standing stance in each distinctive lifting technique exhibit positive and negative aspects and it can't be recommended either one as being better in terms of biomechanical parameters. PMID- 24402847 TI - Modeling the factors affecting unsafe behavior in the construction industry from safety supervisors' perspective. AB - BACKGROUND: There can be little doubt that the construction is the most hazardous industry in the worldwide. This study was designed to modeling the factors affecting unsafe behavior from the perspective of safety supervisors. METHODS: The qualitative research was conducted to extract a conceptual model. A structural model was then developed based on a questionnaire survey (n=266) by two stage Structural Equation Model (SEM) approach. RESULTS: An excellent confirmed 12-factors structure explained about 62% of variances unsafe behavior in the construction industry. A good fit structural model indicated that safety climate factors were positively correlated with safety individual factors (P<0.001) and workplace safety condition (P<0.001). The workplace safety condition was found to play a strong mediating role in linking the safety climate and construction workers' engagement in safe or unsafe behavior. CONCLUSIONS: In order to improve construction safety performance, more focus on the workplace condition is required. PMID- 24402848 TI - Microwave/H2O2 efficiency in pentachlorophenol removal from aqueous solutions. AB - BACKGROUND: Pentachlorophenol (PCP) is one of the most fungicides and pesticides. Acute and chronic poisoning from PCP may be occurred by dermal absorption, and respiration or ingestion. With respect to health and environmental effects of PCP, many methods were considered regarding its removal. Microwave assisted other methods are environmental friendly, safety, and economical method, consequently, in this study; microwave assisted with hydrogen peroxide (MW/H2O2) was used for PCP removal from aquatic solutions. METHODS: The possible of PCP removal was considered by application of a modified domestic microwave. PCP removal rate was considered under different factors such as H2O2 dose (0.01, 0.02, 0.1, 0.2, 0.3 mol/L), PCP concentration (100,200, 300, 400, 500, 750, 1000 mg/L), pH (3, 7, 11), energy intensity (180,450, 600 W), COD (344 mg/L), and scavenger testes (0.02 mol/L from each of Tert- butyl alcohol (TBA), NaCl, NaHCO3, and Na2CO3). The concentration changes of PCP were determined using spectrophotometer and HPLC spectra, respectively. RESULTS: The best PCP removal was obtained in condition of pH 11, 0.2 mol/L H2O2, and 600 W energy intensity. Moreover, COD removal in this condition was 83%. Results obtained from radical scavengers indicated that OH degrees had only an initiator role, and had not a dominant role, and order reaction was in first order. CONCLUSIONS: The results of microwave/H2O2 application showed that this process is suitable for removal of PCP and other chlorinated organic compounds in alkaline pH. PMID- 24402849 TI - Employees' perception of lighting conditions in manufacturing plants: associations with illuminance measurements. AB - BACKGROUND: The aims of this study were to evaluate the employees' subjective assessments of different aspects of lighting condition as well as task area illuminance in manufacturing plants. METHODS: This field study was conducted between March and May 2013, in three packing plants (Saveh, central Iran). Data were collected by questionnaire and measurement of the task area illuminance levels. Data were analysed using contingency coefficient test, Spearman's correlation analysis and non-parametric Friedman tests. RESULTS: The recommended illuminance levels were not met in 46.9% of the work areas. This finding was in agreement with the employees' perception of light level, and with low satisfaction with lighting in the work environment. Adverse effects of lighting condition on job performance, changing posture for better viewing of the work area and eye tiredness were reported as 64%, 33% and 31% of the employees, respectively. Satisfaction with lighting was negatively correlated with the age of respondents (r=-0.229; P<0.010). The employees' satisfaction with lighting was also highly correlated with the employees' subjective assessments of the light level (r=0.779; P<0.001), type of artificial light sources (r=0.591; P<0.001), light colour (r=0.50; P<0.001) and use of daylight (r=0.254; P<0.004). The type of artificial light sources was correlated with job performance (r=0.311, P<0.001) and eye tiredness (r=0.273; P<0.002). CONCLUSIONS: The findings highlight the potential usefulness of subjective assessments to supplement objective measures and provide a more holistic approach to lighting design and planning. PMID- 24402850 TI - A passive noise control approach utilizing air gaps with fibrous materials in the textile industry. AB - BACKGROUND: Noise pollution is currently a major risk factor in industries in both developed and developing countries.The present study assessed noise pollution in the knitting industry in Iran in 2009 and presented a control method to reduce the rate of noise generation. METHODS: The overall noise level was estimated using the network environmental noise assessment method in Sina Poud textile mill in Hamadan. Then, frequency analysis was performed at indicator target stations in the linear network. Finally, a suitable absorbent was recommended for the ceilings, walls, and aerial panels at three phases according to the results found for the sound source and destination environment. RESULTS: The results showed that the highest sound pressure level was 98.5 dB and the lowest was 95.1 dB. The dominant frequency for the industry was 500 Hz. The highest and lowest sound suppression was achieved by intervention at 4000 Hz equivalent to 14.6 dB and 250 Hz in the textile industry. CONCLUSIONS: When noise control at the source is not available or insufficient because of the wide distribution of the acoustic field in the workplace, the best option is to increase the absorptive surface of the workplace using adsorbents such as polystyrene. PMID- 24402851 TI - Determination of affected risk factors on time to recurrence and death in patients with postoperative gastric cancer using copula function. AB - BACKGROUND: In survival studies when the event times are dependent, performing of the analysis by using of methods based on independent assumption, leads to biased. In this paper, using copula function and considering the dependence structure between the event times, a parametric joint distribution has made fitting to the events, and the effective factors on each of these events would be determined. METHODS: This retrospective cohort study was conducted from March 2003 to March 2007. The data collected from 256 patients with gastric cancer who underwent surgery and that the event time of the two outcomes of death and recurrence for them was recorded. Akaike Information Criterion (AIC) was used to determine of suitable parametric models. Moreover, applying copula function with regard to the relationships between the events, the effect of the risk factors of each of the two outcomes was determined. The data analysis was done using R2.12.1 software. RESULTS: According to the AIC criterion, the Weibull distribution had the best fitting in both of the event times. The median times for recurrence and survival of the patients were estimated 20.2 and 28.1 months respectively. Furthermore, with a fitting of Weibull distribution to the two event times using Clayton copula function, the variables of gender, tumor size and tumor pathological stage on survival, and tumor size and tumor pathological stage on recurrence were significant (P<0.001). CONCLUSIONS: Applying copula function for determining specific risk factors of the semi-competing events produces suitable results opposite the common methods which are based on independent assumption of the events. PMID- 24402852 TI - Quality of life and its related factors in infertile couples. AB - BACKGROUND: Health related quality of life (QoL) has now been considered as a main tool for outcome measurement in infertility. The present study aimed to determine the association between general and specified QoL with different psychological aspects of self-esteem, social support, sexual satisfaction, and marital satisfaction in a sample of Iranian infertile couples. METHODS: This cross-sectional study was conducted on 385 infertile couples referred to the Fatemieh Hospital in Hamadan City, western Iran in 2012.To measure the self esteem, the Iseng test was used. The social support scaling developed by Cassidy and Long was used for assessment of social support. The sexual satisfaction was also assessed by the Lindaberg questionnaire. For assessing the general QoL state, the WHO-QoL-BREF and FertiQoL tools were employed. RESULTS: Self-esteem scores were lower in the couples with longer infertility duration. The social support mean score was lower in low income couples. Those with higher educational level, shorter infertility duration, and higher income were more satisfied from their marital relationships. Besides, we revealed that the previous failed efforts for treatment of infertility were adversely associated with the lower social support and sexual satisfaction. The higher educational level, higher monthly income, living in urban area, shorter duration of marriage and infertility, and male gender were associated with better. QoL status in the most components.Associations between QoL and self-esteem, social support, sexual satisfaction, and marital satisfaction were significant (P<0.05). CONCLUSIONS: The QoL status in infertile couples is directly associated with their self esteem, social support, sexual satisfaction, and marital satisfaction. PMID- 24402853 TI - Investigation on the trophic status of Ekbatan reservoir: a drinking water supply reservoir in Iran. AB - BACKGROUND: Eutrophication is one of the detrimental environmental problems in water reservoirs dye to the irregular introducing nutrients (phosphorus and nitrogen). This study aimed to explore the eutrophication state of Ekbatan Reservoir, Hamadan, western Iran. METHODS: Monthly sampling was conducted during April 2010 to March 2011. Seven sampling stations were selected in the various locations of the reservoir and the samples were collected in the depth of 50 cm. The grab sampling of water for nitrogen, phosphorous and chlorophyll-a was carried out at all localities by Hatch sampler. The trophic state of the dam was determined by Carlson's Trophic State Index (TSI) and Chapra's classification. RESULTS: The highest concentrations of phosphorus and chlorophyll-a were measured in August and the lowest concentration for both of the parameters was determined in February. The TSI index according phosphorus concentration showed that the reservoir was in eutrophic status during May to November and was in mesotrophic status over November to May. CONCLUSIONS: It seems that the eutrophication process in the lake was resulted from the rural wastewaters and agricultural fertilizers. Therefore, using long term management methods including prevent of uncontrolled discharge of agricultural wastewaters is recommended in order to reduce the eutrophication in the reservoir. Decrease of phosphorus concentration in the dam by 50% can convert the eutrophic state to mesotrophic state. PMID- 24402854 TI - Heavy metals concentration in vegetables irrigated with contaminated and fresh water and estimation of their daily intakes in suburb areas of Hamadan, Iran. AB - BACKGROUND: This study was conducted to estimate the level of heavy metals accumulate in vegetables irrigated with contaminated water compared with those irrigated with fresh water in Hamadan, west of Iran in 2012. METHODS: Sixty samples of different vegetables i.e., parsley, tarragon, sweat basil and leek irrigated with contaminated water and thirty six samples from three different adjacent areas irrigated with fresh water as control were analyzed to determine heavy metals. The concentration of heavy metals i.e., lead, cadmium and chromium were achieved using atomic adsorption spectrophotometer. RESULTS: The mean concentration of lead, chromium and cadmium regardless of the kind of vegetables irrigated with contaminated water was 6.24, 1.57 and 0.15 mg/kg, respectively. Moreover, metals uptake differences by the vegetables were recognized to vegetable differences in tolerance to heavy metals. Based on the above concentrations the dietary intakes of metals through vegetables consumption were 0.004, 0.0008 and 6E-05 mg/day in infants for lead, chromium and cadmium, respectively. CONCLUSIONS: The high concentration of these heavy metals in some vegetables might be attributed due to the use of untreated sanitary and industrial wastewater by farmers for the irrigation of vegetable lands. Therefore, treating of these wastewater and bioremediation of excess metals from polluted vegetation land could be considered. PMID- 24402855 TI - The impact of training on women's capabilities in modifying their obesity-related dietary behaviors: applying family-centered empowerment model. AB - BACKGROUND: Dietary behaviors affect obesity; therefore, it seems necessary to conduct interventions to modify behavioral patterns leading to weight-gain in the family. Our goal was to determine the impact of training on women's capabilities in modifying their obesity-related dietary behaviors in Urmia, West Azerbaijan Province, Iran: applying family-centered empowerment model. METHODS: A quasi experimental study with Pretest-Posttest design was conducted on 90 over weight/obese women in 2012 in two Health Centers of Urmia. Convenience sampling was done and the participants were randomly assigned to two 'test' and 'control' groups. Data collection was done by completing the demographic data questionnaire, the empowerment tool and dietary behavior checklist. The intervention was conducted in the form of 6 educational classes held for the 'test' group. After two months, posttest was performed by completing the forms once again. Data were analyzed with descriptive tests, t-tests, Chi2 and Fischer's test. RESULTS: The dietary behavior scores of the intervention group had risen from 7.4 +/- 2.11 to 9.95 +/- 2.41 (P<0.001), and the good dietary behaviors had risen from 21.4% to 61.9% (P=0.002). The 'good' capability level of this group had risen from 23.8% to 97.61% (P<0.001), and their mean capability score had risen from 54.61 +/- 7.34 to 70.26 +/- 6.04 (P<0.001). However, the changes were not significant in the control group. CONCLUSIONS: The educational intervention performed whit applying family-centered empowerment model in this study was proven effective in women. Hence it is advised to consider it in behavior changing interventions to promote the health of the family and community. PMID- 24402856 TI - Prediction the groundwater level of Hamadan-Bahar Plain, west of Iran using support vector machines. AB - BACKGROUND: Water is considered as the main source of life but water resources are limited and nonrenewable. Different factors have caused groundwater to decrease. Therefore, modeling and predicting groundwater level is of great importance. METHODS: Monthly groundwater level data of about 20 years (October 1991 to February 2012) from the Hamadan-Bahar Plain, west of Iran were used based on peizometric height related to hydrologic years. The support vector machine (SVM), a new nonlinear regression technique, was used to predict groundwater level. The performance of the SVM model was assessed by using criteria of R(2), root mean square error (RMSE), means absolute error (MAE), means absolute percentage error (MAPE), correlation coefficient and efficiency coefficient (E) and was then compared with the classic time series model. RESULTS: The SVM model had greater R(2) (=0.933), E (=0.950) and Correlation (=0.965). Moreover, SVM had lower RMSE (=0.120), MAPE (=0.140) and MAE (=0.124). There was no significant difference between the estimated values using two models and the observed value. CONCLUSIONS: The SVM outperforms classic time series model in predicting groundwater level. Therefore using the SVM model is reasonable for modeling and predicting fluctuations of groundwater level in Hamadan-Bahar Plain. PMID- 24402857 TI - Prevalence of diabetes in people aged >= 30 years: the results of screen-ing program of Yazd Province, Iran, in 2012. AB - BACKGROUND: Among the non-communicable diseases, diabetes mellitus has an important ranking and with annually increasing rate where it is expected the number of people suffering from the disease will reach to 300 million up to 2025 in all of world. The prevalence of type 2 diabetes in Iran is 4-4.5% and in population aged above 30 years is greater than 14%. The present study is attempting to find out the prevalence rate of the disease and its risk factors in Yazd Province, central Iran. METHODS: This cross-sectional study was carried out in 2012. A total of 14993 subjects were randomly selected and enquired by a pretested questionnaire. Data were analyzed by descriptive statistics and appropriate statistical tests such as chi-square, and multiple logistic regressions. RESULTS: The prevalence rate of known diabetes and impaired fasting glucose was 16.3% & 11.9% respectively. Age, sex, family history of diabetes, high blood pressure, BMI, and history of gestational diabetes were significantly associated with diabetes disease (P=0.001). CONCLUSIONS: The prevalence rate of diabetes is higher than other parts of the world and living in the city. Female gender, increasing age, high blood pressure, increased BMI and positive family history, are independent risk factor for diabetes, therefore performing prevention programs and controlling these high risk groups should be considered as a priority. PMID- 24402858 TI - Prevalence and risk factors of five most common upper extremity disorders in diabetics. AB - BACKGROUND: In addition to macrovascular and along with other microvascular complications, diabetic patients suffer from some common musculoskeletal complications. The aim of this study was to assess the prevalence of five musculoskeletal disorders of upper extremity including shoulder capsulitis (SC), limited joint mobility (LJM), Dupuytren's contracture (DC), carpal tunnel syndrome (CTS), and trigger finger (TF) as well as identify their related risk factors in diabetic patients. METHODS: We recruited 432 types 1 or 2 diabetic patients and evaluated them for the presence of musculoskeletal disorders and their-related risk factors in 2012-13. The patients were examined by an endocrinologist and then suspected subjects evaluated by a rheumatologist for defining final diagnosis. RESULTS: The most prevalent musculoskeletal disorder of upper extremity was SC (8.79%), followed by CTS (8.56%), LJM (6.94%), DC (7.4%), and TF (6.71%). Advanced age, female sex, smoking, and duration of diabetes were associated with the appearance of SC; female sex and duration of diabetes with CTS; advanced age and smoking with LJM; advanced age, duration of diabetes and history of foot ulcer with DC; and history of laser photocoagulation was associated with TF. CONCLUSIONS: The results show lower prevalence of upper musculoskeletal disorders and different associated risk factors in our diabetic population in comparison with previous studies on other populations. PMID- 24402859 TI - Modeling the recurrent failure to thrive in less than two-year children: recurrent events survival analysis. AB - BACKGROUND: This study aimes to evaluate the failure to thrive (FTT) recurrent event over time. METHODS: This longitudinal study was conducted during February 2007 to July 2009. The primary outcome was growth failure. The analysis was done using 1283 children who had experienced FTT several times, based on recurrent events analysis. RESULTS: Fifty-nine percent of the children had experienced the FTT at least one time and 5.3% of them had experienced it up to four times. The Prentice-Williams-Peterson (PWP) model revealed significant relationship between diarrhea (HR=1.26), respiratory infections (HR=1.25), urinary tract infections (HR=1.51), discontinuation of breast-feeding (HR=1.96), teething (HR=1.18), initiation age of complementary feeding (HR=1.11) and hazard rate of the first FTT event. CONCLUSIONS: Recurrence nature of the FTT is a main problem, which taking it into account increases the accuracy in analysis of FTT event process and can lead to identify different risk factors for each FTT recurrences. PMID- 24402860 TI - Assessment of mutational load in biopsy tissue provides additional information about genomic instability to histological classifications of Barrett's esophagus. AB - PURPOSE: Progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) is associated with accumulated genomic instability. Current risk stratification of BE for EAC relies on histological classification and grade of dysplasia. However, histology alone cannot assess the risk of patients with inconsistent or non-dysplastic BE histology. We, therefore, examined the presence and extent of genomic instability in advanced and less advanced BE histology using mutational load (ML). METHODS: ML summarized the presence and clonality of loss of heterozygosity (LOH) mutations and the emergence of new alleles, manifested as microsatellite instability (MSI) mutations, in ten genomic loci around tumor suppressor genes associated with EAC. The ML of 877 microdissected targets from BE biopsies was correlated to their histology. Histological targets were categorized into three levels: no ML, low ML, and high ML. RESULTS: Increasing ML correlated with increasingly severe histology. By contrast, proportions of targets that lacked mutations decreased with increasingly severe histology. A portion of targets with non-dysplastic and low-grade histology shared a similar ML as those with higher risk and EAC disease. The addition of MSI characterization to ML helped to differentiate the ML between advanced and less advanced histology. CONCLUSIONS: Given that EAC is associated with accumulated genomic instability, high ML in less severe histology may identify BE disease at greater risk of progression to EAC. ML may help to better manage BE in early histological stages and when histology alone provides insufficient information. PMID- 24402861 TI - Spatially resolved confocal resonant Raman microscopic analysis of anode-grown Geobacter sulfurreducens biofilms. AB - When grown on the surface of an anode electrode, Geobacter sulfurreducens forms a multi-cell thick biofilm in which all cells appear to couple the oxidation of acetate with electron transport to the anode, which serves as the terminal metabolic electron acceptor. Just how electrons are transported through such a biofilm from cells to the underlying anode surface over distances that can exceed 20 microns remains unresolved. Current evidence suggests it may occur by electron hopping through a proposed network of redox cofactors composed of immobile outer membrane and/or extracellular multi-heme c-type cytochromes. In the present work, we perform a spatially resolved confocal resonant Raman (CRR) microscopic analysis to investigate anode-grown Geobacter biofilms. The results confirm the presence of an intra-biofilm redox gradient whereby the probability that a heme is in the reduced state increases with increasing distance from the anode surface. Such a gradient is required to drive electron transport toward the anode surface by electron hopping via cytochromes. The results also indicate that at open circuit, when electrons are expected to accumulate in redox cofactors involved in electron transport due to the inability of the anode to accept electrons, nearly all c-type cytochrome hemes detected in the biofilm are oxidized. The same outcome occurs when a comparable potential to that measured at open circuit (-0.30 V vs. SHE) is applied to the anode, whereas nearly all hemes are reduced when an exceedingly negative potential (-0.50 V vs. SHE) is applied to the anode. These results suggest that nearly all c-type cytochrome hemes detected in the biofilm can be electrochemically accessed by the electrode, but most have oxidation potentials too negative to transport electrons originating from acetate metabolism. The results also reveal a lateral heterogeneity (x-y dimensions) in the type of c-type cytochromes within the biofilm that may affect electron transport to the electrode. PMID- 24402862 TI - Identification of a novel series of N-phenyl-5-[(2-phenylbenzimidazol-1 yl)methyl]-1,3,4-oxadiazol-2-amines as potent antioxidants and radical scavengers. AB - In this study, some novel 5-[[2-(phenyl/p-chlorophenyl)-benzimidazol-1-yl] methyl]-N-substituted phenyl-1,3,4-oxadiazol-2-amine derivatives (28-45) with an oxadiazole ring were synthesized. The antioxidant properties and radical scavenging activities of the compounds were investigated employing various in vitro systems: hepatic microsomal NADPH-dependent inhibition of lipid peroxidation levels, scavenging of DPPH free radicals, and inhibition of microsomal ethoxyresorufin O-deethylase activity (EROD). Compounds 34 and 41 were found to be good scavengers of DPPH radicals (76% and 84%) when compared to BHT (90%). Almost all of the compounds examined were found to possess a good inhibitor effect on the microsomal EROD activity. Moreover, 32 and 41 were more active analogs (97% and 98%) on the microsomal EROD activity than caffeine (85%). PMID- 24402863 TI - Ectopic fat in youth: the contribution of hepatic and pancreatic fat to metabolic disturbances. AB - OBJECTIVE: To study the relationships between parameters of glucose and insulin metabolism and visceral and abdominal ectopic fat in youth. METHODS: A cross sectional study of 50 children (24 females), 8-18 years old. Anthropometrics, body composition, blood-work and visceral and ectopic fat by magnetic resonance imaging were assessed. Insulin secretion, insulin sensitivity and beta cell function were calculated from an oral glucose tolerance test. RESULTS: BMI z scores ranged between -1.3 and 4.5. The hepatic fat fraction (HFF) ranged between 0 and 36% and pancreatic fat fraction (PFF) between 0 and 14%. Visceral fat, HFF and PFF were associated with clinical and biochemical metabolic abnormalities, and correlated with markers of insulin sensitivity (r = -0.60, P < 0.01; r = 0.64, P < 0.01; r = -0.48, P < 0.01, respectively) insulin secretion (r = 0.55, P < 0.01; r = 0.57, P < 0.01; r = 0.41, P < 0.01, respectively), and beta cell function (r = -0.49, P < 0.01; r = -0.59, P < 0.01; r = -0.39, P < 0.01, respectively). CONCLUSIONS: Accumulations of pancreatic and hepatic fat have complementary clinical consequences in youth. While visceral and hepatic fat demonstrated a dominant effect, even relatively small degrees of pancreatic fat deposition may contribute to metabolic alterations. PMID- 24402865 TI - Relations of omega-3 and omega-6 intake with mammographic breast density. AB - PURPOSE: Omega-3 (n-3) and n-6 fatty acids (FA) intake could influence the occurrence of certain diseases such as breast cancer but little is known about their relation to mammographic density (MD). The purpose of this study is to examine the association of the intake of n-3 FA and n-6 FA with MD among 777 premenopausal and 783 postmenopausal women. METHODS: In this cross-sectional study, FA intake was assessed with a self-administered food-frequency questionnaire and MD was measured using a computer-assisted method. Multivariate analyses were performed by using generalized linear models to evaluate the associations of quartiles of FA intake with MD. RESULTS: For increasing quartiles of total long-chain n-3 FA intake (< 0.11, 0.11-0.20, 0.21-0.32, and >= 0.33 g/day), adjusted mean MD was 29, 29, 27, and 25 %, respectively (P trend = 0.005). This association remained significant among postmenopausal (P trend = 0.006) but not among premenopausal (P trend = 0.21) women. No significant association was found between n-6 FA intake and MD. However, for increasing quartiles of the n-6 FA/long-chain n-3 FA ratio intake (< 31.75, 31.75-52.28, 52.29-94.28, and >= 94.29), adjusted mean MD was 26, 27, 29, and 29 %, respectively (P trend = 0.008). CONCLUSIONS: Higher intake of long-chain n-3 FA was associated with lower MD, suggesting that increased long-chain n-3 FA intake could be a strategy for breast cancer prevention. PMID- 24402866 TI - The source of "fairy rings": 2-azahypoxanthine and its metabolite found in a novel purine metabolic pathway in plants. AB - Rings or arcs of fungus-stimulated plant growth occur worldwide; these are commonly referred to as "fairy rings". In 2010, we discovered 2-azahypoxanthine (AHX), a compound responsible for the fairy-ring phenomenon caused by fungus; AHX stimulated the growth of all the plants tested. Herein, we reveal the isolation and structure determination of a common metabolite of AHX in plants, 2-aza-8 oxohypoxanthine (AOH). AHX is chemically synthesized from 5-aminoimidazole-4 carboxamide (AICA), and AHX can be converted into AOH by xanthine oxidase. AICA is one of the members of the purine metabolic pathway in animals, plants, and microorganisms. However, further metabolism of AICA remains elusive. Based on these results and facts, we hypothesized that plants themselves produce AHX and AOH through a pathway similar to the chemical synthesis. Herein, we demonstrate the existence of endogenous AHX and AOH and a novel purine pathway to produce them in plants. PMID- 24402867 TI - Noninvasive detection of lung cancer using exhaled breath. AB - Early detection of lung cancer is a key factor for increasing the survival rates of lung cancer patients. The analysis of exhaled breath is promising as a noninvasive diagnostic tool for diagnosis of lung cancer. We demonstrate the quantitative analysis of carbonyl volatile organic compounds (VOCs) and identification of lung cancer VOC markers in exhaled breath using unique silicon microreactor technology. The microreactor consists of thousands of micropillars coated with an ammonium aminooxy salt for capture of carbonyl VOCs in exhaled breath by means of oximation reactions. Captured aminooxy-VOC adducts are analyzed by nanoelectrospray Fourier transform-ion cyclotron resonance (FT-ICR) mass spectrometry (MS). The concentrations of 2-butanone, 2-hydroxyacetaldehyde, 3-hydroxy-2-butanone, and 4-hydroxyhexenal (4-HHE) in the exhaled breath of lung cancer patients (n = 97) were significantly higher than in the exhaled breath of healthy smoker and nonsmoker controls (n = 88) and patients with benign pulmonary nodules (n = 32). The concentration of 2-butanone in exhaled breath of patients (n = 51) with stages II though IV non-small cell lung cancer (NSCLC) was significantly higher than in exhaled breath of patients with stage I (n = 34). The carbonyl VOC profile in exhaled breath determined using this new silicon microreactor technology provides for the noninvasive detection of lung cancer. PMID- 24402868 TI - Evolution of actinyl peroxide clusters U28 in dilute electrolyte solution: exploring the transition from simple ions to macroionic assemblies. AB - Actinyl peroxide clusters, a unique class of uranyl-containing nanoclusters discovered in recent years, are crucial intermediates between the(UO2)(2+) aqua ion monomer and bulk uranyl minerals. Herein, two actinyl polyoxometalate nanoclusters of Cs15[(Ta(O2)4)Cs4K12(UO2(O2)1.5)28]?20 H2O (CsKU28) and Na6K9[(Ta(O2)4)Rb4Na12(UO2(O2)1.5)28]?20 H2O (RbNaU28) were synthesized by incorporating a central Ta(O2)4(3-) anion that templates a hollow shell of 28 uranyl peroxide polyhedra. When dissolved in aqueous solutions with additional electrolytes, those 1.8 nm-size macroanions self-assembled into spherical, hollow, blackberry-type supramolecular structures, as was characterized by laser light scattering (LLS) and TEM techniques. These clusters are the smallest macroions reported to date that form blackberry structures in solution, therefore, can be treated as valuable models for investigating the transition from simple ions to macroions. Kinetic studies showed an unusually long lag phase in the initial self-assembly process, which is followed by a rapid formation of the blackberry structures in solution. The small cluster size and high surface charge density are essential in regulating the supramolecular structure formation, as was shown from the high activation energy barrier of 51.2+/-2 kJ mol(-1). Different countercations were introduced into the system to investigate the effect of ion binding to the length of the lag phase. The current research provides yet another scale of self-assembly of uranyl peroxide complexes in aqueous media. PMID- 24402870 TI - Treatment of hereditary epidermolysis bullosa: updates and future prospects. AB - Epidermolysis bullosa (EB) represents a group of inherited blistering skin diseases, some forms of which are associated with considerable morbidity and increased mortality. Notably, in recessive dystrophic EB there can be extensive muco-cutaneous fragility and disease complications such as scars, contractures, anemia, malnutrition, and malignancy. Currently, there is no effective therapy or cure for EB. Over the last decade, however, a number of important advances have been made that are bringing new treatments closer to the clinic, including gene therapy, protein replacement therapy, cell therapies [allogeneic fibroblasts, mesenchymal stromal cells (MSCs), bone marrow stem cell transplantation, culturing/grafting revertant mosaic keratinocytes], gene editing/engineering, and clinical application of inducible pluripotent stem cells. Although a cure for EB still remains elusive, recent data on animal models and initial human clinical trials have raised the expectations of patients, clinicians, and researchers that disease modification and improved quality of life are feasible goals. Furthermore, the lessons learned in treating EB are likely to have significant implications for improving the management of other genetic diseases. PMID- 24402871 TI - ZnII - and AuI-catalyzed regioselective hydrative oxidations of 3-en-1-ynes with Selectfluor: realization of 1,4-dioxo and 1,4-oxohydroxy functionalizations. AB - Catalytic 1,4-dioxo functionalizations of 3-en-1-ynes to (Z)- and (E)-2-en-1,4 dicarbonyl compounds are described. This regioselective difunctionalization was achieved in one-pot operation through initial alkyne hydration followed by in situ Selectfluor oxidation. The presence of pyridine alters the reaction chemoselectivity to give 4-hydroxy-2-en-1-carbonyl products instead. A cooperative action of pyridine and Zn(II) assists the hydrolysis of key oxonium intermediate. PMID- 24402869 TI - Group III mGlu receptor agonist, ACPT-I, exerts potential neuroprotective effects in vitro and in vivo. AB - Many evidence suggest that metabotropic glutamate receptors (mGluRs) may modulate glutamatergic transmission, hence, these receptors are regarded as potential targets for neuroprotective drugs. Since group III mGlu receptor agonists are known to reduce glutamatergic transmission by inhibiting glutamate release, we decided to investigate the neuroprotective potential of the group III mGlu receptor agonist, (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid (ACPT I) against kainate (KA)-induced excitotoxicity in vitro and in vivo. In primary neuronal cell cultures ACPT-I (1-200 MUM), applied 30 min-3 h after starting the exposure to KA (150 MUM), significantly attenuated the KA-induced LDH release, increased cell viability, and inhibited caspase-3 activity both in cortical and hippocampal cell cultures. The effects were dose-, time- and structure-dependent. The neuroprotective effects of ACPT-I were reversed by (RS)-alpha-cyclopropyl-4 phosphonophenyl glycine, a group III mGluR antagonist. In the in vivo studies, KA (2.5 nmol/1 MUl) was unilaterally injected into the rat dorsal CA1 hippocampal region and the size of degeneration was examined by stereological counting of surviving neurons in the CA pyramidal layer. It was found that ACPT-I (7.5 or 15 nmol/1 MUl), injected into the dorsal hippocampus 30 min, 1 or 3 h after KA in dose-dependent manner prevented the KA-induced neuronal damage. Moreover, in vivo microdialysis studies in the rat hippocampus showed that ACPT-I (200 MUM) given simultaneously with KA (50 MUM) significantly diminished the KA-induced glutamate release in the hippocampus. This mechanism seems to play a role in mediating the neuroprotective effect of ACPT-I. PMID- 24402872 TI - Identification and expression profiles of genes and protens in SMMC-7721 cells. AB - In the study presented here, we first evaluated effect of CDDP on liver cancer cells SMMC-7721 apoptosis and motility capacity. Then, we evaluate inhibitory effect of CDDP on tumour growth and its possible molecular mechanism in liver cancer mice model. Results showed that the apoptosis rate of cells decreased with increasing CDDP. Analysis of the effect of the CDDP on cell cycle was performed by flow cytometry and results show a dose-dependent increase in the percentage of cells in the S-phase of the cell cycle, with a decrease in the percentage of cells in the G1 and G2/M phases. CDDP did not close the wound even after 48 h, as opposed to untreated cells (0 mg/l). Similarly, the migratory and invasion capacity of SMMC-7721 cells was also reduced after treatment with CDDP, as evaluated by a transwell assay. Animal experiment indicated that CDDP administration could increase blood WBC, total protein, albumin and A/G, decrease blood alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase levels in hepatocellular carcinomas mice. Immunohistochemistry analysis showed that positive expression of Fas and Bax proteins in the medicine treated (II, III) group was significantly higher, whereas the expression of NF kappaB, P53, Bcl-2 proteins was significantly lower than those of the control group. Gene expression analysis using Real time PCR methods revealed a significant up-regulation in the expression levels of Bax mRNA in the medicne treated (II, III) group when compared to untreated control. In contrast, CDDP treated group showed a significant down regulation in the expression levels of Bcl-2 mRNA as compared to untreated control group. These results are in agreement with immunohistochemistry data. Our observations indicate that CDDP has damaged effects on liver tumour cells SMMC-7721 including apoptosis, motility and cell cycle under in vitro. CDDP can enhance pro-apoptosis gene Fas, Bax expression, decrease anti-apoptosis genes Bcl-2 expression, and mutant genes P53, NF-kappaB proteins expression. PMID- 24402873 TI - Lack of association between cyclooxygenase 2-765G/C gene polymorphism and breast cancer risk in Ahvaz, west-south Iran. AB - Cyclooxygenases are key enzymes in conversion of arachidonic acid into prostaglandin H2. Cyclooxygenase-2 (COX-2) increases prostaglandins in neoplastic tissue. COX-2 has important roles in cell proliferation cancers, angiogenesis, and alzheimer. COX-2 is up-regulated in several types of cancer, and it is hypothesized that COX-2 expression may be genetically influenced. Our main objective was to evaluated the association of polymorphism COX-2 with risk of breast cancer in khouzestan province, and the second objective of the study was to evaluate the association with biochemistry parameters. This study consisting of 150 patients with breast cancer and 120 normal DNA was extracted from the white blood cells. Polymorphism cox2 gene was detected by polymerase chain reaction according to the standard methods. The profile lipids and estrogen were measured in two groups by standard methods. Chi square analysis showed that there was no association between breast cancer risk and COX-2 -765G>C genotype and alleles. Also, no association were observed between -765G>C polymorphism and biochemistry parameters. A multiple logistic regression model with cox2 genotypes and LDL and HDL as covariates revealed that there is no significant association between cox2 genotypes and risk of breast cancer, but higher values of LDL and HDL significantly increase risk of breast cancer. PMID- 24402874 TI - MicroRNAs as biomarkers of cervical cancer development: a literature review on miR-125b and miR-34a. AB - MicroRNAs are non-coding RNAs with important functions in several biological processes, such as, regulation of cell cycle, immune response, inflammation, and apoptosis. In fact, deregulation and abnormal expression of these molecules is associated with human pathologies including cancer and several have already emerged as potential prognostic biomarkers in different neoplasias. miR-34a is directly regulated by p53 and acts as tumor suppressor while miR-125b plays a significant role in immune response and apoptosis. In cervical carcinogenesis, HPV proteins seem to interact with both miR-34a and miR-125b changing its expression and promoting persistent infection and cervical cancer development. In this review we describe the potential role of miR-125b and miR-34a in cervical carcinogenesis, including interaction with HPV and mechanism of deregulation. Additionally, their clinical applications in cervical cancer as prognostic/predictive biomarkers are also briefly discussed. PMID- 24402875 TI - Genetic association of lipid metabolism related SNPs with myocardial infarction in the Pakistani population. AB - Myocardial infarction (MI) is the major cardiovascular disease. This can be caused by mutual interaction of environmental and genetic factors. The current study was designed to investigate the role of lipid metabolism related genetic polymorphisms with the onset of MI in Punjabi population of Pakistan. A total of 384 subjects was studied from April 2011 to July 2012. To determine the genetic associations with MI, the single nucleotide polymorphisms (SNPs) were genotyped by sequencing, as well as one label extension method. Out of eight SNPs in four candidate genes, seven genetic variants were significantly (P < 0.05) associated with elevated risk of MI. In current study two SNPs rs662799 risk allele G (P = 0.03) and rs3135506 risk allele C (P = 0.05) of APOA5 were found to be associated with significant higher risk of triglyceride levels, irrespective of age, sex, obesity, diabetes, hypertension and smoking. Gene variants (rs1558861, rs662799 and rs10750097) in APOA5 showed almost complete linkage disequilibrium and their minor allele frequencies (0.34, 0.28, and 0.41 respectively) were more prevalent (P < 0.05) in cases than controls. We further revealed risk haplotypes (C-T-G-A, G-C-A-G; P = 0.001) and protective haplotypes (G-T-A-G, C-C-G-A; P = 0.005) between these four SNPs for the progression of MI. Current study confirms the correlation between lipid metabolism related SNPs with MI and supports the role of APOA5 in raising plasma triglyceride levels in Pakistanis. However further studies are needed for delineating the role of these SNPs. PMID- 24402876 TI - The gene family of dehydration responsive element-binding transcription factors in grape (Vitis vinifera): genome-wide identification and analysis, expression profiles, and involvement in abiotic stress resistance. AB - The dehydration responsive element-binding (DREB) proteins play a critical role in plant development and abiotic stress-mediated gene expression. Therefore, they represent one of the most attractive regulons for breeding programs. However, no comprehensive summary of grapevine DREB family genes is available. During this study, 38 VvDREB members were identified from the entire grapevine genome and its expression sequence tag assembly. These were organized into the same subgroups, A1 through A6, as for Arabidopsis DREBs. The VvDREB genes were distributed in 15 out of 19 chromosomes in grapevine. Multiple sequence alignments were performed and a three-dimensional structure was created to demonstrate sequence conservation. Microarray analysis showed potential regulatory roles for VvDREBs in responses to various abiotic stresses, hormone treatments, berry ripening, exposure to light, and bud development. Cis-acting regulatory elements, such as W box, MYB-binding site, and light-responsive elements, were the most frequently found in the putative promoter regions. Furthermore, microarray transcriptional profiling of grapevine plants that over-expressed VvDREB23 revealed 248 up regulated and 229 down-regulated genes, with fold-changes of >1.5 when compared with the empty vector control. Gene ontology classifications showed that different genes function in cellular glucan metabolism, lipid transport, the endomembrane system, cell wall structure, and other important metabolic and developmental processes, as well as in the regulation of molecular functions. Our report provides an overview and constitutes a foundation for further study of this VvDREB gene family. All the microarray data and transcription profiling of transgenic versus empty-vector control transformant grapevines were retrieved from the online resources. PMID- 24402877 TI - Interleukin 18 gene polymorphism is a risk factor for multiple sclerosis. AB - Proinflammatory cytokines with immunosuppressive properties play an important role in the pathogenesis of multiple sclerosis (MS). Interleukin 18 (IL-18) is one of the most important innate cytokines produced from macrophages in the early stages of the inflammatory immune response. The purpose of this study was to determine whether there was any relationship between IL18 gene polymorphisms and MS. IL18 genotyping were performed in 101 MS patients and 164 control subjects by using the PCR-restriction fragment length polymorphism (PCR-RFLP) method. The frequency of MS patients with the CC genotype of the IL18 gene at position -137 was significantly higher than with the GG genotype [p = 0.01, odds ratio (OR) 3.17]. In haplotype analysis of two SNPs in the IL18 gene, frequency of the CC haplotype was significantly higher in MS patients (p = 0.002, OR 3.0). However, the genotype distribution of the IL18 -607 C/A polymorphism in the MS patient group was not significantly different from that of the control group. These data suggest that IL18 gene polymorphisms at position -137 might be a genetic risk factor for MS in the Turkish population. PMID- 24402878 TI - Metabolomics identifies changes in fatty acid and amino acid profiles in serum of overweight older adults following a weight loss intervention. AB - The application of metabolomics in nutritional research may be a useful tool to analyse and predict the response to a dietary intervention. The aim of this study was to examine metabolic changes in serum samples following exposure to an energy restricted diet (-15% of daily energy requirements) over a period of 8 weeks in overweight and obese older adults (n = 22) using a gas chromatography/mass spectrometry (GC/MS) metabolomic approach. After 8 weeks, there were significant reductions in weight (7%) and metabolic improvement (glucose and lipid profiles). Metabolomic analysis found that total saturated fatty acids (SFAs), including palmitic acid (C16:0) and stearic acid (C18:0) and monounsaturated fatty acids (MUFAs), were significantly decreased after the 8-week intervention. Furthermore, palmitoleic acid (C16:1) was found to be a negative predictor of change in body fat loss. Both the total omega-6 and omega-3 polyunsaturated fatty acids (PUFAs) significantly decreased, although the overall total amounts of PUFAs did not. The branched chain amino acid (BCAA) isoleucine significantly decreased in the serum samples after the intervention. In conclusion, this study demonstrated that the weight loss intervention based on a hypocaloric diet identified changes in the metabolic profiles of serum in overweight and obese older adults, with a reduction in anthropometric and biochemical parameters also found. PMID- 24402879 TI - Rational design of modular polyketide synthases: morphing the aureothin pathway into a luteoreticulin assembly line. AB - The unusual nitro-substituted polyketides aureothin, neoaureothin (spectinabilin), and luteoreticulin, which are produced by diverse Streptomyces species, point to a joint evolution. Through rational genetic recombination and domain exchanges we have successfully reprogrammed the modular (type I) aur polyketide synthase (PKS) into a synthase that generates luteoreticulin. This is the first rational transformation of a modular PKS to produce a complex polyketide that was initially isolated from a different bacterium. A unique aspect of this synthetic biology approach is that we exclusively used genes from a single biosynthesis gene cluster to design the artificial pathway, an avenue that likely emulates natural evolutionary processes. Furthermore, an unexpected, context-dependent switch in the regiospecificity of a pyrone methyl transferase was observed. We also describe an unprecedented scenario where an AT domain iteratively loads an extender unit onto the cognate ACP and the downstream ACP. This aberrant function is a novel case of non-colinear behavior of PKS domains. PMID- 24402880 TI - Amyloid beta-derived diffusible ligands (ADDLs) induce abnormal expression of insulin receptors in rat hippocampal neurons. AB - Amyloid beta (Abeta) is an important pathogenic factor in Alzheimer's disease (AD). In this study, we investigated the hypothesis that administration of amyloid-derived diffusible ligands (ADDLs) prepared from a synthetic Abeta(1-42) amyloid peptide can cause defective expression of insulin receptors (IRs). To this end, primary rat hippocampal neurons were treated with various concentrations of ADDLs and expression levels of IRs were measured using real time PCR and western blots. In these experiments, the expression of IRs significantly increased following treatment with low concentrations of Abeta(1 42). In contrast, when higher concentrations of Abeta(1-42) were applied, the number of apoptotic cells present increased, and expression of IRs significantly decreased. In combination, these results suggest that ADDLs is able to induce abnormal expression of IRs and interrupt normal insulin signaling, thereby potentially contributing to central insulin resistance that can occur during progression of AD. PMID- 24402881 TI - Presence of sigma shaped right coronary artery is an indicator of poor prognosis in patients with inferior myocardial infarction treated with primary percutaneous coronary intervention. AB - BACKGROUND: The effectiveness of primary percutaneous coronary intervention (PCI) in ST segment elevation myocardial infarction (STEMI) is well established. The clinical variables associated with poor prognosis in patients with STEMI have been extensively investigated. Right coronary artery (RCA) has two anatomical variations detected on coronary angiography namely C-shaped and sigma shaped RCA. The clinical importance of the shape of RCA in patients with STEMI has not been investigated before. PURPOSE: To investigate the prognostic value of RCA shape in patients with inferior STEMI treated with primary PCI. METHODS: Angiographic data of patients with inferior STEMI who were treated with primary PCI were retrospectively recruited. The differentiation of sigma and C-shaped RCAs was shown using single-frame angiograms, obtained during end-diastole of cardiac cycle in the left anterior oblique projection at 25 degrees to 35 degrees with no cranio-caudal angulation. Cardiovascular events at 30-days and on follow up were obtained through review of hospital records and telephone contact with the patient or the patient's relatives. Patients with C-shaped RCAs served as the control group. RESULTS: A total number of 824 patients with inferior STEMI who were treated with primary PCI for RCA were included. Sigma shaped RCA was observed in 15.1% of the subjects. In the sigma shaped RCA group, the door-to balloon times were longer (32.5 +/- 5.1 vs. 27.8 +/- 4.6 min; P = 0.01) and TIMI 3 flow restoration rates were lower (76.8% vs. 94.1%; p=0.01) compared to the controls. Mean SYNTAX scores were significantly higher in patients with sigma shaped RCA. Four patients (3.2%) in the sigma shaped RCA group and 23 patients (3.3%) in the control group died by day 30. The incidence of stent thrombosis, recurrent MI, and target lesion revascularization, were similar between the groups. During the follow-up (mean 37.6 +/- 13.4 months) 15 patients (12.3%) from the sigma shaped RCA group and 28 (4.1%) patients from the control group died (P = 0.01). The incidence of recurrent MI (27.2% vs. 13.7%; P = 0.01) and major adverse cardiovascular events (29.7% vs. 16.3%; P = 0.01) were significantly higher in the sigma shaped RCA group. In multivariate analysis, age, Killip class of >1, the presence of sigma shaped RCA, post PCI TIMI flow <3 and decreased left ventricular ejection fraction were the independent predictors of long term mortality. CONCLUSION: Presence of sigma shaped RCA is associated with more severe form of coronary artery disease and worse clinical outcome in patients with inferior STEMI. PMID- 24402882 TI - Pathway to clozapine use: a comparison between a patient cohort from New Zealand and a cohort from the United Kingdom. AB - BACKGROUND AND OBJECTIVE: Clozapine has been available since the early 1990s. Studies continue to demonstrate its superior efficacy in treatment-resistant schizophrenia. Despite this, numerous studies show under-utilisation, delayed access and reluctance by psychiatrists to prescribe clozapine. This retrospective cross-sectional study compared the prescribing of clozapine in two adult cohorts under the care of large public mental health services in Auckland (New Zealand) and Birmingham (United Kingdom) on 31 March 2007. METHOD: Time from first presentation to clozapine initiation, prior antipsychotics trialled and antipsychotic co-prescribing were compared. Data included demographics, psychiatric diagnosis, co-morbid conditions, year of first presentation, admissions and pharmacological treatment (clozapine dose, start date, prior antipsychotics, co-prescribed antipsychotic). RESULTS: Overall, 664 people were prescribed clozapine (402 Auckland; 262 Birmingham); mean daily dose of 384 mg (Auckland) and 429 mg (Birmingham). 53 % presented after 1990 and the average duration of time before starting clozapine was significantly longer in the Birmingham cohort (6.5 vs. 5.3 years) but this reduced in both cohorts to a 1 year mean in those presenting within the last 3 years. The average number of antipsychotics trialled pre-clozapine for those presenting since 1990 was significantly higher in the Birmingham cohort (4.3 vs. 3.1) but in both cohorts this similarly reduced in those presenting within the last 3 years. Antipsychotic co-prescribing was significantly higher in the Birmingham cohort (22.9 vs. 10.7 %). CONCLUSIONS: There is evidence that access to clozapine has improved over time in both cohorts, with a reduction in the duration between presentation and initiation of clozapine and number of different antipsychotics trialled pre clozapine. These are very positive findings in terms of optimising outcomes with clozapine and are possibly due to the impact of guideline recommendations, increasing clinician, consumer and carer knowledge, and experience with clozapine and funding changes. PMID- 24402883 TI - Frequency study of facial electromyography signals with respect to emotion recognition. AB - Emotional intelligence is one of the key research areas in human-computer interaction. This paper reports the development of an emotion recognition system using facial electromyogram (EMG) signals focusing the ambiguity on the frequency ranges used by different research works. The six emotional states (happiness, sadness, fear, surprise, disgust, and neutral) were elicited in 60 subjects using audio visual stimuli. Statistical features were extracted from the signals at high, medium, low, and very low frequency levels. They were then classified using four classifiers - naive Bayes, regression tree, K-nearest neighbor, and fuzzy K nearest neighbor, and the performance of the system at the different frequency levels were studied using three metrics, namely, % accuracy, sensitivity, and specificity. The post hoc tests in analysis of variance (ANOVA) indicate that the features contain significant emotional information at the very low-frequency range (<0.08 Hz). Similarly, the performance metrics of the classifiers also ensure better recognition rate at very low-frequency range. Though this range of frequency has not been used by researchers, the results of this work indicate that it should not be ignored. Further investigation of the very low frequency range to identify emotional information is still in progress. PMID- 24402884 TI - Principal stratification: a broader vision. PMID- 24402885 TI - Simulation education approaches to enhance collaborative healthcare: a best practices review. AB - Interprofessional simulation can provide health profession program educators with an effective means to prepare future practitioners to engage in meaningful collaboration. This systematic review was conducted to identify best practice recommendations to enhance collaborative healthcare using interprofessional simulation education innovations for learners in pre-licensure nursing programs. Using a systematic review methodology, 375 articles were reviewed and 17 studies met the inclusion criteria. Based on the methodological strength of the research and the impact of the simulation innovations, the following simulation techniques were recommended: high-fidelity human patient simulators, role play, and didactic lecture and audience response didactic lecture, both followed by role play with a standardized patient. Instructor modeling was related to achievement of interprofessional competencies when compared to no modeling. Future research is needed to identify optimal timing for implementing interprofessional education innovations, for development of appropriate evaluation tools, and to determine the effects of collaborative practice on patient care. PMID- 24402886 TI - SPECT gated blood pool phase analysis of lateral wall motion for prediction of CRT response. AB - Amplitude, defined as the magnitude of contraction of the myocardium, is obtained from phase analysis but has not been investigated to the same extent as phase based parameters for predicting the outcome of cardiac resynchronization therapy (CRT). The size of scar present in the lateral wall of the left ventricle (LV) has been shown in some studies to predict response to CRT. Scar is associated with impaired regional LV wall motion and is expected to result in a reduction in the corresponding amplitude values derived from phase analysis. Our objective was to determine the correlation between amplitude and scar, and to evaluate amplitude parameters as surrogates for scar in predicting response to CRT. 49 patients underwent a single photon emission computed tomography (SPECT) radionuclide angiography (RNA) scan as well as FDG viability and Rubidium-82 perfusion PET scans prior to undergoing CRT. Phase analysis was performed on the SPECT RNA data to extract amplitude values used to define amplitude size (AmpSize) and amplitude score (AmpScore) parameters. Scar size and scar score were obtained from the PET scans based on a 5 segment model. Scar parameters were then compared to amplitude parameters in the lateral wall for the whole population as well as both ischemic (N = 27) and non-ischemic (N = 22) populations using Pearson correlation. The ability of amplitude parameters to predict response to CRT was also investigated and compared to scar parameters. The largest ROC AUC values were obtained in the ischemic population where values of 0.67 and 0.68 were observed for lateral wall AmpSize and AmpScore respectively. Both parameters produced the same sensitivity and specificity values of 83 and 67 %. Amplitude size in the lateral wall showed significant correlation with lateral wall scar size in all patients (r = 0.51), which was further strengthened in the ischemic patient sub-group (r = 0.64). Lateral wall amplitude-based parameters obtained from SPECT RNA phase analysis produced an overall accuracy in predicting CRT response in ischemic patients that was not significantly different to that of PET lateral wall scar parameters. A significant correlation existed between amplitude size and scar size in the lateral wall. PMID- 24402887 TI - Interaction of fluorescently labeled triethyleneglycol and peptide derivatives with beta-cyclodextrin. AB - A triethyleneglycol (TEG) chain, a linear peptide, and a cyclic peptide labeled with 7-methoxycoumarin-3-carboxylic acid (MC) and 7-diethylaminocoumarin-3 carboxylic acid (DAC) were used to thoroughly study Forster resonance energy transfer (FRET) in inclusion complexes. (1) H NMR evidence was given for the formation of a 1:1 inclusion complex between beta-cyclodextrin (beta-CD) and the fluorophore moieties of model compounds. The binding constant was 20 times higher for DAC than for MC derivatives. Molecular modeling provided additional information. The UV/Vis absorption and fluorescence properties were studied and the energy transfer process was quantified. Fluorescence quenching was particularly strong for the peptide derivatives. The presence of beta-CDs reduced the FRET efficiency slightly. Dye-labeled peptide derivatives can thus be used to form inclusion complexes with beta-CDs and retain most of their FRET properties. This paves the way for their subsequent use in analytical devices that are designed to measure the activity of matrix metalloproteinases. PMID- 24402888 TI - Randomized clinical trial of stapler versus clamp-crushing transection in elective liver resection. AB - BACKGROUND: Various devices have been developed to facilitate liver transection and reduce blood loss in liver resections. None of these has proven superiority compared with the classical clamp-crushing technique. This randomized clinical trial compared the effectiveness and safety of stapler transection with that of clamp-crushing during open liver resection. METHODS: Patients admitted for elective open liver resection between January 2010 and October 2011 were assigned randomly to stapler transection or the clamp-crushing technique. The primary endpoint was the total amount of intraoperative blood loss. Secondary endpoints included transection time, duration of operation, complication rates and resection margins. RESULTS: A total of 130 patients were enrolled, 65 to clamp crushing and 65 to stapler transection. There was no difference between groups in total intraoperative blood loss: median (i.q.r.) 1050 (525-1650) versus 925 (450 1425) ml respectively (P = 0.279). The difference in total intraoperative blood loss normalized to the transection surface area was not statistically significant (P = 0.092). Blood loss during parenchymal transection was significantly lower in the stapler transection group (P = 0.002), as were the parenchymal transection time (mean(s.d.) 30(21) versus 9(7) min for clamp-crushing and stapler transection groups respectively; P < 0.001) and total duration of operation (mean(s.d.) 221(86) versus 190(85) min; P = 0.047). There were no significant differences in postoperative morbidity (P = 0.863) or mortality (P = 0.684) between groups. CONCLUSION: Stapler transection is a safe technique but does not reduce intraoperative blood loss in elective liver resection compared with the clamp-crushing technique. REGISTRATION NUMBER: NCT01049607 (http://www.clinicaltrials.gov). PMID- 24402889 TI - Psychological care of caregivers, nurses and physicians: a study of a new approach. AB - There is much evidence demonstrating that psychosocial interventions in caregivers and oncological staff produce an improvement in their patients' quality of life. The aim of this explorative study was to evaluate the effect of a new approach in promoting more functional ways to face stressful situations in the constellation of people around patients: caregivers, physicians and nurses. Thirty-four subjects were divided into three groups: 10 caregivers, 11 physicians, and 13 nurses. A "Balint Group" method modified according to a mindfulness technique was used as the intervention. Three assessment tools were administered to the participants at baseline, during, and after completion of the study: the Response Evaluation Measure (REM-71), the Satisfaction Profile (SAT P), and the Group Climate Questionnaire (GCQ). Mean values of defense mechanisms determined by the REM-71 were compared with those of the standard population. At baseline, we observed a prevalence of immature defenses in the three groups, with mean values above those in the standard population. After the psychological intervention, a tendency to normalization of the mean values was observed, indicating the development of more adaptive ways of using defense mechanisms and the effectiveness of the intervention. Group climate, assessed through the GCQ, showed an increase in the "Engagement" factor and a decline in the "Conflict" factor in all groups. This study suggests that group treatment focused on changing personal responses to stressful situations can induce more adaptive strategies enabling caregivers, hematologists, and nurses to help patients better and thereby improve their quality of life. PMID- 24402891 TI - High-frequency (20 to 40 MHz) acoustic response of liquid-filled nanocapsules. AB - Liquid-core nanoparticles are promising candidates for targeted ultrasound controlled therapy, but their acoustic detection remains challenging. High frequency (20 to 40 MHz) tone burst sequences were implemented with a programmable ultrasound biomicroscope to characterize acoustic response from perfluorooctyl bromide-core nanoparticles with thick poly(lactide-coglycolide) (PLGA) shells. Radio-frequency signals were acquired from flowing solutions of nanoparticles with two different shell-thickness-to-particle-radius ratios, solid PLGA nanoparticles, and latex nanobeads (linear controls). Normalized fundamental (20 MHz) and second-harmonic power spectral density (PSD) increased with particle concentration and was highest for the thinnest shelled particles. The second- harmonic PSD was detectable from the nanoparticles for peak rarefactional pressures (PRP) from 0.97 to 2.01 MPa at 23 cycles and for tone bursts from 11 to 23 cycles at 2.01 MPa. Their second-harmonic?to?fundamental ratio increased as a function of PRP and number of cycles. Within the same PRP and cycle ranges, the second-harmonic?to?fundamental ratios from matched concentration solutions of latex nanobeads and solid PLGA nanoparticles was more weakly detectable but also increased with PRP and number of cycles. Nanoparticles were detectable under flow conditions in vitro using the contrast agent mode of a high-frequency commercial scanner. These results characterize linear acoustic response from the nanoparticles (20 to 40 MHz) and demonstrate potential for their highfrequency detection. PMID- 24402892 TI - TR-MUSIC inversion of the density and compressibility contrasts of point scatterers. AB - Time-reversal imaging with multiple signal classification (TR-MUSIC) is a super resolution ultrasound imaging method for detecting point scatterers. This algorithm assumes that there is no contrast between the density of the point targets and that of the background medium, and that ultrasound scattering is caused only by the compressibility contrast. We modify the TR-MUSIC algorithm to account for ultrasound scattering from point targets with both density and compressibility contrasts. In addition, we develop an inversion method for estimating the density and compressibility contrasts of point scatterers with known locations. This approach is an extension of the inversion method previously developed by Devaney et al. for estimating the scattering strengths of point targets that have no density contrasts relative to the background medium. We use numerical phantom data to demonstrate that our new TR-MUSIC inversion algorithm can reliably estimate the density and compressibility contrasts of point scatterers. The estimates of these properties could be used for distinguishing breast calcifications from other tissue scatterers. PMID- 24402893 TI - Automatic respiratory gating for contrast ultrasound evaluation of liver lesions. AB - Dynamic contrast-enhanced ultrasound (DCEUS) has been used in radiology for many years for lesion detection and characterization. In recent years, more emphasis has been placed on tumor perfusion quantification with DCEUS. To ensure accuracy in both quantitative and qualitative evaluation of liver tumors with DCEUS, sources of noise in clinical data must be identified and, if possible, removed. One of the major sources of such noise is respiratory motion. A new automatic respiratory gating (ARG) algorithm is presented and evaluated with clinical data. The results of the evaluation demonstrate the potential of the ARG algorithm for clinical use as a fast and easy-to-implement method for removing respiratory motion from DCEUS loops. PMID- 24402894 TI - Fabrication and performance of a miniaturized 64-element high-frequency endoscopic phased array. AB - We have developed a 40-MHz, 64-element phased-array transducer packaged in a 2.5 x 3.1 mm endoscopic form factor. The array is a forward-looking semi-kerfed design based on a 0.68Pb(Mg(1/3)Nb(2/3))O(3) - 0.32PbTiO3 (PMN-32%PT) single crystal wafer with an element-to-element pitch of 38 um. To achieve a miniaturized form factor, a novel technique of wire bonding the array elements to a polyimide flexible circuit board oriented parallel to the forward looking ultrasound beam and perpendicular to the array was developed. A technique of partially dicing into the back of the array was also implemented to improve the directivity of the array elements. The array was fabricated with a single-layer P(VDF-TrFE)-copolymer matching layer and a polymethylpentene (TPX) lens for passive elevation focusing to a depth of 7 mm. The two-way -6-dB pulse bandwidth was measured to be 55% and the average electromechanical coupling (k(eff)) for the individual elements was measured to be 0.62. The one-way -6-dB directivities from several array elements were measured to be +/-20 degrees , which was shown to be an improvement over an identical kerfless array. The -3-dB elevation focus resulting from the TPX lens was measured to be 152 um at the focal depth, and the focused lateral resolution was measured to be 80 um at a steering angle of 0 degrees . To generate beam profiles and images, the probe was connected to a commercial ultrasound imaging platform which was reprogrammed to allow for phased array transmit beamforming and receive data collection. The collected RF data were then processed offline using a numerical computing script to generate sector images. The radiation pattern for the beamformed transmit pulse was collected along with images of wire phantoms in water and tissue-equivalent medium with a dynamic range of 60 dB. Finally, ex vivo tissue images were generated of porcine brain tissue. PMID- 24402895 TI - Gamma mixture classifier for plaque detection in intravascular ultrasonic images. AB - Carotid and coronary vascular incidents are mostly caused by vulnerable plaques. Detection and characterization of vulnerable plaques are important for early disease diagnosis and treatment. For this purpose, the echomorphology and composition have been studied. Several distributions have been used to describe ultrasonic data depending on tissues, acquisition conditions, and equipment. Among them, the Rayleigh distribution is a one-parameter model used to describe the raw envelope RF ultrasound signal for its simplicity, whereas the Nakagami distribution (a generalization of the Rayleigh distribution) is the two-parameter model which is commonly accepted. However, it fails to describe B-mode images or Cartesian interpolated or subsampled RF images because linear filtering changes the statistics of the signal. In this work, a gamma mixture model (GMM) is proposed to describe the subsampled/interpolated RF images and it is shown that the parameters and coefficients of the mixture are useful descriptors of speckle pattern for different types of plaque tissues. This new model outperforms recently proposed probabilistic and textural methods with respect to plaque description and characterization of echogenic contents. Classification results provide an overall accuracy of 86.56% for four classes and 95.16% for three classes. These results evidence the classifier usefulness for plaque characterization. Additionally, the classifier provides probability maps according to each tissue type, which can be displayed for inspecting local tissue composition, or used for automatic filtering and segmentation. PMID- 24402896 TI - Improved measurement of acoustic output using complex deconvolution of hydrophone sensitivity. AB - The traditional method for calculating acoustic pressure amplitude is to divide a hydrophone output voltage measurement by the hydrophone sensitivity at the acoustic working frequency, but this approach neglects frequency dependence of hydrophone sensitivity. Another method is to perform a complex deconvolution between the hydrophone output waveform and the hydrophone impulse response (the inverse Fourier transform of the sensitivity). In this paper, the effects of deconvolution on measurements of peak compressional pressure (p+), peak rarefactional pressure (p_), and pulse intensity integral (PII) are studied. Time delay spectrometry (TDS) was used to measure complex sensitivities from 1 to 40 MHz for 8 hydrophones used in medical ultrasound exposimetry. These included polyvinylidene fluoride (PVDF) spot-poled membrane, needle, capsule, and fiber optic designs. Subsequently, the 8 hydrophones were used to measure a 4-cycle, 3 MHz pressure waveform mimicking a pulsed Doppler waveform. Acoustic parameters were measured for the 8 hydrophones using the traditional approach and deconvolution. Average measurements (across all 8 hydrophones) of acoustic parameters from deconvolved waveforms were 4.8 MPa (p+), 2.4 MPa (p_), and 0.21 mJ/cm(2) (PII). Compared with the traditional method, deconvolution reduced the coefficient of variation (ratio of standard deviation to mean across all 8 hydrophones) from 29% to 8% (p+), 39% to 13% (p_), and 58% to 10% (PII). PMID- 24402897 TI - Implementing capon beamforming on a GPU for real-time cardiac ultrasound imaging. AB - Capon beamforming is associated with a high computational complexity, which limits its use as a real-time method in many applications. In this paper, we present an implementation of the Capon beamformer that exhibits realtime performance when applied in a typical cardiac ultrasound imaging setting. To achieve this performance, we make use of the parallel processing power found in modern graphics processing units (GPUs), combined with beamspace processing to reduce the computational complexity as the number of array elements increases. For a three-dimensional beamspace, we show that processing rates supporting real time cardiac ultrasound imaging are possible, meaning that images can be processed faster than the image acquisition rate for a wide range of parameters. Image quality is investigated in an in vivo cardiac data set. These results show that Capon beamforming is feasible for cardiac ultrasound imaging, providing images with improved lateral resolution both in element-space and beamspace. PMID- 24402898 TI - An integrated system for the segmentation of atherosclerotic carotid plaque ultrasound video. AB - The robust border identification of atherosclerotic carotid plaque, the corresponding degree of stenosis of the common carotid artery (CCA), and also the characteristics of the arterial wall, including plaque size, composition, and elasticity, have significant clinical relevance for the assessment of future cardiovascular events. To facilitate the follow-up and analysis of the carotid stenosis in serial clinical investigations, we propose and evaluate an integrated system for the segmentation of atherosclerotic carotid plaque in ultrasound videos of the CCA based on video frame normalization, speckle reduction filtering, M-mode state-based identification, parametric active contours, and snake segmentation. Initially, the cardiac cycle in each video is identified and the video M-mode is generated, thus identifying systolic and diastolic states. The video is then segmented for a time period of at least one full cardiac cycle. The algorithm is initialized in the first video frame of the cardiac cycle, with human assistance if needed, and the moving atherosclerotic plaque borders are tracked and segmented in the subsequent frames. Two different initialization methods are investigated in which initial contours are estimated every 20 video frames. In the first initialization method, the initial snake contour is estimated using morphology operators; in the second initialization method, the Chan-Vese active contour model is used. The performance of the algorithm is evaluated on 43 real CCA digitized videos from B-mode longitudinal ultrasound segments and is compared with the manual segmentations of an expert, available every 20 frames in a time span of 3 to 5 s, covering, in general, 2 cardiac cycles. The segmentation results were very satisfactory, according to the expert objective evaluation, for the two different methods investigated, with true negative fractions (TNF-specificity) of 83.7 +/- 7.6% and 84.3 +/- 7.5%; true positive fractions (TPF-sensitivity) of 85.42 +/- 8.1% and 86.1 +/- 8.0%; and between the ground truth and the proposed segmentation method, kappa indices (KI) of 84.6% and 85.3% and overlap indices of 74.7% and 75.4%. The segmentation contours were also used to compute the cardiac state identification and radial, longitudinal, and shear strain indices for the CCA wall and plaque between the asymptomatic and symptomatic groups were investigated. The results of this study show that the integrated system investigated in this study can be successfully used for the automated video segmentation of the CCA plaque in ultrasound videos. PMID- 24402899 TI - Ultrafast imaging in biomedical ultrasound. AB - Although the use of ultrasonic plane-wave transmissions rather than line-per-line focused beam transmissions has been long studied in research, clinical application of this technology was only recently made possible through developments in graphical processing unit (GPU)-based platforms. Far beyond a technological breakthrough, the use of plane or diverging wave transmissions enables attainment of ultrafast frame rates (typically faster than 1000 frames per second) over a large field of view. This concept has also inspired the emergence of completely novel imaging modes which are valuable for ultrasound based screening, diagnosis, and therapeutic monitoring. In this review article, we present the basic principles and implementation of ultrafast imaging. In particular, present and future applications of ultrafast imaging in biomedical ultrasound are illustrated and discussed. PMID- 24402900 TI - Generalized frequency-domain synthetic aperture focusing technique for ultrasonic imaging of irregularly layered objects. AB - In ultrasonic nondestructive testing (NDT), the phase shift migration (PSM) technique, as a frequency-domain implementation of the synthetic aperture focusing technique (SAFT), can be adopted for imaging of regularly layered objects that are inhomogeneous only in depth but isotropic and homogeneous in the lateral direction. To deal with irregularly layered objects that are anisotropic and inhomogeneous in both the depth and lateral directions, a generalized frequency- domain SAFT, called generalized phase shift migration (GPSM), is proposed in this paper. Compared with PSM, the most significant innovation of GPSM is that the phase shift factor is generalized to handle anisotropic media with lateral velocity variations. The generalization is accomplished by computer programming techniques without modifying the PSM model. In addition, SRFFT (split radix fast Fourier transform) input/output pruning algorithms are developed and employed in the GPSM algorithm to speed up the image reconstructions. The experiments show that the proposed imaging techniques are capable of reconstructing accurate shapes and interfaces of irregularly layered objects. The computing time of the GPSM algorithm is much less than the time-domain SAFT combined with the ray-tracing technique, which is, at present, the common method used in ultrasonic NDT industry for imaging layered objects. Furthermore, imaging regularly layered objects can be regarded as a special case of the presented technique. PMID- 24402901 TI - Vector control method applied to a traveling wave in a finite beam. AB - This paper presents the closed-loop control of exciters to produce a traveling wave in a finite beam. This control is based on a dynamical modeling of the system established in a rotating reference frame. This method allows dynamic and independent control of the phase and amplitude of two vibration modes. The condition to obtain the traveling wave is written in this rotating frame, and requires having two vibration modes with the same amplitude, and imposing a phase shift of 90 degrees between them. The advantage of the method is that it allows easy implementation of a closed loop control that can handle parameter drift of the system, after a temperature rise, for example. The modeling is compared with measurement on an experimental test bench which also implements real-time control. We managed to experimentally obtain a settling time of 250 ms for the traveling wave, and a standing wave ratio (SWR) of 1.3. PMID- 24402902 TI - A square-plate piezoelectric linear motor operating in two orthogonal and isomorphic face-diagonal-bending modes. AB - We report a piezoelectric linear motor made of a single Pb(Zr,Ti)O3 square-plate, which operates in two orthogonal and isomorphic face-diagonal-bending modes to produce precision linear motion. A 15 * 15 * 2 mm prototype was fabricated, and the motor generated a driving force of up to 1.8 N and a speed of 170 mm/s under an applied voltage of 100 Vpp at the resonance frequency of 136.5 kHz. The motor shows such advantages as large driving force under relatively low driving voltage, simple structure, and stable motion because of its isomorphic face diagonal-bending mode. PMID- 24402903 TI - The study of piezoelectric lateral-electric-field-excited resonator. AB - The piezoelectric lateral-electric-field-excited resonator based on an X-cut lithium niobate plate has been investigated. Two rectangular electrodes were applied on one side of the plate so that the lateral electric field components were parallel to the crystallographic Y-axis and excited the longitudinal wave in the gap between the electrodes. The region around the electrodes was covered with a special absorbing varnish to suppress the spurious oscillations. The effect of the absorbing coating width on the resonant frequency and Q-factor of the lateral field-excited resonator was studied in detail with the series and parallel resonances for different width of the gap between the electrodes. As a result, we found experimentally the parameter regions of pure resonances and the boundaries of value variation for resonance frequency, Q-factor, and effective electromechanical coupling coefficient. PMID- 24402904 TI - Parametric nonlinear lumped element model for circular CMUTs in collapsed mode. AB - We present a parametric equivalent circuit model for a circular CMUT in collapsed mode. First, we calculate the collapsed membrane deflection, utilizing the exact electrical force distribution in the analytical formulation of membrane deflection. Then we develop a lumped element model of collapsed membrane operation. The radiation impedance for collapsed mode is also included in the model. The model is merged with the uncollapsed mode model to obtain a simulation tool that handles all CMUT behavior, in transmit or receive. Large- and small signal operation of a single CMUT can be fully simulated for any excitation regime. The results are in good agreement with FEM simulations. PMID- 24402905 TI - Spatio-temporally smoothed coherence factor for ultrasound imaging. AB - Coherence-factor-like beamforming methods, such as the coherence factor (CF), the phase coherence factor (PCF), or the sign coherence factor (SCF), have been applied to suppress side and/or grating lobes and clutter in ultrasound imaging. These adaptive weighting factors can be implemented effectively with low computational complexity to improve image contrast properties. However, because of low SNR, the resulting images may suffer from deficiencies, including reduced overall image brightness, increased speckle variance, black-region artifacts surrounding hyperechoic objects, and underestimated magnitudes of point targets. To overcome these artifacts, a new spatio-temporal smoothing procedure is introduced to the CF method. It results in a smoothed coherence factor which measures the signal coherence among the beamsums of the divided subarrays over the duration of a transmit pulse. In addition, the procedure is extended to the SCF using the sign bits of the received signals. Simulated and real experimental data sets demonstrate that the proposed methods can improve the robustness of the CF and SCF with reduced speckle variance and significant removal of black-region artifacts, while preserving the ability to suppress clutter. Consequently, image contrast can be enhanced, especially for anechoic cysts. PMID- 24402906 TI - High-order pseudo-Gaussian scalar acoustical beams. AB - Exact solutions of the scalar Helmholtz equation describing tightly spherically focused beams are introduced without any approximations using the complex source point method in spherical coordinates. The generalized solutions, valid for any integer degree n and order m, describe high-order pseudo-Gaussian vortex, intermediate (vortex), hollow (nonvortex), and trigonometric (non-vortex) beams having an arbitrary beam waist w0. A very useful property of these beams is the efficient and fast computational modeling of tightly focused or quasi-collimated wave-fronts depending on the dimensionless waist parameter kw0, where k is the wave number of the acoustical radiation. Examples that illustrate hollow vortex and non-vortex beams are provided, and numerical simulations for the magnitude, isosurface, and phase plots of the pressure wave field of higher-order quasi Gaussian beams are evaluated with particular emphasis on kw0 for strongly (kw0 = 3) to weakly focused (i.e., quasi-collimated) beams (kw0 = 7). Potential applications are in beam-forming design, imaging, particle sizing and manipulation in acoustical tweezers, and phenomena related to scattering, radiation force, and torque. PMID- 24402907 TI - Ring-type traveling wave ultrasonic motor using a radial bending mode. AB - A traveling wave ultrasonic motor utilizing a radial bending mode of a thick ring is proposed. Twenty PZT stacks and 20 block springs are nested alternately into 40 slots cut in the ring's outer surface to produce a traveling wave. The prototype achieves maximum speed and torque of 146 r/min and 1.0 N.m, respectively. PMID- 24402908 TI - An evaluation of the frequency shift caused by collisions with background gas in the primary frequency standard NPL-CsF2. AB - Collisions between cold cesium atoms and background gas atoms at ambient temperature reduce the cold atom signal in a fountain clock and at the same time produce a shift in the measured clock frequency. We evaluate the shift in the NPL CsF2 cesium fountain primary frequency standard based on measurements of the fractional loss of cold atoms from the atomic cloud during the interrogation time combined with a model by Gibble that quantifies the relationship between the loss and the frequency shift. PMID- 24402909 TI - Fast 2-D ultrasound strain imaging: the benefits of using a GPU. AB - Deformation of tissue can be accurately estimated from radio-frequency ultrasound data using a 2-dimensional normalized cross correlation (NCC)-based algorithm. This procedure, however, is very computationally time-consuming. A major time reduction can be achieved by parallelizing the numerous computations of NCC. In this paper, two approaches for parallelization have been investigated: the OpenMP interface on a multi-CPU system and Compute Unified Device Architecture (CUDA) on a graphics processing unit (GPU). The performance of the OpenMP and GPU approaches were compared with a conventional Matlab implementation of NCC. The OpenMP approach with 8 threads achieved a maximum speed-up factor of 132 on the computing of NCC, whereas the GPU approach on an Nvidia Tesla K20 achieved a maximum speed-up factor of 376. Neither parallelization approach resulted in a significant loss in image quality of the elastograms. Parallelization of the NCC computations using the GPU, therefore, significantly reduces the computation time and increases the frame rate for motion estimation. PMID- 24402910 TI - eIF5A and EF-P: two unique translation factors are now traveling the same road. AB - Translational control is extremely important in all organisms, and some of its aspects are highly conserved among all primary kingdoms, such as those related to the translation elongation step. The previously classified translation initiation factor 5A (eIF5A) and its bacterial homologue elongation factor P (EF-P) were discovered in the late 70's and have recently been the object of many studies. eIF5A and EF-P are the only cellular proteins that undergo hypusination and lysinylation, respectively, both of which are unique posttranslational modifications. Herein, we review all the important discoveries related to the biochemical and functional characterization of these factors, highlighting the implication of eIF5A in translation elongation instead of initiation. The findings that eIF5A and EF-P are important for specific cellular processes and play a role in the relief of ribosome stalling caused by specific amino acid sequences, such as those containing prolines reinforce the hypothesis that these factors are involved in specialized translation. Although there are some divergences between these unique factors, recent studies have clarified that they act similarly during protein synthesis. Further studies may reveal their precise mechanism of ribosome activity modulation as well as the mRNA targets that require eIF5A and EF-P for their proper translation. PMID- 24402911 TI - Solvent migration in microhydrated aromatic aggregates: ionization-induced site switching in the 4-aminobenzonitrile-water cluster. AB - The dependence of the preferred microhydration sites of 4-aminobenzonitrile (4ABN) on electronic excitation and ionization is determined through IR spectroscopy of its clusters with water (W) in a supersonic expansion and through quantum chemical calculations. IR spectra of neutral 4ABN and two isomers of its hydrogen-bonded (H-bonded) 4ABN-W complexes are obtained in the ground and first excited singlet states (S0, S1) through IR depletion spectroscopy associated with resonance-enhanced multiphoton ionization. Spectral analysis reveals that electronic excitation does not change the H-bonding motif of each isomer, that is, H2O binding either to the CN or the NH site of 4ABN, denoted as 4ABN-W(CN) and 4ABN-W(NH), respectively. The IR spectra of 4ABN(+)-W in the doublet cation ground electronic state (D0) are measured by generating them either in an electron ionization source (EI-IR) or through resonant multiphoton ionization (REMPI-IR). The EI-IR spectrum shows only transitions of the most stable isomer of the cation, which is assigned to 4ABN(+)-W(NH). The REMPI-IR spectrum obtained through isomer-selective resonant photoionization of 4ABN-W(NH) is essentially the same as the EI-IR spectrum. The REMPI-IR spectrum obtained by ionizing 4ABN W(CN) is also similar to that of the 4ABN(+)-W(NH) isomer, but differs from that calculated for 4ABN(+)-W(CN), indicating that the H2O ligand migrates from the CN to the NH site upon ionization with a yield of 100%. The mechanism of this CN->NH site-switching reaction is discussed in the light of the calculated potential energy surface and the role of intracluster vibrational energy redistribution. PMID- 24402912 TI - HIF-1alpha expression as a protective strategy of HepG2 cells against fatty acid induced toxicity. AB - Free fatty acid-induced lipotoxicity via increased endoplasmic reticulum (ER) stress and hepatocyte apoptosis is a key pathological mechanism of non-alcoholic steatohepatitis. A role of hypoxia-inducible factor 1alpha (HIF-1alpha) in this process has been suggested, but direct evidence is lacking. Here, we used HepG2 cells as a model to study whether HIF-1alpha can reduce palmitic acid-induced lipotoxicity and ER stress. In HepG2 cells treated with 500 uM palmitic acid, HIF 1alpha expression increased transiently, the decline was associated with increased cleaved caspase-3 expression. Overexpression and knockdown of HIF 1alpha decreased and exacerbated, respectively, palmitic acid-induced lipoapoptosis. The overexpression also blunted upregulation of the ER stress markers, C/EBP homologous protein (CHOP) and chaperone immunoglobulin heavy chain binding protein (Bip), while the knockdown increased the level of CHOP. In line with this, CHOP promoter activity decreased following HIF-1alpha binding to the CHOP promoter hypoxia response element. These results indicate that hepatocyte lipotoxicity is associated with decreased HIF-1alpha expression. It also suggests that upregulation of HIF-1alpha can be a possible strategy to reduce lipotoxicity in non-alcoholic fatty liver disease. PMID- 24402913 TI - Diffuse age-related lumbar mri changes confound diagnosis of single (L5) root lesions. AB - INTRODUCTION: L5 radiculopathy has characteristic clinical and electrodiagnostic features including: radicular pain; weakness or denervation of hip abductors, ankle dorsiflexors, and inverters; and pre-ganglionic dorsal foot sensory loss. It is unknown how often patients with this distinctive clinical-electrodiagnostic presentation have isolated L5-root compression on neuroimaging or more widespread, possibly age-related, lumbar neuroforaminal or spinal stenosis. METHODS: A study-blinded neuroradiologist quantitated lumbosacral neuroforaminal, lateral recess, and spinal stenosis in 26 consecutive patients with unilateral, clinically and EMG-ascertained L5 monoradiculopathy, and quantitated a global neuroforaminal and spinal stenosis score (SSS). RESULTS: Only 9 patients (35%) had isolated L5-root compression, 14 (54%) had multi-root compression, and 3 (12%) had normal neuroimaging. Increasing age correlated with SSS, and the 9 patients with isolated L5-root compression were significantly younger than patients with multi-root involvement. CONCLUSIONS: This study underscores the role of clinical and electrodiagnostic data when interpreting lumbosacral neuroimaging, particularly in older patients. PMID- 24402914 TI - Effects of community based cardiac rehabilitation: Comparison with a hospital based programme. AB - BACKGROUND: With typically fewer than 35% of eligible patients attending outpatient cardiac rehabilitation (CR), more accessible provision is required. Community-based cardiac rehabilitation is one option but its effects need to be compared with those of hospital-based CR. AIMS: The purpose of this study was to compare changes in health-related quality of life (HRQOL), anxiety and depression, and exercise and smoking rates, between attendees at community-based and hospital-based CR programmes. METHOD: A prospective comparative cohort design was used. Consecutive patients admitted to Aberdeen Royal Infirmary and eligible for CR were recruited and followed up by self-report questionnaire. Outcomes were health status (RAND-36), Hospital Anxiety and Depression Scale (HADS), Godin Leisure-Time Exercise and smoking status. RESULTS: There were 136 of 179 (75%) attenders at community-based CR, compared to 169 of 209 (80%) at hospital-based CR (p=0.242). In univariate analysis, there were no significant differences between the two groups in health status, HADS, and frequency or intensity of exercise immediately after the CR programme or six months later. Adjusting for other significant factors, patients who attended community CR reported higher RAND-36 energy scores at six months compared with attenders at hospital CR (p=0.020), but were less likely to undertake frequent exercise (p=0.041). CONCLUSIONS: Community-based CR appears to achieve similar attendance rates and effects on health status and health behaviour as hospital-based CR. This option might help overcome the poor attendance of patients with long travelling times to hospital-based CR. PMID- 24402915 TI - A linear-encoding model explains the variability of the target morphology in regeneration. AB - A fundamental assumption of today's molecular genetics paradigm is that complex morphology emerges from the combined activity of low-level processes involving proteins and nucleic acids. An inherent characteristic of such nonlinear encodings is the difficulty of creating the genetic and epigenetic information that will produce a given self-assembling complex morphology. This 'inverse problem' is vital not only for understanding the evolution, development and regeneration of bodyplans, but also for synthetic biology efforts that seek to engineer biological shapes. Importantly, the regenerative mechanisms in deer antlers, planarian worms and fiddler crabs can solve an inverse problem: their target morphology can be altered specifically and stably by injuries in particular locations. Here, we discuss the class of models that use pre-specified morphological goal states and propose the existence of a linear encoding of the target morphology, making the inverse problem easy for these organisms to solve. Indeed, many model organisms such as Drosophila, hydra and Xenopus also develop according to nonlinear encodings producing linear encodings of their final morphologies. We propose the development of testable models of regeneration regulation that combine emergence with a top-down specification of shape by linear encodings of target morphology, driving transformative applications in biomedicine and synthetic bioengineering. PMID- 24402916 TI - A design protocol for tailoring ice-templated scaffold structure. AB - In this paper, we show, for the first time, the key link between scaffold architecture and latent heat evolution during the production of porous biomedical collagen structures using freeze-drying. Collagen scaffolds are used widely in the biomedical industry for the repair and reconstruction of skeletal tissues and organs. Freeze-drying of collagen slurries is a standard industrial process, and, until now, the literature has sought to characterize the influence of set processing parameters including the freezing protocol and weight percentage of collagen. However, we are able to demonstrate, by monitoring the local thermal events within the slurry during solidification, that nucleation, growth and annealing processes can be controlled, and therefore we are able to control the resulting scaffold architecture. Based on our correlation of thermal profile measurements with scaffold architecture, we hypothesize that there is a link between the fundamental freezing of ice and the structure of scaffolds, which suggests that this concept is applicable not only for collagen but also for ceramics and pharmaceuticals. We present a design protocol of strategies for tailoring the ice-templated scaffold structure. PMID- 24402917 TI - On flaw tolerance of nacre: a theoretical study. AB - As a natural composite, nacre has an elegant staggered 'brick-and-mortar' microstructure consisting of mineral platelets glued by organic macromolecules, which endows the material with superior mechanical properties to achieve its biological functions. In this paper, a microstructure-based crack-bridging model is employed to investigate how the strength of nacre is affected by pre-existing structural defects. Our analysis demonstrates that owing to its special microstructure and the toughening effect of platelets, nacre has a superior flaw tolerance feature. The maximal crack size that does not evidently reduce the tensile strength of nacre is up to tens of micrometres, about three orders higher than that of pure aragonite. Through dimensional analysis, a non-dimensional parameter is proposed to quantify the flaw-tolerance ability of nacreous materials in a wide range of structural parameters. This study provides us some inspirations for optimal design of advanced biomimetic composites. PMID- 24402918 TI - The energy components of stacked chromatin layers explain the morphology, dimensions and mechanical properties of metaphase chromosomes. AB - The measurement of the dimensions of metaphase chromosomes in different animal and plant karyotypes prepared in different laboratories indicates that chromatids have a great variety of sizes which are dependent on the amount of DNA that they contain. However, all chromatids are elongated cylinders that have relatively similar shape proportions (length to diameter ratio approx. 13). To explain this geometry, it is considered that chromosomes are self-organizing structures formed by stacked layers of planar chromatin and that the energy of nucleosome nucleosome interactions between chromatin layers inside the chromatid is approximately 3.6 * 10(-20) J per nucleosome, which is the value reported by other authors for internucleosome interactions in chromatin fibres. Nucleosomes in the periphery of the chromatid are in contact with the medium; they cannot fully interact with bulk chromatin within layers and this generates a surface potential that destabilizes the structure. Chromatids are smooth cylinders because this morphology has a lower surface energy than structures having irregular surfaces. The elongated shape of chromatids can be explained if the destabilizing surface potential is higher in the telomeres (approx. 0.16 mJ m( 2)) than in the lateral surface (approx. 0.012 mJ m(-2)). The results obtained by other authors in experimental studies of chromosome mechanics have been used to test the proposed supramolecular structure. It is demonstrated quantitatively that internucleosome interactions between chromatin layers can justify the work required for elastic chromosome stretching (approx. 0.1 pJ for large chromosomes). The high amount of work (up to approx. 10 pJ) required for large chromosome extensions is probably absorbed by chromatin layers through a mechanism involving nucleosome unwrapping. PMID- 24402920 TI - The evolution of continuous learning of the structure of the environment. AB - Continuous, 'always on', learning of structure from a stream of data is studied mainly in the fields of machine learning or language acquisition, but its evolutionary roots may go back to the first organisms that were internally motivated to learn and represent their environment. Here, we study under what conditions such continuous learning (CL) may be more adaptive than simple reinforcement learning and examine how it could have evolved from the same basic associative elements. We use agent-based computer simulations to compare three learning strategies: simple reinforcement learning; reinforcement learning with chaining (RL-chain) and CL that applies the same associative mechanisms used by the other strategies, but also seeks statistical regularities in the relations among all items in the environment, regardless of the initial association with food. We show that a sufficiently structured environment favours the evolution of both RL-chain and CL and that CL outperforms the other strategies when food is relatively rare and the time for learning is limited. This advantage of internally motivated CL stems from its ability to capture statistical patterns in the environment even before they are associated with food, at which point they immediately become useful for planning. PMID- 24402919 TI - Fascicles from energy-storing tendons show an age-specific response to cyclic fatigue loading. AB - Some tendons, such as the human Achilles and equine superficial digital flexor tendon (SDFT), act as energy stores, stretching and recoiling to increase efficiency during locomotion. Our previous observations of rotation in response to applied strain in SDFT fascicles suggest a helical structure, which may provide energy-storing tendons with a greater ability to extend and recoil efficiently. Despite this specialization, energy-storing tendons are prone to age related tendinopathy. The aim of this study was to assess the effect of cyclic fatigue loading (FL) on the microstructural strain response of SDFT fascicles from young and old horses. The data demonstrate two independent age-related mechanisms of fatigue failure; in young horses, FL caused low levels of matrix damage and decreased rotation. This suggests that loading causes alterations to the helix substructure, which may reduce their ability to recoil and recover. By contrast, fascicles from old horses, in which the helix is already compromised, showed greater evidence of matrix damage and suffer increased fibre sliding after FL, which may partially explain the age-related increase in tendinopathy. Elucidation of helix structure and the precise alterations occurring owing to both ageing and FL will help to develop appropriate preventative and repair strategies for tendinopathy. PMID- 24402925 TI - PD-1 inhibitors raise survival in NSCLC. AB - Two PD-1 inhibitors, Bristol-Myers Squibb's nivolumab and Merck's MK-3475, both demonstrated positive results in phase I trials of previously treated patients with non-small cell lung cancer, reported at the World Conference on Lung Cancer in Sydney, Australia. PMID- 24402921 TI - Nanofilaments on glioblastoma exosomes revealed by peak force microscopy. AB - Exosomes are sub-100 nm extracellular vesicles secreted by normal and cancer cells. We present a high-resolution structure of previously unidentified nanofilaments on glioblastoma-derived exosomes, using nanoscale peak force imaging. These stiff, adhesive, trypsin- and RNAse-resistant surface nanofilaments add a new dimension to the current structural knowledge of exosome mediated intercellular communication. PMID- 24402926 TI - Ariad suspends ponatinib sales. AB - Because of concerns about serious cardiovascular side effects, the U.S. Food and Drug Administration asked Ariad Pharmaceuticals to temporarily suspend sales and marketing of ponatinib to treat chronic myeloid leukemia in patients resistant to first-line therapy. PMID- 24402927 TI - Strategic plan aims to curb drug shortages. AB - The U.S. Food and Drug Administration has released a strategic plan to strengthen its response to imminent and existing drug shortages, as well as a proposed rule requiring manufacturers of drugs and biologics to alert the agency to the impending discontinuation of any products or interruptions in manufacturing that could deplete supply. PMID- 24402929 TI - African cancer institute focuses on early detection. AB - The recently launched African Cancer Institute at Stellenbosch University in Stellenbosch, South Africa will focus on advancing the prevention, diagnosis, and management of cancer in Africa. PMID- 24402930 TI - Q&A: Mitchell Zeller on the FDA and tobacco. AB - By law, the U.S. Food and Drug Administration has the authority, through its Center for Tobacco Products, to regulate the manufacture, marketing, and distribution of tobacco products. Its director, Mitchell Zeller, JD, talks about how the center, though its research, public education, and enforcement activities, aims to "make tobacco-related death and disease a part of America's past." PMID- 24402931 TI - The science of tobacco addiction and cessation. AB - Over the past decade, researchers have found genetic variations that affect how nicotine, the main addictive component of tobacco, interacts with cells in the brain and how fast the body metabolizes it. Carrying a high-risk variant predicts a person's ability to snuff out their cigarettes for good. Genetic testing could help predict which smokers might benefit from nicotine replacement therapy or other prescription medications, much like sequencing of malignant tumors can point to the most effective cancer treatment. PMID- 24402942 TI - Climbing RAS, the everest of oncogenes. AB - SUMMARY: Mutations that activate the small GTP-binding protein KRAS are the most common oncogenic event in human tumors. Thirty years after its discovery, mutant KRAS has yet to be therapeutically conquered. PMID- 24402943 TI - miR-30c-2-3p and miR-30a-3p: new pieces of the jigsaw puzzle in HIF2alpha regulation. AB - Clear cell renal cell carcinoma (ccRCC), the most frequent subtype of renal cell cancer, is characterized by mutation of the von Hippel-Lindau (VHL) tumor suppressor gene, which results in stabilization of hypoxia-inducible factor (HIF) alpha proteins. In this issue of Cancer Discovery, Mathew and colleagues report that miR-30c-2-3p and miR-30a-3p downregulation in ccRCC promotes increased expression of HIF2alpha. PMID- 24402944 TI - Faulty ECM signaling facilitates autoimmune lymphomagenesis. AB - The contribution of the extracellular matrix (ECM) to the microenvironment of solid tumors is appreciated although not completely understood; however, the contribution of the ECM to the development of hematopoietic tumors has not been investigated in depth. A new study by Sangaletti and colleagues demonstrates that faulty ECM signaling can facilitate malignant lymphoproliferation in mice predisposed to autoimmunity. Similar changes in ECM construction, consistent with a loss of inhibitory ECM signaling, were identified in the transition from reactive lymphoid hyperplasia to malignant chronic lymphocytic leukemia in patients. These results reveal a critical contribution of reduced collagen signaling in lymphoma and highlight the importance of appropriate ECM construction for maintenance of tissue homeostasis. PMID- 24402945 TI - Towards a unified model of RAF inhibitor resistance. AB - ATP-competitive RAF inhibitors elicit profound but often temporary antitumor responses in patients with BRAF-mutant melanoma. Analysis of tumor samples collected at the time of disease progression indicates that alterations within the extracellular signal-regulated kinase (ERK) pathway that result in reactivation of ERK signaling are present in most patients. Mutations in the phosphoinositide 3-kinase/AKT pathway that enhance the adaptive response to RAF inhibitors also contribute to RAF inhibitor resistance in a subset of patients. PMID- 24402946 TI - Ibrutinib approved for mantle cell lymphoma. AB - The U.S. Food and Drug Administration (FDA) has approved the targeted therapy ibrutinib (Imbruvica; Johnson & Johnson and Pharmacyclics) for treating patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. PMID- 24402954 TI - HPV vaccine works against nine viral types. AB - In a phase III study, Merck's new V503 human papillomavirus (HPV) vaccine prevented 97% of high-grade, precancerous vaginal, vulvar, and cervical disease caused by HPV types 31, 33, 45, 52, and 58. The new vaccine also generated immune responses to HPV types 6, 11, 16, and 18 that were as good as or better than those generated by the company's Gardasil vaccine. PMID- 24402955 TI - ICR expands CanSAR drug discovery platform. AB - The UK's Institute of Cancer Research, London has broadened its CanSAR knowledgebase, a cancer drug-discovery platform that integrates genomic, chemical, and pharmacologic data. The newly released CanSAR 2.0 adds more prediction methodologies and holds data on more than 8 million experimentally derived measurements, nearly 1 million biologically active chemical compounds, and more than 1,000 cancer cell lines. PMID- 24402956 TI - ASCO forges ahead with CancerLinQ. AB - The American Society of Clinical Oncology is expanding its CancerLinQ health information technology initiative from the pilot stage to a working system, whose first elements will debut by early 2015. PMID- 24402957 TI - Genomics AIDS lung tumor classification and treatment. AB - Analysis of 1,255 lung tumors compared the accuracy of genetic sequencing versus immunohistochemistry in tumor classification and found that the genetic methods allow more accurate assigning of tumors to therapeutically relevant groups, particularly for large cell carcinoma. A subsequent prospective research effort using the project's combined genomic and immunohistochemical diagnostic approach screened 5,145 lung cancer patients for a panel of roughly 20 lung cancer mutations. The authors were able to perform the combined genomic and immunohistochemical analysis on 3,863 patients, and many of them were eligible for approved targeted therapies or for treatment with experimental therapies in clinical trials. PMID- 24402958 TI - Obinutuzumab breaks through to FDA approval. AB - The U.S. Food and Drug Administration approved the monoclonal antibody obinutuzumab for use with chlorambucil in patients with previously untreated chronic lymphocytic leukemia. The drug is the first to receive approval under the agency's breakthrough therapy designation, created in July 2012. PMID- 24402959 TI - Anticipating precision medicine's future. AB - Instead of investing in technologies to test a few genes at a time, researchers and regulators should plan for the routine use whole-genome sequencing in the diagnosis of cancer, according to speakers at the "Transforming Cancer Care through Diagnostics and Personalized Medicine" symposium, held in Washington, DC, in October. PMID- 24402960 TI - Pazopanib outscores sunitinib on tolerability. AB - In a phase III trial for patients with metastatic renal cell carcinoma, pazopanib and sunitinib offered comparable progression-free survival, but pazopanib scored higher on quality-of-life indices. PMID- 24402962 TI - Catalytic, asymmetric synthesis of phosphonic gamma-(hydroxyalkyl)butenolides with contiguous quaternary and tertiary stereogenic centers. AB - A procedure that enables high yielding access to phosphonic gamma (hydroxyalkyl)butenolides with excellent regio-, diastereo- and enantiocontrol is reported. The simultaneous construction of up to two adjacent quaternary stereogenic centers by a catalytic asymmetric vinylogous Mukaiyama aldol reaction unites biologically and medicinally relevant entities, namely alpha-hydroxy phosphonates and gamma-(hydroxyalkyl)butenolides. This is achieved by utilizing a readily available chiral copper-sulfoximine catalyst showing a broad functional group tolerance for both the electrophilic and nucleophilic reactants. A discussion about potential factors affecting the observed level of enantioselectivity, which stems from the enantiopure sulfoximine ligand, is also included. PMID- 24402963 TI - [Mosquitoes (Diptera, Culicidae) of Smir marshes (northwest of Morocco): inventory and biotypology]. AB - The Smir marshes are a favorable environment for the growth of many mosquitoes (Diptera, Culicidae). The inventory of Culicidae species reveals 14 species, is 33% of the species of Morocco, distributed in four genera: Culex, Culiseta, Ochlerotatus and Anopheles (with 5, 2, 5 and 2 species respectively) which Anopheles labranchiae, vector of the agent of the malaria in Morocco until 2004. In this study, we investigated the spatiotemporal mesological affinities and we tried to explain the biotypology of mosquito populations of the site. These analyzes revealed several groups of stations and species according to various parameters, especially salinity. PMID- 24402964 TI - [Scorpion envenomation in Morocco: scorpions of the genus Androctonus, Buthus and Hottentota]. AB - Around the world and especially in summer, the scorpion envenomation is a real public health problem. In Morocco, its gravity is due to the diversity of genera of the Buthidae family whose their venom is potentially lethal, mainly the genus Androctonus, Buthus and Hottentota. The areas most affected by this problematic are the central and southern of Morocco. The lethality of scorpion's venom primarily affects children. It is rich in neurotoxic polypeptides that have targeted ion channel membrane Na(+), K(+) activated or not by Ca(++). The toxins polymorphism causes pathophysiological disorders. The diversity of symptomatic treatment in the absence of immunotherapy is due to variability in clinical pictures, which depends on the species involved and the patient at risk. The objective of this review is to highlight the magnitude of the scorpion envenomation by describing its epidemiological characteristics, elucidate the pathophysiological effects of the venom of the most dangerous scorpions in Morocco the genus Androctonus, Buthus and Hottentota, and their therapeutic treatment. PMID- 24402965 TI - Blood loss and transfusion rates associated with transcatheter aortic valve replacement: recommendations for patients who refuse blood transfusion. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) is less invasive than surgical aortic valve replacement and may be preferred for patients who refuse blood transfusions. OBJECTIVES: Our study sought to define transfusion rates in TAVR, identify predictors and develop recommendations for patients who refuse transfusions. METHODS: A large cohort of consecutive patients undergoing TAVR was prospectively studied. Blood loss and transfusion rates were observed in patients undergoing transfemoral (TF-TAVR) and transapical TAVR (TA-TAVR). Predictors for transfusion were investigated in a multivariate model. RESULTS: Of 373 consecutive patients, 270 underwent TF-TAVR and 103 TA-TAVR. Transfusion rates were significantly lower in TF-TAVR than TA-TAVR (11.1 vs 41.7%; P < 0.001). In patients who did not receive transfusions, blood loss was significantly lower in TF-TAVR than TA-TAVR (23.6 +/- 12.2 g/l vs 28.9 +/- 13.7 g/l; P = 0.004), but did not differ in transfused patients (36.9 +/- 12.9 g/l vs 33.4 +/- 21.2 g/l; P = 0.428). Predictors for transfusions were low baseline hemoglobin, female sex, low body weight and decreased renal function. In seven Jehovah's Witness patients, who refused transfusions, no vascular complications occurred and clinical outcome was excellent. CONCLUSION: In patients, who refuse transfusions, TAVR may be performed with good clinical outcomes provided a high baseline hemoglobin level, careful management of the access site and strict measurements to reduce blood loss. TF-TAVR is associated with less blood loss and a lower rate of transfusions than TA-TAVR, and may be the preferred option for patients, who refuse transfusions. PMID- 24402966 TI - Nickel-catalyzed Mizoroki-Heck reaction of aryl sulfonates and chlorides with electronically unbiased terminal olefins: high selectivity for branched products. AB - Achieving high selectivity in the Heck reaction of electronically unbiased alkenes has been a longstanding challenge. Using a nickel-catalyzed cationic Heck reaction, we were able to achieve excellent selectivity for branched products (>=19:1 in all cases) over a wide range of aryl electrophiles and aliphatic olefins. A bidentate ligand with a suitable bite angle and steric profile was key to obtaining high branched/linear selectivity, whereas the appropriate base suppressed alkene isomerization of the product. Although aryl triflates are traditionally used to access the cationic Heck pathway, we have shown that, by using triethylsilyl trifluoromethanesulfonate, we can effect a counterion exchange of the catalytic nickel complex, such that cheaper and more stable aryl chlorides, mesylates, tosylates, and sulfamates can be used to yield the same branched products with high selectivity. PMID- 24402968 TI - Implementing unpredictability in feeding enrichment for Malayan sun bears (Helarctos malayanus). AB - Bears in the wild spend large proportions of time in foraging activities. In zoos their time budgets differ markedly from those of their wild counterparts. Feeding enrichment has been documented to increase foraging behavior and to reduce stereotypies. But in general these procedures have no long-term effects and result in habituation. As can be expected by the predictions of the optimal foraging theory, foraging activities are restricted as long as the availability of food is predictable. To quantify the effect of spatial unpredictability, three feeding methods have been designed to stimulate functional foraging behavior in captive Malayan sun bears in the long-term. In order to examine if habituation occurs, the most effective method was tested for 12 consecutive days. Activities of four adult sun bears at the Cologne Zoo were recorded by focal animal recording of foraging behaviors and time sampling of activities for a total of 360 hr. Implementing unpredictability significantly increased the time the bears spent foraging and led to a higher diversity of foraging behaviors. The effects lasted throughout the entire day and no habituation occurred in the course of 12 consecutive days. The study shows how functional species typical behavior in captive Malayan sun bears can be stimulated in the long-term by simulating natural characteristics of food availability. PMID- 24402967 TI - Growth factor and signaling pathways and their relevance to prostate cancer therapeutics. AB - Treatments that target the androgen axis represent an effective strategy for patients with advanced prostate cancer, but the disease remains incurable and new therapeutic approaches are necessary. Significant advances have recently occurred in our understanding of the growth factor and signaling pathways that are active in prostate cancer. In conjunction with this, many new targeted therapies with sound preclinical rationale have entered clinical development and are being tested in men with castration-resistant prostate cancer. Some of the most relevant pathways currently being exploited for therapeutic gain are HGF/c-Met signaling, the PI3K/AKT/mTOR pathway, Hedgehog signaling, the endothelin axis, Src kinase signaling, the IGF pathway, and angiogenesis. Here, we summarize the biological basis for the use of selected targeted agents and the results from available clinical trials of these drugs in men with prostate cancer. PMID- 24402969 TI - S100A1 and S100B expression patterns identify differentiation status of human articular chondrocytes. AB - Many studies in the field of cell-based cartilage repair have focused on identifying markers associated with the differentiation status of human articular chondrocytes (HAC) that could predict their chondrogenic potency. A previous study from our group showed a correlation between the expression of S100 protein in HAC and their chondrogenic potential. The aims of the current study were to clarify which S100 proteins are associated with HAC differentiation status and to provide an S100-based assay for measuring HAC chondrogenic potential. The expression patterns of S100A1 and S100B were investigated in cartilage and in HAC cultured under conditions promoting dedifferentiation (monolayer culture) or redifferentiation (pellet culture or BMP4 treatment in monolayer culture), using characterized antibodies specifically recognizing S100A1 and S100B, by immunohistochemistry, immunocytochemistry, Western blot, and gene expression analysis. S100A1 and S100B were expressed homogeneously in all cartilage zones, and decreased during dedifferentiation. S100A1, but not S100B, was re-expressed in pellets and co-localized with collagen II. Gene expression analysis revealed concomitant modulation of S100A1, S100B, collagen type II, and aggrecan: down regulation during monolayer culture and up-regulation upon BMP4 treatment. These results strongly support an association of S100A1, and to a lesser extent S100B, with the HAC differentiated phenotype. To facilitate their potential application, we established an S100A1/B-based flow cytometry assay for accurate assessment of HAC differentiation status. We propose S100A1 and S100B expression as a marker to develop potency assays for cartilage regeneration cell therapies, and as a redifferentiation readout in monolayer cultures aiming to investigate stimuli for chondrogenic induction. PMID- 24402970 TI - Attention-deficit/hyperactivity disorder with inadequate response to stimulants: approaches to management. AB - Attention-deficit/hyperactivity disorder, or ADHD, is the most frequently occurring neurobiological disorder in childhood and is defined by symptoms of inattention and/or hyperactivity and impulsivity that are excessive when compared with other individuals at the same developmental level. ADHD can be successfully treated pharmacologically and stimulant medications are considered a first-line treatment. However, 20-35 % of subjects in clinical trials may have an inadequate response to initial stimulant treatment. There is no standard definition of inadequate response. In many clinical trials, response is defined as a percentage improvement on the Attention-Deficit/Hyperactivity Disorder Rating Scale alone, while in others the change in Clinical Global Impression-Improvement score has also been employed. Other outcome measures have also been used. A more meaningful definition for inadequate response is one that does not produce sufficient reduction of symptoms to produce functional improvement. The literature reveals many factors that may contribute to inadequate response to treatment. Among these are poor adherence, severity and/or complexity of ADHD, inadequate stimulant dosing and/or dose-limiting adverse effects. The reasons for poor adherence should be determined. Common factors include adverse effects, lack of effectiveness, concerns about addictive potential, difficulty ingesting the medication and cost. For patients with inadequate dosing, medication optimization should be tried. For those with dose-limiting adverse effects, switching to another stimulant class or a non-stimulant is an option. For patients who are partial responders to stimulants, despite adequate adherence and dose optimization, the addition of atomoxetine or guanfacine extended release or clonidine extended release may help them achieve adequate response. PMID- 24402971 TI - Label-free measurements of the diffusivity of molecules in lipid membranes. AB - An important and characteristic property of a cell membrane is the lateral mobility of protein molecules in the lipid bilayer. This has conventionally been measured by labeling the molecules with fluorescent markers and monitoring their mobility by different fluorescence-based techniques. However, adding the label to the studied molecule may affect the system, so it is an assumption in almost all experiments that the measured mobility of the biomolecule with its label is the same as that of the unlabeled molecule. However, this assumption is rarely tested due to a lack of suitable methods. In this work, a new technique to perform label free diffusivity measurements is developed and used to measure the effect of the label for two common protein-lipid systems: 1) streptavidin (SA) coupled to a supported lipid bilayer (SLB) through biotinylated lipids and 2) the extracellular part of the T-cell adhesion protein CD2, coupled to an SLB through histidine tags to nickel-chelating lipids. A measurable (~12%) decrease in diffusivity is found for both labeled proteins, even though the molecular mass of the label is almost 100 times smaller than those of the proteins (~50 kDa). The results illustrate the importance of being able to study different biophysical properties of cell membranes and their mimics without relying on fluorescent labels, especially if fluorescent labeling is difficult or is expected to affect the nature of the intermolecular interactions being studied. PMID- 24402972 TI - The significance of dynamin 2 expression for prostate cancer progression, prognostication, and therapeutic targeting. AB - Dynamin 2 (Dyn2) is essential for intracellular vesicle formation and trafficking, cytokinesis, and receptor endocytosis. In this study, we investigated the implication of Dyn2 as a prognostic marker and therapeutic target for progressive prostate cancer (PCA). We evaluated Dyn2 protein expression by immunohistochemistry in two cohorts: men with localized PCA treated by retropubic radical prostatectomy (n = 226), and men with advanced/castrate resistant PCA (CRPC) treated by transurethral resection of prostate (TURP) (n = 253). The role of Dyn2 in cell invasiveness was assessed by in vitro and in vivo experiments using androgen-responsive and refractory PCA preclinical models. Dyn2 expression was significantly increased across advanced stages of PCA compared to benign prostate tissue (P < 0.0001). In the CRPC cohort, high Dyn2 was associated with higher Gleason score (P = 0.004) and marginally with cancer-specific mortality (P = 0.052). In preclinical models, Dyn2 gene silencing significantly reduced cell migration and invasion in vitro, as well as tumor size and lymph node metastases in vivo. In isolated PCA cells, Dyn2 was found to regulate focal adhesion turnover, which is critical for cell migration; this mechanism requires full Dyn2 compared to mutants deficient in GTPase activity. In conclusion, Dyn2 overexpression is associated with neoplastic prostate epithelium and is associated with poor prognosis. Inhibition of Dyn2 prevents cell invasiveness in androgen-responsive and -refractory PCA models, supporting the potential benefit of Dyn2 to serve as a therapeutic target for advanced PCA. PMID- 24402973 TI - Asymmetric N-H insertion of secondary and primary anilines under the catalysis of palladium and chiral guanidine derivatives. AB - Efficient enantioselective N?H insertion reactions of secondary and primary anilines were catalyzed by palladium(0) in combination with chiral guanidine derivatives. A broad range of substituted anilines were tolerated, and the corresponding products were obtained in high yield (up to 99 %) with good enantioselectivity (up to 94 % ee) under mild reaction conditions. The N?H insertion mechanism was examined by the study of kinetic isotope effects, control experiments, HRMS, and spectroscopic analysis. PMID- 24402974 TI - Oxidation of benzyl alcohol and carbon monoxide using gold nanoparticles supported on MnO2 nanowire microspheres. AB - MnO2 was synthesised as a catalyst support material using a hydrothermal method. This involved reacting MnSO4?H2O and (NH4)2S2O8 at 120 degrees C for a range of crystallisation times, which affords control over the morphology and phase composition of the MnO2 formed. Gold was deposited on these supports using sol immobilisation, impregnation and deposition precipitation methods, and the resultant materials were used for the oxidation of benzyl alcohol and carbon monoxide. The effect of the support morphology on the dispersion of the gold nanoparticles and the consequent effect on the catalytic performance is described and discussed. PMID- 24402975 TI - Down the rabbit hole...advice to reviewers. PMID- 24402976 TI - Cancer patients' understanding of prognostic information. AB - Prognostic information is necessary for cancer patients to be fully informed about the likely course of their disease. This information is needed for practical planning and treatment decisions. This study sought to examine how cancer patients understand the prognosis information available to them. The setting is an urban safety net hospital. Six focus groups with cancer patients (N = 39) were digitally recorded and transcribed verbatim then analyzed using phases of content analysis. Participants in all groups discussed the prognosis almost exclusively in terms of mortality and reported that their physicians and nurses mostly provided prognostic information in terms of months or years for survival. This finding held across all cancer types and stages. Patients tend to think of prognosis information as being only estimated limited survival and find the idea upsetting. Due to this view on prognosis, patients need further explanation regarding where the prognosis information comes from and what prognostic information can tell them in order to make use of it. PMID- 24402977 TI - Liability for medical battery in the military health system. PMID- 24402978 TI - Risk factors for disability retirement among active duty Air Force personnel. AB - OBJECTIVE: To determine risk factors for disability retirement in Air Force personnel, as well as the conditions contributing to disability retirement. METHODS: A matched case-control study was conducted. Air Force personnel with accession records who were disability retired between 2002 and 2011 were included as cases. Controls were matched by accession year from the population of accessions not evaluated for disability at a ratio of 2:1. Conditional logistic regression was used to determine the odds of disability retirement. RESULTS: Women and those aged 25 or older were significantly more likely to be disability retired. Deployment was also associated with disability retirement but was significantly protective. Among women, the odds of disability retirement did not vary when stratified by deployment history. Preexisting medical conditions were not associated with disability retirement. Psychiatric conditions were the most common condition type among those who were disability retired in the Air Force. CONCLUSIONS: Additional studies are needed to assess risk factors for psychiatric disability, the most common disability retired condition, as well as to describe the role of occupation and combat exposure in disability retirement from the Air Force. PMID- 24402979 TI - Preliminary evaluation of PTSD Coach, a smartphone app for post-traumatic stress symptoms. AB - PTSD Coach is a mobile application (app) designed to help individuals who have post-traumatic stress disorder (PTSD) symptoms better understand and self-manage their symptoms. It has wide-scale use (over 130,000 downloads in 78 countries) and very favorable reviews but has yet to be evaluated. Therefore, this study examines user satisfaction, perceived helpfulness, and usage patterns of PTSD Coach in a sample of 45 veterans receiving PTSD treatment. After using PTSD Coach for several days, participants completed a survey of satisfaction and perceived helpfulness and focus groups exploring app use and benefit from use. Data indicate that participants were very satisfied with PTSD Coach and perceived it as being moderately to very helpful with their PTSD symptoms. Analysis of focus group data resulted in several categories of app use: to manage acute distress and PTSD symptoms, at scheduled times, and to help with sleep. These findings offer preliminary support for the acceptability and perceived helpfulness of PTSD Coach and suggest that it has potential to be an effective self-management tool for PTSD. Although promising, future research is required to validate this, given study limitations. PMID- 24402980 TI - Mental health in deployed and nondeployed veteran men and women in comparison with their civilian counterparts. AB - OBJECTIVE: We investigated the mental health of deployed and nondeployed veterans compared with civilians, exploring gender differences. METHODS: We sampled 41,903 respondents from the Behavioral Risk Factor Surveillance System survey. Respondents self-reported how many of the previous 30 days mental health was not good; 14 days or more indicated adverse mental health. RESULTS: Women exhibited greater prevalence of adverse mental health than men among civilians (odds ratio [OR] = 1.783 (1.653, 1.924), p < 0.001), deployed veterans [OR = 1.879 (1.019, 3.467), p = 0.043], and nondeployed veterans [OR = 2.621 (1.796, 3.825), p < 0.001]. Compared with civilian status, deployed status was associated with adverse mental health for men [OR = 1.361 (1.055, 1.755), p = 0.018] and possibly women [OR = 1.521 (0.930, 2.487), p = 0.095]. Compared with civilian status, nondeployed status was associated with adverse mental health for women [OR = 1.525 (1.152, 2.018), p = 0.003], but not for men [OR = 1.169 (0.943, 1.448), p = 0.155]. We controlled for age, general health, employment status, marital status, education, race/ethnicity, and state of residence. CONCLUSIONS: Adverse mental health affects male and female combat veterans, as well as women in noncombat military occupations. PMID- 24402981 TI - A qualitative study of chronic pain in Operation Enduring Freedom/Operation Iraqi Freedom veterans: "A burden on my soul". AB - OBJECTIVES: Over half of the veterans returning from the conflicts in Iraq and Afghanistan are burdened with chronic pain. Although these young veterans may have to live with pain for the rest of their lives, little is known about the struggles this new group of veterans faces, or their perceptions of support from family, friends, and others. The purpose of this study is to understand Operation Enduring Freedom/Operation Iraqi Freedom veterans' experiences with chronic pain and social support. METHODS: In-depth qualitative interviews were conducted with veterans who participated in an intervention for chronic pain. Grounded theory guided data analysis. RESULTS: Veterans described a range of emotions associated with chronic pain, including hopelessness, anger, and fear that their pain would worsen. For some, talking about their pain was helpful, but others avoided talking about their pain, often because people did not understand or overreacted. CONCLUSION: Although support from friends and family is often effective, veterans and others with chronic pain are uniquely positioned to offer support to others with pain. Clinically, an approach to pain management in which veteran peers are integrated into chronic pain treatment approaches, similar to the Veterans Affairs' mental health model of care, might offer additional benefits for veterans with chronic pain. PMID- 24402982 TI - Case report and theoretical description of accelerated resolution therapy (ART) for military-related post-traumatic stress disorder. AB - OBJECTIVES: This article describes a new, brief exposure-based psychotherapy known as Accelerated Resolution Therapy (ART) that is currently being evaluated as a treatment for combat-related post-traumatic stress disorder (PTSD). METHODS: We describe a case report of an Army veteran with combat-related PTSD who was treated with 2 sessions of ART and experienced significant clinical improvement. We then discuss the theoretical basis and major components of the ART protocol, including use of lateral left-right eye movements, and differentiate ART with evidence-based psychotherapies currently endorsed by the Department of Defense and Veterans Administration. RESULTS: The number of military personnel who have served in the wars in Iraq and Afghanistan and are afflicted with PTSD is likely in the hundreds of thousands. The ART protocol, which is delivered in 2 to 5 sessions and without homework, uses the psychotherapeutic practices of imaginal exposure and imagery rescripting (IR) facilitated through sets of eye movements. In addition to its brevity, a novel component of ART is use of IR to "replace" negative imagery (and other sensations) with positive imagery. CONCLUSIONS: This theoretical description of ART and single case report provide a rationale for future formal evaluation of ART for treatment of military-related PTSD. PMID- 24402983 TI - New Wide Area Virtual Environment (WAVE) medical education. AB - OBJECTIVE: Accomplish the first large-scale combat casualty training using multiple-modality hybrid simulation in the Uniformed Services University's one-of a-kind three-dimensional Wide Area Virtual Environment (WAVE). METHODS: 91 first year medical students (MS1) completed a WAVE training session as part of their Combat Medical Skills course. In teams of 6 students, they treated two combat casualties with blast wounds (one a SimMan 3G, and another a standardized patient) during15-minute scenarios in the WAVE. The WAVE is a unique medical simulation environment comprising an 8,000-square-foot virtual space composed of two pods surrounded by circumferential 9 * 12-foot movie screens and a high fidelity directional sound system. Students completed WAVE quality assurance surveys to describe their impressions. RESULTS: 91 MS1s were trained in a 4.5 hour period (including pre- and post-briefs) without technical difficulties during this inaugural training experience. Student survey data indicated a strong desire for more WAVE training in the curriculum (2.9 on a 3-point Leikert scale), and a strong preference for training in the WAVE vs. traditional training methods (4.6 on a 5-point Leikert scale). CONCLUSIONS: The novel WAVE platform can be implemented successfully for combat casualty training and represents a significant technological advancement in simulated military medical training. PMID- 24402984 TI - Reliability and validity of a test designed to assess combat medics' readiness to perform life-saving procedures. AB - OBJECTIVES: Reducing preventable deaths because of uncontrolled hemorrhage, tension pneumothorax, and airway loss is a priority. As part of a research initiative comparing different training models, this study evaluated the reliability and validity of a test that assesses combat medic performance during a polytrauma scenario using live animal models. METHODS: Nine procedural checklists and seven global rating scales were piloted with four cohorts of soldiers (n = 94) at two U.S. training sites. Cohorts represented "novice" to "proficient" trainees. Procedure scores and a mean global score were calculated per subject. The intraclass correlation was calculated per procedure, with 0.70 as the threshold for acceptability. An overall difference among cohorts was hypothesized: Cohort 4 (proficient) > Cohort 3 (competent) > Cohort 2 (beginners) > Cohort 1 (novice) trainees. Data were analyzed using Kruskal-Wallis and analysis of variance. RESULTS: At Site A, intraclass correlation coefficients ranged from 74% to 93% for 6 of 9 procedures. Cohorts differed significantly on hemorrhage control, needle decompression, cricothyrotomy, amputation management, chest tube insertion, and mean global scores. Cohort 4 outperformed the others, and Cohorts 2 and 3 outperformed Cohort 1. CONCLUSION: The test differentiates novices from beginners, competent, and proficient trainees on difficult procedures and overall performance. PMID- 24402985 TI - Impact of training patterns on injury incidences in 12 Swiss Army basic military training schools. AB - Non-battle injury rates are a major health problem in the armed forces today. Injury rates are related to physical demands of daily military routine. The aim of this study is to investigate the impact of different physical training patterns on incidences of injuries in 12 Swiss Army basic military training schools. Therefore, injury data of 1,676 voluntary participant recruits and objective sensor data on physical demands of 50 volunteers at each of 12 trainings schools were assembled. Multiple linear regression showed that high physical demands, decreasing development of distances covered on foot, monotony in weekly physical demands, little time spent on sport-related physical training, and little time for night rest were significant risk factors for injuries. Together, those variables describe 98.8% of the variances of total injury incidence rate between military training schools. The new method used to objectively assess training demands allowed this study to investigate the impact of training patterns on injury incidence in a large number of training schools. The results of this study are important for future interventions to reduce injury incidence rates in a military setting by quantifying the injury risk potential of a large number of training patterns. PMID- 24402987 TI - Trends in new U.S. Marine Corps accessions during the recent conflicts in Iraq and Afghanistan. AB - The objective of this study was to analyze trends in preservice characteristics among Marine Corps recruits during the recent operations in Iraq and Afghanistan. Recruits completed a confidential survey during their first week of training at the Marine Corps Recruit Depot in San Diego, California. Demographics, behaviors, and health information were analyzed for trends from 2001 to 2010 using the Cochran-Armitage trend test and F statistic. Data from 131,961 male recruits with a mean age of 19.8 years were analyzed. Overall, entry characteristics remained stable exhibiting only modest changes over the study period. Favorable trends included recent (2009-2010) improvements in body mass index and physical activity levels. Unfavorable trends included increases in smokeless tobacco and caffeine use, and angry outbursts. Although many recruit characteristics remained similar over the past decade, both favorable and unfavorable trends in sociobehavioral characteristics were noted. The ongoing assessment of preservice characteristics is important for detecting emerging trends over time. Findings may guide leadership's understanding of changes to help develop early-service trainings promoting a healthier force and potentially reducing future adverse outcomes. PMID- 24402986 TI - Femoral neck stress fracture in Air Force basic trainees. AB - Stress fractures are a common overuse problem among military trainees resulting in preventable morbidity, prolonged training, and long-term disability following military service. Femoral neck stress fractures (FNSFs) account for 2% of all stress fractures but result in disproportionate burden in terms of cost and convalescence. The purpose of this study was to describe and investigate FNSF in U.S. Air Force basic trainees and to present new data on risks factors for developing FNSF. We examined 47 cases of FNSF occurring in Air Force basic trainees between 2008 and 2011 and 94 controls using a matched case-control model. Analysis with t tests and conditional logistic regression found the risk of FNSF was not associated with body mass index or abdominal circumference. Female gender (p < 0.001) and slower run time significantly increased risk of FNSF (1.49 OR, p < 0.001; 95% CI 1.19-1.86). A greater number of push-up and sit up repetitions significantly reduced risk of FNSF (0.55 OR, p = 0.03; 95% CI 0.32 0.93; 0.62 OR, p = 0.04; 95% CI 0.4-0.98) for females. In this study body mass index was not correlated with FNSF risk; however, physical fitness level on arrival to training and female gender were significantly associated with risk of FNSF. PMID- 24402988 TI - Analysis of evacuations from areas of operation to the Spanish Role 4 medical treatment facility (2008-2013). AB - Since 1987, the Spanish Armed Forces have deployed their troops in a multitude of conflicts and natural disasters worldwide. The Spanish Military Medical Corps has the ability to deploy Role 1, Role 2, and one Role 3 medical treatment facilities. It also has a Role 4 in operation, the "Gomez Ulla" Central Hospital of Defense, in Madrid. The aim of this study is to describe the type of Spanish casualties evacuated from different areas of operation to the Role 4 from 2008 to 2013. A retrospective, cross-sectional study was performed on a sample of 232 patients. Among these, 211 (91%) were noncombat casualties: 126 because of illness, 53 because of an accident, and 32 because of sports injuries. The remaining 21 (9%) were combat casualties: 11 from improvised explosive devices and 10 from gunfire. Afghanistan, followed by Lebanon, is the operational area where most evacuees originate. The authors consider it essential that the Spanish Armed Forces rely on a Role 4 medical treatment facility as part of their medical support to international operations. PMID- 24402989 TI - Refractive surgery policy and its effect on visual acuity qualification rates for the 2004 and 2011 Army ROTC flight applicant pools. AB - OBJECTIVES: The goal of this study was to ascertain the effect of recent U.S. Army Aviation corneal refractive surgery (CRS) policy changes on the size of flight school applicant pools by comparing statistics from the 2004 and 2011 Warrior Forge Army Reserve Officers' Training Corps training camps. METHODS: A retrospective chart review was performed using the United States Army Aeromedical Activity's Aeromedical Electronic Resource Online database. RESULTS: Of the 607 applicants from 2004, 100 (16%) were disqualified for decreased visual acuity and had refractive errors correctable by CRS. Thirty-four cadets (6%) had prior CRS, and 21 qualified for flight school in 2004. Of the 625 applicants from 2011, 105 (17%) were disqualified for decreased visual acuity and had correctable refractive errors. Sixty-four applicants (10%) had prior CRS, and 54 subsequently qualified in 2011. CONCLUSIONS: Changes to Army Aviation CRS policy over the last decade have been associated with an increased number of initial flight applicants who now meet visual acuity standards. However, only a small percentage is using this resource. Army Aviation has the potential to significantly widen its applicant pool if more candidates are made aware of accepted CRS techniques that can help them to meet rigorous vision standards. PMID- 24402990 TI - Vitamin D and prostate cancer survival in veterans. AB - Prostate cancer remains the second most commonly diagnosed cancer among the male population worldwide. Vitamin D deficiency has been linked to prostate cancer and its aggressiveness. Herein, we initiated a retrospective study to evaluate vitamin D status and monitoring in veterans with prostate cancer, and to examine the potential link between vitamin D and survival status and length of survival in this population. We found that veterans who were initially vitamin D deficient were significantly less likely to survive than those who were not initially deficient, and that both initial and follow-up vitamin D deficiency were associated with decreased likelihood of survival after prostate cancer diagnosis. We recommend that vitamin D deficiency be replaced in veterans with prostate cancer. PMID- 24402991 TI - Lower extremity biomechanical changes associated with symmetrical torso loading during simulated marching. AB - The dose-response relationship between biomechanical variables and the magnitude of external loads is unclear. The use of different load distributions (e.g., pack types) may confound results because of changes in torso center of mass. Therefore, we examined the relationship between load magnitude and sagittal plane lower extremity mechanics of Soldiers walking with two symmetrically distributed loads. Fourteen Soldiers marched on a force-sensing treadmill at 1.34 m/s for 10 minutes with no load (BW_00) and while wearing vest-borne loads of 15 kg (BW_15) and 55 kg (BW_55). The effects of the loads on sagittal plane joint angles and moments were compared using 1-way repeated measures analyses of variance. Compared with BW_00, knee extension moment increased with the 15- and the 55-kg loads (both p < 0.003), confirming previously reported load-related biomechanical responses. Knee moment increases during early stance appeared to be the primary means by which the lower extremity counteracted BW_15 during early stance; in contrast, hip extensors and ankle dorsiflexors appeared to be the primary muscular efforts responsible for propulsion during late stance. Findings elucidated the effects of load magnitude on lower extremity mechanics without postural changes that result from pack-related shifts in torso center of mass. PMID- 24402992 TI - Plasma-to-red cell ratio and mechanism of injury in massively transfused combat casualties. AB - STUDY DESIGN: A retrospective review of 930 combat casualties from March 2003 to September 2009 who received a massive transfusion. Mechanism was categorized as explosion (EXPL) (712), gunshot wound (GSW) (190), and blunt trauma (28). Cohorts were also categorized by fresh frozen plasma (FFP) to red blood cell (RBC) ratio: low, <=1:1.5 and high, >1:1.5. Patient characteristics and in-hospital mortality rates were compared among groups. Propensity matching was used to control for confounding variables. RESULTS: Cohorts were similar in demographics, admission vital signs, and laboratory values. Median injury severity score was higher in EXPL compared to GSW. High FFP:RBC ratio was associated with improved survival compared to low ratio in the EXPL group (p < 0.01). The GSW group had similar survival in the high and low FFP:RBC ratio groups (p = 0.06). After propensity matching, a high FFP:RBC ratio was associated with improved survival compared to low ratio in both the EXPL (p < 0.01) and GSW groups (p = 0.05). CONCLUSIONS: High FFP:RBC ratios are associated with improved survival in combat casualties regardless of injury mechanism. PMID- 24402993 TI - An evidence-based review of epinephrine administered via the intraosseous route in animal models of cardiac arrest. AB - OBJECTIVES: Intraosseous (IO) access, enabling the rapid administration of epinephrine during cardiac arrest (CA), is crucial in promoting optimal postresuscitation outcomes in patients with poor vascular access. There is a question whether IO-administered epinephrine is equivalent to intravenously administered epinephrine during CA. METHODS: The question guiding this evidence based review was as follows: in adults suffering CA given epinephrine via the IO route, what is the resulting serum concentration of the drug compared to when administered intravenously? A search was conducted and the evidence appraised and leveled. RESULTS: Four animal studies met the inclusion criteria. The sources showed no definitive evidence supporting equivalence between intravenous and IO epinephrine administered during CA. Intravenously administered epinephrine provides increased and faster appearing serum concentrations than IO-administered epinephrine. Evidence indicated epinephrine given via the sternal IO route more closely approaches equivalence with intravenously administered epinephrine than when administered by the tibial IO route. CONCLUSIONS: The clinician should consider using proximal IO infusion sites such as the sternum or humerus when administering advanced cardiac life support drugs to rapidly achieve maximal therapeutic concentrations. Further studies are needed to determine the differences seen when epinephrine is administered by these routes during CA. PMID- 24402994 TI - Epilepsy at a summer camp for children and young adults with developmental disabilities: a 3-year experience. AB - The comprehensive care of children with epilepsy involves not only the treatment of seizures but also enhancement of their quality of life. Children with developmental disabilities are often unable to attend traditional summer camps because of safety concerns, as their prevalence of epilepsy is high and tends to be more severe. The goal of the current study is to describe our epilepsy experience at a summer camp adapted for children with developmental disabilities, with which the U. S. military has had a long-standing relationship. A retrospective chart review of all children and young adults attending summer sessions between 2008 and 2010 was performed. A total of 1,526 camp sessions were attended by 818 campers (mean 13.7 years), with 32.3% of campers having epilepsy. Of campers with epilepsy, 46.6% had cerebral palsy, 57.6% intellectual disability, and 28.8% autism spectrum disorders. Seizure frequency was at least weekly in 21.2% and at least daily in 13.3%. A history of status epilepticus was reported in 34.9%. There were seven camp infirmary visits because of seizures (incidence 1.4%), including two for status epilepticus. Thus, despite a high prevalence of severe epilepsy, in the setting of appropriate safety precautions, a safe camp experience can be provided, as seizure-related complications are rare. PMID- 24402995 TI - Erythema multiforme following smallpox vaccination. AB - Erythema multiforme (EM) is an acute self-limited eruption with multiple possible precipitators including drugs, infections, and in a small percentage, vaccinations. The lesions of EM can vary in presentation and are frequently misdiagnosed. With the reinstitution of the smallpox vaccination program for deploying service members, there is an increased need for military providers to be aware of the adverse reactions to be expected with this vaccination. We present the case of a 19-year-old active duty male who developed EM 14 days after receiving vaccination for smallpox. PMID- 24402996 TI - ACL reconstruction in a deployed environment in support of operation enduring freedom: a surgical technique. AB - Military orthopaedic surgeons in deployed environments along with orthopaedic surgeons working in more austere environments often find themselves without surgical equipment that they are normally accustomed to having in the operative suite. Today's U.S. Army Combat Support Hospital is appropriately focused on being prepared for modern battlefield trauma but lacks the resources for advanced sports medicine surgery to include arthroscopic equipment and implants. In this report, we describe an autograft anterior cruciate ligament reconstruction procedure using a combined mini-open extra-articular/intra-articular technique. This method could serve as a model for orthopaedic surgeons operating in more austere environments without modern sports medicine equipment and when working with the local national population who do not have access to modern health care facilities. PMID- 24402997 TI - Obstructive sleep apnea and tricyclic antidepressant use presenting as a pseudopheochromocytoma in an active duty sailor: a case report. AB - A 36-year-old active duty male with migraine headaches presented for evaluation of poorly controlled hypertension. The workup included an endocrinological examination, which revealed a moderately elevated urine normetanephrine level, suggesting the possibility of a pheochromocytoma. The evaluation also included a sleep study for possible obstructive sleep apnea (OSA) because of a history of snoring, apneic episodes, and daytime somnolence. The sleep study confirmed the diagnosis of OSA. The patient was treated with continuous positive airway pressure therapy and a plasma normetanephrine level demonstrated improvement, but persistent elevation. The patient was noted to be taking amitriptyline for migraine headache prevention. With approval from Neurology, the medication was discontinued and a repeat urine normetanephrine level revealed normalization. This case demonstrates the well-documented medication-associated false-positive test result that can be seen in patients taking tricyclic antidepressants. Tricyclic antidepressants, along with phenoxybenzamine, account for 41 to 45% of all elevated metanephrine and normetanephrine levels in patients without pheochromocytoma. This case also shows that patients with OSA can develop hypertension through elevated sympathetic tone, mimicking a pheochromocytoma. Treatment with continuous positive airway pressure therapy is recommended to not only improve hypertension and catecholamine excess but also distinguish the condition from a pheochromocytoma. PMID- 24402998 TI - Popliteal artery entrapment syndrome: a common cause of a rare clinical entity- critical leg ischemia in the young. AB - Popliteal artery entrapment syndrome (PAES) is a rare but important cause of leg ischemia and even disability in young athletes. Entrapment occurs because of an abnormal relationship between the popliteal artery and the surrounding muscular structures in the popliteal fossa. These anomalies lead to decreased blood flow to the affected leg with signs of claudication, coldness, and symptoms of exercise-induced leg pain. In this article, we present a case of a young soldier who presented with the above signs and symptoms in his left foot after exercise. On questioning, he admitted to having chronic lower leg pain. He was diagnosed with PAES in both legs and he was emergently treated with an arterial bypass procedure in the left one. He had no postoperative complications. PAES should be considered in the differential diagnosis of chronic or acute lower leg pain in any young patient. Early diagnosis and treatment can prevent limb loss and lead to a good operative outcome. PMID- 24402999 TI - Sigmoid colon penetration by an intrauterine device: a case report and literature review. AB - BACKGROUND: The intrauterine device (IUD) is one of the most effective contraceptive methods available today. However, IUDs can cause some serious complications, such as bleeding, uterine perforation, and bowel perforation. Migration into bowel is a rare but serious complication that requires surgical attention. CASE: A 35-year-old multiparous female was diagnosed with IUD migration into the abdominal cavity. Upon diagnostic laparoscopy by gynecologic surgeons, sigmoid colon penetration by the IUD was strongly suspected. After confirmation of the penetration by abdominal computed tomography scan with oral/rectal and intravenous contrast and colonoscopy, she underwent sigmoid colon resection to retrieve the IUD without complications. CONCLUSION: The symptoms of IUD migration can be nonspecific, requiring a high degree of suspicion. Also, cross-sectional imaging studies are recommended to rule out adjacent organ involvement if IUD migration is suspected. PMID- 24403000 TI - Night and day in the VA: associations between night shift staffing, nurse workforce characteristics, and length of stay. AB - In hospitals, nurses provide patient care around the clock, but the impact of night staff characteristics on patient outcomes is not well understood. The aim of this study was to examine the association between night nurse staffing and workforce characteristics and the length of stay (LOS) in 138 veterans affairs (VA) hospitals using panel data from 2002 through 2006. Staffing in hours per patient day was higher during the day than at night. The day nurse workforce had more educational preparation than the night workforce. Nurses' years of experience at the unit, facility, and VA level were greater at night. In multivariable analyses controlling for confounding variables, higher night staffing and a higher skill mix were associated with reduced LOS. PMID- 24403001 TI - Effects of hypotonic stress and ouabain on the apparent diffusion coefficient of water at cellular and tissue levels in Aplysia. AB - There is evidence that physiological or pathological cell swelling is associated with a decrease of the apparent diffusion coefficient (ADC) of water in tissues, as measured with MRI. However the mechanism remains unclear. Magnetic resonance microscopy, performed on small tissue samples, has the potential to distinguish effects occurring at cellular and tissue levels. A three-dimensional diffusion prepared fast imaging with steady-state free precession sequence for MR microscopy was implemented on a 17.2 T imaging system and used to investigate the effect of two biological challenges known to cause cell swelling, exposure to a hypotonic solution or to ouabain, on Aplysia nervous tissue. The ADC was measured inside isolated neuronal soma and in the region of cell bodies of the buccal ganglia. Both challenges resulted in an ADC increase inside isolated neuronal soma (+31 +/- 24% and +30 +/- 11%, respectively) and an ADC decrease at tissue level in the buccal ganglia (-12 +/- 5% and -18 +/- 8%, respectively). A scenario involving a layer of water molecules bound to the inflating cell membrane surface is proposed to reconcile this apparent discrepancy. PMID- 24403002 TI - Antibody performance in western blot applications is context-dependent. AB - An important concern for the use of antibodies in various applications, such as western blot (WB) or immunohistochemistry (IHC), is specificity. This calls for systematic validations using well-designed conditions. Here, we have analyzed 13 000 antibodies using western blot with lysates from human cell lines, tissues, and plasma. Standardized stratification showed that 45% of the antibodies yielded supportive staining, and the rest either no staining (12%) or protein bands of wrong size (43%). A comparative study of WB and IHC showed that the performance of antibodies is application-specific, although a correlation between no WB staining and weak IHC staining could be seen. To investigate the influence of protein abundance on the apparent specificity of the antibody, new WB analyses were performed for 1369 genes that gave unsupportive WBs in the initial screening using cell lysates with overexpressed full-length proteins. Then, more than 82% of the antibodies yielded a specific band corresponding to the full-length protein. Hence, the vast majority of the antibodies (90%) used in this study specifically recognize the target protein when present at sufficiently high levels. This demonstrates the context- and application-dependence of antibody validation and emphasizes that caution is needed when annotating binding reagents as specific or cross-reactive. WB is one of the most commonly used methods for validation of antibodies. Our data implicate that solely using one platform for antibody validation might give misleading information and therefore at least one additional method should be used to verify the achieved data. PMID- 24403004 TI - Expandable sheath for transfemoral transcatheter aortic valve replacement: procedural outcomes and complications. AB - AIMS: It is currently unknown whether the expandable sheath (e-sheath) for transfemoral Edwards transcatheter aortic valve replacement (TAVR) has a lower rate of access complications than the 18/19F fixed size sheath (f-sheath). Our aim was to compare the incidence of procedural complications when using f-sheath vs. e-sheath during TAVR. METHODS: We included 162 consecutive patients, implanted with the Edwards SAPIEN XT valve in our center. Access closure was obtained with the Prostar system in all cases. E-sheath was used in 80 patients (49%). RESULTS: Minimal ilio-femoral diameter was comparable in e-sheath and f sheath groups: 6.7 (6.1-7.7) vs. 7 (6.2-8) mm, P = 0.25, as was the frequency of peripheral artery disease: 12.5% vs. 13.4%, P = 1.0. VARC major vascular complications rate was similar in the 2 groups: e-sheath 7 (8.8%) vs. f-sheath 6 (7.3%), P = 0.74, as was the incidence of minor vascular complications: 8 (10%) vs. 14 (17.1%), P = 0.19, life-threatening bleeding: 6 (7.5%) vs. 6 (7.3%), P = 0.96, major and minor bleeding and use of covered vascular stents: 9 (11%) vs. 6 (7.5%), P = 0.59. CONCLUSIONS: The e-sheath for TAVR with the Edwards valve did not show an advantage over the f-sheath in reducing vascular and bleeding complications. PMID- 24403005 TI - Definition of novel electrochemotherapy parameters and validation of their in vitro and in vivo effectiveness. AB - Electrochemotherapy (ECT) is a cancer therapy that conjugates the administration of a chemotherapy agent to the delivery of permeabilizing pulses released singularly or as bursts. This approach results in higher number of anticancer molecules delivered to their biological targets, but is also associated to undesirable side effects such as pain and muscular contractions. A new electroporator delivering train of eight biphasic pulses at the voltage of 1,300 V/cm lasting 50 + 50 usec each, with a frequency of 1 Hz, and with 10-usec interpulse intervals (total treatment time: 870 usec/cm(2) of treated area) was tested in vitro on the human lung cancer cell line A549 and in vivo, both in mice xenografts and privately owned rabbits with spontaneous tumors. The tumor cell line was treated with electroporation using the new parameters, that showed improved drug efficacy in causing cell death. Mice with chemoresistant xenografts were treated as well with either the new parameters and with a previous protocol, confirming the higher tolerability and efficacy of the novel parameters. Finally, a cohort of six pet rabbits with advanced skin neoplasms were enrolled in a compassionate trial using the new parameters in adjuvant fashion. In terms of efficacy, none of the rabbits experienced tumor recurrence, showing minimal discomfort during the ECT sessions. The data described, demonstrate that the new permeabilizing protocol adopting biphasic electric pulses displays a significant higher efficacy compared to previous ECT treatments and substantial reduction of the associated morbidity. PMID- 24403006 TI - All-atom and coarse-grained simulations of the forced unfolding pathways of the SNARE complex. AB - The SNARE complex, consisting of three proteins (VAMP2, syntaxin, and SNAP-25), is thought to drive membrane fusion by assembling into a four-helix bundle through a zippering process. In support of the above zippering model, a recent single-molecule optical tweezers experiment by Gao et al. revealed a sequential unzipping of SNARE along VAMP2 in the order of the linker domain -> the C terminal domain -> the N-terminal domain. To offer detailed structural insights to this unzipping process, we have performed all-atom and coarse-grained steered molecular dynamics (sMD) simulations of the forced unfolding pathways of SNARE using different models and force fields. Our findings are summarized as follows: First, the sMD simulations based on either an all-atom force field (with an implicit solvent model) or a coarse-grained Go model were unable to capture the forced unfolding pathway of SNARE as observed by Gao et al., which may be attributed to insufficient simulation time and inaccurate force fields. Second, the sMD simulations based on a reparameterized coarse-grained model (i.e., modified elastic network model) were able to predict a sequential unzipping of SNARE in good agreement with the findings by Gao et al. The key to this success is to reparameterize the intrahelix and interhelix nonbonded force constants against the pair-wise residue-residue distance fluctuations collected from all atom MD simulations of SNARE. Therefore, our finding supports the importance of accurately describing the inherent dynamics/flexibility of SNARE (in the absence of force), in order to correctly simulate its unfolding behaviors under force. This study has established a useful computational framework for future studies of the zippering function of SNARE and its perturbations by point mutations with amino-acid level of details, and more generally the forced unfolding pathways of other helix bundle proteins. PMID- 24403007 TI - Volume-specific parameter optimization of 3D local phase features for improved extraction of bone surfaces in ultrasound. AB - BACKGROUND: Accurate localization of bone surfaces remains a challenge hampering adoption of ultrasound guidance in computer-assisted orthopaedic surgery. Local phase image features have recently been proven efficacious for segmenting bone surfaces from ultrasound images, but the quality of the processing depends on numerous filter parameters that are currently set through a trial and error process that is tedious, unintuitive and subject to large inter-user variability. METHODS: A method is presented for automatically selecting parameters of Log Gabor filters used to extract bone surfaces from 3D ultrasound volumes that is based on properties estimated directly from the specific image. RESULTS: A 15% and 69% average improvement in bone surface localization accuracy on phantom and clinical data, respectively, is demonstrated compared with empirically-set parameters. CONCLUSIONS: These findings imply that Log-Gabor filter parameter optimization is necessary for accurate extraction of bone surfaces from ultrasound data. PMID- 24403008 TI - A permanent mesoporous organic cage with an exceptionally high surface area. AB - Recently, porous organic cage crystals have become a real alternative to extended framework materials with high specific surface areas in the desolvated state. Although major progress in this area has been made, the resulting porous compounds are restricted to the microporous regime, owing to the relatively small molecular sizes of the cages, or the collapse of larger structures upon desolvation. Herein, we present the synthesis of a shape-persistent cage compound by the reversible formation of 24 boronic ester units of 12 triptycene tetraol molecules and 8 triboronic acid molecules. The cage compound bears a cavity of a minimum inner diameter of 2.6 nm and a maximum inner diameter of 3.1 nm, as determined by single-crystal X-ray analysis. The porous molecular crystals could be activated for gas sorption by removing enclathrated solvent molecules, resulting in a mesoporous material with a very high specific surface area of 3758 m(2) g(-1) and a pore diameter of 2.3 nm, as measured by nitrogen gas sorption. PMID- 24403009 TI - Antipsychotic drug exposure and risk of venous thromboembolism: a systematic review and meta-analysis of observational studies. AB - BACKGROUND: Venous thromboembolism (VTE) is a serious disorder that may be complicated by pulmonary embolism (PE). Case reports and observational studies published in the early 1950s suggested that antipsychotic (AP) drugs may represent a risk factor, while observational studies conducted in the last 3 decades have provided conflicting results. OBJECTIVE: The aim was to investigate whether AP drugs increase the risk of VTE and PE, and to ascertain the risk associated with first- and second-generation AP drugs and with exposure to individual drugs. DATA SOURCE: Relevant studies were located by searching MEDLINE, PubMed, EMBASE, PsychINFO, CINAHL and Scopus up to March 2013. Reference lists of relevant papers and previous review articles were hand searched for other relevant studies. STUDY SELECTION: Based on the titles and abstracts of 1,386 citations, we identified 30 potentially relevant studies. Of these, 17 studies were eligible for inclusion and were included in the meta-analysis. MAIN OUTCOMES AND MEASURES: The primary outcome measure of this meta-analysis was the occurrence of VTE or PE in individuals exposed to AP drugs in comparison with individuals unexposed or with past exposure to AP drugs. RESULTS: Antipsychotic exposure was associated with a significant increase in risk of developing VTE [odds ratio (OR) 1.54, 95% confidence interval (CI) 1.28-1.86, 11 studies]. Exposure to APs did not significantly increase the risk of PE (OR 4.90, 95% CI 0.77-30.98, three studies), but the overall estimate was highly heterogeneous and the CI included the possibility of substantial harm. Random-effects meta-analysis on the risk of VTE associated with exposure to first- (OR 1.74, 95% CI 1.28-2.37, six studies) and second-generation (OR 2.07, 95% CI 1.74-2.52, five studies) APs revealed an increased risk. Only a few studies provided data on individual drugs, and estimates of effect were very uncertain. CONCLUSIONS: Antipsychotic exposure in unselected patient populations may be associated with a 50% increase in the risk of developing VTE. However, between-study heterogeneity limits the confidence in this estimate. This increased risk similarly applies to first- and second-generation AP drugs. PMID- 24403010 TI - Chemoradiotherapy response in recurrent rectal cancer. AB - The efficacy of response to preoperative chemoradiotherapy (CRT) in recurrent versus primary rectal cancer has not been investigated. We compared radiological downsizing between primary and recurrent rectal cancers following CRT and determined the optimal size reduction threshold for response validated by survival outcomes. The proportional change in tumor length for primary and recurrent rectal cancers following CRT was compared using the independent sample t-test. Overall survival (OS) was calculated using the Kaplan-Meier product limit method and differences between survival for tumor size reduction thresholds of 30% (response evaluation criteria in solid tumors [RECIST]), 40%, and 50% after CRT in primary and recurrent rectal cancer groups. A total of 385 patients undergoing CRT were analyzed, 99 with recurrent rectal cancer and 286 with primary rectal cancer. The mean proportional reduction in maximum craniocaudal length was significantly higher for primary rectal tumors (33%) compared with recurrent rectal cancer (11%) (P < 0.01). There was no difference in OS for either primary or recurrent rectal cancer when <=30% or <=40% definitions were used. However, for both primary and recurrent tumors, significant differences in median 3-year OS were observed when a RECIST cut-off of 50% was used. OS was 99% versus 77% in primary and 100% versus 42% in recurrent rectal cancer (P = 0.002 and P = 0.03, respectively). Only patients that demonstrated >50% size reduction showed a survival benefit. Recurrent rectal cancer appears radioresistant compared with primary tumors for tumor size after CRT. Further investigation into improving/intensifying chemotherapy and radiotherapy for locally recurrent rectal cancer is justified. PMID- 24403011 TI - Stable isolated metal atoms as active sites for photocatalytic hydrogen evolution. AB - The process of using solar energy to split water to produce hydrogen assisted by an inorganic semiconductor is crucial for solving our energy crisis and environmental problems in the future. However, most semiconductor photocatalysts would not exhibit excellent photocatalytic activity without loading suitable co catalysts. Generally, the noble metals have been widely applied as co-catalysts, but always agglomerate during the loading process or photocatalytic reaction. Therefore, the utilization efficiency of the noble co-catalysts is still very low on a per metal atom basis if no obvious size effect exists, because heterogeneous catalytic reactions occur on the surface active atoms. Here, for the first time, we have synthesized isolated metal atoms (Pt, Pd, Rh, or Ru) stably by anchoring on TiO2 , a model photocatalystic system, by a facile one-step method. The isolated metal atom based photocatalysts show excellent stability for H2 evolution and can lead to a 6-13-fold increase in photocatalytic activity over the metal clusters loaded on TiO2 by the traditional method. Furthermore, the configurations of isolated atoms as well as the originality of their unusual stability were analyzed by a collaborative work from both experiments and theoretical calculations. PMID- 24403012 TI - The structure of Plasmodium yoelii merozoite surface protein 119, antibody specificity and implications for malaria vaccine design. AB - Merozoite surface protein 1 (MSP1) has been identified as a target antigen for protective immune responses against asexual blood stage malaria, but effective vaccines based on MSP1 have not been developed so far. We have modified the sequence of Plasmodium yoelii MSP119 (the C-terminal region of the molecule) and examined the ability of the variant proteins to bind protective monoclonal antibodies and to induce protection by immunization. In parallel, we examined the structure of the protein and the consequences of the amino acid changes. Naturally occurring sequence polymorphisms reduced the binding of individual protective antibodies, indicating that they contribute to immune evasion, but immunization with these variant proteins still provided protective immunity. One variant that resulted in the localized distortion of a loop close to the N terminus of MSP119 almost completely ablated protection by immunization, indicating the importance of this region of MSP119 as a target for protective immunity and in vaccine development. PMID- 24403014 TI - The association of endothelial nitric oxide synthase gene G894T polymorphism and serum nitric oxide concentration with microalbuminuria in patients with gestational diabetes. AB - AIM: Gestational diabetes mellitus (GDM) is a glucose intolerant condition that affects 14% of all pregnancies. Diabetes mellitus (DM) occurs in 30 - 70% of patients with GDM after delivery. DM and GDM are associated with structural and functional deterioration of the renovascular system. Our aim is to investigate the association Glu- 298Asp polymorphism of the endothelial nitric oxide synthase (eNOS) gene with serum nitric oxide levels and microalbuminuria in patients with GDM and healthy pregnancies. MATERIAL AND METHODS: Serum nitric oxide (NO) levels, urinary excretion of albumin and Glu298Asp polymorphism of the eNOS gene were analyzed in 68 patients with GDM and 73 healthy controls. High performance liquid chromatography (HPLC-Griess) method was used to analyze serum NO levels. Microalbuminuria was evaluated by rate nephelometry method. The Glu298Asp polymorphism of the eNOS gene was determined by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). RESULTS: Nitric oxide, glucose, creatinine, and microalbuminuria were significantly different between the patients and the control subjects (p = 0.001, p = 0.001, p = 0.002, and p = 0.005, respectively). There was a significant difference between groups in terms of the ratio of GG/GT+TT of eNOS gene Glu- 298Asp (p = 0.02). The patients with GT+TT genotype had significantly higher microalbuminuria levels and lower NO concentrations (22.16 vs. 9.51, p = 0.005, and 10.56 vs. 12.73, p = 0.021, respectively). The presence of T allele of eNOS gene is an independent predictor of microalbuminuria (OR: 2.346, 95% confidence interval: 1.247 - 5.238, p = 0.02) as well as serum glucose and NO concentration. CONCLUSION: The G894T polymorphism of eNOS gene and decreased NO concentration seem to be independent predictors of increased urinary excretion of albumin in patients with GDM. Determining the frequency of eNOS gene G894T polymorphism may help to identify pregnancies at increased risk of microalbuminuria. PMID- 24403013 TI - Xenopus Cdc7 executes its essential function early in S phase and is counteracted by checkpoint-regulated protein phosphatase 1. AB - The initiation of DNA replication requires two protein kinases: cyclin-dependent kinase (Cdk) and Cdc7. Although S phase Cdk activity has been intensively studied, relatively little is known about how Cdc7 regulates progression through S phase. We have used a Cdc7 inhibitor, PHA-767491, to dissect the role of Cdc7 in Xenopus egg extracts. We show that hyperphosphorylation of mini-chromosome maintenance (MCM) proteins by Cdc7 is required for the initiation, but not for the elongation, of replication forks. Unlike Cdks, we demonstrate that Cdc7 executes its essential functions by phosphorylating MCM proteins at virtually all replication origins early in S phase and is not limiting for progression through the Xenopus replication timing programme. We demonstrate that protein phosphatase 1 (PP1) is recruited to chromatin and rapidly reverses Cdc7-mediated MCM hyperphosphorylation. Checkpoint kinases induced by DNA damage or replication inhibition promote the association of PP1 with chromatin and increase the rate of MCM dephosphorylation, thereby counteracting the previously completed Cdc7 functions and inhibiting replication initiation. This novel mechanism for regulating Cdc7 function provides an explanation for previous contradictory results concerning the control of Cdc7 by checkpoint kinases and has implications for the use of Cdc7 inhibitors as anti-cancer agents. PMID- 24403016 TI - Algorithms for computer detection of symmetry elements in molecular systems. AB - Simple procedures for the location of proper and improper rotations and reflexion planes are presented. The search is performed with a molecule divided into subsets of symmetrically equivalent atoms (SEA) which are analyzed separately as if they were a single molecule. This approach is advantageous in many aspects. For instance, in those molecules that are symmetric rotors, the number of atoms and the inertia tensor of the SEA provide one straight way to find proper rotations of any order. The algorithms are invariant to the molecular orientation and their computational cost is low, because the main information required to find symmetry elements is interatomic distances and the principal moments of the SEA. For example, our Fortran implementation, running on a single processor, took only a few seconds to locate all 120 symmetry operations of the large and highly symmetrical fullerene C720, belonging to the Ih point group. Finally, we show how the interatomic distances matrix of a slightly unsymmetrical molecule is used to symmetrize its geometry. PMID- 24403015 TI - Mitochondrial fragmentation is an important cellular event induced by ruthenium(II) polypyridyl complexes in osteosarcoma cells. AB - A series of ruthenium(II) polypyridyl complexes were synthesized and evaluated for their in vitro anticancer activities. The results showed that ruthenium polypyridyl complexes, especially [Ru(bpy)2 (p-tFPIP)](2+) (2 a; bpy=bipyridine, tFPIP=2-(2-trifluoromethane phenyl)imidazole[4,5-f][1,10]phenanthroline), exhibited novel anticancer activity against human cancer cell lines, but with less toxicity to a human normal cell line. The results of flow cytometry and caspase activities analysis indicated that the 2 a-induced growth inhibition against MG-63 osteosarcoma cells was mainly caused by mitochondria-mediated apoptosis. DNA fragmentation and nuclear condensation as detected by TUNEL-DAPI co-staining further confirmed 2 a-induced apoptotic cell death. Further, fluorescence imaging revealed that ruthenium(II) polypyridyl complexes could target mitochondria to induce mitochondrial fragmentation, accompanied by depletion of mitochondrial membrane potential. Taken together, these findings suggest a potential application of theses ruthenium(II) complexes in the treatment of cancers. PMID- 24403018 TI - Multireference space without first solving the configuration interaction problem. AB - We further develop an idea to generate a compact multireference space without first solving the configuration interaction problem previously proposed for the ground state (GS) (Glushkov, Chem. Phys. Lett. 1995, 244, 1). In the present contribution, our attention is focused on low-lying excited states (ESs) with the same symmetry as the GS which can be adequately described in terms of an high spin open-shell formalism. Two references Moller-Plesset (MP) like perturbation theory for ESs is developed. It is based on: (1) a main reference configuration constructed from the parent molecular orbitals adjusted to a given ES and (2) secondary double excitation configuration built on the GS like orbitals determined by the Hartree-Fock equations subject to some orthogonality constraints. It is shown how to modify the MP zeroth-order Hamiltonian so that the reference configurations and corresponding excitations are eigenfunctions of it and are compatible with orthogonality conditions for the GS and ES. Intruder states appearance is also discussed. The proposed scheme is applied to the GS, ES, and excitation energies of small molecules to illustrate and calibrate our calculations. PMID- 24403017 TI - Are accurate computations of the 13C' shielding feasible at the DFT level of theory? AB - The goal of this study is twofold. First, to investigate the relative influence of the main structural factors affecting the computation of the (13)C' shielding, namely, the conformation of the residue itself and the next nearest-neighbor effects. Second, to determine whether calculation of the (13)C' shielding at the density functional level of theory (DFT), with an accuracy similar to that of the (13)C(alpha) shielding, is feasible with the existing computational resources. The DFT calculations, carried out for a large number of possible conformations of the tripeptide Ac-GXY-NMe, with different combinations of X and Y residues, enable us to conclude that the accurate computation of the (13)C' shielding for a given residue X depends on the: (i) (phi,psi) backbone torsional angles of X; (ii) side-chain conformation of X; (iii) (phi,psi) torsional angles of Y; and (iv) identity of residue Y. Consequently, DFT-based quantum mechanical calculations of the (13)C' shielding, with all these factors taken into account, are two orders of magnitude more CPU demanding than the computation, with similar accuracy, of the (13)C(alpha) shielding. Despite not considering the effect of the possible hydrogen bond interaction of the carbonyl oxygen, this work contributes to our general understanding of the main structural factors affecting the accurate computation of the (13)C' shielding in proteins and may spur significant progress in effort to develop new validation methods for protein structures. PMID- 24403021 TI - LncRNAs: new players in gliomas, with special emphasis on the interaction of lncRNAs With EZH2. AB - Gliomas are the most common primary malignancy in the brain, accounting for 50 60%. Despite all the efforts of cytoreductive surgery in combination with intense chemoradiotherapy, glioma remains an incurable disease. Recent studies have shown that long noncoding RNAs (lncRNAs) are involved in the pathology of gliomas. LncRNAs are involved in many cellular processes, such as angiogenesis, invasion, cell proliferation, and apoptosis. In this review we focus on the dysregulation of lncRNAs in gliomas. We also address that epigenetic modification such as DNA methylation and microRNAs interact with lncRNAs in gliomas. In addition, the interaction of lncRNAs with signaling pathways in gliomas is discussed systematically, with particular emphasis on the interaction of lncRNAs with EZH2. Such approaches provide valuable insights into the potential future applications of lncRNAs in the treatment of gliomas. PMID- 24403024 TI - Systematic comparison of peptidic proteasome inhibitors highlights the alpha ketoamide electrophile as an auspicious reversible lead motif. AB - The ubiquitin-proteasome system (UPS) has been successfully targeted by both academia and the pharmaceutical industry for oncological and immunological applications. Typical proteasome inhibitors are based on a peptidic backbone endowed with an electrophilic C-terminus by which they react with the active proteolytic sites. Although the peptide moiety has attracted much attention in terms of subunit selectivity, the target specificity and biological stability of the compounds are largely determined by the reactive warheads. In this study, we have carried out a systematic investigation of described electrophiles by a combination of in vitro, in vivo, and structural methods in order to disclose the implications of altered functionality and chemical reactivity. Thereby, we were able to introduce and characterize the class of alpha-ketoamides as the most potent reversible inhibitors with possible applications for the therapy of solid tumors as well as autoimmune disorders. PMID- 24403023 TI - Sensitivity of brachial versus femoral vein injection of agitated saline to detect right-to-left shunts with Transcranial Doppler. AB - BACKGROUND: Transcranial Doppler (TCD) can detect a right-to-left shunt (RLS) with high sensitivity but has a 5% chance of a false negative study. TCD is usually performed with injection of agitated saline into an arm vein. We compared the sensitivity of TCD performed from the brachial versus femoral veins. METHODS: Patients presenting to the cardiac catheterization laboratory for percutaneous closure of a patent foramen ovale (PFO) were enrolled. Power M-mode Transcranial Doppler (Terumo 150 PMD) was conducted. After injection of a mixture of 8 cc of agitated saline, 0.5 cc of air, and 1 cc of blood into the brachial vein, embolic tracks were counted over the middle cerebral arteries. The degree of RLS was evaluated by TCD at rest, and with Valsalva at 40 mmHg aided by visual feedback with a manometer device. The test was repeated using femoral venous injections. RESULTS: Sixty five patients were enrolled, mean age 52, 43% male. TCD grades were significantly higher with femoral injections compared to brachial injections at rest (p<0.0001), and with the Valsalva maneuver (p<0.0001). The presence of a RLS was confirmed by intracardiac echocardiography (ICE) during cardiac catheterization in 62 (95.4%) patients. CONCLUSION: The sensitivity of TCD for detection of RLS is increased when agitated saline injections are performed through the femoral vein. In patients with a high clinical suspicion for RLS, low TCD grades obtained with traditional brachial venous access should be interpreted with caution. When possible, a repeat study using femoral venous access may be considered. PMID- 24403025 TI - Validating computer simulations of enantioselective catalysis; reproducing the large steric and entropic contributions in Candida Antarctica lipase B. AB - The prospect for computer-aided refinement of stereoselective enzymes is further validated by simulating the ester hydrolysis by the wild-type and mutants of CalB, focusing on the challenge of dealing with strong steric effects and entropic contributions. This was done using the empirical valence bond (EVB) method in a quantitative screening of the enantioselectivity, considering both k(cat) and k(cat)/K(M) of the R and S stereoisomers. Although the simulations require very extensive sampling for convergence they give encouraging results and major validation, indicating that our approach offers a powerful tool for computer-aided design of enantioselective enzymes. This is particularly true in cases with large changes in steric effects where alternative approaches may have difficulties in capturing the interplay between steric clashes with the reacting substrate and protein flexibility. PMID- 24403027 TI - More on leadership: ambiguity, integrity, wisdom. PMID- 24403026 TI - Hydrophilic polymer embolism induced acute transcatheter aortic valve thrombosis: a novel complication. AB - Hydrophilic polymer coated introducer sheaths and medical devices are widely used in interventional cardiology. Despite the potential procedural advantages that these provide, a risk of polymer embolization has been recently reported. We describe the first reported case of hydrophilic polymer induced acute transcatheter aortic valve thrombosis. PMID- 24403028 TI - Wisdom's whimsical ways. AB - The purpose of this article is to explore the various ways wisdom is manifested in day-to-day living. Selected literature on wisdom is explored from a humanbecoming nurse perspective, perspectives from philosophy, psychiatry, theology, anthropology and the martial arts. A humanbecoming perspective on living wisdom is synthesized from the literature review. PMID- 24403029 TI - Research at the end of life: a sacred undertaking. AB - Conducting research at the end of life is currently a priority for the National Institute of Nursing Research, the Institute of Medicine, and the National Institute of Health. However, attempting to do research with those who are dying is fraught with numerous challenges. In this column, the author discusses some of the issues and presents viable solutions, so that we as the research community can inform clinicians about care at the end of life and improve quality. PMID- 24403030 TI - Conducting end-of-life research: strategies for success. AB - Conducting studies at the end of life is often challenging for researchers due to the sensitive nature of the research, the vulnerability of the participants and the inherent methodological complexities. Methodological challenges include identifying and gaining access to eligible research participants, estimating the duration of patient survival time in the study, minimizing the potential burden of data collection, and attending to issues of consent and confidentiality. In this paper, the authors identify challenges when conducting end-of-life research and draw from collective research experiences to describe strategies to achieve success. PMID- 24403031 TI - The ethics of waiting and anticipating life beyond. AB - Waiting is a common everyday experience. It is particularly important to person(s) and families living with changing complex health patterns and may be especially vital to those who are anticipating the end-of-life and beyond. The author in this column offers a discussion of potential definitions, meanings, and straight thinking responsibilities for healthcare professionals, as they provide professional services with persons and families who may be arduously experiencing the phenomenon of waiting with ever-changing health situations. Implications for professional nurse practice are offered from a humanbecoming perspective. PMID- 24403032 TI - End of life and beyond as hidden curriculum. AB - End-of-life experiences are unique. Most can vividly recall feelings during those times. Governing boards in the United States attempt to guide nursing faculty regarding end of life curriculum. Yet, the beliefs of faculty members arising from those unique experiences can alter the tone and message of what students are actually taught--often surfacing as hidden curriculum. In this column the authors discuss hidden curriculum while presenting the beliefs regarding end of life, of four nursing faculty members from a single university. Heightened awareness and respect for the beliefs of all faculty members within any university setting is imperative in decreasing the development of hidden curriculum. PMID- 24403033 TI - The science of unitary human beings continues to flourish. AB - Much of the nursing discipline scoffed at Martha Rogers' (1914-1994) theory of unitary human beings for many years. Rogers was a visionary. She saw things others never could imagine. Her theory lives on today and if one is open to the possibles, one may actually see what Rogers conceptualized, a differemt way of looking at the human experience and caring for patients. PMID- 24403034 TI - Prenatal yoga in late pregnancy and optimism, power, and well-being. AB - The study reported here explored changes in optimism, power, and well-being over time in women who participated in a six-week prenatal yoga program during their second and third trimesters of pregnancy. The study was conceptualized from the perspective of Rogers' science of unitary human beings. A correlational, one group, pre-post-assessment survey design with a convenience sample was conducted. Increases in mean scores for optimism, power, and well-being were statistically significant from baseline to completion of the prenatal yoga program. Findings from this study suggested that yoga as a self-care practice that nurses might recommend to promote well-being in pregnant women. PMID- 24403035 TI - Life as a nurse researcher. AB - The connection between theory and research is vital. In this paper, Dr. Fawcett presents her views of her life as a researcher. The importance of early mentoring is addressed as is the impact of her research on nursing science. PMID- 24403036 TI - Living on the edge: a parse method study. AB - Living on the edge was explored employing the Parse research method. Ten participants living in the frontier of the American West were asked, "What is the experience of living on the edge?" The findings showed the structure of living on the edge as: Living on the edge is persevering with pioneering ventures amid perilous remoteness, as vacillating sentiments arise with diverse affiliations. Understanding the experience of living on the edge as it relates to health and quality of life is important for nursing practice and advances nursing science. PMID- 24403037 TI - Life closure with the Roy adaptation model. AB - The author of this paper examines the initial conceptualization of death and dying theory within the context of the Roy adaptation model (RAM) and compares it with current knowledge development. An evolved RAM with its philosophic assumptions provides a framework by which to add existential components of spirituality, life meaning, and purposeful existence that were absent in the original work on death and dying. PMID- 24403038 TI - Newman's theory of health as expanding consciousness: a personal evolution. AB - In this article, the authors demonstrate the value of using Newman's theory of health as expanding consciousness for nurses and the clients they serve. A review of the conception and evolution of the theory and its link to spiritual ideology provides a multi-dimensional perspective of Newman's ideas. Additionally, an exploration of the central concepts of the theory offers an in-depth view of the philosophical and practical tenets on which the theory is based. The authors also chronicle one nurse's journey and evolution as a healthcare provider whose practice is rooted in Newman's theory. PMID- 24403039 TI - Nursing in Portugal: a global perspective. AB - This global perspectives column on nursing in Portugal is based primarily on an edited transcript of an interview by the author with Nuno Miguel Dias Pereira, who has a master's degree in nursing management and is a doctoral nursing student at Lisbon University. The interview took place on June 7, 2013. In additional to being a doctoral student, Mr. Periera has a position at the Portuguese Institute of Oncology in Lisbon. PMID- 24403040 TI - Bridging gaps for policy: the doctorally-prepared nurse practitioner and end-of life care. PMID- 24403041 TI - The nurse practitioner and policy in end-of-life care. AB - The focus of this column is the interface between policy and end-of-life care, particularly as provided by advanced nurse practitioners. The complexities of end of-life along with barriers in practice can diminish quality of life for patients and their families. Changes in policy are needed to enable nurse practitioners their full scope of practice in a way that benefits patients and families at end of-life. Three areas particularly relevant to policy for nursing practitioners and end-of-life care are addressed: scope of practice, reimbursement, and prescribing practices. Other recommendations for policy and end-of-life care are discussed. PMID- 24403046 TI - The neomodernism approach: professional development of baccalaureate level nurses. PMID- 24403047 TI - Advancing nursing knowledge: a response to Burns' letter to the editor. PMID- 24403049 TI - Congenital disorder of fucosylation type 2c (LADII) presenting with short stature and developmental delay with minimal adhesion defect. AB - Leukocyte adhesion deficiency type II is a hereditary disorder of neutrophil migration caused by mutations in the guanosine diphosphate-fucose transporter gene (SLC35C1). In these patients, inability to generate key fucosylated molecules including sialyl Lewis X leads to leukocytosis and recurrent infections, in addition to short stature and developmental delay. We report two brothers with short stature and developmental delay who are compound heterozygotes for novel mutations in SLC35C1 resulting in partial in vivo defects in fucosylation. Specifically, plasma glycoproteins including immunoglobulin G demonstrated marked changes in glycoform distribution. While neutrophil rolling on endothelial selectins was partially impeded, residual adhesion proved sufficient to avoid leukocytosis or recurrent infection. These findings demonstrate a surprising degree of immune redundancy in the face of substantial alterations in adhesion molecule expression, and show that short stature and developmental delay may be the sole presenting signs in this disorder. PMID- 24403050 TI - Identification and analysis of large intergenic non-coding RNAs regulated by p53 family members through a genome-wide analysis of p53-binding sites. AB - p53 is one of the most important known tumor suppressor genes, and it is inactivated in approximately half of human cancers. p53 family members execute various functions, such as apoptosis induction and cell cycle arrest, by modulating transcriptional regulation. Therefore, the direct transcriptional targets of the p53 family must be explored to elucidate the functional mechanisms of family members. To identify the direct transcriptional targets of p53 family members, we performed chromatin immunoprecipitation together with next-generation sequencing (ChIP-seq) and searched for p53-binding motifs across the entire human genome. Among the identified ChIP-seq peaks, approximately half were located in an intergenic region. Therefore, we assumed large intergenic non-coding RNAs (lincRNAs) to be major targets of the p53 family. Recent reports have revealed that lincRNAs play an important role in various biological and pathological processes, such as development, differentiation, stemness and carcinogenesis. Through a combination of ChIP-seq and in silico analyses, we found 23 lincRNAs that are upregulated by the p53 family. Additionally, knockdown of specific lincRNAs modulated p53-induced apoptosis and promoted the transcription of a gene cluster. Our results suggest that p53 family members, and lincRNAs constitute a complex transcriptional network involved in various biological functions and tumor suppression. PMID- 24403048 TI - Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance. AB - Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ~5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS. PMID- 24403051 TI - Recurrent genomic alterations in sequential progressive leukoplakia and oral cancer: drivers of oral tumorigenesis? AB - A significant proportion (up to 62%) of oral squamous cell carcinomas (OSCCs) may arise from oral potential malignant lesions (OPMLs), such as leukoplakia. Patient outcomes may thus be improved through detection of lesions at a risk for malignant transformation, by identifying and categorizing genetic changes in sequential, progressive OPMLs. We conducted array comparative genomic hybridization analysis of 25 sequential, progressive OPMLs and same-site OSCCs from five patients. Recurrent DNA copy number gains were identified on 1p in 20/25 cases (80%) with minimal, high-level amplification regions on 1p35 and 1p36. Other regions of gains were frequently observed: 11q13.4 (68%), 9q34.13 (64%), 21q22.3 (60%), 6p21 and 6q25 (56%) and 10q24, 19q13.2, 22q12, 5q31.2, 7p13, 10q24 and 14q22 (48%). DNA losses were observed in >20% of samples and mainly detected on 5q31.2 (35%), 16p13.2 (30%), 9q33.1 and 9q33.29 (25%) and 17q11.2, 3p26.2, 18q21.1, 4q34.1 and 8p23.2 (20%). Such copy number alterations (CNAs) were mapped in all grades of dysplasia that progressed, and their corresponding OSCCs, in 70% of patients, indicating that these CNAs may be associated with disease progression. Amplified genes mapping within recurrent CNAs (KHDRBS1, PARP1, RAB1A, HBEGF, PAIP2, BTBD7) were selected for validation, by quantitative real-time PCR, in an independent set of 32 progressive leukoplakia, 32 OSSCs and 21 non-progressive leukoplakia samples. Amplification of BTBD7, KHDRBS1, PARP1 and RAB1A was exclusively detected in progressive leukoplakia and corresponding OSCC. BTBD7, KHDRBS1, PARP1 and RAB1A may be associated with OSCC progression. Protein-protein interaction networks were created to identify possible pathways associated with OSCC progression. PMID- 24403052 TI - Germline sequence variants in TGM3 and RGS22 confer risk of basal cell carcinoma. AB - To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide association study of 38.5 million single nucleotide polymorphisms (SNPs) and small indels identified through whole genome sequencing of 2230 Icelanders. We imputed genotypes for 4208 BCC patients and 109 408 controls using Illumina SNP chip typing data, carried out association tests and replicated the findings in independent population samples. We found new BCC susceptibility loci at TGM3 (rs214782[G], P = 5.5 * 10(-17), OR = 1.29) and RGS22 (rs7006527[C], P = 8.7 * 10(-13), OR = 0.77). TGM3 encodes transglutaminase type 3, which plays a key role in production of the cornified envelope during epidermal differentiation. PMID- 24403053 TI - Human COX20 cooperates with SCO1 and SCO2 to mature COX2 and promote the assembly of cytochrome c oxidase. AB - Cytochrome c oxidase (CIV) deficiency is one of the most common respiratory chain defects in patients presenting with mitochondrial encephalocardiomyopathies. CIV biogenesis is complicated by the dual genetic origin of its structural subunits, and assembly of a functional holoenzyme complex requires a large number of nucleus-encoded assembly factors. In general, the functions of these assembly factors remain poorly understood, and mechanistic investigations of human CIV biogenesis have been limited by the availability of model cell lines. Here, we have used small interference RNA and transcription activator-like effector nucleases (TALENs) technology to create knockdown and knockout human cell lines, respectively, to study the function of the CIV assembly factor COX20 (FAM36A). These cell lines exhibit a severe, isolated CIV deficiency due to instability of COX2, a mitochondrion-encoded CIV subunit. Mitochondria lacking COX20 accumulate CIV subassemblies containing COX1 and COX4, similar to those detected in fibroblasts from patients carrying mutations in the COX2 copper chaperones SCO1 and SCO2. These results imply that in the absence of COX20, COX2 is inefficiently incorporated into early CIV subassemblies. Immunoprecipitation assays using a stable COX20 knockout cell line expressing functional COX20-FLAG allowed us to identify an interaction between COX20 and newly synthesized COX2. Additionally, we show that SCO1 and SCO2 act on COX20-bound COX2. We propose that COX20 acts as a chaperone in the early steps of COX2 maturation, stabilizing the newly synthesized protein and presenting COX2 to its metallochaperone module, which in turn facilitates the incorporation of mature COX2 into the CIV assembly line. PMID- 24403054 TI - Identification of low-molecular-weight compounds inhibiting growth of corynebacteria: potential lead compounds for antibiotics. AB - The bacterial genus Corynebacteria contains several pathogenic species that cause diseases such as diphtheria in humans and "cheesy gland" in goats and sheep. Thus, identifying new therapeutic targets to treat Corynebacteria infections is both medically and economically important. CG2496, a functionally uncharacterized protein from Corynebacterium glutamicum, was evaluated using an NMR ligand affinity screen. A total of 11 compounds from a library of 460 biologically active compounds were shown to selectively bind CG2496 in a highly conserved region of the protein. The best binder was identified to be methiothepin (KD =54 +/- 19 uM), an FDA-approved serotonin receptor antagonist. Methiothepin was also shown to inhibit the growth of C. glutamicum, but not bacteria that lack CG2496 homologs. Our results suggest that CG2496 is a novel therapeutic target and methiothepin is a potential lead compound or structural scaffold for developing new antibiotics specifically targeting Corynebacteria. PMID- 24403056 TI - Mechanistic insights into the Pd-catalyzed direct amination of allyl alcohols: evidence for an outer-sphere mechanism involving a palladium hydride intermediate. AB - The mechanism of direct amination of allyl alcohol by a palladium triphenylphosphite complex has been explored. Labelling studies show that the reaction proceeds through a pi-allylpalladium intermediate. A second-order dependence of reaction rate on allyl alcohol concentration was observed. Kinetic isotope effect studies and ESI-MS studies are in agreement with a reaction proceeding through a palladium hydride intermediate in which both O-H bond and C O bond cleavages are involved in rate-determining steps. A stereochemical study supports an outer-sphere nucleophilic attack of the pi-allylpalladium intermediate giving complete chiral transfer from starting material to product. PMID- 24403055 TI - The tankyrase-specific inhibitor JW74 affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines. AB - Wnt/beta-catenin is a major regulator of stem cell self-renewal and differentiation and this signaling pathway is aberrantly activated in a several cancers, including osteosarcoma (OS). Attenuation of Wnt/beta-catenin activity by tankyrase inhibitors is an appealing strategy in treatment of OS. The efficacy of the tankyrase inhibitor JW74 was evaluated in three OS cell lines (KPD, U2OS, and SaOS-2) both at the molecular and functional level. At the molecular level, JW74 induces stabilization of AXIN2, a key component of the beta-catenin destruction complex, resulting in reduced levels of nuclear beta-catenin. At the functional level, JW74 induces reduced cell growth in all three tested cell lines, in part due to a delay in cell cycle progression and in part due to an induction of caspase-3-mediated apoptosis. Furthermore, JW74 induces differentiation in U2OS cells, which under standard conditions are resistant to osteogenic differentiation. JW74 also enhances differentiation of OS cell lines, which do not harbor a differentiation block. Interestingly, microRNAs (miRNAs) of the let 7 family, which are known tumor suppressors and inducers of differentiation, are significantly upregulated following treatment with JW74. We demonstrate for the first time that tankyrase inhibition triggers reduced cell growth and differentiation of OS cells. This may in part be due to an induction of let-7 miRNA. The presented data open for novel therapeutic strategies in the treatment of malignant OS. PMID- 24403058 TI - Characterization of the potential energy surfaces of two small but challenging noncovalent dimers: (P2 )2 and (PCCP)2. AB - This work characterizes eight stationary points of the P2 dimer and six stationary points of the PCCP dimer, including a newly identified minimum on both potential energy surfaces. Full geometry optimizations and corresponding harmonic vibrational frequencies were computed with the second-order Moller-Plesset (MP2) electronic structure method and six different basis sets: aug-cc-pVXZ, aug-cc pV(X+d)Z, and aug-cc-pCVXZ where X = T, Q. A new L-shaped structure with C2 symmetry is the only minimum for the P2 dimer at the MP2 level of theory with these basis sets. The previously reported parallel-slipped structure with C2 h symmetry and a newly identified cross configuration with D2 symmetry are the only minima for the PCCP dimer. Single point energies were also computed using the canonical MP2 and CCSD(T) methods as well as the explicitly correlated MP2-F12 and CCSD(T)-F12 methods and the aug-cc-pVXZ (X = D, T, Q, 5) basis sets. The energetics obtained with the explicitly correlated methods were very similar to the canonical results for the larger basis sets. Extrapolations were performed to estimate the complete basis set (CBS) limit MP2 and CCSD(T) binding energies. MP2 and MP2-F12 significantly overbind the P2 and PCCP dimers relative to the CCSD(T) and CCSD(T)-F12 binding energies by as much as 1.5 kcal mol(-1) for the former and 5.0 kcal mol(-1) for the latter at the CBS limit. The dominant attractive component of the interaction energy for each dimer configuration was dispersion according to several symmetry-adapted perturbation theory analyses. PMID- 24403057 TI - Mechanisms for regulating deubiquitinating enzymes. AB - Ubiquitination is a reversible post-translational modification that plays a dynamic role in regulating most eukaryotic processes. Deubiquitinating enzymes (DUBs), which hydrolyze the isopeptide or peptide linkages joining ubiquitin to substrate lysines or N-termini, therefore play a key role in ubiquitin signaling. Cells employ multiple mechanisms to regulate DUB activity and thus ensure the appropriate biological response. Recent structural studies have shed light on several different mechanisms by which DUB activity and specificity is regulated. PMID- 24403060 TI - MicroRNA-542-3p inhibits tumour angiogenesis by targeting angiopoietin-2. AB - Angiopoietin-2 (Angpt2) plays a critical role in angiogenesis and tumour progression. Therapeutic targeting of Angpt2 has been implicated as a promising strategy for cancer treatment. Whereas miRNAs are emerging as important modulators of angiogenesis, regulation of Angpt2 by miRNAs has not been established. Here we firstly report that Ang2 is targeted by a microRNA, miRNA 542-3p, which inhibits tumour progression by impairing Ang2's pro-angiogenic activity. In cultured endothelial cells, miR-542-3p inhibited translation of Angpt2 mRNA by binding to its 3' UTR, and addition of miR-542-3p to cultured endothelial cells attenuated angiogenesis. Administration of miR-542-3p to tumour bearing mice reduced tumour growth, angiogenesis and metastasis. Furthermore, the level of miR-542-3p in primary breast carcinomas correlated inversely with clinical progression in primary tumour samples from stage III and IV patients. Together, these findings uncover a novel regulatory pathway whereby an anti angiogenic miR-542-3p directly targets the key angiogenesis-promoting protein Angpt2, suggesting that miR-542-3p may represent a promising target for anti angiogenic therapy and a potential marker for monitoring disease progression. PMID- 24403061 TI - Lack of an efficient endoplasmic reticulum-localized recycling system protects peroxiredoxin IV from hyperoxidation. AB - Typical 2-Cys peroxiredoxins are required to remove hydrogen peroxide from several different cellular compartments. Their activity can be regulated by hyperoxidation and consequent inactivation of the active-site peroxidatic cysteine. Here we developed a simple assay to quantify the hyperoxidation of peroxiredoxins. Hyperoxidation of peroxiredoxins can only occur efficiently in the presence of a recycling system, usually involving thioredoxin and thioredoxin reductase. We demonstrate that there is a marked difference in the sensitivity of the endoplasmic reticulum-localized peroxiredoxin to hyperoxidation compared with either the cytosolic or mitochondrial enzymes. Each enzyme is equally sensitive to hyperoxidation in the presence of a robust recycling system. Our results demonstrate that peroxiredoxin IV recycling in the endoplasmic reticulum is much less efficient than in the cytosol or mitochondria, leading to the protection of peroxiredoxin IV from hyperoxidation. PMID- 24403062 TI - Protein-tyrosine phosphatase 4A3 (PTP4A3) promotes vascular endothelial growth factor signaling and enables endothelial cell motility. AB - Protein-tyrosine phosphatase 4A3 (PTP4A3) is highly expressed in multiple human cancers and is hypothesized to have a critical, albeit poorly defined, role in the formation of experimental tumors in mice. PTP4A3 is broadly expressed in many tissues so the cellular basis of its etiological contributions to carcinogenesis may involve both tumor and stromal cells. In particular, PTP4A3 is expressed in the tumor vasculature and has been proposed to be a direct target of vascular endothelial growth factor (VEGF) signaling in endothelial cells. We now provide the first in vivo experimental evidence that PTP4A3 participates in VEGF signaling and contributes to the process of pathological angiogenesis. Colon tumor tissue isolated from Ptp4a3-null mice revealed reduced tumor microvessel density compared with wild type controls. Additionally, vascular cells derived from Ptp4a3-null tissues exhibited decreased invasiveness in an ex vivo wound healing assay. When primary endothelial cells were isolated and cultured in vitro, Ptp4a3-null cells displayed greatly reduced migration compared with wild type cells. Exposure to VEGF led to an increase in Src phosphorylation in wild type endothelial cells, a response that was completely ablated in Ptp4a3-null cells. In loss-of-function studies, reduced VEGF-mediated migration was also observed when human endothelial cells were treated with a small molecule inhibitor of PTP4A3. VEGF-mediated in vivo vascular permeability was significantly attenuated in PTP4A3-deficient mice. These findings strongly support a role for PTP4A3 as an important contributor to endothelial cell function and as a multimodal target for cancer therapy and mitigating VEGF regulated angiogenesis. PMID- 24403064 TI - Cytosolic dynamics of annexin A6 trigger feedback regulation of hypertrophy via atrial natriuretic peptide in cardiomyocytes. AB - Malfunctions in regulatory pathways that control cell size are prominent in pathological cardiac hypertrophy. Here, we show annexin A6 (Anxa6) to be a crucial regulator of atrial natriuretic peptide (ANP)-mediated counterhypertrophic responses in cardiomyocytes. Adrenergic stimulation of H9c2 cardiomyocytes by phenylephrine (PE) increased the cell size with enhanced expression of biochemical markers of hypertrophy, concomitant with elevated expression and subcellular redistribution of Anxa6. Stable cell lines with controlled increase in Anxa6 levels were protected against PE-induced adverse changes, whereas Anxa6 knockdown augmented the hypertrophic responses. Strikingly, Anxa6 knockdown also abrogated PE-induced juxtanuclear accumulation of secretory granules (SG) containing ANP propeptides (pro-ANP), a signature of maladaptive hypertrophy having counteractive functions. Mechanistically, PE treatment prompted a dynamic association of Anxa6 with pro-ANP-SG, parallel to their participation in anterograde traffic, in an isoform-specific fashion. Moreover, Anxa6 mutants that failed to associate with pro-ANP hindered ANP mediated protection against hypertrophy, which was rescued, at least partially, by WT Anxa6. Additionally, elevated intracellular calcium (Ca(2+)) stimulated Anxa6-pro-ANP colocalization and membrane association. It also rescued pro-ANP translocation in cells expressing an Anxa6 mutant (Anxa6(DeltaC)). Furthermore, stable overexpression of Anxa6(T356D), a mutant with superior flexibility, provided enhanced protection against PE, compared with WT, presumably due to enhanced membrane-binding capacity. Together, the present study delivers a cooperative mechanism where Anxa6 potentiates ANP-dependent counterhypertrophic responses in cardiomyocytes by facilitating regulated traffic of pro-ANP. PMID- 24403063 TI - Differential loss of prolyl isomerase or chaperone activity of Ran-binding protein 2 (Ranbp2) unveils distinct physiological roles of its cyclophilin domain in proteostasis. AB - The immunophilins, cyclophilins, catalyze peptidyl cis-trans prolyl-isomerization (PPIase), a rate-limiting step in protein folding and a conformational switch in protein function. Cyclophilins are also chaperones. Noncatalytic mutations affecting the only cyclophilins with known but distinct physiological substrates, the Drosophila NinaA and its mammalian homolog, cyclophilin-B, impair opsin biogenesis and cause osteogenesis imperfecta, respectively. However, the physiological roles and substrates of most cyclophilins remain unknown. It is also unclear if PPIase and chaperone activities reflect distinct cyclophilin properties. To elucidate the physiological idiosyncrasy stemming from potential cyclophilin functions, we generated mice lacking endogenous Ran-binding protein-2 (Ranbp2) and expressing bacterial artificial chromosomes of Ranbp2 with impaired C-terminal chaperone and with (Tg-Ranbp2(WT-HA)) or without PPIase activities (Tg Ranbp2(R2944A-HA)). The transgenic lines exhibit unique effects in proteostasis. Either line presents selective deficits in M-opsin biogenesis with its accumulation and aggregation in cone photoreceptors but without proteostatic impairment of two novel Ranbp2 cyclophilin partners, the cytokine-responsive effectors, STAT3/STAT5. Stress-induced STAT3 activation is also unaffected in Tg Ranbp2(R2944A-HA)::Ranbp2(-/-). Conversely, proteomic analyses found that the multisystem proteinopathy/amyotrophic lateral sclerosis proteins, heterogeneous nuclear ribonucleoproteins A2/B1, are down-regulated post-transcriptionally only in Tg-Ranbp2(R2944A-HA)::Ranbp2(-/-). This is accompanied by the age- and tissue dependent reductions of diubiquitin and ubiquitylated proteins, increased deubiquitylation activity, and accumulation of the 26 S proteasome subunits S1 and S5b. These manifestations are absent in another line, Tg-Ranbp2(CLDm HA)::Ranbp2(-/-), harboring SUMO-1 and S1-binding mutations in the Ranbp2 cyclophilin-like domain. These results unveil distinct mechanistic and biological links between PPIase and chaperone activities of Ranbp2 cyclophilin toward proteostasis of selective substrates and with novel therapeutic potential. PMID- 24403065 TI - Crystal structure of a bacterial unsaturated glucuronyl hydrolase with specificity for heparin. AB - Extracellular matrix molecules such as glycosaminoglycans (GAGs) are typical targets for some pathogenic bacteria, which allow adherence to host cells. Bacterial polysaccharide lyases depolymerize GAGs in beta-elimination reactions, and the resulting unsaturated disaccharides are subsequently degraded to constituent monosaccharides by unsaturated glucuronyl hydrolases (UGLs). UGL substrates are classified as 1,3- and 1,4-types based on the glycoside bonds. Unsaturated chondroitin and heparin disaccharides are typical members of 1,3- and 1,4-types, respectively. Here we show the reaction modes of bacterial UGLs with unsaturated heparin disaccharides by x-ray crystallography, docking simulation, and site-directed mutagenesis. Although streptococcal and Bacillus UGLs were active on unsaturated heparin disaccharides, those preferred 1,3- rather than 1,4 type substrates. The genome of GAG-degrading Pedobacter heparinus encodes 13 UGLs. Of these, Phep_2830 is known to be specific for unsaturated heparin disaccharides. The crystal structure of Phep_2830 was determined at 1.35-A resolution. In comparison with structures of streptococcal and Bacillus UGLs, a pocket-like structure and lid loop at subsite +1 are characteristic of Phep_2830. Docking simulations of Phep_2830 with unsaturated heparin disaccharides demonstrated that the direction of substrate pyranose rings differs from that in unsaturated chondroitin disaccharides. Acetyl groups of unsaturated heparin disaccharides are well accommodated in the pocket at subsite +1, and aromatic residues of the lid loop are required for stacking interactions with substrates. Thus, site-directed mutations of the pocket and lid loop led to significantly reduced enzyme activity, suggesting that the pocket-like structure and lid loop are involved in the recognition of 1,4-type substrates by UGLs. PMID- 24403066 TI - A refined model for the TSG-6 link module in complex with hyaluronan: use of defined oligosaccharides to probe structure and function. AB - Tumor necrosis factor-stimulated gene-6 (TSG-6) is an inflammation-associated hyaluronan (HA)-binding protein that contributes to remodeling of HA-rich extracellular matrices during inflammatory processes and ovulation. The HA binding domain of TSG-6 consists solely of a Link module, making it a prototypical member of the superfamily of proteins that interacts with this high molecular weight polysaccharide composed of repeating disaccharides of D glucuronic acid and N-acetyl-D-glucosamine (GlcNAc). Previously we modeled a complex of the TSG-6 Link module in association with an HA octasaccharide based on the structure of the domain in its HA-bound conformation. Here we have generated a refined model for a HA/Link module complex using novel restraints identified from NMR spectroscopy of the protein in the presence of 10 distinct HA oligosaccharides (from 4- to 8-mers); the model was then tested using unique sugar reagents, i.e. chondroitin/HA hybrid oligomers and an octasaccharide in which a single sugar ring was (13)C-labeled. The HA chain was found to make more extensive contacts with the TSG-6 surface than thought previously, such that a D glucuronic acid ring makes stacking and ionic interactions with a histidine and lysine, respectively. Importantly, this causes the HA to bend around two faces of the Link module (resembling the way that HA binds to CD44), potentially providing a mechanism for how TSG-6 can reorganize HA during inflammation. However, the HA binding site defined here may not play a role in TSG-6-mediated transfer of heavy chains from inter-alpha-inhibitor onto HA, a process known to be essential for ovulation. PMID- 24403067 TI - Decorin induces mitophagy in breast carcinoma cells via peroxisome proliferator activated receptor gamma coactivator-1alpha (PGC-1alpha) and mitostatin. AB - Tumor cell mitochondria are key biosynthetic hubs that provide macromolecules for cancer progression and angiogenesis. Soluble decorin protein core, hereafter referred to as decorin, potently attenuated mitochondrial respiratory complexes and mitochondrial DNA (mtDNA) in MDA-MB-231 breast carcinoma cells. We found a rapid and dynamic interplay between peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) and the decorin-induced tumor suppressor gene, mitostatin. This interaction stabilized mitostatin mRNA with concurrent accumulation of mitostatin protein. In contrast, siRNA-mediated abrogation of PGC 1alpha-blocked decorin-evoked stabilization of mitostatin. Mechanistically, PGC 1alpha bound MITOSTATIN mRNA to achieve rapid stabilization. These processes were orchestrated by the decorin/Met axis, as blocking the Met-tyrosine kinase or knockdown of Met abrogated these responses. Furthermore, depletion of mitostatin blocked decorin- or rapamycin-evoked mitophagy, increased vascular endothelial growth factor A (VEGFA) production, and compromised decorin-evoked VEGFA suppression. Collectively, our findings underscore the complexity of PGC-1alpha mediated mitochondrial homeostasis and establish mitostatin as a key regulator of tumor cell mitophagy and angiostasis. PMID- 24403068 TI - Serglycin proteoglycan is required for multiple myeloma cell adhesion, in vivo growth, and vascularization. AB - Recently, it was discovered that serglycin, a hematopoietic cell proteoglycan, is the major proteoglycan expressed and constitutively secreted by multiple myeloma (MM) cells. High levels of serglycin are present in the bone marrow aspirates of at least 30% of newly diagnosed MM patients. However, its contribution to the pathophysiology of MM is unknown. Here, we show that serglycin knockdown (by ~85% compared with normal levels), using lentiviral shRNA, dramatically attenuated MM tumor growth in mice with severe combined immunodeficiency. Tumors formed from cells deficient in serglycin exhibited diminished levels of hepatocyte growth factor expression and impaired development of blood vessels, indicating that serglycin may affect tumor angiogenesis. Furthermore, knockdown of serglycin significantly decreased MM cell adhesion to bone marrow stromal cells and collagen I. Even though serglycin proteoglycan does not have a transmembrane domain, flow cytometry showed that serglycin is present on the MM cell surface, and attachment to the cell surface is, at least in part, dependent on its chondroitin sulfate side chains. Co-precipitation of serglycin from conditioned medium of MM cells using a CD44-Fc chimera suggests that CD44 is the cell surface binding partner for serglycin, which therefore may serve as a major ligand for CD44 at various stages during myeloma progression. Finally, we demonstrate that serglycin mRNA expression in MM cells is up-regulated by activin, a predominant cytokine among those increased in MM patients with osteolytic lesions. These studies provide direct evidence for a critical role for serglycin in MM pathogenesis and show that targeting serglycin may provide a novel therapeutic approach for MM. PMID- 24403069 TI - A nucleotide-dependent and HRDC domain-dependent structural transition in DNA bound RecQ helicase. AB - The allosteric communication between the ATP- and DNA-binding sites of RecQ helicases enables efficient coupling of ATP hydrolysis to translocation along single-stranded DNA (ssDNA) and, in turn, the restructuring of multistranded DNA substrates during genome maintenance processes. In this study, we used the tryptophan fluorescence signal of Escherichia coli RecQ helicase to decipher the kinetic mechanism of the interaction of the enzyme with ssDNA. Rapid kinetic experiments revealed that ssDNA binding occurs in a two-step mechanism in which the initial binding step is followed by a structural transition of the DNA-bound helicase. We found that the nucleotide state of RecQ greatly influences the kinetics of the detected structural transition, which leads to a high affinity DNA-clamped state in the presence of the nucleotide analog ADP-AlF4. The DNA binding mechanism is largely independent of ssDNA length, indicating the independent binding of RecQ molecules to ssDNA and the lack of significant DNA end effects. The structural transition of DNA-bound RecQ was not detected when the ssDNA binding capability of the helicase-RNase D C-terminal domain was abolished or the domain was deleted. The results shed light on the nature of conformational changes leading to processive ssDNA translocation and multistranded DNA processing by RecQ helicases. PMID- 24403070 TI - Mlh1-Mlh3, a meiotic crossover and DNA mismatch repair factor, is a Msh2-Msh3 stimulated endonuclease. AB - Crossing over between homologous chromosomes is initiated in meiotic prophase in most sexually reproducing organisms by the appearance of programmed double strand breaks throughout the genome. In Saccharomyces cerevisiae the double-strand breaks are resected to form three prime single-strand tails that primarily invade complementary sequences in unbroken homologs. These invasion intermediates are converted into double Holliday junctions and then resolved into crossovers that facilitate homolog segregation during Meiosis I. Work in yeast suggests that Msh4 Msh5 stabilizes invasion intermediates and double Holliday junctions, which are resolved into crossovers in steps requiring Sgs1 helicase, Exo1, and a putative endonuclease activity encoded by the DNA mismatch repair factor Mlh1-Mlh3. We purified Mlh1-Mlh3 and showed that it is a metal-dependent and Msh2-Msh3 stimulated endonuclease that makes single-strand breaks in supercoiled DNA. These observations support a direct role for an Mlh1-Mlh3 endonuclease activity in resolving recombination intermediates and in DNA mismatch repair. PMID- 24403071 TI - Monoubiquitination is critical for ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 (Otub1) to suppress UbcH5 enzyme and stabilize p53 protein. AB - Ovarian tumor domain-containing ubiquitin (Ub) aldehyde binding protein 1 (Otub1) regulates p53 stability and activity via non-canonical inhibition of the MDM2 cognate Ub-conjugating enzyme (E2) UbcH5. However, it is not clear how this activity of Otub1 is regulated in cells. Here we report that Otub1 is monoubiquitinated by UbcH5 in cells and in vitro, primarily at the lysine 59 and 109 residues. This monoubiquitination, in turn, contributes to the activity of Otub1 to suppress UbcH5. The lysine-free Otub1 mutant (Otub1(K0)) fails to be monoubiquitinated and is unable to suppress the Ub-conjugating activity of UbcH5 in vitro and the MDM2-mediated p53 ubiquitination in cells. Consistently, this mutant is unable to stabilize p53, induce apoptosis, and suppress cell proliferation. Overexpression of Otub1(K0) inhibits DNA-damage induced apoptosis. Adding either Lys-59 or Lys-109 back to the Otub1(K0) mutant restores the monoubiquitination of Otub1 and its function to stabilize and activate p53. We further show that UbcH5 preferentially binds to the monoubiquitinated Otub1 via Ub interaction with its backside donor Ub-interacting surface, suggesting that this binding interferes with the self-assembly of Ub-charged UbcH5 (UbcH5~Ub) conjugates, which is critical for Ub transfer. Thus, our data reveal novel insights into the Otub1 inhibition of E2 wherein monoubiquitination promotes the interaction of Otub1 with UbcH5 and the function to suppress it. PMID- 24403072 TI - Evolution of mammalian Opn5 as a specialized UV-absorbing pigment by a single amino acid mutation. AB - Opn5 is one of the recently identified opsin groups that is responsible for nonvisual photoreception in animals. We previously showed that a chicken homolog of mammalian Opn5 (Opn5m) is a Gi-coupled UV sensor having molecular properties typical of bistable pigments. Here we demonstrated that mammalian Opn5m evolved to be a more specialized photosensor by losing one of the characteristics of bistable pigments, direct binding of all-trans-retinal. We first confirmed that Opn5m proteins in zebrafish, Xenopus tropicalis, mouse, and human are also UV sensitive pigments. Then we found that only mammalian Opn5m proteins lack the ability to directly bind all-trans-retinal. Mutational analysis showed that these characteristics were acquired by a single amino acid replacement at position 168. By comparing the expression patterns of Opn5m between mammals and chicken, we found that, like chicken Opn5m, mammalian Opn5m was localized in the ganglion cell layer and inner nuclear layer of the retina. However, the mouse and primate (common marmoset) opsins were distributed not in the posterior hypothalamus (including the region along the third ventricle) where chicken Opn5m is localized, but in the preoptic hypothalamus. Interestingly, RPE65, an essential enzyme for forming 11-cis-retinal in the visual cycle is expressed near the preoptic hypothalamus of the mouse and common marmoset brain but not near the region of the chicken brain where chicken Opn5m is expressed. Therefore, mammalian Opn5m may work exclusively as a short wavelength sensor in the brain as well as in the retina with the assistance of an 11-cis-retinal-supplying system. PMID- 24403073 TI - Characterization of the Raptor/4E-BP1 interaction by chemical cross-linking coupled with mass spectrometry analysis. AB - mTORC1 plays critical roles in the regulation of protein synthesis, growth, and proliferation in response to nutrients, growth factors, and energy conditions. One of the substrates of mTORC1 is 4E-BP1, whose phosphorylation by mTORC1 reverses its inhibitory action on eIF4E, resulting in the promotion of protein synthesis. Raptor in mTOR complex 1 is believed to recruit 4E-BP1, facilitating phosphorylation of 4E-BP1 by the kinase mTOR. We applied chemical cross-linking coupled with mass spectrometry analysis to gain insight into interactions between mTORC1 and 4E-BP1. Using the cross-linking reagent bis[sulfosuccinimidyl] suberate, we showed that Raptor can be cross-linked with 4E-BP1. Mass spectrometric analysis of cross-linked Raptor-4E-BP1 led to the identification of several cross-linked peptide pairs. Compilation of these peptides revealed that the most N-terminal Raptor N-terminal conserved domain (in particular residues from 89 to 180) of Raptor is the major site of interaction with 4E-BP1. On 4E BP1, we found that cross-links with Raptor were clustered in the central region (amino acid residues 56-72) we call RCR (Raptor cross-linking region). Intramolecular cross-links of Raptor suggest the presence of two structured regions of Raptor: one in the N-terminal region and the other in the C-terminal region. In support of the idea that the Raptor N-terminal conserved domain and the 4E-BP1 central region are closely located, we found that peptides that encompass the RCR of 4E-BP1 inhibit cross-linking and interaction of 4E-BP1 with Raptor. Furthermore, mutations of residues in the RCR decrease the ability of 4E BP1 to serve as a substrate for mTORC1 in vitro and in vivo. PMID- 24403074 TI - Modification of hyaluronan by heavy chains of inter-alpha-inhibitor in idiopathic pulmonary arterial hypertension. AB - We previously reported an altered hyaluronan (HA) metabolism in idiopathic pulmonary arterial hypertension (IPAH) lung tissue and cultured smooth muscle cells. Hyaluronan was present in the smooth muscle cell layer surrounding the pulmonary vasculature and in plexigenic lesions. Additionally, cultured pulmonary artery smooth muscle cells produced spontaneous HA "cable" structures, without additional stimuli, that were leukocyte-adhesive. We now present evidence that the HA that accumulates in IPAH plexigenic lesions is a pathological form of HA in which heavy chains (HCs) from the serum-derived proteoglycan inter-alpha inhibitor are covalently attached to the HA backbone to form a pathological HC-HA complex. CD45-positive leukocytes were identified within these HC-HA matrices. Elevated mRNA levels of the enzyme that transfers HCs to HA, known as tumor necrosis factor-stimulated gene 6, were detected in IPAH lung tissue. PMID- 24403075 TI - Promotion of enzyme flexibility by dephosphorylation and coupling to the catalytic mechanism of a phosphohexomutase. AB - The enzyme phosphomannomutase/phosphoglucomutase (PMM/PGM) from Pseudomonas aeruginosa catalyzes an intramolecular phosphoryl transfer across its phosphosugar substrates, which are precursors in the synthesis of exoproducts involved in bacterial virulence. Previous structural studies of PMM/PGM have established a key role for conformational change in its multistep reaction, which requires a dramatic 180 degrees reorientation of the intermediate within the active site. Here hydrogen-deuterium exchange by mass spectrometry and small angle x-ray scattering were used to probe the conformational flexibility of different forms of PMM/PGM in solution, including its active, phosphorylated state and the unphosphorylated state that occurs transiently during the catalytic cycle. In addition, the effects of ligand binding were assessed through use of a substrate analog. We found that both phosphorylation and binding of ligand produce significant effects on deuterium incorporation. Phosphorylation of the conserved catalytic serine has broad effects on residues in multiple domains and is supported by small angle x-ray scattering data showing that the unphosphorylated enzyme is less compact in solution. The effects of ligand binding are generally manifested near the active site cleft and at a domain interface that is a site of conformational change. These results suggest that dephosphorylation of the enzyme may play two critical functional roles: a direct role in the chemical step of phosphoryl transfer and secondly through propagation of structural flexibility. We propose a model whereby increased enzyme flexibility facilitates the reorientation of the reaction intermediate, coupling changes in structural dynamics with the unique catalytic mechanism of this enzyme. PMID- 24403076 TI - Ligand independence of the T618I mutation in the colony-stimulating factor 3 receptor (CSF3R) protein results from loss of O-linked glycosylation and increased receptor dimerization. AB - Mutations in the CSF3 granulocyte colony-stimulating factor receptor CSF3R have recently been found in a large percentage of patients with chronic neutrophilic leukemia and, more rarely, in other types of leukemia. These CSF3R mutations fall into two distinct categories: membrane-proximal mutations and truncation mutations. Although both classes of mutation have exhibited the capacity for cellular transformation, several aspects of this transformation, including the kinetics, the requirement for ligand, and the dysregulation of downstream signaling pathways, have all been shown to be discrepant between the mutation types, suggesting distinct mechanisms of activation. CSF3R truncation mutations induce overexpression and ligand hypersensitivity of the receptor, likely because of the removal of motifs necessary for endocytosis and degradation. In contrast, little is known about the mechanism of activation of membrane-proximal mutations, which are much more commonly observed in chronic neutrophilic leukemia. In contrast with CSF3R truncation mutations, membrane-proximal mutations do not exhibit overexpression and are capable of signaling in the absence of ligand. We show that the Thr-615 and Thr-618 sites of membrane-proximal mutations are part of an O-linked glycosylation cluster. Mutation at these sites prevents O glycosylation of CSF3R and increases receptor dimerization. This increased dimerization explains the ligand-independent activation of CSF3R membrane proximal mutations. Cytokine receptor activation through loss of O-glycosylation represents a novel avenue of aberrant signaling. Finally, the combination of the CSF3R membrane proximal and truncation mutations, as has been reported in some patients, leads to enhanced cellular transformation when compared with either mutation alone, underscoring their distinct mechanisms of action. PMID- 24403077 TI - Developmental onset of bilirubin-induced neurotoxicity involves Toll-like receptor 2-dependent signaling in humanized UDP-glucuronosyltransferase1 mice. AB - Biological and signaling events that connect developmentally induced hyperbilirubinemia to bilirubin-induced neurological dysfunction (BIND) and CNS toxicity in humans are poorly understood. In mammals, UDP-glucuronosyltransferase 1A1 (UGT1A1) is the sole enzyme responsible for bilirubin glucuronidation, a rate limiting step necessary for bilirubin metabolism and clearance. Humanized mice that express the entire UGT1 locus (hUGT1) and the UGT1A1 gene, develop neonatal hyperbilirubinemia, with 8-10% of hUGT1 mice succumbing to CNS damage, a phenotype that is presented by uncontrollable seizures. We demonstrate that neuroinflammation and reactive gliosis are prominent features of bilirubin brain toxicity, and a disturbed redox status resulting from activation of NADPH oxidase is an important contributing mechanism found in BIND. Using knock-out mice and primary brain cells, we connect a key pattern recognition receptor, Toll-like receptor 2 (TLR2), to hyperbilirubinemia-induced signaling. We illustrate a requirement for TLR2 signaling in regulating gliosis, proinflammatory mediators, and oxidative stress when neonatal mice encounter severe hyperbilirubinemia. TLR2 mediated gliosis strongly correlates with pronounced neuroinflammation in the CNS with up-regulation of TNFalpha, IL-1beta, and IL-6, creating a pro-inflammatory CNS environment. Gene expression and immunohistochemistry staining show that hUGT1/Tlr2(-/-) mice fail to activate glial cells, proinflammatory cytokines, and stress response genes. In addition, bilirubin-induced apoptosis was significantly enhanced by blocking TLR2 signaling indicating its anti-apoptotic property. Consequently, a higher neonatal death rate (57.1%) in hUGT1/Tlr2(-/-) mice was observed when compared with hUGT1 mice (8.7%). These results suggest that TLR2 signaling and microglia neuroinflammation are linked to a repair and/or protection mode against BIND. PMID- 24403078 TI - Coupling of human DNA excision repair and the DNA damage checkpoint in a defined in vitro system. AB - DNA repair and DNA damage checkpoints work in concert to help maintain genomic integrity. In vivo data suggest that these two global responses to DNA damage are coupled. It has been proposed that the canonical 30 nucleotide single-stranded DNA gap generated by nucleotide excision repair is the signal that activates the ATR-mediated DNA damage checkpoint response and that the signal is enhanced by gap enlargement by EXO1 (exonuclease 1) 5' to 3' exonuclease activity. Here we have used purified core nucleotide excision repair factors (RPA, XPA, XPC, TFIIH, XPG, and XPF-ERCC1), core DNA damage checkpoint proteins (ATR-ATRIP, TopBP1, RPA), and DNA damaged by a UV-mimetic agent to analyze the basic steps of DNA damage checkpoint response in a biochemically defined system. We find that checkpoint signaling as measured by phosphorylation of target proteins by the ATR kinase requires enlargement of the excision gap generated by the excision repair system by the 5' to 3' exonuclease activity of EXO1. We conclude that, in addition to damaged DNA, RPA, XPA, XPC, TFIIH, XPG, XPF-ERCC1, ATR-ATRIP, TopBP1, and EXO1 constitute the minimum essential set of factors for ATR-mediated DNA damage checkpoint response. PMID- 24403079 TI - Zymogen activation confers thermodynamic stability on a key peptide bond and protects human cationic trypsin from degradation. AB - Human cationic trypsinogen, precursor of the digestive enzyme trypsin, can be rapidly degraded to protect the pancreas when pathological conditions threaten, while trypsin itself is impressively resistant to degradation. For either form, degradation is controlled by two necessary initial proteolytic events: cleavage of the Leu81-Glu82 peptide bond by chymotrypsin C (CTRC) and cleavage of the Arg122-Val123 peptide bond by trypsin. Here we demonstrate that the Leu81-Glu82 peptide bond of human cationic trypsin, but not trypsinogen, is thermodynamically stable, such that cleavage by CTRC leads to an equilibrium mixture containing 10% cleaved and 90% uncleaved trypsin. When cleaved trypsin was incubated with CTRC, the Leu81-Glu82 peptide bond was re-synthesized to establish the same equilibrium. The thermodynamic stability of the scissile peptide bond was not dependent on CTRC or Leu-81, as re-synthesis was also accomplished by other proteases acting on mutated cationic trypsin. The Leu81-Glu82 peptide bond is located within a calcium binding loop, and thermodynamic stability of the bond was strictly dependent on calcium and on the calcium-coordinated residue Glu-85. Trypsinolytic cleavage of the Arg122-Val123 site was also delayed in trypsin relative to trypsinogen in a calcium-dependent manner, but for this bond cleavage was modulated by kinetic rather than thermodynamic control. Our results reveal that the trypsinogen to trypsin conformational switch modulates cleavage susceptibility of nick sites by altering both the thermodynamics and kinetics of cleavage to protect human cationic trypsin from premature degradation. PMID- 24403080 TI - Redox control of human mitochondrial outer membrane protein MitoNEET [2Fe-2S] clusters by biological thiols and hydrogen peroxide. AB - The human mitochondrial outer membrane protein mitoNEET is a novel target of the type II diabetes drug pioglitazone. The C-terminal cytosolic domain of mitoNEET hosts a redox-active [2Fe-2S] cluster via an unusual ligand arrangement of three cysteine residues and one histidine residue. Here we report that human mitoNEET [2Fe-2S] clusters are fully reduced when expressed in Escherichia coli cells. In vitro studies show that purified mitoNEET [2Fe-2S] clusters can be partially reduced by monothiols such as reduced glutathione, L-cysteine or N-acetyl-L cysteine and fully reduced by dithiothreitol or the E. coli thioredoxin/thioredoxin reductase system under anaerobic conditions. Importantly, thiol-reduced mitoNEET [2Fe-2S] clusters can be reversibly oxidized by hydrogen peroxide without disruption of the clusters in vitro and in E. coli cells, indicating that mitoNEET may act as a sensor of oxidative signals to regulate mitochondrial functions via its [2Fe-2S] clusters. Furthermore, the binding of the type II diabetes drug pioglitazone in mitoNEET effectively inhibits the thiol mediated reduction of [2Fe-2S] clusters, suggesting that pioglitazone may modulate the function of mitoNEET by blocking the thiol-mediated reduction of [2Fe-2S] clusters in the protein. PMID- 24403082 TI - Chironex fleckeri (box jellyfish) venom proteins: expansion of a cnidarian toxin family that elicits variable cytolytic and cardiovascular effects. AB - The box jellyfish Chironex fleckeri produces extremely potent and rapid-acting venom that is harmful to humans and lethal to prey. Here, we describe the characterization of two C. fleckeri venom proteins, CfTX-A (~40 kDa) and CfTX-B (~42 kDa), which were isolated from C. fleckeri venom using size exclusion chromatography and cation exchange chromatography. Full-length cDNA sequences encoding CfTX-A and -B and a third putative toxin, CfTX-Bt, were subsequently retrieved from a C. fleckeri tentacle cDNA library. Bioinformatic analyses revealed that the new toxins belong to a small family of potent cnidarian pore forming toxins that includes two other C. fleckeri toxins, CfTX-1 and CfTX-2. Phylogenetic inferences from amino acid sequences of the toxin family grouped CfTX-A, -B, and -Bt in a separate clade from CfTX-1 and -2, suggesting that the C. fleckeri toxins have diversified structurally and functionally during evolution. Comparative bioactivity assays revealed that CfTX-1/2 (25 MUg kg(-1)) caused profound effects on the cardiovascular system of anesthetized rats, whereas CfTX-A/B elicited only minor effects at the same dose. Conversely, the hemolytic activity of CfTX-A/B (HU50 = 5 ng ml(-1)) was at least 30 times greater than that of CfTX-1/2. Structural homology between the cubozoan toxins and insecticidal three-domain Cry toxins (delta-endotoxins) suggests that the toxins have a similar pore-forming mechanism of action involving alpha-helices of the N terminal domain, whereas structural diversification among toxin members may modulate target specificity. Expansion of the cnidarian toxin family therefore provides new insights into the evolutionary diversification of box jellyfish toxins from a structural and functional perspective. PMID- 24403081 TI - 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) effect on glucose production, but not energy metabolism, is independent of hepatic AMPK in vivo. AB - Metabolic stress, as well as several antidiabetic agents, increases hepatic nucleotide monophosphate (NMP) levels, activates AMP-activated protein kinase (AMPK), and suppresses glucose production. We tested the necessity of hepatic AMPK for the in vivo effects of an acute elevation in NMP on metabolism. 5 Aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR; 8 mg.kg(-1).min(-1)) euglycemic clamps were performed to elicit an increase in NMP in wild type (alpha1alpha2(lox/lox)) and liver-specific AMPK knock-out mice (alpha1alpha2(lox/lox) + Albcre) in the presence of fixed glucose. Glucose kinetics were equivalent in 5-h fasted alpha1alpha2(lox/lox) and alpha1alpha2(lox/lox) + Albcre mice. AMPK was not required for AICAR-mediated suppression of glucose production and increased glucose disappearance. These results demonstrate that AMPK is unnecessary for normal 5-h fasting glucose kinetics and AICAR-mediated inhibition of glucose production. Moreover, plasma fatty acids and triglycerides also decreased independently of hepatic AMPK during AICAR administration. Although the glucoregulatory effects of AICAR were shown to be independent of AMPK, these studies provide in vivo support for the AMPK energy sensor paradigm. AICAR reduced hepatic energy charge by ~20% in alpha1alpha2(lox/lox), which was exacerbated by ~2-fold in alpha1alpha2(lox/lox) + Albcre. This corresponded to a ~6-fold rise in AMP/ATP in alpha1alpha2(lox/lox) + Albcre. Consistent with the effects on adenine nucleotides, maximal mitochondrial respiration was ~30% lower in alpha1alpha2(lox/lox) + Albcre than alpha1alpha2(lox/lox) livers. Mitochondrial oxidative phosphorylation efficiency was reduced by 25%. In summary, these results demonstrate that the NMP capacity to inhibit glucose production in vivo is independent of liver AMPK. In contrast, AMPK promotes mitochondrial function and protects against a more precipitous fall in ATP during AICAR administration. PMID- 24403083 TI - Distinct subunit-specific alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking mechanisms in cultured cortical and hippocampal neurons in response to oxygen and glucose deprivation. AB - Brain ischemia occurs when the blood supply to the brain is interrupted, leading to oxygen and glucose deprivation (OGD). This triggers a cascade of events causing a synaptic accumulation of glutamate. Excessive activation of glutamate receptors results in excitotoxicity and delayed cell death in vulnerable neurons. Following global cerebral ischemia, hippocampal CA1 pyramidal neurons are more vulnerable to injury than their cortical counterparts. The mechanisms that underlie this difference are unclear. Cultured hippocampal neurons respond to OGD with a rapid internalization of AMPA receptor (AMPAR) subunit GluA2, resulting in a switch from GluA2-containing Ca(2+)-impermeable receptors to GluA2-lacking Ca(2+)-permeable subtypes (CP-AMPARs). GluA2 internalization is a critical component of OGD-induced cell death in hippocampal neurons. It is unknown how AMPAR trafficking is affected in cortical neurons following OGD. Here, we show that cultured cortical neurons are resistant to an OGD insult that causes cell death in hippocampal neurons. GluA1 is inserted at the plasma membrane in both cortical and hippocampal neurons in response to OGD. In contrast, OGD causes a rapid endocytosis of GluA2 in hippocampal neurons, which is absent in cortical neurons. These data demonstrate that populations of neurons with different vulnerabilities to OGD recruit distinct cell biological mechanisms in response to insult, and that a crucial aspect of the mechanism leading to OGD-induced cell death is absent in cortical neurons. This strongly suggests that the absence of OGD-induced GluA2 trafficking contributes to the relatively low vulnerability of cortical neurons to ischemia. PMID- 24403085 TI - Integration of MDCT and fluoroscopy using C-arm computed tomography to guide structural cardiac interventions in the cardiac catheterization laboratory. AB - OBJECTIVES: Our study was aimed at evaluation of three-dimensional (3D)-CT overlay onto the catheterization laboratory fluoroscopy to guide structural cardiac interventions. BACKGROUND: Current imaging for structural cardiac interventions (fluoroscopy, echocardiography) may not provide adequate guidance. The ability to integrate intracardiac 3D-CT imaging data in the cardiac catheterization laboratory may be beneficial, but has not yet been systematically studied. METHODS: Thirty-two patients undergoing various catheterization laboratory procedures (transcatheter aortic valve replacement, paravalvular leak (PVL) closure, pulmonary vein (PV) stenting, etc.) were prospectively enrolled. The goal was to evaluate the feasibility and benefit of overlaying pre-procedural CT data onto the real-time procedural fluoroscopic image using the Syngo DynaCT Cardiac C-arm CT system (Siemens Healthcare, Forcheim, Germany). RESULTS: The overlay was considered most helpful for patients undergoing PVL closure and PV stenting. The additional radiation exposure of the C-arm CT was a fraction of the total procedural dose (3.5% of total skin dose and 9.1% of total DAP). CONCLUSIONS: Overlay of 3D-CT data onto the real-time procedural fluoroscopy in the cardiac catheterization laboratory is feasible to aide procedural guidance. The overlay was considered most helpful for patients undergoing PVL closure and PV stenting. The additional radiation dose is a small fraction of the total dose. (c) 2014 Wiley Periodicals, Inc. PMID- 24403084 TI - Filamin A promotes dynamin-dependent internalization of hyperpolarization activated cyclic nucleotide-gated type 1 (HCN1) channels and restricts Ih in hippocampal neurons. AB - The actin-binding protein filamin A (FLNa) regulates neuronal migration during development, yet its roles in the mature brain remain largely obscure. Here, we probed the effects of FLNa on the regulation of ion channels that influence neuronal properties. We focused on the HCN1 channels that conduct Ih, a hyperpolarization-activated current crucial for shaping intrinsic neuronal properties. Whereas regulation of HCN1 channels by FLNa has been observed in melanoma cell lines, its physiological relevance to neuronal function and the underlying cellular pathways that govern this regulation remain unknown. Using a combination of mutational, pharmacological, and imaging approaches, we find here that FLNa facilitates a selective and reversible dynamin-dependent internalization of HCN1 channels in HEK293 cells. This internalization is accompanied by a redistribution of HCN1 channels on the cell surface, by accumulation of the channels in endosomal compartments, and by reduced Ih density. In hippocampal neurons, expression of a truncated dominant-negative FLNa enhances the expression of native HCN1. Furthermore, acute abrogation of HCN1 FLNa interaction in neurons, with the use of decoy peptides that mimic the FLNa binding domain of HCN1, abolishes the punctate distribution of HCN1 channels in neuronal cell bodies, augments endogenous Ih, and enhances the rebound-response ("voltage-sag") of the neuronal membrane to transient hyperpolarizing events. Together, these results support a major function of FLNa in modulating ion channel abundance and membrane trafficking in neurons, thereby shaping their biophysical properties and function. PMID- 24403086 TI - Management of a large atrial septal occluder embolized to the left ventricular outflow tract without the use of cardiac surgery. AB - Transcatheter closure of secundum-type atrial septal defects (ASDs) using the AMPLATZERTM Septal Occluder (ASO) has been in use for more than a decade since its US Food and Drug Administration approval in 2001. Device embolization remains an uncommon complication, which can sometimes occur after the initial deployment. Previous reports of ASO devices embolized to the left ventricle have primarily been managed by open-heart surgical retrieval. We present a case of an ASO device embolized to the left ventricular outflow tract (LVOT) 18 hr after initial implantation, which was successfully retrieved percutaneously, followed by successful closure of the ASD using a larger device. PMID- 24403087 TI - The basic helix-loop-helix region of the transcriptional repressor hairy and enhancer of split 1 is preorganized to bind DNA. AB - Hairy and enhancer of split 1, one of the main downstream effectors in Notch signaling, is a transcriptional repressor of the basic helix-loop-helix (bHLH) family. Using nuclear magnetic resonance methods, we have determined the structure and dynamics of a recombinant protein, H1H, which includes an N terminal segment, b1, containing functionally important phosphorylation sites, the basic region b2, required for binding to DNA, and the HLH domain. We show that a proline residue in the sequence divides the protein in two parts, a flexible and disordered N-terminal region including b1 and a structured, mainly helical region comprising b2 and the HLH domain. Binding of H1H to a double strand DNA oligonucleotide was monitored through the chemical shift perturbation of backbone amide resonances, and showed that the interaction surface involves not only the b2 segment but also several residues in the b1 and HLH regions. PMID- 24403088 TI - Molecular rotors in porous organic frameworks. AB - Porous organic frameworks perform a variety of functions, owing to their extremely large surface areas, but the dynamics of the structural elements have never been explored. Our discovery of ultra-fast molecular rotors (10(6) Hz at 225 K) in their architectures allows us to look at them from a new perspective. The constructive elements are robust struts and rapid rotors, resulting in a dynamic material whose motion can be frozen or released at will. The rotational motion can be actively regulated in response to guests. As the temperature is increased, the rotors spin ever faster, approaching free-rotational diffusion at 550 K. The unusual combination of remarkable nanoporosity with fast dynamics is intriguing for engineering oscillating dipoles and producing responsive materials with switchable ferroelectricity, and for applications spanning from sensors to actuators, which capture and release chemicals on command. PMID- 24403089 TI - Toward the development of dual-targeted glyceraldehyde-3-phosphate dehydrogenase/trypanothione reductase inhibitors against Trypanosoma brucei and Trypanosoma cruzi. AB - A significant improvement in the treatment of trypanosomiases has been achieved with the recent development of nifurtimox-eflornithine combination therapy (NECT). As an alternative to drug combinations and as a means to overcome most of the antitrypanosomatid drug discovery challenges, a multitarget drug design strategy has been envisaged. To begin testing this hypothesis, we designed and developed a series of quinone-coumarin hybrids against glyceraldehyde-3-phosphate dehydrogenase/trypanothione reductase (GAPDH/TR). These enzymes belong to metabolic pathways that are vital to Trypanosoma brucei and Trypanosoma cruzi, and have thus been considered promising drug targets. The synthesized molecules were characterized for their dual-target antitrypanosomal profile, both in enzyme assays and in in vitro parasite cultures. The merged derivative 2-{[3-(3 dimethylaminopropoxy)-2-oxo-2H-chromen-7-yl]oxy}anthracene-1,4-dione (10) showed an IC50 value of 5.4 MUM against TbGAPDH and a concomitant Ki value of 2.32 MUM against TcTR. Notably, 2-{4-[6-(2-dimethylaminoethoxy)-2-oxo-2H-chromen-3 yl]phenoxy}anthracene-1,4-dione (compound 6) displayed a remarkable EC50 value for T.brucei parasites (0.026 MUM) combined with a very low cytotoxicity toward mammalian L6 cells (7.95 MUM). This promising low toxicity of compound 6 might be at least partially due to the fact that it does not interfere with human glutathione reductase. PMID- 24403090 TI - HPV DNA testing improves CIN2+ risk stratification and detection of CIN2+ in delayed triage of ASCUS and LSIL. A population-based follow-up study from Western Norway. AB - In Norway, Pap smears with atypical squamous cells of uncertain significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) are triaged after 6 months. The aim of the study was to evaluate effects of implementing human papillomavirus (HPV) test (2005) in delayed triage of ASCUS and LSIL in a cohort of women from Western Norway. After a survey of 119,469 cervical Pap smears during 2005-2007, a total of 1055 women with an index ASCUS or LSIL were included in the study and followed up for 3-6 years with respect to progression into cervical intraepithelial neoplasia grade 2 or worse (CIN2+). Overall sensitivity for detection of CIN2+ with HPV testing and cytology was 96% and 72%, respectively. The sensitivity for detection of CIN2+ was not affected by age, but the specificity of the HPV test increased with age. Thus, for the age groups <34 years, 34-50 years, and >50 years, the specificity of a positive HPV test to detect CIN2+ was 47%, 71%, and 82%, respectively. Positive predictive values for CIN2+ in women with positive cytology, positive HPV test, negative cytology, negative HPV test, or negative HPV and cytology tests were 52%, 41%, 8%, 1.5%, and 0.4%, respectively. HPV testing resulted in a net 22% increased detection of CIN2+. Fifty-six percent of CIN2+ was detected at an earlier time point with HPV testing in triage. Implementation of HPV testing in delayed triage of ASCUS and LSIL improved the stratification of CIN2+ risk and increased CIN2+ detection and at an earlier time point than with triage by cytology alone. PMID- 24403091 TI - Enantioselective copper(I/II)-catalyzed conjugate addition of nitro esters to beta,gamma-unsaturated alpha-ketoesters. AB - A highly enantioselective Michael addition of nitroacetates to beta,gamma unsaturated alpha-ketoesters was developed by using chiral copper catalysts. The Michael addition products can be obtained in high yields with up to 99 % ee. With these densely functionalized products, the chiral cyclic nitrones, which are important synthetic intermediates, can be obtained in one step. PMID- 24403092 TI - Loop-loop interactions govern multiple steps in indole-3-glycerol phosphate synthase catalysis. AB - Substrate binding, product release, and likely chemical catalysis in the tryptophan biosynthetic enzyme indole-3-glycerol phosphate synthase (IGPS) are dependent on the structural dynamics of the beta1alpha1 active-site loop. Statistical coupling analysis and molecular dynamic simulations had previously indicated that covarying residues in the beta1alpha1 and beta2alpha2 loops, corresponding to Arg54 and Asn90, respectively, in the Sulfolobus sulfataricus enzyme (ssIGPS), are likely important for coordinating functional motions of these loops. To test this hypothesis, we characterized site mutants at these positions for changes in catalytic function, protein stability and structural dynamics for the thermophilic ssIGPS enzyme. Although there were only modest changes in the overall steady-state kinetic parameters, solvent viscosity and solvent deuterium kinetic isotope effects indicated that these amino acid substitutions change the identity of the rate-determining step across multiple temperatures. Surprisingly, the N90A substitution had a dramatic effect on the general acid/base catalysis of the dehydration step, as indicated by the loss of the descending limb in the pH rate profile, which we had previously assigned to Lys53 on the beta1alpha1 loop. These changes in enzyme function are accompanied with a quenching of ps-ns and us-ms timescale motions in the beta1alpha1 loop as measured by nuclear magnetic resonance studies. Altogether, our studies provide structural, dynamic and functional rationales for the coevolution of residues on the beta1alpha1 and beta2alpha2 loops, and highlight the multiple roles that the beta1alpha1 loop plays in IGPS catalysis. Thus, substitution of covarying residues in the active-site beta1alpha1 and beta2alpha2 loops of indole-3 glycerol phosphate synthase results in functional, structural, and dynamic changes, highlighting the multiple roles that the beta1alpha1 loop plays in enzyme catalysis and the importance of regulating the structural dynamics of this loop through noncovalent interactions with nearby structural elements. PMID- 24403093 TI - Comparative analysis of nucleotide translocation through protein nanopores using steered molecular dynamics and an adaptive biasing force. AB - The translocation of nucleotide molecules across biological and synthetic nanopores has attracted attention as a next generation technique for sequencing DNA. Computer simulations have the ability to provide atomistic-level insight into important states and processes, delivering a means to develop a fundamental understanding of the translocation event, for example, by extracting the free energy of the process. Even with current supercomputing facilities, the simulation of many-atom systems in fine detail is limited to shorter timescales than the real events they attempt to recreate. This imposes the need for enhanced simulation techniques that expand the scope of investigation in a given timeframe. There are numerous free energy calculation and translocation methodologies available, and it is by no means clear which method is best applied to a particular problem. This article explores the use of two popular free energy calculation methodologies in a nucleotide-nanopore translocation system, using the alpha-hemolysin nanopore. The first uses constant velocity-steered molecular dynamics (cv-SMD) in conjunction with Jarzynski's equality. The second applies an adaptive biasing force (ABF), which has not previously been applied to the nucleotide-nanpore system. The purpose of this study is to provide a comprehensive comparison of these methodologies, allowing for a detailed comparative assessment of the scientific merits, the computational cost, and the statistical quality of the data obtained from each technique. We find that the ABF method produces results that are closer to experimental measurements than those from cv-SMD, whereas the net errors are smaller for the same computational cost. PMID- 24403095 TI - An introduction to item response theory for patient-reported outcome measurement. AB - The growing emphasis on patient-centered care has accelerated the demand for high quality data from patient-reported outcome (PRO) measures. Traditionally, the development and validation of these measures has been guided by classical test theory. However, item response theory (IRT), an alternate measurement framework, offers promise for addressing practical measurement problems found in health related research that have been difficult to solve through classical methods. This paper introduces foundational concepts in IRT, as well as commonly used models and their assumptions. Existing data on a combined sample (n = 636) of Korean American and Vietnamese American adults who responded to the High Blood Pressure Health Literacy Scale and the Patient Health Questionnaire-9 are used to exemplify typical applications of IRT. These examples illustrate how IRT can be used to improve the development, refinement, and evaluation of PRO measures. Greater use of methods based on this framework can increase the accuracy and efficiency with which PROs are measured. PMID- 24403096 TI - Patients' experience and perception of hospital-treated Clostridium difficile infections: a qualitative study. AB - BACKGROUND: Clostridium difficile is the leading cause of antibiotic-associated diarrhea and an important source of nosocomial infection. Clinical manifestations can range from mild diarrhea to lethal pseudomembranous colitis. Little is known about the burden of C. difficile infections (CDI) in patients. OBJECTIVE: This qualitative study explored the impact of hospital-treated CDI on patients' lives from the first occurrence of CDI symptoms, through their hospital stay, and after discharge. METHODS: Semi-structured interviews with 12 US and 12 French patients who had experienced CDI were conducted using an interview guide that was developed on the basis of a thorough literature review. Transcripts from these interviews were analyzed to identify concepts related to the research question. FINDINGS: CDI affected numerous aspects of patients' lives. Patients reported that the continuous, watery, and uncontrollable diarrhea characteristic of CDI had the most impact on their daily lives. Diarrhea prevented them from participating in usual daily activities; this caused the collapse of their social lives. Patients felt humiliated and embarrassed. Patients' emotional distress worsened once hospitalized; they reported feelings of loneliness and worry when placed in isolation. From discharge to the time of the interview, patients reported both psychological and physical improvement. However, despite continuing improvement, most patients reported persistent worry and fear of recurrent episodes, and they were thus more careful about their diet and hygiene. CONCLUSION: As one patient in this study explained, CDI is "the worst of everything that I've had." The emotional distress and extreme physical exhaustion associated with CDI result in a traumatic and frightening experience for patients. This trauma persists after recovery and includes lingering fears of a recurrent episode. PMID- 24403097 TI - Drug interactions with sunitinib. AB - PURPOSE: Sunitinib is a tyrosine kinase inhibitor indicated for the treatment of gastrointestinal stromal tumor, advanced renal cell carcinoma, and pancreatic neuroendocrine tumors. The aim of this article is to describe the pharmacological interactions between sunitinib and commonly prescribed drugs. METHOD: We reviewed available information on pharmacological interactions between sunitinib and concomitantly prescribed drugs. Drugs were grouped into different therapeutic groups according to the Anatomical Therapeutic Chemical (ATC) classification. RESULTS: Sunitinib interacts with CYP3A4 inducers or inhibitors and with P glycoprotein and ABCG2 substrates. Pharmacodynamic interactions with drugs have also been found. CONCLUSION: Current information on drug interactions between sunitinib and other drugs is scarce and most of the times it is difficult to apply to clinical practice. Even so, this difficulty in managing drug interactions should not be a reason to ignore them as they can help to explain intolerances and treatment failures. PMID- 24403098 TI - Isolated limb perfusion for in-transit melanoma metastases: melphalan or TNF melphalan perfusion? AB - Indications for treatment of melanoma in-transit metastases (ITMs) confined to the limb with isolated limb perfusion (ILP) are not well defined. This study reports the Groningen regional therapeutic perfusion experience with melphalan (M ILP) and TNF-melphalan (TM-ILP) for ITMs, and reviews of the melanoma TNF melphalan ILP literature. Between 1991 and 2012, 60 patients were treated with ILP. Patients with "small" ITMs received M-ILP (10-13 mg melphalan/L limb volume) and patients with "bulky" disease TM-ILP (1-4 mg TNF); 19 M-ILPs and 41 TM-ILPs were performed, 26 Stage IIIB, 31 Stage IIIB and 1 stage IV disease. Overall response after 57 ILPs was 90%; CR 27 (45%), PR 27 (45%), no response 3 (5%); after 9 M-ILPs CR 6 (32%) and 41 TM-ILPs CR 21 (51%, P = 0.124). For younger patients (<65 years) CR was 69% and for elderly patients 29% (P = 0.003). For low volume disease (<5 ITMs) CR was 75% and for high volume disease (>=5 ITMs) 41% (P = 0.038). After median follow-up of 15 months (range, 1-144) there was local recurrence or disease progression in 36 patients (60%). Positive lymph node status was associated with local progression, absence of CR and Stage IIIC disease; these were independent prognostic factors for progression to systemic disease. M-ILP is an effective regional treatment for melanoma ITMs, whereas for bulky disease TM-ILP should be the first choice. In-field progression-free survival after ILP is determined by the biological behavior of the ITMs and the patient's immune system. PMID- 24403099 TI - Glottic regeneration with a tissue-engineering technique, using acellular extracellular matrix scaffold in a canine model. AB - Acellular extracellular matrix scaffold derived from porcine urinary bladder (UBM) is decellularized material that has shown success for constructive remodelling of various tissues and organs. The regenerative effects of UBM were reported for the tympanic membrane, oesophagus, trachea, larynx, pleura and pericardium in animal studies, with promising results. The aim of this study was to investigate the regenerative effects of UBM on hemilarynx, using a canine model. A left partial hemilaryngectomy was performed and the surgical defects were reconstructed by insertion of UBM scaffold. Although local infection was observed in one dog in 1 week after implantation of the scaffold, all dogs showed good re-epithelialization with minimum complication in 1 month. The effect of regeneration of the larynx was evaluated 6 months after the operation. The excised larynx experiments were performed to measure phonation threshold pressure (PTP), normalized mucosal wave amplitude (NMWA) and normalized glottal gap (NGG). The results of the measurements showed that PTP was normal or near normal in two cases and NMWA was within normal range in three cases, although there were individual variations. Histological examination was completed to evaluate structural changes in the scaffold with the appearance of the new cartilaginous structure. However, the regenerated vocal fold mucosa was mostly scarred. The UBM scaffold has shown to be biocompatible, biodegradable and useful for tissue regeneration of the hemilarynx, with possible restoration of function of the vocal fold. The vocal fold mucosa was scarred, which is the next challenge to be addressed. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 24403100 TI - Long-term clinical experience with Amplatzer Ductal Occluder II for closure of the persistent arterial duct in children. AB - OBJECTIVES: To describe the long-term clinical experience and follow-up with the Amplatzer Ductal Occluder II (ADO II) in children. METHODS: All patients undergoing attempted transcatheter closure of patent arterial duct (PDA) with the ADO II were included. Data collected included demographic, clinical, and echocardiographic parameters. RESULTS: From March 2008 until March 2013, 62 patients with a median age of 1.2 years (range 0.43-11.1 years) and median weight of 9 kg (range 4.7-31.4 kg) underwent the procedure. The median measurement for minimal ductal diameter was 2.7 mm (range 1.3-5 mm). An ADO II was implanted in 60 patients (96.8%). Two patients had significant residual shunting following deployment of the ADO II and underwent closure with the Amplatzer ductal occluder I (ADO I) during the same procedure. In six patients, the initial ADO II was unsatisfactory, and after recapture a different size ADO II was deployed. Device embolization of the ADO II to the pulmonary artery occurred in 6.7% of patients. Of these, one underwent surgical closure and three were closed with an ADO I. Complete occlusion on echocardiography was noted prior to discharge in 87.5% of the deployed occluders and 100% at first follow-up. Five year follow-up (n = 25) revealed a 100% occlusion rate. There were three cases of persistent mild left pulmonary artery stenosis at long-term follow-up. CONCLUSIONS: The ADO II is effective for occlusion of PDA with variable anatomy from either arterial or venous approaches with a low profile delivery system. Stable occluder position is highly dependent on accurate device sizing, good quality imaging to visualize device configuration after deployment and operator experience. PMID- 24403101 TI - Annual meeting of CESAR in Tuebingen, Germany June 27-29, 2013. PMID- 24403102 TI - Survival with good neurological outcome in a patient with prolonged ischemic cardiac arrest--utility of automated chest compression systems in the cardiac catheterization laboratory. AB - The management of refractory cardiac arrest during invasive coronary procedures has substantial logistical challenges and is typically associated with disappointing outcomes. We describe the case of a young woman with recalcitrant ventricular fibrillation due to acute anterior ST-elevation myocardial infarction caused by occlusion of her proximal left anterior descending artery. Survival without neurological deficit or organ failure was achieved following primary percutaneous reperfusion and a total of 52 min of intra-procedural chest compression support, made possible by the use of an automated chest compression device. PMID- 24403103 TI - Covalent inhibition of the lymphoid tyrosine phosphatase. AB - Covalent inhibitors of lymphoid tyrosine phosphatase (LYP) were identified from a screen of the NIH Molecular Libraries Small Molecules Repository (MLSMR). Both of the two lead compounds identified have phosphotyrosine-mimetic benzoic acid moieties as well as electrophilic acrylonitrile groups. Inhibition kinetics of both compounds are consistent with covalent modification of the enzyme, with nanomolar KI and reciprocal millisecond kinact values, representing the best efficiency ratios (kinact /KI ) among currently reported covalent LYP inhibitors. Covalent inhibitors can provide longer efficacy and better selectivity than more conventional noncovalent inhibitors, and these lead compounds are an important step toward the development of protein tyrosine phosphatase (PTP)-targeted covalent therapeutic compounds. PMID- 24403104 TI - Anaplastic lymphoma kinase gene rearrangements in patients with advanced-stage non-small-cell lung cancer: CT characteristics and response to chemotherapy. AB - Few articles have been published on the imaging findings of anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC). To investigate the radiological findings of ALK-positive NSCLC in the advanced stage, CT scans were examined. In addition, the response to chemotherapy was evaluated. Of the 36 patients with ALK-rearranged NSCLC, a mass and a nodule were identified in 17 (47.2%) and 16 (44.4%), respectively, indicating that more than 40% had a small sized tumor. Overall, 31 (86.1%) patients had lymphadenopathy, seven (19.4%) had extranodal lymph node invasion, and three (8.3%) had lymphangitis. A pleural effusion was seen in 15 patients (41.7%). All but one patient had no ground-glass opacity (GGO) lesions, indicating that most ALK-positive tumors showed a solid growth pattern without GGO on CT. Twenty were evaluable for response to chemotherapy; 10 (50.0%) had a partial response (PR), nine (45.0%) had stable disease (SD), and one (5.0%) had progressive disease (PD) with first-line chemotherapy. With second-line chemotherapy, five (26.3%) had PR, 11 (57.9%) had SD, and three (15.8%) had PD. The five patients with PR were all treated by using crizotinib. Time to progression was 8.2 months with first-line chemotherapy, and 6.0 months with second-line chemotherapy. Advanced-stage ALK-positive tumors have a relatively aggressive phenotype, which cannot be inferred from the size of the tumor alone. ALK-positive patients have a good response to first-line cytotoxic drugs and to crizotinib as second-line therapy, but a relatively poor response to cytotoxic drugs as second-line therapy. PMID- 24403105 TI - On the use and interpretation of quantile regression in quality-of-life research. PMID- 24403106 TI - A tetravalent cerium complex containing a Ce=O bond. AB - Whereas terminal oxo complexes of transition and actinide elements are well documented, analogous lanthanide complexes have not been reported to date. Herein, we report the synthesis and structure of a cerium(IV) oxo complex, [Ce?O(LOEt )2 (H2 O)]?MeC(O)NH2 (1; LOEt (-) =[Co(eta(5) -C5 H5 ){P(O)(OEt)2 }3 ](-) ), featuring a short Ce?O bond (1.857(3) A). DFT calculations indicate that the hydrogen bond to cocrystallized acetamide plays a key role in stabilizing the Ce?O moiety of 1 in the solid state. Complex 1 exhibits oxidizing and nucleophilic reactivity. PMID- 24403107 TI - Phosphine-catalyzed [3+2] cycloaddition reactions of azomethine imines with electron-deficient alkenes: a facile access to dinitrogen-fused heterocycles. AB - An efficient method for the phosphine-catalyzed [3+2] cycloaddition reaction of azomethine imines with diphenylsulfonyl alkenes to give dinitrogen-fused bi- or tricyclic heterocyclic compounds in high yields has been described. Moreover, two phenylsulfonyl groups installed on the heterocyclic products could be conveniently removed or transformed to other functional groups, making the reaction more useful. PMID- 24403109 TI - Multifaceted roles of Furry proteins in invertebrates and vertebrates. AB - Furry (Fry) is a large protein that is evolutionarily conserved from yeast to human. Fry and its orthologues in invertebrates (termed Tao3p in budding yeast, Mor2p in fission yeast, Sax-2 in nematode and Fry in fruit fly) genetically and physically interact with nuclear Dbf2-related (NDR) kinases (termed Cbk1p in budding yeast, Orb6p in fission yeast, Sax-1 in nematode and Trc in fruitfly), and function as activators or scaffolds of these kinases. Fry-NDR kinase signals are implicated in the control of polarized cell growth and morphogenesis in yeast, neurite outgrowth in nematode, and epidermal morphogenesis and dendritic tiling in fruit fly. Recent studies revealed that mammalian Fry is a microtubule associated protein that is involved in the control of chromosome alignment, spindle organization and Polo-like kinase-1 activation in mitosis, and promotes microtubule acetylation in mitotic spindles via inhibiting the tubulin deacetylase Sirtuin 2. Here, we review current knowledge about the diverse cellular functions and regulation of Fry proteins in invertebrates and vertebrates. PMID- 24403110 TI - Choice with frequently changing food rates and food ratios. AB - In studies of operant choice, when one schedule of a concurrent pair is varied while the other is held constant, the constancy of the constant schedule may exert discriminative control over performance. In our earlier experiments, schedules varied reciprocally across components within sessions, so that while food ratio varied food rate remained constant. In the present experiment, we held one variable-interval (VI) schedule constant while varying the concurrent VI schedule within sessions. We studied five conditions, each with a different constant left VI schedule. On the right key, seven different VI schedules were presented in seven different unsignaled components. We analyzed performances at several different time scales. At the longest time scale, across conditions, behavior ratios varied with food ratios as would be expected from the generalized matching law. At shorter time scales, effects due to holding the left VI constant became more and more apparent, the shorter the time scale. In choice relations across components, preference for the left key leveled off as the right key became leaner. Interfood choice approximated strict matching for the varied right key, whereas interfood choice hardly varied at all for the constant left key. At the shortest time scale, visit patterns differed for the left and right keys. Much evidence indicated the development of a fix-and-sample pattern. In sum, the procedural difference made a large difference to performance, except for choice at the longest time scale and the fix-and-sample pattern at the shortest time scale. PMID- 24403114 TI - Critical factors to achieve low voltage- and capacitance-based organic field effect transistors. AB - Hydrophobic organo-compatible but low-capacitance dielectrics (10.5 nFcm(-2) ), polystyrene-grafted SiO2 could induce surface-mediated large crystal grains of face-to-face stacked triethylsilylethynyl anthradithiophene (TES-ADT), producing more efficient charge-carrier transport, in comparison to MUm-sized pentacene crystals containing a face-to-edge packing. Low-voltage operating TES-ADT OFETs showed good device performance (MUFET ~ 1.3 cm(2) V(-1) s(-1) , Vth ~ 0.5 V, SS ~ 0.2 V), as well as excellent device reliability. PMID- 24403116 TI - Phase stability and defect physics of a ternary ZnSnN(2) semiconductor: first principles insights. AB - First-principles calculations show that ZnSnN2 has a very small formation enthalpy, and the donor defects such as SnZn antisites and ON impurities have high concentration, making the material degenerately n-type, which explains the observed high electron concentration. ZnSnN2 can be regarded as a new material that combines a metal-like conductivity with an optical bandgap around 2 eV. PMID- 24403117 TI - Thiophene-thiazolothiazole copolymers: significant impact of side chain composition on backbone orientation and solar cell performances. AB - The backbone orientation in the thiophene-thiazolothiazole (TzTz) copolymer system can be altered by tuning of the alky side chain composition. We highlight that the orientation significantly impact their solar cell efficiency in particular when using thicker active layers. PMID- 24403120 TI - Cost-effectiveness of percutaneous coronary intervention with drug-eluting stents in patients with multivessel coronary artery disease compared to coronary artery bypass surgery five-years after intervention. AB - OBJECTIVES: Cost-effectiveness of percutaneous coronary intervention (PCI) using drug-eluting stents (DES), and coronary artery bypass surgery (CABG) was analyzed in patients with multivessel coronary artery disease over a 5-year follow-up. BACKGROUND: DES implantation reducing revascularization rate and associated costs might be attractive for health economics as compared to CABG. METHODS: Consecutive patients with multivessel DES-PCI (n = 114, 3.3 +/- 1.2 DES/patient) or CABG (n = 85, 2.7 +/- 0.9 grafts/patient) were included prospectively. Primary endpoint was cost-benefit of multivessel DES-PCI over CABG, and the incremental cost-effectiveness ratio (ICER) was calculated. Secondary endpoint was the incidence of major adverse cardiac and cerebrovascular events (MACCE), including acute myocardial infarction (AMI), all-cause death, revascularization, and stroke. RESULTS: Despite multiple uses for DES, in-hospital costs were significantly less for PCI than CABG, with 4551 ?/patient difference between the groups. At 5-years, the overall costs remained higher for CABG patients (mean difference 5400 ? between groups). Cost-effectiveness planes including all patients or subgroups of elderly patients, diabetic patients, or Syntax score >32 indicated that CABG is a more effective, more costly treatment mode for multivessel disease. At the 5-year follow-up, a higher incidence of MACCE (37.7% vs. 25.8%; log rank P = 0.048) and a trend towards more AMI/death/stroke (25.4% vs. 21.2%, log rank P = 0.359) was observed in PCI as compared to CABG. ICER indicated 45615 ? or 126683 ? to prevent one MACCE or AMI/death/stroke if CABG is performed. CONCLUSIONS: Cost-effectiveness analysis of DES-PCI vs. CABG demonstrated that CABG is the most effective, but most costly, treatment for preventing MACCE in patients with multivessel disease. PMID- 24403121 TI - Design, synthesis, and biological activity of NCC149 derivatives as histone deacetylase 8-selective inhibitors. AB - We recently discovered N-hydroxy-3-[1-(phenylthio)methyl-1H-1,2,3-triazol-4 yl]benzamide (NCC149) as a potent and selective histone deacetylase 8 (HDAC8) inhibitor from a 151-member triazole compound library using a click chemistry approach. In this work, we present a series of NCC149 derivatives bearing various aromatic linkers that were designed and synthesized as HDAC8-selective inhibitors. A series of in vitro assays were used to evaluate the newly synthesized compounds, four of which showed HDAC8 inhibitory activity similar to that of NCC149, and one of which displayed HDAC8 selectivity superior to that of NCC149. In addition, these top four compounds induced the increase of acetylated cohesin (an HDAC8 substrate) in HeLa cells in a dose-dependent manner, indicating inhibition of HDAC8 in the cells. While none of these compounds enhanced the acetylation of H3K9 (a substrate of HDAC1 and 2), only one compound refrained from increasing alpha-tubulin acetylation, a substrate of HDAC6, indicating that this compound is more selective for HDAC8 than the other derivatives. Furthermore, this HDAC8-selective inhibitor suppressed the growth of T-cell lymphoma cells more potently than did NCC149. These findings are useful for the further development of HDAC8-selective inhibitors. PMID- 24403122 TI - Validation and incremental value of the hybrid algorithm for CTO PCI. AB - OBJECTIVES: To evaluate the outcomes and benefits of using the hybrid algorithm for chronic total occlusion (CTO) percutaneous coronary intervention (PCI). BACKGROUND: The hybrid algorithm harmonizes antegrade and retrograde techniques for performing CTO PCI. It has the potential to increase success rates and improve efficiency for CTO PCI. No previous data have analyzed the impact of this algorithm on CTO PCI success rates and procedural efficiency. METHODS: Retrospective analysis of contemporary CTO PCI performed at two high-volume centers with adoption of the hybrid technique was compared to previously published CTO outcomes in a well matched group of patients and lesion subsets. RESULTS: After adoption of the hybrid algorithm, technical success was significantly higher in the post hybrid algorithm group 189/198 (95.4%) vs the pre-algorithm group 367/462 (79.4%) (P < 0.001). Procedural success in the post hybrid algorithm group 175/198 (88.3%) when compared to the pre-algorithm group 360/462 (77.9%) (P < 0.001) was also significantly improved. Failure rates were significantly lower. Efficiency parameters including procedure time, contrast volume, fluoroscopy time, and radiation doses all favored the post hybrid group but did not reach statistical significance. CONCLUSIONS: The validation of the hybrid algorithm has the potential to disseminate adoption of CTO PCI. PMID- 24403123 TI - Identification of novel candidate compounds targeting TrkB to induce apoptosis in neuroblastoma. AB - Neuroblastoma (NB) is one of the most frequent solid tumors in children and its prognosis is still poor. The neurotrophin receptor TrkB and its ligand brain derived neurotrophic factor (BDNF) are expressed at high levels in high-risk NBs and are involved in defining the poor prognosis of the patients. However, the TrkB targeting therapy has never been realized in the clinic. We performed an in silico screening procedure utilizing an AutoDock/grid computing technology in order to identify novel small chemical compounds targeting the BDNF-binding domain of TrkB. For the first screening, a library of three million synthetic compounds was screened in silico and was ranked according to the Docking energy. The top-ranked 37 compounds were further functionally screened for cytotoxicity by using NB cell lines. We have finally identified seven compounds that kill NB cells with the IC50 values of 0.07-4.6 MUmol/L. The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay showed that these molecules induce apoptosis accompanied by p53 activation in NB cell lines. The candidate compounds and BDNF demonstrated an antagonistic effect on cell growth, invasion, and colony formation, possibly suggesting competition at the BDNF-binding site of TrkB. The candidate compounds had tumor-suppressive activity in xenograft and in vivo toxicity tests (oral and intravenous administrations) using mice, and did not show any abnormal signs. Using in silico Docking screening we have found new candidate TrkB inhibitors against high-risk NBs, which could lead to new anti cancer drugs. PMID- 24403124 TI - Production, characterization, and identification using proteomic tools of a polygalacturonase from Fusarium graminearum. AB - Since enzymatic degradation is a mechanism or component of the aggressiveness of a pathogen, enzymatic activities from a Fusarium graminearum isolate obtained from infected wheat spikes of Argentina Pampa region were studied in order to understand the disease progression, tending to help disease control. In particular, the significance of the study of polygalacturonase activity is based on that such activity is produced in the early stages of infection on the host, suggesting a crucial role in the establishment of disease. In this sense, polygalacturonase activity produced by this microorganism has been purified 375 times from 2-day-old culture filtrates by gel filtration and ion-exchange chromatography successively. The purified sample showed two protein bands in sodium dodecyl sulfate-polyacrylamide gels, with a molecular mass of 40 and 55 kDa. The protein bands were identified as an endopolygalacturonase and as a serine carboxypeptidase of F. graminearum, respectively, by peptide mass fingerprinting (matrix-assisted laser desorption/ionization time-of-flight (MALDI TOF/TOF) fragment ion analysis). The pattern of substrate degradation analyzed by thin layer chromatography confirmed the mode of action of the enzyme as an endopolygalacturonase. High activity of the polygalacturonase against polygalacturonic acid was observed between 4 and 6 of pH, and between 30 and 50 degrees C, being 5 and 50 degrees C the optimum pH and temperature, respectively. The enzyme was fully stable at pH 5 for 120 min and 30 degrees C and sensible to the presence of some metal ions. This information would contribute to understand the most favorable environmental conditions for establishment of the disease. PMID- 24403126 TI - Formation, expansion, and interconversion of metallarings in a sulfur-bridged Au(I) Co(III) coordination system. AB - A novel Au(I) Co(III) coordination system that is derived from the newly prepared [Co(D-nmp)2 ](-) (1(-) ; D-nmp=N-methyl-D-penicillaminate) and a gold(I) precursor Au(I) is reported. Complex 1(-) acts as a sulfur-donating metallaligand and reacts with the gold(I) precursor to give [Au2 Co2 (D-nmp)4 ] (2), which has an eight-membered Au(I) 2 Co(III) 2 metallaring. Treatment of 2 with [Au2 (dppe)2 ](2+) (dppe=1,2-bis(diphenylphosphino)ethane) leads to the formation of [Au4 Co2 (dppe)2 (D-nmp)4 ](2+) (3(2+) ), which consists of an 18-membered Au(I) 4 Co(III) 2 metallaring that accommodates a tetrahedral anion (BF4 (-) , ClO4 (-) , ReO4 ( ) ). In solution, the metallaring structure of 3(2+) is readily interconvertible with the nine-membered Au(I) 2 Co(III) metallaring structure of [Au2 Co(dppe)(D nmp)2 ](+) (4(+) ); this process depends on external factors, such as solvent, concentration, and nature of the counteranion. These results reveal the lability of the Au?S and Au?P bonds, which is essential for metallaring expansion and contraction. PMID- 24403128 TI - Porous M(II)/pyrimidine-4,6-dicarboxylato neutral frameworks: synthetic influence on the adsorption capacity and evaluation of CO2-adsorbent interactions. AB - The understanding of the factors that affect the real pore-network structure for a given bulk material due to different synthetic procedures is essential to develop the material with the best adsorption properties. In this work, we have deeply studied the influence of the crystallinity degree over the adsorption capacity on three new isostructural MOFs with the formula {[CdM(MU4 pmdc)2(H2O)2]?solv}n (in which, pmdc = pyrimidine-4,6-dicarboxylate; solv = corresponding solvent; M(II) = Cd (1), Mn (2), Zn (3)). Compared with other methods, the solvent-free synthesis stands as the most effective route because, apart from enabling the preparation of the heterometallic compounds 2 and 3, it also renders the adsorbents with the highest performance, which is indeed close to the expected one derived from Grand Canonical Monte Carlo (GCMC) calculations. The structural analysis of the as-synthesised and evacuated frameworks reveals the existence of a metal atom exposed to the pore. The accessibility of this site is limited due to its atomic environment, which is why it is considered as a pseudo-open-metal site. The chemical and physical characterisation confirms that this site can be modified as the metal atom is replaced in compounds 2 and 3. To assess the effect of the metal replacement on the adsorption behaviour, an exhaustive study of CO2 experimental isotherms has been performed. The affinity of the pseudo-open metal sites towards CO2 and the distribution of the preferred adsorption sites are discussed on the basis of DFT and GCMC calculations. PMID- 24403129 TI - Study of different reaction schemes for the enzymatic synthesis of polyglycerol polyricinoleate. AB - BACKGROUND: Different strategies for the solvent-free enzymatic production of polyglycerol polyricinoleate (PGPR) were explored in an attempt to simplify and improve the process. Besides the conventional procedure (obtaining polyricinoleic acid, followed by its esterification with polyglycerol), two alternative methods are proposed: (1) reversing the synthesis order, i.e. esterification of polyglycerol with ricinoleic acid and then the condensation of ricinoleic acid with the previously obtained polyglycerol ester; and (2) the enzymatic synthesis of PGPR in a single-step process. RESULTS: The reaction sequences were carried out in an open-air reactor with free and immobilised lipases (triacylglycerol acylhydrolases, E.C. 3.1.1.3): Candida rugosa lipase to obtain polyricinoleic acid and Rhizopus oryzae lipase for the esterification of polyglycerol with the carboxyl group of ricinoleic or polyricinoleic acid. A co-immobilised derivative containing both lipases was used to catalyse the single-stage scheme. The three processes were carried out in a vacuum reactor, obtaining in every case PGPR that complied with the legal specifications of the European Community and recommendations provided in the Food Chemical Codex. CONCLUSION: The results demonstrate that all three protocols are viable for the enzymatic synthesis of PGPR and require similar reaction times. The single-stage scheme is easier to carry out. PMID- 24403125 TI - Assessment, management and knowledge of sport-related concussion: systematic review. AB - BACKGROUND: Sport-related concussions are a subset of mild traumatic brain injuries and are a concern for many sporting activities worldwide. OBJECTIVE: To review and update the literature in regard to the history, pathophysiology, recognition, assessment, management and knowledge of concussion. METHODS: Searches of electronic literature databases were performed to identify studies published up until April 2013. RESULTS: 292 publications focussing on concussion met the inclusion criteria, and so they were quality rated and reviewed. CONCLUSION: Concussion is hard to recognize and diagnose. Initial sideline assessment via the Sports Concussion Assessment Tool 3 (SCAT3), Child-SCAT3 or King-Devick test should be undertaken to identify athletes with concussion as part of a continuum of assessment modalities and athlete management. Sports medicine practitioners should be cognisant of the definition, extent and nature of concussion, and should work with coaches, athletes and trainers to identify and manage concussions. The most common reason for variations in management of concussion is lack of awareness of-and confusion about-the many available published guidelines for concussion. Future research should focus on better systems and tools for recognition, assessment and management of concussion. Sport participants' knowledge of concussion should be evaluated more rigorously, with interventions for sports where there is little knowledge of recognition, assessment and appropriate management of concussion. PMID- 24403131 TI - Bovine serum albumin-confined silver nanoclusters as fluorometric probe for detection of biothiols. AB - Fluorescent bovine serum albumin-confined silver nanoclusters (BSA-AgNCs) were demonstrated to be a novel and environmentally friendly probe for the rapid detection of biothiols such as cysteine (Cys), homocysteine (Hcy) and glutathione (GSH). The sensing was ascribed to the strong affinity between the mercapto group of the biothiols and the silver nanoclusters. The fluorescence intensity of BSA AgNCs was quenched efficiently on increasing the concentration of biothiol, corresponding with a red-shift in emission wavelength. However, the fluorescence of the silver nanoclusters was almost unchanged in the presence of other alpha amino acids at 10-fold higher concentrations. By virtue of this specific response, a new, simple and rapid fluorescent method for detecting biothiols has been developed. The linear ranges for Cys, Hcy and GSH were 2.0 * 10(-6) to 9.0 * 10(-5) M (R(2) = 0.994), 2.0 * 10(-6) to 1.2 * 10(-4) M (R(2) = 0.996) and 1.0 * 10(-5) to 8.0 * 10(-5) M (R(2) = 0.980), respectively. The detection limits were 8.1 * 10(-7) M for Cys, 1.0 * 10(-6) M for Hcy and 1.1 * 10(-6) M for GSH. Our proposed method was successfully applied to the determination of thiols in human plasma and the recovery was 94.83-105.24%. It is potentially applicable to protein-stabilized silver nanoclusters in a chemical or biochemical sensing system. PMID- 24403130 TI - Does the type of first-line regimens influence the receipt of second-line chemotherapy treatment? An analysis of 3211 metastatic colon cancer patients. AB - With new agents entering the market, the sequencing of first-line (Tx1), second line (Tx2), and subsequent chemotherapy/biologics regimens are being examined. We examined how Tx1 regimens impacted the likelihood of receiving Tx2 among metastatic colon cancer (mCC) patients. Surveillance, Epidemiology and End Results (SEER)-Medicare data were used to identify elderly mCC patients between 2003 and 2007. The inverse probability weighting Cox regression method was utilized to study the relationship between receipt of Tx2 and Tx1 regimens, controlling for patient-level factors. Of the 7895 elderly patients identified, 3211 (41%) received Tx1 of which 1440 proceeded to Tx2. The impact of Tx1 on receipt of Tx2 varied by the specific regimens utilized. As compared to 5FU/LV users, IROX (Hazard Ratio [HR] = 0.03; P < 0.01) and IROX + Biologics (HR = 0.20; P < 0.01) users were less likely to receive Tx2; (oxaliplatin) OX + Biologics (HR = 1.26; P < 0.01) users were more likely to receive Tx2. Significant patient level factors included: Hispanic ethnicity (HR = 0.67; P < 0.01); being married (HR = 0.87; P = 0.01); proxy for poor performance status (HR = 0.82; P = 0.05); each 10-year age increment (HR = 1.14; P < 0.01); and State buy-in status (HR = 1.21; P = 0.01). The specific first-line regimen does impact mCC patients' likelihood of receiving Tx2 in clinical practice. Elderly mCC patients, their health care providers, and policy makers will benefit from new evidence about the impact of sequencing of treatment lines. PMID- 24403132 TI - Unmet supportive care needs and characteristics of family caregivers of patients with oral cancer after surgery. AB - OBJECTIVE: The aim of this study was to identify factors associated with unmet supportive care needs in family caregivers of patients with oral cancer after surgery. METHODS: In a cross-sectional study, we recruited patient-family caregiver dyads from the otolaryngology head and neck surgery wards of a medical center in northern Taiwan. Patients were assessed using a set of structured questionnaires to measure symptom distress, sleep quality, and depression. Social support and supportive care needs of family caregivers were measured. RESULTS: Of the 102 dyads surveyed, needs for supportive care in information domain and healthcare professional/healthcare services domain were highest. Patients with more severe symptoms and family caregivers who received less social support from family were associated with greater overall unmet supportive care needs. CONCLUSIONS: Family caregivers report the need for more information and healthcare services after a family member has had oral surgery. Caregiving training programs should be developed for caregivers on the basis of meeting reported needs. PMID- 24403133 TI - Gum arabic capped-silver nanoparticles inhibit biofilm formation by multi-drug resistant strains of Pseudomonas aeruginosa. AB - Clinical isolates (n = 55) of Pseudomonas aeruginosa were screened for the extended spectrum beta-lactamases and metallo-beta-lactamases activities and biofilm forming capability. The aim of the study was to demonstrate the antibiofilm efficacy of gum arabic capped-silver nanoparticles (GA-AgNPs) against the multi-drug resistant (MDR) biofilm forming P. aeruginosa. The GA-AgNPs were characterized by UV-spectroscopy, X-ray diffraction, and high resolution transmission electron microscopy analysis. The isolates were screened for their biofilm forming ability, using the Congo red agar, tube method and tissue culture plate assays. The biofilm forming ability was further validated and its inhibition by GA-AgNPs was demonstrated by performing the scanning electron microscopy (SEM) and confocal laser scanning microscopy. SEM analysis of GA-AgNPs treated bacteria revealed severely deformed and damaged cells. Double fluorescent staining with propidium iodide and concanavalin A-fluorescein isothiocyanate concurrently detected the bacterial cells and exopolysaccharides (EPS) matrix. The CLSM results exhibited the GA-AgNPs concentration dependent inhibition of bacterial growth and EPS matrix of the biofilm colonizers on the surface of plastic catheters. Treatment of catheters with GA-AgNPs at 50 ug ml(-1) has resulted in 95% inhibition of bacterial colonization. This study elucidated the significance of GA-AgNPs, as the next generation antimicrobials, in protection against the biofilm mediated infections caused by MDR P. aeruginosa. It is suggested that application of GA-AgNPs, as a surface coating material for dispensing antibacterial attributes to surgical implants and implements, could be a viable approach for controlling MDR pathogens after adequate validations in clinical settings. PMID- 24403134 TI - Odorless trigeminal stimulus CO2 triggers response in the olfactory cortex. PMID- 24403135 TI - Does illusory flickering result from rhythmic sampling of visual stimuli? PMID- 24403136 TI - SIP30 is required for neuropathic pain-evoked aversion in rats. AB - SIP30 (SNAP25 interacting protein of 30) is a SNAP25 interaction protein of 30 kDa that functions in neurotransmitter release. Using a chronic constriction injury (CCI) model of neuropathic pain, we profiled gene expression in the rat spinal cord and brain and identified sip30, which was upregulated after CCI. Here, we show that CCI induced a bilateral increase of SIP30 in the rostral anterior cingulate cortex (rACC), a key brain region that has been implicated in pain affect. We put rats in a chamber with one half painted white (light area) and the other half painted black (dark area), and measured neuropathic pain evoked place escape/avoidance paradigm (PEAP) to quantify the level of negative emotion evoked by painful stimuli using a Von Frey hair. Inhibition of CCI mediated induction of SIP30 by intra-rACC injection of shRNA targeting the rat sip30 gene reduced PEAP. Interestingly, knockdown of SIP30 did not affect CCI induced evoked pain such as heat hyperalgesia and mechanical allodynia. Neither did it affect general learning and memory. CCI-induced upregulation of SIP30 was correlated with activation of ERK, PKA, and CREB in the rACC. Intra-rACC administration of PKA or ERK inhibitors suppressed CCI-induced SIP30 upregulation and blocked the induction of PEAP. Additionally, knockdown of SIP30 suppressed the frequency of mEPSCs and increased paired-pulse ratios in rACC slices and decreased extracellular glutamate concentrations. Together, our results highlight SIP30 as a target of PKA and ERK in the rACC to mediate neuropathic pain-evoked negative emotion via modulation of glutamate release and excitatory synaptic transmission. PMID- 24403137 TI - Infra-slow EEG fluctuations are correlated with resting-state network dynamics in fMRI. AB - Ongoing neuronal activity in the CNS waxes and wanes continuously across widespread spatial and temporal scales. In the human brain, these spontaneous fluctuations are salient in blood oxygenation level-dependent (BOLD) signals and correlated within specific brain systems or "intrinsic-connectivity networks." In electrophysiological recordings, both the amplitude dynamics of fast (1-100 Hz) oscillations and the scalp potentials per se exhibit fluctuations in the same infra-slow (0.01-0.1 Hz) frequency range where the BOLD fluctuations are conspicuous. While several lines of evidence show that the BOLD fluctuations are correlated with fast-amplitude dynamics, it has remained unclear whether the infra-slow scalp potential fluctuations in full-band electroencephalography (fbEEG) are related to the resting-state BOLD signals. We used concurrent fbEEG and functional magnetic resonance imaging (fMRI) recordings to address the relationship of infra-slow fluctuations (ISFs) in scalp potentials and BOLD signals. We show here that independent components of fbEEG recordings are selectively correlated with subsets of cortical BOLD signals in specific task positive and task-negative, fMRI-defined resting-state networks. This brain system-specific association indicates that infra-slow scalp potentials are directly associated with the endogenous fluctuations in neuronal activity levels. fbEEG thus yields a noninvasive, high-temporal resolution window into the dynamics of intrinsic connectivity networks. These results support the view that the slow potentials reflect changes in cortical excitability and shed light on neuronal substrates underlying both electrophysiological and behavioral ISFs. PMID- 24403138 TI - Restraint stress alters nociceptin/orphanin FQ and CRF systems in the rat central amygdala: significance for anxiety-like behaviors. AB - Corticotropin releasing factor (CRF) is the primary mediator of stress responses, and nociceptin/orphanin FQ (N/OFQ) plays an important role in the modulation of these stress responses. Thus, in this multidisciplinary study, we explored the relationship between the N/OFQ and the CRF systems in response to stress. Using in situ hybridization (ISH), we assessed the effect of body restraint stress on the gene expression of CRF and N/OFQ-related genes in various subdivisions of the amygdala, a critical brain structure involved in the modulation of stress response and anxiety-like behaviors. We found a selective upregulation of the NOP and downregulation of the CRF1 receptor transcripts in the CeA and in the BLA after body restraint. Thus, we performed intracellular electrophysiological recordings of GABAA-mediated IPSPs in the central nucleus of the amygdala (CeA) to explore functional interactions between CRF and N/OFQ systems in this brain region. Acute application of CRF significantly increased IPSPs in the CeA, and this enhancement was blocked by N/OFQ. Importantly, in stress-restraint rats, baseline CeA GABAergic responses were elevated and N/OFQ exerted a larger inhibition of IPSPs compared with unrestraint rats. The NOP antagonist [Nphe1] nociceptin(1-13)NH2 increased the IPSP amplitudes in restraint rats but not in unrestraint rats, suggesting a functional recruitment of the N/OFQ system after acute stress. Finally, we evaluated the anxiety-like response in rats subjected to restraint stress and nonrestraint rats after N/OFQ microinjection into the CeA. Intra-CeA injections of N/OFQ significantly and selectively reduced anxiety like behavior in restraint rats in the elevated plus maze. These combined results demonstrate that acute stress increases N/OFQ systems in the CeA and that N/OFQ has antistress properties. PMID- 24403139 TI - Rab5 and Rab4 regulate axon elongation in the Xenopus visual system. AB - The elongation rate of axons is tightly regulated during development. Recycling of the plasma membrane is known to regulate axon extension; however, the specific molecules involved in recycling within the growth cone have not been fully characterized. Here, we investigated whether the small GTPases Rab4 and Rab5 involved in short-loop recycling regulate the extension of Xenopus retinal axons. We report that, in growth cones, Rab5 and Rab4 proteins localize to endosomes, which accumulate markers that are constitutively recycled. Fluorescence recovery after photo-bleaching experiments showed that Rab5 and Rab4 are recruited to endosomes in the growth cone, suggesting that they control recycling locally. Dynamic image analysis revealed that Rab4-positive carriers can bud off from Rab5 endosomes and move to the periphery of the growth cone, suggesting that both Rab5 and Rab4 contribute to recycling within the growth cone. Inhibition of Rab4 function with dominant-negative Rab4 or Rab4 morpholino and constitutive activation of Rab5 decreases the elongation of retinal axons in vitro and in vivo, but, unexpectedly, does not disrupt axon pathfinding. Thus, Rab5- and Rab4 mediated control of endosome trafficking appears to be crucial for axon growth. Collectively, our results suggest that recycling from Rab5-positive endosomes via Rab4 occurs within the growth cone and thereby supports axon elongation. PMID- 24403141 TI - Transient pupil response is modulated by contrast-based saliency. AB - The sudden appearance of a novel stimulus in the environment initiates a series of orienting responses that include coordinated shifts of gaze and attention, and also transient changes in pupil size. Although numerous studies have identified a significant effect of stimulus saliency on shifts of gaze and attention, saliency effects on pupil size are less understood. To examine salience-evoked pupil responses, we presented visual, auditory, or audiovisual stimuli while monkeys fixated a central visual spot. Transient pupil dilation was elicited after visual stimulus presentation regardless of target luminance relative to background, and auditory stimuli also evoked similar pupil responses. Importantly, the evoked pupil response was modulated by contrast-based saliency, with faster and larger pupil responses following the presentation of more salient stimuli. The initial transient component of pupil dilation was qualitatively similar to that evoked by weak microstimulation of the midbrain superior colliculus. The pupil responses elicited by audiovisual stimuli were well predicted by a linear summation of each modality response. Together, the results suggest that the transient pupil response, as one component of orienting, is modulated by contrast-based saliency, and the superior colliculus is likely involved in its coordination. PMID- 24403140 TI - Rem2 is an activity-dependent negative regulator of dendritic complexity in vivo. AB - A key feature of the CNS is structural plasticity, the ability of neurons to alter their morphology and connectivity in response to sensory experience and other changes in the environment. How this structural plasticity is achieved at the molecular level is not well understood. We provide evidence that changes in sensory experience simultaneously trigger multiple signaling pathways that either promote or restrict growth of the dendritic arbor; structural plasticity is achieved through a balance of these opposing signals. Specifically, we have uncovered a novel, activity-dependent signaling pathway that restricts dendritic arborization. We demonstrate that the GTPase Rem2 is regulated at the transcriptional level by calcium influx through L-VGCCs and inhibits dendritic arborization in cultured rat cortical neurons and in the Xenopus laevis tadpole visual system. Thus, our results demonstrate that changes in neuronal activity initiate competing signaling pathways that positively and negatively regulate the growth of the dendritic arbor. It is the balance of these opposing signals that leads to proper dendritic morphology. PMID- 24403143 TI - alpha2delta3 is essential for normal structure and function of auditory nerve synapses and is a novel candidate for auditory processing disorders. AB - The auxiliary subunit alpha2delta3 modulates the expression and function of voltage-gated calcium channels. Here we show that alpha2delta3 mRNA is expressed in spiral ganglion neurons and auditory brainstem nuclei and that the protein is required for normal acoustic responses. Genetic deletion of alpha2delta3 led to impaired auditory processing, with reduced acoustic startle and distorted auditory brainstem responses. alpha2delta3(-/-) mice learned to discriminate pure tones, but they failed to discriminate temporally structured amplitude-modulated tones. Light and electron microscopy analyses revealed reduced levels of presynaptic Ca(2+) channels and smaller auditory nerve fiber terminals contacting cochlear nucleus bushy cells. Juxtacellular in vivo recordings of sound-evoked activity in alpha2delta3(-/-) mice demonstrated impaired transmission at these synapses. Together, our results identify a novel role for the alpha2delta3 auxiliary subunit in the structure and function of specific synapses in the mammalian auditory pathway and in auditory processing disorders. PMID- 24403142 TI - Mutant LRRK2 toxicity in neurons depends on LRRK2 levels and synuclein but not kinase activity or inclusion bodies. AB - By combining experimental neuron models and mathematical tools, we developed a "systems" approach to deconvolve cellular mechanisms of neurodegeneration underlying the most common known cause of Parkinson's disease (PD), mutations in leucine-rich repeat kinase 2 (LRRK2). Neurons ectopically expressing mutant LRRK2 formed inclusion bodies (IBs), retracted neurites, accumulated synuclein, and died prematurely, recapitulating key features of PD. Degeneration was predicted from the levels of diffuse mutant LRRK2 that each neuron contained, but IB formation was neither necessary nor sufficient for death. Genetic or pharmacological blockade of its kinase activity destabilized LRRK2 and lowered its levels enough to account for the moderate reduction in LRRK2 toxicity that ensued. By contrast, targeting synuclein, including neurons made from PD patient derived induced pluripotent cells, dramatically reduced LRRK2-dependent neurodegeneration and LRRK2 levels. These findings suggest that LRRK2 levels are more important than kinase activity per se in predicting toxicity and implicate synuclein as a major mediator of LRRK2-induced neurodegeneration. PMID- 24403144 TI - The developmental switch in GABA polarity is delayed in fragile X mice. AB - Delays in synaptic and neuronal development in the cortex are key hallmarks of fragile X syndrome, a prevalent neurodevelopmental disorder that causes intellectual disability and sensory deficits and is the most common known cause of autism. Previous studies have demonstrated that the normal progression of plasticity and synaptic refinement during the critical period is altered in the cortex of fragile X mice. Although the disruptions in excitatory synapses are well documented in fragile X, there is less known about inhibitory neurotransmission during the critical period. GABAergic transmission plays a crucial trophic role in cortical development through its early depolarizing action. At the end of cortical critical period, response properties of GABA transform into their mature hyperpolarizing type due to developmental changes in intracellular chloride homeostasis. We found that the timing of the switch from depolarizing to hyperpolarizing GABA is delayed in the cortex of fragile X mice and there is a concurrent alteration in the expression of the neuronal chloride cotransporter NKCC1 that promotes the accumulation of intracellular chloride. Disruption of the trophic effects of GABA during cortical development could contribute to the altered trajectory of synaptic maturation in fragile X syndrome. PMID- 24403145 TI - The control of global brain dynamics: opposing actions of frontoparietal control and default mode networks on attention. AB - Understanding how dynamic changes in brain activity control behavior is a major challenge of cognitive neuroscience. Here, we consider the brain as a complex dynamic system and define two measures of brain dynamics: the synchrony of brain activity, measured by the spatial coherence of the BOLD signal across regions of the brain; and metastability, which we define as the extent to which synchrony varies over time. We investigate the relationship among brain network activity, metastability, and cognitive state in humans, testing the hypothesis that global metastability is "tuned" by network interactions. We study the following two conditions: (1) an attentionally demanding choice reaction time task (CRT); and (2) an unconstrained "rest" state. Functional MRI demonstrated increased synchrony, and decreased metastability was associated with increased activity within the frontoparietal control/dorsal attention network (FPCN/DAN) activity and decreased default mode network (DMN) activity during the CRT compared with rest. Using a computational model of neural dynamics that is constrained by white matter structure to test whether simulated changes in FPCN/DAN and DMN activity produce similar effects, we demonstate that activation of the FPCN/DAN increases global synchrony and decreases metastability. DMN activation had the opposite effects. These results suggest that the balance of activity in the FPCN/DAN and DMN might control global metastability, providing a mechanistic explanation of how attentional state is shifted between an unfocused/exploratory mode characterized by high metastability, and a focused/constrained mode characterized by low metastability. PMID- 24403146 TI - Electrical stimulation of motor cortex in the uninjured hemisphere after chronic unilateral injury promotes recovery of skilled locomotion through ipsilateral control. AB - Partial injury to the corticospinal tract (CST) causes sprouting of intact axons at their targets, and this sprouting correlates with functional improvement. Electrical stimulation of motor cortex augments sprouting of intact CST axons and promotes functional recovery when applied soon after injury. We hypothesized that electrical stimulation of motor cortex in the intact hemisphere after chronic lesion of the CST in the other hemisphere would restore function through ipsilateral control. To test motor skill, rats were trained and tested to walk on a horizontal ladder with irregularly spaced rungs. Eight weeks after injury, produced by pyramidal tract transection, half of the rats received forelimb motor cortex stimulation of the intact hemisphere. Rats with injury and stimulation had significantly improved forelimb control compared with rats with injury alone and achieved a level of proficiency similar to uninjured rats. To test whether recovery of forelimb function was attributable to ipsilateral control, we selectively inactivated the stimulated motor cortex using the GABA agonist muscimol. The dose of muscimol we used produces strong contralateral but no ipsilateral impairments in naive rats. In rats with injury and stimulation, but not those with injury alone, inactivation caused worsening of forelimb function; the initial deficit was reinstated. These results demonstrate that electrical stimulation can promote recovery of motor function when applied late after injury and that motor control can be exerted from the ipsilateral motor cortex. These results suggest that the uninjured motor cortex could be targeted for brain stimulation in people with large unilateral CST lesions. PMID- 24403147 TI - Advanced age dissociates dual functions of the perirhinal cortex. AB - The perirhinal cortex (PRC) is proposed to both represent high-order sensory information and maintain those representations across delays. These cognitive processes are required for recognition memory, which declines during normal aging. Whether or not advanced age affects the ability of PRC principal cells to support these dual roles, however, is not known. The current experiment recorded PRC neurons as young and aged rats traversed a track. When objects were placed on the track, a subset of the neurons became active at discrete locations adjacent to objects. Importantly, the aged rats had a lower proportion of neurons that were activated by objects. Once PRC activity patterns in the presence of objects were established, however, both age groups maintained these representations across delays up to 2 h. These data support the hypothesis that age-associated deficits in stimulus recognition arise from impairments in high-order stimulus representation rather than difficulty in sustaining stable activity patterns over time. PMID- 24403148 TI - Monaural and binaural inhibition underlying duration-tuned neurons in the inferior colliculus. AB - Duration-tuned neurons (DTNs) in the mammalian inferior colliculus (IC) arise from a combination of excitatory and inhibitory synaptic inputs. Previous research has shown that the inhibition responsible for creating DTNs has a shorter latency than that of excitation and lasts longer than the stimulus duration. We used monotic and dichotic paired tone stimulation and recorded responses of DTNs from the IC of the bat to assess the relative contributions of each ear in forming duration-tuned circuits. The stimulus consisted of a short best duration (BD) excitatory tone and a longer duration nonexcitatory (NE) tone. In the monotic condition, when the BD and NE tones were presented to the contralateral ear and were sufficiently close in time, the NE tone always suppressed spikes evoked by the BD tone. In the dichotic condition, when the BD tone was presented to the contralateral ear and the NE tone to the ipsilateral ear, half of DTNs no longer showed spike suppression to the NE tone. Of those DTNs with suppression in both conditions, the latency of the inhibition was shorter and the duration of the inhibition was longer in the monotic condition. Therefore, in the monotic condition, DTNs received a contralaterally evoked inhibitory input that preceded the excitatory input to the same neuron. In the dichotic condition, DTNs received an ipsilaterally evoked inhibitory input that was weaker, longer in latency, and shorter in duration than the inputs from the contralateral ear. These findings indicate that the neural mechanisms that create DTNs in the IC are monaural. PMID- 24403149 TI - Phase-amplitude coupling in rat orbitofrontal cortex discriminates between correct and incorrect decisions during associative learning. AB - Cross-frequency interactions between oscillations in local field potentials (LFPs) are thought to support communication between brain structures by temporally coordinating neural activity. It is unknown, however, whether such interactions differentiate between different levels of performance in decision making tasks. Here, we investigated theta (4-12 Hz) to gamma (30-100 Hz) phase amplitude coupling in LFP recordings from rat orbitofrontal cortex. Across subsequent periods of a task in which rats learned to discriminate two odors associated with positive and negative outcomes, theta-to-gamma phase-amplitude coupling (PAC) was highest during the odor-sampling task period that preceded a Go/NoGo decision. This task-dependent modulation could not be explained by changes in oscillatory power and appeared to be time-locked to odor onset, not to the timing of the behavioral response. We found that PAC strength during odor sampling correlated with learning, as indexed by improved performance across trials. Moreover, this increase in PAC magnitude was apparent only on trials with correct Go and NoGo decisions, but not incorrect Go decisions. In addition, we found that PAC preferred coupling phase showed consistency over sessions only for correct, but not incorrect trials. In conclusion, orbitofrontal cortex theta gamma PAC strength differentiates between different levels of performance in an olfactory decision-making task and may play a role in the generation and utilization of stimulus-based outcome predictions, necessary for adaptive decision-making. PMID- 24403151 TI - Diverse thalamocortical short-term plasticity elicited by ongoing stimulation. AB - To produce sensation, neuronal pathways must transmit and process stimulus patterns that unfold over time. This behavior is determined by short-term synaptic plasticity (STP), which shapes the temporal filtering properties of synapses in a pathway. We explored STP variability across thalamocortical (TC) synapses, measuring whole-cell responses to stimulation of TC fibers in layer 4 neurons of mouse barrel cortex in vitro. As expected, STP during stimulation from rest was dominated by depression. However, STP during ongoing stimulation was strikingly diverse across TC connections. Diversity took the form of variable tuning to the latest interstimulus interval: some connections responded weakly to shorter intervals, while other connections were facilitated. These behaviors did not cluster into categories but formed a continuum. Diverse tuning did not require disynaptic inhibition. Hence, monosynaptic excitatory lemniscal TC connections onto layer 4 do not behave uniformly during ongoing stimulation. Each connection responds differentially to particular stimulation intervals, enriching the ability of the pathway to convey complex, temporally fluctuating information. PMID- 24403150 TI - Medial septum-diagonal band of Broca (MSDB) GABAergic regulation of hippocampal acetylcholine efflux is dependent on cognitive demands. AB - The septohippocampal pathway contains cholinergic, GABAergic, and glutamatergic projections and has an established role in learning, memory, and hippocampal theta rhythm. Both GABAergic and cholinergic neurons in the medial septum diagonal band of Broca (MSDB) have been associated with spatial memory, but the relationship between the two neuronal populations is not fully understood. The present study investigated the effect of selective GABAergic MSDB lesions on hippocampal acetylcholine (ACh) efflux and spatial memory during tasks that varied in memory demand. Male Sprague Dawley rats were given GABAergic lesions of the MSDB using GAT1-saporin (GAT1-SAP) and examined on spontaneous exploration (Experiment 1) and non-matching to position without (NMTP; Experiment 2) and with a delay (DNMTP; Experiment 3), while concurrently using in vivo microdialysis to measure hippocampal ACh efflux. Intraseptal GAT1-SAP treatment did not alter baseline or behaviorally stimulated hippocampal ACh efflux or maze exploration (Experiment 1). Moreover, GAT1-SAP did not alter evoked hippocampal ACh efflux related to NMTP nor did it impair working memory in NMTP (Experiment 2). In contrast, both ACh efflux and performance in DNMTP were impaired by intraseptal GAT1-SAP. Thus, GABAergic MSDB neurons are important for spatial working memory and modulate hippocampal ACh efflux under conditions of high memory load. The relationship between the septohippocampal cholinergic and GABAergic systems and working memory will be discussed. PMID- 24403152 TI - Hippocampal long-term potentiation is disrupted during expression and extinction but is restored after reinstatement of morphine place preference. AB - Learned associations between environmental cues and morphine use play an important role in the maintenance and/or relapse of opioid addiction. Although previous studies suggest that context-dependent morphine treatment alters glutamatergic transmission and synaptic plasticity in the hippocampus, their role in morphine conditioned place preference (CPP) and reinstatement remains unknown. We investigated changes in synaptic plasticity and NMDAR expression in the hippocampus after the expression, extinction, and reinstatement of morphine CPP. Here we report that morphine CPP is associated with increased basal synaptic transmission, impaired hippocampal long-term potentiation (LTP), and increased synaptic expression of the NR1 and NR2b NMDAR subunits. Changes in synaptic plasticity, synaptic NR1 and NR2b expression, and morphine CPP were absent when morphine was not paired with a specific context. Furthermore, hippocampal LTP was impaired and synaptic NR2b expression was increased after extinction of morphine CPP, indicating that these alterations in plasticity may be involved in the mechanisms underlying the learning of drug-environment associations. After extinction of morphine CPP, a priming dose of morphine was sufficient to reinstate morphine CPP and was associated with LTP that was indistinguishable from saline control groups. In contrast, morphine CPP extinguished mice that received a saline priming dose did not show CPP and had disrupted hippocampal LTP. Finally, we found that reinstatement of morphine CPP was prevented by the selective blockade of the NR2b subunit in the hippocampus. Together, these data suggest that alterations in synaptic plasticity and glutamatergic transmission play an important role in the reinstatement of morphine CPP. PMID- 24403153 TI - Neurog1 and Neurog2 control two waves of neuronal differentiation in the piriform cortex. AB - The three-layered piriform cortex, an integral part of the olfactory system, processes odor information relayed by olfactory bulb mitral cells. Specifically, mitral cell axons form the lateral olfactory tract (LOT) by targeting lateral olfactory tract (lot) guidepost cells in the piriform cortex. While lot cells and other piriform cortical neurons share a pallial origin, the factors that specify their precise phenotypes are poorly understood. Here we show that in mouse, the proneural genes Neurog1 and Neurog2 are coexpressed in the ventral pallium, a progenitor pool that first gives rise to Cajal-Retzius (CR) cells, which populate layer I of all cortical domains, and later to layer II/III neurons of the piriform cortex. Using loss-of-function and gain-of-function approaches, we find that Neurog1 has a unique early role in reducing CR cell neurogenesis by tempering Neurog2's proneural activity. In addition, Neurog1 and Neurog2 have redundant functions in the ventral pallium, acting in two phases to first specify a CR cell fate and later to specify layer II/III piriform cortex neuronal identities. In the early phase, Neurog1 and Neurog2 are also required for lot cell differentiation, which we reveal are a subset of CR neurons, the loss of which prevents mitral cell axon innervation and LOT formation. Consequently, mutation of Trp73, a CR-specific cortical gene, results in lot cell and LOT axon displacement. Neurog1 and Neurog2 thus have unique and redundant functions in the piriform cortex, controlling the timing of differentiation of early-born CR/lot cells and specifying the identities of later-born layer II/III neurons. PMID- 24403155 TI - Dopaminergic role in regulating neurophysiological markers of sleep homeostasis in humans. AB - While dopamine affects fundamental brain processes such as movement control, emotional responses, addiction, and pain, the roles for this neurotransmitter in regulating wakefulness and sleep are incompletely understood. Genetically modified animal models with reduced dopamine clearance exhibit hypersensitivity to caffeine, reduced-responsiveness to modafinil, and increased homeostatic response to prolonged wakefulness when compared with wild-type animals. Here we studied sleep-wake regulation in humans and combined pharmacogenetic and neurophysiologic methods to analyze the effects of the 3'-UTR variable-number tandem-repeat polymorphism of the gene (DAT1, SLC6A3) encoding dopamine transporter (DAT). Previous research demonstrated that healthy homozygous 10 repeat (10R/10R) allele carriers of this genetic variant have reduced striatal DAT protein expression when compared with 9-repeat (9R) allele carriers. Objective and subjective estimates of caffeine sensitivity were higher in 10R allele homozygotes than in carriers of the 9R allele. Moreover, caffeine and modafinil affected wakefulness-induced changes in functional bands (delta, sigma, beta) of rhythmic brain activity in wakefulness and sleep in a DAT1 genotype dependent manner. Finally, the sleep deprivation-induced increase in well established neurophysiologic markers of sleep homeostasis, including slow-wave sleep, electroencephalographic slow-wave activity (0.5-4.5 Hz), and number of low frequency (0.5-2.0 Hz) oscillations in non-rapid-eye-movement sleep, was significantly larger in the 10R/10R genotype than in the 9R allele carriers of DAT1. Together, the data suggest that the dopamine transporter contributes to homeostatic sleep-wake regulation in humans. PMID- 24403154 TI - Hypothalamic dysfunction of the thrombospondin receptor alpha2delta-1 underlies the overeating and obesity triggered by brain-derived neurotrophic factor deficiency. AB - Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, are critical components of the neural circuitry controlling appetite and body weight. Diminished BDNF signaling in mice results in severe hyperphagia and obesity. In humans, BDNF haploinsufficiency and the functional Bdnf Val66Met polymorphism have been linked to elevated food intake and body weight. The mechanisms underlying this dysfunction are poorly defined. We demonstrate a chief role of alpha2delta-1, a calcium channel subunit and thrombospondin receptor, in triggering overeating in mice with central BDNF depletion. We show reduced alpha2delta-1 cell-surface expression in the BDNF mutant ventromedial hypothalamus (VMH), an energy balance-regulating center. This deficit contributes to the hyperphagia exhibited by BDNF mutant mice because selective inhibition of alpha2delta-1 by gabapentin infusion into wild-type VMH significantly increases feeding and body weight gain. Importantly, viral-mediated alpha2delta-1 rescue in BDNF mutant VMH significantly mitigates their hyperphagia, obesity, and liver steatosis and normalizes deficits in glucose homeostasis. Whole-cell recordings in BDNF mutant VMH neurons revealed normal calcium currents but reduced frequency of EPSCs. These results suggest calcium channel-independent effects of alpha2delta-1 on feeding and implicate alpha2delta-1-thrombospondin interactions known to facilitate excitatory synapse assembly. Our findings identify a central mechanism mediating the inhibitory effects of BDNF on feeding. They also demonstrate a novel and critical role for alpha2delta-1 in appetite control and suggest a mechanism underlying weight gain in humans treated with gabapentinoid drugs. PMID- 24403156 TI - Distinct neural mechanisms for body form and body motion discriminations. AB - Actions can be understood based on form cues (e.g., static body posture) as well as motion cues (e.g., gait patterns). A fundamental debate centers on the question of whether the functional and neural mechanisms processing these two types of cues are dissociable. Here, using fMRI, psychophysics, and transcranial magnetic stimulation (TMS), all within the same human participants, we show that mechanisms underlying body form and body motion processing are functionally and neurally distinct. Multivoxel fMRI activity patterns in the extrastriate body area (EBA), but not in the posterior superior temporal sulcus (pSTS), carried cue invariant information about the body form of an acting human. Conversely, multivoxel patterns in pSTS, but not in EBA, carried information about the body motion of the same actor. In a psychophysical experiment, we selectively impaired body form and body motion discriminations by manipulating different visual cues: misaligning the ellipses that made up a dynamic walker stimulus selectively disrupted body form discriminations, while varying the presentation duration of the walker selectively affected body motion discriminations. Finally, a TMS experiment revealed causal evidence for a double-dissociation between neural mechanisms underlying body form and body motion discriminations: TMS over EBA selectively disrupted body form discrimination, whereas TMS over pSTS selectively disrupted body motion discrimination. Together, these findings reveal complementing but dissociable functions of EBA and pSTS during action perception. They provide constraints for theoretical and computational models of action perception by showing that action perception involves at least two parallel pathways that separately contribute to the understanding of others' behavior. PMID- 24403157 TI - Amygdala inputs to the ventral hippocampus bidirectionally modulate social behavior. AB - Impairments in social interaction represent a core symptom of a number of psychiatric disease states, including autism, schizophrenia, depression, and anxiety. Although the amygdala has long been linked to social interaction, little is known about the functional role of connections between the amygdala and downstream regions in noncompetitive social behavior. In the present study, we used optogenetic and pharmacological tools in mice to study the role of projections from the basolateral complex of the amygdala (BLA) to the ventral hippocampus (vHPC) in two social interaction tests: the resident-juvenile intruder home-cage test and the three chamber sociability test. BLA pyramidal neurons were transduced using adeno-associated viral vectors (AAV5) carrying either channelrhodopsin-2 (ChR2) or halorhodopsin (NpHR), under the control of the CaMKIIalpha promoter to allow for optical excitation or inhibition of amygdala axon terminals. Optical fibers were chronically implanted to selectively manipulate BLA terminals in the vHPC. NpHR-mediated inhibition of BLA-vHPC projections significantly increased social interaction in the resident-juvenile intruder home-cage test as shown by increased intruder exploration. In contrast, ChR2-mediated activation of BLA-vHPC projections significantly reduced social behaviors as shown in the resident-juvenile intruder procedure as seen by decreased time exploring the intruder and in the three chamber sociability test by decreased time spent in the social zone. These results indicate that BLA inputs to the vHPC are capable of modulating social behaviors in a bidirectional manner. PMID- 24403158 TI - Differential contributions of infralimbic prefrontal cortex and nucleus accumbens during reward-based learning and extinction. AB - Using environmental cues for the prediction of future events is essential for survival. Such cue-outcome associations are thought to depend on mesolimbic circuitry involving the nucleus accumbens (NAc) and prefrontal cortex (PFC). Several studies have identified roles for both NAc and PFC in the expression of stable goal-directed behaviors, but much remains unknown about their roles during learning of such behaviors. To further address this question, we used in vivo oxygen amperometry, a proxy for blood oxygen level-dependent (BOLD) signal measurement in human functional magnetic resonance imaging, in rats performing a cued lever-pressing task requiring discrimination between a rewarded and nonrewarded cue. Simultaneous oxygen recordings were obtained from infralimbic PFC (IFC) and NAc throughout both acquisition and extinction of this task. Activation of NAc was specifically observed following rewarded cue onset during the entire acquisition phase and also during the first days of extinction. In contrast, IFC activated only during the earliest periods of acquisition and extinction, more specifically to the nonrewarded cue. Thus, in vivo oxygen amperometry permits a novel, stable form of longitudinal analysis of brain activity in behaving animals, allowing dissociation of the roles of different brain regions over time during learning of reward-driven instrumental action. The present results offer a unique temporal perspective on how NAc may promote actions directed toward anticipated positive outcome throughout learning, while IFC might suppress actions that no longer result in reward, but only during critical periods of learning. PMID- 24403159 TI - Can simple rules control development of a pioneer vertebrate neuronal network generating behavior? AB - How do the pioneer networks in the axial core of the vertebrate nervous system first develop? Fundamental to understanding any full-scale neuronal network is knowledge of the constituent neurons, their properties, synaptic interconnections, and normal activity. Our novel strategy uses basic developmental rules to generate model networks that retain individual neuron and synapse resolution and are capable of reproducing correct, whole animal responses. We apply our developmental strategy to young Xenopus tadpoles, whose brainstem and spinal cord share a core vertebrate plan, but at a tractable complexity. Following detailed anatomical and physiological measurements to complete a descriptive library of each type of spinal neuron, we build models of their axon growth controlled by simple chemical gradients and physical barriers. By adding dendrites and allowing probabilistic formation of synaptic connections, we reconstruct network connectivity among up to 2000 neurons. When the resulting "network" is populated by model neurons and synapses, with properties based on physiology, it can respond to sensory stimulation by mimicking tadpole swimming behavior. This functioning model represents the most complete reconstruction of a vertebrate neuronal network that can reproduce the complex, rhythmic behavior of a whole animal. The findings validate our novel developmental strategy for generating realistic networks with individual neuron- and synapse-level resolution. We use it to demonstrate how early functional neuronal connectivity and behavior may in life result from simple developmental "rules," which lay out a scaffold for the vertebrate CNS without specific neuron-to-neuron recognition. PMID- 24403160 TI - Neto auxiliary protein interactions regulate kainate and NMDA receptor subunit localization at mossy fiber-CA3 pyramidal cell synapses. AB - Neto1 and Neto2 auxiliary subunits coassemble with NMDA receptors (NMDARs) and kainate receptors (KARs) to modulate their function. In the hippocampus, Neto1 enhances the amplitude and prolongs the kinetics of KAR-mediated currents at mossy fiber (MF)-CA3 pyramidal cell synapses. However, whether Neto1 trafficks KARs to synapses or simply alters channel properties is unresolved. Therefore, postembedding electron microscopy was performed to investigate the localization of GluK2/3 subunits at MF-CA3 synapses in Neto-null mice. Postsynaptic GluK2/3 Immunogold labeling was substantially reduced in Neto-null mice compared with wild types. Moreover, spontaneous KAR-mediated synaptic currents and metabotropic KAR signaling were absent in CA3 pyramidal cells of Neto-null mice. A similar loss of ionotropic and metabotropic KAR function was observed in Neto1, but not Neto2, single knock-out mice, specifically implicating Neto1 in regulating CA3 pyramidal cell KAR localization and function. Additional controversy pertains to the role of Neto proteins in modulating synaptic NMDARs. While Immunogold labeling for GluN2A at MF-CA3 synapses was comparable between wild-type and Neto null mice, labeling for postsynaptic GluN2B was robustly increased in Neto-null mice. Accordingly, NMDAR-mediated currents at MF-CA3 synapses exhibited increased sensitivity to a GluN2B-selective antagonist in Neto1 knockouts relative to wild types. Thus, despite preservation of the overall MF-CA3 synaptic NMDAR-mediated current, loss of Neto1 alters NMDAR subunit composition. These results confirm that Neto protein interactions regulate synaptic localization of KAR and NMDAR subunits at MF-CA3 synapses, with implications for both ionotropic and metabotropic glutamatergic recruitment of the CA3 network. PMID- 24403161 TI - Axon regeneration genes identified by RNAi screening in C. elegans. AB - Axons of the mammalian CNS lose the ability to regenerate soon after development due to both an inhibitory CNS environment and the loss of cell-intrinsic factors necessary for regeneration. The complex molecular events required for robust regeneration of mature neurons are not fully understood, particularly in vivo. To identify genes affecting axon regeneration in Caenorhabditis elegans, we performed both an RNAi-based screen for defective motor axon regeneration in unc 70/beta-spectrin mutants and a candidate gene screen. From these screens, we identified at least 50 conserved genes with growth-promoting or growth-inhibiting functions. Through our analysis of mutants, we shed new light on certain aspects of regeneration, including the role of beta-spectrin and membrane dynamics, the antagonistic activity of MAP kinase signaling pathways, and the role of stress in promoting axon regeneration. Many gene candidates had not previously been associated with axon regeneration and implicate new pathways of interest for therapeutic intervention. PMID- 24403162 TI - Neurons in dorsal anterior cingulate cortex signal postdecisional variables in a foraging task. AB - The dorsal anterior cingulate cortex (dACC) is a key hub of the brain's executive control system. Although a great deal is known about its role in outcome monitoring and behavioral adjustment, whether and how it contributes to the decision process remain unclear. Some theories suggest that dACC neurons track decision variables (e.g., option values) that feed into choice processes and is thus "predecisional." Other theories suggest that dACC activity patterns differ qualitatively depending on the choice that is made and is thus "postdecisional." To compare these hypotheses, we examined responses of 124 dACC neurons in a simple foraging task in which monkeys accepted or rejected offers of delayed rewards. In this task, options that vary in benefit (reward size) and cost (delay) appear for 1 s; accepting the option provides the cued reward after the cued delay. To get at dACC neurons' contributions to decisions, we focused on responses around the time of choice, several seconds before the reward and the end of the trial. We found that dACC neurons signal the foregone value of the rejected option, a postdecisional variable. Neurons also signal the profitability (that is, the relative value) of the offer, but even these signals are qualitatively different on accept and reject decisions, meaning that they are also postdecisional. These results suggest that dACC can be placed late in the decision process and also support models that give it a regulatory role in decision, rather than serving as a site of comparison. PMID- 24403163 TI - Spatial organization of AMPAR subtypes in ON RGCs. AB - Retinal ganglion cells (RGCs) receive glutamatergic input from bipolar cells through NMDA- and AMPA-type glutamate receptors. Both GluA2-containing, Ca(2+) impermeable AMPA receptors (CI-AMPARs) and GluA2-lacking, Ca(2+)-permeable AMPA receptors (CP-AMPARs) contribute to light-evoked responses in ON RGCs; however, specific roles for each subtype are not well understood. Here, we present evidence that light intensity determines the subtype of AMPAR that is activated during the synaptic response in ON RGCs. Using current voltage analysis of the EPSC we show that light intensities near RGC threshold, intensities that travel through the well described primary rod pathway, evoke synaptic currents that are preferentially mediated by CP-AMPARs. Synaptic responses evoked by spontaneous release of transmitter from bipolar cell terminals also preferentially activate CP-AMPARs. Conversely, higher light intensities, most likely carried by secondary rod pathways, activate CI-AMPARs. The same pattern of CP-AMPAR and CI-AMPAR activation was observed in mice containing only functional rods, suggesting that the recruitment of CI-AMPARs at higher light intensity does not require cone stimulation. When glutamate spillover was induced by blocking transporters with TBOA, both the near threshold and spontaneous EPSCs contained a significant CI AMPAR component. We propose that CI-AMPARs are activated by "spillover" of synaptic glutamate only during bright illumination, or when glutamate uptake is blocked. Glutamate may spill over to more distant sites at the same synapse, or perhaps as far as neighboring synapses. Together, our data suggest that the spatial organization of AMPARs at ON RGCs synapses allows for selective, intensity-dependent activation of AMPARs with distinct subunit composition. PMID- 24403165 TI - Modulation of short-term plasticity in the corticothalamic circuit by group III metabotropic glutamate receptors. AB - Recurrent connections in the corticothalamic circuit underlie oscillatory behavior in this network and range from normal sleep rhythms to the abnormal spike-wave discharges seen in absence epilepsy. The propensity of thalamic neurons to fire postinhibitory rebound bursts mediated by low-threshold calcium spikes renders the circuit vulnerable to both increased excitation and increased inhibition, such as excessive excitatory cortical drive to thalamic reticular (RT) neurons or heightened inhibition of thalamocortical relay (TC) neurons by RT. In this context, a protective role may be played by group III metabotropic receptors (mGluRs), which are uniquely located in the presynaptic active zone and typically act as autoreceptors or heteroceptors to depress synaptic release. Here, we report that these receptors regulate short-term plasticity at two loci in the corticothalamic circuit in rats: glutamatergic cortical synapses onto RT neurons and GABAergic synapses onto TC neurons in somatosensory ventrobasal thalamus. The net effect of group III mGluR activation at these synapses is to suppress thalamic oscillations as assayed in vitro. These findings suggest a functional role of these receptors to modulate corticothalamic transmission and protect against prolonged activity in the network. PMID- 24403164 TI - Comparison of sleep spindles and theta oscillations in the hippocampus. AB - Several network patterns allow for information exchange between the neocortex and the entorhinal-hippocampal complex, including theta oscillations and sleep spindles. How neurons are organized in these respective patterns is not well understood. We examined the cellular-synaptic generation of sleep spindles and theta oscillations in the waking rat and during rapid eye movement (REM) sleep by simultaneously recording local field and spikes in the regions and layers of the hippocampus and entorhinal cortex (EC). We show the following: (1) current source density analysis reveals that similar anatomical substrates underlie spindles and theta in the hippocampus, although the hippocampal subregions are more synchronized during spindles than theta; (2) the spiking of putative principal cells and interneurons in the CA1, CA3, and dentate gyrus subregions of the hippocampus, as well as layers 2, 3, and 5 of medial EC, are significantly phase locked to spindles detected in CA1; (3) the relationship between local field potential (LFP) phase and unit spiking differs between spindles and theta; (4) individual hippocampal principal cells generally do not fire in a rhythmic manner during spindles; (5) power in gamma (30-90 Hz) and epsilon (>90 Hz) bands of hippocampal LFP is modulated by the phase of spindle oscillations; and (6) unit firing rates during spindles were not significantly affected by whether spindles occurred during non-REM or transitions between non-REM and REM sleep. Thus, despite the similar current generator inputs and macroscopic appearance of the LFP, the organization of neuronal firing patterns during spindles bears little resemblance to that of theta oscillations. PMID- 24403168 TI - Detection of biofilm production of Yersinia enterocolitica strains isolated from infected children and comparative antimicrobial susceptibility of biofilm versus planktonic forms. AB - BACKGROUND AND OBJECTIVES: The ability of Yersinia species to produce biofilms has not been hitherto systematically studied, although there is evidence, that Y. enterocolitica is able to form biofilms on inanimate surfaces. The present study aimed to detect the production of biofilms by 60 clinical strains of Y. enterocolitica and to compare the antimicrobial susceptibility of planktonic versus biofilm-forming bacteria. METHODS: Y. enterocolitica strains were collected from stool and blood cultures collected from beta-thalassaemic children, with gastroenteritis and/or septicemia. The isolated bacterial strains were grouped by biotyping and serotyping and the antimicrobial susceptibility of the planktonic forms was investigated by MIC determination. Biofilm formation was detected by the use of silicone disks and for the biofilm forming strains the minimum inhibitory concentration for bacterial regrowth (MICBR) of 11 clinically important antimicrobials was determined. The presence of the waaE, a gene reported to be related with biofilm formation was investigated in all the strains. RESULTS: All of 60 strains were positive for biofilm production by the use of silicone disks. The great majority of the biofilm forms were resistant to all the antimicrobials. In antimicrobial concentrations far higher than the CLSI breakpoints, bacterial regrowth from the biofilms was still possible. None of the strains bore the waaE gene. CONCLUSIONS: These results, indicate that biofilm formation by Y. enterocolitica might be an inherent feature. The presence of biofilms increased dramatically the MICBR in all antimicrobials. The way in which biofilms could contribute to Y. enterocolitica pathogenicity in humans is a matter needing further investigation. PMID- 24403167 TI - Comprehensive profiling of EGFR/HER receptors for personalized treatment of gynecologic cancers. AB - The primary gynecologic cancers include cancers of the endometrium, ovary, and cervix. Worldwide, cervical cancer is the most common gynecologic cancer, whereas endometrial cancer is the most common in the US. Ovarian cancer is the fifth most deadly cancer in women, with 5-year survival rates for advanced disease at only 27 %. As such, there is an urgent need for reliable screening tools and novel targeted therapeutic regimens for these malignancies. The epidermal growth factor receptor (EGFR)/human EGFR (HER) family of receptors has been associated with the development and progression of many solid tumors. Despite clear roles for these receptors in other cancers, the expression of HER family members in gynecologic cancers and their relationship with disease stage, grade, and response to treatment remain controversial. In this review, we describe the existing evidence for the use of HER family members as diagnostic and prognostic indicators as well as their potential as therapeutic targets in gynecologic cancers. PMID- 24403169 TI - BRAF and MEK gene rearrangements in melanoma: implications for targeted therapy. AB - The incidence of melanoma has been continuously increasing in the last decades, and faster than any other cancers. Melanoma is the leading cause of death from skin disease. It is estimated that 76,690 Americans will be diagnosed with melanoma in 2013 and 9,480 will die from the disease. Molecular mechanisms underlying melanoma pathogenesis have been extensively studied and novel therapeutic weapons developed. BRAF and MEK pathways emerged as key players in this field. Recently, novel drugs such as vemurafenib, dabrafenib and trametinib were approved for treatment of advanced disease harbouring BRAF V600E and V600K mutations. In addition, an effective strategy to build upon the successes seen with dabrafenib and trametinib monotherapies has been to combine these agents (CombiDT), with the goal of further improving response rates and delaying resistance. Our review gives an overall point of view concerning BRAF and MEK pathways as well as the role of BRAF and MEK testing in directing the personalised treatment of patients with metastatic melanoma. PMID- 24403170 TI - Synthesis, structure-activity, and structure-stability relationships of 2 substituted-N-(4-oxo-3-oxetanyl) N-acylethanolamine acid amidase (NAAA) inhibitors. AB - N-Acylethanolamine acid amidase (NAAA) is a cysteine amidase that preferentially hydrolyzes saturated or monounsaturated fatty acid ethanolamides (FAEs), such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), which are endogenous agonists of nuclear peroxisome proliferator-activated receptor-alpha (PPAR alpha). Compounds that feature an alpha-amino-beta-lactone ring have been identified as potent and selective NAAA inhibitors and have been shown to exert marked anti-inflammatory effects that are mediated through FAE-dependent activation of PPAR-alpha. We synthesized and tested a series of racemic, diastereomerically pure beta-substituted alpha-amino-beta-lactones, as either carbamate or amide derivatives, investigating the structure-activity and structure-stability relationships (SAR and SSR) following changes in beta substituent size, relative stereochemistry at the alpha- and beta-positions, and alpha-amino functionality. Substituted carbamate derivatives emerged as more active and stable than amide analogues, with the cis configuration being generally preferred for stability. Increased steric bulk at the beta-position negatively affected NAAA inhibitory potency, while improving both chemical and plasma stability. PMID- 24403171 TI - Ruthenium complexes of tripodal ligands with pyridine and triazole arms: subtle tuning of thermal, electrochemical, and photochemical reactivity. AB - Electrochemical and photochemical bond-activation steps are important for a variety of chemical transformations. We present here four new complexes, [Ru(L(n) )(dmso)(Cl)]PF6 (1-4), where L(n) is a tripodal amine ligand with 4-n pyridylmethyl arms and n-1 triazolylmethyl arms. Structural comparisons show that the triazoles bind closer to the Ru center than the pyridines. For L(2) , two isomers (with respect to the position of the triazole arm, equatorial or axial), trans-2sym and trans-2un , could be separated and compared. The increase in the number of the triazole arms in the ligand has almost no effect on the Ru(II) /Ru(III) oxidation potentials, but it increases the stability of the Ru?Sdmso bond. Hence, the oxidation waves become more reversible from trans-1 to trans-4, and whereas the dmso ligand readily dissociates from trans-1 upon heating or irradiation with UV light, the Ru?S bond of trans-4 remains perfectly stable under the same conditions. The strength of the Ru?S bond is not only influenced by the number of triazole arms but also by their position, as evidenced by the difference in redox behavior and reactivity of the two isomers, trans-2sym and trans-2un . A mechanistic picture for the electrochemical, thermal, and photochemical bond activation is discussed with data from NMR spectroscopy, cyclic voltammetry, and spectroelectrochemistry. PMID- 24403172 TI - Propane-1,2-diols from dilactides, oligolactides, or poly-L-lactic acid (PLLA): from plastic waste to chiral bulk chemicals. AB - The preparation of racemic or enantioenriched propane-1,2-diol from dilactides, oligolactides, or poly-L-lactic acid (PLLA) is described. The transformation is carried out as tandem reactions in MeOH, covering hydrolysis and subsequent hydrogenation by using copper chromite as a catalyst. The starting material present undesired side products of the PLLA synthesis or PLLA waste. PMID- 24403173 TI - Long residence times revealed by Aurora A kinase-targeting fluorescent probes derived from inhibitors MLN8237 and VX-689. AB - We report the development of three fluorescent probes for protein kinase Aurora A that are derived from the well-known inhibitors MLN8237 and VX-689 (MK-5108). Two of these probes target the ATP site of Aurora A, and one targets simultaneously the ATP and substrate sites of the kinase. The probes were tested in an assay with fluorescence polarisation/anisotropy readout, and we demonstrated slow association kinetics and long residence time of the probes (kon 10(5)-10(7) M(-1) s(-1), koff 10(-3)-10(-4) s(-1); residence time 500-3000 s). The presence of the Aurora A activator TPX2 caused a significant reduction in the on-rate and increase in the off-rate of fluorescent probes targeting ATP site. These observations were supported by Aurora A inhibition assays with MLN8237 and VX 689. Overall, our results emphasise the importance of rational design of experiments with these compounds and correct interpretation of the obtained data. PMID- 24403174 TI - Long-term outcome in patients with ST segment elevation myocardial infarction and multivessel disease treated with culprit-only, immediate, or staged multivessel percutaneous revascularization strategies: Insights from the REAL registry. AB - OBJECTIVES: To examine the differences in cardiac outcomes for patients with ST elevation myocardial infarction (STEMI) and multivessel disease (MVD) as a function of whether they underwent culprit-only primary percutaneous coronary intervention (PPCI) or multivessel PCI, either during PPCI or as a staged procedure. BACKGROUND: MVD occurs in about 40% of patients presenting with STEMI, and it has been associated with a worse outcome compared to single-vessel disease. The most favorable PCI strategy for dealing with significant nonculprit lesions has to be established. METHODS: A total of 2061 STEMI patients with MVD undergoing PPCI, prospectively enrolled in the REAL Registry between July 2002 and December 2010, were considered: 706 underwent culprit-only PPCI; 367 multivessel PCI during the index procedure; 988 had a staged PCI within 60 days. Mortality and outcomes were calculated at 30 days and 2 years. RESULTS: At multivariate analysis, culprit-only PPCI was associated with higher rates of cardiac outcomes as compared to staged multivessel PCI, taken as reference [Hazard Ratio (HR): 2.81, 95% confidence interval (CI): 1.34-5.89, P = 0.006 for 30-day mortality, and HR: 1.93, 95% CI: 1.35-2.74, P = 0.0002 for 2-year mortality, respectively]. Short-term mortality rates were higher in multivessel PCI group as compared to staged PCI group (HR: 2.58, 95% CI: 1.06-6.26, P = 0.03); no differences were observed at 2-year follow-up (HR: 1.08, 95% CI: 0.64 1.82, P = 0.76). CONCLUSIONS: Our findings support the current guidelines recommendation to perform culprit-only PPCI in STEMI patients with MVD without hemodynamic compromise, followed by a staged PCI of noninfarct-related significant lesions. PMID- 24403175 TI - Effect of corn steep liquor on lettuce root rot (Fusarium oxysporum f.sp. lactucae) in hydroponic cultures. AB - BACKGROUND: Recent reports indicate that organic fertilisers have a suppressive effect on the pathogens of plants grown under hydroponic systems. Furthermore, microorganisms exhibiting antagonistic activity to diseases have been observed in organic hydroponic systems. This study evaluated the effect of corn steep liquor (CSL) on controlling lettuce root rot disease [Fusarium oxysporum f.sp. lactucae (FOL)] in a hydroponic system. The effect of CSL and Otsuka A (a chemical fertiliser) on the inhibition of FOL in terms of mycelial growth inhibition was tested in vivo. RESULTS: Addition of CSL suppressed FOL infection rates. CSL inhibited FOL infection by 26.3-42.5% from 2 days after starting incubation. In comparison, Otsuka A inhibited FOL growth by 5.5-19.4%. In addition, four of 10 bacteria isolated from the nutrient media containing CSL exhibited inhibition zones preventing FOL mycelial growth. CONCLUSIONS: We found that CSL suppressed FOL in lettuce via its antifungal and biostimulatory effects. We suggest that activation of beneficial microorganisms present in CSL may be used to decrease lettuce root rot disease and contribute to lettuce root growth. PMID- 24403177 TI - Determination of folates by HPLC-chemiluminescence using a ruthenium(II) cerium(IV) system, and its application to pharmaceutical preparations and supplements. AB - A chemiluminescence (CL) reaction of folic acid (FA) with ruthenium (II) and cerium (IV) was applied to quantify FA-related compounds such as FA, dihydrofolic acid, tetrahydrofolic acid, 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid and methotrexate (MTX). Among the FAs, 5-methyltetrahydrofolic acid provided the highest CL intensity. HPLC-CL detection of FA was applied to quantify FA in pharmaceutical preparations and supplements. Analytical samples were separated on a semi-micro ODS column with a mixture of 20 mM phosphate buffer (pH 5.7) and acetonitrile (94 : 6, v/v %). The separated samples were mixed with a post-column CL reagent consisting of 1.5 mM Ru(bipy)3 (2+) and 1.0 mM Ce(SO4)2 , then the generated CL was monitored. The calibration range for FA was 10-100 MUM and the limit of detection was 1.34 MUM (signal-to-noise ratio of 3). Repeatabilities were 4.2, 4.6 and 5.0 RSD% (10, 25, 50 MUM), and the recoveries for FA supplement, vitamin B complex supplement and FA-containing medication (tablet) were 102.4 +/- 10.5, 103.3 +/- 13.3 and 100.3 +/- 8.5%, respectively. The described method is robust against changes in the chromatographic parameters of +/- 3.3 or +/- 1.5%. The measured FA content corresponded well to the labeled content of FA-containing products (100.6-104.9%), demonstrating the precision and accuracy of this method for the evaluation of FA pharmaceutical preparations. PMID- 24403176 TI - Early detection of antiangiogenic treatment responses in a mouse xenograft tumor model using quantitative perfusion MRI. AB - Angiogenesis plays a major role in tumor growth and metastasis, with tumor perfusion regarded as a marker for angiogenesis. To evaluate antiangiogenic treatment response in vivo, we investigated arterial spin labeling (ASL) magnetic resonance imaging (MRI) to measure tumor perfusion quantitatively. Chronic and 24 h acute treatment responses to bevacizumab were assessed by ASL and dynamic contrast-enhanced (DCE) MRI in the A498 xenograft mouse model. After the MRI, tumor vasculature was assessed by CD34 staining. After 39 days of chronic treatment, tumor perfusion decreased to 44.8 +/- 16.1 mL/100 g/min (P < 0.05), compared to 92.6 +/- 42.9 mL/100 g/min in the control group. In the acute treatment study, tumor perfusion in the treated group decreased from 107.2 +/- 32.7 to 73.7 +/- 27.8 mL/100 g/min (P < 0.01; two-way analysis of variance), as well as compared with control group post dosing. A significant reduction in vessel density and vessel size was observed after the chronic treatment, while only vessel size was reduced 24 h after acute treatment. The tumor perfusion correlated with vessel size (r = 0.66; P < 0.005) after chronic, but not after acute treatment. The results from DCE-MRI also detected a significant change between treated and control groups in both chronic and acute treatment studies, but not between 0 and 24 h in the acute treatment group. These results indicate that tumor perfusion measured by MRI can detect early vascular responses to antiangiogenic treatment. With its noninvasive and quantitative nature, ASL MRI would be valuable for longitudinal assessment of tumor perfusion and in translation from animal models to human. PMID- 24403178 TI - M2 muscarinic receptor activation regulates Schwann cell differentiation and myelin organization. AB - Glial cells express acetylcholine receptors. In particular, rat Schwann cells express different muscarinic receptor subtypes, the most abundant of which is the M2 subtype. M2 receptor activation causes a reversible arrest of the cell cycle. This negative effect on Schwann cell proliferation suggests that these cells may possibly progress into a differentiating program. In this study we analyzed the in vitro modulation, by the M2 agonist arecaidine, of transcription factors and specific signaling pathways involved in Schwann cell differentiation. The arecaidine-induced M2 receptor activation significantly upregulates transcription factors involved in the promyelinating phase (e.g., Sox10 and Krox20) and downregulates proteins involved in the maintenance of the undifferentiated state (e.g., c-jun, Notch-1, and Jagged-1). Furthermore, arecaidine stimulation significantly increases the expression of myelin proteins, which is accompanied by evident changes in cell morphology, as indicated by electron microscopy analysis, and by substantial cellular re-distribution of actin and cell adhesion molecules. Moreover, ultrastructural and morphometric analyses on sciatic nerves of M2/M4 knockout mice show numerous degenerating axons and clear alterations in myelin organization compared with wild-type mice. Therefore, our data demonstrate that acetylcholine mediates axon-glia cross talk, favoring Schwann cell progression into a differentiated myelinating phenotype and contributing to compact myelin organization. PMID- 24403179 TI - Malva sylvestris L. extract suppresses desferrioxamine-induced PGE2 and PGD2 release in differentiated U937 cells: the development and validation of an LC MS/MS method for prostaglandin quantification. AB - Malva sylvestris is a species used worldwide as an alternative to anti inflammatory therapies; however, its mechanism of action remains unknown. In this paper, the anti-inflammatory effects of M. sylvestris alcoholic extracts were evaluated by measuring the pro-inflammatory mediators PGE2 and PGD2 in desferrioxamine-stimulated phorbol 12-myristate 13-acetate-differentiated U937 cells. An HPLC-DAD fingerprint of the M. sylvestris extract was performed and caffeic acid, ferulic acid and scopoletin were identified and quantified. An HPLC MS/MS method was developed and validated to separate and measure the prostaglandins. The lower limits of detection (~0.5 ng/mL for PGE2 and PGD2) and quantification (1.0 ng/mL for PGE2 and PGD2) indicated that the method is highly sensitive. The calibration curves showed excellent coefficients of correlation (r > 0.99) over the range of 1.0-500.0 ng/mL, and at different levels, the accuracy ranged from 96.4 to 106.4% with an RSD < 10.0% for the precision study. This method was successfully applied using U937-d cells. A significant dose-dependent reduction of PGE2 and PGD2 levels occurred using 10 ug/mL (10.74 +/- 2.86 and 9.60 +/- 6.89%) and 50 ug/mL of extract (48.37 +/- 3.24 and 53.06 +/- 6.15%), suggesting that the anti-inflammatory mechanisms evoked by M. sylvestris may be related to modulation of these mediators. PMID- 24403181 TI - A novel planar polarity gene pepsinogen-like regulates wingless expression in a posttranscriptional manner. AB - BACKGROUND: Planar cell polarity (PCP) originally referred to the coordination of global organ axes and individual cell polarity within the plane of the epithelium. More recently, it has been accepted that pertinent PCP regulators play essential roles not only in epithelial sheets, but also in various rearranging cells. RESULTS: We identified pepsinogen-like (pcl) as a new planar polarity gene, using Drosophila wing epidermis as a model. Pcl protein is predicted to belong to a family of aspartic proteases. When pcl mutant clones were observed in pupal wings, PCP was disturbed in both mutant and wild-type cells that were juxtaposed to the clone border. We examined levels of known PCP proteins in wing imaginal discs. The amount of the seven-pass transmembrane cadherin Flamingo (Fmi), one of the PCP "core group" members, was significantly decreased in mutant clones, whereas neither the amount of nor the polarized localization of Dachsous (Ds) at cell boundaries was affected. In addition to the PCP phenotype, the pcl mutation caused loss of wing margins. Intriguingly, this was most likely due to a dramatic decrease in the level of Wingless (Wg) protein, but not due to a decrease in the level of wg transcripts. CONCLUSIONS: Our results raise the possibility that Pcl regulates Wg expression post transcriptionally, and PCP, by proteolytic cleavages. PMID- 24403182 TI - Development of the first oral bioprecursors of bis-alkylguanidine antimalarial drugs. AB - Plasmodium falciparum is responsible of the most severe form of malaria, and new targets and novel chemotherapeutic scaffolds are needed to fight emerging multidrug-resistant strains of this parasite. Bis-alkylguanidines have been designed to mimic choline, resulting in the inhibition of plasmodial de novo phosphatidylcholine biosynthesis. Despite potent in vitro antiplasmodial and in vivo antimalarial activities, a major drawback of these compounds for further clinical development is their low oral bioavailability. To solve this issue, various modulations were performed on bis-alkylguanidines. The introduction of N disubstituents on the guanidino motif improved both in vitro and in vivo activities. On the other hand, in vivo pharmacological evaluation in a mouse model showed that the N-hydroxylated derivatives constitute the first oral bioprecursors in bis-alkylguanidine series. This study paves the way for bis alkylguanidine-based oral antimalarial agents targeting plasmodial phospholipid metabolism. PMID- 24403183 TI - Towards eumelanin@zeolite hybrids: pore-size-controlled 5,6-dihydroxyindole polymerization. AB - 5,6-Dihydroxyindole (1) and its N-methyl derivative (2), key eumelanin building blocks, were inserted into zeolite L by sublimation at 175 degrees C for 5 days. At a 10 mg/300 mg indole/zeolite ratio, the resulting hybrids displayed a stable deep red coloration. CP/MAS (13)C NMR and UV/Vis spectroscopy of the red species suggested the generation and accommodation of quinonoid biindole derivative(s) within the void space of the acidic zeolite channels. Removal of the zeolite matrix by treatment with HF gave a stable species that could be separated by HPLC and characterized by mass spectrometry as an oxygenated biindole derivative (or a mixture of isomers), suggesting addition of water to the original dimer and subsequent re-oxidation. The characterization was corroborated by optimized molecular geometries and simulated UV spectra with density functional calculations. Loading 1 or 2 into the larger pores of SBA-15 type mesoporous silica resulted in black eumelanin-type polymers, confirming channel size dependence over the polymerization process. PMID- 24403184 TI - The effect of grafting zirconia and ceria onto alumina as a support for silicotungstic acid for the catalytic dehydration of glycerol to acrolein. AB - The effect of ceria and zirconia grafting onto alumina (alpha and theta-delta phases) as supports for silicotungstic acid for the dehydration of glycerol to acrolein was studied. 30 % Silicotungstic acid (STA) supported on 5 % zirconia/delta,theta-alumina was the best catalyst, producing 85 % selectivity to acrolein at 100 % glycerol conversion, and it showed stable activity without using oxygen as a co-feed. The catalyst produced a STA of 90 g(acrolein) kg(cat)(-1) h(-1), which was greater than the STA simply supported on delta,theta-alumina, which only demonstrated 75 % selectivity towards acrolein. The effect of grafting on the support material was investigated by means of nitrogen adsorption, ammonia temperature-programmed desorption, thermogravimetric analysis, Raman spectroscopy, and powder X-ray diffraction. A pulsed-field gradient (PFG) NMR technique was also used to study diffusion processes associated with the catalysts. Diffusion studies of the grafted catalysts showed that zirconia contributes to the formation of more tortuous pathways within the pore structure, leading to the diminution of acid strength and making the catalyst less susceptible to coke formation. PMID- 24403185 TI - Melody pulmonary valve bacterial endocarditis: experience in four pediatric patients and a review of the literature. AB - OBJECTIVES: The objectives of this manuscript are two-fold: (a) to describe the clinical characteristics and management of four pediatric patients with bacterial endocarditis (BE) after Melody pulmonary valve implantation (MPVI); and (b) to review the literature regarding Melody pulmonary valve endocarditis. BACKGROUND: There are several reports of BE following MPVI. The clinical course, BE management and outcome remain poorly defined. METHODS: This is a multi-center report of four pediatric patients with repaired tetralogy of Fallot (TOF) and BE after MPVI. Clinical presentation, echocardiogram findings, infecting organism, BE management, and follow-up assessment are described. We review available literature on Melody pulmonary valve endocarditis and discuss the prognosis and challenges in the management of these patients. RESULTS: Of our four BE patients, two had documented vegetations and three showed worsening pulmonary stenosis. All patients remain asymptomatic after medical treatment (4) and surgical prosthesis replacement (3) at follow-up of 17 to 40 months. Analysis of published data shows that over half of patients undergo bioprosthesis explantation and that there is a 13% overall mortality. The most common BE pathogens are the Staphylococcus and Streptococcus species. CONCLUSIONS: Our case series of four pediatric patients with repaired TOF confirms a risk for BE after MPVI. A high index of suspicion for BE should be observed after MPVI. All patients should be advised to follow lifelong BE prophylaxis after MPVI. In case of BE, surgery should be considered for valve dysfunction or no clinical improvement in spite of medical treatment. PMID- 24403186 TI - TOP2A gene copy number change in breast cancer. AB - AIMS: The clinical significance of TOP2A as a prognostic marker has not been clarified. The aims of this study were to investigate the frequency of TOP2A copy number change; to correlate TOP2A with HER2 status, hormone receptor (HR) status and molecular subtype, and further to explore differences in breast cancer specific survival according to TOP2A and HER2. METHODS: In this study, TOP2A, HER2 and chromosome 17 copy number were assessed in 670 cases of breast cancer using in situ hybridisation techniques. Gene to chromosome ratios >=2 were classified as amplification. TOP2A deletion (gene to chromosome ratio <=0.8) or monosomy (only one signal for both gene and chromosome in more than 75% of nuclei) were classified as gene loss. RESULTS: A strong association between TOP2A change and HR and HER2 status was found. During the first 5 years after diagnosis, the risk of death from breast cancer was significantly higher for cases with HER2 amplification irrespective of TOP2A status. CONCLUSIONS: TOP2A copy number change was strongly associated with HR and HER2 status and as a prognostic marker TOP2A is probably of limited value. PMID- 24403187 TI - The prognostic value of Ki67 in systemically untreated patients with node negative breast cancer. AB - AIM: To evaluate the utility of Ki67 as a prognostic marker in a series of patients with node-negative breast cancer untreated with adjuvant systemic therapy. METHODS: The cohort consisted of 203 cases treated with breast conserving surgery and radiation only; median follow-up was 183 months (range 156 277 months). An immunohistochemical panel of oestrogen receptor (ER), progesterone receptor (PR), cytokeratin (CK)5/6 and Ki67 and human epidermal growth factor 2 in situ hybridization (HER2-ISH) was performed on the tumour samples. Ki67 scores were evaluable in 193/203 patients (95.1%). The primary outcome was breast cancer specific survival (BCSS). RESULTS: Of the cohort, 29 (14.2%) died of breast cancer. A cut off of 10% separated tumours into a 'Ki67 low' (n=70) or 'Ki67-high' group (n=123). The breast cancer specific survival was 97.1% and 77.6% for Ki67-low and Ki67-high groups, respectively. Univariate analysis showed that in this lymph node-negative cohort, the predictors for BCSS were tumour size, Ki67, LVI, age and histological grade 3. Multivariable analysis showed that Ki67 index and lymphovascular space invasion were independent predictors of breast cancer death. To examine the utility of Ki67 in assignment of immunohistochemically molecular subtypes, cases were assigned into Luminal A (ER-positive, HER2-negative, Ki67 <=14%), Luminal B (ER-positive, HER2-negative, Ki67 >14%) and triple negative (ER/PR-negative and HER2-negative, any Ki67). The 15-year breast cancer specific survival was 91.7%, 79.4% and 75.8%, respectively. CONCLUSIONS: A statistically significant difference in breast cancer specific survival is seen in groups defined using Ki67 and receptor status, whereas histological grading was not a significant predictor of survival. Ki67 immunostaining provides prognostic information beyond traditionally assessed clinicopathological variables. PMID- 24403188 TI - The aberrant intraepithelial T cells in refractory coeliac disease show epidermotropism. PMID- 24403189 TI - Formation of "quasi" contact or solvent-separated ion pairs in the local environment of probe molecules dissolved in ionic liquids. AB - The change from "quasi" contact to "quasi" solvent-separated ion-pair configuration in the local environment of a probe molecule in ionic liquids depends on the varying interaction strength of the chosen anions. The ion speciation in these Coulomb fluids could be shown by combining infrared spectroscopy, density functional theory calculations, and natural bond orbital analysis using a low-self-clustering probe molecule. PMID- 24403190 TI - Bioproduction of baccatin III, an advanced precursor of paclitaxol, with transgenic Flammulina velutipes expressing the 10-deacetylbaccatin III-10-O acetyl transferase gene. AB - BACKGROUND: 10-Deacetylbaccatin III (10-DAB) and baccatin III are intermediates in the biosynthesis of Taxol (an anti-cancer drug) and useful precursors for semi synthesis of the drug. In this study, a bioconversion system was established for the production of baccatin III, an advanced precursor of paclitaxel, in the transgenic mushroom Flammulina velutipes expressing the 10-deacetylbaccatin III 10beta-O-acetyltransferase gene. The expression vector pgFvs-TcDBAT containing the 10-deacetylbaccatin III-10beta-O-acetyltransferase (DBAT) gene was constructed and transformed into the cells of F. velutipes by polyethylene glycol mediated protoplast transformation. RESULTS: Polymerase chain reaction and Southern blotting analysis verified the successful integration of the exogenous DBAT gene into the genome of F. velutipes. Reverse transcription polymerase chain reaction and enzyme activity analyses confirmed that the DBAT gene was expressed in F. velutipes, and DBAT is able to convert substrate into baccatin III. CONCLUSION: The DBAT gene from the plant Taxus chinensis can be functionally expressed in F. velutipes. Transgenic F. velutipes expressing the DBAT gene is able to produce the target product, baccatin III. This is the first report about the transformation and expression of paclitaxel biosynthetic gene in the edible mushroom F. velutipes. This represents a significant step towards bio-production of paclitaxel and its advanced precursor baccatin III in an edible fungus. PMID- 24403191 TI - In vitro screening of Fe2+-chelating effect by a Fenton's reaction-luminol chemiluminescence system. AB - In vitro screening of a Fe(2+) -chelating effect using a Fenton's reaction luminol chemiluminescence (CL) system is described. The luminescence between the reactive oxygen species generated by the Fenton's reaction and luminol was decreased on capturing Fe(2+) using a chelator. The proposed method can prevent the consumption of expensive seed compounds (drug discovery candidates) owing to the high sensitivity of CL detection. Therefore, the assay could be performed using small volumes of sample solution (150 MUL) at micromolar concentrations. After optimization of the screening conditions, the efficacies of conventional chelators such as ethylenediaminetetraacetic acid (EDTA), diethylentriaminepentaacetic acid (DETAPAC), deferoxamine, deferiprone and 1,10 phenanthroline were examined. EC50 values for these compounds (except 1,10 phenanthroline) were in the range 3.20 +/- 0.87 to 9.57 +/- 0.64 MUM (n = 3). Rapid measurement of the Fe(2+)-chelating effect with an assay run time of a few minutes could be achieved using the proposed method. In addition, the specificity of the method was discussed. PMID- 24403193 TI - [Stocking process for consumables and investement goods in the public health service (first part)]. AB - Hospital procedures to stock tools and equipment supplies for day-by-day clinical diagnosis and treatment place physicians to face up with their ones responsibilities. Nephrologists have to deal with dialysis machines, related technology updating and associated consumables. Overall they have to cope with local health service reality, which looks for progressive doctors skill improvement at lowest or no cost at all. Aim of the first part of this review is to analyze all these issues according European Union, Italian and local main lines and associated laws. Moreover, will be reviewed purchase strategies always looking at patient wellness as final aim of the entire process. They will be illustrated sequences of administrative measures, recent Central Commissioning Headquarters, and laws that since 2006 have defined the related procedures (i.e. open, limited, negotiated, and competitive). PMID- 24403192 TI - A variant upstream of HLA-DRB1 and multiple variants in MICA influence susceptibility to cervical cancer in a Swedish population. AB - In a genome-wide association study, we have previously identified and performed the initial replication of three novel susceptibility loci for cervical cancer: rs9272143 upstream of HLA-DRB1, rs2516448 adjacent to MHC class I polypeptide related sequence A gene (MICA), and rs3117027 at HLA-DPB2. The risk allele T of rs2516448 is in perfect linkage disequilibrium with a frameshift mutation (A5.1) in MICA exon 5, which results in a truncated protein. To validate these associations in an independent study and extend our prior work to MICA exon 5, we genotyped the single-nucleotide polymorphisms at rs9272143, rs2516448, rs3117027 and the MICA exon 5 microsatellite in a nested case-control study of 961 cervical cancer patients (827 carcinoma in situ and 134 invasive carcinoma) and 1725 controls from northern Sweden. The C allele of rs9272143 conferred protection against cervical cancer (odds ratio [OR] = 0.73, 95% confidence interval [CI] = 0.65-0.82; P = 1.6 * 10(-7)), which is associated with higher expression level of HLA-DRB1, whereas the T allele of rs2516448 increased the susceptibility to cervical cancer (OR = 1.33, 95% CI = 1.19-1.49; P = 5.8 * 10(-7)), with the same association shown with MICA-A5.1. The direction and the magnitude of these associations were consistent with our previous findings. We also identified protective effects of the MICA-A4 (OR = 0.80, 95% CI = 0.68-0.94; P = 6.7 * 10( 3)) and MICA-A5 (OR = 0.60, 95% CI = 0.50-0.72; P = 3.0 * 10(-8)) alleles. The associations with these variants are unlikely to be driven by the nearby human leukocyte antigen (HLA) alleles. No association was observed between rs3117027 and risk of cervical cancer. Our results support the role of HLA-DRB1 and MICA in the pathogenesis of cervical cancer. PMID- 24403194 TI - [Prevention of diabetic nephropathy: from bench to bedside]. AB - The early phases of diabetic nephropathy are characterized by an increase of GFR that, according to the tubular hypothesis, is secondary to alterations of proximal tubules. Experimental studies have in fact shown that hyperglycemia induces an increase in proximal re-absorption due to hypertrophy of tubular cells with consequent increment of sodium-glucose co-transport. The increased re absorption in turn causes a reduction of the distal delivery of solutes and, through activation of tubuloglomerular feedback, an increase in single- nephron GFR. The resulting hyper-filtration has been proposed as a main risk factor for progression of diabetic renal disease. Limiting this early alteration may therefore represent a useful strategy for the prevention of diabetic nephropathy, that represents the major cause of ESRD in the western world today. Dapagliflozin, a competitive and highly selective inhibitor of sodium-glucose co transport, reduces proximal tubular glucose re-absorption, increases renal glucose excretion, and reduces hyperglycemia in a dose-dependent manner. This singular mechanism of action may also have a limiting effect on diabetic hyper filtration. Clinical trials are therefore warranted to evaluate the reno protective efficacy of this drug in the long term. PMID- 24403195 TI - [Arterial media calcification: from pathogenesis to diagnosis]. AB - Patients with chronic kidneyl disease (CKD) have a higher cardiovascular mortality than the general population, in partly due to the development of arterial media calcification (AMC). It is still a matter of discussion as to whether arterial intimal calcification (AIC) and AMC should be considered as distinct entities with different pathogenesis or as a single nosological entity. The pathogenesis of mediocalcinosis is multifactorial. It consists of several stages which overlap; oxidative stress, endothelial dysfunction, shear stress, neoangiogenesis, degradation of the extracellular matrix. Endothelial cells stimulate angiogenesis both by passage of inflammatory cytokines and by migration of osteoprogenitor cells through the tunica media. VSMCs and pericytes are transformed into osteoclast-like cells with production of calcifying matrix vesicles through an active process regulated by promoters and inhibitors factors. Currently, radiology modalities are the only imaging methods that can be used to detect AMC in non-overlapping areas of vessels but X-ray imaging only allows us to identify this lesion when the vessel is widely calcified. Recently, ultrasonography and RX mammography has also been used as an alternative tool for the diagnosis of AMC in patients affected by CKD and they can be used to recognize it earlier than X-ray imaging, which will aid in the treatment of high risk patients Calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) have been identified in vascular smooth muscle cells (VSMC). Considering the essential role of VSMC in the pathogenesis of AMC, it could be important to identify in an early stage patients who develop this shape of arterial calcification to start drugs as cinacalcet or paricalcitol when possible. PMID- 24403196 TI - [Peritoneal dialysis in adult patients with prune belly syndrome: an impossible challenge?]. AB - Prune belly syndrome (PBS) is a rare congenital syndrome characterized by hypoplasia of the abdominal muscles, urinary tract malformations, and cryptorchidism in males. The estimated incidence is 1 in 35,000 to 50,000 live births. Chronic renal failure and end-stage renal disease (ESRD), due both to different degrees of renal hypoplasia or dysplasia and infectious complications, develops in 20-30% of patients who survive the neonatal period. No data are available on progression time to ESRD, owing to the variability of the phenotypic features of nephropathy. Nevertheless, PBS is primarily a pathology of pediatric interest as demonstrated, for example, by the reported average age at transplantation which usually does not exceed fifteen years of age. Therefore the need for renal replacement therapy (RRT) in adult patients with PBS is unusual. It is reasonable to suppose that the abdominal muscular defects may represent a limit for peritoneal dialysis (PD) utilization in PBS adult patients in many Kidney Units where, conversely, treatment with hemodialysis would be probably the easier choice. Here we describe the case of a 44 -year- old man with PBS who, at the age of 41, required RRT and was faced with the challenge of accepting PD. After more than three years of nocturnal automated peritoneal dialysis treatment we can safely say, as the following case illustrates, that PD is a feasible option in PBS adult patients. PMID- 24403197 TI - [Optimal use of peritoneal dialysis with multi-disciplinary management]. AB - INTRODUCTION: Considering the increasing incidence of chronic kidney disease and the increased use of peritoneal dialysis, we wanted to assess whether the multidisciplinary management of patients in peritoneal dialysis might produce improvement in the quality of patients' lives when compared to management by a routine team of operators. METHODS: Our study observed 40 patients on peritoneal dialysis in our Department between 2010 and 2012. They were randomly assigned to either group A, the routine team which consisted of a nephrologist and a nurse, or group B, a multidisciplinary team comprising several medical specialists, a nurse, a psychologist and a social worker. Two tests, KDQOL-SF and MMPI-2, were administered to both groups. RESULTS: In group B, the number of days of hospitalization and day hospital were more than 88% lower when compared to group A. The multidisciplinary team achieved better results with the KDQOL-SF test with regards to both emotional and objective dimensions. The Pearson coefficient between the results of the two questionnaires shows how multidisciplinary management can positively influence the perceived well-being of the patient and his or her adherence to treatment. CONCLUSIONS: In a multidisciplinary team, each operator, in addition to his or her specific role, also contributes to the achievement of the overall objective, namely of ensuring an optimal quality of life to the patient on peritoneal dialysis thereby allowing these patients to continue their professional and social lives. PMID- 24403198 TI - [Micro RNA-155 expression in hemodialysis PBMC]. AB - INTRODUCTION: MicroRNAs (miR) are fragments of non-coding RNA acting at post transcriptional level, which modulate gene expression, and play a key role in several pathophysiological pathways. The aim of this study is to analyze the expression of miR-155 in basal Peripheral Blood Mononuclear Cells (PBMC) of chronic hemodialysis (HD) patients, before and after standard 4 -hour sessions, and after PHA stimulation compared with PBMC from healthy subjects. METHODS: miR 155 was isolated from chronic HD patients' PBMC and from PBMC derived from healthy subjects. Expression levels were quantified with Real-Time PCR; PCR reactions were performed using a specific thermocycler and cycle threshold levels were calculated using dedicated software. Blood samples were taken from HD patients after the long inter-dialytic interval. Data were expressed as MSE and statistical differences were calculated with t-test. RESULTS: Relative quantity (RQ) of pre-dialysis MiR-155 was 3.770.62 times higher than the control group (P=0,003). There was no significant difference before and after hemodialysis sessions. Pre-dialysis mir-155 RQ in PHA PBMC was 1.790.59 times higher than non stimulated PBMC (P=0.019). CONCLUSIONS: these preliminary data show a significant miR-155 up-regulation of HD PBMC when compared to PBMC from healthy individuals. An additional up-regulation was observed in HD PHA PBMC. Similar miR-155 expression was found in HD PBMC comparing pre and post-hemodialysis sessions. PMID- 24403199 TI - [New perspectives in the classification and treatment of systemic lupus erythematosus: the central role of kidney involvement]. AB - Systemic lupus erythematosus (SLE) is an autoimmune condition with a wide range of manifestations. Among the various targets of the disease, the kidney holds a very important place. In fact, renal involvement is one of the most important and frequent features of the disease, deeply affecting a patient's prognosis and influencing the therapeutic approach. In the last few years, some progress has been achieved in terms of both disease classification and treatment. In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) published the new classification criteria for SLE and the American College of Rheumatology established recommendations for the screening, treatment, and management of SLE nephritis. These new points of view derived from the recent evolution of medical knowledge, technology, and practice in the field of SLE in general, and lupus nephritis in particular. Moreover, it is important to remember that SLE still remains a systemic disorder and that a multi-disciplinary approach is the optimal way to manage these patients. PMID- 24403200 TI - [The kidney and circadian rhythms: a whole new world?]. AB - Chronobiology is a branch of biomedical sciences devoted to the study of biological rhythms. Biological rhythms exist at any level of living organisms and, according to their cycle length, may be divided into three main types: circadian, ultradian, and infradian rhythms. Circadian rhythms are the most commonly and widely studied. The principal circadian clock is located in the suprachiasmatic nucleus of the hypothalamus, and is supposed to regulate peripheral clocks via neurohumoral modulation. Circadian clocks have been identified within almost all mammalian cell types, and circadian clock genes seem to be essential for cardiovascular health. Disturbance of the renal circadian rhythms is increasingly recognized as a risk factor for hypertension, polyuria, and other diseases and may contribute to renal fibrosis. The origin of these rhythms has been attributed to the reactive response of the kidney to circadian changes in volume and/or in the composition of extracellular fluids regulated by rest/activity and feeding/fasting cycles. However, most of the renal excretory rhythms persist for long periods of time, even in the absence of periodic environmental cues. These observations led to the hypothesis of the existence of a self-sustained mechanism, enabling the kidney to anticipate various predictable circadian challenges to homeostasis. The molecular basis of this mechanism remained unknown until the recent discovery of the mammalian circadian clock, comprising a system of autoregulatory transcriptional/translational feedback loops, which have also been found in the kidney. PMID- 24403201 TI - [Control of HCV, HBV and HIV Infections in Hemodialysis]. AB - Infections with blood-borne pathogens are still common among patients on maintenance dialysis all over the world. The control of infection due to blood borne viruses (particularly HBV) within dialysis units has been a major goal in the management of patients with chronic kidney disease in the industrialized world. Standard precautions and specific procedures have been recommended to prevent infections with HBV, HCV and HIV within dialysis units. Isolation of HBsAg positive patients by dialysis rooms, staff and machines continues to be an important step to control HBV infection within dialysis units, according to the CDC and other regulatory agencies. Some prospective observational studies have reported the complete prevention of HCV transmission to hemodialysis patients in the absence of any isolation policy, and the use of dedicated dialysis machines for HCV-infected patients is not recommended by clinical guidelines. Isolation of HCV-infected patients should be considered in special circumstances only. Vaccination is an important tool against transmission of HBV among patients on long-term dialysis even if the immune response towards the hepatitis B vaccine remains unsatisfactory. Hemodialysis is considered a low risk setting for the transmission of human immunodeficiency virus (HIV) infection, providing that standard and specific procedures are carefully observed. HIV-infected patients do not have to be isolated from other patients or dialyzed separately on dedicated machines. PMID- 24403202 TI - [Project work: formation of health-care personnel for self-care of tunnelled central venous catheters in hemodialysis patients of the territory]. AB - BACKGROUND: Scientific data from current literature demonstrate an incidence of bacteraemia due to tunnelled central venous catheter (tCVC) use accounting for 1.6 / 1000 days per tCVC, with a range of 1.5 to 1.8. In Sicily no data on the incidence of tCVC- related bacteraemia are available. In our hospital, tCVC infection occurs 2.4 times in 1000 days during CVC use. A retrospective analysis carried out from 2006 to 2012 was performed on 650 patients with tunnelled catheters. Of the subjects who received tCVC in our hospital, 90% were destined to undergo haemodialysis in a private health care environment outside our hospital. MATERIALS AND METHODS: In order to improve the aforementioned infection outcome, we planned and implemented a specific work project. The work project (WP) was subdivided into two steps: 1) The first step was further subdivided into two sub-phases. The first was principally concerned with the implementation of educational courses, conducted directly on the ward and aimed at the implementation of meticulous nursing regimes for the care of tCVC by our health care nurse. The courses were entitled Management of Vascular Access: from doing - to teaching to do!. These educational courses were organized by the Nephrology Department, which takes care of the management and handling of the major complications of tCVCs for the maintenance of haemodialysis. After this first step, the nurses who had participated became the promoters of the second part of the course, which concerned the development of know-how within an outpatient clinic, which deals exclusively with the nursing management of tCVCs. 2) The title of the second phase was Therapeutic Education: self-Care and understanding and managing your venous access at home. The aim of this step was the integration of correct in-hospital care with that available in outsourced private institutions, via the involvement of the patient in the management of their own central venous access. During our training project, a more detailed analysis of the stakeholder as well as a swot analysis on the feasibility of the project were used to determine ad interim and final targets of the study. A summary of operative planning is included to explain in greater detail the study design, timing and costs of the various phases. Risk management and corrective measures adopted during the project are also mentioned and monitoring of the phases is described in relation to the fulfilling of intermediate goals. The prompt correction of mistakes allows for safer realisation of outcomes. CONCLUSION: From our experience with this work project, we can conclude that a more accurate management of tCVCs can significantly reduce the morbidity and mortality of patients. The project offers a positive cost-benefit balance through a decrease in costs of hospitalisation for tCVC-related infections and other life.threatening conditions related to the use of tCVCs an important goal for any spending review. PMID- 24403203 TI - [Calcium supplementation in healthy subjects: benefits and risks]. AB - Over recent years the cardiovascular safety of calcium supplementation, taken by millions on a daily basis, has raised concerns. Despite the borderline benefit of calcium supplementation in regards to fracture risk reduction, osteoporosis guidelines continue to advocate daily calcium supplementation assuming that calcium does no harm. However, reanalysis of large randomised controlled trials (RCTs) and observational studies consistently show a modest, but significant increased cardiovascular risk in healthy individuals taking calcium supplementation. The aim of this review is summarise recent data demonstrating elevated cardiovascular risk possibly attributable to oral calcium supplementation in healthy individuals. PMID- 24403204 TI - [Ozone therapy: a potential adjunct approach to lower urinary tract infection? A case series report]. AB - Multi-resistant drug bacteria are an emerging health care concern around the world. A decreased resistance to infection as seen in Chronic Kidney Disease (CKD) and kidney transplanted patients as well as some metabolic abnormalities such as hyperglycemia and glycosuria or clinical conditions such as the neurogenic bladder may indeed portend a great risk of recurrent urinary tract infections (UTI). The common and indiscriminate use of antibiotics often provides the patients with only a transient or partial amelioration of the urinary tract discomforts and increases the risk of multi-resistant drug bacteria selection. Thus a great effort is made in order to develop new antibacterial approaches especially in the setting of multi- antibiotic resistant pathogens. We herein report on some promising yet preliminary results of the use of ozone therapy in UTI. PMID- 24403205 TI - Design and synthesis of tricyclic JAK3 inhibitors with picomolar affinities as novel molecular probes. AB - The Janus kinase (JAK) signaling pathway is of particular importance in the pathology of inflammatory diseases and oncological disorders, and the inhibition of Janus kinase 3 (JAK3) with small molecules has proven to provide therapeutic immunosuppression. A novel class of tricyclic JAK inhibitors derived from the 3 methyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine scaffold was designed based on the tofacitinib-JAK3 crystal structure by applying a rigidization approach. A convenient synthetic strategy to access the scaffold via an intramolecular Heck reaction was developed, and a small library of inhibitors was prepared and characterized using in vitro biochemical as well as cellular assays. IC50 values as low as 220 pM could be achieved with selectivity for JAK3 over other JAK family members. Both activity and selectivity were confirmed in a cellular STAT phosphorylation assay, providing also first-time data for tofacitinib. Our novel inhibitors may serve as tool compounds and useful probes to explore the role of JAK3 inhibition in pharmacodynamics studies. PMID- 24403206 TI - How water interacts with halogenated anesthetics: the rotational spectrum of isoflurane-water. AB - The rotational spectra of several isotopologues of the 1:1 complex between the inhaled anesthetic isoflurane and water have been recorded and analyzed by using Fourier transform microwave spectroscopy. The rotational spectrum showed a single rotamer, corresponding to the configuration in which the most stable conformer of isolated isoflurane is linked to the water molecule through an almost linear C H???O weak hydrogen bond. All transitions display a hyperfine structure due to the (35)Cl (or (37)Cl) nuclear quadrupole effects. PMID- 24403208 TI - Fast-track medical course and its implications. PMID- 24403209 TI - A new approach for the photosynthetic antenna-reaction center complex with a model organized around an s-triazine linker. AB - Two new artificial mimics of the photosynthetic antenna-reaction center complex have been designed and synthesized (BDP-H2 P-C60 and BDP-ZnP-C60). The resulting electron-donor/acceptor conjugates contain a porphyrin (either in its free-base form (H2P) or as Zn-metalated complex (ZnP)), a boron dipyrrin (BDP), and a fulleropyrrolidine possessing, as substituent of the pyrrolidine nitrogen, an ethylene glycol chain terminating in an amino group C60-X-NH2 (X=spacer). In both cases, the three different components were connected by s-triazine through stepwise substitution reactions of cyanuric chloride. In addition to the facile synthesis, the star-type arrangement of the three photo- and redox-active components around the central s-triazine unit permits direct interaction between one another, in contrast to reported examples in which the three components are arranged in a linear fashion. The energy- and electron-transfer properties of the resulting electron-donor/acceptor conjugates were investigated by using UV/Vis absorption and emission spectroscopy, cyclic voltammetry, and femtosecond transient absorption spectroscopy. Comparison of the absorption spectra and cyclic voltammograms of BDP-H2P-C60 and BDP-ZnP-C60 with those of BDP-H2P, BDP ZnP and BDP-C60, which were used as references, showed that the spectroscopic and electrochemical properties of the individual constituents are basically retained, although some appreciable shifts in terms of absorption indicate some interactions in the ground state. Fluorescence lifetime measurements and transient absorption experiments helped to elucidate the antenna function of BDP, which upon selective excitation undergoes a rapid and efficient energy transfer from BDP to H2P or ZnP. This is then followed by an electron transfer to C60, yielding the formation of the singlet charge-separated states, namely BDP-H2(.+) C60(.-) and BDP-ZnP(.+)-C60(.-). As such, the sequence of energy transfer and electron transfer in the present models mimics the events of natural photosynthesis. PMID- 24403210 TI - Multi-color imaging of fluorescent nanodiamonds in living HeLa cells using direct electron-beam excitation. AB - Multi-color, high spatial resolution imaging of fluorescent nanodiamonds (FNDs) in living HeLa cells has been performed with a direct electron-beam excitation assisted fluorescence (D-EXA) microscope. In this technique, fluorescent materials are directly excited with a focused electron beam and the resulting cathodoluminescence (CL) is detected with nanoscale resolution. Green- and red light-emitting FNDs were employed for two-color imaging, which were observed simultaneously in the cells with high spatial resolution. This technique could be applied generally for multi-color immunostaining to reveal various cell functions. PMID- 24403211 TI - Core valve implant failure in the presence of mechanical mitral prosthesis: importance of assessing left ventricular outflow tract. AB - Transcatheter aortic valve replacement in the presence of a mitral prosthetic valve is a technically challenging endeavor. The presence of a mitral prosthesis can alter the geometry of the landing zone for the device. A multi slice computerized tomography with comprehensive review of left ventricular outflow tract and aortic root in its entirety is critical for preventing implant failure. Technical expedients to treat implant failure involve understanding of the device as well its relationship with the mitral prosthesis. PMID- 24403213 TI - Synthesis and application of a targeting diagnosis system via quantum dots coated by amphiphilic polymer for the detection of liver cancer cells. AB - Water-soluble quantum dots (QDs) for liver cancer diagnosis were prepared using QDs with oleylamine ligand coated with poly(aspartate)-graft-poly(ethylene glycol)-dodecylamine (PASP-Na-g-PEG-DDA). Dynamic light scattering and transmission electron microscopy imaging showed that the novel QDs have an ellipsoidal morphology with a size of ~ 45 nm which could be used for biomedical application. Furthermore, the PASP-Na-g-PEG-DDA was then modified with anti (vascular endothelial growth factor) (VEGF antibody), and a 1-(4,5 dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) assay showed that the novel anti VEGF-targeting QDs in vitro had low toxicity. Confocal laser scanning microscopy observations revealed an intracellular (HepG2) distribution of the novel anti VEGF-targeting QDs and the targeting efficiency of anti-VEGF. These novel QDs could be used as a probe for liver cancer cell imaging because of anti-VEGF targeting. PMID- 24403212 TI - Association of polymyalgia rheumatica with socioeconomic status in primary care: a cross-sectional observational study. AB - OBJECTIVE: Polymyalgia rheumatica (PMR) is an inflammatory musculoskeletal condition predominantly diagnosed and managed in the community. Socioeconomic status (SES) is known to be associated with many inflammatory rheumatologic conditions, but has not been investigated in relation to PMR. This study aimed to investigate the association between PMR and SES at both the area and individual levels. METHODS: Patients ages >50 years registered with 8 general practices in North Staffordshire were sent a questionnaire requesting details of their general health, SES, and lifestyle. Individual SES was measured using occupation, educational level, and perceived adequacy of income. Area-level SES was measured using the Index of Multiple Deprivation, derived from respondents' postcodes. Electronic primary care medical records were searched for Read code diagnoses of PMR 2 years before and after the survey. RESULTS: Of the 13,831 respondents, 141 had a recorded PMR diagnosis in their electronic medical records, a prevalence of 10 per 1,000 patients. No association between PMR and SES was seen at either the individual or area level. CONCLUSION: No association was found between PMR and SES at either the area or individual level. Unlike several of the inflammatory arthritides that are more common in the more deprived areas, PMR shows no such association. In part this may be due to PMR affecting an older population. Although socioeconomic factors are important for clinicians and researchers to consider, in patients with PMR, further epidemiologic work is needed to fully characterize this disabling disorder. PMID- 24403214 TI - Downgrading of biopsy based Gleason score in prostatectomy specimens. AB - AIMS: To assess the frequency and possible causes of downgrading from a Gleason score (GS) 7 at biopsy to a GS <=6 at radical prostatectomy (RP) in a Canadian referral centre. METHODS: Data were extracted from diagnostic reports of inhouse biopsies and matching prostatectomy specimens from 2008 to 2011 with a GS 7 at biopsy. Biopsies and corresponding prostatectomy specimens of downgraded cases were reviewed. Pathological features were assessed and possible predictors for downgrading were identified. RESULTS: Based on pathology reports, 29 (8.9%, 95% CI 5.8% to 11.9%) of the 327 eligible cases were downgraded from biopsy GS 7 to RP GS 6, 72% of them representing a GS <=6 with tertiary grade 4 at RP. Agreement at review of downgraded RP specimens for Gleason grading was fair and of borderline significance (kappa=0.34, 95% CI -0.01 to 0.68, p=0.055) with 65% agreement for tertiary grade. The predominant Gleason grade 4 pattern found in the downgraded biopsies was ill-formed glands. The number of cores with Gleason grade 4 component was found to be the strongest negative predictor of downgrading (prereview OR=0.56 (95% CI 0.39 to 0.80, p=0.002), postreview OR=0.19 (95% CI 0.07 to 0.52, p=0.001)). CONCLUSIONS: The frequency of GS 7 in biopsies subsequently downgraded in RP is low and is associated with International Society of Urological Pathology modified Gleason grade 4 patterns. Downgrading could be attributed in most cases to the presence of a tertiary Gleason grade 4 pattern in the RP specimen. Inter-observer agreement for the presence of tertiary grade 4 in RP specimens is moderate. PMID- 24403215 TI - A fluorogenic probe with aggregation-induced emission characteristics for carboxylesterase assay through formation of supramolecular microfibers. AB - Herein, we report a novel fluorescent "light-up" probe useful for carboxylesterase assay that is based on a tetraphenylethylene derivative containing carboxylic ester groups. The specific cleavage of the carboxylic ester bonds by carboxylesterase results in the generation of a relatively hydrophobic moiety that self-assembles into supramolecular microfibers, thus giving rise to "turn-on" fluorescent signals. A high sensitivity towards carboxylesterase was achieved with a detection limit as low as 29 pM, which is much lower than the corresponding assays based on other fluorescent approaches. PMID- 24403216 TI - Inference of bioequivalence for log-normal distributed data with unspecified variances. AB - Two drugs are bioequivalent if the ratio of a pharmacokinetic (PK) parameter of two products falls within equivalence margins. The distribution of PK parameters is often assumed to be log-normal, therefore bioequivalence (BE) is usually assessed on the difference of logarithmically transformed PK parameters (delta). In the presence of unspecified variances, test procedures such as two one-sided tests (TOST) use sample estimates for those variances; Bayesian models integrate them out in the posterior distribution. These methods limit our knowledge on the extent that inference about BE is affected by the variability of PK parameters. In this paper, we propose a likelihood approach that retains the unspecified variances in the model and partitions the entire likelihood function into two components: F-statistic function for variances and t-statistic function for delta. Demonstrated with published real-life data, the proposed method not only produces results that are same as TOST and comparable with Bayesian method but also helps identify ranges of variances, which could make the determination of BE more achievable. Our findings manifest the advantages of the proposed method in making inference about the extent that BE is affected by the unspecified variances, which cannot be accomplished either by TOST or Bayesian method. PMID- 24403217 TI - Strongly luminous tetranuclear gold(I) complexes supported by tetraphosphine ligands, meso- or rac-bis[(diphenylphosphinomethyl)phenylphosphino]methane. AB - A series of tetragold(I) complexes supported by tetraphosphine ligands, meso- and rac-bis[(diphenylphosphinomethyl)phenylphosphino]methane (meso- and rac-dpmppm) were synthesized and characterized to show that the tetranuclear Au(I) alignment varies depending on syn- and anti-arrangements of the two dpmppm ligands with respect to the metal chain. The structures of syn-[Au4 (meso-dpmppm)2X]X'3 (X = Cl; X' = Cl (4 a), PF6 (4 b), BF4 (4 c)) and syn-[Au4 (meso-dpmppm)2]X4 (X = PF6 (4 d), BF4 (4 e), TfO (4 f); TfO = triflate) involved a bent tetragold(I) core with a counter anion X incorporated into the bent pocket. Complexes anti-[Au4 (meso-dpmppm)2]X4 (X = PF6 (5 d), BF4 (5 e), TfO (5 f)) contain a linearly ordered Au4 string and complexes syn-[Au4 (rac-dpmppm)2X2]X'2 (X = Cl, X' = Cl (6 a), PF6 (6 b), BF4 (6 c)) and syn-[Au4 (rac-dpmppm)2]X4 (X = PF6 (6 d), BF4 (6 e), TfO (6 f)) consist of a zigzag tetragold(I) chain supported by the two syn arranged rac-dpmppm ligands. Complexes 4 d-f, 5 d-f, and 6 d-f with non coordinative large anions are strongly luminescent in the solid state (lambdamax = 475-515 nm, Phi = 0.67-0.85) and in acetonitrile (lambdamax = 491-520 nm, Phi = 0.33-0.97); the emission was assigned to phosphorescence from (3) [dsigma*sigma*sigma* psigmasigmasigma] excited state of the Au4 centers on the basis of DFT calculations as well as the long lifetime (a few MUs). The emission energy is predominantly determined by the HOMO and LUMO characters of the Au4 centers, which depend on the bent (4), linear (5), and zigzag (6) alignments. The strong emissions in acetonitrile were quenched by chloride anions through simultaneous dynamic and static quenching processes, in which static binding of chloride ions to the Au4 excited species should be the most effective. The present study demonstrates that the structures of linear tetranuclear gold(I) chains can be modified by utilizing the stereoisomeric tetraphosphines, meso- and rac-dpmppm, which may lead to fine tuning of the strongly luminescent properties intrinsic to the Au(I) 4 cluster centers. PMID- 24403218 TI - Unusual orthogonality in the cleavage process of closely related chelating protecting groups for carboxylic acids by using different metal ions. AB - Three structurally related relay protecting groups for carboxylic acids that are based on chelating amines have been developed. These protecting groups can easily be introduced by coupling the carboxylic acid and the corresponding amine in the presence of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU). In addition to being stable to a whole array of reaction conditions, these protecting groups are also stable under acidic and basic conditions, allowing them to be used in combination with the ester protection of carboxylic acids. The cleavage of these protecting groups is activated by the chelation of metal ions, involving an unusual coordination of the amide nitrogen. Despite their similarity, cleavage of these protecting groups is possible in both a stepwise and an orthogonal fashion by applying different metal salts. PMID- 24403219 TI - An epidemiologic internet survey of fibromyalgia and chronic pain in Japan. AB - OBJECTIVE: To determine the epidemiologic features and symptom characteristics of fibromyalgia (FM) in Japan, and compare them with those for other chronic pain (CP) diagnoses. METHODS: An internet survey was conducted in June and July 2011. The questionnaire consisted of 111 questions, including assessments of the Japanese version of the 2010 American College of Rheumatology preliminary diagnostic criteria for FM, the Japanese Fibromyalgia Impact Questionnaire, and additional questions regarding pain and lifestyle. RESULTS: The questionnaire was completed by 20,407 male and female respondents in all prefectures of Japan. Of the survey population, 2,524 respondents (12.4%) reported symptoms consistent with CP; of these, 425 (2.1%) reported symptoms consistent with FM. Among respondents with FM and CP, 61% and 53%, respectively, were women. Pain severity and Widespread Pain Index scores were significantly higher in respondents meeting the diagnostic criteria for FM than in those meeting the criteria for CP. In terms of symptom severity scores, the proportions of respondents reporting the 3 major symptoms as "highly applicable" and greater numbers of 41 somatic symptoms were higher among respondents with FM than among those with CP. The incidence of FM in the present survey was similar to that reported (1.7%) in a study of FM in Japan in 2003, despite the use of the newer, easier to use 2010 diagnostic criteria. CONCLUSION: Because FM usually presents with more severe and more widely distributed pain, as well as more nonpainful symptoms than CP, our results suggest that FM is a different clinical phenotype of CP. PMID- 24403220 TI - New entangled coordination networks based on charge-tunable keggin-type polyoxometalates. AB - Investigation into a hydrothermal reaction system with transition-metal (TM) ions, 1,4-bis(1,2,4-triazol-1-lmethyl)benzene (BBTZ) and various charge-tunable Keggin-type polyoxometalates (POMs) led to the preparation of four new entangled coordination networks, [Co(II) (HBBTZ)(BBTZ)2.5 ][PMo12 O40 ] (1), [Cu(I) (BBTZ)]5 [BW12 O40 ]?H2 O (2), [Cu(II) (BBTZ)]3 [AsW(V) 3 W(VI) 9 O40 ]?10 H2 O (3), and [Cu(II) 5 (BBTZ)7 (H2 O)6 ][P2 W22 Cu2 O77 (OH)2 ]?6 H2 O (4). All compounds were characterized by using elemental analysis, IR spectroscopy, thermogravimetric analysis, powder X-ray diffraction, and single-crystal X-ray diffraction. The mixed valence of W centers in compound 3 was further confirmed by using XPS spectroscopy and bond-valence sum calculations. In the structural analysis, the entangled networks of 1-4 demonstrate zipper-closing packing, 3D polythreading, 3D polycatenation, and 3D self-penetration, respectively. Moreover, with the enhancement of POM negative charges and the use of different TM types, the number of nodes in the coordination networks of 1-4 increased and the basic metal-organic building motifs changed from a 1D zipper-type chain (in 1) to a 2D pseudorotaxane layer (in 2) to a 3D diamond-like framework (in 3) and finally to a 3D self-penetrating framework (in 4). The photocatalytic properties of compounds 1-4 for the degradation of methylene blue under UV light were also investigated; all compounds showed good catalytic activity and the photocatalytic activity order of Keggin-type species was initially found to be {XMo12 O40 }>{XW12 O40 }>{XW12-n TMn O40 }. PMID- 24403221 TI - Interrater reliability of sleep videofluoroscopy for airway obstruction in obstructive sleep apnea. AB - OBJECTIVES/HYPOTHESIS: Sleep videofluoroscopy (SVF) has been introduced to identify upper airway obstruction. This study was aimed to determine the interrater reliability of SVF in patients with obstructive sleep apnea (OSA). STUDY DESIGN: A retrospective analysis. METHODS: On the basis of apnea-hypopnea index in full-night attended polysomnography, 374 consecutive OSA patients who underwent SVF were enrolled in this study. The SVF was evaluated by three independent reviewers. Interrater reliabilities were assessed by evaluating agreement of the obstructive anatomic structures (soft palate, tongue base, tonsils, and epiglottis) and airway levels (velopharynx, oropharynx, and hypopharynx) between the reviewers. RESULTS: In a comparison between an unblinded and a blinded well-experienced sleep surgeons, the interrater reliability for the presence of obstruction was the highest for the soft palate at the level of the velopharynx (Cohen's kappa value, 0.919) and the lowest for the soft palate at the level of the oropharynx (Cohen's kappa value, 0.757). In a blind comparison between a well-experienced and less-experienced sleep surgeons, the interrater reliability for the presence of obstruction was also the highest for the soft palate at the level of the velopharynx (Cohen's kappa value, 0.938) and the lowest for the palatine tonsils at the level of the oropharynx (Cohen's kappa value, 0.635). CONCLUSION: This study showed that SVF was a diagnostic modality that can be used to evaluate upper airway obstruction without significant interrater disagreements. PMID- 24403222 TI - Heteronuclear cross-relaxation effects in the NMR spectroscopy of hyperpolarized targets. AB - Dissolution dynamic nuclear polarization (DNP) enables high-sensitivity solution phase NMR experiments on long-lived nuclear spin species such as (15)N and (13)C. This report explores certain features arising in solution-state (1)H NMR upon polarizing low-gamma nuclear species. Following solid-state hyperpolarization of both (13)C and (1)H, solution-phase (1)H NMR experiments on dissolved samples revealed transient effects, whereby peaks arising from protons bonded to the naturally occurring (13)C nuclei appeared larger than the typically dominant (12)C-bonded (1)H resonances. This enhancement of the satellite peaks was examined in detail with respect to a variety of mechanisms that could potentially explain this observation. Both two- and three-spin phenomena active in the solid state could lead to this kind of effect; still, experimental observations revealed that the enhancement originates from (13)C->(1)H polarization-transfer processes active in the liquid state. Kinetic equations based on modified heteronuclear cross-relaxation models were examined, and found to well describe the distinct patterns of growth and decay shown by the (13)C-bound (1)H NMR satellite resonances. The dynamics of these novel cross-relaxation phenomena were determined, and their potential usefulness as tools for investigating hyperpolarized ensembles and for obtaining enhanced-sensitivity (1)H NMR traces was explored. PMID- 24403223 TI - Expansion and malapposition characteristics after bioresorbable vascular scaffold implantation. AB - OBJECTIVES: This study sought to investigate the postdeployment expansion and malapposition characteristics of the bioresorbable vascular scaffold (BVS) in real-world practice. BACKGROUND: The material construct of the BVS precludes overexpansion, with consequent potential for scaffold underexpansion and malapposition. In metallic stents, these features are associated with an increased risk of adverse events, including stent thrombosis. The postdeployment characteristics of the BVS are yet to be described outside clinical trials, where implantation occurred in straightforward lesion subsets. METHODS: Data from 25 patients undergoing BVS implantation were analyzed. Optical coherence tomography (OCT) was performed both before and after intervention to assess plaque composition, scaffold expansion and strut apposition. Manufacturer's compliance charts were used to predict expected minimal scaffold diameter and area. RESULTS: OCT pullback (522.2 mm) was analyzed. Overall, BVS achieved 82.5 +/- 8.7 and 79.8 +/- 12.3% of predicted minimal stent diameter and cross-sectional area (SCA), respectively, with expansion reduced in middle third of the scaffold (central SCA 76.7 +/- 10.9% vs. noncentral SCA 81.5 +/- 12.7%, P < 0.0001). Improved measures of SCA were observed with 1:1 balloon:vessel predilatation (1:1 PreD 82.8 +/- 9.5% vs. No 1:1 PredD 78.6 +/- 13.0%, P < 0.0001). Seven thousand six hundred scaffold struts were identified, of which 470 (6.18%) were malapposed. In fibrocalcific (FCa) plaques, malapposition was observed more frequently (FCa 44.4% vs. Other plaques 7.5%, P < 0.001) and at a greater distance from the vessel wall (FCa 0.17 +/- 0.10 mm vs. Other plaques 0.14 +/- 0.08 mm, P = 0.002). CONCLUSIONS: In this study, BVS expansion was significantly improved by 1:1 PreD, while increased rates of malapposition was associated with FCa plaques. PMID- 24403224 TI - The mechanism of gold(I)-catalyzed hydroalkoxylation of alkynes: an extensive experimental study. AB - An extensive experimental study of the mechanism of gold(I)-catalyzed hydroalkoxylation of internal alkynes has been conducted by using NMR spectroscopy. This study was focused on the organogold intermediates, observations of actual catalytic intermediates in situ, and the reaction kinetics that are involved in this reaction. Based on the experimental results, a complete mechanistic picture was established, including on- and off-cycle processes that explain the role of diaurated species. We have shown that gold-catalyzed hydroalkoxylation of internal alkynes is a reaction that requires only one gold atom for the catalytic cycle, disproving a recent hypothesis regarding the involvement of cooperative gold catalysis. PMID- 24403225 TI - Characterization of hERG1 channel role in mouse colorectal carcinogenesis. AB - The human ether-a-go-go-related gene (hERG)1 K(+) channel is upregulated in human colorectal cancer cells and primary samples. In this study, we examined the role of hERG1 in colorectal carcinogenesis using two mouse models: adenomatous polyposis coli (Apc(min/+) ) and azoxymethane (AOM)-treated mice. Colonic polyps of Apc(min/+) mice overexpressed mERG1 and their formation was reverted by the hERG1 blocker E4031. AOM was applied to either hERG1-transgenic (TG) mice, which overexpress hERG1 in the mucosa of the large intestine, or wild-type mice. A significant increase of both mucin-depleted foci and polyps in the colon of hERG1 TG mice was detected. Both the intestine of TG mice and colonic polyps of Apc(min/+) showed an upregulation of phospho-Protein Kinase B (pAkt)/vascular endothelial growth factor (VEGF-A) and an increased angiogenesis, which were reverted by treatment with E4031. On the whole, this article assigns a relevant role to hERG1 in the process of in vivo colorectal carcinogenesis. PMID- 24403226 TI - Treatment with the vascular disruptive agent OXi4503 induces an immediate and widespread epithelial to mesenchymal transition in the surviving tumor. AB - Epithelial to mesenchymal transition (EMT) is considered an important mechanism in tumor resistance to drug treatments; however, in vivo observation of this process has been limited. In this study we demonstrated an immediate and widespread EMT involving all surviving tumor cells following treatment of a mouse model of colorectal liver metastases with the vascular disruptive agent OXi4503. EMT was characterized by significant downregulation of E-cadherin, relocation and nuclear accumulation of beta-catenin as well as significant upregulation of ZEB1 and vimentin. Concomitantly, significant temporal upregulation in hypoxia and the pro-angiogenic growth factors hypoxia-inducible factor 1-alpha, hepatocyte growth factor, vascular endothelial growth factor and transforming growth factor-beta were seen within the surviving tumor. The process of EMT was transient and by 5 days after treatment tumor cell reversion to epithelial morphology was evident. This reversal, termed mesenchymal to epithelial transition (MET) is a process implicated in the development of new metastases but has not been observed in vivo histologically. Similar EMT changes were observed in response to other antitumor treatments including chemotherapy, thermal ablation, and antiangiogenic treatments in our mouse colorectal metastasis model and in a murine orthotopic breast cancer model after OXi4503 treatment. These results suggest that EMT may be an early mechanism adopted by tumors in response to injury and hypoxic stress, such that inhibition of EMT in combination with other therapies could play a significant role in future cancer therapy. PMID- 24403227 TI - BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I. AB - The activation of the transcription factor hypoxia-inducible factor-1 (HIF-1) plays an essential role in tumor development, tumor progression, and resistance to chemo- and radiotherapy. In order to identify compounds targeting the HIF pathway, a small molecule library was screened using a luciferase-driven HIF-1 reporter cell line under hypoxia. The high-throughput screening led to the identification of a class of aminoalkyl-substituted compounds that inhibited hypoxia-induced HIF-1 target gene expression in human lung cancer cell lines at low nanomolar concentrations. Lead structure BAY 87-2243 was found to inhibit HIF 1alpha and HIF-2alpha protein accumulation under hypoxic conditions in non-small cell lung cancer (NSCLC) cell line H460 but had no effect on HIF-1alpha protein levels induced by the hypoxia mimetics desferrioxamine or cobalt chloride. BAY 87 2243 had no effect on HIF target gene expression levels in RCC4 cells lacking Von Hippel-Lindau (VHL) activity nor did the compound affect the activity of HIF prolyl hydroxylase-2. Antitumor activity of BAY 87-2243, suppression of HIF 1alpha protein levels, and reduction of HIF-1 target gene expression in vivo were demonstrated in a H460 xenograft model. BAY 87-2243 did not inhibit cell proliferation under standard conditions. However under glucose depletion, a condition favoring mitochondrial ATP generation as energy source, BAY 87-2243 inhibited cell proliferation in the nanomolar range. Further experiments revealed that BAY 87-2243 inhibits mitochondrial complex I activity but has no effect on complex III activity. Interference with mitochondrial function to reduce hypoxia induced HIF-1 activity in tumors might be an interesting therapeutic approach to overcome chemo- and radiotherapy-resistance of hypoxic tumors. PMID- 24403228 TI - LRP5 knockdown: effect on prostate cancer invasion growth and skeletal metastasis in vitro and in vivo. AB - Prostate cancer (PCa) is a common hormone-dependent malignancy associated with the development of skeletal metastases. This is due to the increased expression of a number of growth factors, cytokines, and proteases which collectively drive the metastatic cascade in general and increased propensity to develop skeletal metastasis in particular. While a number of signaling pathways have been implicated in PCa progression, the highly complex wnt/beta-catenin pathway is unique due to its ability to regulate gene expression, cell invasion, migration, survival, proliferation, and differentiation to contribute in the initiation and progression of PCa. Members of the wnt family bind to the Frizzle proteins or lipoprotein-related receptor proteins 5, 6 (LRP5, -6) to activate this key pathway. In the current study, we have investigated the role of wnt/beta-catenin pathway in PCa progression, skeletal metastasis, and gene expression using the dominant negative plasmid of LRP5 (DN-LRP5) and human PCa cells PC-3. Inactivation of LRP5 resulted in mesenchymal to epithelial shift, lack of translocation of beta-catenin to cell surface, increased tumor cell proliferation, decreased colony formation, migration and invasion in vitro. These effects were attributed to decreased expression of pro-invasive and pro metastatic genes. In in vivo studies, PC-3-DN-LRP5 cells developed significantly smaller tumors and a marked decrease in skeletal lesion area and number as determined by X-ray, micro (MU) CT and histological analysis. Collectively results from these studies demonstrate the dominant role of this key pathway in PCa growth and skeletal metastasis and its potential as a viable therapeutic target. PMID- 24403229 TI - Preimmunization of donor lymphocytes enhances antitumor immunity of autologous hematopoietic stem cell transplantation. AB - Lymphopenia-induced homeostatic proliferation (HP) of T cells following autologous hematopoietic stem cell transplantation (HSCT) skews the T-cell repertoire by engaging tumor-associated antigens (TAAs), leading to an induction of antitumor immunity. Here, as the tumor-reactive lymphocytes preferentially proliferate during the condition of HP, we examined whether the priming of a donor lymphocytes to TAAs could enhance HP-induced antitumor immunity in autologous HSCT recipients. First, to examine whether the tumor-bearing condition of donor influences the antitumor effect of HSCT, the lymphocytes isolated from CT26 tumor-bearing mice were infused into lethally irradiated mice. The growth of tumors was substantially suppressed in the mice that received HSCT from a tumor bearing donor compared with a naive donor, suggesting that a fraction of donor lymphocytes from tumor-bearing mice are primed in response to TAAs and remain responsive upon transplantation. We previously reported that type I interferon (IFN) maturates the dendritic cells and promotes the priming of T cells. We then investigated whether the further priming of donor cells by IFN-alpha can strengthen the antitumor effect of HSCT. The intratumoral IFN-alpha gene transfer significantly increased the number of IFN-gamma-positive lymphocytes in response to CT26 cells but not the syngeneic lymphocytes in donor mice. The infusion of primed donor lymphocytes markedly suppressed the tumor growth in recipient mice, and cured 64% of the treated mice. Autologous HSCT with the infusion of primed donor lymphocytes is a promising strategy to induce an effective antitumor immunity for solid cancers. PMID- 24403230 TI - Gene expression profiling upon (212) Pb-TCMC-trastuzumab treatment in the LS-174T i.p. xenograft model. AB - Recent studies have demonstrated that therapy with (212) Pb-TCMC-trastuzumab resulted in (1) induction of apoptosis, (2) G2/M arrest, and (3) blockage of double-strand DNA damage repair in LS-174T i.p. (intraperitoneal) xenografts. To further understand the molecular basis of the cell killing efficacy of (212) Pb TCMC-trastuzumab, gene expression profiling was performed with LS-174T xenografts 24 h after exposure to (212) Pb-TCMC-trastuzumab. DNA damage response genes (84) were screened using a quantitative real-time polymerase chain reaction array (qRT PCR array). Differentially regulated genes were identified following exposure to (212) Pb-TCMC-trastuzumab. These included genes involved in apoptosis (ABL, GADD45alpha, GADD45gamma, PCBP4, and p73), cell cycle (ATM, DDIT3, GADD45alpha, GTSE1, MKK6, PCBP4, and SESN1), and damaged DNA binding (DDB) and repair (ATM and BTG2). The stressful growth arrest conditions provoked by (212) Pb-TCMC trastuzumab were found to induce genes involved in apoptosis and cell cycle arrest in the G2/M phase. The expression of genes involved in DDB and single strand DNA breaks was also enhanced by (212) Pb-TCMC-trastuzumab while no modulation of genes involved in double-strand break repair was apparent. Furthermore, the p73/GADD45 signaling pathway mediated by p38 kinase signaling may be involved in the cellular response, as evidenced by the enhanced expression of genes and proteins of this pathway. These results further support the previously described cell killing mechanism by (212) Pb-TCMC-trastuzumab in the same LS-174T i.p. xenograft. Insight into these mechanisms could lead to improved strategies for rational application of radioimmunotherapy using alpha-particle emitters. PMID- 24403231 TI - Heterogeneity of d-glucuronyl C5-epimerase expression and epigenetic regulation in prostate cancer. AB - Heparansulfate proteoglycans (HSPG) play an important role in cell-cell and cell matrix interactions and signaling, and one of the key enzymes in heparansulfate biosynthesis is d-glucuronyl C5-epimerase (GLCE). A tumor suppressor function has been demonstrated for GLCE in breast and lung carcinogenesis; however, no data are available as to the expression and regulation of the gene in prostate cancer. In this study, decreased GLCE expression was observed in 10% of benign prostate hyperplasia (BPH) tissues and 53% of prostate tumors, and increased GLCE mRNA levels were detected in 49% of BPH tissues and 21% of tumors. Statistical analysis showed a positive correlation between increased GLCE expression and Gleason score, TNM staging, and prostate-specific antigen (PSA) level in the prostate tumors (Pearson correlation coefficients GLCE/Gleason = 0.56, P < 0.05; GLCE/TNM = 0.62, P < 0.05; and GLCE/PSA = 0.88, P < 0.01), suggesting GLCE as a candidate molecular marker for advanced prostate cancer. Immunohistochemical analysis revealed an intratumoral heterogeneity of GLCE protein levels both in BPH and prostate cancer cells, resulting in a mixed population of GLCE-expressing and nonexpressing epithelial cells in vivo. A model experiment on normal (PNT2) and prostate cancer (LNCaP, PC3, DU145) cell lines in vitro showed a 1.5- to 2.5 fold difference in GLCE expression levels between the cancer cell lines and an overall decrease in GLCE expression in cancer cells. Methyl-specific polymerase chain reaction (PCR), bisulfite sequencing, and deoxy-azacytidin (aza-dC) treatment identified differential GLCE promoter methylation (LNCaP 70-72%, PC3 32 35%, DU145, and PNT2 no methylation), which seems to contribute to heterogeneous GLCE expression in prostate tumors. The obtained results reveal the complex deregulation of GLCE expression in prostatic diseases compared with normal prostate tissue and suggest that GLCE may be used as a potential model to study the functional role of intratumor cell heterogeneity in prostate cancer progression. PMID- 24403232 TI - PD-1 as a potential target in cancer therapy. AB - Recently, an improved understanding of the molecular mechanisms governing the host response to tumors has led to the identification of checkpoint signaling pathways involved in limiting the anticancer immune response. One of the most critical checkpoint pathways responsible for mediating tumor-induced immune suppression is the programmed death-1 (PD-1) pathway, normally involved in promoting tolerance and preventing tissue damage in settings of chronic inflammation. Many human solid tumors express PD ligand 1 (PD-L1), and this is often associated with a worse prognosis. Tumor-infiltrating lymphocytes from patients with cancer typically express PD-1 and have impaired antitumor functionality. Proof-of-concept has come from several preclinical studies in which blockade of PD-1 or PD-L1 enhanced T-cell function and tumor cell lysis. Three monoclonal antibodies against PD-1, and one against PD-L1, have reported phase 1 data. All four agents have shown encouraging preliminary activity, and those that have been evaluated in larger patient populations appear to have encouraging safety profiles. Additional data are eagerly awaited. This review summarizes emerging clinical data and potential of PD-1 pathway-targeted antibodies in development. If subsequent investigations confirm the initial results, it is conceivable that agents blocking the PD-1/PD-L1 pathway will prove valuable additions to the growing armamentarium of targeted immunotherapeutic agents. PMID- 24403233 TI - Systemic treatment of metastatic uveal melanoma: review of literature and future perspectives. AB - Up to 50% of patients with uveal melanoma develop metastatic disease with poor prognosis. Regional, mainly liver-directed, therapies may induce limited tumor responses but do not improve overall survival. Response rates of metastatic uveal melanoma (MUM) to systemic chemotherapy are poor. Insights into the molecular biology of MUM recently led to investigation of new drugs. In this study, to compare response rates of systemic treatment for MUM we searched Pubmed/Web of Knowledge databases and ASCO website (1980-2013) for "metastatic/uveal/melanoma" and "melanoma/eye." Forty studies (one case series, three phase I, five pilot, 22 nonrandomized, and two randomized phase II, one randomized phase III study, data of three expanded access programs, three retrospective studies) with 841 evaluable patients were included in the numeric outcome analysis. Complete or partial remissions were observed in 39/841 patients (overall response rate [ORR] 4.6%; 95% confidence intervals [CI] 3.3-6.3%), no responses were observed in 22/40 studies. Progression-free survival ranged from 1.8 to 7.2, median overall survival from 5.2 to 19.0 months as reported in 21/40 and 26/40 studies, respectively. Best responses were seen for chemoimmunotherapy (ORR 10.3%; 95% CI 4.8-18.7%) though mainly in first-line patients. Immunotherapy with ipilimumab, antiangiogenetic approaches, and kinase inhibitors have not yet proven to be superior to chemotherapy. MEK inhibitors are currently investigated in a phase II trial with promising preliminary data. Despite new insights into genetic and molecular background of MUM, satisfying systemic treatment approaches are currently lacking. Study results of innovative treatment strategies are urgently awaited. PMID- 24403234 TI - Oxyphenisatin acetate (NSC 59687) triggers a cell starvation response leading to autophagy, mitochondrial dysfunction, and autocrine TNFalpha-mediated apoptosis. AB - Oxyphenisatin (3,3-bis(4-hydroxyphenyl)-1H-indol-2-one) and several structurally related molecules have been shown to have in vitro and in vivo antiproliferative activity. This study aims to confirm and extend mechanistic studies by focusing on oxyphenisatin acetate (OXY, NSC 59687), the pro-drug of oxyphenisatin. Results confirm that OXY inhibits the growth of the breast cancer cell lines MCF7, T47D, HS578T, and MDA-MB-468. This effect is associated with selective inhibition of translation accompanied by rapid phosphorylation of the nutrient sensing eukaryotic translation initiation factor 2alpha (eIF2alpha) kinases, GCN2 and PERK. This effect was paralleled by activation of AMP-activated protein kinase (AMPK) combined with reduced phosphorylation of the mammalian target of rapamycin (mTOR) substrates p70S6K and 4E-BP1. Microarray analysis highlighted activation of pathways involved in apoptosis induction, autophagy, RNA/protein metabolism, starvation responses, and solute transport. Pathway inhibitor combination studies suggested a role for AMPK/mTOR signaling, de novo transcription and translation, reactive oxygen species (ROS)/glutathione metabolism, calcium homeostasis and plasma membrane Na(+) /K(+) /Ca(2+) transport in activity. Further examination confirmed that OXY treatment was associated with autophagy, mitochondrial dysfunction, and ROS generation. Additionally, treatment was associated with activation of both intrinsic and extrinsic apoptotic pathways. In the estrogen receptor (ER) positive MCF7 and T47D cells, OXY induced TNFalpha expression and TNFR1 degradation, indicating autocrine receptor-mediated apoptosis in these lines. Lastly, in an MCF7 xenograft model, OXY delivered intraperitoneally inhibited tumor growth, accompanied by phosphorylation of eIF2alpha and degradation of TNFR1. These data suggest that OXY induces a multifaceted cell starvation response, which ultimately induces programmed cell death. PMID- 24403235 TI - Hormone profiling, WHO 2010 grading, and AJCC/UICC staging in pancreatic neuroendocrine tumor behavior. AB - Pancreatic neuroendocrine tumors (pNETs) are the second most common pancreatic neoplasms, exhibiting a complex spectrum of clinical behaviors. To examine the clinico-pathological characteristics associated with long-term prognosis we reviewed 119 patients with pNETs treated in a tertiary referral center using the WHO 2010 grading and the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) staging systems, with a median follow-up of 38 months. Tumor size, immunohistochemistry (IHC) profiling and patient characteristics determining stage were analyzed. Primary clinical outcomes were disease progression or death. The mean age at presentation was 52 years; 55% were female patients, 11% were associated with MEN1 (multiple endocrine neoplasia 1) or VHL (Von Hippel-Lindau); mean tumor diameter was 3.3 cm (standard deviation, SD) (2.92). The clinical presentation was incidental in 39% with endocrine hypersecretion syndromes in only 24% of cases. Nevertheless, endocrine hormone tissue immunoreactivity was identified in 67 (56.3%) cases. According to WHO 2010 grading, 50 (42%), 38 (31.9%), and 3 (2.5%) of tumors were low grade (G1), intermediate grade (G2), and high grade (G3), respectively. Disease progression occurred more frequently in higher WHO grades (G1: 6%, G2: 10.5%, G3: 67%, P = 0.026) and in more advanced AJCC stages (I: 2%, IV: 63%, P = 0.033). Shorter progression free survival (PFS) was noted in higher grades (G3 vs. G2; 21 vs. 144 months; P = 0.015) and in more advanced AJCC stages (stage I: 218 months, IV: 24 months, P < 0.001). Liver involvement (20 vs. 173 months, P < 0.001) or histologically positive lymph nodes (33 vs. 208 months, P < 0.001) were independently associated with shorter PFS. Conversely, tissue endocrine hormone immunoreactivity, independent of circulating levels was significantly associated with less aggressive disease. Age, gender, number of primary tumors, and heredity were not significantly associated with prognosis. Although the AJCC staging and WHO 2010 grading systems are useful in predicting disease progression, tissue endocrine hormone profiling provides additional information of potentially important prognostic value. PMID- 24403236 TI - The impact of patient compliance with adjuvant radiotherapy: a comprehensive cohort study. AB - Postoperative radiotherapy (RT) is the standard of care for early stage breast cancer. It reduces the risk for local recurrence and prolongs survival. We assessed whether, the omission of RT because of patient's preference may influence the prognosis and, thus, the quality of cancer care. Detailed information from a prospectively collected database of a breast cancer center was analyzed. Multiple regression analysis and univariate and multivariate analysis for risk factors for recurrence were performed. The entire cohort of primary breast cancer patients in a given time period was analyzed. Data from 1903 patients undergoing treatment at breast cancer center between 2003 and 2008 were used. All patient underwent breast conserving surgery and RT was performed for all patients of the cohort. Local tumor control and disease-free survival were calculated. After a median follow-up of 2.18 years (maximum 6.39 years), 5.5% of patients did not follow guideline-based recommendations for RT. There was a significant correlation between noncompliance and patient's age, adjuvant hormonal therapy (97.0%), and adjuvant chemotherapy (96.8%). Seventy local recurrences occurred that corresponds to a local recurrence rate of 3.9%. The difference in regard to local recurrence-free 5-year survival between the compliant patients and the noncompliant patients is absolute 17.9 (93.3% and 75.4%). Noncompliant patients had suffered a 5.02-fold increased risk of local recurrence than compliant patients. The omission of RT after breast-conserving surgery results in a higher local failure rate and significantly worsens clinical outcome. Age may play an important role because of the comorbidities of aged patients or the assumed low RT tolerance in this group. On a clinical level, this data suggests that improvement is needed to correct this situation, and the question remains as to how best to improve RT compliance. PMID- 24403237 TI - A population-based comparison of second primary cancers in Germany and Sweden between 1997 and 2006: clinical implications and etiologic aspects. AB - Second primary cancer (SPC) has become an increasing concern in cancer survivorship. Patterns of SPCs in different populations may offer clinical implications and research priorities into SPCs. This study is devoted to compare the occurrences and rank correlations of SPCs between Germany and Sweden. Patients diagnosed with 10 common first primaries between 1997 and 2006 from the Swedish Family-Cancer Database and 10 German cancer registries were included in this population-based study. Spearman's rank correlation coefficients were used to evaluate the strength of the relationship of SPCs between the German and Swedish datasets. Spearman's rank correlation coefficients suggested a strong positive correlation between the German and Swedish datasets based on the ranks of thirty possible SPCs after all selected first cancers. This was also true when we compared the rankings and proportions of the five most common SPCs after site specific first primaries between the two populations. For kidney cancer, non Hodgkin's lymphoma, and leukemia the components of the five most common SPCs was exactly the same. Also, the ranking and the proportions for the three most common SPCs (i.e., colorectal, bladder, and lung cancers) after prostate cancer were identical in the two populations, as were those after most other primary cancers. The strikingly consistent patterns of SPCs in the two populations provide excellent opportunities for joint studies and they also suggest that many underlying reasons for SPC may have universal and tangible causes that await mechanistic dissection. PMID- 24403238 TI - Prognostic value of quantitative fluorodeoxyglucose measurements in newly diagnosed metastatic breast cancer. AB - The aim of this study was to determine the prognostic value of quantitative fluorodeoxyglucose (FDG) measurements (maximum standardized uptake value [SUVmax ], metabolic tumor volume [MTV], and total lesion glycolysis [TLG]) in patients with newly diagnosed metastatic breast cancer (MBC). An IRB-approved retrospective review was performed of patients who underwent FDG positron emission tomography (PET)/computed tomography (CT) from 1/02 to 12/08 within 60 days of diagnosis MBC. Patients with FDG-avid lesions without receiving chemotherapy in the prior 30 days were included. Target lesions in bone, lymph node (LN), liver, and lung were analyzed for SUVmax , MTV, and TLG. Medical records were reviewed for patient characteristics and overall survival (OS). Cox regression was used to test associations between quantitative FDG measurements and OS. A total of 253 patients were identified with disease in bone (n = 150), LN (n = 162), liver (n = 48), and lung (n = 66) at the time of metastatic diagnosis. Higher SUVmax tertile was associated with worse OS in bone metastases (highest vs. lowest tertile hazard ratio [HR] = 3.1, P < 0.01), but not in LN, liver or lung (all P > 0.1). Higher MTV tertile was associated with worse OS in LN (HR = 2.4, P < 0.01) and liver (HR = 3.0, P = 0.02) metastases, but not in bone (P = 0.22) or lung (P = 0.14). Higher TLG tertile was associated with worse OS in bone (HR = 2.2, P = 0.02), LN (HR = 2.3, P < 0.01), and liver (HR = 4.9, P < 0.01) metastases, but not in lung (P = 0.19). We conclude measures of FDG avidity are prognostic biomarkers in newly diagnosed MBC. SUVmax and TLG were both predictors of survival in breast cancer patients with bone metastases. TLG may be a more informative biomarker of OS than SUVmax for patients with LN and liver metastases. PMID- 24403239 TI - Thiocoraline alters neuroendocrine phenotype and activates the Notch pathway in MTC-TT cell line. AB - Medullary thyroid cancer (MTC) is an aggressive neuroendocrine tumor (NET). Previous research has shown that activation of Notch signaling has a tumor suppressor role in NETs. The potential therapeutic effect of thiocoraline on the activation of the Notch pathway in an MTC cell line (TT) was investigated. Thiocoraline was isolated from a marine bacterium Verrucosispora sp. MTT assay (3 [4, 5-dimethylthiazole-2-yl]-2, 5-diphenyltetrazolium bromide) was used to determine the IC50 value and to measure cell proliferation. Western blot revealed the expression of Notch isoforms, NET, and cell cycle markers. Cell cycle progression was validated by flow cytometry. The mRNA expression of Notch isoforms and downstream targets were measured using real-time PCR. The IC50 value for thiocoraline treatment in TT cells was determined to be 7.6 nmol/L. Thiocoraline treatment decreased cell proliferation in a dose- and time-dependent manner. The mechanism of growth inhibition was found to be cell cycle arrest in G1 phase. Thiocoraline activated the Notch pathway as demonstrated by the dose dependent increase in mRNA and protein expression of Notch isoforms. Furthermore, treatment with thiocoraline resulted in changes in the expression of downstream targets of the Notch pathway (HES1, HES2, HES6, HEY1, and HEY2) and reduced expression of NET markers, CgA, and ASCL1. Thiocoraline is a potent Notch pathway activator and an inhibitor of MTC-TT cell proliferation at low nanomolar concentrations. These results provide exciting evidence for the use of thiocoraline as a potential treatment for intractable MTC. PMID- 24403241 TI - Value of information methods for assessing a new diagnostic test. AB - Value-of-information methods are applied to assess the evidence in support of a new diagnostic test and, where the evidence is insufficient for decision making, to determine the optimal sample size for future studies. Net benefit formulations are derived under various diagnostic and treatment scenarios. The expressions for the expected opportunity loss of adopting strategies that include the new test are given. Expressions for the expected value of information from future studies are derived. One-sample and two-sample designs, with or without known prevalence, are considered. An example is given. PMID- 24403240 TI - Racial difference in histologic subtype of renal cell carcinoma. AB - In the United States, renal cell carcinoma (RCC) has rapidly increased in incidence for over two decades. The most common histologic subtypes of RCC, clear cell, papillary, and chromophobe have distinct genetic and clinical characteristics; however, epidemiologic features of these subtypes have not been well characterized, particularly regarding any associations between race, disease subtypes, and recent incidence trends. Using data from the Surveillance, Epidemiology, and End Results (SEER) Program, we examined differences in the age adjusted incidence rates and trends of RCC subtypes, including analysis focusing on racial differences. Incidence rates increased over time (2001-2009) for all three subtypes. However, the proportion of white cases with clear cell histology was higher than among blacks (50% vs. 31%, respectively), whereas black cases were more likely than white cases to have papillary RCC (23% vs. 9%, respectively). Moreover, papillary RCC incidence increased more rapidly for blacks than whites (P < 0.01) over this period. We also observed that increased incidence of papillary histology among blacks is not limited to the smallest size strata. We observed racial differences in proportionate incidence of RCC subtypes, which appear to be increasing over time; this novel finding motivates further etiologic, clinical, molecular, and genetic studies. PMID- 24403243 TI - Template-free preparation of volvox-like Cd(x)Zn(1-x)S nanospheres with cubic phase for efficient photocatalytic hydrogen production. AB - Volvox-like Cdx Zn1-x S solid solutions with a cubic zinc blend structure were synthesized through a template-free ethylene glycol process. Cd(Ac)2 ?2 H2 O, Zn(Ac)2 ?2 H2 O, and thiourea are used as the starting materials and dissolved in ethylene glycol. These reaction precursors and solvent not only contributed to control over the formation of the volvox-like spherical geometry, but also exerted vigorous domination for existence of cubic-phase Cdx Zn1-x S nanostructures. As-prepared volvox-like Cdx Zn1-x S nanospheres have a diameter of around 100 nm with extensional shells. These samples show excellent photocatalytic H2 evolution activity from water splitting under visible-light irradiation without any cocatalyst or scaffolding, owing to their tunable band gap, cubic zinc blend structure, and unique hierarchical porous structure with a high surface area (as high as 95.2 m(2) g(-1) ). PMID- 24403242 TI - "We're all looking for solutions": a qualitative study of the management of knee symptoms. AB - OBJECTIVE: While the prevalence of osteoarthritis (OA) increases with age, the first signs begin in the fourth or fifth decade. Little is known about how younger adults respond to OA. This study explores how people ages 35-65 years manage knee symptoms. METHODS: Six focus groups were conducted with 41 participants (mean age 50.9 years, 63% women) who self-reported a diagnosis of OA or reported knee symptoms (i.e., pain, aching, or stiffness) on most days of the past month. Purposive sampling was used, seeking variation in age and sex. The principles of constructivist grounded theory guided data collection and analysis. Data were analyzed using a constant comparative method. RESULTS: Participants engaged in a process of proactively trying to find ways to control knee symptoms and disease progression. Their approach to management was not linear, but rather a process that moved back and forth between searching for "solutions" and active management (ongoing use of strategies). During the process, participants consulted health care providers, but often perceived that medical care offered limited options and guidance. Management was constructed as a "never-ending" process that entailed effort and personal resources. CONCLUSION: Participants were proactive in seeking ways to manage knee OA symptoms. There is a mismatch between participants' proactive approach and the reactive approach of the health care system that has focused on late-stage disease. Programs and supports within the formal and informal health care system are required to enable people to successfully manage knee symptoms across their lifespan. PMID- 24403244 TI - Dormant versus evolving aminopalladated intermediates: toward a unified mechanistic scenario in Pd(II)-catalyzed aminations. AB - Pd(II)-catalyzed alkene aminopalladation and allylic C-H activation are two competing reaction sequences sharing the same reaction conditions. This study aimed at understanding the factors that bias one or the other path in the intramolecular oxidative cyclization of two types of N-tosyl amidoalkenes. The results obtained are in accord with the initial generation of a high-energy cyclic (5- or 6-membered) aminopalladated intermediate. However, this latter species can evolve only if the following specific conditions are met: the availability of distocyclic beta-H elimination pathway, the presence of a strong terminal oxidant, or the availability of a carbopalladation pathway. Conversely, the cyclic alkylpalladium complex is only a latent species in equilibrium with the initial substrate and cannot evolve. Such a reactivity hurdle leaves the way open for alternative reactivities such as allylic C-H activation of the olefinic substrate to generate a eta(3)-allyl complex followed by its interception by the nitrogen nucleophile, [3,3]-sigmatropic rearrangement, or decomposition. This study proposes a unifying mechanistic picture that connects these competing mechanisms. PMID- 24403245 TI - Fast track occlusion of aorta with atrial septal defect sizing balloon. AB - We describe the case of a 57-year-old woman referred to our emergency service with ruptured abdominal aneurysm. We placed a 34-mm Amplatzer sizing balloon II into the suprarenal level of aorta to immediately control the active massive bleeding and to get the patient out of hemorrhage shock into the stable condition. After the bleeding control, endovascular repair was successfully performed. This is the first case report, to our knowledge, of atrial septal defect (ASD) sizing balloon use for blocking the blood flow through aorta to control the bleeding. ASD sizing balloon has some different properties compared to aortic occlusion balloon catheter (AOBC). Due to availability of sheathless usage, ASD sizing balloon may be preferred over AOBC for some of patient groups with peripheral artery diseases and small femoral artery diameters. PMID- 24403246 TI - Isolation and characterization of lung resident mesenchymal stem cells capable of differentiating into alveolar epithelial type II cells. AB - Controversies and risks continue to be reported about exogenous mesenchymal stem cell-based therapies. In contrast with employing exogenous stem cells, making use of lung resident mesenchymal stem cells (LR-MSCs) could be advantageous. Our study sought to isolate the LR-MSCs and explore their potential to differentiate into alveolar epithelial type II cells (ATII cells). Total lung cells were first precultured, from which the Sca-1(+) CD45(-) CD31(-) population was purified using fluorescence activated cell sorting (FACS). By these methods, it would seem that the Sca-1(+) CD45(-) CD31(-) cells were LR-MSCs. Similar to bone marrow derived mesenchymal stem cells (BM-MSCs), these cells express Sca-1, CD29, CD90, CD44 and CD106, but not CD31 or CD45. They share the same gene expression file with the BM-MSCs and have a similar DNA content during long-term culturing. Furthermore, they could be serially passaged with all these properties being sustained. Above all, LR-MSCs could differentiate into ATII cells when co cultured with ATII cells in a trans-well system. These findings demonstrated that the Sca-1(+) CD45(-) CD31(-) cells appear to be LR-MSCs that can differentiate into ATII cells. This approach may hold promise for their use in the treatment of lung disease. PMID- 24403247 TI - Data processing in Fourier transform ion cyclotron resonance mass spectrometry. AB - The Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer intricately couples advanced physics, instrumentation, and electronics with chemical and particularly biochemical research. However, general understanding of the data processing methodologies used lags instrumentation, and most data processing algorithms we are familiar with in FT-ICR are not well studied; thus, professional skill and training in FT-ICR operation and data analysis is still the key to achieve high performance in FT-ICR. This review article is focused on FT-ICR data processing, and explains the procedures step-by-step for users with the goal of maximizing spectral features, such as mass accuracy, resolving power, dynamic range, and detection limits. PMID- 24403248 TI - Endoscopic-assisted repair of superior canal dehiscence syndrome. PMID- 24403249 TI - Phenotypic modifications in ovarian cancer stem cells following Paclitaxel treatment. AB - Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Despite initial responsiveness, 80% of EOC patients recur and present with chemoresistant and a more aggressive disease. This suggests an underlying biology that results in a modified recurrent disease, which is distinct from the primary tumor. Unfortunately, the management of recurrent EOC is similar to primary disease and does not parallel the molecular changes that may have occurred during the process of rebuilding the tumor. We describe the characterization of unique in vitro and in vivo ovarian cancer models to study the process of recurrence. The in vitro model consists of GFP+/CD44+/MyD88+ EOC stem cells and mCherry+/CD44 /MyD88- EOC cells. The in vivo model consists of mCherry+/CD44+/MyD88+ EOC cells injected intraperitoneally. Animals received four doses of Paclitaxel and response to treatment was monitored by in vivo imaging. Phenotype of primary and recurrent disease was characterized by quantitative polymerase chain reaction (qPCR) and Western blot analysis. Using the in vivo and in vitro models, we confirmed that chemotherapy enriched for CD44+/MyD88+ EOC stem cells. However, we observed that the surviving CD44+/MyD88+ EOC stem cells acquire a more aggressive phenotype characterized by chemoresistance and migratory potential. Our results highlight the mechanisms that may explain the phenotypic heterogeneity of recurrent EOC and emphasize the significant plasticity of ovarian cancer stem cells. The significance of our findings is the possibility of developing new venues to target the surviving CD44+/MyD88+ EOC stem cells as part of maintenance therapy and therefore preventing recurrence and metastasis, which are the main causes of mortality in patients with ovarian cancer. PMID- 24403250 TI - Differential impact of the expression of the androgen receptor by age in estrogen receptor-positive breast cancer. AB - We evaluated the expression of the androgen receptor (AR) to determine its significance in breast cancer. AR expression levels were analyzed in 250 invasive breast cancers by immunohistochemistry and any association with the clinicopathological features was evaluated. AR expression was higher in estrogen receptor (ER)-positive cases than in ER-negative cases (P < 0.0001). AR expression was associated with ER level, and it increased with age in ER-positive cases. The cut-off value was determined to be 75% (Cancer Res. 2009;69:6131 6140), and AR expression was considered to be high in 155 (62%) cases. High AR expression significantly correlated with lower nuclear grade (P < 0.0001), ER and progesterone receptor (PR) positivity (P < 0.0001 and P = 0.0022), HER2 negativity (P = 0.0113), lower Ki67 index (P < 0.0001) and a longer disease-free survival (DFS) and distant metastasis-free survival (DMFS) (P = 0.0003 and 0.0107). This association between a high AR expression and a good DFS and DMFS was significant for ER-positive tumors (P < 0.0001 and P = 0.0018); however, no association existed between AR expression and prognosis for ER-negative tumors. In patients <=51 years old, a high AR expression level significantly correlated with a better prognosis, but this was not significant in patients who were 50 or younger. Multivariate Cox hazard analyses revealed AR expression to be independently associated with a good prognosis in overall patients (HR 0.46, P = 0.0052) and in the ER-positive cohort (HR 0.34, P = 0.0009). AR expression is associated with a less aggressive phenotype and a good prognosis in patients with ER-positive breast cancer. This is considered to be a specific phenomenon for postmenopausal breast cancer patients. PMID- 24403251 TI - Prognostic value of CtIP/RBBP8 expression in breast cancer. AB - CtIP/RBBP8 is a multifunctional protein involved in transcription, DNA replication, DNA repair by homologous recombination and the G1 and G2 checkpoints. Its multiple roles are controlled by its interaction with several specific factors, including the tumor suppressor proteins BRCA1 and retinoblastoma. Both its functions and interactors point to a putative oncogenic potential of CtIP/RBBP8 loss. However, CtIP/RBBP8 relevance in breast tumor appearance, development, and prognosis has yet to be established. We performed a retrospective analysis of CtIP/RBBP8 and RB1 levels by immunohistochemistry using 384 paraffin-embedded breast cancer biopsies obtained during tumor removal surgery. We have observed that low or no expression of CtIP/RBBP8 correlates with high-grade breast cancer and with nodal metastasis. Reduction on CtIP/RBBP8 is most common in hormone receptor (HR)-negative, HER2-positive, and basal-like tumors. We observed lower levels of RB1 on those tumors with reduced CtIP/RBBP8 levels. On luminal tumors, decreased but not absence of CtIP/RBBP8 levels correlate with increased disease-free survival when treated with a combination of hormone, radio, and chemo therapies. PMID- 24403252 TI - Src controls castration recurrence of CWR22 prostate cancer xenografts. AB - Recurrence of prostate cancer (CaP) after androgen-deprivation therapy continues to have the greatest impact on patient survival. Castration-recurrent (CR)-CaP is likely driven by the activation of androgen receptor (AR) through multiple mechanisms including induction of AR coregulators, AR mutants or splice variants, and AR posttranslational modification such as phosphorylation by Src-family and Ack1 tyrosine kinases. Here, we address whether Src is required for the CR growth of human CWR22 CaP xenografts. The shRNA-mediated Src knockdown or treatment with the Src inhibitors, dasatinib or KXO1, reduced CaP recurrence over controls and increased time-to-recurrence following castration. Moreover, CR-CaP [Src-shRNA] tumors that recurred had similar Src protein and activation levels as those of parental cells, strengthening the notion that Src activity is required for progression to CR-CaP. In contrast, the ability of dasatinib or KXO1 to inhibit Src kinase activity in vitro did not correlate with their ability to inhibit serum-driven in vitro proliferation of CR and androgen-dependent stable cell lines derived from CWR22 tumors (CWR22Rv1 and CWR22PC, respectively), suggesting that the in vitro proliferation of these CaP lines is Src independent. Taken together, these findings strongly suggest that Src is a potent and specific therapeutic target for CR-CaP progression. PMID- 24403253 TI - ADAM17-mediated CD44 cleavage promotes orasphere formation or stemness and tumorigenesis in HNSCC. AB - CD44, an extracellular matrix (ECM) receptor, has been described as a cancer stem cell marker in multiple cancers, including head and neck squamous cell carcinoma (HNSCC). HNSCC orasphere formation or stemness was characterized by cleavage of CD44, and thus we hypothesized that this proteolytic processing may be critical to stemness and tumorigenesis. We tested this hypothesis by examining the mechanisms that regulate this process in vitro and in vivo, and by exploring its clinical relevance in human specimens. Sphere assays have been used to evaluate stemness in vitro. Spheres comprised of HNSCC cells or oraspheres and an oral cancer mouse model were used to examine the significance of CD44 cleavage using stable suppression and inhibition approaches. These mechanisms were also examined in HNSCC specimens. Oraspheres exhibited increased levels of CD44 cleavage compared to their adherent counterparts. Given that disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) is a major matrix metalloproteinase known to cleave CD44, we chemically inhibited and stably suppressed ADAM17 expression in HNSCC cells and found that these treatments blocked CD44 cleavage and abrogated orasphere formation. Furthermore, stable suppression of ADAM17 in HNSCC cells also diminished tumorigenesis in an oral cancer mouse model. Consistently, stable suppression of CD44 in HNSCC cells abrogated orasphere formation and inhibited tumorigenesis in vivo. The clinical relevance of these findings was confirmed in matched primary and metastatic human HNSCC specimens, which exhibited increased levels of ADAM17 expression and concomitant CD44 cleavage compared to controls. CD44 cleavage by ADAM17 is critical to orasphere formation or stemness and HNSCC tumorigenesis. PMID- 24403254 TI - Isocitrate dehydrogenase 2 mutation is a frequent event in osteosarcoma detected by a multi-specific monoclonal antibody MsMab-1. AB - Somatic mutations of isocitrate dehydrogenase (IDH) 1 and IDH2 occur in gliomas, acute myeloid leukemia, and cartilaginous tumors. Somatic mosaic IDH1/2 mutations are also reported in Ollier disease and Maffucci syndrome, which are characterized by multiple central cartilaginous tumors. Although IDH1/2 mutation analysis against osteosarcoma has been performed in several studies, no IDH1/2 mutation has been reported. Herein, we newly report the IDH2-R172S mutation in three of 12 (25%) osteosarcoma patients, which was detected by direct DNA sequencing. No monoclonal antibody (mAb) has been reported against IDH2-R172S mutation. However, we demonstrate that the IDH2-R172S peptide was recognized by our established multi-specific anti-mutated IDH1/2 mAb, MsMab-1, in enzyme-linked immunosorbent assay. Western blot analysis revealed that MsMab-1 reacts with PA tag combined recombinant proteins of IDH2-R172S. Furthermore, MsMab-1 stained IDH2-R172S-expressing osteosarcoma tissues in immunohistochemistry. The MsMab-1 stained nine of 32 (28.1%) osteosarcomas in a tissue microarray. This report is the first describing IDH2 mutations in osteosarcoma, which can be detected by MsMab-1 mAb. Taken together, these results show that MsMab-1 can be anticipated for use in immunohistochemical determination of IDH1/2 mutation-bearing osteosarcoma. PMID- 24403255 TI - IL-13 but not IL-4 signaling via IL-4Ralpha protects mice from papilloma formation during DMBA/TPA two-step skin carcinogenesis. AB - Interleukin 4 (IL-4) was shown to be tumor-promoting in full carcinogenesis studies using 3-methylcholanthrene (MCA). Because heretofore the role of IL-4 in DMBA/TPA (9,10-dimethyl-1,2-benz-anthracene/12-O-tetradecanoylphorbol-13-acetate) two-stage carcinogenesis was not studied, we performed such experiments using either IL-4(-/-) or IL-4Ralpha(-/-) mice. We found that IL-4Ralpha(-/-) but not IL-4(-/-) mice have enhanced papilloma formation, suggesting that IL-13 may be involved. Indeed, IL-13(-/-) mice developed more papillomas after exposure to DMBA/TPA than their heterozygous IL-13-competent littermate controls. However, when tested in a full carcinogenesis experiment, exposure of mice to 25 MUg of MCA, both IL-13(-/-) and IL-13(+/-) mice led to the same incidence of tumors. While IL-4 enhances MCA carcinogenesis, it does not play a measurable role in our DMBA/TPA carcinogenesis experiments. Conversely, IL-13 does not affect MCA carcinogenesis but protects mice from DMBA/TPA carcinogenesis. One possible explanation is that IL-4 and IL-13, although they share a common IL-4Ralpha chain, regulate signaling in target cells differently by employing distinct JAK/STAT-mediated signaling pathways downstream of IL-13 or IL-4 receptor complexes, resulting in different inflammatory transcriptional programs. Taken together, our results indicate that the course of DMBA/TPA- and MCA-induced carcinogenesis is affected differently by IL-4 versus IL-13-mediated inflammatory cascades. PMID- 24403256 TI - BRD4 associates with p53 in DNMT3A-mutated leukemia cells and is implicated in apoptosis by the bromodomain inhibitor JQ1. AB - The bromodomain and extra terminal (BET) family protein bromodomain containing protein 4 (BRD4) is an epigenetic regulator recently identified as a therapeutic target for several hematological cancers, notably mixed lineage leukemia-fusion acute myeloid leukemia (MLL-AML). Here, we show that the BRD4 bromodomain inhibitor JQ1 is highly active against the p53-wild-type Ontario Cancer Institute (OCI)-AML3 cell line which carries mutations in nucleophosmin (NPM1) and DNA methyltransferase 3 (DNMT3A) genes commonly associated with poor prognostic disease. We find that JQ1 causes caspase 3/7-mediated apoptosis and DNA damage response in these cells. In combination studies, we show that histone deacetylase (HDAC) inhibitors, the HDM2 inhibitor Nutlin-3, and the anthracycline daunorubicin all enhance the apoptotic response of JQ1. These compounds all induce activation of p53 suggesting that JQ1 might sensitize AML cells to p53 mediated cell death. In further experiments, we show that BRD4 associates with acetylated p53 but that this association is not inhibited by JQ1 indicating that the protein-protein interaction does not involve bromodomain binding of acetylated lysines. Instead, we propose that JQ1 acts to prevent BRD4-mediated recruitment of p53 to chromatin targets following its activation in OCI-AML3 cells resulting in cell cycle arrest and apoptosis in a c-MYC-independent manner. Our data suggest that BET bromodomain inhibition might enhance current chemotherapy strategies in AML, notably in poor-risk DNMT3A/NPM1-mutated disease. PMID- 24403257 TI - Expression profiling of cervical cancers in Indian women at different stages to identify gene signatures during progression of the disease. AB - Cervical cancer is the second most common cancer among women worldwide, with developing countries accounting for >80% of the disease burden. Although in the West, active screening has been instrumental in reducing the incidence of cervical cancer, disease management is hampered due to lack of biomarkers for disease progression and defined therapeutic targets. Here we carried out gene expression profiling of 29 cervical cancer tissues from Indian women, spanning International Federation of Gynaecology and Obstetrics (FIGO) stages of the disease from early lesion (IA and IIA) to progressive stages (IIB and IIIA-B), and identified distinct gene expression signatures. Overall, metabolic pathways, pathways in cancer and signaling pathways were found to be significantly upregulated, while focal adhesion, cytokine-cytokine receptor interaction and WNT signaling were downregulated. Additionally, we identified candidate biomarkers of disease progression such as SPP1, proliferating cell nuclear antigen (PCNA), STK17A, and DUSP1 among others that were validated by quantitative real-time polymerase chain reaction (qRT-PCR) in the samples used for microarray studies as well in an independent set of 34 additional samples. Integrative analysis of our results with other cervical cancer profiling studies could facilitate the development of multiplex diagnostic markers of cervical cancer progression. PMID- 24403258 TI - Suppression of choriocarcinoma invasion and metastasis following blockade of BDNF/TrkB signaling. AB - Brain-derived neurotrophic factor (BDNF) acts through its cognate receptor tyrosine kinase-B (TrkB) to regulate diverse physiological functions in reproductive and other tissues. In normal and malignant trophoblastic cells, the BDNF/TrkB signaling promotes cell growth. Due to the highly malignant nature of choriocarcinoma, we investigated possible involvement of this system in choriocarcinoma cell invasion and metastasis. We demonstrated that treatment of cultured choriocarcinoma cells, known to express both BDNF and TrkB, with a soluble TrkB ectodomain or a Trk receptor inhibitor K252a suppressed cell invasion accompanied with decreased expression of matrix metalloproteinase-2, a cell invasion marker. In vivo studies using a tumor xenograft model in athymic nude mice further showed inhibition of cell invasion from tumors to surrounding tissues following the suppression of endogenous TrkB signaling. For an in vivo model of choriocarcinoma metastasis, we performed intravenous injections of JAR cells expressing firefly luciferase into severe combined immunodeficiency (SCID) mice. Treatment with K252a inhibited metastasis of tumors to distant organs. In vivo K252a treatment also suppressed metastatic tumor growth as reflected by decreased cell proliferation and increased apoptosis and caspases-3/7 activities, together with reduced tissue levels of a tumor marker, human chorionic gonadotropin-beta. In vivo suppression of TrkB signaling also led to decreased expression of angiogenic markers in metastatic tumor, including cluster of differentiation 31 and vascular endothelial growth factor A. Our findings suggested essential autocrine/paracrine roles of the BDNF/TrkB signaling system in choriocarcinoma invasion and metastasis. Inhibition of this signaling could serve as the basis to develop a novel therapy for patients with choriocarcinoma. PMID- 24403260 TI - Small endometrial carcinoma 10 mm or less in diameter: clinicopathologic and histogenetic study of 131 cases for early detection and treatment. AB - Natural history and clinicopathologic features of early endometrial carcinoma are not evident. Its knowledge is essential to make up strategies for prevention, early detection, and treatment of endometrial carcinoma. Especially it is important to know pathways of endometrial carcinogenesis and frequency of endometrial carcinomas arising from endometrial hyperplasia. Clinicopathologically 131 patients with endometrial carcinoma measuring <=10 mm in diameter ("small endometrial carcinoma") were studied to get useful information for early diagnosis, treatment, and histogenesis. The entire endometrium of surgically removed uterus was step-cut and examined. The patients were, on average, 5 years younger than the controls whose carcinomas measure >10 mm (P < 0.0001). Of the 131 patients, 20% were asymptomatic although only 5% of the controls were asymptomatic (P < 0.0001). Seventy-six percent had the carcinomas located in the upper third section of the uterine corpus. Macroscopically 44% of the tumors were flat and 56% were elevated. Incidence of nodal and ovarian metastases were <1%. Forty percent of "small endometrial carcinomas" were associated with endometrial hyperplasia and 60% were not. It is logical to believe that there are two pathways of endometrial carcinogenesis: carcinomas occurring from hyperplasia (40%) and carcinomas occurring from normal endometrium (60%). As hyperplasia-carcinoma sequence is not a main route, we cannot probably prevent carcinomas only by treatment of hyperplasia. Effort must be focused on detecting early de novo carcinomas. As most "small endometrial carcinomas" arise in the upper third of the corpus, careful endometrial sampling there is important for early detection. PMID- 24403259 TI - Therapeutic potential and adverse events of everolimus for treatment of hepatocellular carcinoma - systematic review and meta-analysis. AB - Everolimus is an orally administrated mammalian target of rapamycin (mTOR) inhibitor. Several large-scale randomized controlled trials (RCTs) have demonstrated the survival benefits of everolimus at the dose of 10 mg/day for solid cancers. Furthermore, mTOR-inhibitor-based immunosuppression is associated with survival benefits for patients with hepatocellular carcinoma (HCC) who have received liver transplantation. However, a low rate of tumor reduction and some adverse events have been pointed out. This review summarizes the antitumor effects and adverse events of everolimus and evaluates its possible application in advanced HCC. For the meta-analysis of adverse events, we used the RCTs for solid cancers. The odds ratios of adverse events were calculated using the Peto method. Manypreclinical studies demonstrated that everolimus had antitumor effects such as antiproliferation and antiangiogenesis. However, some differences in the effects were observed among in vivo animal studies for HCC treatment. Meanwhile, clinical studies demonstrated that the response rate of single-agent everolimus was low, though survival benefits could be expected. The meta-analysis revealed the odds ratios (95% confidence interval [CI]) of stomatitis: 5.42 [4.31 6.73], hyperglycemia: 3.22 [2.37-4.39], anemia: 3.34 [2.37-4.67], pneumonitis: 6.02 [3.95-9.16], aspartate aminotransferase levels: 2.22 [1.37-3.62], and serum alanine aminotransferase levels: 2.94 [1.72-5.02], respectively. Everolimus at the dose of 10 mg/day significantly increased the risk of the adverse events. In order to enable its application to the standard conventional therapies of HCC, further studies are required to enhance the antitumor effects and manage the adverse events of everolimus. PMID- 24403261 TI - Oncologists' attitudes toward KRAS testing: a multisite study. AB - Recent discoveries promise increasingly to help oncologists individually tailor anticancer therapy to their patients' molecular tumor characteristics. One such promising molecular diagnostic is Kirsten ras (KRAS) tumor mutation testing for metastatic colorectal cancer (mCRC) patients. In the current study, we examined how and why physicians adopt KRAS testing and how they subsequently utilize the information when discussing treatment strategies with patients. We conducted 34 semi-structured in-person or telephone interviews with oncologists from seven different health plans. Each interview was audiotaped, transcribed, and coded using qualitative research methods. Information and salient themes relating to the research questions were summarized for each interview. All of the oncologists in this study reported using the KRAS test at the time of the interview. Most appeared to have adopted the test rapidly, within 6 months of the publication of National Clinical Guidelines. Oncologists chose to administer the test at various time points, although the majority ordered the test at the time their patient was diagnosed with mCRC. While oncologists expressed a range of opinions about the KRAS test, there was a general consensus that the test was useful and provided benefits to mCRC patients. The rapid adoption and enthusiasm for KRAS suggests that these types of tests may be filling an important informational need for oncologists when making treatment decisions. Future research should focus on the informational needs of patients around this test and whether patients feel informed or confident with their physicians' use of these tests to determine treatment access. PMID- 24403262 TI - Symptom burden and splenomegaly in patients with myelofibrosis in the United States: a retrospective medical record review. AB - Myelofibrosis (MF) is a clonal hematopoietic malignancy characterized by constitutional and localized symptoms, progressive splenomegaly, bone marrow fibrosis, and cytopenias. Although MF is well studied, few studies exist regarding its symptomatic burden in routine clinical practice. This study aimed to characterize symptoms and other clinical features of MF among patients in the United States. We conducted a retrospective medical record review of adult patients with an MF diagnosis between 1 January 2005 and 31 March 2010, stratified by the presence of palpable splenomegaly. Eligible patients had 12 months or more of follow-up after diagnosis (or after detection of splenomegaly, if present) unless death occurred. Demographic and clinical characteristics, MF related symptoms, and treatments were reported by treating physicians. We report on 180 MF patients: 102 with splenomegaly, 78 without. Median age was 66 years, 63% were male, and 82% had intermediate-2 or high-risk MF (International Prognostic Scoring System). Fatigue was reported by ~85% of patients; weight loss, night sweats, and fever (any grade) were each reported by 50% or more of patients. Generalized abdominal pain, left subcostal pain, and early satiety occurred more frequently among patients with splenomegaly. Multiple symptoms were reported by 95% of patients. Common comorbidities were hypertension, diabetes, and chronic pulmonary disease. Symptoms are common in MF patients, regardless of the presence of palpable splenomegaly. Careful assessment of symptom burden is an important aspect of the clinical evaluation of patients with MF. PMID- 24403263 TI - Ipilimumab and radiation therapy for melanoma brain metastases. AB - Ipilimumab, an antibody that enhances T-cell activation, may augment immunogenicity of tumor cells that are injured by radiation therapy. We hypothesized that patients with melanoma brain metastasis treated with both ipilimumab and radiotherapy would have improved overall survival, and that the sequence of treatments may affect disease control in the brain. We analyzed the clinical and radiographic records of melanoma patients with brain metastases who were treated with whole brain radiation therapy or stereotactic radiosurgery between 2005 and 2012. The hazard ratios for survival were estimated to assess outcomes as a function of ipilimumab use and radiation type. Seventy patients were identified, 33 of whom received ipilimumab and 37 who did not. The patients who received ipilimumab had a censored median survival of 18.3 months (95% confidence interval 8.1-25.5), compared with 5.3 months (95% confidence interval 4.0-7.6) for patients who did not receive ipilimumab. Ipilimumab and stereotactic radiosurgery were each significant predictors of improved overall survival (hazard ratio = 0.43 and 0.45, with P = 0.005 and 0.008, respectively). Four of 10 evaluable patients (40.0%) who received ipilimumab prior to radiotherapy demonstrated a partial response to radiotherapy, compared with two of 22 evaluable patients (9.1%) who did not receive ipilimumab. Ipilimumab is associated with a significantly reduced risk of death in patients with melanoma brain metastases who underwent radiotherapy, and this finding supports the need for multimodality therapy to optimize patient outcomes. Prospective studies are needed and are underway. PMID- 24403264 TI - Clinical and demographic characteristics associated with the receipt of chemotherapy treatment among 7951 elderly metastatic colon cancer patients. AB - Among older individuals diagnosed with metastatic colon cancer (mCC) there is limited evidence available that describes the characteristics associated with advancing to second- and subsequent lines of treatment with chemotherapy/biologics. Our objective was to describe the trends and lines of treatment received among elderly mCC patients. Elderly beneficiaries diagnosed with mCC from 2003 to 2007 were identified in the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset. Beneficiaries were followed up until death or censoring. Treatment lines were classified in combinations of chemotherapies and biologics. Modified Poisson regression was used to predict receipt of lines of treatment. Analyses controlled for age, race/ethnicity, gender, marital status, state buy-in during diagnosis year, SEER-registry site, Charlson comorbidity index (CCI), poor performance indicators, surgery of primary site, and surgery of regional/distal sites. Among 7951 Medicare beneficiaries identified with mCC, 3266 initiated therapy. Of these, 1440 advanced to second line treatment. Of these, 274 advanced to a subsequent-line treatment. Surgeries of the primary tumor site and of the regional/distal sites and marital status were the most significant variables associated with advancing through second- and subsequent-line treatments. Greater than 80 years of age, African American race, SEER-registry area, less than 6 months state buy-in assistance in mCC diagnosis year, and having poor performance indicators were inversely associated with receipt of second- or subsequent-line treatments. Among elderly individuals diagnosed with mCC, we identified demographic, clinical, and regional factors associated with receipt of second- and subsequent-line chemotherapy/biologics. Additional research is warranted to understand the role of physician versus patient preferences as well as geographic differences explaining why patients advance through lines of chemotherapy. PMID- 24403265 TI - Comparison of toxicity and outcomes of concurrent radiotherapy with carboplatin/paclitaxel or cisplatin/etoposide in stage III non-small cell lung cancer. AB - Concurrent chemoradiotherapy (CCRT) has become the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC). The comparative merits of two widely used regimens: carboplatin/paclitaxel (PC) and cisplatin/etoposide (PE), each with concurrent radiotherapy, remain largely undefined. Records for consecutive patients with stage III NSCLC treated with PC or PE and >=60 Gy chest radiotherapy between 2000 and 2011 were reviewed for outcomes and toxicity. Survival was estimated using the Kaplan-Meier method and Cox modeling with the Wald test. Comparison across groups was done using the student's t and chi-squared tests. Seventy-five (PC: 44, PE: 31) patients were analyzed. PC patients were older (median 71 vs. 63 years; P = 0.0006). Other characteristics were comparable between groups. With PE, there was significantly increased grade >=3 neutropenia (39% vs. 14%, P = 0.024) and thrombocytopenia (10% vs. 0%, P = 0.039). Radiation pneumonitis was more common with PC (66% vs. 38%, P = 0.033). Five treatment-related deaths occurred (PC: 3 vs. PE: 2, P = 1.000). With a median follow-up of 51.6 months, there were no significant differences in relapse-free survival (median PC 12.0 vs. PE 11.5 months, P = 0.700) or overall survival (median PC 20.7 vs. PE 13.7 months; P = 0.989). In multivariate analyses, no factors predicted for improved survival for either regimen. PC was more likely to be used in elderly patients. Despite this, PC resulted in significantly less hematological toxicity but achieved similar survival outcomes as PE. PC is an acceptable CCRT regimen, especially in older patients with multiple comorbidities. PMID- 24403266 TI - Phase 2, multicenter, open-label study of tigatuzumab (CS-1008), a humanized monoclonal antibody targeting death receptor 5, in combination with gemcitabine in chemotherapy-naive patients with unresectable or metastatic pancreatic cancer. AB - Tigatuzumab is the humanized version of the agonistic murine monoclonal antibody TRA-8 that binds to the death receptor 5 and induces apoptosis of human cancer cell lines via the caspase cascade. The combination of tigatuzumab and gemcitabine inhibits tumor growth in murine pancreatic xenografts. This phase 2 trial evaluated the efficacy of tigatuzumab combined with gemcitabine in 62 chemotherapy-naive patients with histologically or cytologically confirmed unresectable or metastatic pancreatic cancer. Patients received intravenous tigatuzumab (8 mg/kg loading dose followed by 3 mg/kg weekly) and gemcitabine (1000 mg/m(2) once weekly for 3 weeks followed by 1 week of rest) until progressive disease (PD) or unacceptable toxicity occurred. The primary end point was progression-free survival (PFS) at 16 weeks. Secondary end points included objective response rate (ORR) (complete responses plus partial responses), duration of response, and overall survival (OS). Safety of the combination was also evaluated. Mean duration of treatment was 18.48 weeks for tigatuzumab and 17.73 weeks for gemcitabine. The PFS rate at 16 weeks was 52.5% (95% confidence interval [CI], 39.3-64.1%). The ORR was 13.1%; 28 (45.9%) patients had stable disease and 14 (23%) patients had PD. Median PFS was 3.9 months (95% CI, 2.2-5.4 months). Median OS was 8.2 months (95% CI, 5.1-9.6 months). The most common adverse events related to tigatuzumab were nausea (35.5%), fatigue (32.3%), and peripheral edema (19.4%). Tigatuzumab combined with gemcitabine was well tolerated and may be clinically active for the treatment of chemotherapy-naive patients with unresectable or metastatic pancreatic cancer. PMID- 24403267 TI - Human papillomavirus DNA and p16 expression in Japanese patients with oropharyngeal squamous cell carcinoma. AB - Human papillomavirus (HPV) is a major etiologic factor for oropharyngeal squamous cell carcinoma (OPSCC). However, little is known about HPV-related OPSCC in Japan. During the study, formalin-fixed, paraffin-embedded OPSCC specimens from Japanese patients were analyzed for HPV DNA by the polymerase chain reaction (PCR) and for the surrogate marker p16 by immuno-histochemistry. For HPV DNA positive, p16-negative specimens, the methylation status of the p16 gene promoter was examined by methylation-specific PCR. Overall survival was calculated in relation to HPV DNA and p16 status and was subjected to multivariate analysis. OPSCC cell lines were examined for sensitivity to radiation or cisplatin in vitro. The study results showed that tumor specimens from 40 (38%) of the 104 study patients contained HPV DNA, with such positivity being associated with tumors of the tonsils, lymph node metastasis, and nonsmoking. Overall survival was better for OPSCC patients with HPV DNA than for those without it (hazard ratio, 0.214; 95% confidence interval, 0.074-0.614; P = 0.002). Multivariate analysis revealed HPV DNA to be an independent prognostic factor for overall survival (P = 0.015). Expression of p16 was associated with HPV DNA positivity. However, 20% of HPV DNA-positive tumors were negative for p16, with most of these tumors manifesting DNA methylation at the p16 gene promoter. Radiation or cisplatin sensitivity did not differ between OPSCC cell lines positive or negative for HPV DNA. Thus, positivity for HPV DNA identifies a distinct clinical subset of OPSCC with a more favorable outcome in Japanese. PMID- 24403268 TI - Efficacy of salvage stereotactic radiotherapy for recurrent glioma: impact of tumor morphology and method of target delineation on local control. AB - In this study, we assessed the efficacy of salvage stereotactic radiotherapy (SRT) for recurrent glioma. From August 2008 to December 2012, 30 patients with recurrent glioma underwent salvage SRT. The initial histological diagnoses were World Health Organization (WHO) grades II, III, and IV in 6, 9, and 15 patients, respectively. Morphologically, the type of recurrence was classified as diffuse or other. Two methods of clinical target delineation were used: A, a contrast enhancing tumor; or B, a contrast-enhancing tumor with a 3-10-mm margin and/or surrounding fluid attenuation inversion recovery (FLAIR) high-intensity areas. The prescribed dose was 22.5-35 Gy delivered in five fractions at an isocenter using a dynamic conformal arc technique. The overall survival (OS) and local control probability (LCP) after SRT were calculated using the Kaplan-Meier method. A univariate analysis was used to test the effect of clinical variables on OS/LCP. The median follow-up period was 272 days after SRT. The OS and LCP were 83% and 56% at 6 months after SRT, respectively. Morphologically, the tumor type correlated significantly with both OS and LCP (P = 0.006 and <0.001, respectively). The method of target delineation also had a significant influence on LCP (P = 0.016). Grade 3 radiation necrosis was observed in two patients according to Common Terminology Criteria for Adverse Events, version 3. Salvage SRT was safe and effective for recurrent glioma, especially non-diffuse recurrences. Improved local control might be obtained by adding a margin to contrast-enhancing tumors or including increased FLAIR high-intensity areas. PMID- 24403270 TI - Three-year outcomes of a once daily fractionation scheme for accelerated partial breast irradiation (APBI) using 3-D conformal radiotherapy (3D-CRT). AB - The aim of this study was to report 3-year outcomes of toxicity, cosmesis, and local control using a once daily fractionation scheme (49.95 Gy in 3.33 Gy once daily fractions) for accelerated partial breast irradiation (APBI) using three dimensional conformal radiotherapy (3D-CRT). Between July 2008 and August 2010, women aged >=40 years with ductal carcinoma in situ or node-negative invasive breast cancer <=3 cm in diameter, treated with breast-conserving surgery achieving negative margins, were accrued to a prospective study. Women were treated with APBI using 3-5 photon beams, delivering 49.95 Gy over 15 once daily fractions over 3 weeks. Patients were assessed for toxicities, cosmesis, and local control rates before APBI and at specified time points. Thirty-four patients (mean age 60 years) with Tis 0 (n = 9) and T1N0 (n = 25) breast cancer were treated and followed up for an average of 39 months. Only 3% (1/34) patients experienced a grade 3 subcutaneous fibrosis and breast edema and 97% of the patients had good/excellent cosmetic outcome at 3 years. The 3-year rate of ipsilateral breast tumor recurrence (IBTR) was 0% while the rate of contralateral breast events was 6%. The 3-year disease-free survival (DFS), overall survival (OS), and breast cancer-specific survival (BCSS) was 94%, 100%, and 100%, respectively. Our novel accelerated partial breast fractionation scheme of 15 once daily fractions of 3.33 Gy (49.95 Gy total) is a remarkably well-tolerated regimen of 3D-CRT-based APBI. A larger cohort of patients is needed to further ascertain the toxicity of this accelerated partial breast regimen. PMID- 24403269 TI - High RAB25 expression is associated with good clinical outcome in patients with locally advanced head and neck squamous cell carcinoma. AB - Currently there are no molecular markers able to predict clinical outcome in locally advanced head and neck squamous cell carcinoma (HNSCC). In a previous microarray study, RAB25 was identified as a potential prognostic marker. The aim of this study was to analyze the association between RAB25 expression and clinical outcome in patients with locally advanced HNSCC treated with standard therapy. In a retrospective immunohistochemical study (n = 97), we observed that RAB25-negative tumors had lower survival (log-rank, P = 0.01) than patients bearing positive tumors. In an independent prospective mRNA study (n = 117), low RAB25 mRNA expression was associated with poor prognosis. Using classification and regression tree analysis (CART) we established two groups of patients according to their RAB25 mRNA level and their risk of death. Low mRNA level was associated with poor local recurrence-free (log-rank, P = 0.005), progression free (log-rank, P = 0.002) and cancer-specific (log-rank, P < 0.001) survival. Multivariate Cox model analysis showed that low expression of RAB25 was an independent poor prognostic factor for survival (hazard ratio: 3.84, 95% confidence interval: 1.93-7.62, P < 0.001). Patients whose tumors showed high RAB25 expression had a low probability of death after treatment. We also found lower RAB25 expression in tumors than in normal tissue (Mann-Whitney U, P < 0.001). Moreover, overexpression of RAB25 in the UM-SCC-74B HNSCC cell line increased cisplatin sensitivity, and reduced cell migration and invasion. Our findings support a tumor suppressor role for RAB25 in HNSCC and its potential use to identify locally advanced patients with a high probability of survival after genotoxic treatment. PMID- 24403271 TI - Expression of Eph receptor A10 is correlated with lymph node metastasis and stage progression in breast cancer patients. AB - Eph receptor A10 (EphA10) is a valuable breast cancer marker that is highly expressed in breast cancer tissues by comparison with normal breast tissues, as we previously reported. However, the role of EphA10 expression in breast cancer is not well understood. Here, we have analyzed the expression of EphA10 at the mRNA- and protein-level in clinical breast cancer tissues and then evaluated the relationship with clinicopathological parameters for each sample. EphA10 mRNA expression was quantified by real-time polymerase chain reaction using complimentary DNA (cDNA) samples derived from breast cancer patients. Lymph node (LN) metastasis and stage progression were significantly correlated with EphA10 expression at the mRNA level (P = 0.0091 and P = 0.034, respectively). Furthermore, immunohistochemistry (IHC) staining of breast cancer tissue microarrays (TMAs) revealed that EphA10 expression at the protein level was also associated with LN metastasis and stage progression (P = 0.016 and P = 0.011, respectively). These results indicate that EphA10 expression might play a role in tumor progression and metastasis. Our findings will help elucidate the role of EphA10 in clinical breast cancer progression. PMID- 24403272 TI - Occupational dust exposure and head and neck squamous cell carcinoma risk in a population-based case-control study conducted in the greater Boston area. AB - Head and neck cancers account for an estimated 549,000 global cancer diagnoses each year. While tobacco use, alcohol consumption, and HPV16 infection are considered to be the major risk factors for this disease, occupational risk factors, including exposure to asbestos, have also been described, although dust exposures other than asbestos have been historically understudied. We have investigated the relationship between occupational exposures to five types of dusts, including sawdust, concrete dust, leather dust, metal dust, and chimney soot, and head and neck squamous cell carcinomas (HNSCC) in the greater Boston area. We report findings from a population-based case-control study involving 951 incident HNSCC cases and 1193 controls, frequency matched on age (+/-3 years), sex, and town/neighborhood of residence. Multivariable logistic regression was used to assess the association between occupational exposure to each type of dust and HNSCC, overall and by primary tumor site. After adjusting for age, sex, race, smoking, alcohol consumption, education, and HPV16 serology, laryngeal carcinoma risk increased for each decade of occupational exposure to sawdust (OR = 1.2, 95% CI: 1.0, 1.3) and metal dust (OR = 1.2, 95% CI: 1.0, 1.4); and HNSCC risk increased for each decade of occupational leather dust exposure (OR = 1.5, 95% CI: 1.2, 1.9). We have provided evidence for an association between occupational sawdust and metal dust and laryngeal squamous cell carcinoma, and leather dust and HNSCC, with increasing risk with longer duration at the exposed occupation. PMID- 24403273 TI - Health Insurance Status and Psychological Distress among US Adults Aged 18-64 Years. AB - The purpose of this research was to examine the relationship between psychological distress and aspects of health insurance status, including lack of coverage, types of coverage and disruption in coverage, among US adults. Data from the 2001-2010 National Health Interview Survey were used to conduct analyses representative of the US adult population aged 18-64 years. Multivariate analyses regressed psychological distress on health insurance status while controlling for covariates. Adults with private or no health insurance coverage had lower levels of psychological distress than those with public/other coverage. Adults who recently (<=1 year) experienced a change in health insurance status had higher levels of distress than those who had not recently experienced a change. An interaction effect indicated that the relationship between recent change in health insurance status and distress was not dependent on whether an adult had private versus public/other coverage. However, for adults who had not experienced a change in status in the past year, the average absolute level of distress is higher among those with no coverage versus private coverage. Although significant relationships between psychological distress and health insurance status were identified, their strength was modest, with other demographic and health condition covariates also being potential sources of distress. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. PMID- 24403274 TI - Phenylene-coated magnetic nanoparticles that boost aqueous asymmetric transfer hydrogenation reactions. AB - Phenylene-coated organorhodium-functionalized magnetic nanoparticles are developed through co-condensation of chiral 4 (trimethoxysilyl)ethyl)phenylsulfonyl-1,2-diphenylethylene-diamine and 1,4 bis(triethyoxysilyl)benzene onto Fe3O4 followed complexation with [{Cp*RhCl2}2]. This magnetic catalyst exhibits excellent catalytic activity and high enantioselectivity in asymmetric transfer hydrogenation in aqueous medium. Such activity is attributed to the high hydrophobicity and the confined nature of the chiral organorhodium catalyst. The magnetic catalyst can be easily recovered by using a small external magnet and it can be reused for at least 10 times without loss of its catalytic activity. This characteristic makes it an attractive catalyst for environmentally friendly organic syntheses. PMID- 24403275 TI - Highly intensified upconversion luminescence of Ca(2+) -doped Yb/Er:NaGdF(4) nanocrystals prepared by a solvothermal route. AB - Upon introducing Ca(2+) dopants into the grain lattices by substituting Gd(3+) ions, irregular Yb/Er:NaGdF4 nanocrystals prepared through a simple solvothermal route convert into highly uniform nanorods. Meanwhile, their upconversion luminescence intensifies by about 200 times, probably due to a modification of the crystal structure of NaGdF4 and an improvement in the crystallinity of the nanophase. PMID- 24403276 TI - Transcatheter treatment of tricuspid regurgitation by caval valve implantation- experimental evaluation of decellularized tissue valves in central venous position. AB - BACKGROUND: Caval valve implantation has been suggested for transcatheter treatment of severe tricuspid regurgitation (TR). Combining the interventional technique with the promising surgical experience with decellularized valves, we sought to evaluate the functional and structural outcome of decellularized pericardial tissue valves (dTVs) in the low-pressure venous circulation in a chronic model of TR. METHODS AND RESULTS: Sixteen pericardial tissue valves were heterotopically implanted in the inferior and superior vena cava in a sheep model (54-98 kg; median 74.5 kg, n = 8) of severe TR. The devices were assembled using self-expanding nitinol stents and bovine pericardia decellularized by a detergent based protocol (group dTV; n = 8). Glutaraldehyde-fixed pericardial tissue valves served as control (GaTV, n = 8). After 6 months, device function and structural maturation were analyzed using echocardiographic, histologic, immunohistologic, and electron microscopic approaches. After implantation, cardiac output increased significantly from 3.7 +/- 1.1 l/min to 4.8 +/- 1.1 l/min (P < 0.05) and competent valve function was verified by angiography. At 6 months, angiographic and echocardiographic evaluation revealed moderate to severe regurgitation in all GaTV. In contrast, five of the eight dTVs functioned well with only minor regurgitation. In these animals, autopsy revealed preserved valve structure with tender leaflets without signs of thrombosis or calcification. Conversely, GaTV showed severe degeneration with large calcification areas. Microscopic and histologic analysis confirmed endothelial repopulation in both valve types. However, additional interstitial reseeding was observed in decellularized valves. CONCLUSIONS: In the venous circulation in severe TR, decellularized valves show superior functional performance compared to Ga-fixed tissue valves. Macroscopic and microscopic analyses suggest preserved structural integrity and advanced endothelial and interstitial repopulation with evidence of less degradation in dTV. (c) 2014 Wiley Periodicals, Inc. PMID- 24403277 TI - Effects of copper on CHO cells: insights from gene expression analyses. AB - Copper concentration can impact lactate metabolism in Chinese Hamster ovary (CHO) cells. In our previous study, a 20-fold increase in initial copper concentration enabled CHO cultures to shift from net lactate production to net lactate consumption, and achieve higher cell growth and productivity. In this follow-up study, we used transcriptomics to investigate the mechanism of action (MOA) of copper that mediates this beneficial metabolism shift. From microarray profiling (days 0-7), the number of differentially expressed genes increased considerably after the lactate shift (>day 3). To uncouple the effects of copper at early time points (days 0-3) from that of lactate per se (>day 3), and to validate microarray hits, we analyzed samples before the lactate shift by RNA-Seq. Out of 6,398 overlapping genes analyzed by both transcriptomic methods, only the early growth response 1 gene-coding for a transcription factor that activates signaling pathways in response to environmental stimuli-satisfied the differential expression criteria (fold change >= 1.5; P < 0.05). Gene expression correlation and biological pathway analyses further confirmed that copper differences exerted minimal transcriptional impact on the CHO cultures before the lactate shift. By contrast, genes associated with hypoxia network and oxidative stress response were upregulated after the lactate shift. These upregulations should boost cell proliferation and survival, but do not account for the preceding shift in lactate metabolism. The findings here indicate that the primary MOA of copper that enabled the shift in lactate metabolism is not at the transcriptional level. PMID- 24403279 TI - Desymmetrization of 1,4-pentadien-3-ol by the asymmetric 1,3-dipolar cycloaddition of azomethine imines. AB - Desymmetrization of the divinyl carbinol 1,4-pentadien-3-ol was accomplished by the asymmetric 1,3-dipolar cycloaddition of azomethine imines based on a magnesium-mediated, multinucleating chiral reaction system utilizing diisopropyl (R,R)-tartrate as the chiral auxiliary. The corresponding optically active trans pyrazolidines, each with three contiguous stereogenic centers, were obtained with excellent regio-, diastereo-, and enantioselectivity, with results as high as 99% ee. This reaction was shown to be applicable to both aryl- and alkyl-substituted azomethine imines. The use of a catalytic amount of diisopropyl (R,R)-tartrate was also effective when accompanied by the addition of MgBr2. PMID- 24403278 TI - Cancer in indigenous people in Latin America and the Caribbean: a review. AB - Cancer is a leading cause of death in Latin America but there have been few assessments of the cancer burden for the 10% of the population who are indigenous. Evidence from other world regions suggests cancer survival is poorer for indigenous people than for others due to a greater incidence of case-fatal cancers, later stage at diagnosis, and less cancer treatment. A status report on the cancer profile of indigenous people in Latin America and the Caribbean (LAC) is therefore clearly warranted. We undertook a systematic review of the peer reviewed literature in academic databases, and considered evidence from cancer registries from 1980, to assess cancer epidemiology among indigenous people in LAC. We identified 35 peer-reviewed articles pertaining to cancer in indigenous people. Rates of cervical cancer in parts of Brazil, Ecuador, and Guyana, stomach cancer rates in regions of Chile and gallbladder rates in Chile and Bolivia, were higher for indigenous compared to others. Breast cancer rates were lower in Ecuador, Brazil, and Chile. Six cancer registries in Brazil provided incidence data but no other reports of incidence, mortality, or survival were identified. There was a paucity of data surrounding the cancer burden of indigenous people in LAC. In view of predicted increases in cancer rates in ensuing decades, and the disparities in burden already experienced by indigenous people in the region, it is imperative that cancer profiles are obtained and cancer control measures identified and prioritized. PMID- 24403280 TI - Apathy and impaired emotional facial recognition networks overlap in Parkinson's disease: a PET study with conjunction analyses. AB - Apathy is a disabling non-motor symptom that is frequently observed in Parkinson's disease (PD). Its description and physiopathology suggest that it is partially mediated by emotional impairment, but this research issue has never been addressed at a clinical and metabolic level. We therefore conducted a metabolic study using (18)fluorodeoxyglucose positron emission tomography ((18)FDG PET) in 36 PD patients without depression and dementia. Apathy was assessed on the Apathy Evaluation Scale (AES), and emotional facial recognition (EFR) performances (ie, percentage of correct responses) were calculated for each patient. Confounding factors such as age, antiparkinsonian and antidepressant medication, global cognitive functions and depressive symptoms were controlled for. We found a significant negative correlation between AES scores and performances on the EFR task. The apathy network was characterised by increased metabolism within the left posterior cingulate (PC) cortex (Brodmann area (BA) 31). The impaired EFR network was characterised by decreased metabolism within the bilateral PC gyrus (BA 31), right superior frontal gyrus (BAs 10, 9 and 6) and left superior frontal gyrus (BA 10 and 11). By applying conjunction analyses to both networks, we identified the right premotor cortex (BA 6), right orbitofrontal cortex (BA 10), left middle frontal gyrus (BA 8) and left posterior cingulate gyrus (BA 31) as the structures supporting the association between apathy and impaired EFR. These results confirm that apathy in PD is partially mediated by impaired EFR, opening up new prospects for alleviating apathy in PD, such as emotional rehabilitation. PMID- 24403281 TI - Apathy and impaired recognition of emotion: are they related in Parkinson's disease? PMID- 24403282 TI - Persistent anterograde amnesia following limbic encephalitis associated with antibodies to the voltage-gated potassium channel complex. AB - OBJECTIVE: Limbic encephalitis (LE) associated with antibodies to the voltage gated potassium channel complex (VGKC) is a potentially reversible cause of cognitive impairment. Despite the prominence of cognitive dysfunction in this syndrome, little is known about patients' neuropsychological profile at presentation or their long-term cognitive outcome. METHODS: We used a comprehensive neuropsychological test battery to evaluate cognitive function longitudinally in 19 patients with VGKC-LE. RESULTS: Before immunotherapy, the group had significant impairment of memory, processing speed and executive function, whereas language and perceptual organisation were intact. At follow-up, cognitive impairment was restricted to the memory domain, with processing speed and executive function having returned to the normal range. Residual memory function was predicted by the antibody titre at presentation. CONCLUSIONS: The results show that, despite broad cognitive dysfunction in the acute phase, patients with VGKC-LE often make a substantial recovery with immunotherapy but may be left with permanent anterograde amnesia. PMID- 24403283 TI - Potential disease-modifying effects of selective serotonin reuptake inhibitors in multiple sclerosis: systematic review and meta-analysis. PMID- 24403284 TI - Comprehensive educational plan for patients with epilepsy and comorbidity (EDU COM): a pragmatic randomised trial. AB - BACKGROUND: The impact of educational strategies in the management of adverse treatment effects and drug interactions in adult patients with epilepsy with comorbidities remains undetermined. OBJECTIVE: The EDU-COM study is a randomised, pragmatic trial investigating the effect of a patient-tailored educational plan in patients with epilepsy with comorbidity. METHODS: 174 adult patients with epilepsy with chronic comorbidities, multiple-drug therapy and reporting at least one adverse treatment effect and/or drug interaction at study entry were randomly assigned to the educational plan or usual care. The primary endpoint was the number of patients becoming free from adverse treatment events and/or drug interactions after a 6-month follow-up. The number of adverse treatment events and drug interactions, health-related quality of life (HRQOL) summary score changes and the monetary costs of medical contacts and drugs were assessed as secondary outcomes. RESULTS: The primary endpoint was met by 44.0% of patients receiving the educational plan versus 28.9% of those on usual care (p=0.0399). The control group reported a significantly higher risk not to meet successfully the primary endpoint at the end of the study: OR (95% CI) of 2.29 (1.03 to 5.09). A separate analysis on drug adverse effects and drug interactions showed that the latter were more sensitive to the effect of educational treatment. Quality of life and costs were not significantly different in the two groups. CONCLUSIONS: A patient-tailored educational strategy is effective in reducing drug-related problems (particularly drug interactions) in epilepsy patients with chronic comorbidities, without adding significant monetary costs. Registered at ClinicalTrials.gov, identifier NCT01804322, (http://www.clinicaltrials.gov). PMID- 24403286 TI - Fetal grafting for Huntington's disease. Is there a hope? PMID- 24403285 TI - Postpartum relapses increase the risk of disability progression in multiple sclerosis: the role of disease modifying drugs. AB - OBJECTIVE: To assess relapses, disability progression and the role of disease modifying drugs (DMDs) in the year after delivery in women with multiple sclerosis (MS). METHODS: We prospectively followed-up pregnancies occurring between 2002 and 2008 in women with MS, recruited from 21 Italian MS centres. The risk of relapses and disability progression in the year after delivery was assessed using time-dependent Cox regression analysis. RESULTS: 350 out of 423 pregnancies were assessed (pregnancies not resulting in live birth and with a postpartum follow-up period shorter than 1 year were excluded from the analysis). 148 patients (42.3%) had at least one relapse in the year after delivery. An Expanded Disability Status Scale (EDSS) score at conception >=2.0 (HR=1.4; 95% CI 1.1 to 2.0; p=0.046) and a higher number of relapses before (HR=1.5; 95% CI 1.2 to 1.8; p<0.001) and during pregnancy (HR=2.3; 95% CI 1.6 to 3.4; p<0.001) were related to a higher risk of postpartum relapses. On the contrary, early DMD resumption after delivery marginally reduced the risk of postpartum relapses (HR=0.7, 95% CI 0.4 to 1.0; p=0.079). Moreover, 44/338 women progressed by at least one point on the EDSS. Disability progression was associated with a higher number of relapses before (HR=1.4, 95% CI 1.1 to 1.9; p=0.047) and after delivery (HR=2.7, 95% CI 1.4 to 5.2; p=0.002). CONCLUSIONS: Our findings show an increased risk of postpartum relapses and disability accrual in women with higher disease activity before and during pregnancy. Since it may reduce the risk of postpartum relapses, early DMD resumption should be encouraged, particularly in patients with more active disease. PMID- 24403287 TI - Video-based training improves the accuracy of seizure diagnosis. AB - BACKGROUND AND AIM: The difficulties in differentiating epileptic seizures (ES) from psychogenic non-epileptic seizures (PNES) are well known. However, interventions to enhance diagnostic accuracy have not been well studied. We sought to evaluate the accuracy of discrimination between ES and PNES before and after targeted training among medical students. METHODS: A teaching module incorporating videos of typical ES and PNES was used for training. Typical ES and PNES, 10 each, were shown in a random mix. The participants were asked to make a diagnosis as the baseline test, followed by a detailed discussion on videos. One month later, a 1 h lecture was delivered on the diagnosis and classification of seizures, followed by two more tests 3 and 6 months later, using a similar format, but different videos. A group of emergency medicine trainees also went through the preteaching test for comparison. We used summary receiver operating characteristic curves and area under the curve (AUC) to quantify the discriminating ability and z scores to assess the differences between AUC between different stages of training. RESULTS: In medical students, the AUC improved significantly from 0.52 (95% CI 0.49 to 0.55) at the baseline to 0.64 (95% CI 0.59 to 0.69, p<0.001) at 3 months and 0.63 (95% CI 0.57 to 0.69, p<0.001) at 6 months. At 3 and 6 months testing, they achieved results similar to that of emergency medicine trainees (p=0.5). CONCLUSIONS: Targeted video-based training increases the accuracy of visual discrimination of seizures short-term and medium term. PMID- 24403288 TI - Fifty years of tobacco carcinogenesis research: from mechanisms to early detection and prevention of lung cancer. AB - The recognition of the link between cigarette smoking and lung cancer in the 1964 Surgeon General's Report initiated definitive and comprehensive research on the identification of carcinogens in tobacco products and the relevant mechanisms of carcinogenesis. The resultant comprehensive data clearly illustrate established pathways of cancer induction involving carcinogen exposure, metabolic activation, DNA adduct formation, and consequent mutation of critical genes along with the exacerbating influences of inflammation, cocarcinogenesis, and tumor promotion. This mechanistic understanding has provided a framework for the regulation of tobacco products and for the development of relevant tobacco carcinogen and toxicant biomarkers that can be applied in cancer prevention. Simultaneously, the recognition of the link between smoking and lung cancer paved the way for two additional critical approaches to cancer prevention that are discussed here: detection of lung cancer at an early, curable stage, and chemoprevention of lung cancer. Recent successes in more precisely identifying at-risk populations and in decreasing lung cancer mortality with helical computed tomography screening are notable, and progress in chemoprevention continues, although challenges with respect to bringing these approaches to the general population exist. Collectively, research performed since the 1964 Report demonstrates unequivocally that the majority of deaths from lung cancer are preventable. PMID- 24403289 TI - Nutrition and physical activity cancer prevention guidelines, cancer risk, and mortality in the women's health initiative. AB - Healthy lifestyle behaviors are recommended to reduce cancer risk and overall mortality. Adherence to cancer-preventive health behaviors and subsequent cancer risk has not been evaluated in a diverse sample of postmenopausal women. We examined the association between the American Cancer Society (ACS) Nutrition and Physical Activity Cancer Prevention Guidelines score and risk of incident cancer, cancer-specific mortality, and all-cause mortality in 65,838 postmenopausal women enrolled in the Women's Health Initiative Observational Study. ACS guidelines scores (0-8 points) were determined from a combined measure of diet, physical activity, body mass index (current and at age 18 years), and alcohol consumption. After a mean follow-up of 12.6 years, 8,632 incident cancers and 2,356 cancer deaths were identified. The highest ACS guidelines scores compared with the lowest were associated with a 17% lower risk of any cancer [HR, 0.83; 95% confidence interval (CI), 0.75-0.92], 22% lower risk of breast cancer (HR, 0.78; 95% CI, 0.67-0.92), 52% lower risk of colorectal cancer (HR, 0.48; 95% CI, 0.32 0.73), 27% lower risk of all-cause mortality, and 20% lower risk of cancer specific mortality (HR, 0.80; 95% CI, 0.71-0.90). Associations with lower cancer incidence and mortality were generally strongest among Asian, black, and Hispanic women and weakest among non-Hispanic whites. Behaviors concordant with Nutrition and Physical Activity Cancer Prevention Guidelines were associated with lower risk of total, breast, and colorectal cancers and lower cancer-specific mortality in postmenopausal women. PMID- 24403290 TI - Luteolin nanoparticle in chemoprevention: in vitro and in vivo anticancer activity. AB - Cancer prevention (chemoprevention) by using naturally occurring dietary agents has gained immense interest because of the broad safety window of these compounds. However, many of these compounds are hydrophobic and poorly soluble in water. They frequently display low bioavailability, poor systemic delivery, and low efficacy. To circumvent this problem, we explored a novel approach toward chemoprevention using nanotechnology to deliver luteolin, a natural compound present in green vegetables. We formulated water-soluble polymer-encapsulated Nano-Luteolin from hydrophobic luteolin, and studied its anticancer activity against lung cancer and head and neck cancer. In vitro studies demonstrated that, like luteolin, Nano-Luteolin inhibited the growth of lung cancer cells (H292 cell line) and squamous cell carcinoma of head and neck (SCCHN) cells (Tu212 cell line). In Tu212 cells, the IC50 value of Nano-Luteolin was 4.13 MUmol/L, and that of luteolin was 6.96 MUmol/L. In H292 cells, the IC50 of luteolin was 15.56 MUmol/L, and Nano-Luteolin was 14.96 MUmol/L. In vivo studies using a tumor xenograft mouse model demonstrated that Nano-Luteolin has a significant inhibitory effect on the tumor growth of SCCHN in comparison to luteolin. Our results suggest that nanoparticle delivery of naturally occurring dietary agents like luteolin has many advantages and may have potential application in chemoprevention in clinical settings. PMID- 24403291 TI - Kava blocks 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in association with reducing O6-methylguanine DNA adduct in A/J mice. AB - We previously reported the chemopreventive potential of kava against 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)- and benzo(a)pyrene (BaP) induced lung tumorigenesis in A/J mice during the initiation and postinitiation stages. In this study, we investigated the tumorigenesis-stage specificity of kava, the potential active compounds, and the underlying mechanisms in NNK induced lung tumorigenesis in A/J mice. In the first experiment, NNK-treated mice were given diets containing kava at a dose of 5 mg/g of diet during different periods. Kava treatments covering the initiation stage reduced the multiplicity of lung adenomas by approximately 99%. A minimum effective dose is yet to be defined because kava at two lower dosages (2.5 and 1.25 mg/g of diet) were equally effective as 5 mg/g of diet in completely inhibiting lung adenoma formation. Daily gavage of kava (one before, during, and after NNK treatment) completely blocked lung adenoma formation as well. Kavalactone-enriched fraction B fully recapitulated kava's chemopreventive efficacy, whereas kavalactone-free fractions A and C were much less effective. Mechanistically, kava and fraction B reduced NNK-induced DNA damage in lung tissues with a unique and preferential reduction in O(6)-methylguanine (O(6)-mG), the highly tumorigenic DNA damage by NNK, correlating and predictive of efficacy on blocking lung adenoma formation. Taken together, these results demonstrate the outstanding efficacy of kava in preventing NNK-induced lung tumorigenesis in A/J mice with high selectivity for the initiation stage in association with the reduction of O(6)-mG adduct in DNA. They also establish the knowledge basis for the identification of the active compound(s) in kava. PMID- 24403292 TI - Ethnic differences in perceived benefits and barriers to HPV vaccine acceptance: a qualitative analysis of young African American, Haitian, Caucasian, and Latino men. AB - PURPOSE: To examine the attitudes toward human papillomavirus (HPV) vaccination among young men from African American, Haitian, Caucasian, and Latino backgrounds. METHODS: We used in-person surveys at an urban teaching hospital from 2010 to 2012 to examine the racial and ethnic differences in the perceived benefits and barriers to HPV vaccination and vaccine mandate acceptance among 18- to 22-year-old African American, Haitian, Caucasian, and Latino men. RESULTS: A total of 89 men participated (35% African American, 29% Haitian, 20% Latino, and 16% white). Participants from all ethnic groups perceived benefits to HPV vaccination but differed in their perceptions of barriers to vaccination as well as their acceptance of a vaccine mandate. CONCLUSIONS: Culturally competent educational messages may overcome ethnic differences in the attitudes, beliefs, and behaviors regarding vaccination among college-aged men from an urban population. PMID- 24403293 TI - Neuroendocrine and behavioral effects of maternal exposure to oral bisphenol A in female mice. AB - Bisphenol A (BPA) is a widespread estrogenic compound. We investigated the effects of maternal exposure to BPA at reference doses on sexual behavior and neuroendocrine functions of female offspring in C57BL/6J mice. The dams were orally exposed to vehicle alone or vehicle-containing BPA at doses equivalent to the no observed adverse effect level (5 mg/kg body weight per day) and tolerable daily intake (TDI, 0.05 mg/kg body weight per day) level from gestational day 15 until weaning. Developmental exposure to BPA increased the lordosis quotient in naive females exposed to BPA at the TDI dose only. BPA exposure had no effect on olfactory preference, ability to express masculine behaviors or number of calbindin-positive cells, a sexually dimorphic population of the preoptic area. BPA at both doses selectively increased kisspeptin cell number in the preoptic periventricular nucleus of the rostral periventricular area of the third ventricle in adult females. It did not affect the number of GNRH-positive cells or percentage of kisspeptin appositions on GNRH neurons in the preoptic area. These changes were associated with higher levels of estradiol (E2) at the TDI dose while levels of LH, estrus cyclicity, ovarian and uterine weights, and fertility remained unaffected. Delay in the time of vaginal opening was observed during the postnatal period at TDI dose, without any alteration in body growth. This shows that developmental exposure to BPA at reference doses did not masculinize and defeminize the neural circuitry underlying sexual behavior in female mice. The TDI dose specifically exacerbated responses normally induced by ovarian E2, through estrogen receptor alpha, during the postnatal/prepubertal period. PMID- 24403294 TI - Oxytocin-Gly-Lys-Arg stimulates cardiomyogenesis by targeting cardiac side population cells. AB - The functional oxytocin (OT) system is expressed in the human and rodent hearts. OT stimulates differentiation of cardiac stem cells into contracting cardiomyocytes (CM). In this study, we investigated OT receptors (OTR) expressed in the cells of cardiac side population (SP) and the abilities of these cells to differentiate into CM in response to the treatment with OT-Gly-Lys-Arg (OT-GKR), a dominant and biologically active form of OT, in the fetal rodent heart. Immunocytochemistry of whole rat embryo at mid gestation (E11) revealed parallel staining in the heart of OTR and the ATP-binding cassette sub-family G member 2 (brcp1) antigen the marker of the SP phenotype. Using flow cytometry, the SP cells were selected from the newborn CM stained with Hoechst 33342: 5.32%+/-0.06% of SP and 15.2%+/-1.10 of main population expressed OTR on the cell surface. The OTR was detected in CD29 (6.6%) and then in CD31 (4.7%) but less frequently in CD45 (0.7%) positive SP cell subpopulations. Specifically, the phenotype of SP CD31- cell, but not SP CD31+ cells, proliferates in the presence of OT-GKR and develops large cell aggregates. Then, OT-GKR treatment induced the apparition of beating cell colonies after 11 days (10+/-2.78%), which increased until day 16 (52+/-1.21%). The cells in contractile colonies expressed the markers of a CM phenotype, such as troponin, cardiac myosin light chain-2, and actinin. Finally, SP cells stimulated by OT-GKR induced endothelial phenotype. These results suggest that the C-terminally extended OT molecule stimulates cardiac differentiation of SP CD31- cells and is involved in heart growth. PMID- 24403295 TI - Aerobic interval training in patients with heart failure and an implantable cardioverter defibrillator: a controlled study evaluating feasibility and effect. AB - BACKGROUND: Aerobic interval training (AIT) has been shown to be superior to moderate continuous exercise training in improving exercise capacity and endothelial function in patients with both coronary artery disease and heart failure (HF). The objective of this study was to evaluate this training modality in patients with HF and an implantable cardioverter defibrillator (ICD) with regard to feasibility, safety, and effect. METHODS: We prospectively included 38 patients with an ICD: 26 patients participated in an AIT programme for 3 months, while 12 patients served as controls. At baseline and 12-week follow up, patients were assessed with a maximal ergospirometry stress test, echocardiography, endothelial function testing, and ICD interrogation. RESULTS: No exercise-related adverse events occurred during or soon after the training sessions. ICD interrogation revealed no sustained arrhythmias, antitachycardia pacing, or ICD discharge related to exercise sessions. The AIT programme led to a significant increase in peak oxygen uptake, cycle ergometer workload, and endothelial function compared to the control group. The training programme was safe and not associated with any adverse events or ICD-related complications. CONCLUSIONS: An AIT programme is feasible and seems safe in a well-treated, stable ICD population. Further, AIT for 3 months results in significantly increased aerobic capacity and endothelial function in this population. PMID- 24403296 TI - Complete blood count risk score and its components, including RDW, are associated with mortality in the JUPITER trial. AB - BACKGROUND: Previously, we showed that sex-specific complete blood count (CBC) risk scores strongly predicted risk of all-cause mortality in multiple sets of general medical patients. This study evaluated the CBC risk score in an independent, well-studied international primary risk population of lower-risk individuals initially free from cardiovascular (CV) disease. DESIGN: Observational secondary analysis of a randomized trial population. METHODS: The previously derived and validated CBC score was evaluated for association with all cause mortality among CV disease-free females (n = 6568) and males (n = 10,629) enrolled for up to 5 years in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial. Associations of the CBC score with CV mortality and with major CV disease were also tested. RESULTS: The CBC score predicted all-cause mortality, with univariable hazard ratio (HR) 4.83 (95% CI 3.70-6.31) for the third CBC score tertile vs. the first tertile, and HR 2.31 (CI 1.75-3.05) for the second tertile (p trend < 0.001). The CBC score retained significance after adjustment: HR 1.97 (CI 1.46-2.67) and 1.51 (CI 1.13-2.00) for tertiles 3 and 2 vs. 1, respectively (p trend < 0.001). The CBC score also predicted CV mortality (p trend = 0.025) and the primary JUPITER endpoint (p trend = 0.015). c-statistics for mortality were 0.729 among all, and 0.722 and 0.750 for females and males, respectively. CONCLUSIONS: The CBC risk score was strongly associated with all-cause mortality among JUPITER trial participants and had good discrimination. It also predicted CV-specific outcomes. This CBC score may be useful in identifying cardiac disease free individuals at increased risk of mortality. PMID- 24403297 TI - Disability pension after coronary revascularization: a prospective nationwide register-based Swedish cohort study. AB - BACKGROUND: Scientific knowledge on disability pension (DP) after revascularization by coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) is scarce. The aim was to study the incidence of and risk factors for being granted DP in the 5 years following a first CABG or PCI, accounting for socio-demographic and medical factors. METHODS: This is a nationwide population-based study using Swedish registers including all patients 30-63 years of age (n = 34,643, 16.4% women) who had a first CABG (n = 14,107) or PCI (n = 20,536) during 1994-2003. All were alive and without reintervention 30 days after the procedure and were not on DP or old-age pension. Multivariable adjusted Cox proportional hazard ratios (HR) for DP were estimated with 95% confidence intervals (CI). RESULTS: In 5 years following revascularization, 32.4% had been granted DP and the hazard ratio (HR) was higher in women (HR 1.55, 95% CI 1.48-1.62), and in CABG patients compared with PCI patients (HR 1.35, 95% CI 1.30-1.40). Long-term sick leave in the year before intervention was the strongest predictor for DP following revascularization. After adjustments for socio-demographic factors and sick-leave days in the 12 months before revascularization, HR remained high in all patients with diabetes mellitus regardless of type of revascularization. CONCLUSIONS: DP after coronary revascularization was common, especially among women and CABG patients. Most studied medical covariates, including mental and musculoskeletal disorders, were risk factors for future DP, especially long-term sickness absence. PMID- 24403298 TI - Real-time PCR threshold cycle cutoffs help to identify agents causing acute childhood diarrhea in Zanzibar. AB - Molecular assays might improve the identification of causes of acute diarrheal disease but might lead to more frequent detection of asymptomatic infections. In the present study, real-time PCR targeting 14 pathogens was applied to rectal swabs from 330 children aged 2 to 59 months in Zanzibar, including 165 patients with acute diarrhea and 165 asymptomatic control subjects. At least one pathogen was detected for 94% of the patients and 84% of the controls, with higher rates among patients for norovirus genogroup II (20% versus 2.4%; P<0.0001), rotavirus (10% versus 1.8%; P=0.003), and Cryptosporidium (30% versus 11%; P<0.0001). Detection rates did not differ significantly for enterotoxigenic Escherichia coli (ETEC)-estA (33% versus 24%), ETEC-eltB (44% versus 46%), Shigella (35% versus 33%), and Campylobacter (35% versus 33%), but for these agents threshold cycle (CT) values were lower (pathogen loads were higher) in sick children than in controls. In a multivariate analysis, CT values for norovirus genogroup II, rotavirus, Cryptosporidium, ETEC-estA, and Shigella were independently associated with diarrhea. We conclude that this real-time PCR allows convenient detection of essentially all diarrheagenic agents and provides CT values that may be critical for the interpretation of results for pathogens with similar detection rates in patients and controls. The results indicate that the assessment of pathogen loads may improve the identification of agents causing gastroenteritis in children. PMID- 24403299 TI - Rapid resistome fingerprinting and clonal lineage profiling of carbapenem resistant Klebsiella pneumoniae isolates by targeted next-generation sequencing. AB - Thirty-two carbapenem-resistant Klebsiella pneumoniae isolates, representative of different resistance mechanisms and clonal lineages, were analyzed with the Pathogenica HAI BioDetection system, based on targeted next-generation sequencing (NGS) technology. With most strains, the system simultaneously yielded comprehensive information on relevant beta-lactam resistance determinants and accurate discrimination of clonal lineages, in a shorter time frame and in a less labor-intensive manner than currently available methods for molecular epidemiology analysis. Results supported the usefulness of targeted NGS-based technologies for similar applications. PMID- 24403300 TI - Evaluation of the new brilliance GBS chromogenic medium for screening of Streptococcus agalactiae vaginal colonization in pregnant women. AB - Three commercial chromogenic agar media were evaluated for Streptococcus agalactiae screening in 200 vaginal swabs from pregnant women. The sensitivity and specificity were 94.3% and 100% for Granada medium (bioMerieux), 100% and 90.3% for Brilliance GBS medium (Thermo Fisher Scientific), and 100% and 98.8% for ChromID STRB medium (bioMerieux), respectively. PMID- 24403301 TI - Evaluation of matrix-assisted laser desorption ionization-time of flight mass spectrometry for rapid detection of beta-lactam resistance in Enterobacteriaceae derived from blood cultures. AB - The identification of pathogens directly from blood cultures by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) can be a valuable tool for improving the treatment of patients with sepsis and bacteremia. However, the increasing incidence of multidrug-resistant Gram negative bacteria makes it difficult to predict resistance patterns based only on pathogen identification. Most therapy regimens for sepsis caused by Gram-negative rods consist of at least one beta-lactam antibiotic. Thus, it would be of great benefit to have an early marker of resistance against these drugs. In the current study, we tested 100 consecutive blood cultures containing Enterobacteriaceae for resistance against 3rd-generation cephalosporins in a MALDI-TOF MS beta-lactamase assay. Escherichia coli was also tested for resistance against aminopenicillins. The results of the beta-lactamase assay were compared with those of conventional methods. The assay permitted discrimination between E. coli strains that were resistant or susceptible to aminopenicillins with a sensitivity and a specificity of 100%. The same was true for resistance to 3rd-generation cephalosporins in Enterobacteriaceae that constitutively produced class C beta-lactamases. Discrimination was more difficult in species expressing class A beta-lactamases, as these enzymes can generate false-positive results. Thus, the sensitivity and specificity for this group were 100% and 91.5%, respectively. The test permitted the prediction of resistance within 2.5 h after the blood culture was flagged as positive. PMID- 24403302 TI - Impact of new antifungal breakpoints on antifungal resistance in Candida species. AB - We reviewed our antifungal susceptibility data for micafungin, anidulafungin, fluconazole, and voriconazole against Candida species and compared resistance rates determined by the previous and recently revised CLSI antifungal breakpoints. With the new breakpoints, resistance was significantly increased for micafungin (from 0.8% to 7.6%), anidulafungin (from 0.9% to 7.3%), and voriconazole (from 6.1% to 18.4%) against Candida glabrata. Resistance was also increased for fluconazole against Candida albicans (from 2.1% to 5.7%). PMID- 24403303 TI - High frequency of Acinetobacter soli among Acinetobacter isolates causing bacteremia at a tertiary hospital in Japan. AB - Acinetobacter baumannii is generally the most frequently isolated Acinetobacter species. Sequence analysis techniques allow reliable identification of Acinetobacter isolates at the species level. Forty-eight clinical isolates of Acinetobacter spp. were obtained from blood cultures at Tohoku University Hospital. These isolates were identified at the species level by partial sequencing of the RNA polymerase beta-subunit (rpoB), 16S rRNA, and gyrB genes. Then further characterization was done by using the PCR for detection of OXA-type beta-lactamase gene clusters, metallo-beta-lactamases, and carO genes. Pulsed field gel electrophoresis (PFGE) and multilocus sequence typing were also performed. The most frequent isolate was Acinetobacter soli (27.1%). Six of the 13 A. soli isolates were carbapenem nonsusceptible, and all of these isolates produced IMP-1. PFGE revealed that the 13 A. soli isolates were divided into 8 clusters. This study demonstrated that A. soli accounted for a high proportion of Acinetobacter isolates causing bacteremia at a Japanese tertiary hospital. Non-A. baumannii species were identified more frequently than A. baumannii and carbapenem-nonsusceptible isolates were found among the non-A. baumannii strains. These results emphasize the importance of performing epidemiological investigations of Acinetobacter species. PMID- 24403304 TI - Isavuconazole treatment of a patient with disseminated mucormycosis. AB - We report a patient with relapsed acute myelogenous leukemia after allogeneic stem cell transplantation who developed disseminated mucormycosis due to Rhizomucor pusillus/R. miehei involving lung, brain, and skin. After failing posaconazole and being intolerant to amphotericin, he was treated effectively with isavuconazole for over 6 months despite ongoing treatment for relapsed leukemia. PMID- 24403305 TI - Identification, genotypic relation, and clinical features of colistin-resistant isolates of Acinetobacter genomic species 13BJ/14TU from bloodstreams of patients in a university hospital. AB - Colistin resistance remains rare among clinical isolates of Acinetobacter species. We noted the emergence of colistin-resistant bloodstream isolates of the Acinetobacter genomic species (GS) 13BJ/14TU from patients at a university hospital between 2003 and 2011. We report here, for the first time, the microbiological and molecular characteristics of these isolates, with clinical features of Acinetobacter GS 13BJ/14TU bacteremia. All 11 available patient isolates were correctly identified as Acinetobacter GS 13BJ/14TU using partial rpoB gene sequencing but were misidentified using the phenotypic methods Vitek 2 (mostly as Acinetobacter baumannii), MicroScan (mostly as A. baumannii/Acinetobacter haemolyticus), and the API 20 NE system (all as A. haemolyticus). Most isolates were susceptible to commonly used antibiotics, including carbapenems, but all were resistant to colistin, for which it is unknown whether the resistance is acquired or intrinsic. However, the fact that none of the patients had a history of colistin therapy strongly suggests that Acinetobacter GS 13BJ/14TU is innately resistant to colistin. The phylogenetic tree of multilocus sequence typing (MLST) showed that all 11 isolates formed a separate cluster from other Acinetobacter species and yielded five sequence types. However, pulsed-field gel electrophoresis (PFGE) revealed 11 distinct patterns, suggesting that the bacteremia had occurred sporadically. Four patients showed persistent bacteremia (6 to 17 days), and all 11 patients had excellent outcomes with cleared bacteremia, suggesting that patients with Acinetobacter GS 13BJ/14TU-associated bacteremia show a favorable outcome. These results emphasize the importance of precise species identification, especially regarding colistin resistance in Acinetobacter species. In addition, MLST offers another approach to the identification of Acinetobacter GS 13BJ/14TU, whereas PFGE is useful for genotyping for this species. PMID- 24403306 TI - Evaluation of the AID TB resistance line probe assay for rapid detection of genetic alterations associated with drug resistance in Mycobacterium tuberculosis strains. AB - The rapid accurate detection of drug resistance mutations in Mycobacterium tuberculosis is essential for optimizing the treatment of tuberculosis and limiting the emergence and spread of drug-resistant strains. The TB Resistance line probe assay from Autoimmun Diagnostika GmbH (AID) (Strassburg, Germany) was designed to detect the most prevalent mutations that confer resistance to isoniazid, rifampin, streptomycin, amikacin, capreomycin, fluoroquinolones, and ethambutol. This assay detected resistance mutations in clinical M. tuberculosis isolates from areas with low and high levels of endemicity (Switzerland, n=104; South Africa, n=52) and in selected Mycobacterium bovis BCG 1721 mutant strains (n=5) with 100% accuracy. Subsequently, the line probe assay was shown to be capable of rapid genetic assessment of drug resistance in MGIT broth cultures, the results of which were in 100% agreement with those of DNA sequencing and phenotypic drug susceptibility testing. Finally, the line probe assay was assessed for direct screening of smear-positive clinical specimens. Screening of 98 clinical specimens demonstrated that the test gave interpretable results for >95% of them. Antibiotic resistance mutations detected in the clinical samples were confirmed by DNA sequencing. We conclude that the AID TB Resistance line probe assay is an accurate tool for the rapid detection of resistance mutations in cultured isolates and in smear-positive clinical specimens. PMID- 24403307 TI - Identification of past and recent parvovirus B19 infection in immunocompetent individuals by quantitative PCR and enzyme immunoassays: a dual-laboratory study. AB - Parvovirus B19 (B19V) is a member of the family Parvoviridae, genus Erythrovirus. B19V-specific IgG and IgM react differently against conformational and linear epitopes of VP1 and VP2 antigens, leading to the development of IgG avidity and epitope type specificity (ETS) enzyme immunoassays (EIAs) for distinguishing past from recent infection. Additionally, B19V viral load determination (by quantitative PCR [qPCR]) is increasingly used in the staging of B19V infection. In this study, the utility of these methods is compared. A panel of 78 sera was jointly tested by the Virus Reference Department (VRD), London, United Kingdom, and the Haartman Institute (HI), Helsinki, Finland, using a number of EIAs, e.g., B19V-specific IgG and IgM, IgG avidity, and ETS EIAs. At VRD, the sera were also tested by a B19V viral load PCR (qPCR). By consensus analysis, 43 (55.1%) sera represented past infection, 28 (35.9%) sera represented recent infection, and 7 (9.0%) sera were indeterminate. Both VRD B19V qPCR and HI B19V VP2 IgM EIA gave the highest agreement with consensus interpretation for past or recent infection, with an overall agreement of 99% (95% confidence interval [CI], 92 to 100) and positive predictive value (PPV) of 100% (95% CI, 87 to 100). Nine sera designated as representing past infection by consensus analysis were B19V IgM positive by a commercial VRD B19V IgM EIA and B19V IgM negative by a new HI in-house B19V VP2 IgM EIA. A new VRD B19V IgG avidity EIA showed good (>95%) agreement (excluding equivocal results) with consensus interpretations for past or recent infection. Correct discrimination of past from recent B19V infection was achieved through application of qPCR or by appropriate selection of EIAs. PMID- 24403308 TI - The value of postmortem microbiology cultures. AB - Since the inception of evidence-based scientific concepts in medicine in the 19th century, the utility of postmortem microbiologic examinations has been a topic of controversy. For every study describing a lack of correlation between antemortem clinical and laboratory findings and postmortem culture results, there is equal evidence from other studies that indicates at least some limited utility in select cases. While the contributions of autopsies and postmortem microbiologic examinations in the discovery of novel infectious microorganisms are generally appreciated by the medical and scientific societies, the problems of implementing routine procedures in daily autopsy practice clearly relate to the lack of consensus on their broader utility as well as to a lack of regulatory guidelines. This review provides an overview of the literature-based evidence regarding the utility of postmortem microbiologic examinations together with some practical aspects and guidelines for those confronted with the issue of whether to allow or discourage the use of bacteriologic cultures obtained during autopsies. PMID- 24403309 TI - beta-1,4-Galactosyltransferase III suppresses beta1 integrin-mediated invasive phenotypes and negatively correlates with metastasis in colorectal cancer. AB - Metastasis often occurs in colorectal cancer (CRC) patients and is the main difficulty in cancer treatment. The upregulation of poly-N-acetyllactosamine related glycosylation is found in CRC patients and is associated with progression and metastasis in cancer. beta-1,4-Galactosyltransferase III (B4GALT3) is an enzyme responsible for poly-N-acetyllactosamine synthesis, and therefore, we investigated its expression in CRC patients. We found that B4GALT3 negatively correlated with poorly differentiated histology (P < 0.001), advanced stages (P = 0.0052), regional lymph node metastasis (P = 0.0018) and distant metastasis (P = 0.0463) in CRC patients. B4GALT3 overexpression in CRC cells suppressed cell migration, invasion and adhesion, whereas B4GALT3 knockdown enhanced malignant cell phenotypes. The beta1 integrin-blocking antibody reversed the B4GALT3 mediated increase in cell invasion. B4GALT3 expression altered glycosylation on the N-glycan of beta1 integrin probably through changes in poly-N acetyllactosamine expression. Furthermore, more activated beta1 integrin along with the activation of its downstream signaling transduction were found in B4GALT3 knockdown cells, whereas overexpression of B4GALT3 suppressed the expression of active beta1 integrin and inhibited its downstream signaling. Our results suggest that B4GALT3 is negatively associated with CRC metastasis and suppresses cell invasiveness through inhibiting activation of beta1 integrin. PMID- 24403310 TI - Suppressive oligodeoxynucleotides reduce lung cancer susceptibility in mice with silicosis. AB - Silicosis is an inflammatory lung disease induced by the inhalation of silica containing dust particles. There is conflicting data on whether patients with silicosis are more susceptible to lung cancer induced by cigarette smoke. To examine this issue experimentally, a model was developed in which one of the most abundant and potent carcinogens present in cigarette smoke [4-(N-methyl-N nitrosamino)-1-(3-pyridyl)-1-butanone (NNK)] was administered to mice at the peak of silica-induced pulmonary inflammation. Results show that the incidence of lung tumors in silicotic mice treated with NNK was significantly increased compared with mice exposed to silica or NNK alone. Synthetic oligonucleotides (ODN) containing repetitive TTAGGG motifs can block pathologic inflammation. We therefore examined whether treatment with these suppressive (Sup) ODN could block silica-induced pulmonary inflammation and thereby reduce susceptibility to lung cancer. Results show that Sup (but not control) ODN inhibit pulmonary fibrosis and other inflammatory manifestations of chronic silicosis. Of greater import, Sup ODN reduced lung tumor incidence and multiplicity in silicotic mice exposed to NNK. These findings establish an experimental model for examining the role of silicotic inflammation in cancer susceptibility and demonstrate that Sup ODN represent a novel therapy for chronic silicosis. PMID- 24403312 TI - hRAD9 functions as a tumor suppressor by inducing p21-dependent senescence and suppressing epithelial-mesenchymal transition through inhibition of Slug transcription. AB - Senescence and epithelial-mesenchymal transition (EMT) have opposing roles in tumor progression, in that, one is a barrier against tumorigenesis, whereas the other is required for invasive malignancies. Here, we report that the DNA damage response (DDR) protein hRAD9 contributes to induction of senescence and inhibition of EMT. Our data show that hRAD9 is frequently downregulated in breast and lung cancers. Loss of hRAD9 expression is associated with tumor stage in breast and lung cancers, as well as with acquisition of an invasive phenotype. Ectopic hRAD9 expression in highly invasive cancer cell lines, H1299 and MDA-MB 231, with low endogenous hRAD9 induced senescence by upregulation of nuclear p21, independent of the p53 status. Ectopic expression of hRAD9 also significantly attenuated cellular migration and invasion in vitro and tumor growth in a xenograft mouse model in vivo. In contrast, silencing hRAD9 in lower invasive cancer cell lines, A549 and MCF7, with high endogenous hRAD9 dramatically increased their migration and invasion abilities, and simultaneously activated EMT. Knockdown of hRAD9 increased, whereas ectopic expression of hRAD9 decreased, the expression of Slug. Moreover, hRAD9 directly bound to the promoter region of slug gene and repressed its transcriptional activity. Taken together, these results suggest that hRAD9 is a potential tumor suppressor in breast and lung cancers and that it is likely to function by upregulating p21 and inhibiting Slug to regulate tumorigenesis. PMID- 24403311 TI - Integrin alpha6A splice variant regulates proliferation and the Wnt/beta-catenin pathway in human colorectal cancer cells. AB - The integrin alpha6 subunit pre-messenger RNA undergoes alternative splicing to generate two different splice variants, named alpha6A and alpha6B, having distinct cytoplasmic domains. In the human colonic gland, these splice variants display different patterns of expression suggesting specific functions for each variant. We have previously found an up-regulation of the alpha6beta4 integrin in colon adenocarcinomas as well as an increase in the alpha6A/alpha6B ratio, but little is known about the involvement of alpha6Abeta4 versus alpha6Bbeta4 in this context. The aim of this study was to elucidate the function of the alpha6Abeta4 integrin in human colorectal cancer (CRC) cells. Expression studies on a panel of primary CRCs confirmed that the up-regulation of the alpha6 subunit in CRC is a direct consequence of the increase of the alpha6A variant. To investigate the functional significance of an alpha6A up-regulation in CRC, we specifically knocked down its expression in well-established CRC cell lines using a small hairpin RNA approach. Results showed a growth rate reduction in all alpha6A knockdown CRC cell lines studied. The alpha6A silencing was also found to be associated with a significant repression of a number of Wnt/beta-catenin pathway end points. Moreover, it was accompanied by a reduction in the capacity of these cells to develop tumours in xenografts. Taken together, these results demonstrate that the alpha6A variant is a pro-proliferative form of the alpha6 integrin subunit in CRC cells and appears to mediate its effects through the Wnt/beta catenin pathway. PMID- 24403313 TI - Family care for immigrants with dementia: The perspectives of female family carers living in The Netherlands. AB - BACKGROUND: The prevalence of dementia is increasing among non-western immigrants. It is known that family care is provided relatively often among immigrant groups. Until now, however, relatively little was known about how relatives of people with dementia in the immigrant communities perceive family care. This study therefore focuses on describing the perspectives of female Turkish, Moroccan and Surinamese Creole family carers in the Netherlands about providing family care to a close relative with dementia. METHODS: Forty-one individual interviews and six focus group interviews (n=28) were held with female Turkish, Moroccan and Surinamese Creole family carers who are looking after a close relative with dementia. A qualitative analysis of the interviews has been carried out, supported by the software MaxQda. RESULTS: Related to their cultural and religious backgrounds, female family carers with Turkish, Moroccan or Surinamese Creole origins see family care as a task that they should carry out with respect and love. They feel that family care is superior to professional care and that it is principally a task for women. If men do have a role in family care, then it generally covers non-physical aspects. Despite the fact that the family carers interviewed listed aspects that make caring for a close relative with dementia difficult, they do say that they get a great deal of satisfaction from providing this care. In Turkish and Moroccan families in particular this type of care leads to more recognition and appreciation of the daughter or daughter-in-law who is giving it. CONCLUSION: Family carers of Turkish, Moroccan or Surinamese Creole origin derive a great deal of satisfaction from giving family care to a relative with dementia. This fulfilment largely outweighs the burden of care. Professional support or information for these family carers can be improved by also focusing on the positive aspects of providing family care instead of an exclusive focus on reducing the burden. PMID- 24403314 TI - Articulating the strategies for maximising the inclusion of people with dementia in qualitative research studies. AB - It is essential to understand the experience of living with dementia from the perspective of the person with dementia so that services can be appropriately constructed. This review paper, drawing on prior work, identifies key strategies for the meaningful inclusion of persons with dementia within qualitative research studies, it examines the articulation of these strategies and shares how these strategies were operationalised within one national research study in Ireland. Strategies within the literature were categorised and then synthesized into a guide consisting of four main areas; gaining COnsent, maximizing Responses, Telling the story, and Ending on a high (CORTE). The CORTE guideline was used to as a tool for analysing relevant research reports. CORTE is a synthesized account of grouped strategies that could be used to maximize the meaningful involvement of persons with dementia and can also provide a guide for reporting the strategies used so that researchers can learn from each other. PMID- 24403315 TI - Regression of atherosclerosis with anti-CD3 antibody via augmenting a regulatory T-cell response in mice. AB - AIMS: Although recent animal studies have investigated the cellular and molecular mechanisms underlying the process of atherosclerosis regression, it remains unknown whether adaptive immune responses including T cells are involved in this process. We investigated the role of T cells in atherosclerosis regression. METHODS AND RESULTS: LDL receptor-deficient mice were fed a high-cholesterol diet for 8 weeks to form atherosclerotic lesions and were then changed to a standard diet, and atherosclerosis was assessed 4 weeks later. Just before changing the diet, the mice received an iv injection of anti-CD3 antibody (CD3-Ab) or control immunoglobulin G for 5 consecutive days. CD3-Ab treatment regressed atherosclerosis and decreased the accumulation of macrophages and CD4(+) T cells in the plaques. CD3-Ab treatment also dramatically reduced CD4(+) T cells and increased the proportion of regulatory T cells (Tregs). Depletion of Tregs by anti-CD25 antibody injection abolished the regression of atherosclerosis seen in CD3-Ab-treated mice, indicating the essential role for Tregs in this process. CONCLUSION: CD3-Ab treatment induced rapid regression of established atherosclerosis via reducing CD4(+) T cells and increasing the proportion of Tregs. These findings suggest that therapeutic intervention for T-cell-mediated immune responses may represent a novel strategy to induce atherosclerosis regression in combination with lipid-lowering therapy. PMID- 24403316 TI - Survivin gene therapy attenuates left ventricular systolic dysfunction in doxorubicin cardiomyopathy by reducing apoptosis and fibrosis. AB - AIMS: The aim of this study was to investigate anti-apoptotic gene therapy using ultrasound-mediated plasmid delivery of survivin, an inhibitor of apoptosis protein, to prevent apoptosis and to attenuate left ventricular (LV) systolic dysfunction in a model of heart failure induced by doxorubicin. METHODS AND RESULTS: Effect of survivin transduction was investigated in vitro in rat cardiomyoblasts. After survivin transduction, survivin protein was detected in cell culture supernate confirming secretion of extracellular survivin. Under doxorubicin stimulation, survivin-transduced cells had significantly reduced apoptosis; however, incubation with survivin-conditioned media also showed reduced apoptosis that was absent with null-conditioned media. Doxorubicin induced cardiomyopathy was established in Fischer rats. Subsets of animals underwent ultrasound-mediated survivin gene delivery or empty vector gene delivery at Week 3. Control rats received doxorubicin alone. Animals were studied using PCR, immunohistochemistry, echocardiography, and invasive haemodynamic studies out to Week 6. By Week 6, LV % fractional shortening by echocardiography and systolic function by pressure-volume loops were greater in survivin treated when compared with control- and empty-treated animals. There was reduced apoptosis by TUNEL and caspase activity in survivin-treated animals compared with control and empty treated at Week 4, with reduced interstitial fibrosis at Week 6. CONCLUSION: Survivin gene therapy can attenuate the progression of LV systolic dysfunction in doxorubicin cardiomyopathy. This effect can be attributed to decreased myocyte apoptosis and prevention of maladaptive LV remodelling, by both direct myocyte transfection and potentially by paracrine mechanisms. PMID- 24403317 TI - Quantifying cortical EEG responses to TMS in (un)consciousness. AB - We normally assess another individual's level of consciousness based on her or his ability to interact with the surrounding environment and communicate. Usually, if we observe purposeful behavior, appropriate responses to sensory inputs, and, above all, appropriate answers to questions, we can be reasonably sure that the person is conscious. However, we know that consciousness can be entirely within the brain, even in the absence of any interaction with the external world; this happens almost every night, while we dream. Yet, to this day, we lack an objective, dependable measure of the level of consciousness that is independent of processing sensory inputs and producing appropriate motor outputs. Theoretically, consciousness is thought to require the joint presence of functional integration and functional differentiation, otherwise defined as brain complexity. Here we review a series of recent studies in which Transcranial Magnetic Stimulation combined with electroencephalography (TMS/EEG) has been employed to quantify brain complexity in wakefulness and during physiological (sleep), pharmacological (anesthesia) and pathological (brain injury) loss of consciousness. These studies invariably show that the complexity of the cortical response to TMS collapses when consciousness is lost during deep sleep, anesthesia and vegetative state following severe brain injury, while it recovers when consciousness resurges in wakefulness, during dreaming, in the minimally conscious state or locked-in syndrome. The present paper will also focus on how this approach may contribute to unveiling the pathophysiology of disorders of consciousness affecting brain-injured patients. Finally, we will underline some crucial methodological aspects concerning TMS/EEG measurements of brain complexity. PMID- 24403318 TI - Directed information transfer in scalp electroencephalographic recordings: insights on disorders of consciousness. AB - The neural mechanisms underlying electrophysiological changes observed in patients with disorders of consciousness following a coma remain poorly understood. The aim of this study is to investigate the mechanisms underlying the differences in spontaneous electroencephalography (EEG) between patients in vegetative/unresponsive wakefulness syndrome, minimally conscious state, emergence of the minimally conscious state and age-matched healthy control subjects. Forty recordings of spontaneous scalp EEG were performed in 27 patients who were comatose on admission, and on healthy controls. Multivariate Granger causality and transfer entropy were applied to the data. Distinctive patterns of putative bottlenecks of information were associated with each conscious state. Healthy controls are characterized by a greater amount of synergetic contributions from duplets of variables. In conclusion a novel set of measures was tested to get a new insight on the pattern of information transfer in a network of scalp electrodes in patients with disorders of consciousness. PMID- 24403320 TI - Retirement investment theory explains patterns in songbird nest-site choice. AB - When opposing evolutionary selection pressures act on a behavioural trait, the result is often stabilizing selection for an intermediate optimal phenotype, with deviations from the predicted optimum attributed to tracking a moving target, development of behavioural syndromes or shifts in riskiness over an individual's lifetime. We investigated nest-site choice by female golden-winged warblers, and the selection pressures acting on that choice by two fitness components, nest success and fledgling survival. We observed strong and consistent opposing selection pressures on nest-site choice for maximizing these two fitness components, and an abrupt, within-season switch in the fitness component birds prioritize via nest-site choice, dependent on the time remaining for additional nesting attempts. We found that females consistently deviated from the predicted optimal behaviour when choosing nest sites because they can make multiple attempts at one fitness component, nest success, but only one attempt at the subsequent component, fledgling survival. Our results demonstrate a unique natural strategy for balancing opposing selection pressures to maximize total fitness. This time-dependent switch from high to low risk tolerance in nest-site choice maximizes songbird fitness in the same way a well-timed switch in human investor risk tolerance can maximize one's nest egg at retirement. Our results also provide strong evidence for the adaptive nature of songbird nest-site choice, which we suggest has been elusive primarily due to a lack of consideration for fledgling survival. PMID- 24403321 TI - Strong but opposing beta-diversity-stability relationships in coral reef fish communities. AB - The 'diversity-stability hypothesis', in which higher species diversity within biological communities buffers the risk of ecological collapse, is now generally accepted. However, empirical evidence for a relationship between beta-diversity (spatial turnover in community structure) and temporal stability in community structure remains equivocal, despite important implications for theoretical ecology and conservation biology. Here, we report strong beta-diversity-stability relationships across a broad sample of fish taxa on Australia's Great Barrier Reef. These relationships were robust to random sampling error and spatial and environmental factors, such as latitude, reef size and isolation. While beta diversity was positively associated with temporal stability at the community level, the relationship was negative for some taxa, for example surgeonfishes (Acanthuridae), one of the most abundant reef fish families. This demonstrates that the beta-diversity-stability relationship should not be indiscriminately assumed for all taxa, but that a species' risk of extirpation in response to disturbance is likely to be taxon specific and trait based. By combining predictions of spatial and temporal turnover across the study area with observations in marine-protected areas, we conclude that protection alone does not necessarily confer temporal stability and that taxon-specific considerations will improve the outcome of conservation efforts. PMID- 24403319 TI - Evidence of taxon cycles in an Indo-Pacific passerine bird radiation (Aves: Pachycephala). AB - Many insular taxa possess extraordinary abilities to disperse but may differ in their abilities to diversify and compete. While some taxa are widespread across archipelagos, others have disjunct (relictual) populations. These types of taxa, exemplified in the literature by selections of unrelated taxa, have been interpreted as representing a continuum of expansions and contractions (i.e. taxon cycles). Here, we use molecular data of 35 out of 40 species of the avian genus Pachycephala (including 54 out of 66 taxa in Pachycephala pectoralis (sensu lato), to assess the spatio-temporal evolution of the group. We also include data on species distributions, morphology, habitat and elevational ranges to test a number of predictions associated with the taxon-cycle hypothesis. We demonstrate that relictual species persist on the largest and highest islands across the Indo Pacific, whereas recent archipelago expansions resulted in colonization of all islands in a region. For co-occurring island taxa, the earliest colonists generally inhabit the interior and highest parts of an island, with little spatial overlap with later colonists. Collectively, our data support the idea that taxa continuously pass through phases of expansions and contractions (i.e. taxon cycles). PMID- 24403322 TI - On the generality of cascading habitat-formation. PMID- 24403323 TI - Meta-ecosystem dynamics and functioning on finite spatial networks. AB - The addition of spatial structure to ecological concepts and theories has spurred integration between sub-disciplines within ecology, including community and ecosystem ecology. However, the complexity of spatial models limits their implementation to idealized, regular landscapes. We present a model meta ecosystem with finite and irregular spatial structure consisting of local nutrient-autotrophs-herbivores ecosystems connected through spatial flows of materials and organisms. We study the effect of spatial flows on stability and ecosystem functions, and provide simple metrics of connectivity that can predict these effects. Our results show that high rates of nutrient and herbivore movement can destabilize local ecosystem dynamics, leading to spatially heterogeneous equilibria or oscillations across the meta-ecosystem, with generally increased meta-ecosystem primary and secondary production. However, the onset and the spatial scale of these emergent dynamics depend heavily on the spatial structure of the meta-ecosystem and on the relative movement rate of the autotrophs. We show how this strong dependence on finite spatial structure eludes commonly used metrics of connectivity, but can be predicted by the eigenvalues and eigenvectors of the connectivity matrix that describe the spatial structure and scale. Our study indicates the need to consider finite-size ecosystems in meta-ecosystem theory. PMID- 24403324 TI - Catch the wave: prairie dogs assess neighbours' awareness using contagious displays. AB - The jump-yip display of black-tailed prairie dogs (Cynomys ludovicianus) is contagious, spreading through a prairie dog town as 'the wave' through a stadium. Because contagious communication in primates serves to assess conspecific social awareness, we investigated whether instigators of jump-yip bouts adjusted their behaviour relative to the response of conspecifics recruited to display bouts. Increased responsiveness of neighbouring town members resulted in bout initiators devoting a significantly greater proportion of time to active foraging. Contagious jump-yips thus function to assess neighbours' alertness, soliciting social information to assess effective conspecific group size in real time and reveal active probing of conspecific awareness consistent with theory of mind in these group-living rodents. PMID- 24403325 TI - Rates of genomic divergence in humans, chimpanzees and their lice. AB - The rate of DNA mutation and divergence is highly variable across the tree of life. However, the reasons underlying this variation are not well understood. Comparing the rates of genetic changes between hosts and parasite lineages that diverged at the same time is one way to begin to understand differences in genetic mutation and substitution rates. Such studies have indicated that the rate of genetic divergence in parasites is often faster than that of their hosts when comparing single genes. However, the variation in this relative rate of molecular evolution across different genes in the genome is unknown. We compared the rate of DNA sequence divergence between humans, chimpanzees and their ectoparasitic lice for 1534 protein-coding genes across their genomes. The rate of DNA substitution in these orthologous genes was on average 14 times faster for lice than for humans and chimpanzees. In addition, these rates were positively correlated across genes. Because this correlation only occurred for substitutions that changed the amino acid, this pattern is probably produced by similar functional constraints across the same genes in humans, chimpanzees and their ectoparasites. PMID- 24403326 TI - Parental effects improve escape performance of juvenile reef fish in a high-CO2 world. AB - Rising CO2 levels in the oceans are predicted to have serious consequences for many marine taxa. Recent studies suggest that non-genetic parental effects may reduce the impact of high CO2 on the growth, survival and routine metabolic rate of marine fishes, but whether the parental environment mitigates behavioural and sensory impairment associated with high CO2 remains unknown. Here, we tested the acute effects of elevated CO2 on the escape responses of juvenile fish and whether such effects were altered by exposure of parents to increased CO2 (transgenerational acclimation). Elevated CO2 negatively affected the reactivity and locomotor performance of juvenile fish, but parental exposure to high CO2 reduced the effects in some traits, indicating the potential for acclimation of behavioural impairment across generations. However, acclimation was not complete in some traits, and absent in others, suggesting that transgenerational acclimation does not completely compensate the effects of high CO2 on escape responses. PMID- 24403327 TI - Horizontal gene transfer in the acquisition of novel traits by metazoans. AB - Horizontal gene transfer is accepted as an important evolutionary force modulating the evolution of prokaryote genomes. However, it is thought that horizontal gene transfer plays only a minor role in metazoan evolution. In this paper, I critically review the rising evidence on horizontally transferred genes and on the acquisition of novel traits in metazoans. In particular, I discuss suspected examples in sponges, cnidarians, rotifers, nematodes, molluscs and arthropods which suggest that horizontal gene transfer in metazoans is not simply a curiosity. In addition, I stress the scarcity of studies in vertebrates and other animal groups and the importance of forthcoming studies to understand the importance and extent of horizontal gene transfer in animals. PMID- 24403328 TI - Local climatic adaptation in a widespread microorganism. AB - Exploring the ability of organisms to locally adapt is critical for determining the outcome of rapid climate changes, yet few studies have addressed this question in microorganisms. We investigated the role of a heterogeneous climate on adaptation of North American populations of the wild yeast Saccharomyces paradoxus. We found abundant among-strain variation for fitness components across a range of temperatures, but this variation was only partially explained by climatic variation in the distribution area. Most of fitness variation was explained by the divergence of genetically distinct groups, distributed along a north-south cline, suggesting that these groups have adapted to distinct climatic conditions. Within-group fitness components were correlated with climatic conditions, illustrating that even ubiquitous microorganisms locally adapt and harbour standing genetic variation for climate-related traits. Our results suggest that global climatic changes could lead to adaptation to new conditions within groups, or changes in their geographical distributions. PMID- 24403329 TI - Predicting pre-Columbian anthropogenic soils in Amazonia. AB - The extent and intensity of pre-Columbian impacts on lowland Amazonia have remained uncertain and controversial. Various indicators can be used to gauge the impact of pre-Columbian societies, but the formation of nutrient-enriched terra preta soils has been widely accepted as an indication of long-term settlement and site fidelity. Using known and newly discovered terra preta sites and maximum entropy algorithms (Maxent), we determined the influence of regional environmental conditions on the likelihood that terra pretas would have been formed at any given location in lowland Amazonia. Terra pretas were most frequently found in central and eastern Amazonia along the lower courses of the major Amazonian rivers. Terrain, hydrologic and soil characteristics were more important predictors of terra preta distributions than climatic conditions. Our modelling efforts indicated that terra pretas are likely to be found throughout ca 154 063 km(2) or 3.2% of the forest. We also predict that terra preta formation was limited in most of western Amazonia. Model results suggested that the distribution of terra preta was highly predictable based on environmental parameters. We provided targets for future archaeological surveys under the vast forest canopy and also highlighted how few of the long-term forest inventory sites in Amazonia are able to capture the effects of historical disturbance. PMID- 24403330 TI - Birds see the true colours of fruits to live off the fat of the land. AB - Communication is a characteristic of life, but its reliability and basic definition are hotly debated. Theory predicts that trade among mutualists requires high reliability. Here, we show that moderate reliability already allows mutualists to optimize their rewards. The colours of Mediterranean fleshy-fruits indicate lipid rewards (but not other nutrients) to avian seed dispersers on regional and local scales. On the regional scale, fruits with high lipid content were significantly darker and less chromatic than congeners with lower lipid content. On the local scale, two warbler species (Sylvia atricapilla and Sylvia borin) selected fruit colours that were less chromatic, and thereby maximized their intake of lipids-a critical resource during migration and wintering. Crucially, birds were able to maximize lipid rewards with moderate reliability from visual fruit colours (r(2) = 0.44-0.60). We suggest that mutualisms require only that any association between the quality and sensory aspects of signallers is learned through multiple, repeated interactions. Because these conditions are often fulfilled, also in social communication systems, we contend that selection on reliability is less intense than hitherto assumed. This may contribute to explaining the extraordinary diversity of signals, including that of plant reproductive displays. PMID- 24403331 TI - Predicting bycatch hotspots for endangered leatherback turtles on longlines in the Pacific Ocean. AB - Fisheries bycatch is a critical source of mortality for rapidly declining populations of leatherback turtles, Dermochelys coriacea. We integrated use intensity distributions for 135 satellite-tracked adult turtles with longline fishing effort to estimate predicted bycatch risk over space and time in the Pacific Ocean. Areas of predicted bycatch risk did not overlap for eastern and western Pacific nesting populations, warranting their consideration as distinct management units with respect to fisheries bycatch. For western Pacific nesting populations, we identified several areas of high risk in the north and central Pacific, but greatest risk was adjacent to primary nesting beaches in tropical seas of Indo-Pacific islands, largely confined to several exclusive economic zones under the jurisdiction of national authorities. For eastern Pacific nesting populations, we identified moderate risk associated with migrations to nesting beaches, but the greatest risk was in the South Pacific Gyre, a broad pelagic zone outside national waters where management is currently lacking and may prove difficult to implement. Efforts should focus on these predicted hotspots to develop more targeted management approaches to alleviate leatherback bycatch. PMID- 24403332 TI - Competition induces allelopathy but suppresses growth and anti-herbivore defence in a chemically rich seaweed. AB - Many seaweeds and terrestrial plants induce chemical defences in response to herbivory, but whether they induce chemical defences against competitors (allelopathy) remains poorly understood. We evaluated whether two tropical seaweeds induce allelopathy in response to competition with a reef-building coral. We also assessed the effects of competition on seaweed growth and seaweed chemical defence against herbivores. Following 8 days of competition with the coral Porites cylindrica, the chemically rich seaweed Galaxaura filamentosa induced increased allelochemicals and became nearly twice as damaging to the coral. However, it also experienced significantly reduced growth and increased palatability to herbivores (because of reduced chemical defences). Under the same conditions, the seaweed Sargassum polycystum did not induce allelopathy and did not experience a change in growth or palatability. This is the first demonstration of induced allelopathy in a seaweed, or of competitors reducing seaweed chemical defences against herbivores. Our results suggest that the chemical ecology of coral-seaweed-herbivore interactions can be complex and nuanced, highlighting the need to incorporate greater ecological complexity into the study of chemical defence. PMID- 24403333 TI - Deciphering the relative weights of demographic transition and vaccination in the decrease of measles incidence in Italy. AB - In Italy, during the course of the past century to the present-day, measles incidence underwent a remarkable decreasing trend that started well before the introduction of the national immunization programme. In this work, we aim at examining to what extent both the demographic transition, characterized by declining mortality and fertility rates over time, and the vaccination programme are responsible for the observed epidemiological pattern. Making use of a non stationary, age-structured disease transmission model, we show that in the pre vaccination era, from 1901 to 1982, the decline in birth rates has resulted in a drastic decrease in the effective transmission rate, which in turn has determined a declining trend of measles incidence (from 25.2 to 10.3 infections per 1000 individuals). However, since 1983, vaccination appears to have become the major contributing factor in the decrease of measles incidence, which otherwise would have remained stable as a consequence of the nearly constant birth rates. This led to a remarkable decrease in the effective transmission rate, to a level well below the critical threshold for disease persistence. These findings call for the adoption of epidemiological models, which deviate the age structure from stationary equilibrium solutions, to better understand the biology of infectious diseases and evaluate immunization programmes. PMID- 24403334 TI - Is the whole more than the sum of its parts? Evolutionary trade-offs between burst and sustained locomotion in lacertid lizards. AB - Trade-offs arise when two functional traits impose conflicting demands on the same design trait. Consequently, excellence in one comes at the cost of performance in the other. One of the most widely studied performance trade-offs is the one between sprint speed and endurance. Although biochemical, physiological and (bio)mechanical correlates of either locomotor trait conflict with each other, results at the whole-organism level are mixed. Here, we test whether burst (speed, acceleration) and sustained locomotion (stamina) trade off at both the isolated muscle and whole-organism level among 17 species of lacertid lizards. In addition, we test for a mechanical link between the organismal and muscular (power output, fatigue resistance) performance traits. We find weak evidence for a trade-off between burst and sustained locomotion at the whole organism level; however, there is a significant trade-off between muscle power output and fatigue resistance in the isolated muscle level. Variation in whole animal sprint speed can be convincingly explained by variation in muscular power output. The variation in locomotor stamina at the whole-organism level does not relate to the variation in muscle fatigue resistance, suggesting that whole organism stamina depends not only on muscle contractile performance but probably also on the performance of the circulatory and respiratory systems. PMID- 24403335 TI - On pluralism in ecology: seeing the forest and the trees. PMID- 24403336 TI - Infectious disease agents mediate interaction in food webs and ecosystems. AB - Infectious agents are part of food webs and ecosystems via the relationship with their host species that, in turn, interact with both hosts and non-hosts. Through these interactions, infectious agents influence food webs in terms of structure, functioning and stability. The present literature shows a broad range of impacts of infectious agents on food webs, and by cataloguing that range, we worked towards defining the various mechanisms and their specific effects. To explore the impact, a direct approach is to study changes in food-web properties with infectious agents as separate species in the web, acting as additional nodes, with links to their host species. An indirect approach concentrates not on adding new nodes and links, but on the ways that infectious agents affect the existing links across host and non-host nodes, by influencing the 'quality' of consumer resource interaction as it depends on the epidemiological state host involved. Both approaches are natural from an ecological point of view, but the indirect approach may connect more straightforwardly to commonly used tools in infectious disease dynamics. PMID- 24403337 TI - Species detection and individual assignment in species delimitation: can integrative data increase efficacy? AB - Statistical species delimitation usually relies on singular data, primarily genetic, for detecting putative species and individual assignment to putative species. Given the variety of speciation mechanisms, singular data may not adequately represent the genetic, morphological and ecological diversity relevant to species delimitation. We describe a methodological framework combining multivariate and clustering techniques that uses genetic, morphological and ecological data to detect and assign individuals to putative species. Our approach recovers a similar number of species recognized using traditional, qualitative taxonomic approaches that are not detected when using purely genetic methods. Furthermore, our approach detects groupings that traditional, qualitative taxonomic approaches do not. This empirical test suggests that our approach to detecting and assigning individuals to putative species could be useful in species delimitation despite varying levels of differentiation across genetic, phenotypic and ecological axes. This work highlights a critical, and often overlooked, aspect of the process of statistical species delimitation species detection and individual assignment. Irrespective of the species delimitation approach used, all downstream processing relies on how individuals are initially assigned, and the practices and statistical issues surrounding individual assignment warrant careful consideration. PMID- 24403338 TI - Integrating multiple lines of evidence into historical biogeography hypothesis testing: a Bison bison case study. AB - One of the grand goals of historical biogeography is to understand how and why species' population sizes and distributions change over time. Multiple types of data drawn from disparate fields, combined into a single modelling framework, are necessary to document changes in a species's demography and distribution, and to determine the drivers responsible for change. Yet truly integrated approaches are challenging and rarely performed. Here, we discuss a modelling framework that integrates spatio-temporal fossil data, ancient DNA, palaeoclimatological reconstructions, bioclimatic envelope modelling and coalescence models in order to statistically test alternative hypotheses of demographic and potential distributional changes for the iconic American bison (Bison bison). Using different assumptions about the evolution of the bioclimatic niche, we generate hypothetical distributional and demographic histories of the species. We then test these demographic models by comparing the genetic signature predicted by serial coalescence against sequence data derived from subfossils and modern populations. Our results supported demographic models that include both climate and human-associated drivers of population declines. This synthetic approach, integrating palaeoclimatology, bioclimatic envelopes, serial coalescence, spatio temporal fossil data and heterochronous DNA sequences, improves understanding of species' historical biogeography by allowing consideration of both abiotic and biotic interactions at the population level. PMID- 24403339 TI - How body mass and lifestyle affect juvenile biomass production in placental mammals. AB - In mammals, the mass-specific rate of biomass production during gestation and lactation, here called maternal productivity, has been shown to vary with body size and lifestyle. Metabolic theory predicts that post-weaning growth of offspring, here termed juvenile productivity, should be higher than maternal productivity, and juveniles of smaller species should be more productive than those of larger species. Furthermore because juveniles generally have similar lifestyles to their mothers, across species juvenile and maternal productivities should be correlated. We evaluated these predictions with data from 270 species of placental mammals in 14 taxonomic/lifestyle groups. All three predictions were supported. Lagomorphs, perissodactyls and artiodactyls were very productive both as juveniles and as mothers as expected from the abundance and reliability of their foods. Primates and bats were unproductive as juveniles and as mothers, as expected as an indirect consequence of their low predation risk and consequent low mortality. Our results point the way to a mechanistic explanation for the suite of correlated life-history traits that has been called the slow-fast continuum. PMID- 24403341 TI - Habitat collapse due to overgrazing threatens turtle conservation in marine protected areas. AB - Marine protected areas (MPAs) are key tools for combatting the global overexploitation of endangered species. The prevailing paradigm is that MPAs are beneficial in helping to restore ecosystems to more 'natural' conditions. However, MPAs may have unintended negative effects when increasing densities of protected species exert destructive effects on their habitat. Here, we report on severe seagrass degradation in a decade-old MPA where hyper-abundant green turtles adopted a previously undescribed below-ground foraging strategy. By digging for and consuming rhizomes and roots, turtles create abundant bare gaps, thereby enhancing erosion and reducing seagrass regrowth. A fully parametrized model reveals that the ecosystem is approaching a tipping point, where consumption overwhelms regrowth, which could potentially lead to complete collapse of the seagrass habitat. Seagrass recovery will not ensue unless turtle density is reduced to nearly zero, eliminating the MPA's value as a turtle reserve. Our results reveal an unrecognized, yet imminent threat to MPAs, as sea turtle densities are increasing at major nesting sites and the decline of seagrass habitat forces turtles to concentrate on the remaining meadows inside reserves. This emphasizes the need for policy and management approaches that consider the interactions of protected species with their habitat. PMID- 24403342 TI - Early growth trajectories affect sexual responsiveness. AB - The trajectory of an animal's growth in early development has been shown to have long-term effects on a range of life-history traits. Although it is known that individual differences in behaviour may also be related to certain life-history traits, the linkage between early growth or development and individual variation in behaviour has received little attention. We used brief temperature manipulations, independent of food availability, to stimulate compensatory growth in juvenile three-spined sticklebacks Gasterosteus aculeatus. Here, we examine how these manipulated growth trajectories affected the sexual responsiveness of the male fish at the time of sexual maturation, explore associations between reproductive behaviour and investment and lifespan and test whether the perceived time stress (until the onset of the breeding season) influenced such trade-offs. We found a negative impact of growth rate on sexual responsiveness: fish induced (by temperature manipulation) to grow slowest prior to the breeding season were consistently quickest to respond to the presence of a gravid female. This speed of sexual responsiveness was also positively correlated with the rate of development of sexual ornaments and time taken to build a nest. However, after controlling for effects of growth rate, those males that had the greatest sexual responsiveness to females had the shortest lifespan. Moreover, the time available to compensate in size before the onset of the breeding season (time stress) affected the magnitude of these effects. Our results demonstrate that developmental perturbations in early life can influence mating behaviour, with long-term effects on longevity. PMID- 24403343 TI - Historical DNA reveals the demographic history of Atlantic cod (Gadus morhua) in medieval and early modern Iceland. AB - Atlantic cod (Gadus morhua) vertebrae from archaeological sites were used to study the history of the Icelandic Atlantic cod population in the time period of 1500-1990. Specifically, we used coalescence modelling to estimate population size and fluctuations from the sequence diversity at the cytochrome b (cytb) and Pantophysin I (PanI) loci. The models are consistent with an expanding population during the warm medieval period, large historical effective population size (NE), a marked bottleneck event at 1400-1500 and a decrease in NE in early modern times. The model results are corroborated by the reduction of haplotype and nucleotide variation over time and pairwise population distance as a significant portion of nucleotide variation partitioned across the 1550 time mark. The mean age of the historical fished stock is high in medieval times with a truncation in age in early modern times. The population size crash coincides with a period of known cooling in the North Atlantic, and we conclude that the collapse may be related to climate or climate-induced ecosystem change. PMID- 24403344 TI - Visual navigation in starfish: first evidence for the use of vision and eyes in starfish. AB - Most known starfish species possess a compound eye at the tip of each arm, which, except for the lack of true optics, resembles an arthropod compound eye. Although these compound eyes have been known for about two centuries, no visually guided behaviour has ever been directly associated with their presence. There are indications that they are involved in negative phototaxis but this may also be governed by extraocular photoreceptors. Here, we show that the eyes of the coral reef-associated starfish Linckia laevigata are slow and colour blind. The eyes are capable of true image formation although with low spatial resolution. Further, our behavioural experiments reveal that only specimens with intact eyes can navigate back to their reef habitat when displaced, demonstrating that this is a visually guided behaviour. This is, to our knowledge, the first report of a function of starfish compound eyes. We also show that the spectral sensitivity optimizes the contrast between the reef and the open ocean. Our results provide an example of an eye supporting only low-resolution vision, which is believed to be an essential stage in eye evolution, preceding the high-resolution vision required for detecting prey, predators and conspecifics. PMID- 24403345 TI - Island tameness: living on islands reduces flight initiation distance. AB - One of Darwin's most widely known conjectures is that prey are tame on remote islands, where mammalian predators are absent. Many species appear to permit close approach on such islands, but no comparative studies have demonstrated reduced wariness quantified as flight initiation distance (FID; i.e. predator prey distance when the prey begins to flee) in comparison with mainland relatives. We used the phylogenetic comparative method to assess influence of distance from the mainland and island area on FID of 66 lizard species. Because body size and predator approach speed affect predation risk, we included these as independent variables. Multiple regression showed that FID decreases as distance from mainland increases and is shorter in island than mainland populations. Although FID increased as area increased in some models, collinearity made it difficult to separate effects of area from distance and island occupancy. FID increases as SVL increases and approach speed increases; these effects are statistically independent of effects of distance to mainland and island occupancy. Ordinary least-squares models fit the data better than phylogenetic regressions, indicating little or no phylogenetic signal in residual FID after accounting for the independent variables. Our results demonstrate that island tameness is a real phenomenon in lizards. PMID- 24403340 TI - Specialist versus generalist life histories and nucleotide diversity in Caenorhabditis nematodes. AB - Species with broad ecological amplitudes with respect to a key focal resource, niche generalists, should maintain larger and more connected populations than niche specialists, leading to the prediction that nucleotide diversity will be lower and more subdivided in specialists relative to their generalist relatives. This logic describes the specialist-generalist variation hypothesis (SGVH). Some outbreeding species of Caenorhabditis nematodes use a variety of invertebrate dispersal vectors and have high molecular diversity. By contrast, Caenorhabditis japonica lives in a strict association and synchronized life cycle with its dispersal host, the shield bug Parastrachia japonensis, itself a diet specialist. Here, we characterize sequence variation for 20 nuclear loci to investigate how C. japonica's life history shapes nucleotide diversity. We find that C. japonica has more than threefold lower polymorphism than other outbreeding Caenorhabditis species, but that local populations are not genetically disconnected. Coupled with its restricted range, we propose that its specialist host association contributes to a smaller effective population size and lower genetic variation than host generalist Caenorhabditis species with outbreeding reproductive modes. A literature survey of diverse organisms provides broader support for the SGVH. These findings encourage further testing of ecological and evolutionary hypotheses with comparative population genetics in Caenorhabditis and other taxa. PMID- 24403347 TI - Stem cell-bearing suture improves Achilles tendon healing in a rat model. AB - BACKGROUND: Tendon healing is a slow and complicated process that results in inferior structural and functional properties when compared to healthy tendon tissue. It may be possible to improve outcomes of tendon healing with enhancement of biological aspects of the repair including tissue structure, organization, and composition. The purpose of this study was to determine whether use of a stem cell-bearing suture improves Achilles tendon healing in a rat model. METHODS: The Achilles tendon was transected in 108 bilateral hind limbs from 54 rats. Each limb was randomized to repair with suture only (SO), suture plus injection (SI) of mesenchymal stem cells (MSCs) at the repair site, or suture loaded with MSCs (suture with stem cells, SCS). One half of the animals were randomly sacrificed at 14 and 28 days after surgery and the Achilles tendon was harvested. From each repair group at each time point, 12 limbs were randomized to biomechanical testing and 6 to histologic analysis. Tendons were loaded using a 223-N load cell at 0.17 mm/s. A blinded pathologist scored the histology sections. RESULTS: Ultimate failure strength (N/mm(2)) was significantly higher in the SI and SCS groups versus the SO group. In the SI group, ultimate failure strength decreased significantly at 28 days versus 14 days. Histology score in the SCS group was significantly lower (better) than in both other groups (P <= .001). Histology findings at day 28 were significantly higher versus day 14 for all groups (P = .01). CONCLUSIONS: Both the SI and the SCS groups had significantly higher ultimate failure strength versus the SO group, and strength was maintained at 28 days in the SCS group but not in the SI group. Histology in the SCS group was significantly better than in both other groups. CLINICAL RELEVANCE: These findings in a rat model suggest that the use of stem cells enhances healing after Achilles repair and that embedding of stem cells directly into suture offers sustained early benefit to tendon healing. PMID- 24403346 TI - New PTB thermal neutron calibration facility: first results. AB - A new thermal neutron calibration facility based on a moderator assembly has been set up at PTB. It consists of 16 (241)Am-Be radionuclide sources mounted in a graphite block, 1.5 m wide, 1.5 m high and 1.8 m deep. The sources are distributed to eight different positions, at a mean distance of ~1.25 m from the front face of the moderator. The neutron field at the reference position, 30 cm in front of the moderator device and 75 cm above the floor, has been characterised using calculations, Bonner sphere measurements and gold foil activation. First results are shown. The field is highly thermalised: 99 % in terms of fluence. It is quite homogenous within a 20 cm*20 cm area, but the absolute value of the thermal neutron fluence rate is small and yields an ambient dose equivalent rate of 3 uSv h(-1). PMID- 24403348 TI - Survivorship of bipolar fresh total osteochondral ankle allograft. AB - BACKGROUND: Severe posttraumatic ankle arthritis poses a reconstructive challenge in the young and active patient. Bipolar fresh total osteochondral allograft (BFTOA) may represent an intriguing alternative to arthrodesis and prosthetic replacement. The purpose of this article was to evaluate the outcomes of BFTOA performed through an anterior approach to the ankle and to investigate the parameters influencing the results. METHODS: A total of 26 patients (18 males and 8 females with a mean age of 34.9 +/- 7.7 years) underwent BFTOA. The allograft was prepared with the help of specifically designed jigs and the surgery was performed using a direct anterior approach. Patients were evaluated clinically and radiographically at 2, 4, 6, and 12 months after the operation, and at a mean 40.9 +/- 14.1 months of follow-up. Radiographic evaluation included the measurement of allograft size matching and alignment. RESULTS: The AOFAS score improved from 26.6 +/- 6 preoperatively to 77.8 +/- 8.7 after a mean follow-up of 40.9 +/- 14.1 months (P < .0005). Six failures occurred. Joint degeneration was classified as 2 in 12 and as 3 in 14 patients. A statistically significant correlation between low degrees of distal tibial slope and better clinical outcomes was observed (P = .049). CONCLUSION: BFTOA appears to be a viable option to arthrodesis or arthroplasty. Precise allograft sizing, stable fitting, and fixation and delayed weight-bearing were key factors for a successful outcome. In this series the correct alignment of the tibial graft, in terms of slope, was found to play a crucial role in the allograft survivorship. LEVEL OF EVIDENCE: Level IV, case series. PMID- 24403349 TI - Does single ventricle physiology affect survival of children requiring extracorporeal membrane oxygenation support following cardiac surgery? AB - BACKGROUND: Improved survival with postoperative extracorporeal membrane oxygenation (ECMO) has expanded its application to children with single ventricle (SV) anomalies. We examine current-era outcomes of postoperative ECMO with special focus on patients with SV. METHODS: Demographic, anatomic, surgical, and support details of 100 consecutive children requiring postoperative ECMO (2007 2012) were included into multivariable regression models to identify factors affecting survival. RESULTS: Median age was 73 days (4 days-16.2 years), 31 patients had SV physiology. The ECMO indication was failure to wean cardiopulmonary bypass (34%) and postoperative low cardiac output (66%) including 37% having extracorporeal cardiopulmonary resuscitation (ECPR). Median ECMO duration was four days (1-21). The ECMO decannulation and survival to hospital discharge were 62% and 37%. In SV group, decannulation and survival rates were 55% and 32%. The SV-ECMO outcomes were best in ECPR subgroup (54%), following shunt (57%) or Norwood (46%) and worst following Glenn, Fontan, or total anomalous pulmonary venous connection repair (0% survival). On multivariable analysis, factors affecting odds of survival were performing angiogram (odds ratio [OR]: 15.28, confidence interval [CI]: 2.34-99.89, P = .004), prolonged ECMO duration (OR: 0.64, CI: 0.47-0.88 per day, P = .005), leaving cannulation snares (OR: 28.41, CI: 2.65-304.70, P = .006), higher HCO3 (OR: 1.19, CI: 1.04 1.36, P = .01), renal failure requiring hemodialysis (OR: 0.21, CI: 0.06-0.76, P = .02), bleeding requiring re-exploration (OR: 0.21, CI: 0.06-0.75, P = .02), ECPR in patients with SV (OR: 11.84, CI: 1.11-126.07, P = .04), delayed lactate normalization (OR: 0.95, CI: 0.90-0.99 per hour, P = .02), and elevated liver enzymes (OR: 0.97, CI: 0.95-1.00 per 10 unit/L, P = .05). CONCLUSIONS: The ECMO is valuable in patients with SV however results depend on anatomy, procedure, and support indication. Persistent markers of poor perfusion, end-organ injury, and prolonged ECMO duration are associated with mortality. Those factors could be modified by early ECMO application before organ damage, meticulous homeostasis to ensure adequate perfusion, early diagnosis, and reoperation on residual lesions to expedite weaning. PMID- 24403350 TI - Relationship between risk-adjustment tools and the pediatric logistic organ dysfunction score. AB - BACKGROUND: The Risk-Adjusted Classification for Congenital Heart Surgery (RACHS 1) method and Aristotle Basic Complexity (ABC) scores correlate with mortality. However, low mortality rates in congenital heart disease (CHD) make use of mortality as the primary outcome measure insufficient. Demonstrating correlation between risk-adjustment tools and the Pediatric Logistic Organ Dysfunction (PELOD) score might allow for risk-adjusted comparison of an outcome measure other than mortality. METHODS: Data were obtained from the Virtual PICU Systems database. Patients with postoperative CHD between 2009 and 2010 were included. Correlation between RACHS-1 category and PELOD score and between ABC level and PELOD score was examined using Spearman rank correlation. Consistency of PELOD scores across institutions for given levels of case complexity was examined using Kruskal-Wallis nonparametric analysis of variance. RESULTS: A total of 1,981 patient visits among 12 institutions met inclusion criteria. Positive correlations between PELOD score and RACHS-1 category (r s = .353, P < .0001) as well as between PELOD score and ABC level (r s = .328, P < .0001) were demonstrated. Variability in PELOD scores across individual centers for given levels of case complexity was observed (P < .04). CONCLUSIONS: Risk-Adjusted Classification for Congenital Heart Surgery categories and ABC levels correlate with postoperative organ dysfunction as measured by PELOD. However, the correlation was weak, potentially due to limitations of the PELOD score itself. Identification of a more accurate metric of morbidity for the congenital heart disease population is needed. PMID- 24403352 TI - Cardiac catheter procedures during extracorporeal life support: a risk-benefit analysis. AB - BACKGROUND: Extracorporeal life support (ECLS) is a valuable tool for situations in which cardiac disease acutely threatens the life of a child. Residual anatomic lesions have a strong negative influence on survival when ECLS is used after cardiac operations. Accurate diagnostic information is essential, and although noninvasive studies are preferred (eg, echocardiography and thoracic computed tomographic angiography), they are not always logistically practical nor adequate in complex situations under the loading and nonpulsatile flow conditions of ECLS. METHODS: We analyzed our experience (February 2009 to August 2012) with cardiac ECLS for 59 children. Of the 59 children, 22 (median age and weight 19.5 days and 4 kg) with advanced cardiac dysfunction had catheter studies performed during support. RESULTS: The 22 patients had 28 studies, without major adverse events relating to the procedure or transport. Problems leading to further therapeutic procedures (catheter based seven, hybrid two, or surgical eight) were discovered in 17 of the 22 patients. For 22 catheterized patients, total time on ECLS, weaning probability, and survival to discharge were 151.6 +/- 122.6 hours, 81%, and 68%, respectively, similar to that for the 37 cardiac support patients not requiring catheter studies during support (P = 0.94, 0.37, and 0.59, respectively). CONCLUSION: Assuming that undiscovered anatomic and/or hemodynamic issues would have had a strong negative influence on survival, we may conclude that the risk-benefit ratio was positive and favorable. Catheter studies during ECLS are safe and should be performed expeditiously when diagnostic questions cannot be resolved by noninvasive means. PMID- 24403351 TI - Anomalous aortic origin of a coronary artery: a report from the Congenital Heart Surgeons Society Registry. AB - BACKGROUND: Anomalous aortic origin of a coronary artery (AAOCA) is a common congenital heart lesion that may be rarely associated with myocardial ischemia and sudden death in the young. Evidence-based criteria for managing young patients with AAOCA are lacking. The Congenital Heart Surgeons Society (CHSS) established a multicenter registry of patients with AAOCA aged <=30 years to develop these criteria. METHODS: All institutional members of the CHSS are eligible to enroll patients. Patients were enrolled retrospectively if diagnosis of AAOCA occurred between January 1, 1998, and January 20, 2009, and prospectively from January 20, 2009 forward. The first phase of analysis explored possible associations between demographics, symptoms, coronary anatomy, and management using correlation analysis and logistic regression. RESULTS: As of June 2012, 198 patients were enrolled from CHSS member institutions (median age at diagnosis = 10.2 years; 64% male). Data were extracted from clinical records. Fifty-four percent were symptomatic at presentation (most commonly chest pain, N = 78). The AAOCA was diagnosed at autopsy in two patients who presented with sudden death (one with anomalous aortic origin of the left coronary artery [AAOLCA]; one with a single ostium above a commissure giving rise to both left and right coronary arteries). Imaging reports documented anomalous aortic origin of the right coronary artery (AAORCA) in 144 patients, AAOLCA in 51 patients, and AAOLCA/AAORCA in 1 patient. Surgery or autopsy without surgery was performed in 106 patients (71 AAORCA [67%]; 31 AAOLCA [29%]; and 4 AAORCA/AAOLCA [4%]) at a median age of 12.6 years. Overall, 52% of patients with AAORCA versus 67% with AAOLCA had surgery. Most surgical operative reports described an intramural segment of the coronary artery with anomalous origin. Surgery correlated with symptoms, older age, and presence of an intramural segment in the setting of AAOLCA. CONCLUSIONS: Management decisions, including surgical referral, are associated with patient symptoms and coronary morphology. Information derived from annual follow-up of surgically and nonsurgically managed patients enrolled in the registry will eventually form the basis for development of evidence-based protocols to address the spectrum of risk and inform clinical decision making in this heterogeneous population of young patients. PMID- 24403353 TI - Perioperative levels of tumor necrosis factor-alpha correlate with outcomes in children and adults with tetralogy of Fallot undergoing corrective surgery. AB - BACKGROUND: Previous studies reporting on tumor necrosis factor-alpha (TNF-alpha) as a marker of inflammatory response (IR) in patients with congenital heart disease were limited by small sample size and variability in diagnosis. We report perioperative changes in TNF-alpha levels and their correlation with preoperative factors and clinical outcomes in a large homogenous group of patients with tetralogy of Fallot (TOF) undergoing definitive repair at a tertiary care center. METHODS: A total of 167 patients were divided into four groups on the basis of age. Group 1 included infants less than 1 year, group 2 included children between 1 and 12 years, group 3 included adolescents between 12 and 18 years, and group 4 included adults more than 18 years of age. Serum TNF-alpha levels were measured at three time points and correlated with perioperative variables. RESULTS: The baseline TNF-alpha level correlated with patients' nutritional status and degree of cyanosis in all four groups. The magnitude of IR in the postcardiopulmonary bypass (post-CPB) period as measured by TNF-alpha level was much higher and correlated more consistently with adverse clinical outcomes in the younger age group (groups 1 and 2). On multivariable analysis; age at operation, preoperative degree of hypoxemia and TNF-alpha levels were found to be independent predictors of clinical outcomes. CONCLUSION: We demonstrated a rise in serum TNF-alpha levels in patients with TOF undergoing definitive repair on CPB, which correlated with preoperative severity of cyanosis, nutritional status, and adverse clinical outcomes. The TNF-alpha levels may be monitored to identify cyanotic patients at an increased risk of exhibiting augmented IR to CPB. PMID- 24403354 TI - Results of data verification of the Japan congenital cardiovascular database, 2008 to 2009. AB - BACKGROUND: Since 2008, data concerning pediatric cardiovascular surgeries performed in Japan have been collected in the Japan Congenital Cardiovascular Surgery Database (JCCVSD). We assessed the quality of the JCCVSD data through data verification activities conducted in 2010. METHODS: During 2008 to 2009, 3345 patients with 4327 procedures at 25 hospitals were registered in the JCCVSD. Among them, six sites were selected for data verification. The completeness of case registration was assessed by comparison with original operational logs. Also, data accuracy of patient demographics, surgical outcomes, and processes were assessed with 10% of the registered cases by comparison with medical records. RESULTS: Verification of case registration completeness involved 968 (28.9%) patients and 1279 (29.1%) procedures. As to completeness, we confirmed 1266 (99.0%) of the 1279 procedures. Data accuracy was verified for 129 (3.9%) patients. Accuracy of status of discharge and 30 and 90 days after surgery were very high (99.2%, 100%, and 100%, respectively). Data items with numeric information exhibited lower exact accuracy due to typing error and inconsistent use of rounding; however, the differences between the submitted and the original data were not statistically significant. CONCLUSIONS: High completeness and acceptable range of data accuracy were verified for the data submitted to the JCCVSD in 2008 to 2009. The high accuracy regarding follow-up outcomes was especially noteworthy. The initial success of the JCCVSD should be strengthened through further sophistication of registration protocol, continual training of data managers and auditors, and rigorous expansion of verification activities. PMID- 24403355 TI - A complete extracorporeal circulation-free approach to patients with functionally univentricular hearts provides superior early outcomes. AB - OBJECTIVE: We compared the early outcomes of patients undergoing extracardiac total cavopulmonary connection (TCPC) with or without cardiopulmonary bypass (CPB). METHODS: Between February 2012 and February 2013, 27 patients undergoing TCPC without CPB (off-pump group) were compared with matched 27 patients undergoing TCPC on CPB (on-pump group). Outcome parameters studied were inotropic score, time to extubation, intensive care unit (ICU) stay, first 12 hours mediastinal drainage in ICU, average pleural drainage, time to removal of chest tubes, total hospital stay, and saturation at discharge. RESULTS: There was one early death in each group. No patient required conversion from off CPB to CPB. The inotropic score (6.1 +/- 5.91 vs 10.1 +/- 6.80, P = .03), time to extubation (8.7 +/- 6.95 vs 10.31 +/- 8.69 hours, P = .03), first 12 hours mediastinal drainage in ICU (611.9 +/- 341.4 vs 922.2 +/- 145.6 mL, P = .03), and ICU stay (1.6 +/- 0.58 vs 2.9 +/- 1.37 days, P = .001) were significantly less in the off pump group when compared to the on-pump group, and saturation at discharge (99.7 +/- 0.60 vs 98.6 +/- 2.13, P = .026) was higher in the off-pump group. However, the average daily pleural drainage (125 +/- 61.72 vs 150 +/- 103.4 mL, P = .7), time to removal of chest tubes (12.69 +/- 7.1 vs 15.44 +/- 19.26 days, P = .45), and the total hospital stay (14.23 +/- 7.4 vs 18.89 +/- 19.9 days, P = .22) were no different. There were substantial savings in costs in patients undergoing off pump TCPC (P = .016). CONCLUSIONS: The TCPC without CPB is easy to perform, is cost-effective, and is associated with superior early postoperative outcomes as compared to TCPC on CPB. With appropriate modifications, this operation can be performed in almost all morphological subsets of patients who do not need an associated intracardiac procedure. PMID- 24403356 TI - High incidence of abdominal venovenous collaterals after Kawashima operation. AB - INTRODUCTION: Systemic venous collaterals have been found at different stages of single-ventricle palliation, specifically after Kawashima operation. In this study, we present the incidence, clinical features, associated risk factors, and management of such venovenous collaterals (VVCs) after Kawashima procedure. MATERIALS AND METHODS: A retrospective review of all the patients who underwent Kawashima procedure prior to December 2011 at Hamad General Hospital, Qatar, was performed. Data were collected and reviewed from medical records. RESULTS: The study group involved a total of six patients with Kawashima procedure. The median age of patients was 112.7 months (range 46-336 months), and median age at the time of Kawashima operation was 31.7 months (range 15-187 months). Mean systemic arterial oxygen saturation (Spo 2) after Kawashima operation was 94.5% +/- 1.5%. In five patients, during a median follow-up of 53.4 months (range 16.9-147.9 months), the Spo 2 declined to a mean of 78.8% +/- 8.2%. A total of 16 venous collaterals were observed in the study group, and majority (70%) of these collaterals were subdiaphragmatic. CONCLUSION: In our study, abdominal VVCs were observed in 100% of the patients who were followed after Kawashima operation. We therefore recommend that thorough evaluation for such VVCs should be part of the ongoing evaluation of patients after Kawashima operation, especially in those with low Spo 2. We also recommend early surgical rerouting of hepatic veins to pulmonary arteries in all post-Kawashima patients. PMID- 24403357 TI - Transthoracic echocardiographic predictors of left atrial hypertension in patients on venoarterial extracorporeal membrane oxygenation. AB - Decompression of the left heart in patients supported with extracorporeal membrane oxygenation (ECMO) is often warranted to protect the myocardium and facilitate recovery. We studied the ability of standard echocardiographic parameters to predict left atrial hypertension by reviewing 3 cardiac patients supported with ECMO who subsequently underwent left atrial decompression. We found that standard echocardiographic parameters poorly predict the need for left atrial decompression on ECMO. Following a more specific diagnostic algorithm to estimate left-sided filling pressure in patients with depressed ejection fraction may significantly improve the ability of echocardiography to accurately predict left atrial hypertension and the need for decompression. PMID- 24403358 TI - Management of tetralogy of Fallot with unilateral absence of pulmonary artery: an overview. AB - Tetralogy of Fallot with unilateral absence of pulmonary artery (PA) is a rare congenital anomaly that has been reported in isolated case reports and small case series. There is no well-defined treatment algorithm for these patients, and repair has been associated with high mortality, although survival is improving in the more recent era. Recent reports suggest strict case selection criteria based on PA dimensions and size of the left ventricle. PMID- 24403359 TI - Surgical options in rheumatic mitral valve disease in children: a surgeon's perspective. AB - In children with rheumatic heart disease, conservative valve surgery is the best option whenever feasible. Surgeons must develop an attitude and interest in valve repair techniques that can be easily learned. Patients who undergo valve repair at an early age are at risk of requiring additional surgery over time. Mechanical valve replacement, nonetheless, should be reserved for situations where more conservative approaches are not feasible. PMID- 24403360 TI - Palliative switch: a surgical decision after hybrid procedure. AB - The first-stage palliation of newborns with single-ventricle anatomy and transposed great arteries can be very challenging when associated with systemic ventricular outflow obstruction and aortic arch obstruction. Often, the initial intervention is a stage I Norwood procedure. We present the case of a newborn with double inlet left ventricle, discordant ventriculoarterial connection with restrictive ventricular foramen, and severe aortic arch obstruction. A hybrid procedure was performed initially as a means of addressing hemodynamic instability. Three months later, a palliative arterial switch procedure was performed as an alternative to the combined Norwood-Glenn procedure. Palliative arterial switch combined with arch reconstruction can be an effective surgical option in these complex, challenging patients. PMID- 24403361 TI - Fourth time cardiac retransplantation. AB - Beginning at age 11 years, our patient has had four heart transplants. Now, 26 years later at age 37, he is fully active. This case is presented to document a unique experience and to consider the difficult decision-making process and ethical issues of multiple cardiac retransplantation. PMID- 24403362 TI - Video fluoroscopy swallow study and nutritional support during ambulatory venovenous extracorporeal membrane oxygenation as a bridge to lung transplantation. AB - We present the successful completion of a video fluoroscopy swallow study and subsequent nutritional plan of a child bridged to lung transplantation with ambulatory venovenous (VV) extracorporeal membrane oxygenation (ECMO). With a limited number of programs bridging pediatric patients to lung transplantation with VV ECMO, a better understanding of nutritional support is needed to provide optimal care to this patient population awaiting organ donation. PMID- 24403363 TI - Repeated aortopulmonary shunt thrombosis in a neonatal patient with a low antithrombin level. AB - A female infant with unbalanced right ventricular dominant atrioventricular septal defect with double-outlet right ventricle and pulmonary stenosis had recurrent aortopulmonary shunt thrombosis. She was found to have low antithrombin levels and was managed with antithrombin replacement in addition to unfractionated heparin. A subsequent aortopulmonary shunt was successfully placed, and patency was maintained. Her antithrombin levels normalized, and she was continued on low-molecular-weight heparin and aspirin until four months of age when a bidirectional superior cavopulmonary anastomosis was done. A prothrombotic evaluation at the time of the acute thrombosis and repeated at four months of age was negative except for the initially low antithrombin level. A repeat antithrombin level (off supplementation) at the time of the cavopulmonary anastomosis was normal making the diagnosis of congenital antithrombin deficiency unlikely. This case highlights the possibility of neonatal antithrombin deficiency as a cause of aortopulmonary shunt thrombosis and successful management with replacement therapy. PMID- 24403364 TI - Anomalous origin of circumflex coronary artery from right pulmonary artery associated with coarctation of the aorta: a case report of surgical treatment. AB - Origin of the circumflex coronary artery (Cx) from the pulmonary arteries is an extremely rare anomaly. We describe a two-month-old female patient with anomalous origin of the Cx from the right pulmonary artery associated with coarctation of the aorta. Reimplantation of the anomalous Cx to the aorta and coarctation repair were performed. There were no postoperative complications, and the patient was discharged in satisfactory condition. PMID- 24403365 TI - Natural history of newborn with borderline small left heart without interatrial communication. AB - A patient with a borderline small left heart requires difficult clinical decision making during prenatal and neonatal periods. This report describes the unusual natural history of a newborn with prenatally diagnosed hypoplastic left heart structures and early spontaneous postnatal closure of the interatrial communication. Initial deterioration from pulmonary edema and low-cardiac output improved with postnatal intensive care. During the seventh week of life, aortic coarctation was diagnosed and the infant underwent uneventful surgical repair. Despite transient clinical deterioration, early spontaneous closure of the interatrial communication in a newborn with borderline small left heart could be associated with gradual hemodynamic adaptation to postnatal biventricular circulation. PMID- 24403366 TI - Left main coronary artery stenting in a neonate after arterial switch operation for transposition of the great arteries. AB - Anatomical correction of transposition of the great arteries (TGA) with an intramural coronary artery is associated with high risk of coronary complications such as vessel injury and stenosis. Here, we report on a case of left main coronary artery stenting in a neonate with single coronary artery after repair for TGA. PMID- 24403367 TI - Cardiac rhabdomyoma in a neonate with supraventricular tachycardia. AB - Cardiac rhabdomyoma (CR) is a rare tumor commonly associated with tuberous sclerosis. They are often detected prenatally or in early infancy. The case of a Nigerian human immunodeficiency virus (HIV)-exposed neonate with CR who presented with supraventricular tachycardia and cardiovascular collapse is presented. The infant was born to a mother on highly active antiretroviral therapy (HAART). The possible role of HIV and HAART in CR etiology and the difficulty in the management of this case are highlighted. PMID- 24403368 TI - Chest pain and ventricular tachycardia in a patient with surgically corrected anomalous right coronary artery from the left sinus of Valsalva. AB - We present a case of an adult patient who had anomalous origin of the right coronary artery (RCA) from the left sinus of Valsalva that had been treated surgically in the past and who presented years later with chest pain and runs of nonsustained ventricular tachycardia. Coronary angiography showed a patent unroofed RCA with appropriately repositioned origin and no obstructive coronary artery disease. This case presents angiographic documentation of a technically satisfactory repair of anomalous aortic origin of a coronary artery and suggests that potentially lethal arrhythmia can occur despite a technically satisfactory repair. PMID- 24403369 TI - Resuscitation of a neonate with medium chain acyl-coenzyme a dehydrogenase deficiency using extracorporeal life support. AB - We report a neonate with medium chain acyl-coenzyme A dehydrogenase deficiency (MCAD) who had a cardiac arrest due to ventricular tachycardia and fibrillation. Extracorporeal life support (ECLS) was deployed, from which the baby was subsequently separated and discharged from hospital. This case was a rare neonatal presentation of MCAD and an uncommon indication for ECLS. We discuss the presentations of patients with MCAD and the use of ECLS for patients with possible inborn errors of metabolism and other unknown primary diagnoses. PMID- 24403370 TI - Unusual left ventricular pseudoaneurysm in a child after disseminated bacterial infection. AB - Left ventricular pseudoaneurysms are rare in children. A six-year-old boy developed left ventricular pseudoaneurysm despite successful control of sepsis. The pseudoaneurysm was diagnosed by two-dimensional echocardiography and detailed by computed tomography. The child underwent successful surgical correction with partial excision and plication of the aneurysmal sac. PMID- 24403371 TI - Bilateral anomalous pulmonary venous connection to bilateral superior caval veins. AB - A four-year-old girl presented with superior vena cava (SVC) type of sinus venosus defect, right upper pulmonary vein draining into right SVC-right atrium junction, left upper lobe pulmonary veins draining into the lower part of persistent left SVC (LSVC), and a patent ductus arteriosus. The anomalous pulmonary venous drainage to LSVC was overlooked in the preoperative evaluation and was found intraoperatively. Warden procedure was performed for right-sided veins. Lower LSVC draining the anomalous pulmonary veins was anastomosed to the left atrial appendage. The short stump of LSVC was diverted to left pulmonary artery. Anomalous pulmonary venous connections to LSVC are rare. Embryology of venous development is analyzed with respect to this rare anomaly, and options for surgical correction are discussed. PMID- 24403372 TI - Modified transseptal repair for total anomalous pulmonary venous connection repair in all age groups. AB - Little data are available in late-presenting children with unobstructed totally anomalous pulmonary venous connection. Eleven patients underwent repair at a median age of 6.5 months using a modified transseptal approach to improve access and avoid circulatory arrest. There were no early or late deaths, and none of the patients presented pulmonary venous stenosis at a median follow-up of 8.7 years. PMID- 24403373 TI - Infracardiac total anomalous pulmonary venous return: an unusual cause of neonatal portal vein enlargement. AB - We present an unusual cause of aneurysmal dilatation of portal vein in a neonate in a case of infracardiac total anomalous pulmonary venous return. The common descending pulmonary vein was seen joining below the diaphragm with the left branch of portal vein, which was terminating as a blind-ending, aneurysmally dilated vascular channel. PMID- 24403374 TI - Misplacement of left ventricular vent as a cause of cardioplegia failure during routine open-heart surgery. AB - We report an unusual cause of failure of successful delivery of antegrade cardioplegia through the aortic root that was caused by the accidental passage of the left ventricular vent catheter across the aortic valve producing acute aortic regurgitation. This problem is best prevented. PMID- 24403375 TI - Follow the leaders. PMID- 24403377 TI - Nandrolone decanoate inhibits gluconeogenesis and decreases fasting glucose in Wistar male rats. AB - The use of anabolic-androgenic steroids to improve physical performance or appearance has increased notably. The doses used are 10- to 100- fold higher than the therapeutic dose (TD), and this abuse can cause several side effects. Glucose metabolism is significantly affected by anabolic-androgenic steroid abuse, but studies about glycemic regulation during fasting are scarce. There are some evidences showing that testosterone can antagonize glucocorticoids action, which are crucial to glucose production during fasting. Thus, the aim of this study was to determine the impact of supraphysiological doses (SDs) of nandrolone decanoate (DECA) on rat glucose metabolism during fasting. Male Wistar rats were treated with i.m. injections of vehicle, a low TD (0.016 mg/100 g b.w.-TD group) or a high SD (1 mg/100 g b.w.-SD group) of DECA, once a week for 8 weeks. After 12 h fasting, we evaluated glucose and pyruvate tolerance tests, liver glycogen content, serum levels of gluconeogenic substrates, insulin and corticosterone, glucose uptake and hexokinase (HK) activity in skeletal muscle, and the adrenal catecholamine content. SD group had increased serum insulin levels and a blunted response to insulin regarding glucose uptake in skeletal muscle. Fasting serum glucose decreased significantly in SD group, as well as the pyruvate tolerance test and liver glycogen content. Moreover, serum levels of glycerol were increased in SD group. Our data indicate that SDs of DECA exert effects on different regulatory points of glucose metabolism, resulting in defective gluconeogenesis and decreased skeletal muscle glucose uptake in response to insulin. PMID- 24403379 TI - Early enteral nutrition is associated with lower mortality in critically ill children. AB - BACKGROUND: The purpose of this study was to examine the association of early enteral nutrition (EEN), defined as the provision of 25% of goal calories enterally over the first 48 hours of admission, with mortality and morbidity in critically ill children. METHODS: We conducted a multicenter retrospective study of patients in 12 pediatric intensive care units (PICUs). We included patients aged 1 month to 18 years who had a PICU length of stay (LOS) of >=96 hours for the years 2007-2008. We obtained patients' demographics, weight, Pediatric Index of Mortality-2 (PIM2) score, LOS, duration of mechanical ventilation (MV), mortality data, and nutrition intake data in the first 4 days after admission. RESULTS: We identified 5105 patients (53.8% male; median age, 2.4 years). Mortality was 5.3%. EEN was achieved by 27.1% of patients. Children receiving EEN were less likely to die than those who did not (odds ratio, 0.51; 95% confidence interval, 0.34-0.76; P = .001 [adjusted for propensity score, PIM2 score, age, and center]). Comparing those who received EEN to those who did not, adjusted for PIM2 score, age, and center, LOS did not differ (P = .59), and the duration of MV for those receiving EEN tended to be longer than for those who did not, but the difference was not significant (P = .058). CONCLUSIONS: EEN is strongly associated with lower mortality in patients with PICU LOS of >=96 hours. LOS and duration of MV are slightly longer in patients receiving EEN, but the differences are not statistically significant. PMID- 24403380 TI - Prevalence and characteristics of patients with advanced chronic conditions in need of palliative care in the general population: a cross-sectional study. AB - BACKGROUND: Of deaths in high-income countries, 75% are caused by progressive advanced chronic conditions. Palliative care needs to be extended from terminal cancer to these patients. However, direct measurement of the prevalence of people in need of palliative care in the population has not been attempted. AIM: Determine, by direct measurement, the prevalence of people in need of palliative care among advanced chronically ill patients in a whole geographic population. DESIGN: Cross-sectional, population-based study. MAIN OUTCOME MEASURE: prevalence of advanced chronically ill patients in need of palliative care according to the NECPAL CCOMS-ICO((c)) tool. NECPAL+ patients were considered as in need of palliative care. SETTING/PARTICIPANTS: County of Osona, Catalonia, Spain (156,807 inhabitants, 21.4% > 65 years). Three randomly selected primary care centres (51,595 inhabitants, 32.9% of County's population) and one district general hospital, one social-health centre and four nursing homes serving the patients. Subjects were all patients attending participating settings between November 2010 and October 2011. RESULTS: A total of 785 patients (1.5% of study population) were NECPAL+: mean age = 81.4 years; 61.4% female. Main disease/condition: 31.3% advanced frailty, 23.4% dementia, 12.9% cancer (ratio of cancer/non-cancer = 1/7), 66.8% living at home and 19.7% in nursing home; only 15.5% previously identified as requiring palliative care; general clinical indicators of severity and progression present in 94% of cases. CONCLUSIONS: Direct measurement of prevalence of palliative care needs on a population basis is feasible. Early identification and prevalence determination of these patients is likely to be the cornerstone of palliative care public health policies. PMID- 24403378 TI - Adipocytokines in obesity and metabolic disease. AB - The current global obesity pandemic is the leading cause for the soaring rates of metabolic diseases, especially diabetes, cardiovascular disease, hypertension, and non-alcoholic hepatosteatosis. Efforts devoted to find cures for obesity and associated disorders in the past two decades have prompted intensive interest in adipocyte biology, and have led to major advances in the mechanistic understanding of adipose tissue as an essential endocrine organ. Adipose tissue secretes an array of hormones (adipokines) that signal key organs to maintain metabolic homeostasis, and their dysfunction has been causally linked to a wide range of metabolic diseases. In addition, obesity induces production of inflammatory cytokines (often referred to together with adipokines as adipocytokines) and infiltration of immune cells into adipose tissue, which creates a state of chronic low-grade inflammation. Metabolic inflammation has been increasingly recognized as a unifying mechanism linking obesity to a broad spectrum of pathological conditions. This review focuses on classic examples of adipocytokines that have helped to form the basis of the endocrine and inflammatory roles of adipose tissue, and it also details a few newly characterized adipocytokines that provide fresh insights into adipose biology. Studies of adipocytokines in clinical settings and their therapeutic potential are also discussed. PMID- 24403381 TI - Of mice and men. AB - A case study of a patient returning from sub-Saharan Africa with a febrile illness and symptoms reminiscent of a previous malarial infection is discussed. The patient had a relative bradycardia with respect to febrile episodes, a transient macular rash and thrombocytopenia. The illness was conservatively managed for 1 month before positive Rickettsia serology and PCR results were reported. The patient was then treated with doxycycline with a complete resolution of symptoms. PMID- 24403382 TI - Recurrent nephrolithiasis associated with atazanavir use. AB - A 64-year-old man with HIV on antiretroviral therapy (including atazanavir, a protease inhibitor) presented with left flank pain, nausea and vomiting. A kidney stone was suspected, and a CT scan demonstrated left hydronephrosis but failed to demonstrate nephrolithiasis or extrinsic compression. The patient had a ureteral stent placed which relieved his symptoms. A few months later, he underwent left ureteroscopy and a large ureteral calculus was found. The stone was removed and analysis showed 43% atazanavir and 57% calcium oxalate. Several months later, the patient developed flank pain on the opposite side. A renal ultrasound suggested right-sided nephrolithiasis and he subsequently underwent ureteroscopy with laser lithotripsy of two stones. Stone analysis showed that they were composed of 100% atazanavir. This case highlights the fact that patients treated with protease inhibitors remain at risk for developing nephrolithiasis. Ultrasonography can be a useful diagnostic tool in the setting of these radiolucent calculi. PMID- 24403383 TI - Progressive multifocal leukoencephalopathy in a patient with chronic lymphocytic leukaemia treated with alemtuzumab. AB - A 69-year-old Caucasian woman with a 15-year history of refractory chronic lymphocytic B-cell leukaemia (CLL), treated with alemtuzumab in the past 10 months presented with a subacute right foot drop. Initial evaluation with a brain CT scan, lumbosacral MRI, nerve conduction studies and LP was negative. In the following months, progressive right hemibody weakness and dysarthria developed. Brain MRI showed a bilateral parasagittal frontal lesion. Alemtuzumab treatment was withdrawn. Progressive multifocal leukoencephalopathy (PML) was confirmed by PCR. Attempted antiviral therapies proved fruitless. Inexorable clinical deterioration ensued and the patient passed away 10 months after the presentation. This case report intends to call attention for PML as a potential fatal complication of severe immunosuppression, including the possible role of new monoclonal antibodies (such as alemtuzumab) in its pathogenesis. PMID- 24403384 TI - Intrathoracic gossypiboma. AB - Gossypiboma refers to retained sponge or swab in any body cavity after surgery. Although it is a rare occurence, it can lead to various complications which include adhesions, abscess formation and subsequent infections. Gossypiboma occurs as a result of not using radio-opaque sponges, poorly performed sponge counts, inadequate wound explorations on suspicion and misread intraoperative radiographs. Therefore, this event can be avoided if strict preventive measures are taken. Moreover, further complications can be avoided following the correct and early diagnosis of gossypiboma. Gossypiboma is an important topic as it carries great medicolegal consequences for the surgeon. We have presented three cases of intrathoracic gossipiboma following previous cardiothoracic surgeries. They presented years after their surgeries, with features varying from patient to patient, ranging from cough and fever to no sypmtoms at all. CT scan only showed a mass lesion in all cases, therefore we proceeded for CT-guided biopsy which was also found to be inconclusive. It was only after entering the thoracic cavity via video-assisted thoracoscopy/thoracotomy that the diagnosis was made and sponges were taken out successfully. All our cases recovered with no further complications. PMID- 24403385 TI - Fatal hypertriglyceridaemia, acute pancreatitis and diabetic ketoacidosis possibly induced by quetiapine. AB - A 27-year-old man treated with quetiapine for anxiety disorder developed hypertriglyceridaemia-induced acute pancreatitis and diabetic ketoacidosis. He was otherwise physically healthy with no family history of hyperlipidaemia. Despite aggressive intensive therapy he died of multiorgan failure within 36 h from initial presentation. While second-generation antipsychotics are well known to be causally linked to diabetes and hyperlipidaemia, this is to my knowledge the first-described case of a fatal triad of extreme hypertriglyceridaemia, acute pancreatitis and diabetic ketoacidosis possibly induced by quetiapine. Clinicians should be aware of this rare clinical presentation since rapid progression to multiorgan failure can occur. Early supportive therapy should be initiated. Lactescent serum and ketoacidosis in severe acute pancreatitis should not be overlooked-initiate insulin therapy and possibly plasmapheresis in case of extreme hypertriglyceridaemia. PMID- 24403386 TI - Swollen right leg: is it deep vein thrombosis? PMID- 24403387 TI - Portal hypertension-associated gastric polyps. PMID- 24403388 TI - Seat belt syndrome with unstable Chance fracture dislocation of the second lumbar vertebra without neurological deficits. AB - The seat belt syndrome is a recognised complication of seat belt use in vehicles. Unstable Chance fractures of the spine without neurological deficits have been reported infrequently. We describe a young woman with completely disrupted Chance fracture of the second lumbar vertebra in association with left hemidiaphragmatic rupture/hernia, multiple bowel perforations, splenic capsular tear, left humeral shaft and multiple rib fractures. These injuries which resulted from high-speed vehicle collision and led to death of one of the occupants were readily detected by trauma series imaging. The patient was successfully treated by a dedicated multidisciplinary team which adopted a staged surgical approach and prioritisation of care. There were no manifested neurological or other deficits after 1 year of follow-up. To the authors' knowledge, this is the first report of such a case in Australasia. We discuss the challenging surgical management, highlighting the role of radiological imaging in such cases and provide a literature review. PMID- 24403389 TI - Moyamoya disease, revascularisation surgery and anaesthetic considerations. AB - We report a case of a rare disease that requires a unique anaesthetic approach for a unique surgical procedure. Anaesthesiologists need to be familiar with different pathophysiological aspects of this disease and its perioperative management. PMID- 24403390 TI - Congenital triangular alopecia. PMID- 24403393 TI - A bias-free measure of retinotopic tilt adaptation. AB - The traditional method of single stimuli for measuring perceptual illusions and context effects confounds perceptual effects with changes in the observer's decision criterion. By deciding consciously or unconsciously to select one of the two response alternatives more than the other when unsure of the correct response, the observer can shift his or her psychometric function in a manner indistinguishable from a genuine perceptual shift. Here, a spatial two alternative forced-choice method is described to measure a perceptual aftereffect by its influence on the shape of the psychometric function rather than the mean. The method was tested by measuring the effect of motion adaptation on the apparent Vernier offset of stationary Gabor patterns. The shift due to adaptation was found to be comparable in size to the internal noise, estimated from the slope of the psychometric function. By moving the eyes between adaptation and test, it was determined that adaptation is retinotopic rather than spatiotopic. PMID- 24403392 TI - Extrafoveal preview benefit during free-viewing visual search in the monkey. AB - Previous studies have shown that subjects require less time to process a stimulus at the fovea after a saccade if they have viewed the same stimulus in the periphery immediately prior to the saccade. This extrafoveal preview benefit indicates that information about the visual form of an extrafoveally viewed stimulus can be transferred across a saccade. Here, we extend these findings by demonstrating and characterizing a similar extrafoveal preview benefit in monkeys during a free-viewing visual search task. We trained two monkeys to report the orientation of a target among distractors by releasing one of two bars with their hand; monkeys were free to move their eyes during the task. Both monkeys took less time to indicate the orientation of the target after foveating it, when the target lay closer to the fovea during the previous fixation. An extrafoveal preview benefit emerged even if there was more than one intervening saccade between the preview and the target fixation, indicating that information about target identity could be transferred across more than one saccade and could be obtained even if the search target was not the goal of the next saccade. An extrafoveal preview benefit was also found for distractor stimuli. These results aid future physiological investigations of the extrafoveal preview benefit. PMID- 24403394 TI - The relationship between delay period eye movements and visuospatial memory. AB - We investigated whether overt shifts of attention were associated with visuospatial memory performance. Participants were required to study the locations of a set of visual objects and subsequently detect changes to the spatial location of one of the objects following a brief delay period. Relational information regarding the locations among all of the objects could be used to support performance on the task (Experiment 1) or relational information was removed during test and location manipulation judgments had to be made for a singly presented target item (Experiment 2). We computed the similarity of the fixation patterns in space during the study phase to the fixations made during the delay period. Greater fixation pattern similarity across participants was associated with higher accuracy when relational information was available at test (Experiment 1); however, this association was not observed when the target item was presented in isolation during the test display (Experiment 2). Similarly, increased fixation pattern similarity on a given trial (within participants) was associated with successful task performance when the relations among studied items could be used for comparison (Experiment 1), but not when memory for absolute spatial location was assessed (Experiment 2). This pattern of behavior and performance on the two tasks suggested that eye movements facilitated memory for the relationships among objects. Shifts of attention through eye movements may provide a mechanism for the maintenance of relational visuospatial memory. PMID- 24403395 TI - 'Spear' through the right ventricle: pericardial tamponade caused by delayed pacemaker lead-related perforation of a normal thickness free wall which was managed percutaneously using the same lead. PMID- 24403396 TI - Tainted altruism: when doing some good is evaluated as worse than doing no good at all. AB - In four experiments, we found that the presence of self-interest in the charitable domain was seen as tainting: People evaluated efforts that realized both charitable and personal benefits as worse than analogous behaviors that produced no charitable benefit. This tainted-altruism effect was observed in a variety of contexts and extended to both moral evaluations of other agents and participants' own behavioral intentions (e.g., reported willingness to hire someone or purchase a company's products). This effect did not seem to be driven by expectations that profits would be realized at the direct cost of charitable benefits, or the explicit use of charity as a means to an end. Rather, we found that it was related to the accessibility of different counterfactuals: When someone was charitable for self-interested reasons, people considered his or her behavior in the absence of self-interest, ultimately concluding that the person did not behave as altruistically as he or she could have. However, when someone was only selfish, people did not spontaneously consider whether the person could have been more altruistic. PMID- 24403397 TI - Biased predecisional processing of leading and nonleading alternatives. AB - When people obtain information about choice alternatives in a set one attribute at a time, they rapidly identify a leading alternative. Although previous research has established that people then distort incoming information, it is unclear whether distortion occurs through favoring of the leading alternative, disfavoring of the trailing alternative, or both. Prior examinations have not explored the predecisional treatment of the nonleading alternative (or alternatives) because they conceptualized distortion as a singular construct in binary choice and measured it using a relative item comparing the evaluation of both alternatives simultaneously. In this article, we introduce a measure of distortion at the level of the alternative, which allows for measuring whether predecisional distortion favors or disfavors every alternative being considered in choice sets of various sizes. We report that both proleader and antitrailer distortion occur and that the use of antitrailer processing differs between binary choices and multiple-options choices. PMID- 24403398 TI - Similarity measure between patient traces for clinical pathway analysis: problem, method, and applications. AB - Clinical pathways leave traces, described as event sequences with regard to a mixture of various latent treatment behaviors. Measuring similarities between patient traces can profitably be exploited further as a basis for providing insights into the pathways, and complementing existing techniques of clinical pathway analysis (CPA), which mainly focus on looking at aggregated data seen from an external perspective. Most existing methods measure similarities between patient traces via computing the relative distance between their event sequences. However, clinical pathways, as typical human-centered processes, always take place in an unstructured fashion, i.e., clinical events occur arbitrarily without a particular order. Bringing order in the chaos of clinical pathways may decline the accuracy of similarity measure between patient traces, and may distort the efficiency of further analysis tasks. In this paper, we present a behavioral topic analysis approach to measure similarities between patient traces. More specifically, a probabilistic graphical model, i.e., latent Dirichlet allocation (LDA), is employed to discover latent treatment behaviors of patient traces for clinical pathways such that similarities of pairwise patient traces can be measured based on their underlying behavioral topical features. The presented method provides a basis for further applications in CPA. In particular, three possible applications are introduced in this paper, i.e., patient trace retrieval, clustering, and anomaly detection. The proposed approach and the presented applications are evaluated via a real-world dataset of several specific clinical pathways collected from a Chinese hospital. PMID- 24403399 TI - Probability of severe adverse events as a function of hospital occupancy. AB - A unique application of regression modeling is described to compare hospital bed occupancy with reported severe adverse events amongst inpatients. The probabilities of the occurrence of adverse events as a function of hospital occupancy are calculated using logistic and multinomial regression models. All models indicate that higher occupancy rates lead to an increase in adverse events. The analysis identified that at an occupancy level of 100%, there is a 22% chance of one severe event occurring and a 28% chance of at least one severe event occurring. This modeling contributes evidence toward the management of hospital occupancy to benefit patient outcomes. PMID- 24403400 TI - Data mining in bone marrow transplant records to identify patients with high odds of survival. AB - Patients undergoing a bone marrow stem cell transplant (BMT) face various risk factors. Analyzing data from past transplants could enhance the understanding of the factors influencing success. Records up to 120 measurements per transplant procedure from 1751 patients undergoing BMT were collected (Shariati Hospital). Collaborative filtering techniques allowed the processing of highly sparse records with 22.3% missing values. Ten-fold cross-validation was used to evaluate the performance of various classification algorithms trained on predicting the survival status. Modest accuracy levels were obtained in predicting the survival status (AUC = 0.69). More importantly, however, operations that had the highest chances of success were shown to be identifiable with high accuracy, e.g., 92% or 97% when identifying 74 or 31 recipients, respectively. Identifying the patients with the highest chances of survival has direct application in the prioritization of resources and in donor matching. For patients where high-confidence prediction is not achieved, assigning a probability to their survival odds has potential applications in probabilistic decision support systems and in combination with other sources of information. PMID- 24403403 TI - Novel cloud and SOA-based framework for e-health monitoring using wireless biosensors. AB - Various and independent studies are showing that an exponential increase of chronic diseases (CDs) is exhausting governmental and private healthcare systems to an extent that some countries allocate half of their budget to healthcare systems. To benefit from the IT development, e-health monitoring and prevention approaches revealed to be among top promising solutions. In fact, well implemented monitoring and prevention schemes have reported a decent reduction of CDs risk and have narrowed their effects, on both patients' health conditions and on government budget spent on healthcare. In this paper, we propose a framework to collect patients' data in real time, perform appropriate nonintrusive monitoring, and propose medical and/or life style engagements, whenever needed and appropriate. The framework, which relies on service-oriented architecture (SOA) and the Cloud, allows a seamless integration of different technologies, applications, and services. It also integrates mobile technologies to smoothly collect and communicate vital data from a patient's wearable biosensors while considering the mobile devices' limited capabilities and power drainage in addition to intermittent network disconnections. Then, data are stored in the Cloud and made available via SOA to allow easy access by physicians, paramedics, or any other authorized entity. A case study has been developed to evaluate the usability of the framework, and the preliminary results that have been analyzed are showing very promising results. PMID- 24403401 TI - Potential for health screening using long-term cardiovascular parameters measured by finger volume-oscillometry: pilot comparative evaluation in regular and sleep deprived activities. AB - We explored the potential of health screening based on the long-term measurement of cardiovascular parameters using the finger volume-oscillometric technique. An automated instrument made simultaneous measurements of key cardiovascular parameters, including blood pressure, pulse pressure, heart rate, normalized pulse volume as an index of alpha-adrenalin-mediated sympathetic activity, and finger arterial elasticity. These were derived from finger photo-plethysmographic signals during application of cuff pressure. To assess the feasibility of achieving a screening function, measurements were made in ten healthy volunteers during 10 days of day-to-day living (normal condition), and carried out several times at a fixed time every day. During successive 10-day measurements, a 30-hour period of total sleep deprivation was introduced as a physiological challenge (abnormal condition). A linear discriminant analysis of the data was conducted to determine whether these two conditions could be discriminated. Periodic data collection was performed rapidly and easily, and the %-correct classifications of normal and abnormal conditions were 78.2% and 77.5%, respectively. This ability of the method to discriminate between regular and sleep-deprived activities demonstrates its potential for healthcare screening during day-to-day living. Further investigations using larger age and gender groups of subjects including patients with cardiovascular diseases under real-life situations are required. PMID- 24403402 TI - Lifelong personal health data and application software via virtual machines in the cloud. AB - Personal Health Records (PHRs) should remain the lifelong property of patients, who should be able to show them conveniently and securely to selected caregivers and institutions. In this paper, we present MyPHRMachines, a cloud-based PHR system taking a radically new architectural solution to health record portability. In MyPHRMachines, health-related data and the application software to view and/or analyze it are separately deployed in the PHR system. After uploading their medical data to MyPHRMachines, patients can access them again from remote virtual machines that contain the right software to visualize and analyze them without any need for conversion. Patients can share their remote virtual machine session with selected caregivers, who will need only a Web browser to access the pre-loaded fragments of their lifelong PHR. We discuss a prototype of MyPHRMachines applied to two use cases, i.e., radiology image sharing and personalized medicine. PMID- 24403404 TI - Privacy-preserving clinical decision support system using Gaussian kernel-based classification. AB - A clinical decision support system forms a critical capability to link health observations with health knowledge to influence choices by clinicians for improved healthcare. Recent trends toward remote outsourcing can be exploited to provide efficient and accurate clinical decision support in healthcare. In this scenario, clinicians can use the health knowledge located in remote servers via the Internet to diagnose their patients. However, the fact that these servers are third party and therefore potentially not fully trusted raises possible privacy concerns. In this paper, we propose a novel privacy-preserving protocol for a clinical decision support system where the patients' data always remain in an encrypted form during the diagnosis process. Hence, the server involved in the diagnosis process is not able to learn any extra knowledge about the patient's data and results. Our experimental results on popular medical datasets from UCI database demonstrate that the accuracy of the proposed protocol is up to 97.21% and the privacy of patient data is not compromised. PMID- 24403405 TI - An effective approach for detection and segmentation of protein spots on 2-D gel images. AB - Two-dimensional gel image analysis is widely recognized as a particularly challenging and arduous process in proteomics field. The detection and segmentation of protein spots are two significant stages of this process as they can considerably affect the final biological conclusions of a proteomic experiment. The available techniques and commercial software packages deal with the existing challenges of 2-D gel images in a different degree of success. Furthermore, they require extensive human intervention which not only limits the throughput but unavoidably questions the objectivity and reproducibility of results. This paper introduces a novel approach for the detection and segmentation of protein spots on 2-D gel images. The proposed approach is based on 2-D image histograms as well as on 3-D spots morphology. It is automatic and capable to deal with the most common deficiencies of existing software programs and techniques in an effective manner. Experimental evaluation includes tests on several real and synthetic 2-D gel images produced by different technology setups, containing a total of ~ 21,400 spots. Furthermore, the proposed approach has been compared with two commercial software packages as well as with two state of-the-art techniques. Results have demonstrated the effectiveness of the proposed approach and its superiority against compared software packages and techniques. PMID- 24403406 TI - A fully automated system for adherent cells microinjection. AB - This paper proposes an automated robotic system to perform cell microinjections to relieve human operators from this highly difficult and tedious manual procedure. The system, which uses commercial equipment currently found on most biomanipulation laboratories, consists of a multitask software framework combining computer vision and robotic control elements. The vision part features an injection pipette tracker and an automatic cell targeting system that is responsible for defining injection points within the contours of adherent cells in culture. The main challenge is the use of bright-field microscopy only, without the need for chemical markers normally employed to highlight the cells. Here, cells are identified and segmented using a threshold-based image processing technique working on defocused images. Fast and precise microinjection pipette positioning over the automatically defined targets is performed by a two-stage robotic system which achieves an average injection rate of 7.6 cells/min with a pipette positioning precision of 0.23 MUm. The consistency of these microinjections and the performance of the visual targeting framework were experimentally evaluated using two cell lines (CHO-K1 and HEK) and over 500 cells. In these trials, the cells were automatically targeted and injected with a fluorescent marker, resulting in a correct cell detection rate of 87% and a successful marker delivery rate of 67.5%. These results demonstrate that the new system is capable of better performances than expert operators, highlighting its benefits and potential for large-scale application. PMID- 24403407 TI - Semi-automatic segmentation and classification of Pap smear cells. AB - Cytologic screening has been widely used for detecting the cervical cancers. In this study, a semiautomatic PC-based cellular image analysis system was developed for segmenting nuclear and cytoplasmic contours and for computing morphometric and textual features to train support vector machine (SVM) classifiers to classify four different types of cells and to discriminate dysplastic from normal cells. A software program incorporating function, including image reviewing and standardized denomination of file names, was also designed to facilitate and standardize the workflow of cell analyses. Two experiments were conducted to verify the classification performance. The cross-validation results of the first experiment showed that average accuracies of 97.16% and 98.83%, respectively, for differentiating four different types of cells and in discriminating dysplastic from normal cells have been achieved using salient features (8 for four-cluster and 7 for two-cluster classifiers) selected with SVM recursive feature addition. In the second experiment, 70% (837) of the cell images were used for training and 30% (361) for testing, achieving an accuracy of 96.12% and 98.61% for four cluster and two-cluster classifiers, respectively. The proposed system provides a feasible and effective tool in evaluating cytologic specimens. PMID- 24403408 TI - A Bayesian bounded asymmetric mixture model with segmentation application. AB - Segmentation of a medical image based on the modeling and estimation of the tissue intensity probability density functions via a Gaussian mixture model has recently received great attention. However, the Gaussian distribution is unbounded and symmetrical around its mean. This study presents a new bounded asymmetric mixture model for analyzing both univariate and multivariate data. The advantage of the proposed model is that it has the flexibility to fit different shapes of observed data such as non-Gaussian, nonsymmetric, and bounded support data. Another advantage is that each component of the proposed model has the ability to model the observed data with different bounded support regions, which is suitable for application on image segmentation. Our method is intuitively appealing, simple, and easy to implement. We also propose a new method to estimate the model parameters in order to minimize the higher bound on the data negative log-likelihood function. Numerical experiments are presented where the proposed model is tested in various images from simulated to real 3- D medical ones. PMID- 24403409 TI - An explicit shape-constrained MRF-based contour evolution method for 2-D medical image segmentation. AB - Image segmentation is, in general, an ill-posed problem and additional constraints need to be imposed in order to achieve the desired segmentation result. While segmenting organs in medical images, which is the topic of this paper, a significant amount of prior knowledge about the shape, appearance, and location of the organs is available that can be used to constrain the solution space of the segmentation problem. Among the various types of prior information, the incorporation of prior information about shape, in particular, is very challenging. In this paper, we present an explicit shape-constrained MAP-MRF based contour evolution method for the segmentation of organs in 2-D medical images. Specifically, we represent the segmentation contour explicitly as a chain of control points. We then cast the segmentation problem as a contour evolution problem, wherein the evolution of the contour is performed by iteratively solving a MAP-MRF labeling problem. The evolution of the contour is governed by three types of prior information, namely: (i) appearance prior, (ii) boundary-edgeness prior, and (iii) shape prior, each of which is incorporated as clique potentials into the MAP-MRF problem. We use the master-slave dual decomposition framework to solve the MAP-MRF labeling problem in each iteration. In our experiments, we demonstrate the application of the proposed method to the challenging problem of heart segmentation in non-contrast computed tomography data. PMID- 24403410 TI - Automatic motion analysis system for pyloric flow in ultrasonic videos. AB - Ultrasonography has been widely used to evaluate duodenogastric reflux (DGR). But to the best of our knowledge, no automatic analysis system was developed to realize the quantitative computer-aided analysis. In this paper, we propose a system to perform the automatic detection of DGR in the ultrasonic image sequences by applying the automatic motion analysis. The motion field is estimated based on image velocimetry. Then, an intelligent motion analysis is applied. For the DGR detection, the motion and structural information is combined to analyze the transploric motion of the fluid. In order to test the performance of the proposed system, we designed the experiment with the real and synthetic ultrasonic data. The proposed system achieved a good performance in the DGR detection. The automatic results were accordant with the gold standard in analyzing the fluid motion. The proposed system is supposed to be a promising tool for the study and evaluation of DGR. PMID- 24403411 TI - 3-D vascular skeleton extraction and decomposition. AB - We introduce a novel vascular skeleton extraction and decomposition technique for computer-assisted diagnosis and analysis. We start by addressing the problem of vascular decomposition as a cluster optimization problem and present a methodology for weighted convex approximations. Decomposed vessel structures are then grouped using the vessel skeleton, extracted using a Laplace-based operator. The method is validated using presegmented sections of vasculature archived for 98 aneurysms in 112 patients. We test first for vascular decomposition and next for vessel skeleton extraction. The proposed method produced promising results with an estimated 80.5% of the vessel sections correctly decomposed and 92.9% of the vessel sections having the correct number of skeletal branches, identified by a clinical radiological expert. Next, the method was validated on longitudinal study data from n = 4 subjects, where vascular skeleton extraction and decomposition was performed. Volumetric and surface area comparisons were made between expert segmented sections and the proposed approach on sections containing aneurysms. Results suggest that the method is able to detect changes in aneurysm volumes and surface areas close to that segmented by an expert. PMID- 24403412 TI - Ultra-fast hybrid CPU-GPU multiple scatter simulation for 3-D PET. AB - Scatter correction is very important in 3-D PET reconstruction due to a large scatter contribution in measurements. Currently, one of the most popular methods is the so-called single scatter simulation (SSS), which considers single Compton scattering contributions from many randomly distributed scatter points. The SSS enables a fast calculation of scattering with a relatively high accuracy; however, the accuracy of SSS is dependent on the accuracy of tail fitting to find a correct scaling factor, which is often difficult in low photon count measurements. To overcome this drawback as well as to improve accuracy of scatter estimation by incorporating multiple scattering contribution, we propose a multiple scatter simulation (MSS) based on a simplified Monte Carlo (MC) simulation that considers photon migration and interactions due to photoelectric absorption and Compton scattering. Unlike the SSS, the MSS calculates a scaling factor by comparing simulated prompt data with the measured data in the whole volume, which enables a more robust estimation of a scaling factor. Even though the proposed MSS is based on MC, a significant acceleration of the computational time is possible by using a virtual detector array with a larger pitch by exploiting that the scatter distribution varies slowly in spatial domain. Furthermore, our MSS implementation is nicely fit to a parallel implementation using graphic processor unit (GPU). In particular, we exploit a hybrid CPU-GPU technique using the open multiprocessing and the compute unified device architecture, which results in 128.3 times faster than using a single CPU. Overall, the computational time of MSS is 9.4 s for a high-resolution research tomograph (HRRT) system. The performance of the proposed MSS is validated through actual experiments using an HRRT. PMID- 24403413 TI - Smith predictor-based robot control for ultrasound-guided teleoperated beating heart surgery. AB - Performing surgery on fast-moving heart structures while the heart is freely beating is next to impossible. Nevertheless, the ability to do this would greatly benefit patients. By controlling a teleoperated robot to continuously follow the heart's motion, the heart can be made to appear stationary. The surgeon will then be able to operate on a seemingly stationary heart when in reality it is freely beating. The heart's motion is measured from ultrasound images and thus involves a non-negligible delay due to image acquisition and processing, estimated to be 150 ms that, if not compensated for, can cause the teleoperated robot's end effector (i.e., the surgical tool) to collide with and puncture the heart. This research proposes the use of a Smith predictor to compensate for this time delay in calculating the reference position for the teleoperated robot. The results suggest that heart motion tracking is improved as the introduction of the Smith predictor significantly decreases the mean absolute error, which is the error in making the distance between the robot's end-effector and the heart follow the surgeon's motion, and the mean integrated square error. PMID- 24403414 TI - Hypoxic-state estimation of brain cells by using wireless near-infrared spectroscopy. AB - Near-infrared spectroscopy (NIRS) is a modern measuring technology in neuroscience. It can be used to noninvasively measure the relative concentrations of oxyhemoglobin (OxyHb) and deoxyhemoglobin (DeoHb), which can reflect information related to cerebral blood volume and cerebral oxygen saturation. Therefore, it has the potential for noninvasive monitoring of cerebral ischemia. However, there is still a lack of reliable physiological information on the relationship between the concentrations of OxyHb and DeoHb in cerebral blood and the exact hypoxic state of brain cells under cerebral ischemia. In this study, we describe a wireless multichannel NIRS system, which we designed to noninvasively monitor the relative concentrations of OxyHb and DeoHb in bilateral cerebral blood before, during, and after middle cerebral artery occlusion. By comparing the results with the lactate/pyruvate ratio measured by microdialysis, we investigated the correlation between the relative concentrations of OxyHb and DeoHb in cerebral blood and the hypoxic state of brain cells. The results showed that the relationship between the concentration changes of DeoHb in cerebral blood and the hypoxic state of brain cells was significant. Therefore, by monitoring the changes in concentrations of DeoHb, the wireless NIRS can be used to estimate the hypoxic state of brain cells indirectly. PMID- 24403415 TI - Model-based verification of a non-linear separation scheme for ballistocardiography. AB - The current rise in popularity of ballisto-cardiography-related research has led to the development of new sensor concepts and recording methods. Measuring the ballistocardiogram using bed mounted pressure sensors opens up new possibilities for home monitoring applications. The signals measured with these sensors contain a mixture of cardiac and respiratory components, which can be used for detection of comorbidities of heart failure like apnea or arrhythmia. However, the separation of the cardiac and respiratory components has proven to be difficult, since there is significant overlap in the spectra of both components. In this paper, an algorithm for the separation task is presented, which can overcome the problem of overlapping spectra. Additionally, a model has been developed for the generation of artificial ballistocardiograms, which are used to analyze the separation performance. Furthermore, the algorithm is tested on preliminary data from a clinical study. PMID- 24403416 TI - A level-crossing based QRS-detection algorithm for wearable ECG sensors. AB - In this paper, an asynchronous analog-to-information conversion system is introduced for measuring the RR intervals of the electrocardiogram (ECG) signals. The system contains a modified level-crossing analog-to-digital converter and a novel algorithm for detecting the R-peaks from the level-crossing sampled data in a compressed volume of data. Simulated with MIT-BIH Arrhythmia Database, the proposed system delivers an average detection accuracy of 98.3%, a sensitivity of 98.89%, and a positive prediction of 99.4%. Synthesized in 0.13 MUm CMOS technology with a 1.2 V supply voltage, the overall system consumes 622 nW with core area of 0.136 mm (2), which make it suitable for wearable wireless ECG sensors in body-sensor networks. PMID- 24403417 TI - Development of an automated updated Selvester QRS scoring system using SWT-based QRS fractionation detection and classification. AB - The Selvester score is an effective means for estimating the extent of myocardial scar in a patient from low-cost ECG recordings. Automation of such a system is deemed to help implementing low-cost high-volume screening mechanisms of scar in the primary care. This paper describes, for the first time to the best of our knowledge, an automated implementation of the updated Selvester scoring system for that purpose, where fractionated QRS morphologies and patterns are identified and classified using a novel stationary wavelet transform (SWT)-based fractionation detection algorithm. This stage informs the two principal steps of the updated Selvester scoring scheme--the confounder classification and the point awarding rules. The complete system is validated on 51 ECG records of patients detected with ischemic heart disease. Validation has been carried out using manually detected confounder classes and computation of the actual score by expert cardiologists as the ground truth. Our results show that as a stand-alone system it is able to classify different confounders with 94.1% accuracy whereas it exhibits 94% accuracy in computing the actual score. When coupled with our previously proposed automated ECG delineation algorithm, that provides the input ECG parameters, the overall system shows 90% accuracy in confounder classification and 92% accuracy in computing the actual score and thereby showing comparable performance to the stand-alone system proposed here, with the added advantage of complete automated analysis without any human intervention. PMID- 24403418 TI - In-silico modeling of glycosylation modulation dynamics in hERG ion channels and cardiac electrical signals. AB - Cardiac action potentials (AP) are produced by the orchestrated functions of ion channels. A slight change in ion channel activity may affect the AP waveform, thereby potentially increasing susceptibility to abnormal cardiac rhythms. Cardiac ion channels are heavily glycosylated, with up to 30% of a mature protein's mass comprised of glycan structures. However, little is known about how reduced glycosylation impacts the gating of hERG (human ether-a-go-go related gene) channel, which is partially responsible for late phase 2 and phase 3 of the AP. This paper integrates the data from in vitro experiments with in-silico models to predict the glycosylation modulation dynamics in hERG ion channels and cardiac electrical signals. The gating behaviors of hERG channels expressed in Chinese Hamster Ovary (CHO) cells were measured under four glycosylation conditions, i.e., full glycosylation, reduced sialylation, mannose-rich. and N glycanase treated. Further, we developed in-silico models to simulate glycosylation-channel interactions and predict the effects of reduced glycosylation on multiscale cardiac processes (i.e., cardiac cells, 1-D and 2-D tissues). From the in-silico models, reduced glycosylation was shown to shorten the repolarization phase of cardiac APs, thereby influencing electrical propagation in cardiac fibers and tissues. In addition, the patterns of derived electrocardiogram show that reduced glycosylation of hERG channel shortens the QT interval and decreases the re-entry rate of spiral waves. This work suggests new pharmaceutical targets for the long QT syndrome and potentially other cardiac disorders. PMID- 24403419 TI - Individualized estimation of the central aortic blood pressure waveform: a comparative study. AB - This paper presents a comparative study on the relative performance of alternative strategies for estimating an individualized central aortic blood pressure (BP) waveform. Based on the transmission line representation of the central aortic-radial arterial line, a fully individualized (ITF 1), two partially individualized (ITF 2 and ITF 3 ), and a fully nonindividualized (NITF) transfer functions (i.e., frequency-dependent central aortic-radial BP relationships) were constructed using experimental data collected from nine swine subjects. The central aortic BP waveforms estimated by these transfer functions were compared against their measured gold standards, with the root-mean-squared waveform error and the absolute errors associated with systolic and pulse pressures as performance measures. Overall, the advantage of the individualized over the nonindividualized approach was modest but significant. The superiority of the individualized approach to its nonindividualized counterpart was increasingly pronounced under nonnominal or extreme physiologic conditions, as the subject's pulse transit time deviated from the averaged nominal value. The results suggest that the use of a fully individualized transfer function (ITF 1) is strongly recommended for nonnominal physiologic conditions, whereas a partially (ITF 2 and ITF 3) or even fully nonindividualized transfer function (NITF) may also yield acceptable performance under nominal physiologic conditions. PMID- 24403420 TI - The single equivalent moving dipole model does not require spatial anatomical information to determine cardiac sources of activation. AB - Radio-frequency catheter ablation (RCA) is an established treatment for ventricular tachycardia (VT). A key feature of the RCA procedure is the need for a mapping approach that facilitates the identification of the target ablation site. In this study, we investigate the effect of the location of the reference potential and spatial anatomical constraints on the accuracy of an algorithm to identify the target site for ablation therapy of VT. This algorithm involves processing body surface potentials using the single equivalent moving dipole (SEMD) model embedded in an infinite homogeneous volume conductor to model cardiac electrical activity. We employed a swine animal model and an electrode array of nine electrodes that was sutured on the epicardial surface of the right ventricle. We identified two potential reference electrode locations: at an electrode most far away from the heart (R1) and at the average of all 64 body surface electrode potentials (R2). Also, we developed three spatial "constraining" schemes of the algorithm used to obtain the SEMD location: one that does not impose any constraint on the inverse solution (S1), one that constrains the solution into a volume that corresponds to the heart (S2), and one that constrains the solution into a volume that corresponds to the body surface (S3). We have found that R2S1 is the most accurate approach (p < 0.05 versus R1S1 at earliest activation time-EAT) for localizing epicardial electrical sources of known locations in vivo. Although the homogeneous volume conductor introduces systematic error in the estimated compared to the true dipole location, we have observed that the overall error of the estimated interelectrode distance compared to the true one was 0.4 +/- 0.4 cm and 0.4 +/- 0.1 cm for the R1S1 and R2S1 combinations, respectively, at the EAT (p = N.S.) and 1.0 +/- 0.6 and 0.5 +/- 0.4 cm, respectively, at the pacing spike time (PST, ). In conclusion, our algorithm to estimate the SEMD parameters from body surface potentials can potentially be a useful method to rapidly and accurately guide the catheter tip to the target site during a RCA procedure without the need for spatial anatomical information obtained by conventional imaging modalities. PMID- 24403421 TI - On-line detection of apnea/hypopnea events using SpO2 signal: a rule-based approach employing binary classifier models. AB - This paper presents an online method for automatic detection of apnea/hypopnea events, with the help of oxygen saturation (SpO2) signal, measured at fingertip by Bluetooth nocturnal pulse oximeter. Event detection is performed by identifying abnormal data segments from the recorded SpO2 signal, employing a binary classifier model based on a support vector machine (SVM). Thereafter the abnormal segment is further analyzed to detect different states within the segment, i.e., steady, desaturation, and resaturation, with the help of another SVM-based binary ensemble classifier model. Finally, a heuristically obtained rule-based system is used to identify the apnea/hypopnea events from the time sequenced decisions of these classifier models. In the developmental phase, a set of 34 time domain-based features was extracted from the segmented SpO2 signal using an overlapped windowing technique. Later, an optimal set of features was selected on the basis of recursive feature elimination technique. A total of 34 subjects were included in the study. The results show average event detection accuracies of 96.7% and 93.8% for the offline and the online tests, respectively. The proposed system provides direct estimation of the apnea/hypopnea index with the help of a relatively inexpensive and widely available pulse oximeter. Moreover, the system can be monitored and accessed by physicians through LAN/WAN/Internet and can be extended to deploy in Bluetooth-enabled mobile phones. PMID- 24403422 TI - Pulse rate variability analysis for discrimination of sleep-apnea-related decreases in the amplitude fluctuations of pulse photoplethysmographic signal in children. AB - A technique for ambulatory diagnosis of the obstructive sleep apnea syndrome (OSAS) in children based on pulse photoplethysmographic (PPG) signal is presented. Decreases in amplitude fluctuations of the PPG signal (DAP) events have been proposed as OSAS discriminator, since they are related to vasoconstriction associated to apnea. Heart rate variability (HRV) analysis during these DAP events has been proposed to discriminate between DAP events related or unrelated to an apneic event. The use of HRV requires electrocardiogram (ECG) as an additional recording, meaning a disadvantage that takes more relevance in sleep studies context where the number of sensors is tried to be minimized in order not to affect the physiological sleep. This study proposes the use of pulse rate variability (PRV) extracted from the PPG signal instead of HRV. Polysomnographic registers from 21 children (aged 4.47 +/-2.04 years) were studied. The subject classification based on DAP events and PRV analysis obtained an accuracy of 86.67% which represents an improvement of 6.67% with respect to the HRV analysis. These results suggest that PRV can be used in apnea detectors based on DAP events, to discriminate apneic from nonapneic events avoiding the need for ECG recordings. PMID- 24403423 TI - Dynamic dictionary for combined EEG compression and seizure detection. AB - A novel technique for real-time electroencephalogram (EEG) compression is proposed in this paper. This technique makes use of the redundancy between the different frequency subbands present in EEG segments of one channel. It uses discrete wavelet transform (DWT) and dynamic reference lists to compute and send the decorrelated subband coefficients. Set partitioning in hierarchical trees (SPIHT) is also used as source coder. Experimental results showed that the proposed method can not only compress EEG channels in one dimension (1- D), but also detect seizure-like activity. A diagnostics-oriented performance assessment was performed to evaluate the performance of both the compression and detection capabilities of the proposed method. In this paper, we show that the algorithm can positively detect seizure sections in the recordings at bitrates down to 2 bits per sample. PMID- 24403424 TI - Dynamical characteristics of surface EMG signals of hand grasps via recurrence plot. AB - Recognizing human hand grasp movements through surface electromyogram (sEMG) is a challenging task. In this paper, we investigated nonlinear measures based on recurrence plot, as a tool to evaluate the hidden dynamical characteristics of sEMG during four different hand movements. A series of experimental tests in this study show that the dynamical characteristics of sEMG data with recurrence quantification analysis (RQA) can distinguish different hand grasp movements. Meanwhile, adaptive neuro-fuzzy inference system (ANFIS) is applied to evaluate the performance of the aforementioned measures to identify the grasp movements. The experimental results show that the recognition rate (99.1%) based on the combination of linear and nonlinear measures is much higher than those with only linear measures (93.4%) or nonlinear measures (88.1%). These results suggest that the RQA measures might be a potential tool to reveal the sEMG hidden characteristics of hand grasp movements and an effective supplement for the traditional linear grasp recognition methods. PMID- 24403425 TI - FEEL: a system for frequent event and electrodermal activity labeling. AB - The wide availability of low-cost wearable biophysiological sensors enables us to measure how the environment and our experiences impact our physiology. This creates a challenge: in order to interpret the longitudinal data, we require the matching contextual information as well. Collecting continuous biophysiological data makes it unfeasible to rely solely on our memory for contextual information. In this paper, we first present an architecture and implementation of a system for the acquisition, processing, and visualization of biophysiological signals and contextual information. Next, we present the results of a user study: users wore electrodermal activity wrist sensors that measured their autonomic arousal. These users uploaded the sensor data at the end of each day. At first, they annotated their events at the end of each day; then, after a two-day break, they annotated the data from two days earlier. One group of users had access to both the signal and the contextual information collected by the mobile phone and the other group could only access the biophysiological signal. At the end of the study, the users filled in a system usability scale and user experience surveys. Our results show that the system enables the users to annotate biophysiological signals at a greater effectiveness than the current state of the art while also providing very good usability. PMID- 24403426 TI - Food intake monitoring: automated chew event detection in chewing sounds. AB - The analysis of the food intake behavior has the potential to provide insights into the development of obesity and eating disorders. As an elementary part of this analysis, chewing strokes have to be detected and counted. Our approach for food intake analysis is the evaluation of chewing sounds generated during the process of eating. These sounds were recorded by microphones applied to the outer ear canal of the user. Eight different algorithms for automated chew event detection were presented and evaluated on two datasets. The first dataset contained food intake sounds from the consumption of six types of food. The second dataset consisted of recordings of different environmental sounds. These datasets contained 68,094 chew events in around 18 h recording data. The results of the automated chew event detection were compared to manual annotations. Precision and recall over 80% were achieved by most of the algorithms. A simple noise reduction algorithm using spectral subtraction was implemented for signal enhancement. Its benefit on the chew event detection performance was evaluated. A reduction of the number of false detections by 28% on average was achieved by maintaining the detection performance. The system is able to be used for calculation of the chewing frequency in laboratory settings. PMID- 24403427 TI - Intelligent closed-loop insulin delivery systems for ICU patients. AB - Good glycemic control through insulin administration among intensive care unit (ICU) patients can reduce mortality significantly; however, it remains a big challenge because of scarcity of individualized models for ICU patients. To deal with this challenge, a new combination of particle swarm optimization (PSO) and model predictive control (MPC) has been proposed to identify the model online as well as to optimally design the input, i.e., the insulin delivery rate automatically. According to the population distribution, ten typical linear dynamic models were selected such that any patient's model could be approximated by a linear combination of these ten typical models. PSO was used to update the weight coefficients while MPC was used to design the insulin delivery rate based on the combination model identified by using PSO. The proposed strategy was compared with the Yale protocol on 30 virtual subjects. According to the control variability grid analysis, the percentage values in A + B zone were, respectively, 100% under the proposed strategy and while 51% under the Yale protocol, which demonstrates the superior performance of the proposed strategy. As a good candidate for the full closed-loop insulin delivery method, this new combination can control the glucose level by bringing it to a safe range promptly thereby reducing the risk of death. PMID- 24403428 TI - A novel approach to joint flexion/extension angles measurement based on wearable UWB radios. AB - In this paper, a new method for measuring and monitoring human body joint angles, which uses wearable ultrawideband (UWB) transceivers mounted on body segments, is proposed and investigated. The model is based on providing a high ranging accuracy (intersensor distance) between a pair of transceivers placed on the adjacent segments of the joint center of rotation. The measured distance is then used to compute the joint angles based on the law of cosines. The performance of the method was compared with a flexible goniometer by simultaneously measuring joint flexion-extension angles at different angular velocities, ranging between 8 and 90( degrees ) /s. The measurement errors were evaluated by the average differences between two sets of data (ranging from 0.8( degrees ) for slow movement to 2.8( degrees ) for fast movement), by standard deviation (ranging from 1.2( degrees ) to 4.2( degrees ) for various movement speeds) and by the Pearson correlation coefficient (greater than 0.99) which demonstrates the very good performance of the UWB-based approach. The experimental results have shown that the system has sufficient accuracy for clinical applications, such as rehabilitation. PMID- 24403429 TI - Highly accurate recognition of human postures and activities through classification with rejection. AB - Monitoring of postures and activities is used in many clinical and research applications, some of which may require highly reliable posture and activity recognition with desired accuracy well above 99% mark. This paper suggests a method for performing highly accurate recognition of postures and activities from data collected by a wearable shoe monitor (SmartShoe) through classification with rejection. Signals from pressure and acceleration sensors embedded in SmartShoe are used either as raw sensor data or after feature extraction. The Support vector machine (SVM) and multilayer perceptron (MLP) are used to implement classification with rejection. Unreliable observations are rejected by measuring the distance from the decision boundary and eliminating those observations that reside below rejection threshold. The results show a significant improvement (from 97.3% +/- 2.3% to 99.8% +/- 0.1%) in the classification accuracy after the rejection, using MLP with raw sensor data and rejecting 31.6% of observations. The results also demonstrate that MLP outperformed the SVM, and the classification accuracy based on raw sensor data was higher than the accuracy based on extracted features. The proposed approach will be especially beneficial in applications where high accuracy of recognition is desired while not all observations need to be assigned a class label. PMID- 24403430 TI - A novel and lightweight system to secure wireless medical sensor networks. AB - Wireless medical sensor networks (MSNs) are a key enabling technology in e healthcare that allows the data of a patient's vital body parameters to be collected by the wearable or implantable biosensors. However, the security and privacy protection of the collected data is a major unsolved issue, with challenges coming from the stringent resource constraints of MSN devices, and the high demand for both security/privacy and practicality. In this paper, we propose a lightweight and secure system for MSNs. The system employs hash-chain based key updating mechanism and proxy-protected signature technique to achieve efficient secure transmission and fine-grained data access control. Furthermore, we extend the system to provide backward secrecy and privacy preservation. Our system only requires symmetric-key encryption/decryption and hash operations and is thus suitable for the low-power sensor nodes. This paper also reports the experimental results of the proposed system in a network of resource-limited motes and laptop PCs, which show its efficiency in practice. To the best of our knowledge, this is the first secure data transmission and access control system for MSNs until now. PMID- 24403431 TI - A distributed scheme to manage the dynamic coexistence of IEEE 802.15.4-based health-monitoring WBANs. AB - The overlap of transmission ranges between wireless networks as a result of mobility is referred to as dynamic coexistence. The interference caused by coexistence may significantly affect the performance of wireless body area networks (WBANs) where reliability is particularly critical for health monitoring applications. In this paper, we analytically study the effects of dynamic coexistence on the operation of IEEE 802.15.4-based health monitoring WBANs. The current IEEE 802.15.4 standard lacks mechanisms for effectively managing the coexistence of mobile WBANs. Considering the specific characteristics and requirements of health monitoring WBANs, we propose the dynamic coexistence management (DCM) mechanism to make IEEE 802.15.4-based WBANs able to detect and mitigate the harmful effects of coexistence. We assess the effectiveness of this scheme using extensive OPNET simulations. Our results indicate that DCM improves the successful transmission rates of dynamically coexisting WBANs by 20%-25% for typical medical monitoring applications. PMID- 24403432 TI - Compressive-sampling-based positioning in wireless body area networks. AB - Recent achievements in wireless technologies have opened up enormous opportunities for the implementation of ubiquitous health care systems in providing rich contextual information and warning mechanisms against abnormal conditions. This helps with the automatic and remote monitoring/tracking of patients in hospitals and facilitates and with the supervision of fragile, elderly people in their own domestic environment through automatic systems to handle the remote drug delivery. This paper presents a new modeling and analysis framework for the multipatient positioning in a wireless body area network (WBAN) which exploits the spatial sparsity of patients and a sparse fast Fourier transform (FFT)-based feature extraction mechanism for monitoring of patients and for reporting the movement tracking to a central database server containing patient vital information. The main goal of this paper is to achieve a high degree of accuracy and resolution in the patient localization with less computational complexity in the implementation using the compressive sensing theory. We represent the patients' positions as a sparse vector obtained by the discrete segmentation of the patient movement space in a circular grid. To estimate this vector, a compressive-sampling-based two-level FFT (CS-2FFT) feature vector is synthesized for each received signal from the biosensors embedded on the patient's body at each grid point. This feature extraction process benefits in the combination of both short-time and long-time properties of the received signals. The robustness of the proposed CS-2FFT-based algorithm in terms of the average positioning error is numerically evaluated using the realistic parameters in the IEEE 802.15.6-WBAN standard in the presence of additive white Gaussian noise. Due to the circular grid pattern and the CS-2FFT feature extraction method, the proposed scheme represents a significant reduction in the computational complexity, while improving the level of the resolution and the localization accuracy when compared to some classical CS-based positioning algorithms. PMID- 24403433 TI - Biomedical sensing analyzer (BSA) for mobile-health (mHealth)-LTE. AB - The rapid expansion of mobile-based systems, the capabilities of smartphone devices, as well as the radio access and cellular network technologies are the wind beneath the wing of mobile health (mHealth). In this paper, the concept of biomedical sensing analyzer (BSA) is presented, which is a novel framework, devised for sensor-based mHealth applications. The BSA is capable of formulating the Quality of Service (QoS) measurements in an end-to-end sense, covering the entire communication path (wearable sensors, link-technology, smartphone, cell towers, mobile-cloud, and the end-users). The characterization and formulation of BSA depend on a number of factors, including the deployment of application specific biomedical sensors, generic link-technologies, collection, aggregation, and prioritization of mHealth data, cellular network based on the Long-Term Evolution (LTE) access technology, and extensive multidimensional delay analyses. The results are studied and analyzed in a LabView 8.5 programming environment. PMID- 24403434 TI - An adaptable and flexible framework for assistive living of cognitively impaired people. AB - On account of chronic neurocognitive disorders, many people progressively lose their autonomy and become more dependent on others, finally reaching the stage when they need round-the-clock care from caregivers. Over time, as patients' needs increase with the evolution of their diseases, caregivers experience increasing levels of stress and burden. Therefore, an assistive solution that is able to adapt to the changing needs of the end-users is needed. This need was considered as a major requirement that emerged from our field work and deployment experience in Singapore. In this paper, we focus on the technical aspects of our deployment, where we were interested in solving the technical requirement of adaptability and extendibility of the framework that has emerged from our predeployment analysis and discussions with professional caregivers. We expose our approach for dynamic integration of assistive services with their related sensing technologies and interaction devices and provide the technical results of the deployment of this solution. We also provide guidelines for real-world deployment of assistive solutions. PMID- 24403435 TI - Intervention tailoring in augmented cognition systems for elders with dementia. AB - We present an approach for personalizing nonpharmacological interventions for people with dementia (PwD) using ontologies. We conducted two case studies to derive an ontological model to personalize the planning and execution of interventions to address problematic behaviors. The paper describes how the ontology was derived, and illustrates how it is used to tailor an ambient assisted intervention system (AAIS) at two stages: first, to decide on the services that the AAIS will offer the PwD, and then to adapt these services at runtime using contextual information. The results of a deployment of an AAIS during 2 months in the home of a PwD, indicate that the AAIS successfully addressed some of the problematic behaviors exhibited by the PwD, helping to reduce the burden of the caregiver. PMID- 24403436 TI - An assistive navigation system based on augmented reality and context awareness for people with mild cognitive impairments. AB - This paper presents a system for supplying spatial orientation and support to cognitively impaired people in their daily activities. The system is a technological solution based on external aid at a practical level (substitution based rehabilitation). In particular, we propose a model focused on points of interest or well-known places, in which user-friendly routes to a destination are generated based on the user context rather than the conventional street names and quantitative distances. Moreover, the system offers augmented reality views that include contextual information. This philosophy of navigation more closely matches the needs of the user than do conventional navigation systems; the proposal is especially useful for users who are not accustomed to using new technologies (e.g., elderly people), people experiencing disorientation and, more generally, individuals with a slight cognitive deficit. The system also includes an application that allows the relatives of the user to establish tasks that must be performed at a specific location and to monitor the activities of the user to detect potentially risky situations. PMID- 24403437 TI - A predictive model for assistive technology adoption for people with dementia. AB - Assistive technology has the potential to enhance the level of independence of people with dementia, thereby increasing the possibility of supporting home-based care. In general, people with dementia are reluctant to change; therefore, it is important that suitable assistive technologies are selected for them. Consequently, the development of predictive models that are able to determine a person's potential to adopt a particular technology is desirable. In this paper, a predictive adoption model for a mobile phone-based video streaming system, developed for people with dementia, is presented. Taking into consideration characteristics related to a person's ability, living arrangements, and preferences, this paper discusses the development of predictive models, which were based on a number of carefully selected data mining algorithms for classification. For each, the learning on different relevant features for technology adoption has been tested, in conjunction with handling the imbalance of available data for output classes. Given our focus on providing predictive tools that could be used and interpreted by healthcare professionals, models with ease-of-use, intuitive understanding, and clear decision making processes are preferred. Predictive models have, therefore, been evaluated on a multi-criterion basis: in terms of their prediction performance, robustness, bias with regard to two types of errors and usability. Overall, the model derived from incorporating a k-Nearest-Neighbour algorithm using seven features was found to be the optimal classifier of assistive technology adoption for people with dementia (prediction accuracy 0.84 +/- 0.0242). PMID- 24403438 TI - Statistical anomaly detection for individuals with cognitive impairments. AB - We study anomaly detection in a context that considers user trajectories as input and tries to identify anomalies for users following normal routes such as taking public transportation from the workplace to home or vice versa. Trajectories are modeled as a discrete-time series of axis-parallel constraints ("boxes") in the 2 D space. The anomaly can be estimated by considering two trajectories, where one trajectory is the current movement pattern and the other is a weighted trajectory collected from N norms. The proposed system was implemented and evaluated with eight individuals with cognitive impairments. The experimental results showed that recall was 95.0% and precision was 90.9% on average without false alarm suppression. False alarms and false negatives dropped when axis rotation was applied. The precision with axis rotation was 97.6% and the recall was 98.8%. The average time used for sending locations, running anomaly detection, and issuing warnings was in the range of 15.1-22.7 s. Our findings suggest that the ability to adapt anomaly detection devices for appropriate timing of self-alerts will be particularly important. PMID- 24403439 TI - The role of virtual motor rehabilitation: a quantitative analysis between acute and chronic patients with acquired brain injury. AB - Acquired brain injury (ABI) is one of the main problems of disability and death in the world. Its incidence and survival rate are increasing annually. Thus, the number of chronic ABI patients is gradually growing. Traditionally, rehabilitation programs are applied to postacute and acute patients, but recent publications determine that chronic patients may benefit from rehabilitation. Also, in the last few years, the potential of virtual rehabilitation (VR) systems has been demonstrated. However, until now, no previous studies have been carried out to compare the evolution of chronic patients with acute patients in a VR program. To perform this study, we developed a VR system for ABI patients. The system, vestibular virtual rehabilitation (V2R), was designed with clinical specialists. V2R has been tested with 21 people ranging in age from 18 to 80 years old that were classified in two groups: chronic patients and acute patients. The results demonstrate a similar recovery for chronic and acute patients during the intervention period. Also, the results showed that chronic patients stop their improvement when they finish their training. This conclusion encourages us to direct our developments toward VR systems that can be easily integrated at home, allowing chronic patients to have a permanent VR training program. PMID- 24403440 TI - The interaction between DAP1 and autophagy in the context of human carcinogenesis. AB - Autophagy is an evolutionarily-conserved catabolic process which furthers cell survival, especially in times of nutritional stress. Whilst being by itself a pro survival mechanism, it has many areas of overlap with apoptosis. Autophagic cell death is recognised as a subset of programmed cell death, with features more typical of autophagy rather than classical apoptosis. The mechanisms preventing autophagy from unravelling into autophagic cell death are still the subject of much controversy. We discuss the current understanding of these mechanisms, including recent research regarding the role of death-associated protein-1 in autophagy and apoptosis. PMID- 24403441 TI - Nutrition and pancreatic cancer. AB - BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer death in men and women. Prognosis is poor with a 5-year survival rate of less than 5%. As there is no effective screening modality, the best way to reduce morbidity and mortality due to pancreatic cancer is by effective primary prevention. AIM: To evaluate the role of dietary components in pancreatic cancer. MATERIALS AND METHODS: Bibliographical searches were performed in PubMed using the terms "pancreatic cancer", together with "nutrition", "diet", "dietary factors", "lifestyle", "smoking", "alcohol" and "epidemiology". RESULTS: Fruits (particularly citrus) and vegetable consumption may be beneficial. The consumption of whole grains has been shown to reduce pancreatic cancer risk and fortification of whole grains with folate may confer further protection. Red meat, cooked at high temperatures, should be avoided, and replaced with poultry or fish. Total fat should be reduced. The use of curcumin and other flavonoids should be encouraged in the diet. There is no evidence for benefit from vitamin D supplementation. There may be benefit for dietary folate. Smoking and high Body Mass Index have both been inversely associated with pancreatic cancer risk. CONCLUSION: The lack of randomized trials and the presence of confounding factors including smoking status, physical activity, distance of habitat from the equator, obesity, and diabetes may often result in inconclusive results. There is evidence to encourage the use of whole grain in the staple diet and supplementation within the diet of folate, curcumin and other flavanoids. Carefully designed randomized trials are required to further elucidate these important matters. PMID- 24403442 TI - The key role of bisphosphonates in the supportive care of cancer patients. AB - The present review aims at providing an assessment of the clinical significance of Biphosphonates (BPs) in the treatment of patients with cancer. MATERIALS AND METHODS: A systematic literature review was performed based on database search in PubMed/Medline and included articles up to August 2013. RESULTS: BPs can reduce, delay, and prevent complications related to bone metastases. They improve mobility, functionality, pain, and quality of life. They limit survival of any inactive cancer cells in the microenvironment of the bone marrow, contributing to their death from anti-neoplastic treatments. Moreover, they limit and delay bone morbidity due to osteoporosis related to hormonotherapy in breast and prostate cancer. Finally, benefits can be derived from the combination of BPs with radiotherapy in bone density, recalcification, opioid use, and patient's quality of life and performance status. CONCLUSION: The contribution of BPs in the course of certain neoplasms is preventive and synergistic to other treatments. PMID- 24403443 TI - Counseling patients on cancer diets: a review of the literature and recommendations for clinical practice. AB - BACKGROUND: Many cancer patients use cancer diets. MATERIALS AND METHODS: We listed 13 cancer diets simulating an internet search for which we systematically reviewed clinical data. In the next step we derived recommendations on counseling patients using a Delphi process. RESULTS: We evaluated the following diets: raw vegetables and fruits, alkaline diet, macrobiotics, Gerson's regime, Budwig's and low carbohydrate or ketogenic diet. We did not find clinical evidence supporting any of the diets. Furthermore, case reports and pre-clinical data point to the potential harm of some of these diets. From published recommendations on counseling on complementary and alternative medicine, we were able to derive 14 recommendations for counseling on cancer diets. CONCLUSION: Considering the lack of evidence of benefits from cancer diets and potential harm by malnutrition, oncologists should engage more in counseling cancer patients on such diets. Our recommendations could be helpful in this process. PMID- 24403444 TI - Tumor-specific localization of self-assembled nanoparticle PET/MR modalities. AB - AIM: The aim of this work was to synthesize and study in vitro and in vivo nanocarriers used as magnetic resonance imaging (MRI) contrast agents that accumulate in tumor cells specifically overexpressing folate receptors. MATERIALS AND METHODS: Nanoparticles were prepared by self-assembly of poly-gamma-glutamic acid and chitosan biopolymers and were complexed with gadolinium ions. Folic acid served as a targeting molecule. Rat hepatocellular carcinoma (HeDe) cells overexpressing folate receptors were used as a model system. For in vivo experiments, HeDe cells were transplanted under the renal capsule of F344 rats. RESULTS: In vitro results showed the significant internalization of nanoparticles into HeDe cells. MRI measurements revealed that targeting nanocarriers accumulated in tumors. The MRI/PET fusion images resulted in the exact localization of tumors. CONCLUSION: The nanocarrier provides a suitable means for the early diagnosis of tumors based on their overexpression of folate receptors. PMID- 24403445 TI - Wilms' tumor 1 is involved in tumorigenicity of glioblastoma by regulating cell proliferation and apoptosis. AB - The prognosis for patients with glioblastoma is very poor, despite intensive treatment, including surgery and chemoradiotherapy. Wilms' tumor 1 (WT1) is expressed in most glioblastoma samples, and immunotherapy targeting WT1 has proven to be effective in recurrent glioblastoma. However, the functional roles of WT1 in glioblastoma are not clear. To examine the functional roles of WT1 in glioblastoma, glioblastoma cell lines with reduced WT1 expression were generated using short hairpin RNA(shRNA)-expressing lentivirus. Proliferation of WT1 knockdown glioblastoma cells was significantly slower than control cells with high WT1 expression. In addition, apoptosis was increased in WT1-knockdown glioblastoma cells. Furthermore, WT1-knockdown glioblastoma cells, and control glioblastoma cells were intra-cranially injected into immunodeficient mice. In vivo tumor growth of WT1-knockdown glioblastoma cells was significantly reduced compared to control glioblastoma cells. These results show that WT1 is involved in glioblastoma cell proliferation and apoptosis and that this protein has oncogenic roles in glioblastoma. PMID- 24403446 TI - NOTCH4 is a potential therapeutic target for triple-negative breast cancer. AB - BACKGROUND/AIM: The prognosis for triple-negative breast cancer (TNBC) is poor. In the present study, we evaluated whether NOTCH4 receptor is a potential new therapeutic target for TNBC. MATERIALS AND METHODS: In vitro proliferation and invasiveness were evaluated in TNBC cells with or without small-interfering RNA (siRNA) for NOTCH4, and with or without NOTCH4 plasmid transfection. In vivo, MDA MB-231 cells with or without NOTCH4 siRNA were subcutaneously implanted into the flank regions of mice. The frequency of nuclear translocation of NOTCH4 was assessed by immunohistochemistry in 21 TNBC samples and 46 non-TNBC samples. RESULTS: NOTCH4 inhibition in TNBC cells reduced proliferation and invasiveness, and NOTCH4 overexpression in TNBC cells increased proliferation and invasiveness. NOTCH4 inhibition reduced tumour volume and tumourigenicity of mouse xenografts. TNBC cells had a higher frequency of nuclear translocation of NOTCH4 than other cells. CONCLUSION: NOTCH4 is a new potential therapeutic target for triple negative breast cancer. PMID- 24403447 TI - Modified arabinoxylan from rice bran, MGN-3/biobran, sensitizes metastatic breast cancer cells to paclitaxel in vitro. AB - BACKGROUND: There is an increased interest in alternative treatments that reduce the toxicity of chemotherapy by lowering the drug concentration, whilst maintaining potency against cancer cells. Previous studies have demonstrated that arabinoxylan from rice bran, MGN-3/Biobran, sensitizes human breast cancer cells (BCC) to daunorubicin (DNR). In the present study, we further evaluated the ability of MGN-3 to sensitize cells to another chemotherapy agent, paclitaxel. MATERIALS AND METHODS: Non-metastatic MCF-7 (human BCC) and metastatic 4T1 (murine BCC) cells were cultured with different concentrations of paclitaxel in the presence or absence of MGN-3. Cell survival, DNA damage, and cell proliferation were examined. RESULTS: MGN-3 increased the susceptibility of both types of cancer cells to paclitaxel by over 100-fold. Mechanistically, MGN-3 works synergistically with paclitaxel by causing DNA damage, enhancing apoptosis, and inhibiting cell proliferation in 4T1 cells. CONCLUSION: Our data demonstrate that MGN-3 is an effective chemosensitizer and may represent a novel adjuvant for the treatment of metastatic breast cancer. PMID- 24403448 TI - The therapeutic potential of a novel PSMA antibody and its IL-2 conjugate in prostate cancer. AB - Prostate-specific membrane antigen (PSMA) is an attractive target for treatment of prostate cancer. Using the PSMA-recognizing mouse monoclonal antibody 2C9 obtained in our previous study, the biological activities of PSMA antibody were evaluated. Mouse-human chimeric IgG1 of 2C9 (KM2777) showed antibody-dependent cellular cytotoxicity activity against PSMA-expressing prostate cancer cells in the presence of human peripheral blood mononuclear cells (PBMCs). To increase lymphocyte-mediated cytotoxicity of KM2777, C-terminus interleukin-2 (IL-2)-fused KM2777 (KM2812) was constructed. KM2812 retained binding activity to PSMA and exhibited growth-stimulating activity equivalent to IL-2 on the IL-2-dependent T cell line CTLL-2. Moreover, KM2812 exhibited enhanced cytotoxic activity against PSMA-expressing prostate cancer cells in the presence of PBMCs compared with KM2777. In a xenograft tumor model using PSMA-expressing prostate cancer cells, KM2812 exhibited marked antitumor activity, accompanied by complete regression of tumor in some of the KM2812-treated mice. These results suggest that KM2812 has a therapeutic potential for prostate cancer by stimulating lymphocyte-mediated antitumor cytotoxicity. PMID- 24403449 TI - Hypersensitivity and growth adaptation of oestrogen-deprived MCF-7 human breast cancer cells. AB - BACKGROUND: Efficacy of endocrine therapy is compromised when human breast cancer cells circumvent imposed growth inhibition. The model of long-term oestrogen deprived MCF-7 human breast cancer cells has suggested the mechanism results from hypersensitivity to low levels of residual oestrogen. MATERIALS AND METHODS: MCF 7 cells were maintained for up to 30 weeks in phenol-red-free medium and charcoal stripped serum with 10(-8) M 17beta-oestradiol and 10 MUg/ml insulin (stock 1), 10(-8) M 17beta-oestradiol (stock 2), 10 MUg/ml insulin (stock 3) or no addition (stock 4). RESULTS: Loss of growth response to oestrogen was observed only in stock 4 cells. Long-term maintenance with insulin in the absence of oestradiol (stock 3) resulted in raised oestrogen receptor-alpha (ERalpha) levels (measured by western immunoblotting) and development of hypersensitivity (assayed by oestrogen-responsive reporter gene induction and dose response to oestradiol for proliferation under serum-free conditions), but with no loss of growth response to oestrogen. CONCLUSION: Hypersensitivity can develop without any growth adaptation and therefore is not a prerequisite for loss of growth response in MCF 7 cells. PMID- 24403450 TI - ERCC1 expression and chemosensitivity in uterine cervical adenocarcinoma cells. AB - BACKGROUD/AIM: We previously demonstrated that high protein expression of excision repair cross-complementation group-1 (ERCC1) was associated with poor disease-free survival in patients who received adjuvant cisplatin-based chemotherapy or chemoradiotherapy with cisplatin, and was shown to be an independent prognostic factor. In the present study, we evaluated ERCC1 expression levels in uterine cervical adenocarcinoma cell lines to assess whether they are affected by treatment with cisplatin with and without 5-fluorouracil (5 FU). MATERIALS AND METHODS: Firstly, half-maximal (50%) inhibitory concentration (IC50) values for cisplatin or 5-FU were calculated in cervical adenocarcinoma, HCA-1, and TCO-2 cell lines by 3-(4,5-di-methylthiazol-2-yl)-2,5 diphenyltetrazolium bromide, yellow tetrazole (MTT) assay. ERCC1 mRNA and protein levels were investigated by reverse transcription-polymerase chain reaction (RT PCR) and western blotting. Secondly, cisplatin-resistant HCA-1 cells, designated HCA-1R cells were established, and IC50 values for cisplatin and 5-FU were calculated by the MTT assay. ERCC1 mRNA expression levels were investigated using quantitative RT-PCR following treatment with cisplatin with and without 5-FU. RESULTS: HCA-1 and TCO-2 cells exhibited similar sensitivity to cisplatin, and 5 FU, and comparable expression of ERCC1 mRNA and protein levels. HCA-1R cells exhibited two-fold higher resistance to cisplatin and a significantly higher level of ERCC1 mRNA expression compared to native HCA-1 cells. ERCC1 expression was significantly elevated by cisplatin treatment, which was reduced by co administration of 5-FU in HCA-1, TCO-2 and HCA-1R cells. CONCLUSION: The current study demonstrated an association between ERCC1 expression and sensitivity to cisplatin in cervical adenocarcinoma cells. Co-administration of cisplatin and 5 FU revealed synergistic or additive effects through inhibition of ERCC1 expression in cervical adenocarcinoma cells. Therefore, it is possible that a combination therapy of cisplatin and 5-FU or 5-FU derivatives constitutes an ideal treatment regimen, from the ERCC1 inhibition point of view in cervical adenocarcinoma. PMID- 24403451 TI - A novel approach for enriching cancer stem cells from the human SW-13 adrenocortical carcinoma cell line. AB - The present study was undertaken to develop a new method for enriching cancer stem cells (CSCs) from the human adrenal cortical carcinoma (ACC) cell line SW 13. Given that the existence of CSCs in ACC causes resistance to conventional chemotherapies, treatment with cyclophosphamide was used for in vivo selection of CSCs in a BALB/c nude mouse tumor xenograft model established using the ACC cell line SW-13. The characteristics of CSCs in three generations of tumor xenografts were assessed for single-cell colony formation, flat colony formation, and cell sphere formation in serum-free suspension culture. The formation rates of single cell colonies, flat colonies, and cell spheres were significantly higher for tumor xenograft cells treated with cyclophosphamide than for untreated engrafted tumor cells. Flow cytometry to examine expression of the CSC markers C-X-C chemokine receptor type-4 (CXCR4; CD184) and ATP-binding cassette sub-family G member-2 (ABCG2; CDw338) revealed markedly higher levels of CXCR4 and ABCG2 in cyclophosphamide-treated xenograft tumor cells compared to untreated tumor cells. Together, these results indicate that cyclophosphamide treatment of tumor xenograft cells caused enrichment of CSCs with a strong capability for self renewal and proliferation. In this method, the administration of cyclophosphamide selectively kills cancer cells without toxicity to CSCs and thereby provides a practical approach for achieving the enrichment of CSCs in ACC. PMID- 24403452 TI - Pregnancy stimulates tumor angiogenesis in breast carcinoma. AB - The mechanisms responsible for the poor prognosis of pregnancy-associated breast cancer (PABC) remain not well-understood. We studied angiogenesis and lymphangiogenesis as they are known prognostic factors in breast cancer. We conducted a case control study of breast cancer comparing women with and without PABC matched for age and histological parameters. Surgical specimen sections were immunostained with anti-CD31 for angiogenesis and anti-D2-40 for lymphangiogenesis, then analyzed using vessel density, ratio of the vascular area and the Chalkley count. Seventeen patients with PABC and 22 controls were included. Angiogenesis was significantly increased in tumor tissues, and tended to be higher in healthy breast tissues from the PABC group compared to controls. In contrast, no difference between the two groups was found concerning lymphangiogenesis both in tumor and healthy breast tissues. Pregnancy enhances angiogenesis in breast cancer. This phenomenon appears to explain the poor prognosis of PABC. PMID- 24403453 TI - Demethylation of RUNX3 by vincristine in colorectal adenocarcinoma cells. AB - BACKGROUND: Methylation-mediated inactivation of tumor-suppressor genes is a critical event during the pathogenesis of many malignancies. Vincristine is a conventional anticancer drug used to treat various types of cancers. However, few studies describe the epigenetic-based effects of vincristine. In this study, changes in the methylation of runt-related transcription factor-3 (RUNX3) were investigated in CCD18Co normal colon cells and DLD-1 colorectal adenocarcinoma cells. MATERIALS AND METHODS: CCD18Co and DLD-1 cells were treated with vincristine, and the methylation status was assessed using quantitative methylation-specific polymerase chain reaction (QMSP). Eleven normal colon tissues and 105 colorectal cancer tissues were investigated by methylation and mRNA expression of RUNX3 using QMSP and real-time reverse transcription polymerase chain reaction (real time-PCR). RESULTS: RUNX3 was demethylated after vincristine treatment in DLD-1 cells. The expression of RUNX3 mRNA was down regulated in DLD-1 cells because of DNA hypermethylation, but was restored after vincristine treatment. In addition, hypermethylation of RUNX3 was detected in 70 out of 105 colorectal carcinomas (66.7%). RUNX3 hypermethylation was greater in colon cancer tissues than in rectal cancer tissues. The expression of RUNX3 mRNA was reduced in 68 out of 105 colorectal cancer tissues (64.8%). CONCLUSION: These results demonstrate that vincristine demethylates RUNX3 in colorectal adenocarcinoma cells, and restores its expression. PMID- 24403454 TI - Active hexose-correlated compound down-regulates HSP27 of pancreatic cancer cells, and helps the cytotoxic effect of gemcitabine. AB - BACKGROUND/AIM: Active hexose-correlated compound (AHCC), an extract of basidiomycete mushroom, is used as health food to enhance the therapeutic effects and reduce the adverse effects of chemotherapy. Our previous proteomic analysis revealed that up-regulation of heat-shock protein 27 (HSP27) was responsible for gemcitabine resistance of pancreatic cancer cells. The aim of the present study was to investigate the effect of AHCC on the expression of HSP27 and the effect of combinatorial treatment of AHCC and gemcitabine on the gemcitabine-resistant pancreatic cancer cell line KLM1-R. MATERIALS AND METHODS: KLM1-R cells were treated with AHCC, and the expression of HSP27 as well as the cytotoxic effects of combinatorial treatment of AHCC and gemcitabine were investigated with western blotting and MTS assay, respectively. RESULTS: AHCC down-regulated HSP27 and exhibited a cytotoxic effect on KLM1-R cells. Furthermore, the cytotoxic effect of the combinatorial treatment of AHCC and gemcitabine was synergistic. CONCLUSION: This study supports the potential therapeutic benefits of combinatorial treatment of AHCC and gemcitabine for patients with pancreatic cancer. PMID- 24403455 TI - Novel and differential accumulation of mitochondrial DNA deletions in Swedish and vietnamese patients with colorectal cancer. AB - BACKGROUND: Mitochondrial DNA (mtDNA) has been proposed to be involved in carcinogenesis and aging. The mtDNA 4977 bp deletion is one of the most frequently observed mtDNA mutations in human tissues and may play a role in colorectal cancer (CRC). In the present study, we aimed to evaluate the frequency of mtDNA 4977 bp deletion in CRC tissues and its association with clinical factors. PATIENTS AND METHODS: We determined the presence of the 4977 bp common deletion in cancer and normal paired tissue samples from 105 Swedish and 88 Vietnamese patients with CRC using polymerase chain reaction (PCR) assays. RESULTS: The mtDNA 4977 bp deletion was shown to be significantly more frequent in normal tissues in comparison with paired cancer tissues in both Swedish and Vietnamese patients. The 4977 bp common deletion was significantly more frequent in cancer tissues of the Vietnamese patients compared to the Swedish patients, and in Vietnamese cancer tissues, the 4977 bp deletion was significantly over represented in those with localized disease compared to those with disseminated disease. Moreover, we detected nine novel mtDNA deletions and found a significantly higher rate of these in CRC tissues in Swedish in comparison to Vietnamese patients. CONCLUSION: The mtDNA 4977 bp deletion seems to have an impact on the clinical outcome of CRC in Vietnamese patients, that the Swedish patients accumulate more of the detected novel deletions in CRC tissue compared to Vietnamese patients probably indicates divergent mechanisms in colorectal carcinogenesis. PMID- 24403456 TI - Touch imprint cytology of core needle biopsy specimens for the breast and quick stain procedure for immediate diagnosis. AB - AIM: To investigate the validity and reproducibility of touch imprint cytology (TIC) of core needle biopsies (CNBs) in the assessment of conspicuous breast findings. MATERIALS AND METHODS: One hundred and fifty-eight conspicuous breast findings were assessed by CNB during a two-year period in this prospective study. TIC of the CNBs was used for cytological analysis. The performance of this technique was evaluated by comparing the results with the histology of the CNB, and in cases of a subsequent surgery, with the final histology. In addition, inter-observer reproducibility was analyzed. RESULTS: The inter-observer variability was very high (kappa-value of 0.8508; excluding inadequate imprints, 0.9502). Inadequate cellularity for cytological analysis was found in 11.4% (18/158) of findings. Compared with CNB histology, the sensitivity, specificity, positive predictive value, negative predictive value and overall accuracy of TIC was 99%, 100%, 100%, 94%, and 99%, respectively. CONCLUSION: TIC of CNB specimens of the breast may be a valid option for providing a diagnosis without delay for a histological procedure, assuming good quality of the specimen. PMID- 24403457 TI - Expression of cytokeratin 20 indicates invasive histological phenotype in poorly differentiated colorectal adenocarcinoma. AB - BACKGROUND/AIM: Cytokeratin (CK) 20 expression is an independent prognostic factor of poorly differentiated adenocarcinoma (PDA) of the colon and rectum. We aimed to investigate the mechanism of its involvement through a clinicopathological study. PATIENTS AND METHODS: We analyzed 156 surgically resected PDAs, which were sub-classified as solid type (Por1) showing expansive growth, or non-solid type (Por2) showing infiltrative growth. Associations of CK20 expression with morphological features and molecular markers were analyzed. RESULTS: CK20(+) PDA (n=91) was associated with more advanced disease stage and unfavorable prognosis compared with CK20(-) PDA (n=65). Pathologically, CK20(+) PDA was significantly associated with p53 overexpression, Por2, abundant fibrous stroma, and stepwise de-differentiation, while CK20(-) PDA was significantly associated with mismatch repair deficiency, Por1, sparse fibrous stroma, and de novo histogenesis. CONCLUSION: CK20 expression in PDA is closely associated with invasive histological features, providing prognostic significance, and may also point to a specific histogenetic pathway. PMID- 24403458 TI - Gene expression analysis using a highly sensitive DNA microarray for colorectal cancer screening. AB - BACKGROUND/AIM: Half of all patients with small, right-sided, non-metastatic colorectal cancer (CRC) have negative results for the fecal occult blood test (FOBT). In the present study, the usefulness of CRC screening with a highly sensitive DNA microarray was evaluated in comparison with that by FOBT using fecal samples. MATERIALS AND METHODS: A total of 53 patients with CRC and 61 healthy controls were divided into "training" and "validation sets". For the gene profiling, total RNA extracted from 0.5 g of feces was hybridized to a highly sensitive DNA chip. RESULTS: The expressions of 43 genes were significantly higher in the patients with CRC than in healthy controls (p<0.05). In the training set, the sensitivity and specificity of the DNA chip assay using six genes were 85.4% and 85.2%, respectively. On the other hand, in the validation set, the sensitivity and specificity of the DNA chip assay were 85.2% and 85.7%, respectively. The sensitivities of the DNA chip assay were higher than those of FOBT in cases of the small, right-sided, early-CRC, tumor invading up to the muscularis propria (i.e. surface tumor) subgroups. In particular, the sensitivities of the DNA chip assay in the surface tumor and early-CRC subgroups were significantly higher than those of FOBT (p=0.023 and 0.019, respectively.). CONCLUSION: Gene profiling assay using a highly sensitive DNA chip was more effective than FOBT at detecting patients with small, right-sided, surface tumor, and early-stage CRC. PMID- 24403459 TI - Cytokeratin 7 as a predictive factor for response to concommitant radiochemotherapy for locally advanced cervical cancer: a preliminary study. AB - BACKGROUND: The role of completion surgery after concurrent radiochemotherapy (CCRC) for advanced cervical cancer remains controversial. Individual predictive factors of CCRC response and survival are mandatory for treatment adaptation and to determine a population who would take interest in completion surgery after CCRC. The aim of this study was to evaluate the ability of biomarkers to predict the response to CCRC. PATIENTS AND METHODS: Between 1996 and 2008, in 58 patients with advanced cervical cancer for whom pre-therapeutic cone biopsy was available, we tested several biomarkers (ALDH1, CD44, CD24, IDO, Ki67, P63, CK7, p-Stat3, Foxp3 and IDO). RESULTS: Residual disease was found in 49.1% of cases (n=26). We found a significant association between progression-free survival and residual disease on completion hysterectomy (p=0.044). Univariate analysis of the different factors showed that negativity for cytokeratin 7 expression was a strong predictor for the presence of residual tumor (p=0.001). CONCLUSION: These results are encouraging and CK7 could be used as a predictive factor of response to CCRC. PMID- 24403460 TI - Detection of lung cancer by FDG-PET cancer screening program: a nationwide Japanese survey. AB - AIM: The aim of this study was to analyze the lung cancer detection rate in asymptomatic individuals by the Fluorine-18 fluorodeoxyglucose-positron emission tomography FDG-PET cancer screening program in Japan. MATERIALS AND METHODS: A total of 153,775 asymptomatic individuals underwent the FDG-PET cancer screening program; the 854 cases with findings that indicated suspected lung cancer by any detection method were analyzed. RESULTS: Among the 854 cases, 319 were verified as lung cancer. The relative sensitivity and positive predictive value (PPV) of FDG-PET were 86.5% and 38.9% for lung cancer, respectively. The sensitivity of PET/computed tomography (CT) scanner was higher than that of dedicated PET (100.0% vs. 63.2%), indicating that CT imaging was effective for lung cancer screening. The majority of lung carcinomas detected by FDG-PET screening were UICC stage IA or IB, but detection of smaller or less invasive carcinomas was limited. CONCLUSION: The FDG-PET screening program in Japan detected lung cancer at an early stage. PMID- 24403461 TI - Usefulness of monthly chemotherapy for patients with unresectable metastatic colorectal cancer. AB - BACKGROUND/AIM: Unresectable metastatic colorectal cancer with very slow tumour growth rate does not necessarily require for strong short-interval chemotherapy. In the present study, we administered monthly chemotherapy and aimed to evaluate the usefulness of the specific treatment schedule in patients with unresectable metastatic colorectal cancer with slow tumour growth rate. PATIENTS AND METHODS: Since 2009, at our Institution, patients' whose serum carcinoembryogenic antigen (CEA) values on the treatment day were not higher than those before initial chemotherapy, and patients who did not wish to undergo intensive chemotherapy, were prospectively scheduled for specific chemotherapy. Between January 2009 and December 2011, 10 patients with unresectable metastatic colorectal cancer who received monthly chemotherapy were enrolled in the current study. During the same period, 14 patients with unresectable metastatic colorectal cancer were administered conventional-interval chemotherapy, oxaliplatin with oral S-1 (SOX) or capecitabine (XELOX), and comprised the control group. RESULTS: Three patients received first-line, four patients received second-line, and three patients received third-line treatment. All patients were able to receive a single-regimen of chemotherapy for more than a year. The survival of patients who received monthly chemotherapy was significantly better than survival of those who received SOX or XELOX within 30 months after starting chemotherapy (p<0.05). CONCLUSION: For patients with very slow tumour growth rates, our monthly chemotherapy may be beneficial. PMID- 24403462 TI - Prospective phase II trial of second-line FOLFIRI in patients with advanced colorectal cancer including analysis of UGT1A1 polymorphisms: FLIGHT 2 study. AB - AIM: This is a multicenter phase II study to assess the efficacy and toxicity of FOLFIRI treatment agents in full and the influence of UGT1A1*28 polymorphism in Japanese patients with advanced/metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Fifty patients with mCRC participated in this study. Treatment consisted of FOLFIRI (irinotecan; 150 mg/m(2)) as second-line chemotherapy; 34 patients consented to the evaluation of UGT1A1 genotype. RESULTS: The overall response rate was 12% for all 50 evaluable patients; 31 patients (62.0%) had stable disease, and only in 12 (24.0%) did disease progress. The median progression-free survival was 5.8 months. The tolerance treatment was acceptable, with only 15 out of 50 patients (30%) experiencing grade 3/4 neutropenia, and grade 4 thrombocytopenia was observed in only one case. Grade 3 non-hematological adverse reactions included stomatitis in three, diarrhea in one, and a clinically insignificant increase in serum alkaline phosphatases in one patient, respectively. There was no definite relation between the UGT1A1*28 polymorphism and toxicity. CONCLUSION: Standard FOLFIRI regimen can be administered to Japanese patients. The results showed good tolerability and efficacy for second line FOLFIRI, provided that evaluation of UGT1A1 polymorphism is properly implemented before the start of the chemotherapy. PMID- 24403463 TI - Multimodal treatment for t1-2 supraglottic cancer: the impact of tumor location. AB - AIM: To examine the outcome and prognostic factors after multimodal treatment of T1-2 supraglottic cancer. PATIENTS AND METHODS: We analyzed 49 patients with T1-2 supraglottic cancer who received multimodal treatment between 1990 and 2011. Their age range was 43-86 years (median=66 years). Fifteen patients had a T1 tumor and 34 had a T2 tumor (40 N0, 3 N1, 4 N2, and 2 N3). Debulking using transoral laser excision was employed in 25 patients. Neck dissection was performed in four patients. Chemotherapy was administered to 29 patients: intra arterial infusion in four and systemic infusion in 25. Radiotherapy was administered at a median dose of 64.8 Gy (range=30-70 Gy) with once- or twice daily fractionation. Median follow-up time was 60 months (range=12-153 months). RESULTS: Two patients interrupted radiotherapy because of a poor response at 30 Gy (T2N2) and 49.9 Gy (T2N0). They underwent total laryngectomy and were still alive without any evidence of cancer 48 and 28 months after treatment, respectively. The other 47 patients (96%) had a complete local response to treatment. Locoregional failure was observed in six tumor sites, and one patient had simultaneous locoregional recurrence. The 5-year local control, disease-free, overall survival, and laryngeal preservation rates were 82%, 74%, 82%, and 90%, respectively. The location of a primary tumor within the supraglottis (epilarynx or elsewhere) was identified as the only factor predictive of progression-free survival by univariate and multivariate analyses (p=0.04). Acute adverse reactions of grade 3 or more were: one grade 3 laryngeal edema, one grade 3 dyspnea, and one grade 5 hematological toxicity (disseminated intravascular coagulation). Among late adverse events, one grade 1, one grade 2 hoarseness, and grade 3 laryngeal necrosis were observed. CONCLUSION: Multimodal radiotherapy produced a good outcome. Localization of the tumor in the epilarynx was associated with a better progression-free survival rate than that in the other parts of the supraglottis. PMID- 24403464 TI - A phase I study of concurrent chemoradiotherapy using oral s-1 for head and neck cancer. AB - AIM: S-1 is a novel oral anticancer agent containing a combination of two modulators and tegafur. We conducted a phase I study of concurrent chemoradiotherapy with S-1 for head and neck cancer. PATIENTS AND METHODS: S-1 was administered once daily, and radiotherapy was performed by 2 Gy/day, five days/week, for a total of 30 fractions. S-1 dosage was started at level 1 (55.3 mg/m(2)/day), and was increased to level 2 (66.7 mg/m(2)/day). RESULTS: A total of 12 patients were registered. Concerning hematological toxicities, no grade >=3 or more hematological toxicity was confirmed at any level. With regard to non hematological toxicities, at level 2, three cases of grade 3 mucositis and two cases of grade 3 dermatitis were confirmed. CONCLUSION: The results showed that the maximum tolerated dose was level 2 and that dose-limiting toxicity was mucositis. Having determined that the recommended dose is level 1, we have begun the phase II clinical study. PMID- 24403465 TI - Pemetrexed combined with platinum-based chemotherapy for advanced malignant peritoneal mesothelioma: retrospective analysis of six cases. AB - BACKGROUND: Malignant peritoneal mesothelioma (PM) is an extremely rare disease. Pemetrexed and platinum have been used for advanced PM following malignant pleural mesothelioma (PLM). Because PM differs considerably from PLM in clinical features, the efficacy and safety of these therapies have yet to be established. PATIENTS AND METHODS: Six Japanese patients with PM who had been treated with pemetrexed-based chemotherapy in four Institutions were retrospectively identified. Treatment response, progression-free survival, and overall survival were examined. Toxicities of therapy were also evaluated. RESULTS: Three patients with mild ascites achieved clinical benefits (one with partial response and two with stable disease). Treatments with reduced cisplatin or carboplatin for patients with massive ascites were safely performed. Median PFS and OS were 7.2 and 13.1 months, respectively. Grade 3 hematological toxicities appeared in two patients with massive ascites. CONCLUSION: Selection of chemotherapy based on the patient's condition, such as ascites, might be important for advanced PM. PMID- 24403466 TI - Early predictive value of non-response to docetaxel in neoadjuvant chemotherapy in breast cancer using 18F-FDG-PET. AB - BACKGROUND: The aim of this prospective study of patients with breast cancer was to identify non-responders to docetaxel in neoadjuvant chemotherapy (NCT) using fluorine-18-fluorodeoxyglucose positron-emission tomography ((18)F-FDG-PET). PATIENTS AND METHODS: We analyzed the maximum standardized uptake value (SUVmax) of (18)F-FDG-PET before and after the first course and the reduction rate in tumor size shown by magnetic resonance imaging (MRI) before the first and after the fourth course of docetaxel. RESULTS: None of the eight patients (0%) whose SUVmax decrease was less than 18% revealed a clinical partial response or clinical complete response; Seven out of the sixteen patients (44%) with an SUVmax decrease over 45% achieved a complete response. CONCLUSION: An SUVmax reduction rate less than 18% is observed in patients with breast cancer after the first course of docetaxel in NCT and may be indicator of non-response to docetaxel. PMID- 24403467 TI - Hypertension as a predictive marker for bevacizumab in metastatic breast cancer: results from a retrospective matched-pair analysis. AB - BACKGROUND: Several phase-III studies have shown improvements in terms of progression-free survival (PFS) with bevacizumab when added to chemotherapy in advanced breast cancer. However, the extent of improvement varied and none of the trials showed benefit in terms of overall survival (OS). PATIENTS AND METHODS: All patients with metastatic breast cancer treated with bevacizumab at our Institution between 2005 and 2011 were retrospectively analyzed. A control group was matched according to the following variables: receptor status, treatment line, type of chemotherapy, presence of visceral disease and age. RESULTS: All 212 patients were evaluable for toxicity, and 198 for response; 430 controls allowed a complete matching for 85 bevacizumab-treated patients. The addition of bevacizumab to chemotherapy significantly prolonged PFS (9.3 vs. 7.6 months, hazard ratio [HR]=0.70, 95% confidence interval [CI]=0.51-0.97, p=0.031) and OS (28.9 vs. 22.6 months, HR=0.67, 95% CI=0.45-0.99, p=0.043). Clinical benefit rate (overall response rate + stable disease for at least six months) was significantly better in the bevacizumab group (75% vs. 59%, p=0.002), while ORR did not differ significantly (48% vs. 35%, p=0.21). Patients developing hypertension during treatment had a more favourable outcome (PFS 13.7 vs. 6.6 months, HR=0.34, 95% CI=0.23-0.49 p<0.001; 2-year OS 78% vs. 30%, HR=0.20, 95% CI=0.12-0.35, p<0.001). CONCLUSION: Bevacizumab in addition to chemotherapy prolonged PFS and OS in a non-selected, partly intensively pre-treated breast cancer population. Hypertension induced by bevacizumab predicted therapy efficacy. PMID- 24403468 TI - Lack of evidence for predictive and prognostic value of cyclin D1 gene polymorphism CCND1 G870A for oral squamous cell carcinoma. AB - BACKGROUND/AIM: Cyclin D1 gene (CCND1) has a G to A polymorphism at the splice donor site of exon 4, position 870. The A allele codes for a truncated variant, cyclin D1b, which may have higher transforming activity. Data regarding the predictive and prognostic value of the CCND1 G870A polymorphism in tumors are controversial. We aimed to examine this polymorphism in patients with oral carcinoma. MATERIALS AND METHODS: Genotyping of CCND1 G870A was determined by means of direct sequencing in 83 patients with oral carcinomas and in 102 healthy controls. Association with clinical outcomes was evaluated statistically. RESULTS: We failed to find any significant association of CCND1 G870A with risk of oral carcinomas in this German population, with clinical and pathological features of the tumours or with overall survival of the patients. CONCLUSION: Our results suggest that CCND1 G870A has no, or only very limited, predictive and prognostic value for oral carcinoma. PMID- 24403469 TI - Anaplastic pelvic carcinoma secondary to low-grade endometrial carcinoma. AB - BACKGROUND: Low-grade endometrial carcinoma has an excellent prognosis. The risk of secondary cancer after endometrial carcinoma is moderately increased and is mostly related to the field of postoperative radiation (small intestine, colon, vagina, and urinary bladder). Anaplastic (undifferentiated) pelvic carcinoma (APC) is rare and probably under-reported. To date, only one publication has reported six cases of APC that were secondary to low-grade endometrial carcinoma. CASE REPORT: We have analyzed the fulminant course of APC-preceded by paraneoplastic arthritis-four months after hysterectomy and adnexectomy for low grade endometrial carcinoma (endometrioid type, moderately differentiated, tumor diameter: 2 cm, infiltration depth 3 of 15 mm). The 73-year-old patient died five weeks after the diagnosis of the second malignancy. CONCLUSION: The prognosis of APC is poor and the limitations of the therapy result from aggressive tumor biology and rapid deterioration of the patients' general condition. Rheumatological symptoms can precede cancer diagnosis. Immunohistochemistry facilitates the differentiation between primary and secondary carcinoma. PMID- 24403470 TI - Initial experience with oropharynx-targeted radiation therapy for metastatic squamous cell carcinoma of unknown primary of the head and neck. AB - AIM: Metastasis of unknown primary (MUP) is commonly treated with radiation therapy (RT) to the entire mucosal surfaces and bilateral neck nodes (LN). We report outcomes of oropharynx-targeted RT, retropharyngeal nodes (RPN) and bilateral LN in this context. PATIENTS AND METHODS: Single-Institution retrospective study of 68 patients. Forty percent were treated with intensity modulated radiation therapy (IMRT). Fifty-six percent received concurrent chemoradiotherapy (CCRT). The median age was 58 years, 82% were Caucasian, and 75% males. Stage III disease was present in 9%, stage IVA in 75% and IVB in 16%. RESULTS: At a median follow-up of 3.5 years, the actuarial locoregional control was 95.5%. The emergence of primary developed in 1patient (1.5%) and 2patients (3%) failed in the neck. The median time-to-locoregional failure (LRF) was 18 months. Actuarial long-term RT toxicity was grade 1 xerostomia (68%), dysphagia (35%), neck stiffness (15%) and trismus (6%). CONCLUSION: RT to the oropharynx, RPN, and bilateral neck provides excellent oncological and functional outcomes in MUP in non-Asian patients. Sparing the mucosal surfaces of the nasopharynx, hypopharynx, and larynx seems reasonable without impacting on survival and locoregional control. PMID- 24403471 TI - Is endometrial cancer really a neurophobic tumor? A case report and review of the literature. AB - Brain metastases due to endometrial cancer are rare and usually occur in the context of widespread disease. We present a rare case of a 74-year-old woman with recurrent endometrial cancer in terms of a solitary brain lesion two years after initial diagnosis. She was treated with local resection of the brain metastasis and subsequent whole-brain radiotherapy. She then experienced relapse twice, presenting two solitary metastases at two different time points at the same location as at initial diagnosis, but never showed any signs of extracranial widespread disease. The patient has been alive for 13 months after detection of her initial brain metastasis. Despite the identification of some risk factors, there is still very limited knowledge why some patients develop brain metastases as the only sign of distant spread. Our review of the literature revealed that the combination of two treatment modalities yields higher survival rates than single treatment-alone, as was the case in the presented patient. Further case reports, as well as large and prospective studies, may contribute to a better understanding of the etiology and dynamics of this disease and allow better evaluation of treatment options. PMID- 24403472 TI - Prognostic significance of Ki-67 in chemotherapy-naive breast cancer patients with 10-year follow-up. AB - BACKGROUND/AIM: In order to define accurate survival outcome in breast cancer, 10 year follow-up is required and such long-term survival information are few and difficult to gather. PATIENTS AND METHODS: We recruited 253 breast cancer patients who undertook operation with no prior chemotherapy. Ten-year survival outcomes were evaluated by clinicopathological factors. RESULTS: Significant univariate prognostic factors were: T factor, N factor, preoperative values of tumor markers, and biological factors. T-factor, CEA, hormone receptor, and Ki-67 were the final independent prognostic factors of recurrence-free survival through multivariate analysis. The Luminal A group except for the Ki-67-positive cases showed the best survival outcomes, while the HER2-positive or triple-negative (TN) groups showed worse prognosis than the Luminal A group, and Ki-67 was shown to be an excellent prognostic factor in each stage (p<0.01). CONCLUSION: Ki-67 has a great potential as a prognostic biomarker while prognostic information of this sort could be beneficial for development of novel therapeutic strategies. PMID- 24403473 TI - Association between tumor size and immunohistochemical expression of Ki-67, p53 and BCL2 in a node-negative breast cancer population selected from a breast cancer screening program. AB - BACKGROUND/AIM: Breast cancer is the most common type of cancer among women. Breast infiltrating ductal carcinoma (IDC) is the most common type of breast cancer, approximately 80% of all breast carcinomas. The aim of this study was to analyze the association of tumor size, evaluated after histopathological analysis, with different clinical and biological parameters in IDC. MATERIALS AND METHODS: The study group included 251 women with IDC without axillary lymph node involvement, aged between 27 and 81 years. Analyzed parameters were: age, histological grade, menopausal status, menarche, pregnancy, abortion, breastfeeding, contraceptive use, hormone replacement therapy, estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), Ki-67, p53 and BCL2. RESULTS: Pathological tumor size was between 0.2 and 5.1 cm (1.43+/-0.86 cm). Tumors in 45 cases exceeded 2 cm, in eight 3 cm and only in one 5 cm. Pathological size was significantly associated with age >70 vs. <50 years (p=0.054), histological grade III vs. I (p=0.0003), positivity for Ki-67 (p=0.0003) and for p53 (p=0.0032). CONCLUSION: Tumor size was significantly associated with age >70 years, histological grade 3 and immunohistochemically augmented expression of Ki-67 and p53. PMID- 24403474 TI - Bevacizumab plus weekly paclitaxel with or without carboplatin for previously treated non-squamous non-small cell lung cancer. AB - AIM: The aim of this retrospective study was to evaluate bevacizumab combined with weekly paclitaxel with and without carboplatin in pre-treated patients with non-squamous non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Between November 2009 and October 2011, 43 pre-treated patients with non-squamous NSCLC received bevacizumab (15 mg/kg, day 1) plus weekly paclitaxel (60-80 mg/m(2), days 1, 8, 15) with carboplatin (area under the curve=4-5, day 1) (n=36), or bevacizumab plus weekly paclitaxel (n=7) alone every four weeks. RESULTS: The response rate and disease control rates were 48.8% (21/43) and 86.0% (37/43), respectively. Median progression-free survival was 5.7 months, and overall survival was 14.5 months. Grade 3/4 neutropenia was observed in 37.2% of patients and peripheral neurotoxicity in 0%. No bevacizumab-related death was observed. CONCLUSION: Even for heavily pre-treated patients, bevacizumab plus weekly paclitaxel with or without carboplatin was effective and tolerable in non squamous NSCLC. PMID- 24403475 TI - Effectiveness of FDG-PET in screening of synchronous cancer of other organs in patients with esophageal cancer. AB - AIM: We investigated the significance of pre-treatment screening by (18)F fluorodeoxyglucose positron-emission tomography (FDG-PET) in patients with esophageal cancer. PATIENTS AND METHODS: We retrospectively evaluated the clinical significance of screening in 200 patients with primary esophageal cancer using FDG-PET. RESULTS: Out of 200 patients, 34 (17%) had synchronous multiple primary tumors; 31 patients had two types of cancers (15.5%) and three patients had three types (1.5%). The 37 second and third primary tumors were 13 stomach cancers (35.1%), 13 head and neck cancers (35.1%), seven colon (18.9%) and two lung (5.4%) cancers. When PET was performed at initial treatment for esophageal cancer, the diagnostic sensitivity of FDG-PET/Computed tomography (CT) for the second and third synchronous primary cancer were 53.8% (7/13) for the stomach; head and neck, 61.5% (8/13); colon, 42.9% (3/7); and lung, 50% (1/2), for an overall sensitivity of 54.1% (20/37 sites). CONCLUSION: FDG-PET/CT for patients with esophageal cancer may find both metastases from the primary esophageal cancer and other types of synchronous primary cancers. PMID- 24403476 TI - Safety and preliminary efficacy of ultrasound-guided percutaneous irreversible electroporation for treatment of localized pancreatic cancer. AB - BACKGROUND: Irreversible electroporation (IRE) is a local tumor treatment. Thin needles are placed percutaneously around the tumor under ultrasound guidance. Short pulses of direct current sent through the tissue irreversibly increase cell membrane permeability leading to cell death. We report a phase 1 study assessing the safety of ultrasound guided percutaneous IRE in patients with localized pancreatic cancer (LPC). PATIENTS AND METHODS: Five patients (three males) with LPC, judged unsuitable for surgery, chemotherapy, or non-resectable after standard oncological treatment, were treated with IRE. The treatment was given under general anesthesia with muscle relaxation. RESULTS: No serious treatment related adverse events were observed. There was no 30-day mortality. One patient went on to laparotomy and had a R0 pancreaticoduodenectomy with portal vein resection. Six months after the treatment, two patients had no signs of recurrence on computed tomography or contrast-enhanced ultrasound. CONCLUSION: IRE for LPC can be safely performed percutaneously under ultrasound guidance, with promising initial results regarding efficacy. PMID- 24403477 TI - Zinc supplementation improves anticancer activity of monocytes in type-2 diabetic patients with metabolic syndrome. AB - BACKGROUND: Transmembrane tumor necrosis factor (TNF)-alpha, found on monocytes, is a body's key defense against cancer. In patients with type 2 diabetes mellitus (DM) and metabolic syndrome, immunity is suppressed, resulting in a high risk of several inflammatory disorders and cancer. PATIENTS AND METHODS: Seventeen patients with type 2 DM and metabolic syndrome were supplemented with either 30 mg of elemental zinc/day or placebo for eight weeks. Transmembrane TNF-alpha expressing monocytes and lymphocytes, and plasma TNF-alpha levels were analyzed before and after supplementation. RESULTS: The present study revealed that zinc supplementation significantly increased the proportion of monocytes expressing transmembrane TNF-alpha. While the plasma TNF-alpha levels and TNF-alpha expressing lymphocytes were not significantly altered in the zinc-treated and placebo groups, higher proportion of TNF-alpha bound monocytes were observed in the zinc-treated group. CONCLUSION: Because functional transmembrane TNF-alpha was shown to be implicated in defense mechanisms, these findings suggest that zinc supplementation may benefit immune response against cancer in patients with DM and metabolic syndrome. PMID- 24403478 TI - Successful use of Trastuzumab with anthracycline-based chemotherapy followed by trastuzumab maintenance in patients with advanced HER2-positive gastric cancer. AB - BACKGROUND: There is no standard chemotherapy regimen that is universally accepted for the treatment of advanced gastric cancer. Trastuzumab added to chemotherapy improves survival in patients with metastatic human epidermal growth factor receptor-2 (Her2/neu)-overexpressing gastric cancer. Data are lacking for the combination of trastuzumab with other chemotherapy regimens, apart from the cisplatin/fluorouracil backbone used in the pivotal TOGA trial. PATIENTS AND METHODS: In this retrospective analysis, we included patients with gastric cancer with HER2 overexpression who received trastuzumab in addition to their first-line chemotherapy, with or without trastuzumab maintenance therapy. The end-points were response and tolerance to treatment. RESULTS: We identified seven patients who met the search criteria; six had metastatic disease and one had locally advanced unresectable disease. Four patients received epirubicin/oxaliplatin/capecitabine/trastuzumab, and the others had non anthracycline-based chemotherapy with trastuzumab. All patients had radiological responses to treatment - one had a complete response and six had partial responses. Among the four patients who received anthracycline-based chemotherapy with trastuzumab, there was a transient decline in cardiac ejection fraction in three, but all resolved without sequelae. All patients received a period of chemotherapy induction followed by trastuzumab monotherapy for maintenance. The median progression-free survival was 14.6 months and median overall survival was 16.4 months. CONCLUSION: Trastuzumab is an important agent for the treatment of HER2-overexpressing gastric cancer. We recorded an acceptable safety and efficacy profile in this small cohort treated with anthracycline-based chemotherapy with trastuzumab followed by trastuzumab maintenance. PMID- 24403479 TI - Latent hypothyreosis as a clinical biomarker for therapy response under abiraterone acetate therapy. AB - BACKGROUND: Abiraterone acetate (AA) is a selective oral inhibitor of Steroid 17alpha-Hydroxylase, for patients with castration-resistant prostate cancer. Not all patients respond to therapy, however, there are no biomarkers predicting response to AA therapy. The aim of the present study was the identification of a biomarker for patients who are likely to respond to AA therapy. PATIENTS AND METHODS: We measured thyroid parameters in a collective of 30 patients before and during AA therapy. For statistical analyses, paired and unpaired t-tests were used. RESULTS: During AA therapy, responders developed a significant increase in thyroid stimulating hormone (TSH) compared to non-responders (p=0.03). In the subgroup of responders, 16 out of 21 patients (76.1%) had a significant increase in TSH level (p=0.001), suggesting that TSH increase is predictive of therapy response. Non-responders showed no change in TSH level during AA therapy. CONCLUSION: Hypothyreosis may serve as a simple predictive biomarker for therapy response under AA therapy. PMID- 24403480 TI - Predictive scoring system assessing the need for intraoperative blood transfusions during hepatectomy for hepatocellular carcinoma. AB - BACKGROUND: It is of great clinical concern to preoperatively predict the need for blood transfusions during hepatectomy for hepatocellular carcinoma (HCC). PATIENTS AND METHODS: A total of 168 consecutive patients undergoing elective hepatectomy for HCC were retrospectively reviewed. We investigated preoperative factors potentially influencing intraoperative blood transfusion and established a predictive scoring system for intraoperative blood transfusion. RESULTS: Thirty eight patients (22.6%) received red cell blood transfusion during surgery. A preoperative predicting scoring system for blood transfusion was constructed using the following four factors: platelet count <10*10(4)/mm(3) (2 points), alpha-fetoprotein >=80 ng/ml (1 point), tumor size >=4.0 cm (1 point), and major hepatectomy (1 point). The nomogram showed an area under the curve (AUC) of 0.760. This scoring system was highly predictive for blood transfusion (AUC=0.758). When the score was 0 points, the incidence of intraoperative blood transfusion was 3%. The rate increased to 10% and 38% when the score was 1 and 2 points, respectively, and reached 45% when the score was 3 points or more. CONCLUSION: This predictive scoring system would be useful for preoperatively assessing the need for intraoperative blood transfusions during hepatectomy for HCC. PMID- 24403481 TI - Complete metabolic remission with Gefitinib in a hemodialysis patient with bone metastases from non-small cell lung cancer. AB - Gefitinib is highly active in patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring activating mutation of the epidermal growth factor receptor (EGFR) gene. The feasibility and the degree of response to treatment with gefitinib in patients with chronic renal failure (CRF) undergoing hemodialysis has not yet been fully described in literature. We describe the case of a 70-year-old man with CRF undergoing hemodialysis three times-a-week who developed vertebral and rib bone metastasis three years after lobectomy. The bone biopsy confirmed the pulmonary origin and pyrosequencing analysis revealed deletion in E746-E750 of exon 19. We started daily administration of 250 mg gefitinib with no changes in the hemodialysis schedule. Gefitinib was well tolerated without any adverse event. After three months, the (18)F-fluoro-2-deoxy d-glucose positron emission tomography/computed tomography (FDG PET/CT) showed complete metabolic remission of bone lesions. The patient is still under treatment and maintains response (30 months to date). To our knowledge, this is the first description of complete metabolic remission in this type of patient. In conclusion, gefitinib has been safely administered to a patient with NSCLC with EGFR-activating mutation undergoing chronic hemodialysis and its use has achieved an excellent and prolonged response on bone metastases. PMID- 24403482 TI - Survival and prognostic factors in children with brain tumors: long-term follow up single center study in Poland. AB - AIM: Analysis of risk factors for survival in long-term follow-up of children treated at a single pediatric center in Poland. PATIENTS AND METHODS: Out of 623 children diagnosed with cancer between 1995-2005, 110 were treated for brain tumors and followed-up, with a mean survival of 11.4 years. RESULTS: Overall 5 year survival in the whole cohort was 60.9+/-4.7%, while 10-year survival was 58.2+/-4.7%. No relapse, progression or death occurred after six years from initial diagnosis. Survival was 48.1+/-9.6% for patients with medulloblastoma and primitive neuroectodermal tumors; 83.3+/-6.2% for low-grade astrocytoma; 56.6+/ 16.6% for ependymoma, while 0% at 72 months for high-grade glioma. Patients with cerebellar tumors had a survival rate 69.0+/-7.1% at 10 years. Multivariate analysis showed that factors predicting poor outcome were: grade III-IV tumor, incomplete surgical resection, and complications after surgical resection, while diagnosis of low-grade glioma was the only factor predicting good outcome. Progression of the disease during therapy was an additional independent adverse risk factor for survival. CONCLUSION: Long-term survival was achieved by 58% of children with brain tumors. Advanced tumor stage, incomplete surgical resection, complications of surgical treatment, and progression of the disease during treatment predicted poor outcome. PMID- 24403483 TI - CA125 and HE4 levels in a Czech female population diagnosed with endometrial cancer in preoperative management. AB - AIM: The aim of the present study was to compare the use of cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) biomarkers in patients with endometrial cancer for preoperative management and to particularly focus on relationship between CA125 and HE4 and disease stage in predicting myometrial invasion or intrauterine tumor spread. PATIENTS AND METHODS: Thirty-four patients diagnosed with endometrial cancer and 32 healthy controls were enrolled into the pilot study in the period between May 2012 and March 2013. Blood from all the females was collected and examined for CA125 and HE4. Based on standardized ultrasound examination, including gynecological examination, the clinical disease stage was determined. RESULTS: We found a significant difference (p<0.0001) for means of serum levels of HE4: females with endometrial cancer, 75.5 pmol/l, versus healthy females, 40.0 pmol/l. A non-significant statistical difference was found for mean serum CA125 levels (p=0.4442): females with endometrial cancer 19.0 IU/l, versus healthy females, 15 IU/l. A significant correlation with histopathological disease stage was found for both biomarkers (Spearman correlation). Sensitivity and specificity, and the related cut-off for HE4 suggest that HE4 would be a more appropriate biomarker for differential diagnosis between benign and malignant states. CONCLUSION: Based on our pilot study, we found that parallel examination of HE4 and CA125 may support endometrial ultrasound finding verification prior to biopsy. This study is ongoing and we expect that results on a larger population may enable HE4 measurement to be implemented in routine practice. PMID- 24403484 TI - Adjuvant radiotherapy for stage III/IV urothelial carcinoma of the upper tract. AB - AIM: In order to define the role of adjuvant radiotherapy (RT), the clinical outcomes of patients with stage III/IV urothelial carcinoma of the upper urinary tract (UTUC) were reviewed. PATIENTS AND METHODS: Clinical data from a total of 127 patients who underwent radical nephroureterectomy with bladder cuff were analyzed. While 36 patients underwent adjuvant RT following surgery, 91 were treated with surgery-alone. Differences in risk-adjusted treatment outcomes between the two groups were assessed using a multivariable Cox proportional hazards model and inverse probability of treatment weighting with propensity score for balancing covariates including use of chemotherapy between the two groups was estimated. RESULTS: With a median follow-up of 38.3 months, 3-year actuarial locoregional recurrence-free survival rates were 89% vs. 61% in the RT vs. non-RT groups, respectively (p=0.01). Three-year bladder recurrence-free survival rates were 73% and 52% in favor of the RT group (p=0.02). After adjustment for differences in covariates, the risks of locoregional, bladder, and disease recurrence were found significantly lower in the RT group. CONCLUSION: Adjuvant RT may be beneficial in terms of locoregional and bladder control in patients with stage III/IV UTUC. Further prospective studied are needed to verify these findings. PMID- 24403485 TI - Prognostic value of erythrocyte sedimentation rate and C-reactive protein in the blood of patients with glioma. AB - AIM: To determine any correlation between inflammation parameters in blood glioma patients, with some of the established glioma biomarkers and to evaluate the possible prognostic impact of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) for patient survival. PATIENTS AND METHODS: This retrospective study evaluated ESR values in 94 patients and measured CRP values prior to the excision of primary glioma in 165 patients. Overall survival probabilities were determined separately for all patients with glioma in low-grade glioma (LGG), high-grade (HGG) and in glioblastoma multiforme (GBM) using the Kaplan-Meier log rank test. The correlation between blood ESR and CRP values and between immunohistochemical (IHC) assessment of cluster of differentiation-68 (CD68), cathepsin B and nestin were evaluated. RESULTS: An ESR above 15 mm/h was significant for poor survival prognosis for patients overall (p<0.001) and in the HGG (p<0.01) and GBM (p<0.04) subgroups. A serum CRP level above 5 mg/l was also identified as prognostic in patients overall (p<0.01), and in the HGG (p=0.02) and GBM (p=0.04) subgroups. CONCLUSION: Correlations of ESR and serum levels of CRP have been revealed with prognostic tissue biomarkers i.e. cathepsin B, nestin, CD68. Moreover, preoperative measurement of both parameters could be used for survival prognosis in patients with glioma. PMID- 24403486 TI - Characteristics and natural history of patients with colorectal cancer complicated by infectious endocarditis. Case control study of 25 patients. AB - Association between streptococcal endocarditis and gastrointestinal disease has been well-documented in the literature. However oncological impact of this complicated presentation has not yet been reported. We have conducted to our knowledgethe first case-control study on this subject. PATIENTS AND METHODS: Two groups of five patients with colorectal cancer and either active endocarditis (CRC E+), or without endocarditis (CRC, n=20) were matched 1:4 for age, sex, and location of colorectal tumor. RESULTS: All 25 patients were male, with a median age of 63 (range: 53-85) years. Twenty (80%) had colon cancer and 5 (20%) rectal cancer. There was no post-operative mortality in this population. The overall morbidity was 28% (n=7). The overall 3-year survival and recurrence rates were similar in both groups 80% and 95%; 0% and 30% for group CRC E+ and CRC (p=0.4603). CONCLUSION: This is the first case-control study demonstrating that during the first two years of follow-up, occurrence of endocarditis did not alter the prognosis of patients with CRC. PMID- 24403488 TI - Esophageal stenosis: a differential diagnosis between esophageal cancer and metastasis from other neoplasia. AB - BACKGROUND: The occurrence of radiological mediastinal lymphadenopathy as the only evidence of tumor recurrence of cervical carcinoma is very rare. We report on such a case with stenosis of the esophagus. CASE REPORT: A 36-year-old Caucasian woman, without any relevant history of gynecological cancer, underwent a trans-vaginal ultrasound with evidence of any cervical lesion locally extended. After histologically-proven diagnosis of squamous cell carcinoma of the cervix uterine, the patient was treated by neoadjuvant chemoradiation, followed by total abdominal hysterectomy with bilateral salpingoophorectomy. A subsequent close follow-up was negative for recurrence of disease until December 2008, two years after diagnosis. At that period, the patient experienced cough and severe dysphagia and for this reason she underwent several examinations including esophagogastroduodenoscopy, whole-body computed tomographic scan and bronchoscopy with transbronchial needle aspiration. Histology led to diagnosis of recurrence of cervical cancer, HPV31-positive, in multiple mediastinal lymphnodes, with infiltration of the esophageal mucosa. CONCLUSION: Mediastinal lymphade-nopathy in patients with a history of cervical carcinoma should be suspicious of metastatic disease, even if there is no radiological evidence of distant metastases. PMID- 24403487 TI - Long-term statin therapy improves oncological outcome after radical gastrectomy for stage II and III gastric cancer. AB - BACKGROUND/AIM: Although several epidemiological studies have indicated that statins may have antitumor properties, the effect of statins on patient survival after curative resection of gastric cancer is unknown. The aim of the present study was to determine whether statin use could improve long-term outcomes after radical gastrectomy. PATIENS AND METHODS: We conducted a matched case-control study of 65 statin users and 176 non-users who underwent radical gastrectomy for stage II and III gastric cancer from January 2006 to December 2009. RESULTS: No significant differences were found in recurrence-free survival (RFS) or overall survival (OS) between statin users and non-users. However, subgroup analysis showed that patients who used statins for more than six months had more favorable outcomes than non-users or those who used statins for less than six months [adjusted hazard ratio of death (non-users as reference); statin use <6 months: 2.405, 95% confidence interval (CI)=1.056-5.477 and statin use >6 months: 0.168, 95% CI=0.032-0.881, p=0.006]. CONCLUSION: Statin use did not improve RFS or OS after curative resection of stage II or III gastric cancer in the overall study population. However, statin use of more than six months was associated with increased survival. PMID- 24403489 TI - Over-expression of the overexpressed in lung cancer-1 is associated with poor prognosis in colorectal cancer. AB - BACKGROUND/AIM: The overexpressed in lung cancer-1 (OLC1) protein is overexpressed in a variety of human tumors. The purpose of the present study was to determine whether increased expression of OLC1 is associated with colorectal cancer. MATERIALS AND METHODS: OLC1 expression was assayed in 150 colorectal cancer tissues by immunohistochemical staining (IHC). Multivariate and univariate analyses were performed to determine the association between OLC1 expression and prognosis. RESULTS: Immunohistochemical results revealed that 107 out of 150 colorectal cancer patients had increased levels of OLC1. OLC1 expression was significantly correlated with UICC stage (p<0.001) and histological differentiation (p<0.001) in colorectal cancer patients. The 5-year overall survival (OS) rates in patients with strong-positive and weak OLC1 staining were 16.6% and 95.3%, respectively (p<0.0001). CONCLUSION: OLC1 overexpression is an important factor in colorectal carcinoma prognosis and can be an interesting potential novel biomarker for colorectal cancer. PMID- 24403490 TI - TNF-alpha 308 G/A polymorphism and cervical intraepithelial neoplasia. AB - AIM: The purpose of the present study was the analysis of the relationship between tumor necrosis factor-alpha (TNF-alpha) -308 G/A and cervical intraepithelial neoplasia (CIN). MATERIALS AND METHODS: A prospective case control study was performed, enrolling 78 cases of cervical intraepithelial neoplasia and 107 controls. Every patient had a complete gynecological examination with cervical sampling and colposcopy and TNF-alpha 308 G/A genotyping. RESULTS: The homozygous AA genotype was extremely rare in the study group. The GG genotype was the one most frequently encountered in all classes of cervical intraepithelial neoplasia (CIN) and controls. No statistical differences were found in global comparison between cases and controls [odds ratio (OR)=3, p=0.09], nor between well-documented cases of more evolved high-grade squamous cervical intraepithelial lesion versus controls (OR=1.2, p=0.68). However, the results were significant for invasive carcinoma (OR=10.8261, 95% confidence interval=1.0748-109.0511, p=0.0433). CONCLUSION: The presence of an A allele at 308 TNF-alpha represents a risk for invasive carcinoma. PMID- 24403491 TI - Association between visceral fat, IL-8 and endometrial cancer. AB - BACKGROUND/AIM: In endometrial cancer, visceral obesity, as a risk factor, is associated with a chronic inflammatory process, confirmed by the elevation of serum inflammatory markers in obese patients. The aim of the present study was to evaluate the correlation between visceral fat, assessed by ultrasonography, and the systemic levels of interleukin (IL)-8 in patients with endometrial cancer. This study also evaluated the usefulness of abdominal ultrasonography in assessing the visceral fat correlated with systemic inflammatory status, as an alternative method to identify patients at risk of endometrial cancer. MATERIALS AND METHODS: The study was a case-control analysis including two groups of patients: Group I: 44 patients diagnosed with endometrial cancer; group II: 44 patients with no gynecological pathology. The diagnosis of endometrial cancer was performed following histopathological examination that evaluated the tissue material obtained through endometrial biopsy. These patients underwent ultrasound examination by which intraperitoneal fat was determined. IL-8 levels were determined for each patient. The Student's t-test was used for the comparison of the means and the Mann-Whitney test for rank comparison of two independent samples. RESULTS: In patients diagnosed with endometrial cancer, the visceral fat area evaluated by ultrasound was significantly larger (p<0.0001) compared to that of the control group. The plasma levels of IL-8 in the endometrial cancer group were significantly elevated (p<0.001) compared to the control group. A positive linear correlation was also found between the visceral fat area and plasma levels of IL-8. CONCLUSION: The plasma levels of IL-8 are positively linearly correlated with visceral fat. Determination of visceral fat in association with IL-8 levels may be a predictive factor for endometrial cancer. PMID- 24403493 TI - ERCC1 expression as a predictor of resistance to platinum-based chemotherapy in primary ovarian cancer. AB - AIM: The purpose of the present study was to investigate the possible association between Excision repair cross-complementing group 1 (ERCC1) score and platinum resistance in first-line chemotherapy for ovarian cancer. PATIENTS AND METHODS: ERCC1 Expression was determined using immunohisto-chemistry in 68 patients with platinum-responding tumor and 30 with platinum-resistant tumors. The primary end point of this study was the association between the expression of ERCC1 protein with resistance to standard platinum-based chemotherapy in primary ovarian cancer. RESULTS: In pairwise comparisons, the overall survival (OS) for patients with ovarian cancer, who were non-responders to platinum-based chemotherapy with low or intermediate H-score for ERCC1 was better than that of non-responders with high H-score for ERCC1 [median OS=21 (16.8-25.2 months) and 28 (14.6-41.4 months) vs. 15 months (6.2-23.8 months), p-value=0.048, and p-value=0.017, respectively]. CONCLUSION: There were no significant differences in the progression-free survival between those with low, intermediate and high H-score for ERCC1. There is no statistically significant relationship between ERCC1 score and response to platinum-based chemotherapy in patients with primary ovarian cancer. PMID- 24403492 TI - Role of serum VEGFA, TIMP2, MMP2 and MMP9 in monitoring response to adjuvant radiochemotherapy in patients with primary cervical cancer--results of a companion protocol of the randomized NOGGO-AGO phase III clinical trial. AB - AIM: The aim of the current study was to analyze the type of variations in expression profiles of matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), tissue inhibitor of metalloproteinase 2 (TIMP2), and vascular endothelial growth factor A (VEGFA) before and after radiochemotherapy in patients with locally advanced FIGO stage Ib-IIb cervical cancer. We analyzed the role of these biomarkers in monitoring response to treatment. PATIENTS AND METHODS: Serum from 72 patients with cervical cancer treated within a phase III trial with either simultaneous radiochemotherapy (S-RC) with cisplatin, or systemic paclitaxel and carboplatin followed by percutaneous radiation (PC-R) was analyzed by ELISA. Sera were obtained during surgery and after the end of adjuvant treatment. RESULTS: The median age at time of diagnosis was 46 years (range=30-71 years). The most common histological types were squamous cell (73.6%) and adenocarcinoma (25%). Thirty-five (48.6%) patients underwent surgery followed by S-RC and 37 (51.4%) patients were treated with surgery followed by PC R. Five patients developed recurrence within six months after radiochemotherapy. VEGFA levels were significantly higher before and after adjuvant treatment in patients who developed early recurrence (p=0.001). An increase of more than 500 pg/ml VEGFA and a decrease of more than 9% of the pre-therapeutic value of TIMP2 were significantly associated with a higher risk of early recurrence (RR=8.5, 95% CI=1.8-39.8 and RR=11.0, 95% CI=2.5-48.2, respectively). TIMP2 expression and risk score for early relapse (which is calculated using values of VEGFA and TIMP2) were independent prognostic factors for overall survival (p=0.043, HR=0.96, 95% CI=0.93-0.99 and p=0.002, HR=1.09, 95% CI=1.03-1.15, respectively). CONCLUSION: Our results indicate a predictive value of VEGFA and TIMP2 in monitoring cervical cancer patients undergoing radiochemotherapy. PMID- 24403494 TI - ERCC1 expression as a predictive marker of cervical cancer treated with cisplatin based chemoradiation. AB - AIM: The purpose of the present study was to evaluate the correlation between repair cross-complementing group-1 (ERCC1) status and the outcome of platin-based chemoradiation of locally advanced cervical cancer. PATIENTS AND METHODS: Tumor specimens from 112 patients with locally advanced cervical cancer were evaluated for ERCC1 expression. The outcome of these patients was retrospectively assessed in correlation with ERCC1 expression. RESULTS: Increased expression of ERCC1 correlates with a better prognosis of cervical cancer. The 2-year overall survival was 68.6% in the group with low H-score for ERCC-1 and gradually increased in the intermediate and high H-score groups to 71.7% and 90.7%, respectively. CONCLUSION: The present study did not confirm the correlation of low levels of ERCC1 expression with unfavorable outcomes of patients with locally advanced cervical cancer treated with platin-based radiochemotherapy. PMID- 24403495 TI - A case of primary peritoneal carcinoma: evidence for a precursor in the fallopian tube. AB - BACKGROUND: Primary high-grade serous peritoneal carcinoma (PPSC) is a rare malignancy with an ambiguous pathogenesis. CASE REPORT: We report on a 51-year old woman presenting with a routine smear test cytology suspicious of adenocarcinoma. She underwent hysteroscopy, laparsocopy with multiple biopsies and bilateral salpingoophorectomy. She was diagnosed with a serous tubal intraepithelial carcinoma in situ (STIC) in the right fallopian tube. Subsequently, she underwent radical surgery and was diagnosed with peritoneal high-grade serous carcinoma. Interestingly, both ovaries remained histologically tumour-free. DISCUSSION: High-grade serous carcinomas that arise on the peritoneum with tumour-free ovaries are rare. The findings in this case, coupled with current evidence, strongly suggest a precursor lesion in the fallopian tube (STIC lesions). The clinical implications of this theory reside in the potential for improving early detection strategies. Nonetheless, more data on precursor lesions in the fallopian tubes and their transformation to serous carcinoma are required to plan for future screening methods. PMID- 24403497 TI - Biography of professor barnett rosenberg: a tribute to his life and his achievements. PMID- 24403496 TI - The role of inhibitor of DNA-binding 1 (ID-1) protein and angiogenesis in serous ovarian cancer. AB - BACKGROUND: Overexpression of Inhibitor of DNA-binding 1 protein (ID-1) is correlated with poor prognosis in some malignancies and few studies have assessed its role in ovarian cancer. This led us to investigate its association with the microvessel density (MVD) in patients with ovarian cancer. MATERIALS AND METHODS: Fifty-six patients with epithelial serous ovarian cancer were selected. The early stage group consisted of 14 patients and the advanced-stage group comprised 42 patients. ID-1 expression and MVD were evaluated by immunohistochemistry. RESULTS AND CONCLUSION: The histoscore for ID-1 and MVD were significantly higher in advanced-stage cancer (p<0.05). The MVD was significantly higher in the high ID-1 expression group compared to the low ID-1 expression group (p<0.001). The mean follow-up time was 52 months. The survival period in patients with high ID-1 expression was not significantly shorter than for those with low ID-1 expression (p=0.62). The role of ID-1 protein requires further investigation. PMID- 24403498 TI - Targeted agents and oxaliplatin-containing regimens for the treatment of colon cancer. AB - Oxaliplatin and fluoropyrimidines are synergic combinations very active for the treatment of advanced colorectal cancer and for the adjuvant treatment of stage III colon cancer. Oxaliplatin-based regimens can be further strengthened by the addition of a third component, either a traditional drug such as irinotecan or targeted agents such as anti-vascular endothelial growth factor (VEGF) drugs, bevacizumab and aflibercept, or the anti-epidermal growth factor receptor (EGFR), cetuximab and panitumumab. The availabilty of all these active agents prompted several clinical trials on different lines of treatment of advanced colorectal cancer patients and in the adjuvant setting. Clinical studies involving the administration of anti-EGFR drugs also helped identify mutations in KRAS as a negative marker for the activity of these agents. However, positive selection criteria for targeted agents have not been identified. The results of oxaliplatin containing regimens are critically presented and discussed in this review. PMID- 24403499 TI - Predictive role of repair enzymes in the efficacy of Cisplatin combinations in pancreatic and lung cancer. AB - Platinum combinations are the mainstay of treatment for non-small cell lung cancer (NSCLC), while for pancreatic cancer platinum combinations are being given to good-performance status patients. These platinum combinations consist of cis- or carboplatin with gemcitabine, while, for non-squamous NSCLC and mesothelioma, of pemetrexed. The combination of gemcitabine and cisplatin is based on gemcitabine-induced increased formation and retention of DNA-platinum adducts, which can be explained by a decrease of excision repair cross-complementing group 1 (ERCC1)-mediated DNA repair. In these patients, survival and response is prolonged when ERCC1 has a low protein or mRNA expression. A low expression of ribonucleotide reductase (RR) is related to a better treatment outcome after both gemcitabine and gemcitabine-platinum combinations. For pemetrexed combinations, ERCC1 expression was not related to survival. For both NSCLC and pancreatic cancer, polymorphisms in ERCC1 (C118T) and Xeroderma pigmentosum group D (XPD) (A751C) were related to survival. In currently ongoing and future prospective studies, patients should be selected based on their DNA repair status, but it still has to be determined whether this should be by immunohistochemistry, mRNA expression, or a polymorphism. PMID- 24403500 TI - New use of metals as nanosized radioenhancers. AB - Since the discovery of cisplatin about 40 years ago, the design of innovative metal-based anticancer drugs is a growing area of research. Transition metal coordination complexes offer potential advantages over the more common organic based drugs, including a wide range of coordination number and geometries, accessible redox states, tunability of the thermodynamics and kinetics of ligand substitution, as well as a wide structural diversity. Metal-based substances interact with cell molecular targets, affecting biochemical functions resulting in cancer cell destruction. Radionuclides are another way to use metals as anticancer therapy. The metal nucleus of the unstable radionuclide becomes stable by emitting energy. The biological effect in different tissues is obtained by the absorption of this energy from the radiation emitted by the radionuclide, the principal target generally agreed for ionizing radiations being DNA. A new area of clinical research is now emerging using the same experimental metal elements, but in a radically different manner: metals and metal oxides used as crystalline nanosized particles. In this field, man-made functionalized nanoparticles of high electron density and well-defined size and shape offer the possibility of entering cancer cells and depositing high amounts of energy in the tumor only when exposed to ionizing radiations (on/off activity). These nanoparticles, such as hafnium oxide engineered as 50 nm-sized spheres, functionalized with a negative surface (NBTXR3 nanoparticles), have been developed as selective radioenhancers, which represents a breakthrough approach for the local treatment of solid tumors. The properties of NBTXR3 nanoparticles, their chemistry, size, shape and surface charge, have been designed for efficient tumor cell uptake. NBTXR3 brings a physical mode of action, that of radiotherapy, within the cancer cells themselves. Physicochemical characteristics of NBTXR3 have demonstrated a very promising benefit-risk ratio for human healthcare across a broad non clinical program. NBTXR3 has entered clinical development in therapy of advanced soft tissue sarcomas and head and neck cancer. PMID- 24403501 TI - Dicycloplatin, a novel platinum analog in chemotherapy: synthesis of chinese pre clinical and clinical profile and emerging mechanistic studies. AB - Dicycloplatin (DCP) has better solubility and stability than both cisplatin and carboplatin. Pre-clinical and phase I studies demonstrated significant antitumor activity and fewer adverse events than carboplatin. Phase II clinical trials in advanced non-small cell lung cancer found efficacy and safety of DCP-plus paclitaxel comparable to carboplatin-plus-paclitaxel but better tolerability. This article summarizes and reviews pre-clinical and clinical data for dicycloplatin from the Chinese medical literature. We also report on new mechanistic findings in our laboratory in West Virginia, USA. Patient blood samples were collected for DCP-prototype determination by liquid chromatography mass spectrometry (LC-MS/MS). Molecular studies of ovarian cancer cells treated with DCP or cisplatin were carried out for gene-signature profiling using immunoblotting. Pharmacokinetic mass-spectrometry showed different spectrum profiles of DCP and carboplatin in plasma. Plasma concentration of DCP prototype was 17.1 MUg/ml 2h after administration, with a peak concentration of 26.9 MUg/ml at 0.5 h. Immunoblotting showed DCP-induced activation of DNA damage pathways, including double-phosphorylated checkpoint kinase 2 (CHK2) and breast cancer 1 (BRCA1) and triple-phosphorylated p53, compared to controls. Cisplatin produced a similar profile, with increased p53 protein. DCP and cisplatin activate DNA damage response through similar pathways. DCP may be more soluble and stable, and better-tolerated. PMID- 24403502 TI - Standardization of chemotherapy and individual dosing of platinum compounds. AB - Platinum compounds represent a pharmacological class essential for the treatment of certain types of cancer. Cisplatin, carboplatin, and oxaliplatin, share some physiochemical and pharmacological properties, in particular the ability to form DNA adducts. Carboplatin may be considered as an analog of cisplatin, but its pharmacokinetic properties, side-effects, and intrinsic activity are significantly different from those of cisplatin. The choice of one of these two compounds may be made rationally based on the individual patient's characteristics. PMID- 24403503 TI - Understanding and improving platinum anticancer drugs--phenanthriplatin. AB - Approximately half of all patients who receive anticancer chemotherapy are treated with a platinum drug. Despite the widespread use of these drugs, the only cure that can be claimed is that of testicular cancer following cisplatin treatment. This article reviews some of our recent work on phenanthriplatin, a cisplatin derivative in which a chloride ion is replaced by phenanthridine, and on one of its analogues, the previously reported pyriplatin. These cationic complexes form monofunctional adducts on DNA that do not significantly distort the duplex, yet efficiently block transcription. Cell-based assays reveal altered cellular uptake properties and a cancer cell-killing profile different from those of established platinum drugs. Mechanistic work, including a crystal structure analysis of platinum-modified DNA in the active site of RNA polymerase II, is discussed herein. PMID- 24403504 TI - From platinum compounds to targeted therapies in advanced thoracic malignancies. AB - Improved understanding of the molecular mechanisms involved in development, growth and spread of cancer have led to develpment of targeted therapies for many cancers. Based on their superior tolerability and efficacy, targeted therapies with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) or crizotinib are preferred first-line treatments over platinum-based chemotherapies in patients whose tumours harbour EGFR-activating mutations and anaplastic lymphoma kinase (ALK) translocations, respectively. Active areas of research in EGFR-mutant and ALK-translocated NSCLC include identification of mechanisms of resistance and overcoming them. Therapeutic targeting of several other targets including ROS, RET and discoidin domain receptor 2 (DDR2) tyrosine kinases are in early phases of clinical evaluation. Despite the advances in tumour genomic sequencing, a substantial fraction of patients with non-small cell lung cancer (NSCLC) do not have any targetable genetic alteration. Ongoing research is focused on identifying mechanisms of carcinogenesis in these patients. Targeted therapies in small cell lung cancer (SCLC) and thymic malignancies have not yielded meaningful clinical benefits, and platinum-based therapies remain the cornerstone of treating patients with advanced disease. PMID- 24403505 TI - Neuronal drug transporters in platinum drugs-induced peripheral neurotoxicity. AB - To gain a better insight into the neurotoxicity of platinum drugs, it is important to increase our knowledge over the phenomena allowing their entry into dorsal root ganglia neurons. A deeper understanding of platinum-drug transport mechanisms in neurons would represent not only a step forward in the pathogenetic interpretation of their neurotoxicity, but would also disclose possible treatment options to prevent this severe side-effect achievable through modulation of transporter activity. Copper transporters and organic cation transporters have been identified as putative targets for the pharmacological modulation of neuronal cell accumulation of platinum drugs and damage, and this possibility has been demonstrated by animal studies. The modulation of drug transporter activity is a promising strategy to limit the neurotoxicity of platinum drugs, provided that a) complete characterization of drug transporters is obtained and b) selective neuronal activity is targeted without reducing anticancer drug efficacy. PMID- 24403506 TI - Beyond platinums: gold complexes as anticancer agents. AB - The accidental discovery of the anticancer properties of cisplatin in the mid 1960s triggered the development of alternative platinum-based drugs. However, the platinum-based treatment of tumor diseases is massively hampered by severe side effects and development of resistance. Sulfur-containing biomolecules play a significant role in platinum anticancer chemotherapy because of their high affinity to the platinum(II) ion. Sulfur is involved in the entire metabolic processing of platinum drugs. Strong and irreversible binding of cisplatin to intracellular thiolato ligands is considered a major step of inactivation, and reactions with sulfur donors in proteins are believed to affect enzymatic processes. Consequently, the development of novel metal-based compounds with a pharmacological profile different from that of clinically-established platinum drugs is a major goal of modern medicinal chemistry and drug design. Among the non-platinum antitumor agents, gold(III) complexes have recently gained increasing attention due to their strong tumor cell growth-inhibiting effects, generally achieved by exploiting non-cisplatin-like mechanisms of action. The real breakthrough is not simply the use of gold compounds to treat cancer, but the rational design of gold-based drugs which may be very effective, non-toxic and potentially selective towards cancer cells, their potential impact relying on the possible site-specific delivery in localized cancer, thus strongly improving cellular uptake and minimizing unwanted side-effects. Cancer cells are known to overexpress specific proteins and receptors needed for tumor growth. Among them, two integral plasma membrane proteins mediate the cellular uptake of di- and tripeptides and peptide-like drugs. They are present predominantly in epithelial cells of the small intestine, bile duct, mammary glands, lung, choroid plexus, and kidney but are also localized in other tissues and are up-regulated in some types of tumors. Accordingly, we have been designing gold(III)-peptide dithiocarbamato derivatives which combine both the antitumor properties and reduced side-effects of the previously reported gold(III) analogues with enhanced bioavailability and tumor selectivity achieved by exploiting peptide transporters. Our compounds showed interesting cytotoxic properties towards a number of cancer cell lines in vitro and in vivo on xenograft models, together with negligible organ and acute toxicity. With respect to their mechanisms of action, we identified mitochondria and proteasome as major in vitro and in vivo targets. These results allowed the filing of an international patent for the use of gold(III) peptidomimetics in cancer chemotherapy, as well as providing a solid starting point for them to enter phase I clinical trials in a few months. PMID- 24403507 TI - Platinum drugs and DNA repair mechanisms in lung cancer. AB - The standard first-line treatment for around 80% of newly-diagnosed advanced non small cell lung cancer (NSCLC) is chemotherapy. Currently, patients are allocated to chemotherapy on the basis of clinical conditions, comorbidities and histology. If feasible, platinum-based chemotherapy is considered as the most efficacious option. Due to the heterogeneity in terms of platinum-sensitivity among patients with NSCLC, great efforts have been made in order to identify molecular predictive markers of platinum resistance. Based on the mechanism of action of platinum, several components of DNA repair pathways have been investigated as potential predictive markers. The main DNA repair pathways involved in the repair of platinum-induced DNA damage are nucleotide excision repair and homologous recombination. The most studied potential predictive markers of platinum sensitivity are Excision Repair Cross Complementing-1 (ERCC1) and Brest Cancer Type-I Susceptibility protein (BRCA1); however, increasing biological knowledge about DNA repair pathways suggests the potential clinical usefulness of integrated analysis of multiple DNA repair components. PMID- 24403508 TI - Collateral sensitivity to cisplatin in KB-8-5-11 drug-resistant cancer cells. AB - BACKGROUND: KB-8-5-11 cells are a drug-resistant cervical cell model that overexpresses ABCB1 (P-glycoprotein). KB-8-5-11 has become sensitive to non-ABCB1 substrate cisplatin. Understanding the mechanism of collateral sensitivity to cisplatin may lead to biomarker discovery for platinum sensitivity in patients with cancer. MATERIALS AND METHODS: A Taqman low-density array was used to characterize the expression of 380 genes previously associated with chemoresistance. Identified pathways were further analyzed using cytotoxicity assays, metabolomics and western blots. RESULTS: KB-8-5-11 cells were sensitive to CuSO4 and the glutathione inhibitor buthionine sulphoximine. Expression of ATPase, Cu(2+) transporting alpha (ATP7A) and ATP7B were decreased at the protein and gene levels respectively in KB-8-5-11. KB-8-5-11 had decreased gene expression of glutathione S-transferase pi 1 (GSTP1), GSTA4 and GSTK1. Cisplatin treatment significantly lowered total cellular glutathione in parental KB-3-1 cells. Glutathione also tended to be lower in KB-8-5-11 cells compared to KB-3-1 cells. CONCLUSION: KB-8-5-11 cells have alterations in their copper transporters and glutathione metabolism, contributing to their cisplatin-sensitive phenotype. PMID- 24403509 TI - Antidepressants and platinum drugs. AB - BACKGROUND/AIM: Antidepressants are frequently prescribed concurrently with anti cancer drugs and may have synergistic, additive or antagonistic effects. The present work investigated the effect of antidepressants on the cytotoxicity of platinum agents cisplatin, carboplatin and oxaliplatin. MATERIALS AND METHODS: The cytotoxicity of platinum drugs alone or in combination with antidepressants was measured in HCT116 wild-type (wt), HCT116 (p53 -/-), HT-29, SKOV3 and A2780 cells using an apoptosis-based assay. RESULTS: The effect of antidepressants on platinum cytotoxicity is both cell type- and drug dependent. Mostly additive effects were observed. Desipramine and fluoxetine caused the greatest effects, with cisplatin in general being most sensitive to their presence. There is little effect of p53 status on the drug-drug interaction while the calmodulin inhibitor W7 augmented cisplatin cytotoxicity relative to carboplatin and oxaliplatin. CONCLUSION: The drug-drug interaction between antidepressants and platinum anti cancer agents requires detailed evaluation for optimization of patient care. PMID- 24403510 TI - Characterization of and protection from neurotoxicity induced by oxaliplatin, bortezomib and epothilone-B. AB - AIM: To characterize neurotoxicity induced by oxaliplatin, bortezomib, and epothilone-B as well as protection against their neurotoxicity using an in vitro model. MATERIALS AND METHODS: Neurotoxicity was evaluated using the neurite outgrowth method in PC12 rat pheochromo-cytoma cells differentiated towards a mature neuronal phenotype, while neuroprotection was explored by simultaneous exposure to 0.5 mM amifostine. The potential markers of neuronal differentiation, cyclin-B2 (Ccnb2) and baculoviral inhibitor of apoptosis repeat-containing 5 (Birc5), were evaluated by quantitative reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Bortezomib, epothilone-B, and oxaliplatin reduced neurite length to 68%, 78% and 66%, respectively (p<0.05). The percentage of neurite-forming-cells (discriminating neurotoxicity from general cytotoxicity) decreased from 70% (control) to 55% (bortezomib), 46% (epothilone-B), and 51% (oxaliplatin). Amifostine was neuroprotective against oxaliplatin-induced neurotoxicity, increasing both neurite length and neurite-forming-cells. Quantitative-RT-PCR showed a 2.7-fold decrease in Ccnb2 expression in differentiated PC12 vs. undifferentiated cells. CONCLUSION: Oxaliplatin, bortezomib, and epothilone-B are neurotoxic in the PC12 model. Amifostine has a neuroprotective effect only against oxaliplatin-induced neurotoxicity, suggesting that these compounds have different mechanisms of neurotoxicity. PMID- 24403511 TI - How liposomal Cisplatin overcomes chemoresistance in ovarian tumour cells. AB - The frequent development of cellular resistance to cisplatin in cancer patients is a serious limitation for clinical drug therapy. However, cisplatin resistance is incompletely understood. We have shown that cisplatin-resistant A2780 ovarian cancer cells (A2780cis) can efficiently be eliminated by liposomal cisplatin, which displayed similar cytotoxicity towards both A2780 and A2780cis cells. This may, at least in part, be related to a higher intracellular accumulation of the drug within the resistant cells after liposomal entry. However, the superior cytotoxicity of the liposomal drug was not reflected by DNA platination. This suggests a more complex mode of action of liposomal cisplatin, most likely affecting different signaling pathways. To gain insight into the resistance gene signature, a whole-genome gene expression analysis was performed for A2780cis cells, untreated or treated with half-minimal inhibitory concentration (IC50) of free and liposomal cisplatin. Strong differences in the functional networks affected by free and liposomal cisplatin became evident. p53 was identified as a key factor directing differences in the apoptotic processes. While free cisplatin induced the intrinsic pathway of apoptosis, liposomal cisplatin induced expression of genes of DNA damage pathways and of the extrinsic pathway of apoptosis. These predictions from gene expression data were confirmed at the protein and function level. This sheds new light on liposomal drug carrier approaches in cancer and suggests liposomal cisplatin as a promising strategy for the treatment of cisplatin-resistant ovarian carcinoma. PMID- 24403512 TI - Oxoglaucine-lanthanide complexes: synthesis, crystal structure and cytotoxicity. AB - AIM: To evaluate the in vitro cytotoxicity of oxoglaucine (OG) complexes: [Sm(OG)2(NO3)3]*H2O (1), [Eu(OG)2(NO3)3]*1.5CH3OH (2) and [Er(OG)2(NO3)3]*H2O (3) through comparison to oxoglaucine and lanthanide salts. MATERIALS AND METHODS: The reactions of OG with corresponding lanthanide salts gave rise to complexes 1 3. The crystal structures of complexes 1-3 were determined by single-crystal X ray diffraction analysis. The in vitro cytotoxicity of oxoglaucine and complexes 1-3 against five human cancer cell lines were evaluated by the 3-(4,5-dimethyl-2 thiazolyl)-2,5-diphenyl tetrazolium Bromide (MTT) method. RESULTS: Complexes 1-3 have similar mononuclear structures. The 50% inhibitory concentration (IC50) of complex 1 against SGC7901 cells was 32.1 MUM; that of complex 2 against MCF-7 cells was 3.2 MUM; those of complex 3 on HeLa and MCF-7 cells were 8.3 and 1.4 MUM, respectively. CONCLUSION: The three OG-lanthanide complexes exhibited significantly enhanced cytotoxicity vs. OG and corresponding lanthanide salts. PMID- 24403513 TI - Skin test protocol for the prevention of hypersensitivity reactions to oxaliplatin. AB - BACKGROUND/AIM: Several hypersensitivity reactions (HSRs) to oxaliplatin have been reported. Presently, there is no reliable way to predict the development of this adverse reaction. The aim of the present study was to evaluate the reliability of skin tests in the detection of patients at risk of developing HSRs to oxaliplatin. PATIENTS AND METHODS: Patients under treatment with oxaliplatin underwent the prick test at a concentration of 1 mg/ml and, if negative, intradermal injection at a concentration of 0.1 mg/ml, one hour before each course of oxaliplatin, starting from the second administration. RESULTS: A group of 101 patients were submitted to skin tests: two were positive, whereas five developed HSR despite negative tests (false-negative rate: 5.05%). These patients underwent desensitization, which permitted to conclude the planned schedule in five cases. CONCLUSION: A negative skin test to oxaliplatin has a good reliability in predicting HSRs. We suggest performing tests only in patients that have received at least five courses of oxaliplatin. PMID- 24403514 TI - Combinations of platinums and selected phytochemicals as a means of overcoming resistance in ovarian cancer. AB - Cancer sufferers are often found to use herbal products along with targeted therapy although not much information (whether beneficial or harmful) is available about the effects of such combinations. In this study, we investigated synergism from the combination of platinum drugs and a number of tumour-active phytochemicals including curcumin, epigallocatechin-3-gallate, thymoquinone, genistein, resveratrol, betulinic acid and ursolic acid in three human ovarian cancer cell lines A2780, A2780(cisR) and A2780(ZD0473R), as a function of concentration and the sequence of administration. Both the dose-effect curves and combination indices show that the binary combinations of platinum drugs with the phytochemicals exert concentration- and sequence-dependent synergism in the cell lines. Generally the degree of synergism is found to be greater in sequenced administration such as 0/2 h, 2/0 h, 0/4 h and 4/0 h than the bolus. The variation in the nature of the combined drug action from being highly synergistic to antagonistic with the change in sequence of administration clearly indicates that the action of one drug modulates that of the other (towards the induction or inhibition of apoptosis). We have also used sequenced combinations of platinum drugs and bortezomib (a proteasome inhibitor that prevents cisplatin-induced proteasomal degration of copper transporter CTR1) to enhance cellular platinum accumulation and the level of platinum-DNA binding especially in the resistant human ovarian tumour models. Proteomic studies to identify the key proteins associated with platinum resistance are ongoing. We have identified 59 proteins associated with platinum resistance in ovarian tumor models. PMID- 24403515 TI - Membrane transporters as mediators of cisplatin side-effects. AB - The clinical use of the efficient chemotherapeutic drug cisplatin is limited by its specific severe organ toxicities such as nephro-, oto-, and also peripheral neurotoxicity. Membrane transporters such as the copper transporter-1 (Ctr1), the copper transporter-2 (Ctr2), the P-type copper-transporting ATPases ATP7A and ATP7B, the organic cation transporter-2 (OCT2), and the multidrug extrusion transporter-1 (MATE1) mediate cellular transport of cisplatin. Since OCT2 is specifically expressed in the kidneys, its role as possible target of specific organ protection against undesired cisplatin toxicity is under investigation. We could show that OCT2 is also expressed in the cochlea in hair cells and in cells of the stria vascularis and also in dorsal root ganglia of mice. Moreover, we could show in a mouse model of cisplatin acute toxicities that the expression of OCT is critical for the development of ototoxicity, peripheral neurotoxicity and nephrotoxicity. Competition of cisplatin transport by the OCT2 substrate cimetidine was able to suppress ototoxicity, and reduce nephrotoxicity. Only few human tumors express OCT2, its expression being apparently down-regulated by epigenetic modifications, suggesting that a protective therapy by competition for the transport of cisplatin by OCT2 may be generally feasible without affecting its antitumor potency. There is already some evidence that patients bearing a mutation in OCT2 gene or co-medicated with cimetidine are protected against cisplatin nephrotoxicity. In conclusion, OCT2 seems to be an ideal target for the establishment of protective therapies aimed to specifically reduce cisplatin side effects and increase the quality of life of the patients. PMID- 24403516 TI - Platinum and other heavy metal coordinating compounds in cancer chemotherapy: overview of Verona ISPCC XI. PMID- 24403517 TI - 20-HETE regulates the angiogenic functions of human endothelial progenitor cells and contributes to angiogenesis in vivo. AB - Circulating endothelial progenitor cells (EPC) contribute to postnatal neovascularization. We identified the cytochrome P450 4A/F-20 hydroxyeicosatetraenoic acid (CYP4A/F-20-HETE) system as a novel regulator of EPC functions associated with angiogenesis in vitro. Here, we explored cellular mechanisms by which 20-HETE regulates EPC angiogenic functions and assessed its contribution to EPC-mediated angiogenesis in vivo. Results showed that both hypoxia and vascular endothelial growth factor (VEGF) induce CYP4A11 gene and protein expression (the predominant 20-HETE synthases in human EPC), and this is accompanied by an increase in 20-HETE production by ~1.4- and 1.8-fold, respectively, compared with the control levels. Additional studies demonstrated that 20-HETE and VEGF have a synergistic effect on EPC proliferation, whereas 20 HETE antagonist 20-HEDGE or VEGF-neutralizing antibody negated 20-HETE- or VEGF induced proliferation, respectively. These findings are consistent with the presence of a positive feedback regulation on EPC proliferation between the 20 HETE and the VEGF pathways. Furthermore, we found that 20-HETE induced EPC adhesion to fibronectin and endothelial cell monolayer by 40 +/- 5.6 and 67 +/- 10%, respectively, which was accompanied by a rapid induction of very late antigen-4 and chemokine receptor type 4 mRNA and protein expression. Basal and 20 HETE-stimulated increases in adhesion were negated by the inhibition of the CYP4A 20-HETE system. Lastly, EPC increased angiogenesis in vivo by 3.6 +/- 0.2-fold using the Matrigel plug angiogenesis assay, and these increases were markedly reduced by the local inhibition of 20-HETE system. These results strengthened the notion that 20-HETE regulates the angiogenic functions of EPC in vitro and EPC mediated angiogenesis in vivo. PMID- 24403518 TI - Experimental nonalcoholic steatohepatitis increases exposure to simvastatin hydroxy acid by decreasing hepatic organic anion transporting polypeptide expression. AB - Simvastatin (SIM)-induced myopathy is a dose-dependent adverse drug reaction (ADR) that has been reported to occur in 18.2% of patients receiving a 40- to 80 mg dose. The pharmacokinetics of SIM hydroxy acid (SIMA), the bioactive form of SIM, and the occurrence of SIM-induced myopathy are linked to the function of the organic anion transporting polypeptide (Oatp) hepatic uptake transporters. Genetic polymorphisms in SLCO1B1, the gene for human hepatic OATP1B1, cause decreased elimination of SIMA and increased risk of developing myopathy. Nonalcoholic steatohepatitis (NASH) is the most severe form of nonalcoholic fatty liver disease, and is known to alter drug transporter expression and drug disposition. The purpose of this study was to assess the metabolism and disposition of SIM in a diet-induced rodent model of NASH. Rats were fed a methionine- and choline-deficient diet for 8 weeks to induce NASH and SIM was administered intravenously. Diet-induced NASH caused increased plasma retention and decreased biliary excretion of SIMA due to decreased protein expression of multiple hepatic Oatps. SIM exhibited increased volume of distribution in NASH as evidenced by increased muscle, decreased plasma, and no change in biliary concentrations. Although Cyp3a and Cyp2c11 proteins were decreased in NASH, no alterations in SIM metabolism were observed. These data, in conjunction with our previous data showing that human NASH causes a coordinated downregulation of hepatic uptake transporters, suggest that NASH-mediated transporter regulation may play a role in altered SIMA disposition and the occurrence of myopathy. PMID- 24403519 TI - Rising alcohol consumption and a high prevalence of problem drinking in black men and women in Cape Town: the CRIBSA study. AB - BACKGROUND: To determine the prevalence and determinants of problematic alcohol use (CAGE >=2) in 25-74-year-old black population in Cape Town in 2008/2009 and examine the changes in self-reported alcohol consumption between 1990 and 2008/2009 in 25-64-year-olds. METHODS: In 2008/2009, a representative cross sectional sample, stratified for age and sex, was randomly selected from the same townships sampled in 1990. Socio-demographic characteristics, the ability to cope with psychosocial stress (sense of coherence) and adverse life events were determined. Ordinal logistic regression analysis assessed the determinants of problem drinking. RESULTS: There were 1099 participants, 392 men and 707 women, in 2008/2009. Prevalence of alcohol consumption in 2008/2009 (men: 68.5%, 95% CI 62.7 to 73.7; women: 27.4%, 95% CI 23.7 to 31.5) was higher than in 1990 (men: 56.7%, women: 15.1%). Prevalence of problem drinking was significantly higher in men (49.7%, 95% CI 44.6 to 54.9) than in women (18.1% 95% CI 15.3 to 21.2) (p<0.001). In men, greater alcohol use was associated with >7 years of education (p=0.012), being unemployed compared with employed (p=0.008) and coping poorly with stress (OR 1.02, 95% CI 1.01 to 1.05, p=0.042), and in women with spending more than half their life in the city (p<0.001) and coping poorly with stress (OR 1.02, 95% CI 1.01 to 1.04, p=0.039). The odds for greater alcohol use with increasing number of adverse life events, after adjusting for the other factors, was significant in men (OR 1.11, 95% CI 1.02 to 1.19, p=0.010) and women (OR 1.09, 95% CI 1.03 to 1.16, p=0.005). CONCLUSIONS: Problem drinking is a major problem in this population and requires urgent interventions to curtail the misuse. PMID- 24403521 TI - 'I sort of balance it out'. Living with facial acne in emerging adulthood. AB - Many emerging adults live with mild-to-moderate visible facial acne, but little is known about their experiences. A qualitative interview study was conducted with 11 adults aged 18-22 years, which aimed to explore the meaning of living with visible acne. A thematic analysis revealed three superordinate themes: coping strategies, self-perceptions and interpersonal relationships. Results revealed the utility of researching visible acne in emerging adulthood, including the use of multiple coping strategies. Health psychologists need to consider individual differences for young adults who are living with a visible difference. The importance of the peer group and family is also explicated. PMID- 24403520 TI - Protective activity of a novel resveratrol analogue, HS-1793, against DNA damage in 137Cs-irradiated CHO-K1 cells. AB - Resveratrol has received considerable attention as a polyphenol with anti oxidant, anti-carcinogenic, and anti-inflammatory effects. Radiation is an important component of therapy for a wide range of malignant conditions. However, it causes damage to normal cells and, hence, can result in adverse side effects. This study was conducted to examine whether HS-1793, a novel resveratrol analogue free from the restriction of metabolic instability and the high dose requirement of resveratrol, induces a protective effect against radiation-induced DNA damage. HS-1793 effectively scavenged free radicals and inhibited radiation-induced plasmid DNA strand breaks in an in vitro assay. HS-1793 significantly decreased reactive oxygen species and cellular DNA damage in 2 Gy-irradiated Chinese hamster ovary (CHO)-K1 cells. In addition, HS-1793 dose-dependently reduced the levels of phosphorylated H2AX in irradiated CHO-K1 cells. These results indicate that HS-1793 has chemical radioprotective activity. Glutathione levels and superoxide dismutase activity in irradiated CHO-K1 cells increased significantly following HS-1793 treatment. The enhanced biological anti-oxidant activity and chemical radioprotective activity of HS-1793 maintained survival of irradiated CHO-K1 cells in a clonogenic assay. Therefore, HS-1793 may be of value as a radioprotector to protect healthy tissue surrounding tumor cells during radiotherapy to obtain better tumor control with a higher dose. PMID- 24403522 TI - B-cell-specific peptides of leptospira interrogans LigA for diagnosis of patients with acute leptospirosis. AB - Leptospirosis is a reemerging infectious disease that is underdiagnosed and under recognized due to low-sensitivity and cumbersome serological tests. Rapid reliable alternative tests are needed for early diagnosis of the disease. Considering the importance of the pathogenesis-associated leptospiral LigA protein expressed in vivo, we have evaluated its application in the diagnosis of the acute form of leptospirosis. The C-terminal coding sequence of ligA (ligA-C) was cloned into pET15b and expressed in Escherichia coli. Furthermore, the B-cell specific epitopes were predicted and were synthesized as peptides for evaluation along with recombinant LigA-C. Epitope 1 (VVIENTPGK), with a VaxiJen score of 1.3782, and epitope 2 (TALSVGSSK), with a score of 1.2767, were utilized. A total of 140 serum samples collected from leptospirosis cases during the acute stage of the disease and 138 serum samples collected from normal healthy controls were utilized for evaluation. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated for the recombinant LigA-C-specific IgM enzyme-linked immunosorbent assay (ELISA) and were found to be 92.1%, 97.7%, 92.8%, and 97.5%, respectively. Epitopes 1 and 2 used in the study showed 5.1 to 5.8% increased sensitivity over recombinant LigA-C in single and combination assays for IgM antibody detection. These findings suggest that these peptides may be potential candidates for the early diagnosis of leptospirosis. PMID- 24403523 TI - Virus-like particle vaccine confers protection against a lethal newcastle disease virus challenge in chickens and allows a strategy of differentiating infected from vaccinated animals. AB - In this study, we developed Newcastle disease virus (NDV) virus-like particles (VLPs) expressing NDV fusion (F) protein along with influenza virus matrix 1 (M1) protein using the insect cell expression system. Specific-pathogen-free chickens were immunized with oil emulsion NDV VLP vaccines containing increasing dosages of VLPs (0.4, 2, 10, or 50 MUg of VLPs/0.5-ml dose). Three weeks after immunization, the immunogenicity of the NDV VLP vaccines was determined using a commercial enzyme-linked immunosorbent assay (ELISA) kit, and a lethal challenge using a highly virulent NDV strain was performed to evaluate the protective efficacy of the NDV VLP vaccines. NDV VLP vaccines elicited anti-NDV antibodies and provided protection against a lethal challenge in a dose-dependent manner. Although the VLP vaccines containing 0.4 and 2 MUg of VLPs failed to achieve high levels of protection, a single immunization with NDV VLP vaccine containing 10 or 50 MUg could fully protect chickens from a lethal challenge and greatly reduced challenge virus shedding. Furthermore, we could easily differentiate infected from vaccinated animals (DIVA) using the hemagglutination inhibition (HI) test. These results strongly suggest that utilization of NDV VLP vaccine in poultry species may be a promising strategy for the better control of NDV. PMID- 24403524 TI - Comparison of four commercial one-dose porcine circovirus type 2 (PCV2) vaccines administered to pigs challenged with PCV2 and porcine reproductive and respiratory syndrome virus at 17 weeks postvaccination to control porcine respiratory disease complex under Korean field conditions. AB - Under Korean field conditions, coinfection with porcine circovirus type 2 (PCV2) and porcine reproductive and respiratory syndrome virus (PRRSV) is most commonly observed in porcine respiratory disease complex (PRDC). Despite the wide use of PCV2 vaccination, PRDC remains a serious respiratory problem. Thus, the objective of this study was to determine and compare the efficacy of 4 one-dose PCV2 vaccines on 3-week-old pigs with an experimental PCV2-PRRSV challenge at 17 weeks postvaccination. Regardless of which commercial PCV2 vaccine was used, the vaccination of piglets at 3 weeks of age was efficacious against cochallenge of PCV2 and PRRSV, on the basis of growth performance and PCV2-associated lesions. However, the inactivated chimeric PCV1-2 and the PCV2 vaccines induced higher PCV2-specific neutralizing antibody (NA) titers and PCV2-specific gamma interferon-secreting cells and lower PCV2 viremia levels than the two PCV2 subunit vaccines. The vaccination of piglets against PCV2 at 3 weeks of age was effective in reducing PCV2 viremia and PCV2-associated lesions during the finishing period, which is an age at which pigs are frequently affected by PRDC caused by coinfection with PCV2 and PRRSV under Korean field conditions. PMID- 24403526 TI - Development of a luciferase immunoprecipitation system assay to detect IgG antibodies against human respiratory syncytial virus nucleoprotein. AB - The nucleoprotein of respiratory syncytial virus (RSV-N) is immunogenic and elicits an IgG response following infection. The RSV-N gene was cloned into a mammalian expression vector, pREN2, and the expressed luciferase-tagged protein (Ruc-N) detected anti-RSV-N-specific IgG antibodies using a high-throughput immunoprecipitation method (the luciferase immunoprecipitation system [LIPS] N(RSV) assay). The specificity of the assay was evaluated using monoclonal antibodies (MAbs) and monospecific pre- and postimmunization rabbit antisera. Blood serum samples from chimpanzees and humans with proven/probable RSV infection were also tested. The pre- and postimmunization serum samples from rabbits given human metapneumovirus (HMPV) or measles virus were negative when tested by the LIPS-N(RSV) assay, while antisera obtained after immunization with either the RSV-A or RSV-B strain gave positive signals in a dose-dependent manner. RSV-N MAb 858-3 gave a positive signal in the LIPS-N(RSV) assay, while MAbs against other paramyxovirus nucleoproteins or RSV-F or RSV-G did not. Serum samples from chimpanzees simultaneously immunized with vaccinia-RSV-F and vaccinia-RSV-G recombinant viruses were negative in the LIPS-N(RSV) assay; however, anti-RSV-N IgG responses were detected following subsequent RSV challenge. Seven of the 12 infants who were seronegative at 9 months of age had detectable anti-RSV-N antibodies when they were retested at 15 to 18 months of age. The LIPS-N(RSV) assay detects specific anti-RSV-N IgG responses that may be used as a biomarker of RSV infection. PMID- 24403525 TI - Performance of a redesigned HIV Selectest enzyme-linked immunosorbent assay optimized to minimize vaccine-induced seropositivity in HIV vaccine trial participants. AB - Vaccine-induced seropositivity (VISP) or seroreactivity (VISR), defined as the reaction of antibodies elicited by HIV vaccines with antigens used in HIV diagnostic immunoassays, can result in reactive assay results for vaccinated but uninfected individuals, with subsequent misclassification of their infection status. The eventual licensure of a vaccine will magnify this issue and calls for the development of mitigating solutions in advance. An immunoassay that discriminates between antibodies elicited by vaccine antigens and those elicited by infection has been developed to address this laboratory testing need. The HIV Selectest is based on consensus and clade-specific HIV peptides that are omitted in many HIV vaccine constructs. The assay was redesigned to enhance performance across worldwide clades and to simplify routine use via a standard kit format. The redesigned assay was evaluated with sera from vaccine trial participants, HIV infected and uninfected individuals, and healthy controls. The HIV Selectest exhibited specificities of 99.5% with sera from uninfected recipients of 6 different HIV vaccines and 100% with sera from normal donors, while detecting HIV 1 infections, including intercurrent infections, with 95 to 100% sensitivity depending on the clade, with the highest sensitivities for clades A and C. HIV Selectest sensitivity decreased in very early seroconversion specimens, which possibly explains the slightly lower sensitivity observed for asymptomatic blood donors than for clinical HIV cases. Thus, the HIV Selectest provides a new laboratory tool for use in vaccine settings to distinguish the immune response to HIV vaccine antigens from that due to true infection. PMID- 24403527 TI - Development and preclinical evaluation of a trivalent, formalin-inactivated Shigella whole-cell vaccine. AB - Studies were undertaken to manufacture a multivalent Shigella inactivated whole cell vaccine that is safe, effective, and inexpensive. By using several formalin concentrations, temperatures, and incubation periods, an optimized set of inactivation conditions was established for Shigella flexneri 2a, S. sonnei, and S. flexneri 3a to produce inactivated whole cells expressing a full repertoire of Ipa proteins and lipopolysaccharide (LPS). The inactivation conditions selected were treatment with 0.2% formalin (S. flexneri 2a and 3a) or 0.6% formalin (S. sonnei) for 48 h at 25 degrees C. Vaccine formulations prepared under different inactivation conditions, in different doses (10E5, 10E7, and 10E9 cells), and with or without the inclusion of double-mutant heat-labile toxin (dmLT) were evaluated in mice. Two intranasal immunizations with >=10E7 inactivated whole cells resulted in high levels of anti-Invaplex and moderate levels of LPS specific IgG and IgA in serum and in lung and intestinal wash samples. Addition of dmLT to the vaccine formulations did not significantly enhance humoral immunogenicity. Minimal humoral responses for IpaB, IpaC, or IpaD were detected after immunization with inactivated whole Shigella cells regardless of the vaccine inactivation conditions. In guinea pigs, monovalent formulations of S. flexneri 2a of 3a or S. sonnei consisting of 10E8, 10E9, or 10E10 cells were protective in a keratoconjunctivitis assay. A trivalent formulation provided protection against all three serotypes (S. flexneri 2a, P = 0.018; S. flexneri 3a, P = 0.04; S. sonnei, P < 0.0001). The inactivated Shigella whole-cell vaccine approach incorporates an uncomplicated manufacturing process that is compatible with multivalency and the future development of a broadly protective Shigella vaccine. PMID- 24403528 TI - Lifestyle factors and the risk of a second breast cancer after ductal carcinoma in situ. AB - BACKGROUND: Little information exists on lifestyle factors that affect prognosis after treatment for ductal carcinoma in situ (DCIS) breast cancer. Improved understanding of the role of lifestyle factors is important to survivors wishing to reduce their risk of a second breast cancer diagnosis. METHODS: We examined the association between body mass index (BMI), physical activity, and alcohol intake, and risk of a second breast cancer diagnosis among 1,925 DCIS survivors in the Wisconsin In Situ Cohort. Exposures were self-reported during biennial patient interviews. Second breast cancer diagnoses were validated via pathology report. Cox proportional hazards regression was used to estimate the association between prediagnosis, postdiagnosis, and change in exposure levels and the risk of a second diagnosis, with adjustment for patient, tumor, and treatment factors. RESULTS: Over a mean of 6.7 years of follow-up, 162 second breast cancer diagnoses were reported, including 57 invasive events, 60 in situ events, and 45 diagnoses of unknown stage. A significant trend of increasing risk of a second diagnosis was found over increasing categories of postdiagnosis alcohol intake (Ptrend = 0.02). Among premenopausal women, increased prediagnosis BMI was associated with a reduced risk of a second diagnosis (HR = 0.93; 95% confidence interval, 0.88-0.99). CONCLUSION: DCIS survivors may reduce their risk of a second diagnosis by reducing postdiagnosis alcohol consumption. IMPACT: The population of DCIS survivors is projected to surpass one million by the year 2016. Our results suggest that these women may be able to reduce their risk of a second diagnosis through moderation of alcohol consumption. PMID- 24403529 TI - Smoking, lower gastrointestinal endoscopy, and risk for colorectal cancer. AB - BACKGROUND: Lower gastrointestinal endoscopy can decrease colorectal cancer risk strongly through detection and removal of adenomas. Thus, we aimed to investigate whether utilization of lower gastrointestinal endoscopy modifies the effect of lifetime smoking exposure on colorectal cancer risk in a population-based case control study. METHODS: In this study from Southern Germany including 2,916 patients with colorectal cancer and 3,044 controls, information about lifetime smoking and other risk factors was obtained from standardized interviews. Self reported endoscopies were validated by medical records. Multivariate logistic regression was performed to investigate associations of smoking with colorectal cancer risk after stratification by utilization of lower gastrointestinal endoscopy in the preceding 10 years. RESULTS: Median age of patients and controls was 69 and 70 years, respectively. Former regular smoking was associated with increased colorectal cancer risk in the group with no previous endoscopy [adjusted OR, 1.50; 95% confidence interval (CI), 1.28-1.75], whereas no association was found in the group with preceding endoscopy (OR, 1.05; CI, 0.83 1.33; P for interaction <0.01). Lower gastrointestinal endoscopy did not modify the association of smoking and colorectal cancer risk among current smokers and among the more recent quitters. CONCLUSIONS: Our results suggest that the increased risk of colorectal cancer among former regular smokers is essentially overcome by detection and removal of adenomas at lower gastrointestinal endoscopy. However, risk of colorectal cancer was increased if smoking was continued into higher adult age. IMPACT: The strong protective effect of lower gastrointestinal endoscopy may be compromised by continued smoking. Smoking cessation may increase the efficacy of lower gastrointestinal endoscopy. PMID- 24403530 TI - Dual-specificity phosphatase 14 (DUSP14/MKP6) negatively regulates TCR signaling by inhibiting TAB1 activation. AB - T cell activation is dependent upon phosphorylation of MAPKs, which play a critical role in the regulation of immune responses. Dual-specificity phosphatase 14 (DUSP14; also known as MKP6) is classified as a MAPK phosphatase. The in vivo functions of DUSP14 remain unclear. Thus, we generated DUSP14-deficient mice and characterized the roles of DUSP14 in T cell activation and immune responses. DUSP14 deficiency in T cells resulted in enhanced T cell proliferation and increased cytokine production upon T cell activation. DUSP14 directly interacted with TGF-beta-activated kinase 1 (TAK1)-binding protein 1 (TAB1) and dephosphorylated TAB1 at Ser(438), leading to TAB1-TAK1 complex inactivation in T cells. The phosphorylation levels of the TAB1-TAK1 complex and its downstream molecules, including JNK and IkappaB kinase, were enhanced in DUSP14-deficient T cells upon stimulation. The enhanced JNK and IkappaB kinase activation in DUSP14 deficient T cells was attenuated by TAB1 short hairpin RNA knockdown. Consistent with that, DUSP14-deficient mice exhibited enhanced immune responses and were more susceptible to experimental autoimmune encephalomyelitis induction. Thus, DUSP14 negatively regulates TCR signaling and immune responses by inhibiting TAB1 activation. PMID- 24403531 TI - Mutagenesis of Ly49B reveals key structural elements required for promiscuous binding to MHC class I molecules and new insights into the molecular evolution of Ly49s. AB - Ly49B is a potentially important immunoregulator expressed on mouse myeloid cells, and it is thus an unusual member of the wider Ly49 family whose members are ordinarily found on NK cells. Ly49B displays substantial sequence divergence from other Ly49s and in particular shares virtually no amino acid sequence identity with the residues that have been reported to bind to MHC class I (cI) ligands in other Ly49s. Despite this, we show in this study that the BALB/c, but not the C57, isoform of Ly49B displays promiscuous cI binding. Binding was not significantly affected by inactivation of any of the four predicted N-linked glycosylation sites of Ly49B, nor was it affected by removal of the unique 20-aa C-terminal extension found in Ly49B. However, transfer of these C-terminal 20 aa to Ly49A inhibited cI binding, as did the addition of a hemagglutinin tag to the C terminus of Ly49B, demonstrating unexpectedly that the C-terminal region of Ly49s can play a significant role in ligand binding. Systematic exchange of BALB/c and C57 residues revealed that Trp(166), Asn(167), and Cys(251) are of major importance for cI binding in Ly49B. These residues are highly conserved in the Ly49 family. Remarkably, however, Ly49B(BALB) variants that have C57 residues at positions 166 or 167, and are unable to bind cI multimers, regain substantial cI binding when amino acid changes are made at distal positions, providing an explanation of how highly divergent Ly49s that retain the ability to bind cI molecules might have evolved. PMID- 24403533 TI - IDO-independent suppression of T cell effector function by IFN-gamma-licensed human mesenchymal stromal cells. AB - Human bone marrow-derived mesenchymal stromal cells (MSCs) inhibit proliferation of activated T cells, and IFN-gamma plays an important role in this process. This IFN-gamma-licensed veto property is IDO-dependent. To further decipher the mechanistic underpinnings of MSC veto function on T cells, we investigated the effect of MSCs and IFN-gamma-licensed MSCs on T cell effector function as assayed by cytokine secretion of T cells. Although MSCs and IFN-gamma-licensed MSCs inhibit T cell proliferation, only IFN-gamma-licensed MSCs significantly inhibit Th1 cytokine (IFN-gamma, TNF-alpha, and IL-2) production by T cells. Additionally, IFN-gamma-licensed MSCs inhibit T cell degranulation as well as single, double, and triple cytokine-producing T cells. Although IFN-gamma licensed MSCs upregulate their IDO activity, we found that MSC IDO catalytic function is dispensable with regard to MSC-driven inhibition of T cell effector function. Novel flow cytometry based functional screening of MSC-expressed, IFN gamma-licensed inhibitory molecules identified B7H1 and B7DC/PD1 pathways as essential effectors in blocking T cell function. Small interfering RNA-mediated blocking of B7H1 and B7DC reverses the inhibitory potential of IFN-gamma-licensed MSCs on T cell effector function. Mechanistic analysis revealed that clustering of MHC and coinhibitory molecules are indispensable for the inhibitory effect of IFN-gamma MSCs. Although exogenous IL-2 reverses B7H1-Ig-mediated inhibition of T cell proliferation, it does not affect the veto function of IFN-gamma MSCs on both T cell proliferation and effector function. Our results reveal a new immunosuppressive property of IFN-gamma-licensed MSCs that inhibits T cell effector function independent of IDO but through the ligands for PD1. PMID- 24403532 TI - Hydrogen sulfide [corrected] increases survival during sepsis: protective effect of CHOP inhibition. AB - Sepsis is a major cause of mortality, and dysregulation of the immune response plays a central role in this syndrome. H2S, a recently discovered gaso transmitter, is endogenously generated by many cell types, regulating a number of physiologic processes and pathophysiologic conditions. We report that H2S increased survival after experimental sepsis induced by cecal ligation and puncture (CLP) in mice. Exogenous H2S decreased the systemic inflammatory response, reduced apoptosis in the spleen, and accelerated bacterial eradication. We found that C/EBP homologous protein 10 (CHOP), a mediator of the endoplasmic reticulum stress response, was elevated in several organs after CLP, and its expression was inhibited by H2S treatment. Using CHOP-knockout (KO) mice, we demonstrated for the first time, to our knowledge, that genetic deletion of Chop increased survival after LPS injection or CLP. CHOP-KO mice displayed diminished splenic caspase-3 activation and apoptosis, decreased cytokine production, and augmented bacterial clearance. Furthermore, septic CHOP-KO mice treated with H2S showed no additive survival benefit compared with septic CHOP-KO mice. Finally, we showed that H2S inhibited CHOP expression in macrophages by a mechanism involving Nrf2 activation. In conclusion, our findings show a protective effect of H2S treatment afforded, at least partially, by inhibition of CHOP expression. The data reveal a major negative role for the transcription factor CHOP in overall survival during sepsis and suggest a new target for clinical intervention, as well potential strategies for treatment. PMID- 24403534 TI - The aryl hydrocarbon receptor promotes IL-10 production by NK cells. AB - The cytokine IL-10 has an important role in limiting inflammation in many settings, including toxoplasmosis. In the present studies, an IL-10 reporter mouse was used to identify the sources of this cytokine following challenge with Toxoplasma gondii. During infection, multiple cell types expressed the IL-10 reporter but NK cells were a major early source of this cytokine. These IL-10 reporter(+) NK cells expressed high levels of the IL-12 target genes T-bet, KLRG1, and IFN-gamma, and IL-12 depletion abrogated reporter expression. However, IL-12 signaling alone was not sufficient to promote NK cell IL-10, and activation of the aryl hydrocarbon receptor (AHR) was also required for maximal IL-10 production. NK cells basally expressed the AHR, relevant chaperone proteins, and the AHR nuclear translocator, which heterodimerizes with the AHR to form a competent transcription factor. In vitro studies revealed that IL-12 stimulation increased NK cell AHR levels, and the AHR and AHR nuclear translocator were required for optimal production of IL-10. Additionally, NK cells isolated from T. gondii-infected Ahr(-/-) mice had impaired expression of IL-10, which was associated with increased resistance to this infection. Taken together, these data identify the AHR as a critical cofactor involved in NK cell production of IL 10. PMID- 24403536 TI - Maternal prefrontal cortex activation by newborn infant odors. AB - Mothers are attracted by infant cues of a variety of different modalities. To clarify the possible neural mechanisms underlying maternal attraction to infant odor cues, we used near-infrared spectroscopy to examine prefrontal cortex (PFC) activity during odor detection tasks in which 19 mothers and 19 nulliparous females (nonmothers) were presented with infant or adult male odors. They were instructed to make a judgment about whether they smelled an odor during each task. We estimated the PFC activity by measuring the relative oxyhemoglobin (oxyHb) concentrations. The results showed that while detecting the infant odors, bilateral PFC activities were increased in mothers but not in nonmothers. In contrast, adult male odors activated the PFC similarly in mothers and nonmothers. These findings suggest that maternal activation of the PFC in response to infant odors explains a part of the neural mechanisms for maternal attraction to infant odors. PMID- 24403535 TI - Autoimmune vitiligo does not require the ongoing priming of naive CD8 T cells for disease progression or associated protection against melanoma. AB - Vitiligo is a CD8 T cell-mediated autoimmune disease that has been shown to promote the longevity of memory T cell responses to melanoma. However, mechanisms whereby melanocyte/melanoma Ag-specific T cell responses are perpetuated in the context of vitiligo are not well understood. These studies investigate the possible phenomenon of naive T cell priming in hosts with melanoma-initiated, self-perpetuating, autoimmune vitiligo. Using naive pmel (gp10025-33-specific) transgenic CD8 T cells, we demonstrate that autoimmune melanocyte destruction induces naive T cell proliferation in skin-draining lymph nodes, in an Ag dependent fashion. These pmel T cells upregulate expression of CD44, P-selectin ligand, and granzyme B. However, they do not downregulate CD62L, nor do they acquire the ability to produce IFN-gamma, indicating a lack of functional priming. Accordingly, adult thymectomized mice exhibit no reduction in the severity or kinetics of depigmentation or long-lived protection against melanoma, indicating that the continual priming of naive T cells is not required for vitiligo or its associated antitumor immunity. Despite this, depletion of CD4 T cells during the course of vitiligo rescues the priming of naive pmel T cells that are capable of producing IFN-gamma and persisting as memory, suggesting an ongoing and dominant mechanism of suppression by regulatory T cells. This work reveals the complex regulation of self-reactive CD8 T cells in vitiligo and demonstrates the overall poorly immunogenic nature of this autoimmune disease setting. PMID- 24403537 TI - Regional heritability advanced complex trait analysis for GPU and traditional parallel architectures. AB - MOTIVATION: Quantification of the contribution of genetic variation to phenotypic variation for complex traits becomes increasingly computationally demanding with increasing numbers of single-nucleotide polymorphisms and individuals. To meet the challenges in making feasible large-scale studies, we present the REgional heritability advanced complex trait analysis software. Adapted from advanced complex trait analysis (and, in turn, genome-wide complex trait analysis), it is tailored to exploit the parallelism present in modern traditional and graphics processing unit (GPU)-accelerated machines, from workstations to supercomputers. RESULTS: We adapt the genetic relationship matrix estimation algorithm to remove limitations on memory, allowing the analysis of large datasets. We build on this to develop a version of the code able to efficiently exploit GPU-accelerated systems for both the genetic relationship matrix and REstricted maximum likelihood (REML) parts of the analysis, offering substantial speedup over the traditional central processing unit version. We develop the ability to analyze multiple small regions of the genome across multiple compute nodes in parallel, following the 'regional heritability' approach. We demonstrate the new software using 1024 GPUs in parallel on one of the world's fastest supercomputers. AVAILABILITY: The code is freely available at http://www.epcc.ed.ac.uk/software products CONTACT: a.gray@ed.ac.uk. PMID- 24403538 TI - Allerdictor: fast allergen prediction using text classification techniques. AB - MOTIVATION: Accurately identifying and eliminating allergens from biotechnology derived products are important for human health. From a biomedical research perspective, it is also important to identify allergens in sequenced genomes. Many allergen prediction tools have been developed during the past years. Although these tools have achieved certain levels of specificity, when applied to large-scale allergen discovery (e.g. at a whole-genome scale), they still yield many false positives and thus low precision (even at low recall) due to the extreme skewness of the data (allergens are rare). Moreover, the most accurate tools are relatively slow because they use protein sequence alignment to build feature vectors for allergen classifiers. Additionally, only web server implementations of the current allergen prediction tools are publicly available and are without the capability of large batch submission. These weaknesses make large-scale allergen discovery ineffective and inefficient in the public domain. RESULTS: We developed Allerdictor, a fast and accurate sequence-based allergen prediction tool that models protein sequences as text documents and uses support vector machine in text classification for allergen prediction. Test results on multiple highly skewed datasets demonstrated that Allerdictor predicted allergens with high precision over high recall at fast speed. For example, Allerdictor only took ~6 min on a single core PC to scan a whole Swiss-Prot database of ~540 000 sequences and identified <1% of them as allergens. AVAILABILITY AND IMPLEMENTATION: Allerdictor is implemented in Python and available as standalone and web server versions at http://allerdictor.vbi.vt.edu CONTACT: lawrence@vbi.vt.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 24403540 TI - Integrative analysis of histone ChIP-seq and transcription data using Bayesian mixture models. AB - MOTIVATION: Histone modifications are a key epigenetic mechanism to activate or repress the transcription of genes. Datasets of matched transcription data and histone modification data obtained by ChIP-seq exist, but methods for integrative analysis of both data types are still rare. Here, we present a novel bioinformatics approach to detect genes that show different transcript abundances between two conditions putatively caused by alterations in histone modification. RESULTS: We introduce a correlation measure for integrative analysis of ChIP-seq and gene transcription data measured by RNA sequencing or microarrays and demonstrate that a proper normalization of ChIP-seq data is crucial. We suggest applying Bayesian mixture models of different types of distributions to further study the distribution of the correlation measure. The implicit classification of the mixture models is used to detect genes with differences between two conditions in both gene transcription and histone modification. The method is applied to different datasets, and its superiority to a naive separate analysis of both data types is demonstrated. AVAILABILITY AND IMPLEMENTATION: R/Bioconductor package epigenomix. CONTACT: h.klein@uni-muenster.de Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 24403539 TI - Correlations between predicted protein disorder and post-translational modifications in plants. AB - MOTIVATION: Protein structural research in plants lags behind that in animal and bacterial species. This lag concerns both the structural analysis of individual proteins and the proteome-wide characterization of structure-related properties. Until now, no systematic study concerning the relationships between protein disorder and multiple post-translational modifications (PTMs) in plants has been presented. RESULTS: In this work, we calculated the global degree of intrinsic disorder in the complete proteomes of eight typical monocotyledonous and dicotyledonous plant species. We further predicted multiple sites for phosphorylation, glycosylation, acetylation and methylation and examined the correlations of protein disorder with the presence of the predicted PTM sites. It was found that phosphorylation, acetylation and O-glycosylation displayed a clear preference for occurrence in disordered regions of plant proteins. In contrast, methylation tended to avoid disordered sequence, whereas N-glycosylation did not show a universal structural preference in monocotyledonous and dicotyledonous plants. In addition, the analysis performed revealed significant differences between the integral characteristics of monocot and dicot proteomes. They included elevated disorder degree, increased rate of O-glycosylation and R methylation, decreased rate of N-glycosylation, K-acetylation and K-methylation in monocotyledonous plant species, as compared with dicotyledonous species. Altogether, our study provides the most compelling evidence so far for the connection between protein disorder and multiple PTMs in plants. CONTACT: tokmak@phoenix.kobe-u.ac.jp or tetsuya.sakurai@riken.jp Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 24403542 TI - The Infectious Diseases Society of America emerging infections network: bridging the gap between clinical infectious diseases and public health. AB - In 1995, the Centers for Disease Control and Prevention granted a Cooperative Agreement Program award to the Infectious Diseases Society of America to develop a provider-based emerging infections sentinel network, the Emerging Infections Network (EIN). Over the past 17 years, the EIN has evolved into a flexible, nationwide network with membership representing a broad cross-section of infectious disease physicians. The EIN has an active electronic mail conference (listserv) that facilitates communication among infectious disease providers and the public health community, and also sends members periodic queries (short surveys on infectious disease topics) that have addressed numerous topics relevant to both clinical infectious diseases and public health practice. The article reviews how the various functions of EIN contribute to clinical care and public health, identifies opportunities to further link clinical medicine and public health, and describes future directions for the EIN. PMID- 24403543 TI - Dengue shock syndrome or dehydration? The importance of considering clinical severity when classifying patients with dengue. PMID- 24403541 TI - Prediction of therapeutic microRNA based on the human metabolic network. AB - MOTIVATION: MicroRNA (miRNA) expression has been found to be deregulated in human cancer, contributing, in part, to the interest of the research community in using miRNAs as alternative therapeutic targets. Although miRNAs could be potential targets, identifying which miRNAs to target for a particular type of cancer has been difficult due to the limited knowledge on their regulatory roles in cancer. We address this challenge by integrating miRNA-target prediction, metabolic modeling and context-specific gene expression data to predict therapeutic miRNAs that could reduce the growth of cancer. RESULTS: We developed a novel approach to simulate a condition-specific metabolic system for human hepatocellular carcinoma (HCC) wherein overexpression of each miRNA was simulated to predict their ability to reduce cancer cell growth. Our approach achieved >80% accuracy in predicting the miRNAs that could suppress metastasis and progression of liver cancer based on various experimental evidences in the literature. This condition-specific metabolic system provides a framework to explore the mechanisms by which miRNAs modulate metabolic functions to affect cancer growth. To the best of our knowledge, this is the first computational approach implemented to predict therapeutic miRNAs for human cancer based on their functional role in cancer metabolism. Analyzing the metabolic functions altered by the miRNA-identified metabolic genes essential for cell growth and proliferation that are targeted by the miRNAs. AVAILABILITY AND IMPLEMENTATION: See supplementary protocols and http://www.egr.msu.edu/changroup/Protocols%20Index.html CONTACT: krischan@egr.msu.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 24403544 TI - Long-term persistence of immunity and B-cell memory following Haemophilus influenzae type B conjugate vaccination in early childhood and response to booster. AB - BACKGROUND: Protection against Haemophilus influenzae type b (Hib), a rapidly invading encapsulated bacteria, is dependent on maintenance of an adequate level of serum antibody through early childhood. In many countries, Hib vaccine booster doses have been implemented after infant immunization to sustain immunity. We investigated the long-term persistence of antibody and immunological memory in primary-school children following infant (with or without booster) Hib vaccination. METHODS: Anti-polyribosylribitol phosphate (PRP) immunoglobulin G (IgG) concentration and the frequency of circulating Hib-specific memory B cells were measured before a booster of a Hib-serogroup C meningococcal (MenC) conjugate vaccine and again 1 week, 1 month, and 1 year after the booster in 250 healthy children aged 6-12 years in an open-label phase 4 clinical study. RESULTS: Six to 12 years following infant priming with 3 doses of Hib conjugate vaccine, anti-PRP IgG geometric mean concentrations were 3.11 ug/mL and 0.71 ug/mL and proportions with anti-PRP IgG >=1.0 ug/mL were 79% and 43% in children who had or had not, respectively, received a fourth Hib conjugate vaccine dose (mean age, 3.9 years). Higher baseline and post-Hib-MenC booster responses (anti PRP IgG and memory B cells) were found in younger children and in those who had received a fourth Hib dose. CONCLUSIONS: Sustained Hib conjugate vaccine-induced immunity in children is dependent on time since infant priming and receipt of a booster. Understanding the relationship between humoral and cellular immunity following immunization with conjugate vaccines may direct vaccine design and boosting strategies to sustain individual and population immunity against encapsulated bacteria in early childhood. Clinical Trials Registration ISRCTN728588998. PMID- 24403545 TI - Reply to Thomas et al. PMID- 24403546 TI - In vivo chronic and in vitro acute effects of di(2-ethylhexyl) phthalate on pseudopregnant rabbit corpora lutea: possible involvement of peroxisome proliferator-activated receptor gamma. AB - The in vivo chronic and in vitro acute effects of di(2-ethylhexyl) phthalate (DEHP) on the reproductive function of peroxisome proliferator-activated receptor gamma (PPARG) were studied in rabbit corpora lutea (CL) at early stage (Day 4), midstage (Day 9), and late stage (Day 13) of pseudopregnancy. The rabbits were in vivo treated with DEHP for 15 days before induction of pseudopregnancy. Immunohistochemistry provided evidence for the presence of PPARG, prostaglandin endoperoxide synthase 1 (PTGS1), PTGS2, prostaglandin E2-9-ketoreductase (PGE2-9 K), and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) in all the luteal cells during pseudopregnancy. DEHP decreased progesterone plasma levels and CL production in all the luteal stages and PPARG protein and gene expressions in early and mid-CL. DEHP in vivo treatment reduced PTGS2 protein expression at the late stage and that of PGE2-9-K at all the stages, whereas PTGS1 and 3beta-HSD were not affected. In in vitro cultured CL, DEHP alone, the PPARG antagonist T0070907 alone, or DEHP plus T0070907 diminished progesterone production and 3beta-HSD activity and increased PGF2alpha and PTGS2 in early and mid-CL, whereas DEHP plus the PPARG agonist 15d-PGJ2 did not affect these hormones and enzymes. All the in vitro treatments did not affect PGE2 secretion as well as PTGS1 and PGE2-9-K enzymatic activities in all the luteal stages. These results provided evidence that DEHP favors functional luteolysis of pseudopregnant rabbit CL, with a mechanism that seems to involve PPARG expression down-regulation, an increase of PTGS2 activity and prostaglandin F2alpha secretion, 3beta-HSD down-regulation, and decrease in progesterone. PMID- 24403547 TI - Spermatogenic cycle length and sperm production in the freshwater turtle Kinosternon scorpioides. AB - Kinosternon scorpioides is a Brazilian freshwater turtle that belongs to the class Reptilia, encompassing almost 10,000 species. Nevertheless, very little is known about the testicular quantitative parameters, particularly those related to spermatogenesis, in this vertebrate class. Our main objectives were to investigate in detail the structure and function of the testis in K. scorpioides, particularly the aspects related to spermatogenic cycle length and Sertoli cell (SC) and spermatogenic efficiencies. Nine sexually mature turtles were examined, and intraperitoneal bromodeoxyuridine injections were administered to estimate duration of spermatogenesis. Based on the acrosome development in spermatids and the overall germ cell associations, 10 stages of the seminiferous epithelium cycle were characterized. Similar to birds, humans, and some primate species, several stages were observed per seminiferous tubule cross-sections. One spermatogenic cycle and the entire spermatogenic process lasted, respectively, 12 and 53 days. The SC efficiency (number of round spermatids per SC) and daily sperm production per gram of testis were, respectively, 20 and 40 million spermatids. As established for mammals, our findings suggest that SC efficiency is also a critical determinant of sperm production in reptiles. To our knowledge, this is the first study to investigate the kinetics of spermatogenesis and testis function in any reptilian species. Besides allowing a better understanding of reproductive biology in reptiles, these data will be useful in comparative studies. Moreover, these results could provide the basis for investigations related to the evaluation of spermatogonial stem cell physiology niche in Kinosternon scorpioides. PMID- 24403549 TI - Intersex gonad differentiation in cultured Russian (Acipenser gueldenstaedtii) and Siberian (Acipenser baerii) sturgeon. AB - Among sturgeons, the occurrence of individuals with gonads containing both testis and ovary components is considered pathological, and such fish are described as intersex individuals or intersexes. Intersexes are observed in both wild and cultured populations of sturgeon, usually at low frequencies. In the present study, intersex Russian (Acipenser gueldenstaedtii) and Siberian (Acipenser baerii) sturgeons constituted 30% of the studied populations. Macroscopically, intersex gonads were recognizable from 500 days posthatching (dph). Initially, gonads with predominantly male characteristics (testis-ova) were observed, but in older fish gonads with predominantly female traits (ova-testis) were more frequent. Using microscopic analysis, intersex gonads were discernible by 130-200 dph. Observations of intersex germinal epithelium development and analysis of sex distribution in the study populations indicated that feminization was occurring. Histological analysis revealed that differentiation of the germinal epithelium in such gonads was accompanied by various morphological alterations (transformations) that were described using quantitative and localization criteria. The most common type of transformations, massive subepithelial transformations, was manifested by the presence of abundant female germinal tissue located under the gonad surface epithelium in the developing testis. These transformations were identified in the early development stage (100-200 dph). In this type of transformation, differentiation of female germinal tissue at the gonad surface and male tissue at the mesorchium/mesovarium resulted in complete formation of both male and female germinal epithelia within the same gonad. PMID- 24403548 TI - The fatty acid beta-oxidation pathway is important for decidualization of endometrial stromal cells in both humans and mice. AB - Embryo implantation and development requires the endometrial stromal cells (ESCs) to undergo decidualization. This differentiation process requires glucose utilization, and blockade of the pentose phosphate pathway inhibits decidualization of ESCs both in vitro and in vivo. Glucose and fatty acids are energy substrates for many cell types, and fatty acid beta-oxidation is critical for embryo implantation. Here, we investigated whether beta-oxidation is required for decidualization of ESCs. As assessed by marker gene expression, decidualization of human primary ESCs was blocked by reducing activity of carnitine calmitoyltransferase I, the rate-limiting enzyme in beta-oxidation, either by short hairpin RNA-mediated silencing or by treatment with the inhibitor etomoxir. Ranolazine (RAN), a partial beta-oxidation inhibitor, blocked early decidualization of a human ESC line. However, decidualization resumed after several days, most likely due to a compensatory up-regulation of GLUT1 expression and an increase in glucose metabolism. Simultaneous inhibition of the beta oxidation pathway with RAN and the pentose phosphate pathway with glucosamine (GlcN) impaired in vitro decidualization of human ESCs more strongly than inhibition of either pathway alone. These findings were confirmed in murine ESCs in vitro, and exposure to RAN plus GlcN inhibited decidualization in vivo in a deciduoma model. Finally, intrauterine implantation of time-release RAN and GlcN pellets reduced pup number. Importantly, pup number returned to normal after the end of the pellet-active period. This work indicates that both fatty acids and glucose metabolism pathways are important for ESC decidualization, and suggests novel pathways to target for the design of future nonhormonal contraceptives. PMID- 24403550 TI - Toll-like receptor 11-initiated innate immune response in male mouse germ cells. AB - Toxoplasma gondii and uropathogenic Escherichia coli (UPEC) may infect the testis and impair testicular function. Mechanisms underlying testicular innate immune response to these two pathogens remain to be clarified. The present study examined the function of TLR11, which can be recognized by T. gondii-derived profilin and UPEC, in initiating innate immune response in male mouse germ cells. TLR11 is predominantly expressed in spermatids. Profilin and UPEC induced the expressions of different inflammatory cytokine profiles in the germ cells. In particular, profilin induced the expressions of macrophage chemotactic protein 1 (MCP1), interleukin 12 (IL12), and interferon gamma (IFNG) through nuclear factor KB (NFKB) activation. UPEC induced the expressions of MCP1, IL12, and IFNG, as well as tumor necrosis factor alpha (TNFA), IL6, and IFNB, through the activation of NFKB, IFN regulatory factor 3, and mitogen-activated protein kinases. Evidence showed that profilin induced the innate response in male germ cells through TLR11 signaling, and UPEC triggered the response through TLR11 and other TLR-signaling pathways. We also provided evidence that local injection of profilin or UPEC induces the innate immune response in the germ cells. Data describe TLR11 mediated innate immune function of male germ cells in response to T. gondii profilin and UPEC stimulations. This system may play a role in testicular defense against T. gondii and UPEC infections in mice. PMID- 24403551 TI - Kcne2 deletion creates a multisystem syndrome predisposing to sudden cardiac death. AB - BACKGROUND: Sudden cardiac death (SCD) is the leading global cause of mortality, exhibiting increased incidence in patients with diabetes mellitus. Ion channel gene perturbations provide a well-established ventricular arrhythmogenic substrate for SCD. However, most arrhythmia-susceptibility genes, including the KCNE2 K(+) channel beta subunit, are expressed in multiple tissues, suggesting potential multiplex SCD substrates. METHODS AND RESULTS: Using whole-transcript transcriptomics, we uncovered cardiac angiotensinogen upregulation and remodeling of cardiac angiotensinogen interaction networks in P21 Kcne2(-/-) mouse pups and adrenal remodeling consistent with metabolic syndrome in adult Kcne2(-/-) mice. This led to the discovery that Kcne2 disruption causes multiple acknowledged SCD substrates of extracardiac origin: diabetes mellitus, hypercholesterolemia, hyperkalemia, anemia, and elevated angiotensin II. Kcne2 deletion was also a prerequisite for aging-dependent QT prolongation, ventricular fibrillation and SCD immediately after transient ischemia, and fasting-dependent hypoglycemia, myocardial ischemia, and AV block. CONCLUSIONS: Disruption of a single, widely expressed arrhythmia-susceptibility gene can generate a multisystem syndrome comprising manifold electric and systemic substrates and triggers of SCD. This paradigm is expected to apply to other arrhythmia-susceptibility genes, the majority of which encode ubiquitously expressed ion channel subunits or regulatory proteins. PMID- 24403552 TI - Voriconazole metabolism, toxicity, and the effect of cytochrome P450 2C19 genotype. AB - BACKGROUND: Prospective evaluation of the antifungal drug, voriconazole, is needed to determine whether drug toxicity correlates with CYP2C19 genotype or serum concentrations of voriconazole or its metabolites. METHODS: We conducted a prospective study of 95 patients to determine voriconazole toxicity and its relationship to genotype and serum levels of voriconazole and its two metabolites. Efficacy was not evaluated because, in most cases, the drug was given for empirical or prophylactic therapy. RESULTS: Hallucinations occurred in 16 patients (16.8%), visual changes in 17 (17.9%), photosensitivity in 10 (10.5%), and hepatotoxicity in 6 (6.3%). There was no correlation between photosensitivity or hepatotoxicity and levels of voriconazole or metabolites. Patients with hallucinations had higher average voriconazole levels (4.5 vs 2.5 MUg/mL) but with extensive overlap. The recommended oral dose of 200 mg did not provide consistently detectable serum voriconazole levels in adults. CYP2C19 and CYP2C9 genotypes had a minor influence over levels, though the 4 patients homozygous for the 2C19*2 genotype had higher average levels for voriconazole (4.3 vs 2.5 MUg/mL) and lower N-oxide levels (1.6 vs 2.5 MUg/mL). CONCLUSIONS: CYP2C19 and 2C9 genotypes were not major determinants of voriconazole metabolism. No toxic serum level of voriconazole or its metabolites could be identified. PMID- 24403554 TI - miR-155 suppresses bacterial clearance in Pseudomonas aeruginosa-induced keratitis by targeting Rheb. AB - miR-155 (microRNA-155) is an important noncoding RNA in regulating host inflammatory responses. However, its regulatory role in ocular infection remains unclear. Our study first explored the function of miR-155 in Pseudomonas aeruginosa-induced keratitis, one of the most common sight-threatening ocular diseases. We found that miR-155 expression was enhanced in human and mouse corneas after P. aeruginosa infection and was mainly expressed in macrophages but not neutrophils. In vivo studies demonstrated that miR-155 knockout mice displayed more resistance to P. aeruginosa keratitis, with a higher inducible nitric oxide synthase level and a lower bacterial burden. More importantly, in vitro data indicated that miR-155 suppressed the macrophage-mediated bacterial phagocytosis and intracellular killing of P. aeruginosa by targeting Rheb (Ras homolog enriched in brain). To the best of our knowledge, this is the first study to explore the role of miR-155 in bacterial keratitis, which may provide a promising target for clinical treatment of P. aeruginosa keratitis and other infectious diseases. PMID- 24403553 TI - Intrauterine growth restriction caused by underlying congenital cytomegalovirus infection. AB - BACKGROUND: Human cytomegalovirus (HCMV) is the major viral etiology of congenital infection and birth defects. Fetal transmission is high (30%-40%) in primary maternal infection, and symptomatic babies have permanent neurological, hearing, and vision defects. Recurrent infection is infrequently transmitted (2%) and largely asymptomatic. Congenital infection is also associated with intrauterine growth restriction (IUGR). METHODS: To investigate possible underlying HCMV infection in cases of idiopathic IUGR, we studied maternal and cord sera and placentas from 19 pregnancies. Anti-HCMV antibodies, hypoxia related factors, and cmvIL-10 were measured in sera. Placental biopsy specimens were examined for viral DNA, expression of infected cell proteins, and pathology. RESULTS: Among 7 IUGR cases, we identified 2 primary and 3 recurrent HCMV infections. Virus replicated in glandular epithelium and lymphatic endothelium in the decidua, cytotrophoblasts, and smooth muscle cells in blood vessels of floating villi and the chorion. Large fibrinoids with avascular villi, edema, and inflammation were significantly increased. Detection of viral proteins in the amniotic epithelium indicated transmission in 2 cases of IUGR with primary infection and 3 asymptomatic recurrent infections. CONCLUSIONS: Congenital HCMV infection impairs placental development and functions and should be considered as an underlying cause of IUGR, regardless of virus transmission to the fetus. PMID- 24403555 TI - Chikungunya vaccine candidate is highly attenuated and protects nonhuman primates against telemetrically monitored disease following a single dose. AB - Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes major epidemics of rash, fever, and debilitating arthritis. Currently, there are no vaccines or antivirals available for prevention or treatment. We therefore generated 2 live-attenuated vaccine candidates based on the insertion of a picornavirus internal ribosome entry site (IRES) sequence into the genome of CHIKV. Vaccination of cynomolgus macaques with a single dose of either vaccine produced no signs of disease but was highly immunogenic. After challenge with a subcutaneous inoculation of wild-type CHIKV, both vaccine candidates prevented the development of detectable viremia. Protected animals also exhibited no significant changes in core body temperature or cardiovascular rhythm, whereas sham-vaccinated animals showed hyperthermia, followed by sustained hypothermia, as well as significant changes in heart rate. These CHIKV/IRES vaccine candidates appear to be safe and efficacious, supporting their strong potential as human vaccines to protect against CHIKV infection and reduce transmission and further spread. PMID- 24403556 TI - Impact of vancomycin on sarA-mediated biofilm formation: role in persistent endovascular infections due to methicillin-resistant Staphylococcus aureus. AB - BACKGROUND: Staphylococcus aureus is the most common cause of endovascular infections. The staphylococcal accessory regulator A locus (sarA) is a major virulence determinant that may potentially impact methicillin-resistant S. aureus (MRSA) persistence in such infections via its influence on biofilm formation. METHODS: Two healthcare-associated MRSA isolates from patients with persistent bacteremia and 2 prototypical community-acquired MRSA strains, as well as their respective isogenic sarA mutants, were studied for in vitro biofilm formation, fibronectin-binding capacity, autolysis, and protease and nuclease activities. These assays were done in the presence or absence of sub-minimum inhibitory concentrations (MICs) of vancomycin. In addition, these strain pairs were compared for intrinsic virulence and responses to vancomycin therapy in experimental infective endocarditis, a prototypical biofilm model. RESULTS: All sarA mutants displayed significantly reduced biofilm formation and binding to fibronectin but increased protease production in vitro, compared with their respective parental strains. Interestingly, exposure to sub-MICs of vancomycin significantly promoted biofilm formation and fibronectin-binding in parental strains but not in sarA mutants. In addition, all sarA mutants became exquisitely susceptible to vancomycin therapy, compared with their respective parental strains, in the infective endocarditis model. CONCLUSIONS: These observations suggest that sarA activation is important in persistent MRSA endovascular infection, potentially in the setting of biofilm formation. PMID- 24403558 TI - Antimicrobial effects promoting biofilm formation and persistent disease: the role of a DNA-binding regulator, SarA, in staphylococcal endocarditis. PMID- 24403559 TI - Massive mobilization of dendritic cells during influenza A virus subtype H5N1 infection of nonhuman primates. AB - Highly pathogenic avian influenza virus infection is characterized by a marked inflammatory response, but the impact of infection on dendritic cells (DCs) is unknown. We show that influenza A virus subtype H5N1 infection rapidly and profoundly impacts DCs in cynomolgus macaques, increasing the number of blood myeloid and plasmacytoid DCs by 16- and 60-fold, respectively. Infection was associated with recruitment, activation, and apoptosis of DCs in lung-draining lymph nodes; granulocyte and macrophage infiltration in lungs was also detected, together with expression of CXCL10. This degree of DC mobilization is unprecedented in viral infection and suggests a potential role for DCs in the pathogenesis of highly pathogenic avian influenza virus. PMID- 24403557 TI - Specificity and 6-month durability of immune responses induced by DNA and recombinant modified vaccinia Ankara vaccines expressing HIV-1 virus-like particles. AB - BACKGROUND: Clade B DNA and recombinant modified vaccinia Ankara (MVA) vaccines producing virus-like particles displaying trimeric membrane-bound envelope glycoprotein (Env) were tested in a phase 2a trial in human immunodeficiency virus (HIV)-uninfected adults for safety, immunogenicity, and 6-month durability of immune responses. METHODS: A total of 299 individuals received 2 doses of JS7 DNA vaccine and 2 doses of MVA/HIV62B at 0, 2, 4, and 6 months, respectively (the DDMM regimen); 3 doses of MVA/HIV62B at 0, 2, and 6 months (the MMM regimen); or placebo injections. RESULTS: At peak response, 93.2% of the DDMM group and 98.4% of the MMM group had binding antibodies for Env. These binding antibodies were more frequent and of higher magnitude for the transmembrane subunit (gp41) than the receptor-binding subunit (gp120) of Env. For both regimens, response rates were higher for CD4(+) T cells (66.4% in the DDMM group and 43.1% in the MMM group) than for CD8(+) T cells (21.8% in the DDMM group and 14.9% in the MMM group). Responding CD4(+) and CD8(+) T cells were biased toward Gag, and >70% produced 2 or 3 of the 4 cytokines evaluated (ie, interferon gamma, interleukin 2, tumor necrosis factor alpha, and granzyme B). Six months after vaccination, the magnitudes of antibodies and T-cell responses had decreased by <3-fold. CONCLUSIONS: DDMM and MMM vaccinations with virus-like particle-expressing immunogens elicited durable antibody and T-cell responses. PMID- 24403560 TI - Bacteria in the vaginal microbiome alter the innate immune response and barrier properties of the human vaginal epithelia in a species-specific manner. AB - BACKGROUND: Bacterial vaginosis increases the susceptibility to sexually transmitted infections and negatively affects women's reproductive health. METHODS: To investigate host-vaginal microbiota interactions and the impact on immune barrier function, we colonized 3-dimensional (3-D) human vaginal epithelial cells with 2 predominant species of vaginal microbiota (Lactobacillus iners and Lactobacillus crispatus) or 2 prevalent bacteria associated with bacterial vaginosis (Atopobium vaginae and Prevotella bivia). RESULTS: Colonization of 3-D vaginal epithelial cell aggregates with vaginal microbiota was observed with direct attachment to host cell surface with no cytotoxicity. A. vaginae infection yielded increased expression membrane-associated mucins and evoked a robust proinflammatory, immune response in 3-D vaginal epithelial cells (ie, expression of CCL20, hBD-2, interleukin 1beta, interleukin 6, interleukin 8, and tumor necrosis factor alpha) that can negatively affect barrier function. However, P. bivia and L. crispatus did not significantly upregulate pattern recognition receptor-signaling, mucin expression, antimicrobial peptides/defensins, or proinflammatory cytokines in 3-D vaginal epithelial cell aggregates. Notably, L. iners induced pattern-recognition receptor-signaling activity, but no change was observed in mucin expression or secretion of interleukin 6 and interleukin 8. CONCLUSIONS: We identified unique species specific immune signatures from vaginal epithelial cells elicited by colonization with commensal and bacterial vaginosis-associated bacteria. A. vaginae elicited a signature that is consistent with significant disruption of immune barrier properties, potentially resulting in enhanced susceptibility to sexually transmitted infections during bacterial vaginosis. PMID- 24403561 TI - Human classical monocytes control the intracellular stage of Leishmania braziliensis by reactive oxygen species. AB - Leishmania braziliensis are intracellular parasites that cause unique clinical forms of cutaneous leishmaniasis. Previous studies with other leishmania species demonstrated that reactive oxygen species (ROS) control promastigotes, the infective stage of the parasite, but not the amastigote form that exists in the mammalian host. Here we show that ROS inhibits growth of L. braziliensis amastigotes in resting monocytes, and that classical monocytes are primarily responsible for this control. ROS, but not nitric oxide, also contributed to killing of L. braziliensis by IFN-gamma activated monocytes. Furthermore, by gene expression profiling of human lesions we found greater expression of genes associated with ROS, but not nitric oxide, compared to normal skin. This study shows that ROS are important for control of L. braziliensis both at the initial stages of infection, as well as at later time points, and highlights that monocyte subsets may play different roles during leishmaniasis. PMID- 24403562 TI - Dantrolene: from better bacon to a treatment for ventricular fibrillation. PMID- 24403563 TI - Dantrolene improves survival after ventricular fibrillation by mitigating impaired calcium handling in animal models. AB - BACKGROUND: Resistant ventricular fibrillation, refibrillation. and diminished myocardial contractility are important factors leading to poor survival after cardiac arrest. We hypothesized that dantrolene improves survival after ventricular fibrillation (VF) by rectifying the calcium dysregulation caused by VF. METHODS AND RESULTS: VF was induced in 26 Yorkshire pigs for 4 minutes. Cardiopulmonary resuscitation was then commenced for 3 minutes, and dantrolene or isotonic saline was infused at the onset of cardiopulmonary resuscitation. Animals were defibrillated and observed for 30 minutes. To study the effect of VF on calcium handling and its modulation by dantrolene, hearts from 14 New Zealand rabbits were Langendorff-perfused. The inducibility of VF after dantrolene administration was documented. Optical mapping was performed to evaluate diastolic spontaneous calcium elevations as a measure of cytosolic calcium leak. The sustained return of spontaneous circulation (systolic blood pressure >=60 mm Hg) was achieved in 85% of the dantrolene group in comparison with 39% of controls (P=0.02). return of spontaneous circulation was achieved earlier in dantrolene-treated pigs after successful defibrillation (21 +/- 6 s versus 181 +/ 57 s in controls, P=0.005). The median number of refibrillation episodes was lower in the dantrolene group (0 versus 1, P=0.04). In isolated rabbit hearts, the successful induction of VF was achieved in 83% of attempts in controls versus 41% in dantrolene-treated hearts (P=0.007). VF caused diastolic calcium leaks in the form of spontaneous calcium elevations. Administration of 20 MUmol/L dantrolene significantly decreased spontaneous calcium elevation amplitude versus controls. (0.024 +/- 0.013 versus 0.12 +/- 0.02 arbitrary unit [200-ms cycle length], P=0.001). CONCLUSIONS: Dantrolene infusion during cardiopulmonary resuscitation facilitates successful defibrillation, improves hemodynamics postdefibrillation, decreases refibrillation, and thus improves survival after cardiac arrest. The effects are mediated through normalizing VF-induced dysfunctional calcium cycling. PMID- 24403564 TI - Effective gene targeting in rabbits using RNA-guided Cas9 nucleases. PMID- 24403565 TI - Retinal implants: a systematic review. AB - Retinal implants present an innovative way of restoring sight in degenerative retinal diseases. Previous reviews of research progress were written by groups developing their own devices. This systematic review objectively compares selected models by examining publications describing five representative retinal prostheses: Argus II, Boston Retinal Implant Project, Epi-Ret 3, Intelligent Medical Implants (IMI) and Alpha-IMS (Retina Implant AG). Publications were analysed using three criteria for interim success: clinical availability, vision restoration potential and long-term biocompatibility. Clinical availability: Argus II is the only device with FDA approval. Argus II and Alpha-IMS have both received the European CE Marking. All others are in clinical trials, except the Boston Retinal Implant, which is in animal studies. Vision restoration: resolution theoretically correlates with electrode number. Among devices with external cameras, the Boston Retinal Implant leads with 100 electrodes, followed by Argus II with 60 electrodes and visual acuity of 20/1262. Instead of an external camera, Alpha-IMS uses a photodiode system dependent on natural eye movements and can deliver visual acuity up to 20/546. Long-term compatibility: IMI offers iterative learning; Epi-Ret 3 is a fully intraocular device; Alpha-IMS uses intraocular photosensitive elements. Merging the results of these three criteria, Alpha-IMS is the most likely to achieve long-term success decades later, beyond current clinical availability. PMID- 24403566 TI - Fluorescein angiographic observations of peripheral retinal vessel growth in infants after intravitreal injection of bevacizumab as sole therapy for zone I and posterior zone II retinopathy of prematurity. AB - AIM: To evaluate vascularisation of the peripheral retina using fluorescein angiography (FA) digital recordings of infants who had been treated with intravitreal bevacizumab (IVB) as sole therapy for zone I and posterior zone II retinopathy of prematurity (ROP). METHODS: A retrospective evaluation was performed of medical records, RetCam fundus images and RetCam fluorescein angiogram videos of 10 neonates (20 eyes) who received intravitreal bevacizumab injections as the only treatment for zone I and posterior zone II ROP between August 2007 and November 2012. RESULTS: All eyes had initial resolution of posterior disease after IVB injection as documented by RetCam colour fundus photographs. Using a distance of 2 disc diameters from the ora serrata to vascular termini as the upper limit of allowable avascular retina in children, the FA of these infants demonstrated that 11 of 20 eyes had not achieved normal retinal vascularisation. CONCLUSIONS: Although bevacizumab appears effective in bringing resolution of zone I and posterior zone II ROP and allowing growth of peripheral retinal vessels, in our series of 20 eyes, complete normal peripheral retinal vascularisation was not achieved in half of the patients. PMID- 24403567 TI - Retinal oxygen metabolism in healthy subjects and glaucoma patients. AB - BACKGROUND: To test whether retinal oxygen metabolism is different in glaucoma patients compared with healthy subjects. METHODS: This was a two-centre study where retinal vessel oxygen saturation was measured in glaucoma patients and healthy individuals with a non-invasive spectrophotometric retinal oximeter. Visual fields were obtained in the glaucoma patients. RESULTS: No statistical difference was found in retinal oxygen saturation in arterioles (p=0.16), venules (p=0.16) and arteriovenous difference (p=0.24) when all glaucoma patients (n=74) were compared with healthy individuals (n=89). When patients with advanced glaucoma (visual field mean defect (MD >= 10 dB, n=21)) were compared with healthy individuals, the oxygen saturation in venules was higher in glaucoma patients (58.2% +/- 5.4% vs 53.8% +/- 6.4%; p=0.0054, mean +/- SD) and the arteriovenous difference was lower in glaucoma patients (36.4% +/- 4.7% vs 39.5% +/- 5.7%; p=0.021). In glaucoma patients with mild glaucoma (visual field MD <= 5 dB, n=33), no statistical differences were found in retinal oxygen saturation compared with healthy individuals. CONCLUSIONS: Glaucoma patients with advanced glaucoma have higher oxygen saturation in venules and lower arteriovenous difference in oxygen saturation compared with healthy individuals. The decreased arteriovenous difference in severe glaucoma may be related to lower oxygen consumption secondary to neuropathy. PMID- 24403569 TI - Under the influence: 4. Election prospects triumph over public health. PMID- 24403568 TI - PCP4: a regulator of aldosterone synthesis in human adrenocortical tissues. AB - Purkinje cell protein 4 (PCP4) is a calmodulin (CaM)-binding protein that accelerates calcium association and dissociation with CaM. It has been previously detected in aldosterone-producing adenomas (APA), but details on its expression and function in adrenocortical tissues have remained unknown. Therefore, we performed the immunohistochemical analysis of PCP4 in the following tissues: normal adrenal (NA; n=15), APA (n=15), cortisol-producing adenomas (n=15), and idiopathic hyperaldosteronism cases (IHA; n=5). APA samples (n=45) were also submitted to quantitative RT-PCR of PCP4, CYP11B1, and CYP11B2, as well as DNA sequencing for KCNJ5 mutations. Transient transfection analysis using PCP4 siRNA was also performed in H295R adrenocortical carcinoma cells, following ELISA analysis, and CYP11B2 luciferase assays were also performed after PCP4 vector transfection in order to study the regulation of PCP4 protein expression. In our findings, PCP4 immunoreactivity was predominantly detected in APA and in the zona glomerulosa of NA and IHA. In APA, the mRNA levels of PCP4 were significantly correlated with those of CYP11B2 (P<0.0001) and were significantly higher in cases with KCNJ5 mutation than WT (P=0.005). Following PCP4 vector transfection, CYP11B2 luciferase reporter activity was significantly higher than controls in the presence of angiotensin-II. Knockdown of PCP4 resulted in a significant decrease in CYP11B2 mRNA levels (P=0.012) and aldosterone production (P=0.011). Our results indicate that PCP4 is a regulator of aldosterone production in normal, hyperplastic, and neoplastic human adrenocortical cells. PMID- 24403570 TI - How a minimum unit price for alcohol was scuppered. PMID- 24403571 TI - Teen fitness is linked to reduced risk of myocardial infarction in later life, Swedish study finds. PMID- 24403572 TI - Under the influence: 2. How industry captured the science on minimum unit pricing. PMID- 24403573 TI - Under the influence: 3. Role of parliamentary groups. PMID- 24403574 TI - Editorial. PMID- 24403576 TI - A conformational transition observed in single HIV-1 Gag molecules during in vitro assembly of virus-like particles. AB - The conformational changes within single HIV-1 Gag molecules that occur during assembly into immature viruses are poorly understood. Using an in vitro assembly assay, it has been proposed that HIV-1 Gag undergoes a conformational transition from a compact conformation in solution to an extended rod-like conformation in virus-like particles (VLPs). Here we used single-molecule Forster resonance energy transfer (smFRET) to test this model by directly probing the conformation of single HIV-1 Gag molecules. We demonstrate that monomeric HIV-1 Gag lacking the p6 domain and the N-terminal myristoyl moiety is found in solution predominantly in a compact conformation. Gag in this conformation, and in the presence of nucleic acid, assembles into 30-nm-diameter particles. However, with the addition of inositol hexakisphosphate, Gag adopts a linear conformation and assembles into full-sized ~100-to-150-nm-diameter VLPs. Parallel fluorescence correlation spectroscopy measurements show that this conformational transition occurs early in the assembly process when Gag oligomers are small, perhaps as early as upon dimerization. Thus, smFRET measurements confirm that HIV-1 Gag transitions from a compact to a linear conformation during the formation of VLPs. Our results are consistent with a model whereby binding of HIV-1 Gag to phosphoinositides at the plasma membrane stabilizes an extended conformation and promotes oligomerization into the radially aligned immature capsid. IMPORTANCE: The establishment of single-molecule fluorescence techniques reveals the conformational state of individual HIV-1 Gag molecules prior to and during in vitro assembly into virus-like particles. The data demonstrate that Gag in distinct conformations forms particles with different morphologies. In the compact conformation, in the presence of nucleic acid, Gag forms spherical particles of a diameter of approximately 30 nm. In the extended conformation, Gag forms spherical virus-like particles of approximately 100-nm diameter. The adoption of the extended conformation required the presence of inositol hexakisphosphate in addition to nucleic acid. Our results are consistent with a model whereby binding of HIV-1 Gag to phosphoinositides at the plasma membrane stabilizes an extended conformation and promotes oligomerization into the radially aligned immature capsid. PMID- 24403578 TI - Virulence factor NSs of rift valley fever virus recruits the F-box protein FBXO3 to degrade subunit p62 of general transcription factor TFIIH. AB - The nonstructural protein NSs is the main virulence factor of Rift Valley fever virus (RVFV; family Bunyaviridae, genus Phlebovirus), a serious pathogen of livestock and humans in Africa. RVFV NSs blocks transcriptional upregulation of antiviral type I interferons (IFN) and destroys the general transcription factor TFIIH subunit p62 via the ubiquitin/proteasome pathway. Here, we identified a subunit of E3 ubiquitin ligases, F-box protein FBXO3, as a host cell interactor of NSs. Small interfering RNA (siRNA)-mediated depletion of FBXO3 rescued p62 protein levels in RVFV-infected cells and elevated IFN transcription by 1 order of magnitude. NSs interacts with the full-length FBXO3 protein as well as with a truncated isoform that lacks the C-terminal acidic and poly(R)-rich domains. These isoforms are present in both the nucleus and the cytoplasm. NSs exclusively removes the nuclear pool of full-length FBXO3, likely due to consumption during the degradation process. F-box proteins form the variable substrate recognition subunit of the so-called SCF ubiquitin ligases, which also contain the constant components Skp1, cullin 1 (or cullin 7), and Rbx1. siRNA knockdown of Skp1 also protected p62 from degradation, suggesting involvement in NSs action. However, knockdown of cullin 1, cullin 7, or Rbx1 could not rescue p62 degradation by NSs. Our data show that the enzymatic removal of p62 via the host cell factor FBXO3 is a major mechanism of IFN suppression by RVFV. IMPORTANCE: Rift Valley fever virus is a serious emerging pathogen of animals and humans. Its main virulence factor, NSs, enables unhindered virus replication by suppressing the antiviral innate immune system. We identified the E3 ubiquitin ligase FBXO3 as a novel host cell interactor of NSs. NSs recruits FBXO3 to destroy the general host cell transcription factor TFIIH-p62, resulting in suppression of the transcriptional upregulation of innate immunity. PMID- 24403577 TI - Beta interferon regulation of glucose metabolism is PI3K/Akt dependent and important for antiviral activity against coxsackievirus B3. AB - An effective type I interferon (IFN)-mediated immune response requires the rapid expression of antiviral proteins that are necessary to inhibit viral replication and virus spread. We provide evidence that IFN-beta regulates metabolic events important for the induction of a rapid antiviral response: IFN-beta decreases the phosphorylation of AMP-activated protein kinase (AMPK), coincident with an increase in intracellular ATP. Our studies reveal a biphasic IFN-beta-inducible uptake of glucose by cells, mediated by phosphatidylinositol 3-kinase (PI3K)/Akt, and IFN-beta-inducible regulation of GLUT4 translocation to the cell surface. Additionally, we provide evidence that IFN-beta-regulated glycolytic metabolism is important for the acute induction of an antiviral response during infection with coxsackievirus B3 (CVB3). Last, we demonstrate that the antidiabetic drug metformin enhances the antiviral potency of IFN-beta against CVB3 both in vitro and in vivo. Taken together, these findings highlight an important role for IFN beta in modulating glucose metabolism during a virus infection and suggest that the use of metformin in combination with IFN-beta during acute virus infection may result in enhanced antiviral responses. IMPORTANCE: Type I interferons (IFN) are critical effectors of an antiviral response. These studies describe for the first time a role for IFN-beta in regulating metabolism--glucose uptake and ATP production--to meet the energy requirements of a robust cellular antiviral response. Our data suggest that IFN-beta regulates glucose metabolism mediated by signaling effectors similarly to activation by insulin. Interference with IFN beta-inducible glucose metabolism diminishes the antiviral response, whereas treatment with metformin, a drug that increases insulin sensitivity, enhances the antiviral potency of IFN-beta. PMID- 24403579 TI - Molecular events accompanying rous sarcoma virus rescue from rodent cells and the role of viral gene complementation. AB - Transformation of rodent cells with avian Rous sarcoma virus (RSV) opened new ways to studying virus integration and expression in nonpermissive cells. We were interested in (i) the molecular changes accompanying fusion of RSV-transformed mammalian cells with avian cells leading to virus rescue and (ii) enhancement of this process by retroviral gene products. The RSV-transformed hamster RSCh cell line was characterized as producing only a marginal amount of env mRNA, no envelope glycoprotein, and a small amount of unprocessed Gag protein. Egress of viral unspliced genomic RNA from the nucleus was hampered, and its stability decreased. Cell fusion of the chicken DF-1 cell line with RSCh cells led to production of env mRNA, envelope glycoprotein, and processed Gag and virus-like particle formation. Proteosynthesis inhibition in DF-1 cells suppressed steps leading to virus rescue. Furthermore, new aberrantly spliced env mRNA species were found in the RSCh cells. Finally, we demonstrated that virus rescue efficiency can be significantly increased by complementation with the env gene and the highly expressed gag gene and can be increased the most by a helper virus infection. In summary, Env and Gag synthesis is increased after RSV-transformed hamster cell fusion with chicken fibroblasts, and both proteins provided in trans enhance RSV rescue. We conclude that the chicken fibroblast yields some factor(s) needed for RSV replication, particularly Env and Gag synthesis, in nonpermissive rodent cells. IMPORTANCE: One of the important issues in retrovirus heterotransmission is related to cellular factors that prevent virus replication. Rous sarcoma virus (RSV), a member of the avian sarcoma and leukosis family of retroviruses, is able to infect and transform mammalian cells; however, such transformed cells do not produce infectious virus particles. Using the well defined model of RSV-transformed rodent cells, we established that the lack of virus replication is due to the absence of chicken factor(s), which can be supplemented by cell fusion. Cell fusion with permissive chicken cells led to an increase in RNA splicing and nuclear export of specific viral mRNAs, as well as synthesis of respective viral proteins and production of virus-like particles. RSV rescue by cell fusion can be potentiated by in trans expression of viral genes in chicken cells. We conclude that rodent cells lack some chicken factor(s) required for proper viral RNA processing and viral protein synthesis. PMID- 24403580 TI - Specific residues of PB2 and PA influenza virus polymerase subunits confer the ability for RNA polymerase II degradation and virus pathogenicity in mice. AB - Influenza virus transcription requires functional coupling with cellular transcription for the cap-snatching process. Despite this fact, RNA polymerase II (RNAP II) is degraded during infection in a process triggered by the viral polymerase. Reassortant viruses from the A/PR/8/34 (PR8) strain that induce (hvPR8) or do not induce (lvPR8) RNAP II degradation led to the identification of PA and PB2 subunits as responsible for the degradation process. Three changes in the PB2 sequence (I105M, N456D, and I504V) and two in PA (Q193H and I550L) differentiate PA and PB2 of lvPR8 from those of hvPR8. Using recombinant viruses, we observed that changes at position 504 of PB2, together with 550 of PA, confer the ability on lvPR8 for RNAP II degradation and, conversely, abolish hvPR8 degradation capacity. Since hvPR8 is more pathogenic than lvPR8 in mice, we tested the potential contribution of RNAP II degradation in a distant viral strain, the 2009 pandemic A/California/04/09 (CAL) virus, whose PA and PB2 subunits are of avian origin. As in the hvPR8 virus, mutations at positions 504 of PB2 and 550 of PA in CAL virus abolished its RNAP II degradation capacity. Moreover, in an in vivo model, the CAL-infected mice lost more body weight, and 75% lethality was observed in this situation compared with 100% survival in mutant-CAL- or mock-infected animals. These results confirm the involvement of specific PB2 and PA residues in RNAP II degradation, which correlates with pathogenicity in mice of viruses containing human or avian polymerase PB2 and PA subunits. IMPORTANCE: The influenza virus polymerase induces the degradation of RNAP II, which probably cooperates to avoid the antiviral response. Here, we have characterized two specific residues located in the PA and PB2 polymerase subunits that mediate this degradation in different influenza viruses. Moreover, a clear correlation between RNAP II degradation and in vivo pathogenicity in mice was observed, indicating that the degradative process constitutes a viral pathogenicity factor. PMID- 24403581 TI - MyD88-dependent immunity to a natural model of vaccinia virus infection does not involve Toll-like receptor 2. AB - Although the pattern recognition receptor Toll-like receptor 2 (TLR2) is typically thought to recognize bacterial components, it has been described to alter the induction of both innate and adaptive immunity to a number of viruses, including vaccinia virus (VACV). However, many pathogens that reportedly encode TLR2 agonists may actually be artifactually contaminated during preparation, possibly with cellular debris or merely with molecules that sensitize cells to be activated by authentic TLR2 agonists. In both humans and mice, the most relevant natural route of infection with VACV is through intradermal infection of the skin. Therefore, we examined the requirement for TLR2 and its signaling adaptor MyD88 in protective immunity to VACV after intradermal infection. We find that although TLR2 may recognize virus preparations in vitro and have a minor role in preventing dissemination of VACV following systemic infection with large doses of virus, it is wholly disposable in both control of virus replication and induction of adaptive immunity following intradermal infection. In contrast, MyD88 is required for efficient induction of CD4 T cell and B cell responses and for local control of virus replication following intradermal infection. However, even MyD88 is not required to induce local inflammation, inflammatory cytokine production, or recruitment of cells that restrict virus from spreading systemically after peripheral infection. Thus, an effective antiviral response does require MyD88, but TLR2 is not required for control of a peripheral VACV infection. These findings emphasize the importance of studying relevant routes of infection when examining innate sensing mechanisms. IMPORTANCE: Vaccinia virus (VACV) provides the backbone for some of the most widely used and successful viral vaccine vectors and is also related to the human pathogens Cantagalo virus and molluscum contagiosum virus that infect the skin of patients. Therefore, it is vital to understand the mechanisms that induce a strong innate immune response to the virus following dermal infection. Here, we compare the ability of the innate sensing molecule Toll-like receptor 2 (TLR2) and the signaling molecule MyD88 to influence the innate and adaptive immune response to VACV following systemic or dermal infection. PMID- 24403582 TI - Small noncoding RNAs in cells transformed by human T-cell leukemia virus type 1: a role for a tRNA fragment as a primer for reverse transcriptase. AB - The present study employed mass sequencing of small RNA libraries to identify the repertoire of small noncoding RNAs expressed in normal CD4(+) T cells compared to cells transformed with human T-cell leukemia virus type 1 (HTLV-1), the causative agent of adult T-cell leukemia/lymphoma (ATLL). The results revealed distinct patterns of microRNA expression in HTLV-1-infected CD4(+) T-cell lines with respect to their normal counterparts. In addition, a search for virus-encoded microRNAs yielded 2 sequences that originated from the plus strand of the HTLV-1 genome. Several sequences derived from tRNAs were expressed at substantial levels in both uninfected and infected cells. One of the most abundant tRNA fragments (tRF-3019) was derived from the 3' end of tRNA-proline. tRF-3019 exhibited perfect sequence complementarity to the primer binding site of HTLV-1. The results of an in vitro reverse transcriptase assay verified that tRF-3019 was capable of priming HTLV-1 reverse transcriptase. Both tRNA-proline and tRF-3019 were detected in virus particles isolated from HTLV-1-infected cells. These findings suggest that tRF-3019 may play an important role in priming HTLV-1 reverse transcription and could thus represent a novel target to control HTLV-1 infection. IMPORTANCE: Small noncoding RNAs, a growing family of regulatory RNAs that includes microRNAs and tRNA fragments, have recently emerged as key players in many biological processes, including viral infection and cancer. In the present study, we employed mass sequencing to identify the repertoire of small noncoding RNAs in normal T cells compared to T cells transformed with human T cell leukemia virus type 1 (HTLV-1), a retrovirus that causes adult T-cell leukemia/lymphoma. The results revealed a distinct pattern of microRNA expression in HTLV-1-infected cells and a tRNA fragment (tRF-3019) that was packaged into virions and capable of priming HTLV-1 reverse transcription, a key event in the retroviral life cycle. These findings indicate tRF-3019 could represent a novel target for therapies aimed at controlling HTLV-1 infection. PMID- 24403583 TI - Unconventional sequence requirement for viral late gene core promoters of murine gammaherpesvirus 68. AB - Infection with the human gammaherpesviruses, Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), is associated with several cancers. During lytic replication of herpesviruses, viral genes are expressed in an ordered cascade. However, the mechanism by which late gene expression is regulated has not been well characterized in gammaherpesviruses. In this study, we have investigated the cis element that mediates late gene expression during de novo lytic infection with murine gammaherpesvirus 68 (MHV-68). A reporter system was established and used to assess the activity of viral late gene promoters upon infection with MHV-68. It was found that the viral origin of lytic replication, orilyt, must be on the reporter plasmid to support activation of the late gene promoter. Furthermore, the DNA sequence required for the activation of late gene promoters was mapped to a core element containing a distinct TATT box and its neighboring sequences. The critical nucleotides of the TATT box region were determined by systematic mutagenesis in the reporter system, and the significance of these nucleotides was confirmed in the context of the viral genome. In addition, EBV and KSHV late gene core promoters could be activated by MHV-68 lytic replication, indicating that the mechanisms controlling late gene expression are conserved among gammaherpesviruses. Therefore, our results on MHV 68 establish a solid foundation for mechanistic studies of late gene regulation. PMID- 24403584 TI - The Nef-like effect of murine leukemia virus glycosylated gag on HIV-1 infectivity is mediated by its cytoplasmic domain and depends on the AP-2 adaptor complex. AB - Human immunodeficiency virus type 1 (HIV-1) Nef enhances the infectivity of progeny virions. However, Nef is dispensable for the production of HIV-1 virions of optimal infectivity if the producer cells are superinfected with certain gammaretroviruses. In the case of the ecotropic Moloney murine leukemia virus (M MLV), the Nef-like effect is mediated by the glycosylated Gag (glycoGag) protein. We now show that the N-terminal intracellular domain of the type II transmembrane protein glycoGag is responsible for its effect on HIV-1 infectivity. In the context of a fully active minimal M-MLV glycoGag construct, truncations of the cytoplasmic domain led to a near total loss of activity. Furthermore, the cytoplasmic domain of M-MLV glycoGag was fully sufficient to transfer the activity to an unrelated type II transmembrane protein. Although the intracellular region of glycoGag is relatively poorly conserved even among ecotropic and xenotropic MLVs, it was also fully sufficient for the rescue of nef deficient HIV-1 when derived from a xenotropic virus. A mutagenic analysis showed that only a core region of the intracellular domain that exhibits at least some conservation between murine and feline leukemia viruses is crucial for activity. In particular, a conserved YXXL motif in the center of this core region was critical. In addition, expression of the MU2 subunit of the AP-2 adaptor complex in virus producer cells was essential for activity. We conclude that the ability to enhance HIV-1 infectivity is a conserved property of the MLV glycoGag cytoplasmic domain and involves AP-2-mediated endocytosis. IMPORTANCE: The Nef protein of HIV-1 and the entirely unrelated glycosylated Gag (glycoGag) protein of a murine leukemia virus (MLV) similarly enhance the infectiousness of HIV-1 particles by an unknown mechanism. MLV glycoGag is an alternative version of the structural viral Gag protein with an extra upstream region that provides a cytosolic domain and a plasma membrane anchor. We now show for the first time that the cytosolic domain of MLV glycoGag contains all the information needed to enhance HIV-1 infectivity and that this function of the cytosolic domain is conserved despite limited sequence conservation. Within the cytosolic domain, a motif that resembles a cellular sorting signal is critical for activity. Furthermore, the enhancement of HIV-1 infectivity depends on an endocytic cellular protein that is known to interact with such sorting signals. Together, our findings implicate the endocytic machinery in the enhancement of HIV-1 infectivity by MLV glycoGag. PMID- 24403585 TI - Assessment of influenza virus hemagglutinin stalk-based immunity in ferrets. AB - Therapeutic monoclonal antibodies that target the conserved stalk domain of the influenza virus hemagglutinin and stalk-based universal influenza virus vaccine strategies are being developed as promising countermeasures for influenza virus infections. The pan-H1-reactive monoclonal antibody 6F12 has been extensively characterized and shows broad efficacy against divergent H1N1 strains in the mouse model. Here we demonstrate its efficacy against a pandemic H1N1 challenge virus in the ferret model of influenza disease. Furthermore, we recently developed a universal influenza virus vaccine strategy based on chimeric hemagglutinin constructs that focuses the immune response on the conserved stalk domain of the hemagglutinin. Here we set out to test this vaccination strategy in the ferret model. Both strategies, pretreatment of animals with a stalk-reactive monoclonal antibody and vaccination with chimeric hemagglutinin-based constructs, were able to significantly reduce viral titers in nasal turbinates, lungs, and olfactory bulbs. In addition, vaccinated animals also showed reduced nasal wash viral titers. In summary, both strategies showed efficacy in reducing viral loads after an influenza virus challenge in the ferret model. IMPORTANCE: Influenza virus hemagglutinin stalk-reactive antibodies tend to be less potent yet are more broadly reactive and can neutralize seasonal and pandemic influenza virus strains. The ferret model was used to assess the potential of hemagglutinin stalk based immunity to provide protection against influenza virus infection. The novelty and significance of the findings described in this report support the development of vaccines stimulating stalk-specific antibody responses. PMID- 24403586 TI - The mitochondrial translocator protein, TSPO, inhibits HIV-1 envelope glycoprotein biosynthesis via the endoplasmic reticulum-associated protein degradation pathway. AB - The HIV-1 Env glycoprotein is folded in the endoplasmic reticulum (ER), which is necessary for viral entry and replication. Currently, it is still unclear how this process is regulated. The glycoprotein folding in the ER is controlled by the ER-associated protein degradation (ERAD) pathway, which specifically targets misfolded proteins for degradation. Previously, we reported that HIV-1 replication is restricted in the human CD4(+) T cell line CEM.NKR (NKR). To understand this mechanism, we first analyzed cellular protein expression in NKR cells and discovered that levels of the mitochondrial translocator protein TSPO were upregulated by ~64-fold. Notably, when NKR cells were treated with TSPO antagonist PK-11195, Ro5-4864, or diazepam, HIV restriction was completely disrupted, and TSPO knockdown by short hairpin RNAs (shRNAs) achieved a similar effect. We next analyzed viral protein expression, and, interestingly, we discovered that Env expression was specifically inhibited. Both TSPO knockdown and treatment with TSPO antagonist could restore Env expression in NKR cells. We further discovered that Env proteins were rapidly degraded and that kifunensine, an ERAD pathway inhibitor, could restore Env expression and viral replication, indicating that Env proteins were misfolded and degraded through the ERAD pathway in NKR cells. We also knocked out the TSPO gene in 293T cells using CRISPR/Cas9 (clustered, regularly interspaced, short palindromic repeat [CRISPR]/CRISPR associated-9) technology and found that TSPO could similarly inhibit Env expression in these cells. Taken together, these results demonstrate that TSPO inhibits Env protein expression through the ERAD pathway and suggest that mitochondria play an important role in regulating the Env folding process. IMPORTANCE: The HIV-1 Env glycoprotein is absolutely required for viral infection, and an understanding of its expression pathway in infected cells will identify new targets for antiretroviral therapies. Env proteins are folded in the ER and secreted through the classical secretory pathway. The Env folding process involves extensive cross-linking of 10 Cys residues by disulfide bond formation and heavy N-glycosylation on ~30 Asn residues. Currently, it is still unclear how this process is regulated. Here, we studied this mechanism in the HIV nonpermissive human CD4(+) T cell line CEM.NKR. We found that Env proteins were rapidly degraded through a cellular pathway that specifically targets misfolded proteins, resulting in inhibition of Env expression. Importantly, we have identified a mitochondrial translocator protein, TSPO, which could trigger this degradation by interfering with the Env folding process. Further characterization of TSPO antiviral activity will reveal a novel antiretroviral mechanism that targets the Env protein. PMID- 24403587 TI - Superinfection exclusion in alphabaculovirus infections is concomitant with actin reorganization. AB - Superinfection exclusion is the ability of an established virus to interfere with a second virus infection. This effect was studied in vitro during lepidopteran specific nucleopolyhedrovirus (genus Alphabaculovirus, family Baculoviridae) infection. Homologous interference was detected in Sf9 cells sequentially infected with two genotypes of Autographa californica multiple nucleopolyhedrovirus (AcMNPV), each one expressing a different fluorescent protein. This was a progressive process in which a sharp decrease in the signs of infection caused by the second virus was observed, affecting not only the number of coinfected cells observed, but also the level of protein expression due to the second virus infection. Superinfection exclusion was concurrent with reorganization of cytoplasmic actin to F-actin in the nucleus, followed by budded virus production (16 to 20 h postinfection). Disruption of actin filaments by cell treatment with cytochalasin D resulted in a successful second infection. Protection against heterologous nucleopolyhedrovirus infection was also demonstrated, as productive infection of Sf9 cells by Spodoptera frugiperda nucleopolyhedrovirus (SfMNPV) was inhibited by prior infection with AcMNPV, and vice versa. Finally, coinfected cells were observed following inoculation with mixtures of these two phylogenetically distant nucleopolyhedroviruses--AcMNPV and SfMNPV--but at a frequency lower than predicted, suggesting interspecific virus interference during infection or replication. The temporal window of infection is likely necessary to maintain genotypic diversity that favors virus survival but also permits dual infection by heterospecific alphabaculoviruses. IMPORTANCE: Infection of a cell by more than one virus particle implies sharing of cell resources. We show that multiple infection, by closely related or distantly related baculoviruses, is possible only during a brief window of time that allows additional virus particles to enter an infected cell over a period of ca. 16 h but then blocks multiple infections as newly generated virus particles begin to leave the infected cell. This temporal window has two important consequences. First, it allows multiple genotypes to almost simultaneously infect cells within the host, thus generating genetically diverse virus particles for transmission. Second, it provides a mechanism by which different viruses replicating in the same cell nucleus can exchange genetic material, so that the progeny viruses may be a mosaic of genes from each of the parental viruses. This opens a completely new avenue of research into the evolution of these insect pathogens. PMID- 24403589 TI - Influenza H7N9 and H9N2 viruses: coexistence in poultry linked to human H7N9 infection and genome characteristics. AB - Avian influenza virus A of the novel H7N9 reassortant subtype was recently found to cause severe human respiratory infections in China. Live poultry markets were suspected locations of the human H7N9 infection sources, based on the cases' exposure histories and sequence similarities between viral isolates. To explore the role of live poultry markets in the origin of the novel H7N9 virus, we systematically examined poultry and environmental specimens from local markets and farms in Hangzhou, using real-time reverse transcription-PCR (RT-PCR) as well as high-throughput next-generation sequencing (NGS). RT-PCR identified specimens positive for the H7 and N9 genomic segments in all of the 12 poultry markets epidemiologically linked to 10 human H7N9 cases. Chickens, ducks, and environmental specimens from the markets contained heavily mixed subtypes, including H7, N9, H9, and N2 and sometimes H5 and N1. The idea of the coexistence of H7N9 and H9N2 subtypes in chickens was further supported by metagenomic sequencing. In contrast, human H7N9 infection cases (n = 31) were all negative for H9N2 virus according to real-time RT-PCR. The six internal segments were indistinguishable for the H7N9 and H9N2 viruses. The H9, N2, and internal-segment sequences were very close to the sequence of the H9N2 virus circulating in chickens in China recently. Our results provide direct evidence that H9N2 strains coexisted with the novel human-pathogenic H7N9 influenza virus in epidemiologically linked live poultry markets. Avian influenza A virus of the H9N2 subtype likely made a recent contribution to the evolution of the H7N9 virus and continues to do so. IMPORTANCE: Our results suggest that avian influenza A virus of the H9N2 subtype likely made a recent contribution to the evolution of the H7N9 virus, a novel reassortant avian influenza virus A subtype, and continues to do so. The finding helps shed light on how the H7N9 virus emerged, spread, and transmitted to humans. It is of considerable interest for assessing the risk of the possible emergence of novel reassortant viruses with enhanced transmissibility to humans. PMID- 24403588 TI - A novel poxvirus-based vaccine, MVA-CHIKV, is highly immunogenic and protects mice against chikungunya infection. AB - There is a need to develop a single and highly effective vaccine against the emerging chikungunya virus (CHIKV), which causes a severe disease in humans. Here, we have generated and characterized the immunogenicity profile and the efficacy of a novel CHIKV vaccine candidate based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA) expressing the CHIKV C, E3, E2, 6K, and E1 structural genes (termed MVA-CHIKV). MVA-CHIKV was stable in cell culture, expressed the CHIKV structural proteins, and triggered the cytoplasmic accumulation of Golgi apparatus-derived membranes in infected human cells. Furthermore, MVA-CHIKV elicited robust innate immune responses in human macrophages and monocyte-derived dendritic cells, with production of beta interferon (IFN-beta), proinflammatory cytokines, and chemokines. After immunization of C57BL/6 mice with a homologous protocol (MVA-CHIKV/MVA-CHIKV), strong, broad, polyfunctional, and durable CHIKV-specific CD8(+) T cell responses were elicited. The CHIKV-specific CD8(+) T cells were preferentially directed against E1 and E2 proteins and, to a lesser extent, against C protein. CHIKV specific CD8(+) memory T cells of a mainly effector memory phenotype were also induced. The humoral arm of the immune system was significantly induced, as MVA CHIKV elicited high titers of neutralizing antibodies against CHIKV. Remarkably, a single dose of MVA-CHIKV protected all mice after a high-dose challenge with CHIKV. In summary, MVA-CHIKV is an effective vaccine against chikungunya virus infection that induced strong, broad, highly polyfunctional, and long-lasting CHIKV-specific CD8(+) T cell responses, together with neutralizing antibodies against CHIKV. These results support the consideration of MVA-CHIKV as a potential vaccine candidate against CHIKV. IMPORTANCE: We have developed a novel vaccine candidate against chikungunya virus (CHIKV) based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA) expressing the CHIKV C, E3, E2, 6K, and E1 structural genes (termed MVA-CHIKV). Our findings revealed that MVA-CHIKV is a highly effective vaccine against chikungunya virus, with a single dose of the vaccine protecting all mice after a high-dose challenge with CHIKV. Furthermore, MVA-CHIKV is highly immunogenic, inducing strong innate responses: high, broad, polyfunctional, and long-lasting CHIKV-specific CD8(+) T cell responses, together with neutralizing antibodies against CHIKV. This work provides a potential vaccine candidate against CHIKV. PMID- 24403590 TI - HIV DNA subspecies persist in both activated and resting memory CD4+ T cells during antiretroviral therapy. AB - The latent HIV reservoir is a major impediment to curing HIV infection. The contribution of CD4(+) T cell activation status to the establishment and maintenance of the latent reservoir was investigated by enumerating viral DNA components in a cohort of 12 individuals commencing antiretroviral therapy (ART) containing raltegravir, an integrase inhibitor. Prior to ART, the levels of total HIV DNA were similar across HLA-DR(+) and HLA-DR(-) (HLA-DR(+/-)) CD38(+/-) memory CD4(+) T cell phenotypes; episomal two-long terminal repeat (2-LTR) HIV DNA levels were higher in resting (HLA-DR(-) CD38(-)) cells, and this phenotype exhibited a significantly higher ratio of 2-LTR to integrated HIV DNA (P = 0.002). After 1 year of ART, there were no significant differences across each of the memory phenotypes of any HIV DNA component. The decay dynamics of integrated HIV DNA were slow within each subset, and integrated HIV DNA in the resting HLA DR(-) CD38(-) subset per mm(3) of peripheral blood exhibited no significant decay (half-life of 25 years). Episomal 2-LTR HIV DNA decayed relative to integrated HIV DNA in resting cells with a half-life of 134 days. Surprisingly, from week 12 on, the decay rates of both total and episomal HIV DNA were lower in activated CD38(+) cells. By weeks 24 and 52, HIV RNA levels in plasma were most significantly correlated with the numbers of resting cells containing integrated HIV DNA. On the other hand, total HIV DNA levels in all subsets were significantly correlated with the numbers of HLA-DR(+) CD38(-) cells containing integrated HIV DNA. These results provide insights into the interrelatedness of cell activation and reservoir maintenance, with implications for the design of therapeutic strategies targeting HIV persistence. IMPORTANCE: It is generally believed that HIV is not cleared by extensive antiretroviral therapy (ART) due to the difficulty in eradicating the latent reservoir in resting CD4(+) T cells. New therapies that attempt to activate this reservoir so that immune or viral cytopathic mechanisms can remove those infected cells are currently being investigated. However, results obtained in this research indicate that activation, at least on some level, already occurs within this reservoir. Furthermore, we are the first to describe the dynamics of different HIV DNA species in resting and activated memory CD4+ T cell subsets that point to the role different levels of activation play in maintaining the HIV reservoir. PMID- 24403591 TI - NF-kappaB inhibition facilitates the establishment of cell lines that chronically produce human T-lymphotropic virus type 1 viral particles. AB - Most human T-lymphotropic virus type 1 (HTLV-1)-infected HeLa and SupT1 cells cease proliferation and become senescent immediately after infection by HTLV-1 or transduction of the HTLV-1 tax gene. The cellular senescence response triggered by Tax is caused by hyperactivated NF-kappaB and mediated by cyclin-dependent kinase inhibitors, p21(CIP1/WAF1) and p27(KIP1). When NF-kappaB activity is blocked by a degradation-resistant form of IkappaBalpha, DeltaN-IkappaBalpha, Tax induced senescence is averted. Here, we show that NF-kappaB inhibition through the expression of DeltaN-IkappaBalpha allows cells of a human osteosarcoma (HOS) cell line to be chronically infected by HTLV-1. Stable HTLV-1-producing HOS cell clones can be readily established and isolated. These clones continue to proliferate in culture; express Tax, Rex, Gag, and Env proteins persistently; and transmit HTLV-1 to naive HOS, SupT1, and Jurkat T reporter cell lines readily after cocultivation. As HOS cells are adherent to culture plates, infected T cells in suspension can be easily collected and characterized. The ease with which chronic and productive HTLV-1 infection can be established in cell culture through inhibition of NF-kappaB affords a useful means to examine in depth the molecular events of HTLV-1 replication and the mechanisms of action of viral genes. IMPORTANCE: This paper describes a system for establishing cell lines that can be productively infected by human T-lymphotropic virus type 1 (HTLV-1) and can spread HTLV-1 to susceptible cells. Such a system can facilitate the study of HTLV-1 replication in cell culture. PMID- 24403592 TI - Amino acid substitutions in polymerase basic protein 2 gene contribute to the pathogenicity of the novel A/H7N9 influenza virus in mammalian hosts. AB - A novel avian-origin influenza A/H7N9 virus emerged in 2013 to cause more than 130 cases of zoonotic human disease, with an overall case fatality rate of around 30% in cases detected. It has been shown that an E-to-K amino acid change at residue 627 of polymerase basic protein 2 (PB2) occurred frequently in the H7N9 isolates obtained from humans but not in viruses isolated from poultry. Although this mutation has been reported to confer increased mammalian pathogenicity in other avian influenza subtypes, it has not been experimentally investigated in the H7N9 virus. In this study, we determined the contribution of PB2-E627K in H7N9 virus to its pathogenicity in mammalian hosts. In addition, the compensatory role of the PB2 mutations T271A, Q591K, and D701N in H7N9 virus was investigated. We characterized the activity of polymerase complexes with these PB2 mutations and found that they enhance the polymerase activity in human 293T cells. The rescued mutants enhanced growth in mammalian cells in vitro. Mice infected with the H7N9 mutant containing the avian signature protein PB2-627E showed a marked decrease in disease severity (weight loss) and pathology compared to mice infected with the wild-type strain (PB2-627K) or other PB2 mutants. Also, mutants with PB2-627E showed lower virus replication and proinflammatory cytokine responses in the lungs of the virus-infected mice, which may contribute to pathogenicity. Our results suggest that these amino acid substitutions contribute to mouse pathogenicity and mammalian adaptation. IMPORTANCE: A novel avian H7N9 influenza A virus emerged in east China in 2013 to cause zoonotic human disease associated with significant mortality. It is important to understand the viral genetic markers of mammalian adaptation and disease severity in this H7N9 virus. Since many human (but not avian) H7N9 virus isolates have an amino acid substitution at position E627K in the polymerase basic protein 2 (PB2) gene, we investigated the role of this and other functionally related mutations for polymerase activity in vitro, virus replication competence, and pathogenicity in the mouse model. We found that E627K and functionally related mutations are associated with increased polymerase activity, increased viral replication competence, and increased disease severity in mice. PMID- 24403593 TI - Insights into the structure and assembly of the bacteriophage 29 double-stranded DNA packaging motor. AB - The tailed double-stranded DNA (dsDNA) bacteriophage 29 packages its 19.3-kbp genome into a preassembled procapsid structure by using a transiently assembled phage-encoded molecular motor. This process is remarkable considering that compaction of DNA to near-crystalline densities within the confined space of the capsid requires that the packaging motor work against significant entropic, enthalpic, and DNA-bending energies. The motor consists of three phage-encoded components: the dodecameric connector protein gp10, an oligomeric RNA molecule known as the prohead RNA (pRNA), and the homomeric ring ATPase gp16. Although atomic resolution structures of the connector and different pRNA subdomains have been determined, the mechanism of self-assembly and the resulting stoichiometry of the various motor components on the phage capsid have been the subject of considerable controversy. Here a subnanometer asymmetric cryoelectron microscopy (cryo-EM) reconstruction of a connector-pRNA complex at a unique vertex of the procapsid conclusively demonstrates the pentameric symmetry of the pRNA and illuminates the relative arrangement of the connector and the pRNA. Additionally, a combination of biochemical and cryo-EM analyses of motor assembly intermediates suggests a sequence of molecular events that constitute the pathway by which the motor assembles on the head, thereby reconciling conflicting data regarding pRNA assembly and stoichiometry. Taken together, these data provide new insight into the assembly, structure, and mechanism of a complex molecular machine. IMPORTANCE: Viruses consist of a protein shell, or capsid, that protects and surrounds their genetic material. Thus, genome encapsidation is a fundamental and essential step in the life cycle of any virus. In dsDNA viruses, powerful molecular motors essentially pump the viral DNA into a preformed protein shell. This article describes how a viral dsDNA packaging motor self-assembles on the viral capsid and provides insight into its mechanism of action. PMID- 24403594 TI - Induction of HIV-blocking anti-CCR5 IgA in Peyers's patches without histopathological alterations. AB - The chemokine receptor CCR5 is essential for HIV infection and is thus a potential target for vaccine development. However, because CCR5 is a host protein, generation of anti-CCR5 antibodies requires the breaking of immune tolerance and thus carries the risk of autoimmune responses. In this study, performed in mice, we compared 3 different immunogens representing surface domains of murine CCR5, 4 different adjuvants, and 13 different immunization protocols, with the goal of eliciting HIV-blocking activity without inducing autoimmune dysfunction. In all cases the CCR5 sequences were presented as fusions to the Flock House virus (FHV) capsid precursor protein. We found that systemic immunization and mucosal boosting elicited CCR5-specific antibodies and achieved consistent priming in Peyer's patches, where most cells showed a phenotype corresponding to activated B cells and secreted high levels of IgA, representing up to one-third of the total HIV-blocking activity. Histopathological analysis revealed mild to moderate chronic inflammation in some tissues but failed in reporting signs of autoimmune dysfunction associated with immunizations. Antisera against immunogens representing the N terminus and extracellular loops 1 and 2 (Nter1 and ECL1 and ECL2) of CCR5 were generated. All showed specific anti-HIV activity, which was stronger in the anti-ECL1 and -ECL2 sera than in the anti Nter sera. ECL1 and ECL2 antisera induced nearly complete long-lasting CCR5 downregulation of the receptor, and especially, their IgG-depleted fractions prevented HIV infection in neutralization and transcytosis assays. In conclusion, the ECL1 and ECL2 domains could offer a promising path to achieve significant anti-HIV activity in vivo. IMPORTANCE: The study was the first to adopt a systematic strategy to compare the immunogenicities of all extracellular domains of the CCR5 molecule and to set optimal conditions leading to generation of specific antibodies in the mouse model. There were several relevant findings, which could be translated into human trials. (i) Prime (systemic) and boost (mucosal) immunization is the best protocol to induce anti-self antibodies with the expected properties. (ii) Aluminum is the best adjuvant in mice and thus can be easily used in nonhuman primates (NHP) and humans. (iii) The Flock House virus (FHV) system represents a valid delivery system, as the structure is well known and is not pathogenic for humans, and it is possible to introduce constrained regions able to elicit antibodies that recognize conformational epitopes. (iv) The best CCR5 vaccine candidate should include either extracellular loop 1 or 2 (ECL1 or ECL2), but not N terminus domains. PMID- 24403595 TI - The human papillomavirus E7 proteins associate with p190RhoGAP and alter its function. AB - Using mass spectrometry, we identified p190RhoGAP (p190) as a binding partner of human papillomavirus 16 (HPV16) E7. p190 belongs to the GTPase activating protein (GAP) family and is one of the primary GAPs for RhoA. GAPs stimulate the intrinsic GTPase activity of the Rho proteins, leading to Rho inactivation and influencing numerous biological processes. RhoA is one of the best-characterized Rho proteins and is specifically involved in formation of focal adhesions and stress fibers, thereby regulating cell migration and cell spreading. Since this is the first report that E7 associates with p190, we carried out detailed interaction studies. We show that E7 proteins from other HPV types also bind p190. Furthermore, we found that conserved region 3 (CR3) of E7 and the middle domain of p190 are important for this interaction. More specifically, we identified two residues in CR3 of E7 that are necessary for p190 binding and used mutants of E7 with mutations of these residues to determine the biological consequences of the E7-p190 interaction. Our data suggest that the interaction of E7 with p190 dysregulates this GAP and alters the actin cytoskeleton. We also found that this interaction negatively regulates cell spreading on a fibronectin substrate and therefore likely contributes to important aspects of the HPV life cycle or HPV-induced tumorigenesis. IMPORTANCE: This study identifies p190RhoGAP as a novel cellular binding partner for the human papillomavirus (HPV) E7 protein. Our study shows that a large number of different HPV E7 proteins bind p190RhoGAP, and it identifies regions in both E7 and p190RhoGAP which are important for the interaction to occur. This study also highlights the likelihood that the E7-p190RhoGAP interaction may have important biological consequences related to actin organization in the infected cell. These changes could be an important contributor to the viral life cycle and during progression to cancer in HPV-infected cells. Importantly, this work also emphasizes the need for further study in a field which has largely been unexplored as it relates to the HPV life cycle and HPV-induced transformation. PMID- 24403596 TI - A protein profile of visceral adipose tissues linked to early pathogenesis of type 2 diabetes mellitus. AB - Adipose tissue is increasingly recognized as an endocrine organ playing important pathophysiological roles in metabolic abnormalities, such as obesity, cardiovascular disease, and type 2 diabetes mellitus (T2DM). In particular, visceral adipose tissue (VAT), as opposed to subcutaneous adipose tissue, is closely linked to the pathogenesis of insulin resistance and T2DM. Despite the importance of VAT, its molecular signatures related to the pathogenesis of T2DM have not been systematically explored. Here, we present comprehensive proteomic analysis of VATs in drug-naive early T2DM patients and subjects with normal glucose tolerance. A total of 4,707 proteins were identified in LC-MS/MS experiments. Among them, 444 increased in abundance in T2DM and 328 decreased. They are involved in T2DM-related processes including inflammatory responses, peroxisome proliferator-activated receptor signaling, oxidative phosphorylation, fatty acid oxidation, and glucose metabolism. Of these proteins, we selected 11 VAT proteins that can represent alteration in early T2DM patients. Among them, up regulation of FABP4, C1QA, S100A8, and SORBS1 and down-regulation of ACADL and PLIN4 were confirmed in VAT samples of independent early T2DM patients using Western blot. In summary, our profiling provided a comprehensive basis for understanding the link of a protein profile of VAT to early pathogenesis of T2DM. PMID- 24403597 TI - Advancing the high throughput identification of liver fibrosis protein signatures using multiplexed ion mobility spectrometry. AB - Rapid diagnosis of disease states using less invasive, safer, and more clinically acceptable approaches than presently employed is a crucial direction for the field of medicine. While MS-based proteomics approaches have attempted to meet these objectives, challenges such as the enormous dynamic range of protein concentrations in clinically relevant biofluid samples coupled with the need to address human biodiversity have slowed their employment. Herein, we report on the use of a new instrumental platform that addresses these challenges by coupling technical advances in rapid gas phase multiplexed ion mobility spectrometry separations with liquid chromatography and MS to dramatically increase measurement sensitivity and throughput, further enabling future high throughput MS-based clinical applications. An initial application of the liquid chromatography--ion mobility spectrometry-MS platform analyzing blood serum samples from 60 postliver transplant patients with recurrent fibrosis progression and 60 nontransplant patients illustrates its potential utility for disease characterization. PMID- 24403598 TI - Methyl-accepting chemotaxis proteins 3 and 4 are responsible for Campylobacter jejuni chemotaxis and jejuna colonization in mice in response to sodium deoxycholate. AB - Methyl-accepting chemotaxis proteins (MCPs), also termed transducer-like proteins (Tlps), serve as sensors in bacterial chemotactic signalling, and detect attractants and promote bacterial movement towards suitable sites for colonization. Campylobacter jejuni is a leading cause of human enteritis, but the mechanisms responsible for bacterial chemotaxis and early colonization in the jejunum of hosts are poorly understood. In the present study, we identified several types of bile and sodium deoxycholate (SDC) acting as chemotactic attractants of C. jejuni strain NCTC 11168-O in vitro, in which SDC was the most efficient chemoattractant. In mice with bile duct ligation, the wild-type strain displayed a markedly attenuated ability for colonization. Blockage of Tlp3 or Tlp4 protein with antibody or disruption of the tlp3 or tlp4 gene (Deltatlp3 or Deltatlp4) caused a significant inhibition of SDC-induced chemotaxis and attenuation for colonization on jejunal mucosa in mice of the bacterium. Disruption of both the genes (Deltatlp3/Deltatlp4) resulted in the absence of bacterial chemotaxis and colonization, while the tlp-gene-complemented mutants (CDeltatlp3 and CDeltatlp4) reacquired these abilities. The results indicate that SDC is an effective chemoattractant for C. jejuni, and Tlp3 and Tlp4 are the SDC specific sensor proteins responsible for the bacterial chemoattraction. PMID- 24403599 TI - Analysis of community- and hospital-acquired bacteraemia during a recent 5-year period. AB - There are sparse data concerning sex- and age-specific characteristics of community-acquired bacteraemia (CAB) and hospital-acquired bacteraemia (HAB). Between January 2008 and December 2012, we identified 2956 bacteraemia cases, which we classified as CAB, HAB or healthcare-associated bacteraemia (HCAB). Almost half of the pathogens were Escherichia coli in CAB patients. By contrast, Staphylococcus aureus was most frequent (16.2%) in HAB patients. HCAB showed mixed features of CAB and HAB. In CAB, E. coli was significantly more abundant in females than in males (56.9 vs 24.3%, respectively). This trend was most striking in young adults (20-39 years) (77.2% in females vs 11.4% in males). HAB cases showed greater heterogeneity in their associated pathogens. The extended-spectrum beta-lactamase-positive rates of E. coli and Klebsiella pneumoniae, respectively, were 31.3 and 33.8% in HAB and 8.8 and 8.4% in CAB. The non-susceptibility rates of S. aureus to oxacillin were 37.4% in CAB and 73.0% in HAB. In conclusion, CAB and HAB showed different distributions of micro-organisms, and these distributions also differed with patient age and sex. In addition, antimicrobial susceptibility needs to be monitored separately. PMID- 24403600 TI - Initiation of multicellular differentiation in Dictyostelium discoideum is regulated by coronin A. AB - Many biological systems respond to environmental changes by activating intracellular signaling cascades, resulting in an appropriate response. One such system is represented by the social amoeba Dictyostelium discoideum. When food sources become scarce, these unicellular cells can initiate a cAMP-driven multicellular aggregation program to ensure long-term survival. On starvation, the cells secrete conditioned medium factors that initiate cAMP signal transduction by inducing expression of genes such as cAMP receptors and adenylate cyclase. The mechanisms involved in the activation of the first pulses of cAMP release have been unclear. We here show a crucial role for the evolutionarily conserved protein coronin A in the initiation of the cAMP response. On starvation, coronin A-deficient cells failed to up-regulate the expression of cAMP-regulated genes, thereby failing to initiate development, despite a normal prestarvation response. Of importance, external addition of cAMP to coronin A deficient cells resulted in normal chemotaxis and aggregate formation, thereby restoring the developmental program and suggesting a functional cAMP relay in the absence of coronin A. These results suggest that coronin A is dispensable for cAMP sensing, chemotaxis, and development per se but is part of a signal transduction cascade essential for system initiation leading to multicellular development in Dictyostelium. PMID- 24403602 TI - CXCR4 drives the metastatic phenotype in breast cancer through induction of CXCR2 and activation of MEK and PI3K pathways. AB - Aberrant expression of CXCR4 in human breast cancer correlates with metastasis to tissues secreting CXCL12. To understand the mechanism by which CXCR4 mediates breast cancer metastasis, MCF-7 breast carcinoma cells were transduced to express wild-type CXCR4 (CXCR4WT) or constitutively active CXCR4 (CXCR4DeltaCTD) and analyzed in two-dimensional (2D) cultures, three-dimensional reconstituted basement membrane (3D rBM) cultures, and mice using intravital imaging. Two dimensional cultures of MCF-7 CXCR4DeltaCTD cells, but not CXCR4WT, exhibited an epithelial-to-mesenchymal transition (EMT) characterized by up-regulation of zinc finger E box-binding homeobox 1, loss of E-cadherin, up-regulation of cadherin 11, p120 isoform switching, activation of extracellular signal-regulated kinase 1/2, and matrix metalloproteinase-2. In contrast to the 2D environment, MCF-7 CXCR4WT cells cultured in 3D rBM exhibited an EMT phenotype, accompanied by expression of CXCR2, CXCR7, CXCL1, CXCL8, CCL2, interleukin-6, and granulocyte macrophage colony stimulating factor. Dual inhibition of CXCR2 with CXCR4, or inhibition of either receptor with inhibitors of mitogen-activated protein kinase 1 or phosphatidylinositol 3-kinase, reversed the aggressive phenotype of MCF-7 CXCR4-expressing or MDA-MB-231 cells in 3D rBM. Intravital imaging of CXCR4 expressing MCF-7 cells revealed that tumor cells migrate toward blood vessels and metastasize to lymph nodes. Thus CXCR4 can drive EMT along with an up-regulation of chemokine receptors and cytokines important in cell migration, lymphatic invasion, and tumor metastasis. PMID- 24403601 TI - A phosphatidylinositol transfer protein integrates phosphoinositide signaling with lipid droplet metabolism to regulate a developmental program of nutrient stress-induced membrane biogenesis. AB - Lipid droplet (LD) utilization is an important cellular activity that regulates energy balance and release of lipid second messengers. Because fatty acids exhibit both beneficial and toxic properties, their release from LDs must be controlled. Here we demonstrate that yeast Sfh3, an unusual Sec14-like phosphatidylinositol transfer protein, is an LD-associated protein that inhibits lipid mobilization from these particles. We further document a complex biochemical diversification of LDs during sporulation in which Sfh3 and select other LD proteins redistribute into discrete LD subpopulations. The data show that Sfh3 modulates the efficiency with which a neutral lipid hydrolase-rich LD subclass is consumed during biogenesis of specialized membrane envelopes that package replicated haploid meiotic genomes. These results present novel insights into the interface between phosphoinositide signaling and developmental regulation of LD metabolism and unveil meiosis-specific aspects of Sfh3 (and phosphoinositide) biology that are invisible to contemporary haploid-centric cell biological, proteomic, and functional genomics approaches. PMID- 24403603 TI - A microscopy-based screen employing multiplex genome sequencing identifies cargo specific requirements for dynein velocity. AB - The timely delivery of membranous organelles and macromolecules to specific locations within the majority of eukaryotic cells depends on microtubule-based transport. Here we describe a screening method to identify mutations that have a critical effect on intracellular transport and its regulation using mutagenesis, multicolor-fluorescence microscopy, and multiplex genome sequencing. This screen exploits the filamentous fungus Aspergillus nidulans, which has many of the advantages of yeast molecular genetics but uses long-range microtubule-based transport in a manner more similar to metazoan cells. Using this method, we identified seven mutants that represent novel alleles of components of the intracellular transport machinery: specifically, kinesin-1, cytoplasmic dynein, and the dynein regulators Lis1 and dynactin. The two dynein mutations identified in our screen map to dynein's AAA+ catalytic core. Single-molecule studies reveal that both mutations reduce dynein's velocity in vitro. In vivo these mutants severely impair the distribution and velocity of endosomes, a known dynein cargo. In contrast, another dynein cargo, the nucleus, is positioned normally in these mutants. These results reveal that different dynein functions have distinct stringencies for motor performance. PMID- 24403604 TI - Functional genomic screen identifies novel mediators of collagen uptake. AB - Tissue fibrosis occurs when matrix production outpaces matrix degradation. Degradation of collagen, the main component of fibrotic tissue, is mediated through an extracellular proteolytic pathway and intracellular pathway of cellular uptake and lysosomal digestion. Recent studies demonstrate that disruption of the intracellular pathways can exacerbate fibrosis. These pathways are poorly characterized. Here we identify novel mediators of the intracellular pathway of collagen turnover through a genome-wide RNA interference screen in Drosophila S2 cells. Screening of 7505 Drosophila genes conserved among metazoans identified 22 genes that were required for efficient internalization of type I collagen. These included proteins involved in vesicle transport, the actin cytoskeleton, and signal transduction. We show further that the flotillin genes have a conserved and central role in collagen uptake in Drosophila and human cells. Short hairpin RNA-mediated silencing of flotillins in human monocyte and fibroblasts impaired collagen uptake by promoting lysosomal degradation of the endocytic collagen receptors uPARAP/Endo180 and mannose receptor. These data provide an initial characterization of intracellular pathways of collagen turnover and identify the flotillin genes as critical regulators of this process. A better understanding of these pathways may lead to novel therapies that reduce fibrosis by increasing collagen turnover. PMID- 24403605 TI - The fate of the primary cilium during myofibroblast transition. AB - Myofibroblasts, the culprit of organ fibrosis, can originate from mesenchymal and epithelial precursors through fibroblast-myofibroblast and epithelial myofibroblast transition (EMyT). Because certain ciliopathies are associated with fibrogenesis, we sought to explore the fate and potential role of the primary cilium during myofibroblast formation. Here we show that myofibroblast transition from either precursor results in the loss of the primary cilium. During EMyT, initial cilium growth is followed by complete deciliation. Both EMyT and cilium loss require two-hit conditions: disassembly/absence of intercellular contacts and transforming growth factor-beta1 (TGFbeta) exposure. Loss of E-cadherin dependent junctions induces cilium elongation, whereas both stimuli are needed for deciliation. Accordingly, in a scratch-wounded epithelium, TGFbeta provokes cilium loss exclusively along the wound edge. Increased contractility, a key myofibroblast feature, is necessary and sufficient for deciliation, since constitutively active RhoA, Rac1, or myosin triggers, and down-regulation of myosin or myocardin-related transcription factor prevents, this process. Sustained myosin phosphorylation and consequent deciliation are mediated by a Smad3-, Rac1-, and reactive oxygen species-dependent process. Transitioned myofibroblasts exhibit impaired responsiveness to platelet-derived growth factor AA and sonic hedgehog, two cilium-associated stimuli. Although the cilium is lost during EMyT, its initial presence contributes to the transition. Thus myofibroblasts represent a unique cilium-less entity with profoundly reprogrammed cilium-related signaling. PMID- 24403607 TI - The spindle and kinetochore-associated (Ska) complex enhances binding of the anaphase-promoting complex/cyclosome (APC/C) to chromosomes and promotes mitotic exit. AB - The spindle and kinetochore-associated (Ska) protein complex is a heterotrimeric complex required for timely anaphase onset. The major phenotypes seen after small interfering RNA-mediated depletion of Ska are transient alignment defects followed by metaphase arrest that ultimately results in cohesion fatigue. We find that cells depleted of Ska3 arrest at metaphase with only partial degradation of cyclin B1 and securin. In cells arrested with microtubule drugs, Ska3-depleted cells exhibit slower mitotic exit when the spindle checkpoint is silenced by inhibition of the checkpoint kinase, Mps1, or when cells are forced to exit mitosis downstream of checkpoint silencing by inactivation of Cdk1. These results suggest that in addition to a role in fostering kinetochore-microtubule attachment and chromosome alignment, the Ska complex has functions in promoting anaphase onset. We find that both Ska3 and microtubules promote chromosome association of the anaphase-promoting complex/cyclosome (APC/C). Chromosome-bound APC/C shows significantly stronger ubiquitylation activity than cytoplasmic APC/C. Forced localization of Ska complex to kinetochores, independent of microtubules, results in enhanced accumulation of APC/C on chromosomes and accelerated cyclin B1 degradation during induced mitotic exit. We propose that a Ska-microtubule-kinetochore association promotes APC/C localization to chromosomes, thereby enhancing anaphase onset and mitotic exit. PMID- 24403606 TI - Essential and nonredundant roles for Diaphanous formins in cortical microtubule capture and directed cell migration. AB - Formins constitute a large family of proteins that regulate the dynamics and organization of both the actin and microtubule cytoskeletons. Previously we showed that the formin mDia1 helps tether microtubules at the cell cortex, acting downstream of the ErbB2 receptor tyrosine kinase. Here we further study the contributions of mDia1 and its two most closely related formins, mDia2 and mDia3, to cortical microtubule capture and ErbB2-dependent breast carcinoma cell migration. We find that depletion of each of these three formins strongly disrupts chemotaxis without significantly affecting actin-based structures. Further, all three formins are required for formation of cortical microtubules in a nonredundant manner, and formin proteins defective in actin polymerization remain active for microtubule capture. Using affinity purification and mass spectrometry analysis, we identify differential binding partners of the formin homology domain 2 (FH2) of mDia1, mDia2, and mDia3, which may explain their nonredundant roles in microtubule capture. The FH2 domain of mDia1 specifically interacts with Rab6-interacting protein 2 (Rab6IP2). Further, mDia1 is required for cortical localization of Rab6IP2, and concomitant depletion of Rab6IP2 and IQGAP1 severely disrupts cortical capture of microtubules, demonstrating the coinvolvement of mDia1, IQGAP1, and Rab6IP2 in microtubule tethering at the leading edge. PMID- 24403608 TI - CHES1/FOXN3 regulates cell proliferation by repressing PIM2 and protein biosynthesis. AB - The expression of the forkhead transcription factor checkpoint suppressor 1 (CHES1), also known as FOXN3, is reduced in many types of cancers. We show here that CHES1 decreases protein synthesis and cell proliferation in tumor cell lines but not in normal fibroblasts. Conversely, short hairpin RNA-mediated depletion of CHES1 increases tumor cell proliferation. Growth suppression depends on the CHES1 forkhead DNA-binding domain and correlates with the nuclear localization of CHES1. CHES1 represses the expression of multiple genes, including the kinases PIM2 and DYRK3, which regulate protein biosynthesis, and a number of genes in cilium biogenesis. CHES1 binds directly to the promoter of PIM2, and in cells expressing CHES1 the levels of PIM2 are reduced, as well as the phosphorylation of the PIM2 target 4EBP1. Overexpression of PIM2 or eIF4E partially reverses the antiproliferative effect of CHES1, indicating that PIM2 and protein biosynthesis are important targets of the antiproliferative effect of CHES1. In several human hematopoietic cancers, CHES1 and PIM2 expressions are inversely correlated, suggesting that repression of PIM2 by CHES1 is clinically relevant. PMID- 24403609 TI - Role of turgor pressure in endocytosis in fission yeast. AB - Yeast and other walled cells possess high internal turgor pressure that allows them to grow and survive in the environment. This turgor pressure, however, may oppose the invagination of the plasma membrane needed for endocytosis. Here we study the effects of turgor pressure on endocytosis in the fission yeast Schizosaccharomyces pombe by time-lapse imaging of individual endocytic sites. Decreasing effective turgor pressure by addition of sorbitol to the media significantly accelerates early steps in the endocytic process before actin assembly and membrane ingression but does not affect the velocity or depth of ingression of the endocytic pit in wild-type cells. Sorbitol also rescues endocytic ingression defects of certain endocytic mutants and of cells treated with a low dose of the actin inhibitor latrunculin A. Endocytosis proceeds after removal of the cell wall, suggesting that the cell wall does not contribute mechanically to this process. These studies suggest that endocytosis is governed by a mechanical balance between local actin-dependent inward forces and opposing forces from high internal turgor pressure on the plasma membrane. PMID- 24403610 TI - A Fresh Look at the Discriminant Function Approach for Estimating Crude or Adjusted Odds Ratios. AB - Assuming a binary outcome, logistic regression is the most common approach to estimating a crude or adjusted odds ratio corresponding to a continuous predictor. We revisit a method termed the discriminant function approach, which leads to closed-form estimators and corresponding standard errors. In its most appealing application, we show that the approach suggests a multiple linear regression of the continuous predictor of interest on the outcome and other covariates, in place of the traditional logistic regression model. If standard diagnostics support the assumptions (including normality of errors) accompanying this linear regression model, the resulting estimator has demonstrable advantages over the usual maximum likelihood estimator via logistic regression. These include improvements in terms of bias and efficiency based on a minimum variance unbiased estimator of the log odds ratio, as well as the availability of an estimate when logistic regression fails to converge due to a separation of data points. Use of the discriminant function approach as described here for multivariable analysis requires less stringent assumptions than those for which it was historically criticized, and is worth considering when the adjusted odds ratio associated with a particular continuous predictor is of primary interest. Simulation and case studies illustrate these points. PMID- 24403612 TI - Pages From Old Issues of IJA Silver Jubilee 1977. PMID- 24403611 TI - DOI Determination by Rise Time Discrimination in Single-Ended Readout for TOF PET Imaging. AB - Clinical TOF PET systems achieve detection efficiency using thick crystals, typically of thickness 2-3cm. The resulting dispersion in interaction depths degrades spatial resolution for increasing radial positions due to parallax error. Furthermore, interaction depth dispersion results in time pickoff dispersion and thus in degraded timing resolution, and is therefore of added concern in TOF scanners. Using fast signal digitization, we characterize the timing performance, pulse shape and light output of LaBr3:Ce, CeBr3 and LYSO. Coincidence timing resolution is shown to degrade by ~50ps/cm for scintillator pixels of constant cross section and increasing length. By controlling irradiation depth in a scintillator pixel, we show that DOI-dependence of time pickoff is a significant factor in the loss of timing performance in thick detectors. Using the correlated DOI-dependence of time pickoff and charge collection, we apply a charge-based correction to the time pickoff, obtaining improved coincidence timing resolution of <200ps for a uniform 4*4*30mm3 LaBr3 pixel. In order to obtain both DOI identification and improved timing resolution, we design a two layer LaBr3[5%Ce]/LaBr3[30%Ce] detector of total size 4*4*30mm3, exploiting the dependence of scintillator rise time on [Ce] in LaBr3:Ce. Using signal rise time to determine interaction layer, excellent interaction layer discrimination is achieved, while maintaining coincidence timing resolution of <250ps and energy resolution <7% using a R4998 PMT. Excellent layer separation and timing performance is measured with several other commercially-available TOF photodetectors, demonstrating the practicality of this design. These results indicate the feasibility of rise time discrimination as a technique for measuring event DOI while maintaining sensitivity, timing and energy performance, in a well known detector architecture. PMID- 24403613 TI - Pages From Old Issues of IJA 1965. PMID- 24403614 TI - Continuous paravertebral infusion of ropivacaine with or without fentanyl for pain relief in unilateral multiple fractured ribs. AB - BACKGROUND: Continuous thoracic paravertebral block (TPVB) provides effective analgesia for unilateral multiple fractured ribs (MFR). However, prolonged infusion of local anaesthetic (LA) in high doses can predispose to risk of LA toxicity, which may be reduced by using safer drugs or drug combinations. This study was conducted to assess efficacy and safety of paravertebral infusion of ropivacaine and adrenaline with or without fentanyl to provide analgesia to patients with unilateral MFR. METHODS: Thirty adults, having >=3 unilateral MFR, with no significant trauma outside chest wall, were studied. All received bolus of 0.5% ropivacaine 0.3 ml/kg through paravertebral catheter, followed by either 0.1-0.2 ml/kg/hr infusion of ropivacaine 0.375% with adrenaline 5 MUg/ml in group RA or ropivacaine 0.2% with adrenaline 5 MUg/ml and fentanyl 2 MUg/ml in group RAF. Rescue analgesia was provided by IV morphine. RESULTS: Statistical analysis was performed using unpaired Student t-test, Chi-square test and repeated measures ANOVA. After TPVB, VAS scores, respiratory rate and PEFR improved in both groups with no significant inter-group differences. Duration of ropivacaine infusion, morphine requirements, length of ICU and hospital stay, incidence of pulmonary complications and opioid-related side-effects were similar in both groups. Ropivacaine requirement was higher in group RA than group RAF. No patient showed signs of LA toxicity. CONCLUSION: Continuous paravertebral infusion of ropivacaine 0.375% with adrenaline 5 MUg/ml at 0.1-0.2 ml/kg/hr provided effective and safe analgesia to patients with unilateral MFR. Addition of fentanyl 2 MUg/ml allowed reduction of ropivacaine concentration to 0.2% without decreasing efficacy or increasing opioid-related side-effects. PMID- 24403615 TI - Perioperative respiratory complications in cleft lip and palate repairs: An audit of 1000 cases under 'Smile Train Project'. AB - BACKGROUND AND AIM: Anaesthesia for cleft surgery in children is associated with a variety of airway related problems. This study aims to review the frequency of associated anomalies and other conditions as well as perioperative respiratory complications during the cleft lip/palate repair surgeries. METHODS: An audit of 1000 cleft surgeries in children enrolled under "Smile Train" is presented. Following informed consent, general anaesthesia was induced with endotracheal (ET) intubation using halothane in O2 and/or intravenous thiopentone 5 mg/kg or propofol 1.5 mg/kg, suxamethonium 1.5 mg/kg or rocuronium 0.8 mg/kg and maintained with halothane/isoflurane 0.4-1% in 50% N2O in O2 with rocuronium. The observational data regarding the occurrence of perioperative complications in 1000 cleft surgeries are mentioned as mean (standard deviation), number and percentage as appropriate. 'Two sample t-test between percentage' is applied for significance. RESULTS: The frequency of isolated cleft lip was 263 (36.4%), cleft palate 183 (25.3%) and combined defect 277 (38.3%) of the operated cases. Other congenital anomalies were present in 21 (2.8%) of the children. The intraoperative airway complications occurred in 13 (2.4%) of cleft lip and 40 (8.7%) of cleft palate repairs (P < 0.05). Post-operative respiratory complications were observed in 9 (1.7%) and 34 (7.4%) patients of cleft lip and palate repairs respectively (P < 0.05). Mortality occurred post-operatively in 2 (0.2%) of cleft repairs (n = 1000). CONCLUSION: Cleft deformities in children when associated with other congenital anomalies or respiratory problems pre dispose them to difficult airway and pulmonary complications. Frequency of perioperative respiratory complications were significantly higher with cleft palate repair than with cleft lip repair. Anaesthetic expertise, optimum monitoring facility and specialised post-operative care is necessary to decrease the morbidity. PMID- 24403616 TI - Difficult laryngoscopy and intubation in the Indian population: An assessment of anatomical and clinical risk factors. AB - BACKGROUND AND AIM: Differences in patient characteristics due to race or ethnicity may influence the incidence of difficult airway. Our purpose was to determine the incidence of difficult laryngoscopy and intubation, as well as the anatomical features and clinical risk factors that influence them, in the Indian population. METHODS: In 330 adult patients receiving general anaesthesia with tracheal intubation, airway characteristics and clinical factors were determined and their association with difficult laryngoscopy (Cormack and Lehane grade 3 and 4) was analysed. Intubation Difficulty Scale score was used to identify degree of difficult laryngoscopy. RESULTS: The incidence of difficult laryngoscopy and intubation was 9.7% and 4.5%, respectively. Univariate analysis showed that increasing age and weight, male gender, modified Mallampati class (MMC) 3 and 4 in sitting and supine positions, inter-incisor distance (IID) <=3.5 cm, thyromental (TMD) and sternomental distance, ratio of height and TMD, short neck, limited mandibular protrusion, decreased range of neck movement, history of snoring, receding mandible and cervical spondylosis were associated with difficult laryngoscopy. Multivariate analysis identified four variables that were independently associated with difficult laryngoscopy: MMC class 3 and 4, range of neck movement <80 degrees , IID <= 3.5 cm and snoring. CONCLUSIONS: We found an incidence of 9.7% and 4.5% for difficult laryngoscopy and difficult intubation, respectively, in Indian patients with apparently normal airways. MMC class 3 and 4, range of neck movement <80 degrees , IID <= 3.5 cm and snoring were independently related to difficult laryngoscopy. There was a high incidence (48.5%) of minor difficulty in intubation. PMID- 24403617 TI - Effect of hyperosmolar sodium lactate infusion on haemodynamic status and fluid balance compared with hydroxyethyl starch 6% during the cardiac surgery. AB - BACKGROUND AND AIM: No solution has been determined ideal for fluid therapy during cardiac surgery. Previous studies have shown that hyperosmolar sodium lactate (HSL) infusion has improved cardiac performance with smaller volume infusion, which resulted in negative fluid balance. This study compared the effects between a patent-protected HSL infusion and hydroxyethyl starch (HES) 6% on haemodynamic status of the patients undergoing cardiac surgery. METHODS: In this open-label prospective controlled randomized study, patients were randomly assigned to receive loading dose of either HSL or HES 6%, at 3 mL/kgBW within 15 min, at the beginning of surgery. Haemodynamic parameters and fluid balance were evaluated, while biochemical parameters and any adverse effect were also recorded. Haemodynamic and laboratory parameters were analyzed through repeated measures analysis of variance. Statistical assessment of fluid management was carried out through Student t-test. All statistical analyses were performed using the statistical package for the social sciences((r)) version 15, 2006 (SPSS Inc., Chicago, IL). RESULTS: Out of 100 enrolled patients in this study (50 patients in each arm), 98 patients were included in analysis (50 in HSL group; 48 in HES group). Cardiac index increased higher in HSL group (P = 0.01), whereas systemic vascular resistance index decreased more in HSL than HES group (P = 0.002). Other haemodynamic parameters were comparable between HSL and HES group. Fluid balance was negative in HSL group, but it was positive in HES group (-445.94 +/- 815.30 mL vs. +108.479 +/- 1219.91 mL, P < 0.009). CONCLUSION: Administration of HSL solution during the cardiac surgery improved cardiac performance and haemodynamic status better than HES did. PMID- 24403618 TI - Nebulised fentanyl for post-operative pain relief, a prospective double-blind controlled randomised clinical trial. AB - BACKGROUND AND AIM: Intravenous (IV) route for fentanyl administration is the gold standard for post-operative pain relief, but complications such as respiratory depression, bradycardia and hypotension have limited this route. The aim of this randomised controlled trial was to compare the efficacy of nebulised fentanyl with IV fentanyl for post-operative pain relief after lower abdominal surgery. METHODS: In the post-operative care unit, at the time of first onset of pain (visual analogue scale- VAS score > 4) patients were randomised into three groups and fentanyl was administered either IV 2 MUg/kg or by nebulisation of solution containing 3 or 4 MUg/kg fentanyl over 8 min in 90 patients divided into three groups of 30 each. Observation were made for pain relief by visual analogue scale score 0-10. Adverse effects such as respiratory depression, bradycardia and hypotension were also recoded. Statistical analysis was performed using Medcalc software version 12, 2012. (MedCalc Software, Ostend, Belgium). RESULTS: In the nebulisation group, it was observed that the analgesic efficacy of fentanyl was dose dependent with a delayed onset of analgesia (10 min vs. 5 min). Nebulisation with 4 MUg/kg fentanyl produced analgesia at par to 2 MUg/kg IV fentanyl with prolonged duration (90 min vs. 30 min) and with significantly less adverse effects. CONCLUSIONS: This study shows that nebulisation with 4 MUg/kg fentanyl may be used as an alternative to IV 2 MUg/kg fentanyl for adequate post-operative pain relief. PMID- 24403619 TI - The P-POSSUM scoring systems for predicting the mortality of neurosurgical patients undergoing craniotomy: Further validation of usefulness and application across healthcare systems. AB - BACKGROUND AND AIMS: Continuous audit of clinical practice is an essential part of making improvements in medicine and enhancing patient care. Validated tools are needed to gather evidence for comparisons. Recently, Physiological and Operative Severity Score for the enumeration of Mortality and morbidity (POSSUM) and Portsmouth-POSSUM (P-POSSUM) scores were evaluated in Indian patients undergoing elective craniotomy and it was concluded that P-POSSUM was highly accurate in predicting overall mortality. We wished to study whether this system could be used in a different country and health care system [United Kingdom, UK]. We have evaluated these scores in patients undergoing elective and emergency craniotomies in a tertiary centre in the UK. METHODS: Data was collected from all neurosurgical patients who underwent craniotomy overone year. Preoperative variables were collected prior to induction of anaesthesia, and operative variables were also collected. Chi-square test was used for expected and actual mortality differences. Survivor and non-survivor demographics were compared by one-way ANOVA for continuous and Chi-square for categorical variables. RESULTS: One hundred and forty-five patients were studied. Mean [SD] physiologic score of the patients was 18.83 [5.07], and mean [SD] operative score was 18.09 [3.75]. P POSSUM was a better predictor for elective patients and for those undergoing immediate life-saving surgery. CONCLUSION: This study confirms and validates the findings of previous work that P-POSSUM is an accurate and reliable tool for estimating in-hospital mortality. It also confirms its usefulness in comparison of results across healthcare systems internationally. Larger scale evaluations may be needed to examine its usefulness in emergency procedures. PMID- 24403620 TI - Airway management in cervical spine ankylosing spondylitis: Between a rock and a hard place. AB - We report the perioperative course of a patient with long standing ankylosing spondylitis with severe dysphagia due to large anterior cervical syndesmophytes at the level of the epiglottis. He was scheduled to undergo anterior cervical decompression and the surgical approach possibly precluded an elective pre operative tracheostomy. We performed a modified awake fibreoptic nasal intubation through a split nasopharyngeal airway while adequate oxygenation was ensured through a modified nasal trumpet inserted in the other nares. We discuss the role of nasal intubations and the use of both the modified nasopharyngeal airways we used to facilitate tracheal intubation. This modified nasal fibreoptic intubation technique could find the application in other patients with cervical spine abnormalities and in other anticipated difficult airways. PMID- 24403621 TI - Anaesthetic management in a child with an atypical triad for reconstructive scoliosis surgery. AB - Scoliosis may be of varied aetiology and may be associated with severe congenital anomalies. It often poses a challenge in its anaesthetic management. We present anaesthetic management of a child who underwent scoliosis reconstruction with a rare triad of cerebral palsy, glucose-6-phosphate dehydrogenase deficiency and severe mitral regurgitation. Anaesthetic management in these patients should focus primarily on associated co-morbidities and congenital anomalies affecting the course of the perioperative management and thereafter comprehensive pre operative strategies must be executed to enhance the safety profile during the surgery. PMID- 24403622 TI - Perioperative management of liver transplantation with concurrent coronary artery disease: Report of two cases. AB - Coronary artery disease (CAD), even if asymptomatic, has been known to complicate the perioperative management of patients undergoing liver transplantation. Perioperative outcome for such patients is worse than those without CAD despite improvement in risk stratification and management of CAD. We hereby report the successful perioperative management of two patients with CAD undergoing living related liver transplantation. Maintaining systemic vascular resistance, goal directed volume administration and surgical technique avoiding total clamping of IVC was the mainstay of stable intraoperative course. Moreover, a lower model for end stage liver disease (MELD) score at the time of liver transplant may also have been contributory to successful outcome in our patients. PMID- 24403623 TI - Airway management in Escobar syndrome: A formidable challenge. AB - Escobar syndrome is a rare autosomal recessive disorder characterized by flexion joint and digit contractures, skin webbing, cleft palate, deformity of spine and cervical spine fusion. Associated difficult airway is mainly due to micrognathia, retrognathia, webbing of neck and limitation of the mouth opening and neck extension. We report a case of a 1 year old child with Escobar syndrome posted for bilateral hamstrings to quadriceps transfer. The child had adequate mouth opening with no evidence of cervical spine fusion, yet we faced difficulty in intubation which was ultimately overcome by securing a proseal laryngeal mask airway (PLMA) and then by intubating with an endotracheal tube railroaded over a paediatric fibreoptic bronchoscope passed through the lumen of a PLMA. PMID- 24403624 TI - Anaesthetic management of two different cases of mediastinal mass. AB - We report the management of two paediatric cases undergoing median sternotomy and right lateral thoracotomy for mediastinal mass. An 8-year-old boy presented with a history of intermittent fever and episodes of respiratory illness since 3 years and a 16-year-old girl presented with dyspnoea, cough, fever and dysphagia for solid foods. Radiological investigation confirmed the diagnoses. Absence of pressure symptoms pointed towards a compressible mass in the boy and indicated a non-compressible mass in the girl. We discuss the anaesthetic management of the younger patient with an uneventful course as opposed to the older patient where airway obstruction ensued soon after induction and led to near-cardiopulmonary arrest necessitating rescue measures. Swift measures at securing airway while simultaneously resuscitating the patient served to successfully revert an otherwise fateful eventuality. PMID- 24403625 TI - Ultrasound guided percutaneous electro-coagulation of ilioinguinal and iliohypogastric nerves for treatment of chronic groin pain. PMID- 24403626 TI - Laparoscopic surgeries during second and third trimesters of pregnancy in a tertiary care centre in South India: Anaesthetic implications and long-term effects on children. PMID- 24403627 TI - Unusual occurrence of massive subcutaneous emphysema during ERCP under general anaesthesia. PMID- 24403628 TI - Airway management for tracheal stent insertion in a patient with difficult airway. PMID- 24403629 TI - Airway management in severe post-burn contracture of the neck using Airtraq: A case series. PMID- 24403630 TI - Tracheal perforation in a neonate: A devastating complication following traumatic endotracheal intubation. PMID- 24403631 TI - Neuraxial block in a patient with dural ectasia. PMID- 24403632 TI - A rare case of fatal acute respiratory distress syndrome following diesel oil siphonage. PMID- 24403633 TI - Neuraxial techniques in patients with lumbar tattoos: A national survey from New Zealand. PMID- 24403634 TI - Phenytoin induced sinoatrial bradyarrhythmia in the perioperative period. PMID- 24403635 TI - Impacted foreign body bronchus: Role of percussion in removal. PMID- 24403636 TI - An indigenous method to prevent intraoperative kinking of gas sampling line. PMID- 24403637 TI - Anaesthesia challenges in Freeman-Sheldon syndrome. PMID- 24403638 TI - Ginko biloba may cause asymptomatic ventricular premature contractions! PMID- 24403639 TI - Use of laryngeal mask airway in premature infant. PMID- 24403640 TI - Comment on "Anaesthetic management of a patient with amyotrophic lateral sclerosis for transurethral resection of bladder tumour". PMID- 24403641 TI - Response to Comments: Anaesthetic management of a patient with amyotrophic lateral sclerosis for transurethral resection of bladder tumour. PMID- 24403642 TI - Comment on "Spinal anaesthesia in poliomyelitis patients with scoliotic spine: A case control study". PMID- 24403643 TI - Response to Comments: Spinal anaesthesia in poliomyelitis patients with scoliotic spine: A case control study. PMID- 24403645 TI - Educational Paths and Substance Use from Adolescence into Early Adulthood. AB - This study examined how substance use trajectories from ages 15 to 23 in a community sample (N=921) were related to educational pathways. Rates of heavy drinking converged across different paths, but starting college at a 2-year college before transferring to a 4-year college was related to later increase in drinking after high school. Higher future educational attainment was negatively associated with high school marijuana use, but marijuana use increased after high school for individuals who went to 4-year colleges compared to those who did not. Noncollege youth had the highest rates of daily cigarette smoking throughout adolescence and early adulthood, while college dropouts had higher rates of smoking than college students who did not drop out. The findings support the need for universal prevention for early adult heavy drinking, addressing increases in drinking and marijuana use in 4-year colleges, and targeting marijuana use and cigarette smoking interventions at noncollege youth and college dropouts. PMID- 24403644 TI - Understanding the Molecular Basis of RNA Polymerase II Transcription. AB - Synthetic nucleic acid analogues have profoundly advanced our knowledge of DNA and RNA, as well as the complex biological processes that involve nucleic acids. As a pivotal enzyme, eukaryotic RNA polymerase II (Pol II) is responsible for transcribing DNA into messenger RNA, which serves as a template to direct protein synthesis. Chemically modified nucleic acid analogues have greatly facilitated the structural elucidation of RNA Pol II elongation complex and understanding the key chemical interactions governing RNA Pol II transcriptional fidelity. This review addresses major progress in RNA polymerase II mechanistic studies using modified nucleic acid analogues in recent years. PMID- 24403646 TI - Using the Stereotype Content Model to examine group depictions in Fascism: An Archival Approach. AB - The Stereotype Content Model (SCM) suggests potentially universal intergroup depictions. If universal, they should apply across history in archival data. Bridging this gap, we examined social groups descriptions during Italy's Fascist era. In Study 1, articles published in a Fascist magazine- La Difesa della Razza were content analyzed, and results submitted to correspondence analysis. Admiration prejudice depicted ingroups; envious and contemptuous prejudices depicted specific outgroups, generally in line with SCM predictions. No paternalistic prejudice appeared; historical reasons might explain this finding. Results also fit the recently developed BIAS Map of behavioral consequences. In Study 2, ninety-six undergraduates rated the content-analysis traits on warmth and competence, without knowing their origin. They corroborated SCM's interpretations of the archival data. PMID- 24403647 TI - Lifecourse Priorities Among Appalachian Emerging Adults: Revisiting Wallace's Organization of Diversity. AB - We examine how social demographics (gender, age, or race-ethnicity), census tract characteristics, and family environment during childhood relate to variability in the lifecourse priorities of 344 Cherokee and white youth during emerging adulthood (age 19-24). Analyses were performed using recursive partitioning and random forest methods to examine determinants of prioritizing education, family formation, economic establishment, self characteristics and close relationships, youth independence, conspicuous consumption, and community reliance. Overall, characteristics of census tracts were the most common and influential predictors of lifecourse priorities. Childhood family poverty, parental relationship problems, parental crime, and stressful life events were also important predictors. Race-ethnicity or cultural group (Cherokee vs. white), age, and gender were relatively unimportant. At this developmental stage and in this population, community characteristics and childhood family experiences may be better proxies for developmental settings (and resulting enculturated values and preferences) than social demographic variables (e.g., ethnicity or gender). PMID- 24403648 TI - Histogram Curve Matching Approaches for Object-based Image Classification of Land Cover and Land Use. AB - The classification of image-objects is usually done using parametric statistical measures of central tendency and/or dispersion (e.g., mean or standard deviation). The objectives of this study were to analyze digital number histograms of image objects and evaluate classifications measures exploiting characteristic signatures of such histograms. Two histograms matching classifiers were evaluated and compared to the standard nearest neighbor to mean classifier. An ADS40 airborne multispectral image of San Diego, California was used for assessing the utility of curve matching classifiers in a geographic object-based image analysis (GEOBIA) approach. The classifications were performed with data sets having 0.5 m, 2.5 m, and 5 m spatial resolutions. Results show that histograms are reliable features for characterizing classes. Also, both histogram matching classifiers consistently performed better than the one based on the standard nearest neighbor to mean rule. The highest classification accuracies were produced with images having 2.5 m spatial resolution. PMID- 24403649 TI - Systematic Approach for Trace Level Quantification of 2-N-butyl-4 spirocyclopentane-2-imidazole-5-one Genotoxic Impurity in Irbesartan Using LC MS/MS. AB - 2-N-butyl-4-spirocyclopentane-2-imidazoline-5-one has been highlighted as a potential genotoxic impurity in irbesartan. A sensitive LC-MS/MS method was developed and validated for the determination of 2-N-butyl-4-spirocyclopentane-2 imidazoline-5-one in irbesartan. Good separation between 2-N-butyl-4 spirocyclopentane-2-imidazoline-5-one and irbesartan was achieved with Symmetry C18 (100*4.6 mm, 3.5 MUm) column using 65:35 v/v mixture of 0.1% formic acid and acetonitrile as mobile phase with a flow rate of 0.7 ml/min. The proposed method was specific, linear, accurate, and precise. The calibration curve shows good linearity over the concentration range of 0.1-2.0 MUg/ml, which matches the range of limit of quantitation-20*limit of quantitation of estimated permitted level (1.0 MUg/ml) of 2-N-butyl-4-spirocyclopentane-2-imidazoline-5-one. The method was validated as per International Conference on Harmonization guidelines and was able to quantitate 2-N-butyl-4-spirocyclopentane-2-imidazoline-5-one impurity at 1.0 MUg/ml with respect to 2 mg/ml of irbesartan. 2-N-butyl-4-spirocyclopentane-2 imidazoline-5-one was not present in the three studied pure and formulation batches of irbesartan and the developed method was a good quality control tool for quantitation of 2-N-butyl-4-spirocyclopentane-2-imidazole-5-one at very low levels in irbesartan. PMID- 24403651 TI - Evaluation of Antitumor and Antioxidant Activity of Melothria heterophylla (Lour.) Cogn. AB - Melothria heterophylla (Lour.) Cogn., (family-Cucurbitaceae) popularly known as kundari, has been shown to exhibit antioxidant effects. The main objective was to isolate active constituents of the plant extract. In this study, the ability of M. heterophylla to induce apoptosis was studied in Ehrlich ascites carcinoma cells. Treatment of the Ehrlich ascites carcinoma cells with a variety of concentrations of the ethanol extracts of M. heterophylla and gallic acid (100 1000 MUM), to determine the sequences of events marked by apoptosis, assayed by the spectrofluorometric method. Gallic acid and rutin were isolated from plant extract which were quantified by high-performance liquid chromatography. Our results indicate that ethanol extracts of M. heterophylla and gallic acid-induced apoptotic cell death in a dose dependent manner could be due to the generation of reactive oxygen species, especially H2O2, which is confirmed by caspase 3 activation. Treatment of Ehrlich ascites carcinoma bearing Swiss albino mice with varied doses (200 and 400 mg/kg, b.w.) of plant extract significantly reduced tumor volume and viable tumor cell count and improved hemoglobin content, RBC count, mean survival time, tumor inhibition, and percentage life span. The enhanced antioxidant status in extract-treated animals were evident from the decline in the levels of lipid peroxidation and increased levels of glutathione, catalase, and superoxide dismutase. The data suggest that M. heterophylla exerts anticancer activity, valuable for application in food and drug products. PMID- 24403650 TI - A Novel Metabolite from Aspergillus ochraceus JGI 25 Showing Cytotoxicity to Hela Cells. AB - This study aims at the isolation of filamentous fungi, extraction of metabolites, and evaluation of the cytotoxic properties on HeLa cells and normal human lymphocytes. We isolated fungi from the soil by serial dilution method. One of the isolates was chosen and identified as Aspergillus ochraceus Wilhelm (Trichocomaceae) by standard techniques. The metabolites were extracted using methanol. Different concentrations of the extract were evaluated for their potential anticancer activity on HeLa cells by 3-(4,5-dimethylthiazol-2yl)-2,5 diphenyl tetrazolium bromide assay and the safety of the extract was checked on normal human lymphocytes. The extract was purified by chromatographic techniques like thin-layer chromatography and high-performance liquid chromatography, and subjected to mass spectrometric analysis. The extract showed significant cytotoxic potential on HeLa cells at low concentrations with a half maximal inhibitory concentration value of <50 MUg/ml. The extract gave 10 fractions by thin layer chromatography, and fraction B had higher toxicity than the rest. This fraction gave a single peak by high-performance liquid chromatography and had a mass-to-charge ratio of 905.65, which did not match any of the earlier known fungal metabolites or metabolites from other strains of A. ochraceus. The metabolite from A. ochraceus is alkaloid in nature, cytotoxic to HeLa cells, and appears to be a novel with anticancer potentials, which could be explored further for characterization of the active component. PMID- 24403652 TI - Drug resinates an attractive approach of solubility enhancement of atorvastatin calcium. AB - A substantial number of new chemical entities and marketed drugs show poor solubility characteristics and amorphisation is one of the favorable approaches to enhance solubility characteristics of such poorly soluble drugs. Formulation efforts in the present study were devoted to investigate amorphisation of a model poorly soluble drug, atorvastatin calcium by molecular complexation with anion exchange resin, Duolite((r))AP 143/1093 and hence enhancement in its solubility characteristics. Drug resinates in 1:1, 1:2, and 1:4 weight ratios were prepared by simple batch operation and subsequently studied for drug content, residual solvent content, molecular interactions, solid state characterisation and solubility characteristics. During initial characterisation, all the proportions of drug resinates, except 1:1 proportion showed partial amorphisation of the drug, whereas 1:1 proportion showed complete amorphisation of the drug. This proportion reported distinctly enhanced solubility characteristics over pure drug and other proportions. Such amorphisation and solubility enhancement could be attributed to the binding of individual drug molecules to the functional sites of the resin molecules, either partially or completely, resulting in reduction of crystal lattice energy, a main barrier to dissolution. Hydrophilic nature of ion exchange resin matrices also assisted in enhancing dissolution of the drug from the resinates. During accelerated stability study, there was an insignificant decrease in solubility characteristics of the drug and its amorphous form was also found to be stable in 1:1 proportion. Atorvastatin resinates formed in 1:1 weight ratio were in stoichiometric proportion and such drug resinates in stoichiometric proportion showed to have tremendous potential in conversion of crystalline form of drug substances to its amorphous form and subsequent stabilisation. It hence proved to be a very effective, yet simple approach for improving solubility characteristics of poorly soluble actives. PMID- 24403653 TI - Effects of Methanol Extract of Wedelia chinensis Osbeck (Asteraceae) Leaves against Pathogenic Bacteria with Emphasise on Bacillus cereus. AB - The antibacterial activity of the methanol extract of Wedelia chinensis leave was studied and tested against three pathogenic Gram positive bacteria (Bacillus cereus, B. subtilis and Stapylococcus aureus) and three pathogenic Gram negative bacteria (Escherichia coli, Proteus rettgeri and Pseudomonas aeruginosa) by the disk diffusion assay and broth dilution methods. The extract exhibited favourable antibacterial activity against the bacterial cells but was more potent against Gram positive bacteria with the minimum inhibition concentration of 3.12 to 6.25 mg/ml compared to the Gram negative bacteria which had minimum inhibition concentration values of 25 mg/ml. The time-kill study suggested that the extract possessed bactericidal properties at higher concentrations and eradicated the growth of bacterial cells. The major abnormalities occurred to the bacterial cells after exposed to the extract were complete alterations in their morphology and collapsed of the cells beyond repair. The methanol extract of W. chinensis may be an effective antibacterial agent to treat bacterial infections. PMID- 24403654 TI - Study the Expression of ompf Gene in Esherichia coli Mutants. AB - The outer membrane porin proteins are the major factors in controlling the permeability of cell membrane. OmpF is an example of porin proteins in Esherichia coli. In normal growth condition a large amount of this protein is synthesised, but under stress condition, such as the presence of antibiotics in environment its expression is decreased inhibiting the entrance of antibiotics into cell. The expression of ompF is inhibited by antisense RNA transcribed from micF. In normal condition the expression of micF is low, but in the presence of antibiotics its expression is increased and causes multiple resistances to irrelevant antibiotics. The aims of this research were to study first, the intactness of micF and then quantify the expression of ompF in ciprofloxacin and tetracycline resistant mutants of E. coli. For this purpose the 5' end of micF was amplified and then sequenced. None of these mutants except one and its clone has a mutation in this gene. Then the relative expression of ompF in these mutants was quantified by real time PCR. There was no significant difference between ompF transcription of mutants and wild type strain. Based on this study and previous study it is concluded that low to intermediate levels of resistance to ciprofloxacin and tetracycline does not decrease ompF transcription. PMID- 24403655 TI - Synthesis and Antimicrobial Evaluation of Some New Thiazoline and Thiazolidinone Derivatives Incorporating [1,2,4]Triazolo[1,5-a]benzimidazole. AB - Two new series of 3-[2-(3,4-disubstituted-2,3-dihydrothiazol-2 ylidene)hydrazonopropylidenyl]-2-(methylthio)-3H-[1,2,4]triazolo[1,5 a]benzimidazole (6-29) and 3-[2-(3-substituted-4-oxothiazolidin-2 ylidene)hydrazonopropylidenyl]-2-(methylthio)-3H-[1,2,4]triazolo[1,5 a]benzimidazole (30-33) were synthesised starting from 1-[2-(methylthio)-3H [1,2,4]triazolo[1,5-a]benzimidazol-3-yl] acetone N(4)-alkyl (aryl) thiosemicarbazones (2-5). Chemical structures of the compounds have been elucidated by different spectral data as well as elemental microanalysis. The newly synthesised compounds were tested for their in vitro antimicrobial activity using the standard agar cup diffusion method. Results revealed that most of the test compounds showed promising broad spectrum antibacterial and antifungal profiles against tested microorganisms, relative to references. PMID- 24403656 TI - Patient Medication Adherence and Physician Prescribing among Congestive Heart Failure Patients of Yemen. AB - Congestive heart failure has been associated with high morbidity and mortality requiring hospitalisation and is further complicated by noncompliance and under prescriptions. We aim to determine medication adherence and percentage deviation among Asians population in general and Yemenis in particular. A cross-sectional, prospective observational study with purposive sampling was conducted at two cardiac outpatient centers in 70 congestive heart failure patients for a period of 3 months. An Arabic translated Morisky 4 item scale assessed the adherence of patients. Deviation in prescribing was determined by chart review. All 70 patients had mean age of 56.6+/-16 years. Morisky 4 item scale predicted low adherence (n=33; 47.1%) and overall nonadherencerate (n=38; 54.2%) was slightly higher than adherence. Percentage nonadherence versus adherence was high with diuretics (53 vs. 46%) and, digoxin (40 vs. 29%). The adherence percentage of angiotensin receptor blockers (9%) and beta blockers (8%) was low. Diuretics were the most prescribed drugs (n=69; 99%), followed by angiotensin converting enzyme inhibitors (n=51; 73%), cardiac glycoside (n=48; 69%), few patients were on angiotensin receptor blockers (n=8; 11%) and (n=9; 13%) beta blockers. The maximum prescribing rate deviation was seen with angiotensin receptor blockers ( 89%) and beta blockers (-87%) followed by nitrates (-77%). Digoxin (-31%) and angiotensin converting enzymes (-27%) deviated comparatively less. Prescribing as well as utilisation rates generally were low resulting in nonachievement of therapeutic goals which could be resolved using multimodel approach. PMID- 24403657 TI - Spectrofluorimetric Determination of alpha-Tocopherol in Capsules and Human Plasma. AB - A simple, sensitive and rapid spectrofluorimetric method for determination of alpha-tocopherol in pharmaceutical capsule and human plasma was developed and validated. The native fluorescence of alpha-tocopherol was measured at 334 nm with excitation at 291 nm, after extraction of alpha-tocopherol from human plasma hexane:dichloromethane mixture. The calibration curves were linear (R>=0.9993) in the concentration range of 0.25-2.5 MUg/ml of alpha-tocopherol in both standard solutions and plasma samples. The developed method was directly and easily applied for determination of alpha-tocopherol in the plasma of healthy volunteers and different type of bladder cancer and stomach cancer patients and also pharmaceutical capsule. PMID- 24403658 TI - Ketotifen Fumarate and Salbutamol Sulphate Combined Transdermal Patch Formulations: In vitro release and Ex vivo Permeation Studies. AB - The present work was performed to develop and evaluate transdermal patches of combined antiasthmatic drugs (salbutamol sulphate and ketotifen fumarate). Polyvinyl alcohol membrane was used as backing membrane and eudragit RL-100 was used as matrix material to suspend the drugs in the continuous thickness of the patch. Methanol was solvent and propylene glycol was used as plasticizer. Tween 20, isopropyl myristate, eucalyptus oil, castor oil and span-20 were used as permeability enhancers. Thickness, weight variation and drug uniformity were investigated. The patch formulations were also subjected to drug release in dissolution media and permeation through rabbit skin. Effects of different enhancers were evaluated on release and permeation of drugs. F3 formulations having isopropyl myristate as permeation enhancer, showed maximum amounts of drugs release (88.11% of salbutamol sulphate and 88.33% of ketotifen fumarate) at the end of 24 h dissolution study. F3 also showed maximum permeation of both drugs (4.235 mg salbutamol sulphate and 1.057 mg ketotifen fumarate) after 24 h permeation study through rabbit skin mounted in Franz cell. The patches having no enhancer in the formulation also showed some drug release and permeation due to the presence of plasticizer. The results of the study suggested that new controlled release transdermal formulations of combined antiasthmatic drugs can be suitably developed as an alternate to conventional dosage forms. PMID- 24403659 TI - Antiproliferative Activity of the Chinese Medicinal Compound, Delisheng, Compared With Rg3 and Gemcitabine in HepG2 Cells. AB - Delisheng consists of radix ginseng, radix astragali, venenum bufonis and mylabris. It has been reported that delisheng inhibits the proliferation of adenocarcinoma cells and stimulates their apoptosis. Delisheng can also enhance the body's immunity and induce the redifferentiation of carcinoma cells. Delisheng inhibited the proliferation of HepG2 cells in MTT assay and promoted apoptosis more effectively in contrast to the active components of ginseng extract, Rg3 and gemcitabine. It is possible that Rg3 has an important role in delisheng because they all could regulate the cell cycle, apoptosis and expression of endostatin and VEGFR-2. Delisheng caused the cell cycle to arrest at the S phase, while gemcitabine blocked the cells at the G0/G1 phase in cell cycle analysis. Consequently, the apoptosis rate of the HepG2 cell line can be increased significantly by delisheng in combination with gemcitabine, compared with the single drug. The expression of the procaspase proteins, caspase protein, and dr5 detected by Western blot were increased while bcl-2 and survivin decreased in the delisheng group, compared with controls. The observations suggest that the delisheng induced apoptotic effect might be closely related to the mitochondrial apoptosis pathway, and the death receptor signaling pathway. PMID- 24403660 TI - Preparation and characterisation of fluconazole vaginal films for the treatment of vaginal candidiasis. AB - Objective of the present study was to develop and evaluate vaginal films with essential in vitro studies. Films were developed using hydroxypropyl methylcellulose as a polymer and formulations were coded. The developed films were evaluated with Fourier transform infrared spectroscopy, drug content, viscosity, surface pH, thickness, mechanical characterisation and in vitro drug release study. Fourier transform infrared spectroscopy results confirmed that there is no chemical interaction between drug and stabilisers/excipients. The batch variation was not more than 5% for average thickness and weight of the films. The drug content for the prepared formulation was in the range of 72.32+/ 0.18% to 94.48+/-0.54%. Viscosity of the formulations increased with the increase in concentration of polymer. Mechanical characterisation revealed that tensile strength and percentage elongation of the films improved as there is increase in degree of substitution of the polymer, but the values of modulus decreased which confirmed that all the prepared films are soft in nature. The in vitro study indicated that 1 and 2% concentrations of polymer are the least concentrations to control the release of drug whereas the 4% concentration of polymer is a good and more effective concentration to control the release. Only one prepared formulation released the drug by following anomalous transport whereas other film formulations released the fluconazole by following Fickian diffusion mechanism. Prepared vaginal films may be an important alternative for the treatment of vaginal candidiasis, because these prepared films suggest the benefits of controlled release of fluconazole at the site of absorption. PMID- 24403661 TI - Simvastatin Solid Lipid Nanoparticles for Oral Delivery: Formulation Development and In vivo Evaluation. AB - Solid lipid nanoparticles have been increasingly utilised for improving oral bioavailability of drugs. Simvastatin is biopharmaceutical class 2 drug with poor oral bioavailability of 5%. In the present study, simvastatin solid lipid nanoparticles were successfully prepared by hot melt emulsification process and optimised with respect to surfactant and lipid concentration, and drug loading. The nanoparticles were characterised for entrapment efficiency, particle size, morphology, crystallinity and thermal behavior. Optimised formulations prepared from solid lipids glyceryl behenate and glyceryl palmitostearate containing Tween 80 as surfactant exhibited satisfactory entrapment efficiencies above 96% and mean particle size below 200 nm. The electron micrographs indicated that lipid nanocarriers were almost spherical in appearance. X-ray diffraction and differential calorimetric studies proved that the drug was amorphised in the lipid matrix and did not crystallise out. To improve the physical as well as chemical stability of formulations, dry adsorbed nanoparticles were prepared by evaporative drying method using a carrier. The adsorbed nanoparticles demonstrated good flow properties and satisfactory reconstitution properties. Pharmacodynamic studies of simvastatin solid lipid nanoparticles revealed improved reduction in total cholesterol values as compared to pure drug powder indicating improved bioavailability. PMID- 24403662 TI - Development and Validation of RP-HPLC Method for the Simultaneous Estimation of Montelukast Sodium and Ebastine in Tablet Dosage Form. AB - A rapid and sensitive RP-HPLC method with UV detection (244 nm) for routine analysis of montelukast sodium and ebastine in a pharmaceutical formulation (Ebast-M) was developed. Chromatography was performed with mobile phase containing a mixture of methanol:acetonitrile:ammonium acetate (80:10:10, % v/v/v), pH of mobile phase was adjusted 5.5 using glacial acetic acid and flow rate was 1.2 ml/min. The method was validated for linearity, accuracy, robustness and intermediate precision. The linearity was established over the concentration range of 0.01-0.06 mg/ml for both drugs. The correlation coefficients (r (2)) for ebastine and montelukast were 0.9989 and 0.9955, respectively. Statistical analysis of the data showed that the method was precise, accurate, reproducible and selective for the analysis of ebastine and montelukast drugs. The method was successfully employed for the determination of ebastine and montelukast in commercially available tablet dosage form. PMID- 24403663 TI - Azadirachta indica Attenuates Colonic Mucosal Damage in Experimental Colitis Induced by Trinitrobenzene Sulfonic Acid. AB - Azadirachta indica leaves indicated the presence of active principles with proven antioxidants, antiinflammatory, immunomodulatory, free radical scavenging and healing properties. In the present study we evaluated the healing effects of 50% ethanol extract of dried leaves of Azadirachta indica on trinitrobenzene sulfonic acid-induced colitis in rats. Azadirachta indica extract (500 mg/kg) was administered orally, once daily for 14 days and studied for its effects on diarrhoea, food and water intake, body weight changes, colonic damage and inflammation, histology, antibacterial activity and free radicals (nitric oxide and lipid peroxidation), antioxidants (superoxide dismutase, catalase and reduced glutathione) and myeloperoxidase activities in colonic tissue. Intracolonic trinitrobenzene sulfonic acid increased colonic mucosal damage and inflammation, diarrhea, but decreased body weight which were reversed by Azadirachta indica extract and sulfasalazine (positive control) treatments. Azadirachta indica extract showed antibacterial activity. Azadirachta indica extract and sulfasalazine enhanced the antioxidants but decreased free radicals and myeloperoxidase activities affected in trinitrobenzene sulfonic acid-induced colitis. Azadirachta indica extract, thus seemed to be effective in healing trinitrobenzene sulfonic acid-induced colitis in rats. PMID- 24403664 TI - Biosynthesis of Silver Nanoparticles from Marine Seaweed Sargassum cinereum and their Antibacterial Activity. AB - Seaweed extracts of Sargassum cinereum was used as a reducing agent in the eco friendly extracellular synthesis of silver nanoparticles from an aqueous solution of silver nitrate (AgNO3). High conversion of silver ions to silver nanoparticles was achieved with a reaction temperature of 100( degrees ) and a seaweed extract concentration of 10% with a residential time of 3 h. Formation of silver nanoparticles was characterised by spectrophotometry and the scanning electron microscope. The average particles size was ranging from 45 to 76 nm. Antimicrobial activities indicate the minimum inhibitory concentration of biologically synthesised nanoparticles tested against the pathogen Staphylococcus aureus with 2.5 MUl (25 MUg/disc). High inhibitions over the growth of Enterobacter aerogenes, Salmonella typhi and Proteus vulgaris were witnessed against the concentrations of 100 MUg/disc. Promising potential and the future prospects of S. cinereum nanoparticles in pharmaceutical research are the highlights in this paper. PMID- 24403665 TI - Antidiabetic and Antioxidant Activity of Scoparia dulcis Linn. AB - The hypoglycaemic activity of methanol extract of Scoparia dulcis was performed on both in vitro and in vivo models along with determination of total extractable polyphenol. Methanol extract of Scoparia dulcis contains 4.9% and water extract contains 3.2% of total extractable polyphenol. The antioxidant activity showed very promising result in both the tested methods that is 2,2-diphenyl-1 picrylhydrazyl and ferric ion reducing capacity. The antioxidant activity is directly correlated to the antidiabetic potential of drug. The two enzymes (amylase and glycosidase) found in intestine are responsible for the increasing postprandial glucose in body. In vitro model was performed on these enzymes and the results showed that methanol extract of Scoparia dulcis was effective to check the postprandial glucose level. The in vivo hypoglycaemic activity of methanol extract of Scoparia dulcis was performed on streptozotocin-induced diabetes mellitus showed significant inhibition of blood glucose level as compared to control and similar to that of standard glibenclamide. The overall data potentiates the traditional value of Scoparia dulcis as an antidiabetic drug. PMID- 24403666 TI - Sensitive fluorometric method for the determination of rutin in combined tablet dosage form. AB - A sensitive method based on the fluorescence enhancement was developed for the determination of rutin. It was found that the rutin could form a fluorescent complex with ytterium (III), and the fluorescence intensity of which could be enhanced by sodium dodecyl benzene sulfonate. Under the optimum conditions, the enhanced fluorescence intensity was in proportion to the concentration of rutin in the range of 12-1200 ng/ml and the detection limit (S/N=3) was 1.3 ng/ml. This method possessed the properties of simplicity, fast assay process and high sensitivity, and has been satisfactorily applied for the analysis of actual sample. The possible interaction mechanism of this system was also discussed in this manuscript. PMID- 24403667 TI - Evaluation and Treatment of Enthesitis-Related Arthritis. PMID- 24403668 TI - Maintaining a Positive Self-Image by Stereotyping Others: Self-Threat and the Stereotype Content Model. AB - The present study examines how target group's stereotype content (on warmth and competence dimensions) influences subsequent target evaluation following self threat related to one's competence. Participants first received threatening or non-threatening feedback on their competence. They evaluated then a job candidate who was stereotyped either as competent and cold (Asian) or as warm and incompetent (working mother). As predicted, threatened participants derogated only the Asian target on her perceived warmth and her suitability for a job, but did not derogate the working mother. Moreover, perceived warmth mediated the observed differences in the evaluation of the targets' job suitability. These results extend research on self-threat and prejudice by including Stereotype Content Model in this link. PMID- 24403669 TI - Clinical trial registration in physiotherapy journals: recommendations from the international society of physiotherapy journal editors. PMID- 24403670 TI - L'enregistrement des essais cliniques dans les revues de physiotherapie : recommandations de l'International Society of Physiotherapy Journal Editors. PMID- 24403671 TI - Prehabilitation improves physical function of individuals with severe disability from hip or knee osteoarthritis. AB - PURPOSE: To evaluate the effects of prehabilitation (enhancing physical capacity before total hip or knee joint arthroplasty) on pain and physical function of adults with severe hip and knee osteoarthritis (OA). METHODS: Consecutive patients (n=650) from 2006 to 2008 with hip or knee OA awaiting total joint arthroplasty (TJA) attended a hospital outpatient clinic for a prehabilitation assessment. All participants completed self-report (Lower Extremity Functional Scale [LEFS] and visual analogue scale for pain [VAS]) and functional performance measures (self-paced walk [SPW], timed stair, and timed up-and-go [TUG] tests). A subset of 28 participants with severe disability participated in a structured outpatient prehabilitation programme. Between-group differences were assessed via independent t-tests; paired Student's t-tests and Wilcoxon signed rank tests were used to compare changes in pain and function following the prehabilitation programme. RESULTS: A total of 28 individuals (16 female) with mean age 67 (SD 10) years and BMI 33 (8) kg/m(2) awaiting TJA (10 hips, 18 knees) participated in a prehabilitation programme of 9 (6) weeks' duration. Relative to baseline, there was significant improvement in LEFS score (mean change 7.6; 95% CI, 1.7-13.5; p=0.013), SPW (mean change 0.17 m/s; 95% CI, 0.07-0.26; p=0.001), TUG (mean change 4.2 s; 95% CI, 2.0-6.4; p<0.001), and stair test performance (mean change 3.8 s [SD 14.6]; p=0.005) following prehabilitation. CONCLUSION: This study presents preliminary evidence that prehabilitation improves physical function even in the most severely compromised patients with OA awaiting TJA. PMID- 24403672 TI - Decision makers' allocation of home-care therapy services: a process map. AB - PURPOSE: To explore decision-making processes currently used in allocating occupational and physical therapy services in home care for complex long-stay clients in Ontario. METHOD: An exploratory study using key-informant interviews and client vignettes was conducted with home-care decision makers (case managers and directors) from four home-care regions in Ontario. The interview data were analyzed using the framework analysis method. RESULTS: The decision-making process for allocating therapy services has four stages: intake, assessment, referral to service provider, and reassessment. There are variations in the management processes deployed at each stage. The major variation is in the process of determining the volume of therapy services across home-care regions, primarily as a result of financial constraints affecting the home-care programme. Government funding methods and methods of information sharing also significantly affect home-care therapy allocation. CONCLUSION: Financial constraints in home care are the primary contextual factor affecting allocation of therapy services across home-care regions. Given the inflation of health care costs, new models of funding and service delivery need to be developed to ensure that the right person receives the right care before deteriorating and requiring more costly long-term care. PMID- 24403673 TI - Clinician's Commentary on Mohammed et al.(1.). PMID- 24403674 TI - Interrater Reliability of the Adapted Fresno Test across Multiple Raters. AB - PURPOSE: The Adapted Fresno Test (AFT) is a seven-item instrument for assessing knowledge and skills in the major domains of evidence-based practice (EBP), including formulating clinical questions and searching for and critically appraising research evidence. This study examined the interrater reliability of the AFT using several raters with different levels of professional experience. METHOD: The AFT was completed by physiotherapists and occupational therapists, and a random sample of 12 tests was scored by four raters with different levels of professional experience. Interrater reliability was calculated using intra class correlation coefficients (ICC [2, 1]) for the individual AFT items and the total AFT score. RESULTS: Interrater reliability was moderate to excellent for items 1 and 7 (ICC=0.63-0.95). Questionable levels of reliability among raters were found for other items and for the total score. For these items, the raters were clustered into two groups-"experienced" and "inexperienced"-and then examined for reliability. The reliability estimates for rater 1 and rater 2 ("inexperienced") increased slightly for items 2 and 5 and for the total score, but not for other items. For raters 3 and 4 ("experienced"), ICCs increased considerably, indicating excellent reliability for all items and for the total score (0.80-0.99), except for item 4, which showed a further decrease in ICC. CONCLUSION: Use of the AFT to assess knowledge and skills in EBP may be problematic unless raters are carefully selected and trained. PMID- 24403675 TI - Validity and Reliability of the Swedish Version of the Activities-specific Balance Confidence Scale in People with Chronic Stroke. AB - PURPOSE: To evaluate the validity and reliability of the Swedish version of the Activities-specific Balance Confidence (ABC) scale in people >1 year after stroke. METHOD: In a multi-centre study design, using initial cross-sectional data collection with follow-up, the timed up-and-go (TUG) test, 10 m timed walk (10TW), and 6-Minute Walk Test (6MWT) were performed; ABC scale and Short Form 36 Health Survey (SF-36) were completed; and falls history data were collected during one session. One week later, the ABC scale was sent to participants for a second rating. Spearman correlation coefficients were calculated, and reliability was assessed via the intra-class correlation coefficient (ICC) and Cronbach alpha. RESULTS: A convenience sample of 67 people was included (mean age 68 y). The median score for the ABC scale changed from 57 at the first rating to 43 at the second; 19 participants (28%) reported falls during the previous 3 months. Scores on the ABC scale were moderately correlated with the TUG (r=-0.48), 10TW (r=-0.52), 6MWT (r=0.45), and SF-36 physical component summary score (r=0.43). Internal consistency was high for the ABC scale at test and retest (alpha=0.95 0.97). The ICC was 0.82 (95% CI, 0.72-0.88). CONCLUSIONS: The Swedish version of the ABC scale is a valid and reliable measure for investigating balance confidence in people >1 year after stroke. PMID- 24403676 TI - Perceptions on the essential competencies for intraprofessional practice. AB - PURPOSE: To gather the perspectives of physiotherapists and physiotherapist assistants on essential competencies for intraprofessional (physiotherapist physiotherapist assistant) collaboration. METHOD: A survey was developed to gather physiotherapist and physiotherapist assistant perceptions of the essential elements of effective and efficient intraprofessional collaborative practice. Participants were asked to rate the importance of 36 elements in 6 different categories (communication, collaboration, consultation, assignment of tasks, conflict management, and roles/responsibilities) involved in intraprofessional practice. RESULTS: A total of 1049 physiotherapists and 121 physiotherapist assistants responded to the survey. Analysis identified 10 competency elements perceived by participants as essential to effective and efficient intraprofessional collaboration. Comparisons using demographic variables consistently yielded the same top 10 elements. CONCLUSIONS: Our results indicated that physiotherapists and physiotherapist assistants working in private and public practice share very similar views on what is essential for effective intraprofessional practice. The consensus is that communication is key; open lines of communication help to determine responsibilities. Physiotherapy pre licensure and continuing education programmes should include opportunities to work on communication, listening, and the skills needed to interact and collaborate effectively. PMID- 24403677 TI - Clinician's Commentary on Jelley et al.(1.). PMID- 24403678 TI - Dissemination of student research in a canadian master of science in physical therapy programme. AB - PURPOSE: To determine the extent of presentation and publication, as well as time to publication, of student research completed as a component of a Master of Science in Physical Therapy (MScPT) degree at a Canadian university. METHOD: The authors conducted a retrospective cross-sectional study of MScPT research projects completed between 2003 and 2009, each undertaken by a group of MScPT students who carried out protocol development, ethics submission, data collection, analysis, and manuscript and poster preparation under the supervision of research advisors. Research advisors were e-mailed a request for citations of presentations and publications. RESULTS: Advisors from 102 of 113 research projects completed from 2003 through 2009 provided information, for a response rate of 90.3%. Of the 102 groups, 53.9% disseminated findings through publication or presentation, 33.3% presented at one or more conferences, and 30.4% published at least one peer-reviewed journal article. Median time to publication was 21 months. Almost half the journal articles (47%) were published in Physiotherapy Canada. CONCLUSIONS: MScPT student research groups are disseminating their findings through publication or presentation at a moderate rate. Investigation of factors influencing dissemination is needed to develop strategies to facilitate knowledge transfer. PMID- 24403679 TI - Clinician's Commentary on Salbach et al.(1.). PMID- 24403680 TI - A Systematic Review of Head-to-Head Comparison Studies of the Roland-Morris and Oswestry Measures' Abilities to Assess Change. AB - PURPOSE: To determine if the sensitivity to change of Roland-Morris Questionnaire (RMQ) and Oswestry Disability Index (ODI) scores differ when applied to patients with low back pain (LBP). A secondary purpose was to critique the methodological rigour of the identified head-to-head comparison studies. METHODS: A systematic review of five online databases was performed to locate head-to-head comparison studies of the RMQ and the ODI that assessed the sensitivity to change of the two measures. Studies were eligible if they met a pre-determined set of inclusion criteria. A newly developed quality criteria form was used to evaluate the methodological rigour of head-to-head comparison studies. RESULTS: Nine articles met the inclusion criteria. Although there was a statistically significant difference in favour of the RMQ for two studies, there was no apparent consistent advantage of one measure over the other. Frequent methodological deficiencies included no formal sample size calculation, no formal between-measure comparison, and no independent reference standard. CONCLUSION: There was no consistent evidence supporting one measure over the other. Many studies displayed methodological deficiencies. PMID- 24403681 TI - Beliefs and practice patterns in spinal manipulation and spinal motion palpation reported by canadian manipulative physiotherapists. AB - PURPOSE: This practice survey describes how Fellows of the Canadian Academy of Manipulative Physiotherapy (FCAMPT) use spinal manipulation and mobilization and how they perceive their competence in performing spinal assessment; it also quantifies relationships between clinical experience and use of spinal manipulation. METHODS: A cross-sectional survey was designed based on input from experts and the literature was administered to a random sample of the FCAMPT mailing list. Descriptive (including frequencies) and inferential statistical analyses (including linear regression) were performed. RESULTS: The response rate was 82% (278/338 eligible FCAMPTs). Most (99%) used spinal manipulation. Two thirds (62%) used clinical presentation as a factor when deciding to mobilize or manipulate. The least frequently manipulated spinal region was the cervical spine (2% of patients); 60% felt that cervical manipulation generated more adverse events. Increased experience was associated with increased use of upper cervical manipulation among male respondents (14% more often for every 10 years after certification; beta, 95% CI=1.37, 0.89-1.85, p<0.001) but not among female respondents. Confidence in palpation accuracy decreased in lower regions of the spine. CONCLUSION: The use of spinal manipulation/mobilization is prevalent among FCAMPTs, but is less commonly used in the neck because of a perceived association with adverse events. PMID- 24403682 TI - Power training in patients with knee osteoarthritis: a pilot study on feasibility and efficacy. AB - PURPOSE: To explore the feasibility and efficacy of using a power training exercise programme for the quadriceps femoris (QF) in elderly women with knee osteoarthritis (OA). METHOD: A one-group quasi-experimental design with pre- and post-intervention measurements was conducted on 17 older adult women with knee OA pain. A bilateral QF exercise programme (24 sessions over 8 weeks) consisting of 3 series of 10 repetitions of flexion-extension as fast as possible at 40% of their one-repetition maximum (1RM) was performed in an outpatient physiotherapy clinic. The primary outcome measures were the knee function and associated problems using the Knee injury Osteoarthritis Outcome Score (KOOS) questionnaire and the weekly mean pain score from pain diaries using a visual analogue scale (VAS). QF strength (QFS), power (QFP) and work (QFW) were measured with an isokinetic dynamometer as secondary outcomes. RESULTS: Significant improvements (p<0.05) were noted on the five categories of the KOOS. Significant decrease (p<0.01) was noted in pain intensity on VAS. QFP and QFW increased significantly on both sides (p<0.05). Exercise compliance was 99.5% for 16 participants. CONCLUSIONS: A short power-training exercise programme is a feasible training modality for patients with knee OA, and significant functional improvements can be achieved. Further studies must be conducted to better understand the effects of the programme parameters and the generalizability of the findings. PMID- 24403683 TI - The effect of prospective monitoring and early physiotherapy intervention on arm morbidity following surgery for breast cancer: a pilot study. AB - PURPOSE: Significant arm morbidity is reported following surgery for breast cancer, yet physiotherapy is not commonly part of usual care. This study compared the effect on arm morbidity after surgery for breast cancer of a clinical care pathway including preoperative education, prospective monitoring, and early physiotherapy (experimental group) to that of preoperative education alone (comparison group). METHODS: A prospective quasi-experimental pretest-posttest, non-equivalent group design compared two clinical sites; Site A (n=41) received the experimental intervention, and Site B (n=31) received the comparison intervention. At baseline (preoperative) and 7 months postoperative, shoulder range of motion (ROM), upper-extremity (UE) strength, UE circumference, pain, UE function, and quality of life were assessed. RESULTS: The experimental group maintained shoulder flexion ROM at 7 months, whereas the comparison group saw a decrease (mean 1 degrees [SD 9 degrees ] vs. -6 degrees [SD 15 degrees ], p=0.03). A lower incidence of arm morbidity and better quality of life were observed in the experimental group, but these findings were not statistically significant. Baseline characteristics and surgical approaches differed between the two sites, which may have had an impact on the findings. CONCLUSION: Initial results are promising and support the feasibility of integrating a surveillance approach into follow-up care. This pilot study provides the foundation for a larger, more definitive trial. PMID- 24403684 TI - Clinician's Commentary on Singh et al.(1.). PMID- 24403685 TI - What Does the Cochrane Collaboration Say about Strength Training? PMID- 24403686 TI - Rehabilitation research: who is participating? PMID- 24403687 TI - Physiotherapy needs assessment of people with stroke following discharge from hospital, stratified by acute functional independence measure score. AB - PURPOSE: To determine the physiotherapy-related needs of people with stroke at discharge, 6 months after discharge, and 1 year after discharge from hospital, and to examine the results stratified by participants' acute Functional Independence Measure (FIM) scores. METHODS: A total of 241 adults with recent stroke were recruited into this longitudinal cohort study. As well as participating in a semi-structured interview that included questions about mobility needs and barriers, participants were asked to complete and return a closed-ended needs-assessment survey. RESULTS: During the interview, participants reported needs and barriers related to motor control, walking, stairs, fatigue, prevention of falls, and access to physiotherapy services. The survey identified many more needs, including transfers, wheelchair use, higher-level balance and mobility skills, and access to physiotherapy and suitable exercise facilities. Frequencies of needs and barriers tended to be lower among participants with higher acute FIM scores. There was no consistent trend for needs and barriers to decrease over time. CONCLUSIONS: Over the first year after discharge from hospital, people with stroke report a large and varied number of persistent mobility-related needs. Physiotherapists have a role to play in advocating for adequate follow-up services and informing health policy with respect to the needs of their patients with stroke. PMID- 24403688 TI - Clinician's Commentary on DePaul et al.(1.). PMID- 24403689 TI - The Effect of Parkinson Drug Timing on Cardiovascular Response during Treadmill Exercise in a Person with Parkinson Disease and Freezing of Gait. AB - PURPOSE: To examine the response of cerebral oxygenation during treadmill walking in a person with Parkinson disease (PD) who experiences freezing of gait (FOG) and to determine whether the oxygen response was related to the timing of his PD medication. Client Description: A 61-year-old man with PD performed two bouts of treadmill testing on the same day, during the on- and off-phases of his PD medication. Measures and Outcome: The client experienced two FOG episodes during the first testing session (on-phase with hypokinetic movement session). Cerebral oxygen response (measured by near-infrared spectroscopy) was stable until the FOG episodes occurred, at which point it decreased until the FOG episode was over. No electrocardiogram (ECG) changes or lightheadedness were noted; blood pressure (BP) remained stable. During the second exercise testing session (off-phase with dyskinetic movement session), the client did not experience any FOG episodes, and his cerebral oxygen response remained stable. Toward the end of the second testing session, he experienced lightheadedness and a drop in BP of approximately 30 mmHg, along with significant ST segment depression on his ECG. IMPLICATIONS: Haemodynamic and cerebral oxygen changes occurred that were specific to the timing of the client's PD medication and to his FOG episodes. This case study shows a person with PD demonstrating decreased cerebral oxygenation during FOG, which may be based on his variable response to levodopa medication or may be attributable to as yet unidentified physiologic mechanisms. PMID- 24403690 TI - An intensive programme of passive stretch and motor training to manage severe knee contractures after traumatic brain injury: a case report. AB - PURPOSE: While contemporary management of contractures (a common secondary problem of acquired brain injury that can be difficult to treat) includes passive stretch, recent evidence indicates that this intervention may not be effective. This may be because clinical trials have not provided a sufficient dose or have not combined passive stretch with other treatments. The purpose of this case report is to describe a programme of intensive passive stretch combined with motor training administered over a 1.5-year period to treat severe knee contractures. METHOD: Five months after traumatic brain injury, an adolescent client with severe contractures in multiple joints underwent an intensive stretch programme for his knee contractures, including serial casting and splinting, which was administered for 10 months in conjunction with a motor training programme administered for 1.5 years. RESULTS: The client regained full extension range in his knees and progressed from being totally dependent to walking short distances with assistance; these effects were maintained at follow-up 5.5 years after injury. CONCLUSION: The use of a high dose of passive stretch in conjunction with motor training may be an option to consider for correcting severe contractures following acquired brain injury. PMID- 24403691 TI - The Relationship of Knee-Extensor Strength and Rate of Torque Development to Sit to-Stand Performance in Older Adults. AB - PURPOSE: To investigate the association of knee-extensor strength and power to performance in the 30-second sit-to-stand test (30sSTS) in healthy older adults. METHOD: In a cross-sectional study of 29 healthy older adults aged 60-82 years (12 male, 17 female), hierarchical regression was used to determine the relationship of knee-extensor concentric and eccentric strength, peak rate of torque development (peak RTD) using isokinetic dynamometry, and momentum variables with the number of sit-to-stand repetitions completed in 30 seconds (30sSTSreps). RESULTS: Concentric (180 degrees /s) and eccentric (90 degrees /s) knee-extensor strength were significant independent predictors of 30sSTSreps after controlling for physical activity level, height and weight (adjusted R (2)=0.425, p=0.004; adjusted R (2)=0.427, p=0.004 respectively), as was concentric (90 degrees /s) knee-extensor peak RTD (adjusted R (2)=0.424, p=0.004). Peak linear vertical momentum (PLVM) (adjusted R (2)=0.615, p<0.001) accounted for 36% of the variance. CONCLUSIONS: Generation of PLVM is an important predictor of 30sSTSreps; knee-extensor concentric and eccentric strength and power are associated with improved performance in this common functional task. Focusing on these parameters in exercise interventions may improve functional performance and give insight into specific factors related to success on the test. PMID- 24403692 TI - Clinician's Commentary on Crockett et al.(1.). PMID- 24403693 TI - Wait times for physical and occupational therapy in the public system for people with arthritis in quebec. AB - PURPOSE: Although arthritis is the leading cause of pain and disability in Canada, and physical therapy (PT) and occupational therapy (OT) are beneficial both for chronic osteoarthritis (OA) and for inflammatory arthritis such as rheumatoid arthritis (RA), there appear to be problems with access to such services. The aim of this study was to document wait times from referral by physician to consultation with PT or OT in the public health care system for people with arthritis in Quebec, Canada. METHOD: Appointments were requested by telephone, using hypothetical case scenarios; wait times were defined as the time between initial request and appointment date. Descriptive statistics were used to examine the wait times in relation to diagnosis, service provider and geographic area. RESULTS: For both scenarios (OA and RA) combined, 13% were offered an appointment within 6 months, 13% offered given an appointment within 6-12 months, 24% were told they would need to wait longer than 12 months, and 22% were refused services. The remaining 28% were told they would require an evaluation appointment for functional assessment before being given an appointment for therapy. No difference was found between RA and OA diagnoses. CONCLUSIONS: Our study suggests that most people with arthritis living in the province of Quebec are not receiving publicly accessible PT or OT intervention in a timely manner. PMID- 24403694 TI - Assessing the amount of change in an outcome measure is not the same as assessing the importance of change. AB - PURPOSE: To determine whether a difference exists between patients' self-ratings of amount of change and their self-ratings of importance of change. METHODS: Eighty-eight patients receiving treatment of low-back pain completed two global rating of change (GRC) scales 4 to 6 weeks after their initial assessments. The scales were similar in format, differing only in that one asked respondents about the amount of change and the other about the importance of change. RESULTS: Our analysis was restricted to 86 patients who reported improvement or no change. The chance-corrected agreement between patients' self-ratings of amount of change and their self-ratings of importance of change was low (kappa=0.35; 95% CI, 0.23 0.48). Of 47 disagreements, 44 reported a greater importance of change than amount of change and 3 reported a greater amount of change than importance of change. CONCLUSIONS: Assessing the amount of change is not the same as assessing the importance of change. When the goal is to estimate important change, the reference standard should direct patients to judge the importance of the change. PMID- 24403695 TI - Quantity and quality of physical activity are influenced by outdoor temperature in people with knee osteoarthritis. AB - PURPOSE: Environmental factors are known to influence physical activity (PA) levels of healthy people, but little work has explored these factors in people with osteoarthritis (OA). The purpose of this study was to explore the influence of outdoor temperature on PA in people with knee OA. METHODS: A total of 38 people with knee OA (10 women; mean age 54 y) wore an accelerometer around their waist for 7 consecutive days. Dependent variables from the accelerometers were three PA measures: (1) activity counts/day and time spent at or above moderate levels of PA with (2) a cut-point of 1,041 activity counts/minute (MVPA1041) and (3) a cut-point of 1,952 activity counts/minute (MVPA1952). Independent variables were age, sex, body mass index (BMI), and maximum daily outdoor temperature. Three linear regression analyses were conducted using the three PA dependent variables and independent variables. RESULTS: After controlling for age, sex, and BMI, maximum daily outdoor temperature explained 9% of the variance in activity counts/day (p=0.042), 10% of variance in MVPA1041 (p=0.032), and 14% of variance in MVPA1952 (p=0.016). Participants who engaged in more PA were younger and were exposed to warmer temperatures. CONCLUSIONS: Outdoor temperature and age influence the PA levels of people with knee OA. These factors should be considered when designing PA programmes. PMID- 24403696 TI - Determining adverse events in patients with neck pain receiving orthopaedic manual physiotherapy: a pilot and feasibility study. AB - PURPOSE: To pilot and determine the feasibility of estimating adverse events in patients with neck pain treated with cervical manipulation/mobilization by Canadian orthopaedic manual physiotherapists (OMPTs) using an online data collection system to provide estimates for a future larger multi-centre international study. METHODS: In a prospective multi-site two-group cohort study, participants received usual care and either (a) combined manipulation and mobilization or (b) mobilization only. Study feasibility objectives and criteria for success were set a priori. Data were analyzed using descriptive statistics. RESULTS: A total of 20 patients were recruited from 6 of 16 participating centres, 17 to the mobilization group and 3 to the combined group. Barriers to data collection included low recruitment, difficulties in using the online data collection system, and clinicians' and patients' being too busy to participate. Missing data for the primary outcome averaged 28.5%. A total of 69 symptom occurrences were reported during the treatment phase, all benign and transient. Most began within 0-12 hours after treatment (66/69, 95.6%) and lasted for 0-2 days (56/69, 81.2%). Kappa estimates of agreement between therapists and patients on reporting of adverse symptoms across visits 1-5 was substantial (kappa=0.68; 95% CI, 0.52-0.84; p<0.01). CONCLUSIONS: This pilot study demonstrates substantial challenges in conducting a large multi-centre trial. Brief, benign, and transient adverse events were common; no substantial adverse events were observed. PMID- 24403697 TI - Hip-fracture care in rural southwestern ontario: an ethnographic study of patient transitions and physiotherapy handoffs. AB - PURPOSE: To examine information exchange by physiotherapists during care handoffs of patients with hip fracture in a rural health care setting. METHODS: This qualitative ethnographic study used observation and interviews of 11 networks of patients with hip fracture (n=11), family caregivers (n=8), and health care providers (n=24). Patients were followed from acute care through each subsequent care setting. Data were supplemented by health care records and policy documents. RESULTS: Findings revealed that handoffs were less successful when information transfer was untimely or incomplete. Family caregivers experienced challenges in obtaining information required to facilitate the handoff, especially when direct contact with physiotherapists was not possible as a result of distance or other factors. Physiotherapists had to navigate multiple data sources to retrieve important information, and managed information gaps in various ways. Information flow was often unidirectional and suggested no further clinical accountability for the discharging physiotherapist. CONCLUSIONS: Providing information in a structured and timely fashion facilitated physiotherapy handoffs. Inadequate handoffs compromised continuity of care, delayed progress in rehabilitation, and resulted in families' missing information of vital importance to their caregiving role. A multi-directional exchange of information is needed between patients, families, and health care providers across care settings. PMID- 24403698 TI - An example of end-digit preference in physiotherapy practice. AB - PURPOSE: Standardizing and improving the validity of range of motion (ROM) measurements is of clinical relevance to physiotherapists. The purpose of this study was to assess whether end-digit preference exists in the measurement of knee ROM in people after knee replacement. METHOD: Following total knee replacement, 100 people underwent active-assisted knee ROM measurements using a goniometer calibrated in 1 degrees increments. RESULTS: The data showed strong end-digit preferences for 0s and 5s (p<0.001). CONCLUSIONS: End-digit preference does exist in the measurement of knee ROM. This has the potential to influence both the validity of ROM measurements and clinical decisions. PMID- 24403699 TI - Indoor and Outdoor Mobility following Total Knee Arthroplasty. AB - PURPOSE: To determine the relationship between indoor and outdoor mobility capacity in older adults with unilateral total knee arthroplasty (TKA) and, secondarily, to determine walking intensity in the same population and to compare all outcomes to a control group of older adults without knee pathology. METHOD: In this cross-sectional study, participants (TKA=16, mean 22.9 (SD 9.7) mo post TKA; control=22) completed indoor walking tests and a 580 m outdoor course that included varying terrain (e.g., curbs, grass, sidewalk) and frequent changes in direction. Walking capacity was assessed using stopwatches, global positioning system watches and accelerometers. RESULTS: Outdoor walking time was moderately correlated (p<0.05) with the timed up-and-go (TUG) test (r=0.65), stair-climb test (SCT) (r=0.67 ascending, r=0.79 descending), 10 m walk test (10 mWT) (r=0.73), and 6-minute walk test (6 MWT) (r=-0.75). Based on activity counts, walking intensity levels for participants in both groups were moderate (outdoor walk and 6 MWT). There was no significant difference in walking capacity between groups (TUG, SCT, 10 mWT, 6 MWT, outdoor walk). CONCLUSIONS: Common clinical walking tests are moderately correlated with outdoor mobility. Mobility capacity of individuals post TKA was similar to controls in both indoor and outdoor environments, and participants in both groups achieved moderate physical activity levels with walking. PMID- 24403700 TI - Usage Patterns and Beliefs about Therapeutic Ultrasound by Canadian Physical Therapists: An Exploratory Population-Based Cross-Sectional Survey. AB - PURPOSE: To explore the frequency and patterns of ultrasound (US) usage among physical therapists, to describe the most common purposes for using therapeutic US, and to investigate beliefs about therapeutic US. METHODS: A survey was sent to 95% of physical therapists licensed to practise in the province of Alberta, Canada. RESULTS: Of 2,269 physical therapists to whom email invitations were sent, 438 (19.3%) provided full responses. RESULTS indicate that US is still frequently incorporated into treatment regimens and is widely believed to be effective; however, the study also found a decrease in US usage over the past 15 years. While physical therapists recognize the lack of evidence for the effectiveness of US, many consider it clinically useful. Physical therapists using US rely largely on their clinical experience when making decisions about its use, but this depends on level of education: clinicians with an MScPT degree tended to base more of their US decisions on research evidence, likely because of the increasing emphasis on research evidence in graduate education. CONCLUSIONS: Despite the questionable effectiveness of therapeutic US, physical therapists still commonly use this treatment modality, largely because of a belief that US is clinically useful. However, US usage has decreased over the past 15 years. PMID- 24403702 TI - What Does the Cochrane Collaboration Say about Stretching Exercises? PMID- 24403701 TI - Clinician's Commentary on Armijo-Olivo et al.(1.). PMID- 24403703 TI - Recombinant activated factor VII in post partum haemorrhage. AB - Post-partum haemorrhage (PPH) is a life-threatening obstetric complication and the leading cause of maternal death. Any bleeding that results in or could result in haemodynamic instability, if untreated, must be considered as PPH. There is no controversy about the need for prevention and treatment of PPH. The keystone of management of PPH entails first, non-invasive and nonsurgical methods and then invasive and surgical methods. However, mortality remains high. Therefore, new advancements in the treatment are most crucial. One such advancement has been the use of recombinant activated factor VII (rFVIIa) in PPH. First used 12 years back in PPH, this universal haemostatic agent has been effectively used in controlling PPH. The best available indicator of rFVIIa efficacy is the arrest of haemorrhage, which is judged by visual evidence and haemodynamic stabilization. It also reduces costs of therapy and the use of blood components in massive PPH. In cases of intractable PPH with no other obvious indications for hysterectomy, administration of rFVIIa should be considered before surgery. We share our experience in a series of cases of PPH, successfully managed using rFVIIa. PMID- 24403704 TI - Bone mineral density among elderly patients with chronic obstructive pulmonary disease patients in India. AB - BACKGROUND: Osteoporosis is one of the major extra-pulmonary manifestations of chronic obstructive pulmonary disease (COPD), which limits the physical activity. The present study was undertaken to study the bone mineral density (BMD) and osteoporosis in the elderly COPD patients. MATERIALS AND METHODS: This was a cross-sectional study carried out among elderly COPD patients. After a detailed clinical history spirometry was done to stage the severity of COPD. DEXA scan of the lumbar spine was performed using bone densitometer to determine osteoporosis. Statistical analysis was based on Chi-square test. Risk factors were identified by univariate and multivariate logistic regression analysis. RESULTS: A total of 70 elderly COPD patients were included. Fourty-six patients (65.7%) had osteoporosis and 13 (18.6%) had osteopenia. Majority of the osteoporosis patients had stage III or stage IV COPD disease (77.2%). As the severity grade of COPD increased, the risk of osteoporosis also increased. Also, with the increasing severity of COPD, BMD decreased. Patients with lower body mass index (BMI) had higher prevalence of osteoporosis (45.7%). Using multivariate regression analysis, stage IV COPD, number of acute exacerbations >3 and steroid cumulative dose >1000 mg were independent risk factors for osteoporosis in elderly COPD patients. CONCLUSIONS: The prevalence of osteoporosis was 65.7%, and 18.6% had osteopenia. Stage III and IV patients had significantly lower BMI in elderly COPD patients. High clinical suspicion and early diagnosis and treatment are required in the evaluation of osteoporosis in elderly COPD patients. PMID- 24403705 TI - The impact of various assessment parameters on medical students' performance in first professional examination in physiology. AB - BACKGROUND: This study was carried out to assess the relationship between thevarious assessment parameters, viz. continuous assessment (CA), multiple choice questions (MCQ), essay, practical, oral with the overall performance in the first professional examination in Physiology. MATERIALS AND METHODS: The results of all 244 students that sat for the examination over 4 years were used. The CA, MCQ, essay, practical, oral and overall performance scores were obtained. All the scores were rounded up to 100% to give each parameter equal weighting. RESULTS: Analysis showed that the average overall performance was 50.8 +/- 5.3. The best average performance was in practical (55.5 +/- 9.1), while the least was in MCQ (44.1 +/- 7.8). In the study, 81.1% of students passed orals, 80.3% passed practical, 72.5% passed CA, 58.6% passed essay, 22.5% passed MCQ and 71.7% of students passed on the overall performance. All assessment parameters significantly correlated with overall performance. Continuous assessment had the best correlation (r = 0.801, P = 0.000), while oral had the least correlation (r = 0.277, P = 0.000) with overall performance. Essay was the best predictor of overall performance (beta = 0.421, P = 000), followed by MCQ (beta = 0.356, P = 000), while practical was the least predictor of performance (beta = 0.162, P = 000). CONCLUSION: We suggest that the department should uphold the principle of continuous assessment and more effort be made in the design of MCQ so that performance can improve. PMID- 24403706 TI - Comparison of the effect of selected muscle groups fatigue on postural control during bipedal stance in healthy young women. AB - BACKGROUND: The maintenance of balance is an essential requirement for the performance of daily tasks and sporting activities and muscular fatigue is a factor to impair postural control, so this study was done to compare the effect of selected muscle groups fatigue on postural control during bipedal stance in healthy subjects. MATERIALS AND METHODS: Fifteen healthy female students (24.3 +/ 2.6 years) completed three testing session with a break period of at least 2 days. During each session, postural control was assessed during two 30-s trials of bipedal stance with eyes close before and after the fatigue protocol. Fatigue protocols were performed by 60% of their unfatigued Maximum Voluntary Contraction of unilateral ankle plantar flexors, bilateral lumbar extensors and bilateral neck extensors. One of the three fatigue protocols was performed on each session. RESULTS: The result showed that fatigue had a significant effect on COP velocity and it increase COP velocity but there was not found any difference in postural sway between muscle groups. CONCLUSION: Localized muscle fatigue caused deficits in postural control regardless of the location of fatigue. Authors suggest the possibility of the contributions of central mechanisms to postural deficits due to fatigue and it seems that difference was not between muscle groups due to central fatigue. PMID- 24403707 TI - Liver enzymes derangement and the influence of diet in animals given oral albendazole. AB - BACKGROUND: Albendazole is used as an anthelmintic in the treatment of some parasitic infections. This study determined how the effects of albendazole on liver enzymes are influenced by diet. MATERIALS AND METHOD: Thirty adult male Wistar rats of mean weight 304.12 +/- 11.34 g were randomly grouped into five: Group A: Control, was given rat pellets and water only; Group B received 15 mg/kg/d of albendazole while fasting; Group C received 15 mg/kg/d of albendazole with fatty meal; Group D received 15 mg/kg/d of albendazole with normal diet (rat pellets); and, Group E received 30 mg/kg/d of albendazole with normal diet (rat pellets); they were given orally for 3 consecutive days. The animals were sacrificed thereafter and blood samples obtained for quantitative study of the serum activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). RESULTS: Significant elevation in the serum levels of the transaminases especially in animals which were on their normal diet (rat pellets), while ALP was either reduced or increased based on dietary factors. CONCLUSIONS: Oral administration of albendazole before meal or with a fatty diet could help limit severe elevation of liver enzymes associated with its use, while still ensuring optimal efficacy. PMID- 24403708 TI - Anogenital warts in Northern Nigeria: A ten-year Review. AB - BACKGROUND: Anogenital warts are a common cause of morbidity affecting mainly the productive age group of the economy. Paucity of data in Nigeria necessitated this study. MATERIALS AND METHODS: The pathology records of anogenital warts diagnosed in the Department of Pathology, Ahmadu Bello University Zaria between 1(st) January 2000 and 31(st) December 2009 were reviewed. RESULTS: A total of 68 warts were diagnosed within the study period with anogenital warts constituting 39.7%. Majority of cases (62%) were in the 20-39 years age group (range: 5-50 years) and vulva was the most common site affected. CONCLUSION: Genital warts are common in our environment, biopsy of suspicious lesions is recommended for diagnostic yield. PMID- 24403709 TI - Knowledge, attitude and practice of cervical cancer screening among market women in Zaria, Nigeria. AB - BACKGROUND: Cervical cancer is the most common genital cancer and one of the leading causes of death among female population. Fortunately, this cancer is preventable by screening for premalignant lesions but this is rarely provided and hardly utilised. We assessed the knowledge, attitude and utilisation of cervical cancer screening among market women in Sabon Gari, Zaria. MATERIALS AND METHODS: This was a cross-sectional study to evaluate the knowledge, attitude and practice of cervical cancer screening among market women. A total of 260 women were administered with questionnaires which were both self and interviewer administered. These were analysed using SPSS version 11. RESULTS: Respondents exhibited a fair knowledge of cervical cancer and cervical cancer screening (43.5%); however, their knowledge of risk factors was poor. There was generally good attitude to cervical cancer screening (80.4%), but their level of practice was low (15.4%). CONCLUSIONS: There was a fair knowledge of cervical cancer and cervical cancer screening among Nigerian market women in this study, their practice of cervical cancer screening was poor. PMID- 24403710 TI - Brain sonography in African infants with complicated sporadic bacterial meningitis. AB - BACKGROUND: To determine the structural findings in brain sonography of African infants with complicated sporadic bacterial meningitis. MATERIALS AND METHODS: Retrospective assessment of medical records of patients who underwent brain sonography on account of complicated bacterial meningitis. The brain sonography was carried out over a 4-year period (between September 15, 2004 and September 14, 2008). RESULT: A total of 86 infants were studied (40 boys and 46 girls in a ratio of 1:1.1); more than 70% of the patients were aged below 6 months. Presenting complaint included convulsion with fever in 34 (39.53%), persistent fever 20 (23.26%), bulging fontanelles 8 (9.30%), coma 7 (8.14%) and sepsis with convulsion 6 (6.98%), among others. Patients' place of previous treatment included specialist hospitals 33 (38.37%), private hospitals 21 (24.42%), herbal home centres 12 (13.95%), nursing homes 8 (9.30%), patent medicine stores 7 (8.14%) and other non-doctor attended clinics 5 (5.81%) infants. The sonographic findings included hydrocephalus 36 (41.86%), cerebral infarction 12 (13.95%), encephalocoele 9 (10.49%) and intracerebral abscess 7 (8.14%) infants. Cerebritis 5 (5.81%), intracerebral hemorrhage 3 (3.49%), porocephalic cysts 2 (2.33%), cerebral oedema 2 (2.33%), intraventricular haemorrhage 1 (1.16%) and subdural collection 1 (1.16%) infants; 8 patients (9.30%) had normal findings. CONCLUSION: Hydrocephalus, cerebral infarction and intracerebral abscess were the most common complications elicited by sonography in this study. Early and adequate treatment with antibiotics in patients with persistent fever and convulsion with fever will reduce the complications of meningitis and its long-term neurological sequelae. PMID- 24403711 TI - Correlation between blood lead concentration and iron deficiency in Iranian children. AB - BACKGROUND: Iron deficiency anaemia is the most common nutritional anaemia among children. Lead toxicity is a serious health threat, especially in developing countries due to environmental pollution. It was thus aimed to investigate correlation between blood lead concentration and iron deficiency in children of Mashhad, Iran. MATERIALS AND METHODS: This cross sectional study was performed on children between 1 year and 10 years, in Imam Reza teaching hospital of Mashhad, Iran, in 2010. Indeed during complete blood count (CBC), we measured iron and total iron binding capacity (TIBC) by colorimetric methods, ferritin by radioimmune assay and blood lead concentration by atomic absorption method. Results were analysed by Statistical Package for Social Sciences (SPSS) (version 11.5), using statistical tests including independent sample t-test, Mann-Whitney U test, Spearman's test and analysis of variance (ANOVA) and Pearson's or Spearman's correlation coefficient. P value <= 0.05 was considered as a significant level. RESULTS: We studied 223 cases including 98 control children and 125 patients. All children had lead intoxication. Mean (+/-SD) blood lead concentration in the control group was 57.1 +/- 25.3 (ranged 20-212) MUg/dl and in the patient group was 57 +/- 20.4 (ranged 10.9-159) MUg/dl with no significant difference (P value = 0.713). We also did not find any correlation between blood lead concentration and haemoglobin, ferritin, iron, TIBC, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), white blood cells (WBC) and platelets. CONCLUSION: Based on these results, no correlation was found between blood lead concentration and iron deficiency in the children. Because all children had lead intoxication, further studies in highly polluted and a comparison with a low polluted area are necessary to make a general conclusion. PMID- 24403712 TI - Percutaneous K-wire fixation in paediatric Supracondylar fractures of humerus: A retrospective study. AB - BACKGROUND: Supracondylar fractures are the commonest elbow injury in children. Most displaced Supracondylar fractures are manipulated and held with a medial/lateral entry or two lateral Kirschner wires. It was the purpose of this study to investigate the treatment of this injury in this unique patient population. MATERIALS AND METHODS: This study was conducted in the Department of Orthopaedic surgery in M. M. Medical College from July 2005 to July 2010. One hundred seventy patients were recruited from Emergency and outpatient department having closed displaced Supracondylar fractures of humerus in children. They were treated either with medial-lateral pin fixation (n = 85) or with 2-lateral pin fixation (n = 85). All patients were operated under general anaesthesia. All patients were followed for 6 months. Results were analysed using Flynn's criteria. STATISTICAL ANALYSIS USED: Chi Square Test. Chi Square calculator was used as a software. RESULTS: All children achieved union in a mean time of 4 weeks (range: 3-6 weeks). Post-operatively, eight patients (4.70%) got ulnar nerve injury and six (3.52%) patients got pin tract infection. Comparison between two groups such as cross K-wire group (85) and lateral K-wire group (n = 85) by using the Chi Square Test showed that in case of 8 weeks with (P-values = 0.89), in 16 weeks (P = 0.91) and 24 weeks (P = 0.85) with respective excellent, good, fair and poor categories were not found statistically significant. CONCLUSION: The lateral percutaneous pinning technique of displaced Supracondylar fractures of the humerus offers a viable alternative to the crossed pinning group as it offers the same stability without the incipient risk of iatrogenic ulnar nerve injury. PMID- 24403713 TI - Alveolar Osteitis: Patients' compliance to post-extraction instructions following extraction of molar teeth. AB - BACKGROUND: To evaluate the effect of various combination of post-extraction regimen administered to patients who had intra-alveolar molar tooth extraction. PATIENTS AND METHODS: One year prospective study involving 76 consenting patients who came for 1-week post-extraction review. The patients were placed on warm saline mouth rinse with (verbal instruction) or without antibiotic and or analgesic therapy (written prescription), after intra-alveolar molar tooth extraction. Information was obtained from the patients through questionnaire and clinical examination. RESULTS: The patients were placed on warm saline mouth rinse (n = 29, 38.2%) only, warm saline rinse, antibiotics (Amoxicillin and metronidazole) and Paracetamol (n = 31, 40.8%), Paracetamol and warm saline rinse (n = 12, 15.8%) and antibiotics (Amoxicillin and metronidazole) and Paracetamol (n = 4, 5.3%). A total of 63 (82.9%) patients complied with the post-extraction regimen, giving a significant high compliance to the post-extraction instructions (P = 0.001). There were 10 (13.2%) cases of post-extraction localised alveolar osteitis, with predilection for the lower molar teeth (n = 6, 7.9%) and a significant predilection for females (n = 8, 10.5%) [P = 0.005]. Overall, there were five (6.6%) cases each of localised alveolar osteitis in the compliant patients (n = 63, 82.9%) and non-compliant patients (n = 13, 17.1%), giving a ratio of 1:13 and 1:3, respectively. There was significant association of compliance with post-extraction instruction and the reduced incidence of localized alveolar osteitis (P = 0.015). CONCLUSION: This study showed a significant patients' compliance with post-extraction warm saline rinse, prophylactic antibiotics and analgesic and a corresponding significant reduction in the incidence of localised alveolar osteitis following intra-alveolar molar tooth extraction. This study emphasises the need to properly educate patients on the effect of compliance to various combination of post-extraction regimen. PMID- 24403714 TI - Distribution pattern of surgically treated symptomatic prolapsed lumbar and sacral intervertebral discs in males. AB - BACKGROUND: The pattern of distribution of surgically treated symptomatic prolapsed lumbar and sacral intervertebral discs has been published, though scantily, especially in males. We decided to look at our own series, compare and contrast ours with some of those published. MATERIALS AND METHODS: We treated 88 locations of this lesion in 68 males. The clinical features were those of lower back pains, with or without radiation into the lower extremities, sensory loss and paresis of the limbs. There was a case of loss of urinary bladder and ano rectal control. All lesions were confirmed through cauda-equinograms and treated under general anaesthesia in knee-chest position (MECCA position). The patients were followed up for 3-6 months post-operatively. RESULTS: There were 88 locations in 68 males of 21-70 years of age, with 29 prolapses occurring during the age range 31-40 years, while 54 locations were on the left and 48 at L4/5. The procedures were well tolerated by all patients and there were no post operative complications. CONCLUSION: This lesion in our series occurred mostly on the left, at the L4/5 level and peaked at 31-40 years age range. The predictability of occurrence of this disease, using side, level and age is still not feasible in males from our series. PMID- 24403715 TI - Prognostic risk factors for early diagnosing of Preeclampsia in Nulliparas. AB - BACKGROUND: Preeclampsia is of major complications of pregnancy that is associated with maternal morbidity and mortality. Therefore, prediction and early diagnosis of preeclampsia would be helpful for better controlling of related complications. Our study aimed to investigate risk factors helping to predict and early diagnose of preeclampsia. MATERIALS AND METHODS: A total of 739 nulliparous women at their 24-28(th) weeks of the first pregnancy were enrolled in this multi center cohort study. Incidence or absence of preeclampsia in this population was evaluated up to the end of pregnancy period. For each case, a record sheet was assigned that contained information about haematocrit level in weeks 24-28(th) of pregnancy, blood pressure, result of roll-over test in weeks 24-28(th) of pregnancy and the presence of disease up to end of the study. Diagnosis of preeclampsia was made based on gold standard. RESULTS: Overall, 3.9 % of all cases developed preeclampsia. The mean maternal age, body mass index (BMI), years of education and positive roll-over test were significantly higher in preeclampsia group (P < 0.001). However, the mean gestational age and changes in the levels of haematocrit were significantly higher in normotensive cases (P < 0.001). Our combined model could predict preeclampsia with a sensitivity of 93% and a specificity of 80%. CONCLUSION: Simple combined model of demographic characteristics including maternal age, BMI, years of education and positive roll over tests can predict preeclampsia without any cost for the patients. PMID- 24403716 TI - Demodex spp. Infestation in a breast-cancer patient: A case report. AB - Demodex folliculorum and Demodex brevis are obligatory parasites that live in sebaceous glands and follicles. When immune system becomes suppressed by any reason, patients become vulnerable to obligatory parasites like D. folliculorum and D. brevis. Immune system becomes suppressed in cancer patients who undergo chemotherapy, and as a result these patients become vulnerable to infestations. In our case, a 45 year-old female has been admitted to oncology clinic for a medical treatment of breast cancer. Her systematic physical examination was normal, except redness on her cheeks and forehead. There was no abnormality in biochemical and haematological laboratory values. We have decided to apply chemotherapy of Adriamycin, cyclophosphamide and 5-fluorouracil. Due to the itchy redness on her cheeks and forehead, we had performed an examination for demodex before chemotherapy; and we have identified 20 mites/cm(2) on her right and left cheeks, and 15 mites/cm(2) on her forehead. When our patient had came our clinic with increasing complaint of itchy rash, after the first course of chemotherapy we have reexamined demodex. The result of microscopic examination revealed large amount of demodex of 50 mites/cm(2) on her right and left cheeks and 30 mites/cm(2) on her forehead, which were nearly 2.5-times higher than the previous examination. This increase probably was associated with immune suppression of chemotherapy. PMID- 24403717 TI - A case of concurrent several forms of thyroid cancer. AB - Simultaneous occurrence of papillary and follicular thyroid cancer, known as differentiated thyroid cancer, has been reported with various presentations, but presence of an anaplastic cancer, as an undifferentiated cancer, in addition to differentiated thyroid cancer is rarely reported. We here report a 40-year-old man with papillary thyroid cancer on his right thyroid lobe and metastasized to the right posterior triangle of the neck. Survey on the mass in the right posterior triangle revealed presence of simultaneous papillary, follicular, and anaplastic thyroid cancer. The patient underwent right thyroid lobectomy and he received adjuvant radiotherapy in combination with chemotherapy. PMID- 24403718 TI - Bilateral impacted femoral neck fracture in a renal disease patient. AB - Spontaneous bilateral femoral neck facture in a renal disease patient is not common. We report a case of 47-year-old female patient with chronic renal failure and on regular hemodialysis for the past 5 years who sustained bilateral impacted femoral neck fracture without history of trauma and injury and refused any surgical intervention. The patient was mobilised on wheel chair one year after the fractures. The cause of the fracture and the literature review of the bilateral femoral neck fracture in renal disease are discussed. PMID- 24403719 TI - Percutaneous Kirschner wire (K-wire) fixation for humerus shaft fractures in children: A treatment concept. AB - BACKGROUND: Fractures of the humeral shaft are uncommon, representing less than 10 percent of all fractures in children. Humeral shaft fractures in children can be treated by immobilisation alone. A small number of fractures are unable to be reduced adequately or maintained in adequate alignment, and these should be treated surgically. In the present study, Kirschner wires (K-wire) were used to achieve a closed intramedullary fixation of humeral shaft fractures. The objective of this study was to evaluate the efficacy of intramedullary K-wires for the treatment of humeral shaft fracture in children. PATIENTS AND METHODS: This prospective study was conducted in the Department of Orthopaedic surgery in M. M. Medical College from June 2005 to June 2010. Sixty-eight children with a mean age of 7.7 years (range, 2-14 years) were recruited from Emergency and out patient department having closed fracture of humerus shaft. All patients were operated under general anaesthesia. All patients were followed for 12 months. RESULTS: Out of 68 patients, 64 patients underwent union in 42-70 days with a mean of 56 days. Complications found in four patients who had insignificant delayed union which were united next 3 weeks. Intramedullary K-wires were removed after an average of 5 months without any complications. The results were excellent in 94.11% and good in 5% children. CONCLUSION: This technique is simple, quick to perform, safe and reliable and avoids prolonged hospitalization with good results and is economical. PMID- 24403720 TI - Chronic haemodynamic disturbances in neurointensive care: First description. PMID- 24403721 TI - Uric acid: A hypothetical cause of preeclampsia-eclampsia. PMID- 24403722 TI - A NEW APPROACH TO THE SYNTHESIS OF SUBSTITUTED PHENAZINES VIA PALLADIUM-CATALYZED ARYL LIGATIONi. AB - A new method for the "ligation" of two aromatic rings has been achieved via synthesis of functionalized phenazines by double Buchwald-Hartwig cyclization of a variety of substituted bromoanilines. PMID- 24403723 TI - The Impact of Ethnoracial Appearance on Substance Use in Mexican Heritage Adolescents in the Southwest United States. AB - Latinos are a multiracial ethnic group, and as such, within-group differences in ethnoracial appearance deserve to be studied and understood within the racialized American context and in connection to specific health and mental health outcomes. This article presents the findings of a study conducted with middle school Mexican heritage students (n = 1,150) in Phoenix, Arizona, and tested how non White majority ethnoracial appearance predicted adolescent substance use, and whether the relationship differed by generation status and strength of ethnic identity. Logistic regression results revealed that generation status and ethnic identity moderate the relationship between ethnoracial appearance and substance use among Mexican heritage youth. The odds of using substances were significantly higher for third-generation adolescents who reported a less European appearance, but significantly lower for second-generation youth who were more indigenous in appearance. These findings indicate that a stronger indigenous ethnic appearance can be both a protective and risk factor for substance use for adolescents. Implications are discussed in terms of incorporating ethnoracial appearance content in prevention interventions for Mexican heritage and other Latino adolescents. PMID- 24403724 TI - Random effects structure for confirmatory hypothesis testing: Keep it maximal. AB - Linear mixed-effects models (LMEMs) have become increasingly prominent in psycholinguistics and related areas. However, many researchers do not seem to appreciate how random effects structures affect the generalizability of an analysis. Here, we argue that researchers using LMEMs for confirmatory hypothesis testing should minimally adhere to the standards that have been in place for many decades. Through theoretical arguments and Monte Carlo simulation, we show that LMEMs generalize best when they include the maximal random effects structure justified by the design. The generalization performance of LMEMs including data driven random effects structures strongly depends upon modeling criteria and sample size, yielding reasonable results on moderately-sized samples when conservative criteria are used, but with little or no power advantage over maximal models. Finally, random-intercepts-only LMEMs used on within-subjects and/or within-items data from populations where subjects and/or items vary in their sensitivity to experimental manipulations always generalize worse than separate F1 and F2 tests, and in many cases, even worse than F1 alone. Maximal LMEMs should be the 'gold standard' for confirmatory hypothesis testing in psycholinguistics and beyond. PMID- 24403725 TI - Dynamic intrinsic optical signal monitoring of electrically stimulated inner retinal neural response. AB - Dynamic monitoring of stimulus-evoked inner neural response is important for functional validation of stimulation protocols of retinal prosthetic devices. In this paper, we demonstrate label-free intrinsic optical signal (IOS) imaging of electrically stimulated inner neural response in freshly isolated mouse retinas. While single-pulse stimulation evoked rapid IOS within 20 ms, pulse-train stimulation indicated that the fast IOS response can follow frequency stimulation up to at least 8 Hz. Fast IOS imaging promises a noninvasive method for high resolution examination of electrically evoked retinal response, without artifact contamination of electrical stimulus. PMID- 24403726 TI - The economics, culture and politics of hospital contributory schemes: The case of inter war Leeds. PMID- 24403727 TI - Interaction effects of selected pesticides on soil enzymes. AB - The laboratory studies were conducted to resolute the effects of imidacloprid (insecticide) and triadimefon (fungicide) singly and in combination on enzymatic activities of soil microorganisms in tomato cultivated soils at different concentrations of 0.2, 0.5 and 0.7 kg/ha. The rate of amylase activity was stimulated by the application of pesticides at field rate. High dosage decreased the activity of amylase. Decline in the activity of cellulase was observed at all concentrations than control. Imidacloprid had an improved activity of cellulase at 0.5 MUg/g than tridimefon and combination. At higher concentration (0.7 MUg/g), the combination of insecticide and fungicide showed an antagonistic interaction toward cellulase. After 24 h, maximum inhibition was observed in invertase enzyme rate at all examined dosages. After 48 h, the activity was revived to some extent and imidacloprid showed enhanced activity at 0.5 MUg/g (field rate). However at 0.7 MUg/g, imidacloprid has a noticeable effect on the invertase. The pesticide application in single and in combination (0.2-0.7 MUg/g soil) triggered the dehydrogenase activity. At field rate triadimefon significantly quickened the activity. PMID- 24403728 TI - Neuroprotective Actions of Clinoptilolite and Ethylenediaminetetraacetic Acid Against Lead-induced Toxicity in Mice Mus musculus. AB - OBJECTIVES: Oxidative stress is considered as a possible molecular mechanism involved in lead (Pb(2+)) neurotoxicity. Very few studies have been investigated on the occurrence of oxidative stress in developing animals due to Pb(2+) exposure. Considering the vulnerability of the developing brain to Pb(2+), this study was carried out to investigate the effects of Pb(2+) exposure in brain regions especially on antioxidant enzyme activities along with ameliorative effects of ethylenediaminetetraacetic acid (EDTA) and clinoptilolite. METHODS: Three-week old developing Swiss mice Mus musculus were intraperitoneally administered with Pb(2+) acetate in water (w/v) (100 mg/kg body weight/day) for 21 days and control group was given distilled water. Further Pb(2+)-toxicated mice were made into two subgroups and separately supplemented with EDTA and clinoptilolite (100 mg/kg body weight) for 2 weeks. RESULTS: In Pb(2+)-exposed mice, in addition to increased lipid peroxidation, the activity levels of catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH) found to decrease in all regions of brain indicating, existence of severe oxidative stress due to decreased antioxidant function. Treatment of Pb(2+)-exposed mice with EDTA and clinoptilolite lowered the lipid peroxidation (LPO) levels revealing their antioxidant potential to prevent oxidative stress. Similarly their administration led to recover the level of catalase, SOD, and GPx enzymes affected during Pb(2+) toxicity in different regions of brain. CONCLUSIONS: The protection of brain tissue against Pb(2+)-induced toxicity by clinoptilolite and EDTA in the present experiment might be due to their ability to react faster with peroxyl radicals there by reducing the severity of biochemical variable indicative of oxidative damage. Thus, the results of present study indicate the neuroprotective potential of clinoptilolite and EDTA against Pb(2+) toxicity. PMID- 24403729 TI - Genetic diversity of pinus roxburghii sarg. Collected from different himalayan regions of India assessed by random amplified polymorphic DNA analysis. AB - Present study was aimed at molecular genetic fingerprint profile of 15 genotypes of three populations of Pinus roxburghii Sarg. from Himalayan regions of India using random amplified polymorphic DNA (RAPD) based markers. Needles of Pinus roxburghii Sarg. were collected from Dharamshala, Himachal Pradesh (HP), Nainital, Uttarakhand (UK) and Darjeeling, West Bengal (WB) regions of India. The samples were subjected to DNA extraction and RAPD analysis using oligonucleotide purification cartridge (OPC) primers. Out of 15 primers tested, nine primers gave scorable bands. Altogether 48 bands were obtained, out of which 43 were found to be polymorphic. Number of amplified fragments with RAPD primers ranged from four to eight with the size of amplicon ranging from 500 to 7,000bp. Investigation of natural diversity at intraspecies level was performed with 15 genotypes. Forty eight amplification products were scored by RAPD and showed 89.58% polymorphism with a mean intrapopulation genetic diversity (Hpop) of 0.2754. A significant inter- and intrapopulation diversity was observed, with the percentage of polymorphic loci (Pp) ranging from 50.09 to 70.83%, Shannon's information index (I) from 0.3262 to 0.4689 and Nei's gene diversity (h) from 0.2032 to 0.3335 with mean Nei's gene diversity 0.377 and the overall estimate of gene flow being (Nm) 1.3555. Unweighted pair-group method with arithmetic average (UPGMA) analysis based Dendrogram showed single cluster. The variation amongst the samples of the three ecological regions can be attributed to varied climatic conditions and may help in conservation/future cultivation of these species. PMID- 24403730 TI - Prognostic significance of estimation of pseudocholinesterase activity and role of pralidoxime therapy in organophosphorous poisoning. AB - BACKGROUND: Organophosphorous (OP) poisoning is one of the most common poisonings seen in India. OP compounds act through inhibition of enzyme acetylcholinesterase and estimation of pseudocholinesterase (PCE) activity strengthens the diagnosis in clinically uncertain cases of OP poisoning. The role of pralidoxime (PAM) therapy in OP poisoning has been controversial. STUDY OBJECTIVES: This study was aimed to determine the prognostic significance of estimation of PCE activity and also to assess the role of PAM therapy in OP poisoning. MATERIALS AND METHODS: Patients of suspected OP poisoning of age >12 years admitted to emergency unit at a tertiary healthcare center of north India were enrolled. Patients were categorized into two groups; group A who were given intravenous atropine and group B who were given injectable PAM along with atropine. Serum PCE level was estimated at the time of admission in all patients and severity of OP poisoning was assessed according to PCE level. Requirement of atropine, oxygen inhalation, intubation and ventilatory support, total hospital stay, and mortality were compared between different classes of severity and also between Groups A and B. RESULTS: This study included a total of 70 subjects, 35 in each group with mean age of 24.99 +/- 8.7 years. Out of 70 subjects 49 (70%) were male and 21 (30%) were female. Forty nine patients (70%) of OP poisoning were with suicidal intent while 21 (30%) cases were accidentally poisoned. In all suicidal cases route of poisoning was ingestion whereas in all the accidental cases route of exposure was inhalational. PCE levels were reduced in all the cases and the mean level was 3,154.16 +/- 2,562.40 IU/L. The total dose of atropine required, need for oxygen inhalation and need for intubation and ventilatory support, mean duration of hospital stay and mortality rate (P = 0.003) were higher in moderate to severe cases and did not have significant difference between Groups A and B. CONCLUSION: The study recommends estimation of PCE level at admission to classify severity of OP poisoning and to estimate prognosis. This study did not find any beneficial role of PAM therapy in reducing morbidity as well as mortality. PMID- 24403731 TI - Lipid metabolism disorders, lymphocytes cells death, and renal toxicity induced by very low levels of deoxynivalenol and fumonisin b1 alone or in combination following 7 days oral administration to mice. AB - SCOPE: In our previous study focused on in vitro interactive effect of Fusarium mycotoxins deoxynivalenol (DON) and fumonisin B1 (FB1), we reported that these toxins tested at low level and in association could lead to additive or synergistic cytotoxic effect. The aim of the present study is to confirm those findings by in vivo study. MATERIALS AND METHODS: Swiss mice were orally administered with low doses of DON (45 MUg/kg bw/day), FB1 (110 MUg/kg bw/day), and their mixture (DON + FB1) for 7 days. RESULTS: As results, no death or abnormal symptoms were observed in all groups. The significant of loss of weight was observed in females group treated with FB1 and its association with DON. Serum chemistry examinations revealed that disorders in lipid metabolism, renal filtration perturb and a rhabdomyolysis. DON has been found as particular inducer of kidney cell deoxyribonucleic acid (DNA) methylation and blood lymphocytes cell death as measured by lymphocytes DNA fragmentation. Female mice were more sensitive and the mixture of DON and FB1 led to additive or more than additive effect particularly for their target kidney which showed different pattern of toxicity. CONCLUSION: Based on the results of this study, the no-observed-adverse effect level (NOAEL) o both DON and FB1 should be low than 45 MUg/kg bw/day and 110 MUg/kg bw/day, respectively in mice. PMID- 24403732 TI - A new method for determining acute toxicity in animal models. AB - BACKGROUND: The intake of pharmacological substances by man has solely increased and this may be in the form of food, medicines and beverages, other industrial and household products. These substances are capable of eliciting chronic and acute toxicity, which may be mild or severe, depending upon their nature. Acute toxicity is defined as the unwanted effect(s) that occurs either immediately or at a short time interval after a single or multiple administration of such substance within 24 hours. The principal aim of this paper is to introduce a new method for testing toxicity, which if adopted, should produce more accurate and reproducible results using few animals. MATERIALS AND METHODS: The proposed method is divided into three stages, with the outcome of each stage determining whether to terminate testing of proceed to the next stage. A confirmatory (confidence) test is used to validate the final test result. The method shows enormous advantages, which include the use of few animals, exploration of a wide range of doses, it is simple and inexpensive. CONCLUSION: Furthermore, accurate and reproducible result can be gotten through this method. We therefore recommend that the method should be considered for endorsement for the testing of acute toxicity by the regulatory bodies. PMID- 24403733 TI - Amelioration of renal carcinogenesis by bee propolis: a chemo preventive approach. AB - OBJECTIVE: The present study was designed to investigate the chemo preventive efficacy of bee propolis (BP) against diethylnitrosamine (DEN) initiated and ferric nitrilotriacetate (Fe-NTA) promoted renal carcinogenesis in Wistar rats. Chronic treatment of Fe-NTA induced oxidative stress, inflammation and cellular proliferation in Wistar rats. BP is a resinous material collected by bees from various plants which has been used from centuries in folk medicine. MATERIALS AND METHODS: Renal cancer was initiated by single intraperitoneal injection of N nitrosodiethylamine (DEN 200 mg/kg body weight) and promoted by twice weekly administration of Fe-NTA 9 mg Fe/kg body weight for 16 weeks. The chemo preventive efficacy of BP was studied in terms of lipid peroxidation (LPO), renal anti-oxidant armory such as catalase, superoxide dismustase, glutathione S transferase, glutathione peroxidase, glutathione reductase and glutathione (GSH), serum toxicity markers, cell proliferation, tumor suppressor protein and inflammation markers. RESULTS: Administration of Fe-NTA enhances renal LPO, with concomitant reduction in reduced GSH content and antioxidant enzymes. It induces serum toxicity markers, viz., blood urea nitrogen, creatinine and lactate dehydrogenase. Chemo preventive effects of BP were associated with upregulation of antioxidant armory and down regulation of serum toxicity markers. BP was also able to down regulate expression of proliferative cell nuclear antigen, cyclooxygenase-2, tumor necrosis factor-alpha and upregulated p53 along with induction of apoptosis. Histopathological changes further confirmed the biochemical and immunohistochemical results. CONCLUSION: These results provide a powerful evidence for the chemo preventive efficacy of BP against renal carcinogenesis possibly by modulation of multiple molecular pathways. PMID- 24403734 TI - Prediction of an Epitope-based Computational Vaccine Strategy for Gaining Concurrent Immunization Against the Venom Proteins of Australian Box Jellyfish. AB - BACKGROUND: Australian Box Jellyfish (C. fleckeri) has the most rapid acting venom known to in the arena of toxicological research and is capable enough of killing a person in less than 5 minutes inflicting painful, debilitating and potentially life-threatening stings in humans. It has been understood that C. fleckeri venom proteins CfTX-1, 2 and HSP70-1 contain cardiotoxic, neurotoxic and highly dermatonecrotic components that can cause itchy bumpy rash and cardiac arrest. SUBJECTS AND METHODS: As there is no effective drug available, novel approaches regarding epitope prediction for vaccine development were performed in this study. Peptide fragments as nonamers of these antigenic venom proteins were analyzed by using computational tools that would elicit humoral and cell mediated immunity, were focused for attempting vaccine design. By ranking the peptides according to their proteasomal cleavage sites, TAP scores and IC50<250 nM, the predictions were scrutinized. Furthermore, the epitope sequences were examined by in silico docking simulation with different specific HLA receptors. RESULTS: Interestingly, to our knowledge, this is the maiden hypothetical immunization that predicts the promiscuous epitopes with potential contributions to the tailored design of improved safe and effective vaccines against antigenic venom proteins of C. fleckeri which would be effective especially for the Australian population. CONCLUSION: Although the computational approaches executed here are based on concrete confidence which demands more validation and in vivo experiments to validate such in silico approach. PMID- 24403735 TI - Mutagenicity Assessment of Organophosphates using Polymerase Chain Reaction Restriction Fragment Length Polymorphism Assay. AB - OBJECTIVES: In this study we have evaluated the mutagenicity of organophosphate pesticides acephate, chlorpyrifos, and profenofos using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay with the mosquito Culex quinquefasciatus taken as an experimental model. MATERIALS AND METHODS: Second instar larvae were treated with LC20 of each pesticide for 24 h and mutations induced in the sequence of mitochondrial COII gene (690bp) were studied from restriction patterns generated with AluI, PacI, and PsiI restriction endonucleases. RESULTS: Variations in the number and size of digested fragments were recorded from treated individuals compared with controls showing that the restriction enzymes created a cut at different locations. In addition, sequences of COII gene from control and treated individuals were also used to confirm the RFLP patterns. From the sequence alignment data, it was found that mutations caused the destruction and generation of restriction sites in the gene sequence of treated individuals. CONCLUSION: This study indicates that all the three pesticides had potential to induce mutations in the normal sequence of COII gene and also advocates the use of PCR-RFLP assay as an efficient, rapid, and sensitive technique to detect mutagenicity of pesticides. PMID- 24403736 TI - Cyanide and Aflatoxin Loads of Processed Cassava (Manihot esculenta) Tubers (Garri) in Njaba, Imo State, Nigeria. AB - OBJECTIVES: The present study sought to investigate the role of palm oil, in conjunction with the duration of fermentation, on cyanide and aflatoxin (AFT) loads of processed cassava tubers (Garri). MATERIALS AND METHODS: Matured cassava (Manihot esculenta Crantz) tubers were harvested from three different locations (Akunna, Mkporo-Oji and Durungwu) in Njaba Local Government Area, Imo State, Nigeria. The cassava tubers were processed into Garri according to standard schemes with required modifications and measured for cyanide content using titrimetric methods. Samples of Garri for determination of AFT levels were stored for 30 days before the commencement of spectrophotometric analysis. RESULTS: Cyanide content of peeled cassava tubers was within the range of 4.07 +/- 0.16 5.20 +/- 0.19 mg hydrocyanic acid (HCN) equivalent/100 g wet weight, whereas the various processed cassava tubers was within the range of 1.44 +/- 0.34-3.95 +/- 0.23 mg HCN equivalents/100 g. For the 48 h fermentation scheme, Garri treated with palm oil exhibited marginal reduction in cyanide contents by 0.96%, 3.52% and 3.69%, whereas 4 h fermentation scheme is in concurrence with palm oil treatment caused 4.42%, 7.47% and 5.15% elimination of cyanide contents compared with corresponding untreated Garri samples (P > 0.05). Levels of AFT of the various Garri samples ranged between 0.26 +/- 0.07 and 0.55 +/- 0.04 ppb/100 g. There was no significant difference (P > 0.05) in AFT levels among the various samples in relation to their corresponding sources. CONCLUSION: The present study showed that the 48 h fermentation scheme for Garri production caused significant (P < 0.05) reduction, but did not obliterate the cyanide content of cassava tubers. Conversely, the 48 h fermentation scheme promoted the elevation of AFT levels, but was relatively reduced in Garri samples treated with palm oil. PMID- 24403737 TI - Synthesis, hematological, biochemical, and neurotoxicity screening of some mannich base hydrochlorides. AB - BACKGROUND: Mannich bases are an important class of compounds in medicinal chemistry with a wide spectrum of biological activities, however, knowledge on their toxicity is limited. MATERIALS AND METHODS: Two Mannich base hydrochlorides 1a (2-thienyl-beta-dimethylaminoethyl ketone hydrochloride) and 1b (beta dimethylaminopropiophenone hydrochloride) were synthesized and characterized on the basis of their infrared and nuclear magnetic resonance spectral data. The potential effects of the synthesized compounds (5 mg/kg, i.p, during 30 days) on relative weight, hematological parameters, biochemical parameters, and neurotoxicity were tested using male Wistar rat. RESULTS: The results showed that compound 1b alters body weight on the first 10 days (182%, P < 0.01) and on the last 10 days (107%, P < 0.01) of treatment. The same treatment decreases food intake (P < 0.01) and increases water intake (P < 0.05). Both compounds induced a deficit on rotarod test manifested by a decrease of grasping time (1a: 65.33%, P < 0.01; 1b: 60.55%, P < 0.01) and fall time (1a: 59.75%, P < 0.01; 1b: 56.81%, P < 0.01) only on the last day of training. Moreover, Mannich base 1b decreases the liver relative weight (22.24%, P < 0.01). It was also observed that both products decrease the total serum cholesterol (Ch) levels (1a: 52.87%, P < 0.01; 1b: 64.70%, P < 0.01). Interestingly, compounds 1a and 1b affect hematological parameters manifested by an increase of the number of white blood cells (1a: 32.29%, P < 0.05; 1b: 20.64%, P < 0.05) and red blood cells (RBCs) (1a: 12.57%, P < 0.05; 1b: 20.11%, P < 0.05), an increase of red cell hemoglobin concentration (1a: 10.48%, P < 0.05; 1b: 16.12%, P < 0.05) and of the volume occupied by RBCs or hematocrit (1a: 18.28%, P < 0.05; 1b: 15.56%, P < 0.05), and an increase of the number of platelets (1a: 16.80%, P < 0.05; 1b: 39.96%, P < 0.05) accompanied by a decrease in hemoglobin level only with the compound 1a (7.41%, P < 0.05). CONCLUSION: These results show that both compounds 1a and 1b induced a hypoxia status associated to low level of Ch and liver toxicity. The deficit observed by rotarod could be explained by the myorelaxant effect of the used products. PMID- 24403738 TI - Multi-organ Dysfunction Syndrome with Dual Organophosphate Pesticides Poisoning. AB - Organophosphate (OP) pesticide self-poisoning is common in developing countries. Poisoning with dual OP compounds is rare. Multi-organ dysfunction after OP poisoning has a high mortality rate. We report the case of a 27-year-old man who developed multi-organ dysfunction syndrome with fatal outcome after intentional ingestion of 50:50 mixture of two OP compounds, dichlorvos and profenofos. PMID- 24403739 TI - Open reduction and internal fixation of high fibular fractures in ankle injuries: Is it necessary? - A review of the literature. PMID- 24403740 TI - A study of the usefulness of a periarticular multimodal drug cocktail injection for pain management after total hip arthroplasty. AB - BACKGROUND: Measures for pain management after total hip arthroplasty (THA) are important for early improvement in the quality of life after operation and early postoperative rehabilitation. We investigated the analgesic effect of locally injected drugs around the total hip prosthesis. METHODS: 54 patients undergoing THA were randomized either to receive a periarticular intraoperative injection of a 30-ml mixture containing morphine hydrochloride 10 mg, 0.5% bupivacaine 20 ml, epinephrine 0.3 mg, and saline 8.7 ml or to receive no injection. The perioperative analgesic regimen was standardized. The evaluation items included assessment of pain using a 100-point visual analog scale (VAS) after the patients awoke on the day of the operation and on postoperative day 1, the dose of diclofenac sodium suppository, the number of days for acquiring assisted ambulation with a walking cane, and side effects. RESULTS: The VAS score on the day of the operation was significantly low in the injection group. No cardiac or central nervous system toxicity was observed. CONCLUSIONS: Intraoperative periarticular injection with multimodal drugs can significantly reduce pain on the day of the operation, with no apparent risks, following THA. PMID- 24403741 TI - Prevalence of symptomatic and asymptomatic rotator cuff tears in the general population: From mass-screening in one village. AB - PURPOSE: Rotator cuff tear is the most common shoulder disease in patients with shoulder problems, but its prevalence is not well known. METHODS: We performed a health care check-up of locomotive organs in 664 residents (21.3% of the population) in one village. Ultrasonography on bilateral shoulders was performed in all the participants. RESULTS: One hundred and forty seven out of 664 subjects (22.1%) had full-thickness rotator cuff tears. The prevalence of tear in each decade was 0% in the 20s to 40s, 10.7% in the 50s, 15.2% in the 60s, 26.5% in the 70s, and 36.6% in the 80s. Symptomatic rotator cuff tears accounted for 34.7% of all tears and asymptomatic tears for 65.3%. The prevalence of asymptomatic rotator cuff tears was one-half of all tears in the 50s, whereas it accounted for two-thirds of those over the age of 60. The prevalence of tear was significantly greater in male than in female in the 50s and 60s, but not in the 70s and 80s. CONCLUSION: The prevalence of rotator cuff tear in the general population was 22.1%, which increased with age. Asymptomatic tear was twice as common as symptomatic tear. PMID- 24403742 TI - Minimally invasive surgery through endoscopic laminotomy and foraminotomy for the treatment of lumbar spinal stenosis. AB - BACKGROUND: Lumbar spinal stenosis is a common cause of radicular and generalized back pain among older adults. Endoscopic minimally invasive surgery, in contrast to open decompression, may provide the opportunity for a less invasive surgical intervention. Thus, the purpose of this study is to evaluate the safety (operative complications, estimated blood loss, operative room time) and effectiveness (pre- versus postoperative level of disability and pain severity) of minimally invasive surgery using endoscopic laminotomy and foraminotomy among a large sample of patients with lumbar spinal stenosis. METHODS: This study is composed of 320 consecutive patients with lumbar spinal stenosis who underwent posterior lumbar laminotomy and foraminotomy between 2008 and 2011. Outcome measures consisted of perioperative complications, estimated blood loss, operative room time, level of disability, and pain severity. Pain severity and level of disability were prospectively analyzed to an average of 18 months (12-36 months) post-surgery. RESULTS: There was an average estimated blood loss of 39.3 cc and a mean operative room time of 74 min. Seven patients experienced minor operative complications. All patients were discharged the same day as surgery and reported a significantly lower level of disability (p = 0.00) and pain severity (p = 0.00) postoperative compared to preoperative. CONCLUSIONS: Minimally invasive surgery using endoscopy for the treatment of lumbar spinal stenosis has a short operative time, a low operative complication rate, and minimal estimated blood loss. This study also indicates that MIS for the treatment of LSS can significantly reduce pain and disability level. Thus, minimally invasive surgery using endoscopic laminotomy and foraminotomy appears to be a safe and effective alternative surgical treatment for open decompression surgery in adult patients with lumbar spinal stenosis. PMID- 24403743 TI - Complications of Elastic Stable Intramedullary Nailing for treating paediatric long bone fractures. AB - This study reports the complications observed in children with long bone fractures treated using Elastic Stable Intramedullary Nailing (ESIN). One hundred and sixty-four (n = 164) fractures in 160 patients under the age of 16 years formed the basis of our review. This included 108 boys and 52 girls with the median age of 11 years and median follow up of 7.5 months. The analysis included fractures of the radius/ulna, humerus, femur and tibia. All pathological fractures were excluded. In this series 54 patients (34%) had complications however majority of these were minor complications with irritation due to prominent nail ends being the commonest complication. No long-term sequelae were encountered in our patients. PMID- 24403744 TI - Variation in the insertion of the latissimus dorsi & its clinical importance. AB - The latissimus dorsi is the larger, flat, dorso-lateral muscle on the trunk, posterior to the arm, and partly covered by the trapezius on its median dorsal region. Origin of the latissimus dorsi is from spinous processes of thoracic T7 T12, thoracolumbar fascia, iliac crest and inferior 3 or 4 ribs, inferior angle of scapula and insertion on floor of intertubercular groove of the humerus. We have studied 50 cadavers in the different medical colleges in which we found 2% case of anterior and posterior slip of the muscle fibers with their extension up to the pectoralis major and teres major respectively. Usually, latissimus dorsi involve in extension, adduction, transverse extension also known as horizontal abduction, flexion from an extended position, and internal rotation of the shoulder joint. It also has a synergistic role in extension and lateral flexion of the lumbar spine. The latissimus dorsi may be used for the tendon graft surgeries. Tight latissimus dorsi has been shown to be one cause of chronic shoulder pain and chronic back pain. Because the latissimus dorsi connects the spine to the humerus, tightness in this muscle can manifest as either sub-optimal glenohumeral joint function (which leads to chronic shoulder pain) or tendinitis in the tendinous fasciae connecting the latissimus dorsi to the thoracic and lumbar spine. Latissimus dorsi used for pedicle transplant rotator cuff repair reconstruction of breast, face, scalp and cranium defect. The extra slip of the latissimus dorsi may puzzle any transplant operations. We as anatomist discuss the clinical implication of the extra slip of latissimus dorsi. PMID- 24403745 TI - Computational modelling of long bone fractures fixed with locking plates - How can the risk of implant failure be reduced? AB - BACKGROUND AND PURPOSE: The Locking Compression Plate (LCP) is part of a new plate generation requiring an adapted surgical technique and new thinking about commonly used concepts of internal fixation using plates. Knowledge of the fixation stability provided by these new plates is very limited and clarification is still necessary to determine how the mechanical stability and the risk of implant failure can best be controlled. METHODS: Upon validation, a finite element model of an LCP attached to a cylinder was developed to simulate and analyse the biomechanics of a transverse long bone fracture fixed with a locking plate. Of special interest were the factors influencing the mechanical conditions at the fracture site, the control of interfragmentary movement and implant failure. RESULTS: Several factors were shown to influence stability in compression. Increasing translation and/or fracture angle post fixation reduced construct stability. Axial stiffness was also influenced by the working length and plate-bone distance. The fracture gap had no effect on the construct stability when no bone contact occurred during loading. Stress analysis of the LCP demonstrated that the maximum Von Mises stresses were found in the innermost screws at the screw-head junction. INTERPRETATION: For the clinical use of the LCP as a locked internal fixator in fractures with an interfragmentary gap of 1 mm, at least two to four plate holes near the fracture gap should be omitted to allow fracture motion and bone contact to occur. This will also achieve a larger area of stress distribution on the plate and reduce the likelihood of fatigue failure due to cyclic loading. PMID- 24403746 TI - Popliteal lesion due to traction during unicompartmental knee revision surgery. AB - Popliteal artery injury is a rare but known complication in knee surgery. Only one article in current literature reports that the risk increases during revision knee surgery. A new case is described in which an injury to the popliteal artery occurred during lateral unicompartmental to total knee arthroplasty revision surgery. This vascular injury occurred 5-10 cm below the tibial resection level in a healthy patient with a history of cruris fracture with plate osteosynthesis and lateral unicompartmental knee arthroplasty. This paper stresses the importance of being aware that trauma and surgery can create fibrosis in which the popliteal artery can get fixated, thus reducing the scope for safe manipulation of the knee during secondary surgery. PMID- 24403747 TI - Outcomes of minimally 1 year follow-up for the arthroscopic Remplissage technique with Hill-Sachs lesion. AB - PURPOSE: We evaluated minimal 1 year follow-up results for the Remplissage technique to fill a Hill-Sachs lesion with anterior instability. METHODS: The subjects were 12 patients, who could be followed-up for more than 12 months after the "Remplissage" procedures in our hospital from August 2008 to May 2010. Their mean age was 28.6 years old and the mean follow-up was 19 months. The evaluations included the ROM, the ASES score, the KSSI score, the ROWE score and postoperative MRI. RESULTS: On the postoperative functional evaluation after an average 16 months, the ASES score improved 51.4 in preoperative to 86.6 in postoperatively, the KSSI score improved from 46.6 preoperatively to 84.9 postoperatively and the ROWE score improved from 43.6 preoperatively to 91.4 postoperatively. After an average 14 months for all the cases, the range of movement was nearly in the normal range which is 174.3 +/- 5.04 (170-180) degrees in foreward flexion, and 56.4 +/- 9.60 (50-60) degrees in external rotation. CONCLUSION: For recurrent shoulder instability with a large Hill-Sachs lesion, the Remplissage technique has a good outcome after more than 1 year follow-up in terms of shoulder stability, and the clinical and functional results. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 24403748 TI - A combination of Latarjet and Remplissage for treatment of severe glenohumeral instability and bone loss. A case report. AB - Recurrent glenohumeral instability is challenging to treat when large bony defects are present in the anterior glenoid and there is a large Hill-Sachs lesion. We present a case with extensive glenoid and humeral bone loss treated with open Latarjet procedure combined with posterior arthroscopic Remplissage. 3.5 years after surgery, there have been no dislocations or any subjective signs of instability. After half a year, the patient was able to return to work as an airline pilot. Constant score has improved from 33 to 74 and the Oxford instability score from 8 to 46. We find that in young patients with difficult instability combining the Latarjet and Remplissage is a good and replicable method. PMID- 24403749 TI - The epidemiology and outcome of open distal radial fractures. PMID- 24403750 TI - Comparing results of posterior spine fusion in patients with AIS: Are two surgeons better than one? AB - AIMS: Spinal deformity surgery is one of the most complicated procedures performed in pediatric orthopedics. These surgeries can account for long operative times and blood losses. Finding ways to limit patient morbidity undergoing these procedures may benefit many. We hypothesized that utilizing two fellowship trained pediatric spinal deformity surgeons would lead to decreased operative time and blood loss when compared with single surgeon. We felt very little difference would be found in terms of curve correction. METHODS: A retrospective review of spinal deformity surgeries performed at two institutions was performed. At one institution, the standard of care was to have two fellowship deformity trained surgeons perform all deformity surgeries simultaneously, while at the second institution posterior spinal fusions performed by individual surgeons were performed. The single surgeon cohort was further divided based on instrumentation type (pedicle screw vs hybrid constructs). Cases for this review were limited to posterior spinal fusions without osteotomies in patients with idiopathic or idiopathic like curves. Cohorts were compared pre-operatively for age at surgery, sex, BMI, largest Cobb angle. Intra-operative comparisons included total EBL, instrumentation type screws vs hybrid, levels fused, and operative time. Comparisons between largest remaining Cobb, EBL/level, time/level, lowest recorded Hb, allogenic transfusion requirements, length of PICU stay, and total length of hospital stay were then made. Pair-wise student t-tests was performed between cohorts with significance defined as a p-value of 0.05 or less. CONCLUSIONS: Twenty-four patients were found in the (BMP) cohort, where as eighty-two were found in the control group. No significant difference in age, sex, starting hemoglobin, BMI*, or maximum pre operative Cobb between cohorts was found. A significantly lower number of levels were fused in the BMP cohort than the control (9 +/- 2 vs 11 +/- 2) p < 0.001, and likewise a significantly shorter operative time (average >2 h) was seen in the BMP cohort. Interestingly, no difference in estimated blood loss, blood loss/level fused, operative time/level fused was observed, yet a significantly greater drop in hemoglobin (average 1 g) p = 0.001 and allogenic transfusion rate was seen in the control group (4% (1/24) vs 29% (24/82)) p = 0.01. A greater improvement in Cobb angle was seen in the BMP group 46 +/- 8 vs 35 +/- 10 degrees p < 0.001. No differences were seen in nights in the PICU and peri-operative complications, however patients in the BMP averaged nearly 1day less in the hospital than in the control group. Utilizing a blood management program including two surgeons in spinal deformity surgery appears to decrease operative time, blood loss, and improve curve correction. Confounding factors such as differences in number of fusion levels, curve types, instrumentation type, and institutional practices prevents drawing definitive conclusions. This is the first study to show potential benefits of utilizing a blood management program with dual surgeons in spinal deformity cases. PMID- 24403751 TI - Long-term follow-up of trapeziectomy with abductor pollicis longus tendon interposition arthroplasty for osteoarthritis of the thumb carpometacarpal joint. AB - PURPOSE: To evaluate the long-term clinical and radiographic outcomes of trapeziectomy with abductor pollicis longus tendon interposition arthroplasty for moderate to severe osteoarthritis of the thumb carpometacarpal joint (Eaton stages III-IV). METHODS: We evaluated 13 patients (15 thumbs) who underwent trapeziectomy and abductor pollicis longus tendon interposition arthroplasty for end-stage osteoarthritis of the thumb carpometacarpal joint, at an average follow up of 15 years. Subjective clinical outcomes evaluated included visual analogue scale scores and disability of arm shoulder and hand score questionnaires. Objective clinical evaluation included lateral pinch and grip tests, and a range of active and passive thumb movements. All patients underwent a radiological assessment by two independent senior radiologists. Wherever possible, results obtained from the operated thumbs were compared to the non-operated side. RESULTS: At a mean of 15 years post operation (range 15-17 years), there was no statistical difference between the operated and non-operated hands with regards to grip and pinch strength. In all cases CMC and MCPJ range of motion in the operative hand was either equal to or greater than non-operative counterparts. Mean visual analogue scale score was 2.13 and mean DASH score was 16.85. Mean carpal height was 0.52 and mean trapezial space ratio was 0.163. There were no early or late complications recorded and no revision surgery was required. CONCLUSION: It is the opinion of these authors that abductor pollicis longus tendon interposition arthroplasty is able to provide high-quality long-term results for patients who suffer from moderate to severe osteoarthritis of the thumb carpometacarpal joint. LEVEL OF EVIDENCE: Therapeutic Level IV. PMID- 24403752 TI - Total hip arthroplasty using S-ROM prosthesis in elder patients with type C and B bone. AB - OBJECTIVE: The purpose of this study was to evaluate the clinical and radiological results using S-ROM prosthesis in patients with type C and B femoral bone requiring primary total hip arthroplasty (THA) for multiple reasons. METHODS: Sixteen hips were followed up for a mean of 38 months (range, 26-48), with a mean age at surgery of 72 years (range, 65-75). RESULTS: The average Harris hip score improved from 52.2 points to 88.5 points. All femoral stems showed stable fixation. Neither osteolysis around the femoral stem nor subsidence of the femoral stem were found at the final follow-up. CONCLUSION: For the patients with poor bone quality, total hip arthroplasty with the use of the proximal modular femoral stem yielded good short-to-mid-term results with respect to the clinical and radiological criteria. PMID- 24403753 TI - Predictive role of scintigraphy (BS) in bone union induction using extracorporeal shock wave treatment (ESWT). AB - AIMS: Pseudoarthrosis and delayed bone union are the main complications in the healing process of long bones fractures. The surgical intervention is currently the treatment of choice, but there is a number of non-operative interventions are being developed, such as extracorporeal shock wave therapy (ESWT). There is a range of issues related to the proper qualification, monitoring, and outcome assessment measures. Bone scintigraphy (BS) exclusively allows the assessment of the bone turnover dynamics in non-invasive, semi quantitative method. METHODS: The study group comprised of 31 subjects with bone healing complications. The study population was divided in two subgroups as related to the treatment outcome assessed 24 weeks after ESWT procedure. Group I (n = 19) included the cases with no complete bone union. Group II (n = 12) covered the subjects with complete bone union. BS was performed right before ESWT and 2 weeks after the procedure. RESULTS: Increase of agent uptake after ESWT procedure was noted in both groups which proves that ESWT increases bone metabolism dynamics in most patients. Significantly higher uptake increase was noted in patients with complete bone union. In patients with unsuccessful treatment the agent uptake before ESWT was much higher. Two weeks after ESWT procedure BS reveals an increase in bone metabolism in the area of complicated fracture proving positive reaction of bony tissue on mechanical waves. CONCLUSION: Scintigraphy may facilitate qualification patients with bone union disorders for further mode of treatment. One can suppose that positive bone reaction is achievable only in bone where the metabolism is lowered. PMID- 24403754 TI - Posterior femoral translation in medial pivot total knee arthroplasty of posterior cruciate ligament retaining type. AB - PURPOSE: To report clinical results and demonstrate posterior femoral translation (PFT) in medial pivot total knee arthroplasty (TKA) of posterior cruciate ligament (PCL) retaining type. MATERIALS AND METHODS: A prospective study was performed upon thirty consecutive subjects who were operated on with medial pivot TKA of PCL retaining type between March 2009 and March 2010 and had been followed up for at least 2 years. Clinically, the knee society knee score and function score were used. In full extension and active flexion lateral radiograph, anteroposterior (AP) condylar position and magnitude of PFT was determined. RESULTS: At last follow-up, the mean knee society knee score and function score improved significantly compared to preoperative scores. The AP condylar positions were consistently posterior to midline throughout the entire range of flexion. The PFTs averaged 0.31 (+/-0.12) of half length of tibial base plate and were greater in higher flexion cases (r = 0.56, p = 0.0012). There were no cases having either component migration or radiolucent line wider than 2 mm except for one case showing instability related to trauma. CONCLUSIONS: In medial pivot TKA of PCL retaining type, clinical outcomes were satisfactory and posterior femoral translations were consistently observed during progressive flexions of knees at two- to three-year follow-up. PMID- 24403755 TI - Internal fixation of displaced middle third fractures of clavicle with precontoured locking plate. AB - BACKGROUND: The traditional method of treating displaced mid clavicular fractures with conservative methods gives poor results. When there is displacement more than 2 cm and shortening, internal fixation of the clavicle, when performed properly, gives better results. METHODS: We reviewed the results of 20 cases of middle third clavicle fractures (Edinburg type 2B) with displacement more than 2 cm which were treated with open reduction and internal fixation with precontoured locking plate and screws. RESULTS: In all the fractures radiological union was evident by 10-16 weeks. None of the patients had complications like malunion, nonunion, deep infections, and implant failure and neurovascular damage. There was no problem with hardware and implant removal was not done. The average constant score was 95.45. All the patients were satisfied with the cosmetic appearance of surgical scar. CONCLUSIONS: Precontoured locking plate fixation gives excellent results, facilitates early return to function, results in better cosmesis and avoids complications of conservative methods like nonunion, malunion and also implant removal is not necessary. PMID- 24403756 TI - Osteomyelitis and septic arthritis from infection with Burkholderia pseudomallei: A 20-year prospective melioidosis study from northern Australia. AB - BACKGROUND: The gram-negative organism, Burkholderia pseudomallei, is responsible for the disease melioidosis. Septic arthritis and osteomyelitis due to B. pseudomallei are rare but recognised presentations of the disease. METHODS: A prospective database of all cases of melioidosis in the Northern Territory of Australia has been kept since October 1989. Entries to April 2009 were reviewed and cases involving bone and/or joint were investigated. We also present in detail the case reports of 3 presentations of bone and joint melioidosis. RESULTS: There were 536 presentations of melioidosis during the 20-year study period. Amongst these, there were 13 patients with primary septic arthritis and 7 cases of primary osteomyelitis. Septic arthritis and osteomyelitis were secondary to primary melioidosis elsewhere in 14 and 7 patients respectively. Melioidosis patients with bone/joint involvement were more likely to be Indigenous (p = 0.006) and female (p = 0.023) compared to patients with other presentations of disease. CONCLUSIONS: Timely microbiological diagnosis and prompt treatment of melioidosis involving bone and/or joint with appropriate intravenous antibiotics is important, as is adequate surgical drainage and debridement where indicated. A subsequent protracted course of antibiotic eradication therapy is important to avoid relapse of disease. PMID- 24403757 TI - Controlling pain after total knee arthroplasty using a multimodal protocol with local periarticular injections. AB - BACKGROUND: Measures for pain management after total knee arthroplasty (TKA) are important for early improvement in the quality of life after operation and early postoperative rehabilitation. We investigated the benefits and safety analgesic effect of locally injected drugs around the total knee prosthesis. METHODS: 60 patients undergoing TKA for osteoarthritis were divided randomly into three groups.Group A (20 knees; control group), this group did not receive multimodal drug cocktailtherapy; group B (21 knees), received intra-articular injection of a multimodal drug cocktail; and group C (19 knees), received localperiarticular injection of a multimodal drug cocktail. All analgesics administered in the first 24 h after surgery were recorded. The evaluation items included assessment of pain using a 100-point visual analogue scale (VAS) after the patients awoke on the day of the operation and on postoperative day 1, the dose of diclofenac sodium suppository, the number of days for acquiring assisted ambulation with a walking cane, and side effects. Assessment of flexion angles was conducted at postoperativeweek 1 and at theconclusion of the study. RESULTS: The VAS scores on the day of surgery and the amounts of diclofenac sodium used indicated good pain relief in groups B and C; the level of pain control was higher in group C than in group B. No cardiac or central nervous system toxicity was observed. CONCLUSIONS: Periarticular injection with multimodal drugs can significantly reduce the requirements for analgesia, with no apparent risks, following TKA. PMID- 24403758 TI - Laser etching causing fatigue fracture at the neck-shoulder junction of an uncemented femoral stem: A case report. AB - Fatigue fracture of a femoral component in total hip arthroplasty is a rare occurrence but well documented in the literature. It is understood that proximal loosing of a femoral stem with a well fixed stem distally will result in cantilever bending and eventual fatigue fracture of the stem. Other factors which may potentiate a fatigue fracture are material design, implant positioning, and patient characteristics. More recently, laser etching on the femoral neck of an implant has resulted in fatigue fracture. We report a case of a fatigue fracture at the neck-shoulder junction in a well fixed, uncemented, femoral component due to laser etching in the region of high tensile stress. PMID- 24403759 TI - The influence of rotator cuff pathology on functional outcome in total shoulder replacement. AB - INTRODUCTION: Total shoulder replacement (TSR) is a reliable treatment for glenohumeral osteoarthritis. In addition to proper component orientation, successful arthroplasty requires accurate restoration of soft tissues forces around the joint to maximize function. We hypothesized that pathological changes within the rotator cuff on preoperative magnetic resonance imaging (MRI) adversely affect the functional outcome following TSR. MATERIALS AND METHODS: A retrospective analysis of case notes and MRI of patients undergoing TSR for primary glenohumeral osteoarthritis over a 4-year period was performed. Patients were divided into three groups based upon their preoperative MRI findings: (1) normal rotator cuff, (2) the presence of tendonopathy within the rotator cuff, or (3) the presence of a partial thickness rotator cuff tear. Intra-operatively tendonopathy was addressed with debridement and partial thickness tears with repair. Functional outcome was assessed with the Oxford Shoulder Score (OSS), and quick disabilities of the arm, shoulder and hand score (quick-DASH). RESULTS: We had a full dataset of complete case-notes, PACS images, and patient reported outcome measures available for 43 patients, 15 in group 1, 14 in group 2, and 14 in group 3. Quick-DASH and OSS were calculated at a minimum of 24 months following surgery. There was no statistically significant difference between the results obtained between the three groups of either the OSS (P = 0.45), or quick DASH (P = 0.46). CONCLUSIONS: TSR is an efficacious treatment option for patients with primary glenohumeral osteoarthritis in the medium term, even in the presence of rotator cuff tendonopathy or partial tearing. Minor changes within the cuff do not significantly affect functional outcome following TSR. PMID- 24403761 TI - Lateral releases of the subscapularis tendon. AB - The technique of arthroscopic subscapularis repair continues to evolve. A three sided subscapularis release (e.g. anterior, posterior, superior) is commonly advocated for improving tendon excursion to bone. However, a lateral release is commonly required as well, particularly for full thickness, upper subscapularis tears and full thickness, complete subscapularis tears. We describe the techniques to identify and release the lateral subscapularis border, which aids in the completion of other releases. PMID- 24403760 TI - Acromioclavicular reconstruction using hook plate and anterior tibial tendon allograft with triple tunnel: The early results of revision surgery using a novel surgical technique. AB - In this study, a new modified surgical technique is presented for anatomic acromioclavicular (AC) joint reconstruction made by the application of anterior tibialis tendon autograft, three-way tunnel (two clavicular and one coracoid) and hook plate. The study is aimed to evaluate the post-operative short-term results of patients who underwent this treatment. A total of 11 patients underwent AC joint reconstruction because of persistent AC subluxation. In this reconstruction, a triple tunnel was made between the coracoid and the clavicle to anatomically restore the coracoclavicular (CC) ligament and an allograft was passed through the tunnels resembling conoid and trapezoid ligaments. The tendon had to be non-weight bearing at the appropriate tension to provide rapid and appropriate integration of the tendon in the tunnel. This was maintained by applying a hook plate. The hook plate method was used to protect the reconstructed ligament during the healing process as it has a similar hardness to that of the natural AC joint and provides rigid fixation. For a more comprehensive description of the technique, a cadaver demonstration was also performed. The mean follow-up period was 25.3 months (range: 18-34 month). None of the patients had a loss of reduction at the final follow-up. When the constant scores were examined, of the total 11 patients, 2 (18.2%) 38,39 had excellent results, 6 (54.5%) had good results and 3 (27.3%) had fair results. It can be seen that this newly described reconstruction technique has successful short-term results as an anatomic method and can be used effectively in revision cases. However, there is a need for further biomechanical and clinical studies to make comparisons with other techniques. PMID- 24403762 TI - Management of failed metal-backed glenoid component in patients with bilateral total shoulder arthroplasty. AB - Total shoulder arthroplasty (TSA) is successful in providing pain relief and functional improvements for patients with shoulder arthritis. Outcomes are directly correlated with implant position and fixation, which ultimately affects wear and longevity. Metal-backed glenoid components were introduced as an alternative to the standard cemented glenoid fixation. Early loosening and cavitary glenoid bone loss has been reported as a major complication associated with these metal-backed glenoids, which presents the surgeon with a challenging revision situation. Furthermore, failure of bilateral TSA in patients with metal backed glenoids is extremely rare. We present two patients with early failure of bilateral TSA secondary to loosening of the metal-backed glenoids. Both patients had significant glenoid bone loss and were treated with four different types of revision techniques. A description of treatments and outcomes of both patients are reported along with the simple shoulder test and American Shoulder and Elbow Surgeons scores. One patient underwent revision to bilateral reverse prosthesis and experienced a much-improved outcome in comparison to the patient revised to a hemiarthroplasty and resection arthroplasty, for each shoulder respectively. In patients who present with failed TSA, revision to a reverse prosthesis with or without staged glenoid bone graft should be considered as an option of treatment. It is also important to rule out infection with intraoperative tissue biopsy before proceeding to revision surgery. However, in patients with catastrophic glenoid bone loss, both hemiarthroplasty and resection arthroplasty can provide an alternative treatment option, but they are associated with a poorer functional outcome and pain relief. PMID- 24403763 TI - Successful treatment of fractures of the base of the acromion after reverse shoulder arthroplasty: Case report and review of the literature. AB - Fractures of the acromion and scapula are known to occur after reverse shoulder arthroplasty. We present a case of a fracture at the base of the acromion 5 months after arthroplasty treated successfully with dual plating of the acromion. Eighteen months after fracture fixation, the patient had 160 degrees of active forward flexion, a QuickDASH of 29.5, a Constant score of 69 and she was satisfied with the result. A concomitant review of the literature produced, in addition to our patient, 56 cases. These were used to produce a classification system, based on bony and functional anatomy as follows. Tip fractures are of the most lateral or anterior portion of the acromion, those of the body of the acromion are medial to the tip but lateral to the beginning of the scapular base. Fractures at the scapular base are termed fractures of the base of the acromion and those more medial to that, fractures of the scapular spine. The functional results of these case series demonstrated poorer functional outcomes for more medial fractures. As future research in this domain increases, clarity on the nomenclature of these fractures will allow for prognostication and treatment based on fracture location as well as comparison between studies. PMID- 24403764 TI - Clavicle diaphyseal fracture, ipsilateral type 3 acromioclavicular joint dislocation stabilized with double plate. PMID- 24403765 TI - Proceedings of the 7(th) World Congress of Hair Research. PMID- 24403766 TI - Canities subita: a reappraisal of evidence based on 196 case reports published in the medical literature. AB - We have reviewed the medical literature on unusually rapid Canities of body hair to assess whether the reported clinical evidence can be explained with the current hypotheses of pathogenetic mechanisms. We screened the medical literature from 1800 onward, searching for as many case reports as possible. We assessed literature in Dutch, English, French, German, Italian and Spanish and included all cases, which contained an explicit mention or description of unusually rapid graying or whitening of hair. Case reports were classified into three categories: Cases are "authenticated" when the authors personally observed the rapid color change, "non-authenticated" when they saw the subject only after the alleged color change and "anecdotal" when authors were told about the case by a third party. In total, we found 196 cases of which 44 were authenticated. These studies reported the graying of human hair in the context of aging, somatic diseases, emotional trauma or stress and psychiatric disorders. Numerous cases involved not only scalp hair, but also beards, eyelashes and other body hair. Several authors stressed that there was no alopecia. Although plausible explanations exist to explain Canities subita occurring together with an effluvium, the observation of viable hair losing color along the axis within a timespan shorter than its growth rate remain as yet unexplained. PMID- 24403767 TI - Hormonal profile in Indian men with premature androgenetic alopecia. AB - INTRODUCTION: Alopecia in male is considered as a genetically determined disorder characterized by increased level of local androgen metabolite and increase androgen receptor binding in balding areas. Frequent deviations of hormones from normal values have been reported in men diagnosed with premature androgenetic alopecia (AGA) especially for androgens, gonadotropins and sex hormone binding globulin (SHBG). Different studies in the past have inferred that premature baldness before the age of thirty in males could be considered equivalent to the polycystic ovary syndrome (PCOS) in female. MATERIALS AND METHODS: Hormonal profile of 50 men with severe premature balding before 30 years of age were compared with same numbers of age matched controls. The serum concentrations of total testosterone, dehydroepiandrosterone sulfate, luteinizing hormone, follicle stimulating hormone, SHBG, insulin and fasting blood sugar were estimated. Statistical analysis was performed with paired Student's t-test for cases and controls. RESULTS: Decreased levels of SHBG with high free androgen index were found in cases when compared with the controls. CONCLUSION: Though altered hormonal profile may coexist in some of men with premature AGA it can't be considered as male equivalent to PCOS in female or the metabolic syndrome. PMID- 24403768 TI - Evaluation of Perifollicular Inflammation of Donor Area during Hair Transplantation in Androgenetic Alopecia and its Comparison with Controls. AB - BACKGROUND: Mild perifollicular inflammation is seen in both androgenetic alopecia (AGA) cases and normal controls, whereas moderate or dense inflammation with concentric layers of collagen, is seen in AGA cases but only in very few normal controls, and may lessen the response to topical minoxidil. Moderate or dense lymphocytic inflammation and perifollicular fibrosis have poor hair growth following transplantation. AIM: The purpose of the study is to evaluate the perifollicular lymphocytic inflammation and fibrosis in AGA patients during follicular unit hair transplantation (FUT) and its comparison in normal controls. MATERIALS AND METHODS: A total of 21 male patients with AGA and 7 matched controls participated in the study. Histopathological analysis of biopsy specimens from donor strip of patients during the hair transplantation and two 4 mm punch biopsies on controls were performed. Morphometric analysis was performed and perifollicular fibrosis was scored based on the width of the condensed collagen at the lower infundibulum and isthmus from 0 to 3. Perifollicular infiltrate was also scored 0-3 and a total score of 3 or more out of 6 was considered significant. RESULTS: Nearly 76% of AGA patients had perifollicular fibrosis more than 50 MUm at *200 magnification. Almost 33.33% patients had moderate/dense perifollicular lymphocytic infiltrate whereas none of the controls had it. Total score in AGA cases was significantly higher than controls (P = 0.012) using Chi-square test. Out of 21 patients, 13 had a score of 3 or more and were followed-up with monthly treatment with intralesional steroids using a dermaroller. CONCLUSION: Histopathological evaluation of the donor area is a must during hair transplantation to evaluate the extent of perifollicular inflammation and achieve better results by following it up with treatment directed to decrease the inflammation. PMID- 24403769 TI - Evaluation of the degree of knee joint osteoarthritis in patients with early gray hair. AB - BACKGROUND: Osteoarthritis (OA) is the most common form of arthritis and one of the causes of pain and disability. The hair graying characteristic correlates strictly with chronological aging and take places to varying degrees in all individuals, disregarding gender or race. AIMS: Comparison of the degrees of clinical and radiologic severity of the knee OA in individuals with early hair graying compared to ordinary individuals. MATERIALS AND METHODS: A total of 60 patients with knee OA and similar demographic characteristics were enrolled in this study. All patients were classified in to 3 age subgroups in each of the case and control groups (30-40 year, 41-50 year, 51-60 year). In the case group, the patients must had early hair graying, too. Knee OA were classified using the Kellgren-Lawrence (KL) grading scale. Western Ontario McMaster University Osteoarthritis index (WOMAC) was applied to assess clinical severity of the knee OA. RESULTS: The mean +/- SD of WOMAC index in the case group was 60.7 +/- 15.9 and in the control group was 55.3 +/- 15.3 (P = 0.1). The mean rank of KL scale in case group was 35.3 and in the control group was 25.6 (P = 0.02). CONCLUSION: Even at the same age of OA onset, the rate of progression of radiological findings and the grade of joint destruction in individuals with early hair graying are greater than normal individuals. However, clinical and functional relevant remain unclear. PMID- 24403770 TI - Severe onycholysis in a card illusionist with alopecia areata universalis. AB - In patients with alopecia areata (AA), nail abnormalities due to nail matrix inflammation are common and usually not severe. We report the case of a 23-year old man with AA universalis, who developed severe abnormalities of all his fingernails. Systemic steroids improved the onycholysis that had an important impact on the patient's job, as he was a card illusionist. PMID- 24403771 TI - Cylindroma of the breast: a rare case report. AB - Cylindroma is a benign adnexal tumor, which occurs as solitary dermal nodules on the scalp and forehead. Cylindroma of the breast is a rare lesion. Fine-needle aspiration is often the first line of investigation. In this communication, we illustrate the cytomorphological feature of cylindroma in a 61-year-old female patient who presented with a breast lump. Fine-needle aspiration cytology in this case reveals the islands of tumor cells formed a "jig-saw" pattern, along with the bland, basaloid cells associated with globular, extracellular material. These features are typical of cylindroma, but differential diagnosis of adenoidcystic carcinoma should always be kept in mind as the management of both tumors are different. PMID- 24403772 TI - Familial trichotillomania in three generations. AB - Trichotillomania (TTM) is a type of impulse control disorder, characterized by recurrent pulling of hair. The etiology of TTM is complex, but a genetic contribution to this condition was advocated based on a limited number of reports on familial TTM. We report a 13-year-old male with history of focal hair loss in the scalp. Examination showed a patchy area of hair loss, with several short broken hairs of varying lengths. Dermoscopy and pathology examinations were consistent with TTM. Upon further questioning, his father admitted repeated pulling of his beard. The paternal grandfather also suffers from severe hair pulling of his beard since puberty. To our knowledge, this is the first report of TTM in a 3 generation family. This report strengthens the possibility that TTM is a genetic disease, probably with a complex inheritance pattern. It also highlights the importance of appropriate family history taking when examining a TTM patient. PMID- 24403773 TI - Isolated collagenoma on the scalp: a rare presentation. AB - Connective tissue nevi of the skin are benign hamartomatous lesions consisting predominantly of one of the components of the extracellular matrix comprising of collagen, elastin or glycosaminoglycans type. Connective tissue nevi may be solitary or multiple, sporadic or inherited. Collagenomas are asymptomatic and usually occurs over upper trunk, arms, back, thighs and soles. We, hereby report a young boy with collagenoma over the scalp, a rare site. PMID- 24403774 TI - Annular alopecia areata: report of two cases. AB - Alopecia areata (AA) is an auto-immune disorder characterized by the appearance of non-scarring bald patches affecting the hair bearing areas of the body. Scalp is the most common site of involvement. AA can affect any age group. The usual pattern of the hair loss is oval or round. We hereby, report two cases of annular and circinate pattern of AA due to its unusual morphology. PMID- 24403775 TI - A case of neurodermatitis circumscipta of scalp presenting as patchy alopecia. AB - Neurodermatitis or Lichen simplex chronicus (LSC) is chronic skin disease in which emotional factors have a key role in the initiation of disease. A sixty year old lady presented with itcy lesion of scalp with localised area of loss of hair. After proper history taking and investigations she was diagnosed as LSC of scalp. She was treated with intralesional steroids,oral doxepin and psychotherapy. Complete remission of symptoms with total regrowth of hair occured in 3 months. The key role of emotional factors in causation of LSC and a proper psychotherapy along with dermatological treatment is necessary for complete cure of this condition. PMID- 24403776 TI - Stem Cell Niche is Partially Lost during Follicular Plucking: A Preliminary Pilot Study. AB - BACKGROUND: Clinical hair transplant studies have revealed that follicular unit extraction (FUE) is superior in terms of stable hair growth in comparison to follicular plucking (FP). Various reasons have been cited for this clinical outcome. FUE and FP are employed to obtain the hair follicle units for hair transplant and recently for cell based therapies in vitiligo. However, there is no scientific data available on the comparison of stem cell fraction in the cell suspension obtained by FUE and FP. Therefore, we undertook this study to compare the percentage of stem cells in the hair follicle obtained by FUE and FP. OBJECTIVE: The purpose of the following study is to evaluate the quantitative stem cell pool in the hair follicle obtained by FUE and FP. MATERIALS AND METHODS: A total of 3 human subjects were enrolled with age groups of 17-25 years. Both methods of tissue harvest: FUE and FP; were employed on each subject. There was no vitiligo lesion on the scalp in any of the patients. Hair follicles were incubated with trypsin-EDTA solution at 37 degrees C for 90 min to separate outer root sheath cells. The cell suspension was passed through a 70 MUm cell strainer; filtrate was centrifuged to obtain the cell pellet. Cells were labeled with cluster of differentiation (CD200) antibody and acquired with flowcytometry. RESULTS: The mean percentage of CD200 positive cells in FUE and FP method come out to be 8.43 and 1.63 respectively (P = 0.0152). CONCLUSION: FUE is a better method of the hair follicle harvesting for cell based applications as the stem cell fraction is significantly higher in comparison to FP. PMID- 24403777 TI - Mudichood: Well-known but Rare Entity. PMID- 24403778 TI - Trichothiodystrophy: role of a dermato-trchologist. PMID- 24403779 TI - Tuft of hair at an unusual location. PMID- 24403780 TI - Unusual case of hypertrichosis. PMID- 24403781 TI - HIV/AIDS - Accomplishments and challenges? PMID- 24403782 TI - A new concept in hybridization: Bromelain enzyme for deproteinizing dentin before application of adhesive system. AB - OBJECTIVE: The objective of this study is to assess the deproteinizing effect of bromelain enzyme and compare it with neodymium-doped yttrium aluminum garnet (Nd:YAG) laser and 10% sodium hypochlorite (NaOCl) by using scanning electron microscope (SEM) and polarized microscope. MATERIALS AND METHODS: A total of 60 extracted human upper premolars were selected to be given standardized buccal and lingual class V cavities. The teeth were divided into three groups each one consisted of 20 teeth. Thirty teeth were recruited for SEM study and the other 30 for polarized microscope. Group 1: Teeth were deproteinized with Nd:YAG laser, Group 2: Teeth were deproteinized with bromelain enzyme and Group 3: Teeth were deproteinized with 10% NaOCl. RESULTS AND CONCLUSIONS: Application of bromelain enzyme has led to removing collagen network and significantly decreased the global leakage scores of the adhesive system. PMID- 24403783 TI - Effect of transcutaneous electrical nerve stimulation induced parotid stimulation on salivary flow. AB - AIMS AND OBJECTIVES: The main objective of this study was to evaluate the duration of stimulation over the parotid salivary flow following the use of transcutaneous electric nerve stimulation (TENS) in different age groups. MATERIALS AND METHODS: The study was carried out in three different age groups. Under group A individuals from 21 to 35 years of age, group B 36-50 years and group C above 51 years were considered. In each group 30 subjects were taken of whom 15 were males and 15 were females. The placement of pads was approximated bilaterally over the parotid glands. The working parameters of TENS unit were fixed at 50 Hz and the unit was in normal mode. RESULTS: Subjects belonging to group B were showing statistically significant increases in the duration of stimulated parotid salivary flow following the use of TENS. CONCLUSION: TENS can be considered as a non-pharmacological alternative to improve salivation for longer period in xerostomia patients. PMID- 24403784 TI - Comparative evaluation of debris removal from root canal wall by using EndoVac and conventional needle irrigation: An in vitro study. AB - CONTEXT: Microbial control is of paramount importance in Clinical Endodontics. Therefore, cleaning and disinfection of root canals are essential to achieve endodontic success. AIMS: The purpose of this study is to compare the efficacy of EndoVac irrigation system and conventional needle (30 gauges side venting needle) irrigation for removal of debris from the root canal walls at coronal, middle and apical third by using the scanning electron microscopy (SEM). SETTINGS AND DESIGN: An in vitro randomized control trial study. MATERIALS AND METHODS: A total of 20 mandibular premolars with completely formed roots were selected and randomly divided into two groups - Group 1: Irrigation with the Conventional system and Group 2: EndoVac irrigation. After access opening and working length determination biomechanical preparation completed up to a rotary protaper F4 file. Groupwise irrigation with sodium hypochlorite and ethylenediaminetetraacetic acid was done with each canal in between instrumentation. Then, the teeth were sectioned in buccolingual direction and the halves were sputter-coated with gold palladium and coronal, middle and apical third were examined by SEM at x2000 magnification. STATISTICAL ANALYSIS: Mann Whitney test for comparison between methods, Kruskal-Wallis test for comparison among thirds and Miller test for individual comparisons. RESULTS: The apical, middle and cervical root canal thirds were evaluated and the results were analyzed statistically by the Mann-Whitney test for comparison between methods, Kruskal-Wallis test for comparison among thirds and Miller test for individual comparisons. CONCLUSIONS: EndoVac group resulted in significantly less debris at apical third compared with the conventional needle irrigation group. There was no statistical significant difference found in debris removal at coronal and middle third of root canal wall between the EndoVac group and conventional needle irrigation group. PMID- 24403785 TI - The effects of silorane composites on levels of cytokines and periodontal parameters. AB - AIMS: The purpose of this pilot study was to determine the effects of silorane composites on gingival crevicular fluid (GCF) levels of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and IL-8, GCF volume and clinical periodontal parameters in patients with silorane composite restorations before and after restorative treatment. MATERIALS AND METHODS: A total of 20 systemically healthy non-smokers, 12 female and 8 male (age range: 24-46 years), presenting with 25 instances of primary dentine caries with subgingival margins were selected for this study. Approval was obtained from the university ethics committee and treatment plans were approved by the patients. GCF samples were obtained with periopaper strips from relevant teeth for IL-6, IL-8 and TNF-alpha measurements. Each sample was stored at - 80 degrees C and analyzed using the enzyme-linked immunosorbent assay (ELISA) kits. Cavities were prepared according to the common principles for adhesive restorations and restored with a silorane adhesive system (Silorane System Adhesive (3M ESPE) and silorane composite (Filtek Silorane, 3M ESPE). Cytokine levels were reassessed 2 weeks after restorative treatment. Data were analyzed using the independent t-test at a significance level of alpha =0.05. Associations between parameters were analyzed using Pearson correlation analysis. RESULTS: A significant increase in gingival index (GI) and plaque index (PI) were observed after 15 days (P < 0.05). GCF volume, IL-6, IL-8 and TNF-alpha levels exhibited significant differences before and after restorative treatment (P < 0.05). There were strong positive correlations among parameters except for PI/GCF volume and GI/GCF volume. CONCLUSION: Within the limitations of this investigation, silorane composites may have some negative effects on cytokine levels, clinical parameters and GCF volume. PMID- 24403786 TI - Effect of different adhesion strategies on fiber post cementation: Push-out test and scanning electron microscopy analysis. AB - AIM: The aim of this study was to investigate the effect of phosphoric acid etching and the dentin pre-treatment with sodium hypochlorite (NaOCl) on the push out bond strength between fiber post and root canal dentin. MATERIALS AND METHODS: Root canals of 48 human incisors were selected, post spaces were prepared and assigned to four groups: G1-37% phosphoric acid (15 s); G2-5.25% NaOCl (2 min) +37% phosphoric acid (15 s); G3-37% phosphoric acid (60 s); and G4 5.25% NaOCl (2 min) +37% phosphoric acid (60 s). Fiber post cementation was performed with two-step etch-and-rinse adhesive system/dual-cured resin cement according to the manufacturer's recommendation. After 24 h, each root was sectioned transversally into three slices (cervical, middle and apical) and the bond strength of each section was determined using a push-out bond strength test. Morphology analysis of the bonded interface was evaluated using a scanning electron microscopy. Push-out strength data (MPa) were analyzed by Analysis of Variance and Tukey-Kramer (alpha = 0.05). RESULTS: Considering the NaOCl pre treatment, no statistically significant differences were observed among groups; however, when the phosphoric acid was applied during 60 s in the apical portion without NaOCl pre-treatment, the bond strength was statistically significant increased. CONCLUSION: The NaOCl pre-treatment did not improve the bond strength of adhesive luting cement to root canal dentin. The findings suggest that the use of 37% phosphoric acid for 60 s may have a beneficial effect on bond strength in the apical root third. PMID- 24403787 TI - Role of dermatoglyphics as an indicator of precancerous and cancerous lesions of the oral cavity. AB - BACKGROUND: Oral squamous cell carcinoma (SCC) is one name that causes panic and holds an undeserved high ranking as a killer. Another important condition which has become a major public health issue in South East Asia is oral submucous fibrosis (OSF). Not all the people using tobacco suffer from these diseases. Genetic predisposition might explain such an individual variability that can be predicted by using various cytogenetic markers. However, these studies are far more costly and complicated. So, dermatoglyphics may be of immense clinical significance to segregate those individuals who are at an increased risk for developing these diseases. AIM: The present study was conducted to analyze the palmar dermatoglyphics in SCC and OSF and find a dermatoglyphic marker, if any. STUDY DESIGN: Cross sectional study. MATERIALS AND METHODS: 120 individuals were divided into four groups based upon their habits of tobacco/areca nut usage and presence of OSF/SCC. Dermatoglyphic patterns were recorded using standard ink method. Various patterns were analysed statistically in the four groups. RESULTS AND CONCLUSION: In SCC, there was an increase in frequency of arch and ulnar loop patterns on fingertips, decrease in frequency of simple whorl patterns on fingertips, decrease in frequency of palmar accessory triradii on right and left hands. Significant findings in OSF included an increase in frequency of arch and ulnar loop pattern, decrease in frequency of simple whorl patterns on fingertips, decrease in atd angle on right hand, decrease in frequency of palmar accessory triradii on right hand. The results revealed that the field of dermatoglyphics holds promising results for determining the genetic susceptibility of individuals to develop SCC and OSF. PMID- 24403788 TI - Adrenomedullin, periodontitis, diabetes-unraveling the equivocal relationship: A clinicobiochemical cross-sectional study. AB - CONTEXT: Antimicrobial proteins and peptides constitute a diverse class of host defense molecules that act early to combat invasion and infection with bacteria and other microorganisms. Among the various antimicrobial peptides in the oral cavity, adrenomedullin (ADM), a cationic peptide, is found in gingival crevicular fluids (GCFs) in amounts twice as high in periodontal disease sites as healthy sites. Studies have also shown that plasma levels of ADM increased in patients with type 2 diabetes mellitus as compared with controls. AIMS: This clinico biochemical study was undertaken to try to decipher the probable link between ADM, diabetes and periodontitis. MATERIALS AND METHODS: The study comprised of 90 patients who were divided into three groups based on community periodontal index scores and diabetes status. Probing pocket depth and clinical attachment level were measured in all subjects. GCF was collected from all the participants using micropipettes and blood samples were collected from subjects in Groups III, for analysis of glycated hemoglobin. ADM levels were measured in GCF samples by the enzyme-linked immunosorbent assay. STATISTICAL ANALYSIS USED: The data obtained were subjected to analysis of variance, Bonferroni test and Pearson's correlation. RESULTS: An increase in GCF levels of ADM from periodontal health to disease and in periodontitis patients with type 2 diabetes was noted. CONCLUSIONS: Increase in GCF levels of ADM from periodontal health to disease and in periodontitis patients with type 2 diabetes reinforces the perio-systemic interlink concept. PMID- 24403789 TI - Cephalometric norms for orthognathic surgery for North Indian population. AB - OBJECTIVE: The objective of this study is to establish the cephalometric hard tissue norm for orthognathic surgery for North Indian subjects. MATERIALS AND METHODS: A total of 100 young adults which consists of 46 males and 54 females with the age range of 14-24 years with balanced facial profile and minimum arch length discrepancies were chosen for the study. Lateral cephalograms with teeth in occlusion were recorded and analyzed manually to establish the norm. The mean values of various cephalometric hard tissue variables for North Indian males and females were compared with those Caucasians. P < 0.05 was considered to be statistically significant. RESULTS: All the cephalometric parameters for orthognathic surgery except mandibular length and lower incisor inclination were comparable among North Indian males and females. The mandibular length was significantly more among North Indian males than females (P < 0.05) and the inclination of lower incisors was significantly more among North Indian females than males (P < 0.05). However, many of the cephalometric parameters for orthognathic surgery were significantly different among North Indian and Caucasian males and females. CONCLUSION: The cephalometric norms for orthognathic surgery were established for North Indians and many measurements were different from those for Caucasians. PMID- 24403790 TI - Associated oral lesions in human immunodefeciency virus infected children of age 1 to 14 years in anti retroviral therapy centers in Tamil Nadu. AB - AIM: To evaluate the prevalence of oral lesions status in human immunodeficiency virus (HIV) infected children of age 1 to 14 years in Anti Retro viral therapy (ART) centres in Tamil Nadu. MATERIALS AND METHODS: A of total 326 HIV infected children, age 1 to 14 years of which 174 male children and 152 female children were examined for Oral lesions in the Department of Pedodontics and Preventive Dentistry, Rajah Muthiah Dental College and Hospital, Annamalai University in association with the ART centers in Villupuram, Vellore and HIV Homes in Thiruvannamalai, Trichy and Salem in Tamil Nadu towns. STATISTICAL ANALYSIS: Statistical Package for Social Science for Windows (version 11 code: 3000135939012345). RESULT: Of the total 326 children, 201 (61.65%) had oral lesions. (68 [20.86%] with Oral Candidiasis [OC], 54 [16.56%] with Angular Cheilitis, 27 [8.28%] with Necrotizing Ulcerative Gingivitis [NUG], 25 [7.66%] with Necrotizing Ulcerative Periodontitis [NUP], 18 [5.53%] with Linear Gingival Erythema [LGE] and 9 [2.76%] with Apthous Ulcer.) Conclusion Among the oral lesions in HIV infected children, OC 20.86% was the predominant oral lesion followed by Angular Chelitis 16.56%, NUG 8.28%, NUP 7.66%, LGE5.53% and Apthous Ulcer 2.76%. PMID- 24403791 TI - Evaluation of marginal leakage of different temporary restorative materials in Endodontics. AB - AIM: The aim of this study is to assess the coronal marginal leakage of three temporary restorative materials used for root canal sealing after endodontic treatment. MATERIALS AND METHODS: A total of 88 single-rooted teeth were submitted to biomechanical preparation and filled by lateral condensation technique. After obturation process, the teeth were randomly separated into four groups, being two teeth of each group used as positive and negative control. Temporary sealing was performed as follows: GI - Clip F (VOCO); GII - Bioplic (Biodinbetamica); GIII - Vitremer (3M ESPE) and GIV - Ketak N100 (3M ESPE). Next, the specimens were immersed into Indian ink for 30 and 60- days, being 10 specimens for each time interval and then submitted to diaphanization to verify the amount of coronal leakage using a measuring microscope. RESULTS: Leakage mean values within the 30-day period were as follows: Vitremer (0.3 mm), Ketak N100 and Clip F (0.6 mm) and Bioplic (1.7 mm). Within the 60-day period, leakage means were 1.1 mm, 1.5 mm, 2.2 mm and 2.6 mm, respectively. CONCLUSIONS: None of the materials was capable of preventing marginal leakage within the 30- and 60-day period. In both time intervals, Bioplic presented the highest mean of leakage and Vitremer the lowest. PMID- 24403792 TI - Comparative distribution of Lysyl Oxidase (G473A) and NQO1 (C609T) polymorphism among tea-garden workers (habitual chewers of betel quid) of Darjeeling district and Kolkata city of West Bengal. AB - CONTEXT: Chewing of processed arecanut products with tobacco and betel quid has been attributed to many oral pathological conditions. These products are very popular among the youngsters of lower economic groups. Genetic predisposition has been now identified as a major risk factor for increasing the susceptibility toward the disease among these chewers. AIMS: Our study mainly aims to find out the predisposition of LOX (G473A) and NQO1 (C609T) polymorphisms and present a comparison between the population (habitually exposed to processed arecanut and smokeless tobacco products) of a metro-city Kolkata and the tea-garden workers of Darjeeling district of West Bengal. SETTINGS AND DESIGN: Subjects for the study was recruited from various oral health check-up camps organized in the tea gardens of Darjeeling district and Kolkata city. MATERIALS AND METHODS: Genotyping analysis was done through a Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP)-based approach. STATISTICAL ANALYSIS USED: A two-way contingency table analysis software (JAVASTAT: http://statpages.org/ctab2 * 2.html) using 95% confidence interval was used to study the distribution of genotypes among the populations. A P < 0.05 was considered to be significant. RESULTS: The results indicates both the heterozygous and homozygous carriers of NQO1 C > T (609) was found to be significantly higher among the north Bengal tea-garden workers [OR 0.480 (0.280 0.82) P = 0.01; 0.218 (0.091-0.524) P = 0.0001], respectively. Interestingly CT (21% in both) and TT (8% and 7%, respectively) were found to be equally distributed in the two populations. For LOX G > A (473) a significantly higher number of Kolkata individuals were found to carry the heterozygous GA allele in individuals aged <30 years [OR 3.779 (1.684-6.547) P = 0.001]. However, none were carrier of heterozygous GA allele of Kolkata population as compared with 29% north Bengal tea-garden workers aged above 31 years. CONCLUSIONS: A close observation of occurrence of oral diseases over time among such a population will be helpful to identify risk genotypes responsible for betel quid-induced oral diseases. PMID- 24403793 TI - Prevalence of dental caries and treatment needs in children in coastal areas of West Bengal. AB - OBJECTIVE: This study was carried out to measure the caries prevalence and treatment needs in school children of 6-14 year old residing in coastal areas of West Bengal. MATERIALS AND METHODS: A total of 1764 children of 6-14 years age group, studying in different primary and high schools of the coastal areas were examined using World Health Organization criteria (1997) to record the prevalence of dental caries. The treatment needs were also calculated according to that given criteria. STATISTICAL ANALYSIS: The results were subjected to statistical analysis using the Chi-square test and unpaired 't' test. RESULTS: Dental caries were founded low in the studied population. The overall all caries prevalence in the permanent dentition was 28.06%, in boys it was 25.39% and in girls it was 30.86%. Therefore caries prevalence in female was higher and which was statistically highly significant (P < 0.05). The most frequently required treatment was one surface filling followed by other treatments irrespective of sex and age group. DISCUSSION: The presence of sea foods containing high fluoride and least availability of refined carbohydrate in the diet may be the reason of lower prevalence. CONCLUSION: child oral health is always a matter of concern for a developing country so further research is required to explore actual causes. PMID- 24403794 TI - Evaluation of salivary calcium and salivary parathyroid levels in postmenopausal women with and without oral dryness. AB - OBJECTIVE: The primary objective of this study is to estimate and secondary objective is to compare the salivary calcium levels, salivary parathyroid hormone (PTH) levels in postmenopausal women with and without oral dryness (OD). MATERIALS AND METHODS: A case-control study was carried out on 80 selected postmenopausal women. Salivary calcium concentrations were assessed through Semi Autoanalyzer by Arsenazo III reaction. The salivary PTH concentration was measured by the enzyme linked immunosorbent assay. Severity of OD was assessed by a questionnaire through which the xerostomia inventory (XI) score could be measured. Statistical analysis of Student's t-test, Mann-Whitney test and Pearson's correlation was used. RESULTS: There was a significant difference in mean values of both salivary calcium concentration and XI score in postmenopausal women with/without OD (P < 0.001). No statistically significant difference (P > 0.05) was found in salivary parathyroid levels in postmenopausal women in both groups. A positive correlation was found between the salivary calcium concentration and XI score in both case and control groups (P < 0.05). CONCLUSION: Severity of OD in postmenopausal women is associated with the high levels of salivary calcium. However, the correlation of severity of OD with PTH could not be established. PMID- 24403795 TI - School based oral health promotional intervention: Effect on knowledge, practices and clinical oral health related parameters. AB - BACKGROUND: No organized school oral health program is existent in India. AIM: The aim of this study is to test the feasibility and efficacy of an economical school oral health promotional intervention with educational and preventive components. SETTINGS AND DESIGN: School oral health promotional intervention carried out in one of the randomly selected school and evaluated through short duration prospective model. MATERIALS AND METHODS: A total of 100 children with an age range of 10-12 years with no previous history of dental intervention were enrolled. Interventions comprised of oral health education (delivered through lecture and demonstrations by an undergraduate dental student) and topical antibacterial therapy (fluoride varnish and povidone iodine). Outcomes consisted of Knowledge and practices (KAP) regarding oral health, clinical oral health related parameters such as plaque index (PI), gingival index (GI) and caries activity as per Modified Snyder's test. These were reported at baseline, 3 weeks and 6 months follow-up examination by a calibrated examiner. STATISTICAL ANALYSIS: McNemar Bowker's test, Student's t-test, Pearson Chi-square tests were used. RESULTS: Highly significant (P < 0.001) improvements in KAP scores, PI scores, GI scores and caries activity were reported at 3 weeks and 6 months follow-up examination. CONCLUSION: This small economical school oral health program positively influenced oral health related practices and parameters of oral health such as oral cleanliness, gingival health and caries activity. PMID- 24403796 TI - Spindle cell carcinoma of the gingiva: A rare occurrence. AB - Of the many neoplasms known, squamous cell carcinoma (SCC) is the most common to affect the oral cavity. Spindle cell carcinoma (SpCC) is considered a rare high malignant variant of SCC occurring predominantly in the upper aerodigestive tract. Soft-tissue spindle cell neoplasms are quite uncommon in the oral cavity reportedly accounting for lesser than 1% of all tumors in the oral region. Our case shows an unusual presentation of SpCC involving the mandibular gingiva in a 46-year-old smoker patient, which presented as a firm, erythematous swelling with surface necrosis. An incisional biopsy was performed for microscopic evaluation to confirm the clinical diagnosis and for treatment planning. PMID- 24403797 TI - Importance of ultrasonography and magnetic resonance imaging in diagnosis of cysticercosis of temporalis muscle mimicking temporal space infection. AB - Cysticercosis cellulosae, caused by the larval stage of Taenia solium is a common parasitic infection in Indian subcontinent. Although cysticercosis is common in other parts of the human body, its involvement with temporalis muscle is an extremely rare entity and demands documentation. This paper reports a case of cysticercosis cellulosae in a 35-year-old male patient within the temporalis muscle mimicking temporal space infection; due to the presence of concomitant dental infection, which was diagnosed with the help of high resolution ultrasonography and magnetic resonance imaging and managed conservatively using oral antiparasitic medication. Here, in this case report, we are emphasizing the importance of imaging modalities in diagnosing space infection and cysticercosis. PMID- 24403798 TI - Overdenture locator attachments for atrophic mandible. AB - Implant-supported overdentures provide a good opportunity for dentists to improve oral health and quality-of-life of patients. Atrophic mandible poses a significant challenge to successful oral rehabilitation with dental implants. In this article, the fabrication of lower overdenture by two narrow platform implants is described with dual retentive, resilient, self-locating locator attachment system. The locator attachment system has the lowest profile in comparison with the ball and bar attachments and is versatile up to 40 degrees of divergence between two implants. By using locators as attachments, we can meet functional, economic and social expectation of patients with ease and satisfaction. PMID- 24403799 TI - Unusual solitary neurofibroma on the lower lip of a child. AB - Neurofibromas (NF) are benign tumors with involvement of the peripheral nerve, which is not frequently located in the oral cavity, and especially, extraordinary rarity on lower lip of a child. This report describes a case of a NF on lower lip in a 12-year-old Brazilian child. NF consists of a wide variety of cell types, including Schwann cells, perineurial cells, and fibroblasts. Due to cellular heterogeneity, several hypotheses have been proposed to explain the histogenesis of this lesion. One of them, it support an origin of Schwannian, while others emphasize the participation of both Schwann cells and perineural cells. Excisional biopsy was performed to establish definitive diagnosis. Microscopically, the lesion was composed of interlacing bundles of elongated cells with wavy nuclei and small nerve fibers. Immunohistopathologic assessment showed cells positive for S-100, confirming the diagnosis of NF. No recurrence was observed after 1-year follow-up. Pediatric dentists must have a thorough knowledge of this unusual lesion. PMID- 24403801 TI - Rootless teeth: Dentin dysplasia type I. AB - A rare case of hereditary disturbance of dentine, Dentin dysplasia type I is presented, which is characterized by short or total absence of roots, obliterated pulp chambers, and peri-apical radiolucencies. It affects both primary and secondary dentition. Management of patients with dentinal dysplasia is difficult and requires a multidisciplinary approach. An overview of dentin dysplasia and its management along with a case report is discussed. PMID- 24403800 TI - A new modified tandem appliance for management of developing Class III malocclusion. AB - Most developing Class III patients display a retruded maxilla. Early intervention in mixed dentition is associated with better patient compliance and possibly a better orthopedic response, which can produce favorable results. The aim of this article is to present the fabrication of the new modified tandem appliance and its use in management of developing Class III malocclusion. The therapeutic results of a new modified tandem appliance are presented in an 8 year-old male patient with anterior cross bite and retrognathic maxilla at the mixed dentition stage. Anterior cross bite was corrected in 3 months and the positive overjet of 4 mm after continued use of the appliance for 1 year. There was a significant improvement in profile of the patient. The use of this appliance in this type of malocclusion enabled the correction of malocclusion in a few months and encouraging favorable skeletal growth in the future. PMID- 24403802 TI - Modified quad helix appliance for thumb sucking and cross bite correction. AB - Digit sucking habit is a learned pattern of behavior commonly seen in children of preschool age. Prolonged digit sucking beyond the preschool age, lead to the development of malocclusion such as anterior open bite, maxillary constriction and posterior crossbite. Treatment strategies include interception of habit and correction of the malocclusion. The present case report describes a modified quad helix appliance used successfully in a 9-year-old child to intercept thumb sucking habit and simultaneous correction of posterior crossbite. The appliance has the advantage of easy fabrication, being versatile and more patients compliant. PMID- 24403803 TI - Juvenile pleomorphic adenoma of masticator space: The first case report. AB - Pleomorphic adenoma (PA), also called benign mixed tumor, is the most common tumor of the salivary glands. About 90% of these tumors occur in the parotid gland and 10% in the minor salivary glands. Juvenile PAs are uncommon and about 5 10% of minor salivary gland PA affects patients aged 20 years and under. The most common sites of PA of the minor salivary glands are the palate followed by lips and cheek. Other rare reported sites include the throat, floor of the mouth, tongue, tonsil, pharynx, retromolar area and nasal cavity. The masticator space is a deep facial space with a complex anatomical structure where PA is not known to occur. Here, we report an unusual case of PA of left masticator space in a 16 year-old girl patient, which to the best of our knowledge is the first reported case in English language literature. PMID- 24403804 TI - Full mouth rehabilitation of a patient with reduced vertical dimension using multiple metal ce ramic restorations. AB - Rehabilitation of a patient with severely worn dentition after restoring the vertical dimension is a complex procedure and assessment of the vertical dimension is an important aspect in these cases. This clinical report describes the full mouth rehabilitation of a patient who was clinically monitored to evaluate the adaptation to a removable occlusal splint to restore vertical dimension for a period 1 month and provisional restorations to determine esthetic and functional outcome for a period of 3 months. It is necessary to recognizing that form follows function and that anterior teeth play a vital role in the maintenance of oral health. Confirmation of tolerance to changes in the vertical dimension of occlusion (VDO) is of paramount importance. Articulated study casts and a diagnostic wax-up can provide important information for the evaluation of treatment options. Alteration of the VDO should be conservative and should not be changed without careful consideration. PMID- 24403805 TI - Invasive cervical root resorption: Engineering the lost tissue by regeneration. AB - Invasive cervical resorption (ICR) is a localized resorptive process that commences on the surface of the root below the epithelial attachment and the coronal aspect of the supporting alveolar process, namely the zone of the connective tissue attachment' early diagnosis, elimination of the resorption and restorative management are the keys to a successful outcome. Treatment done was a combined non-surgical root canal therapy, surgical treatment to expose the resorptive defect and the resorptive defect was filled up with reverse sandwich technique and finally the bony defect filled with platelet rich fibrin (PRF), hydroxylapatite and PRF membrane. Significant bone fill was obtained in our case after a 2 year follow-up period. This case report presents a treatment strategy that might improve the healing outcomes for patients with ICR. PMID- 24403806 TI - Orthodontic management of non-syndromic multiple supernumerary teeth. AB - Hyperdontia amounts to an odontostomatologic anomaly wherein, there is an increase in tooth number irrespective of the location. This case report represents a form of hyperdontia characterized by bilateral multiple supernumerary teeth in both the jaws without any evident familial history. PMID- 24403807 TI - Retrieval of a metallic obstruction from the root canal of a premolar using Masserann technique. AB - A metallic obstruction in the root canal blocks canal cleaning and shaping procedures and requires either bypassing or retrieval. Many methods have been recommended to retrieve a metallic obstruction from the root canal. This article describes the retrieval of a metallic obstruction from the root canal of a premolar using Masserann technique to facilitate endodontic retreatment. Masserann technique is said to have limited application in posteriors. However, in this case, the obstruction was successfully retrieved by employing Masserann technique which consisted of using a trephan to cut the dentine and extractor tube to retrieve the obstruction. The retrieved obstruction was found to be a separated H-file. Endodontic retreatment was completed following the detection and negotiation of an extra canal in the same tooth. PMID- 24403808 TI - Gorlin-Goltz syndrome: A rare case report. AB - Gorlin-Goltz syndrome is an uncommon autosomal dominant inherited disorder characterized by numerous basal cell carcinomas, odontogenic keratocysts (OKCs) and musculoskeletal malformations. A rare case of this syndrome observed in a 13 year-old male patient is presented in which multiple OKCs were causing disfigurement of the lower jaw as well as displacement and malocclusion of the teeth. Early diagnosis and treatment of this syndrome is important to reduce the severity of complications including cutaneous and cerebral malignancy and oromaxillofacial deformation and destruction due to jaw cysts. PMID- 24403809 TI - Gingival enlargement unveiling sarcoidosis: Report of a rare case. AB - Sarcoidosis is classified as an acquired systemic granulomatous disease. Because of the fact that sarcoidosis affects multiple tissues and organs, it is characterized by many potential signs and symptoms, as well as by the presence of non-caseating granulomas in the organs involved. Although oral sarcoidosis is relatively rare, it may however, present in the oral cavity. This report presents a rare case of sarcoidosis with the initial presenting symptom as severe generalized gingival enlargement. The gingival enlargement was treated by gingivectomy. After histopathological examination of gingival biopsy and certain special investigations, a diagnosis of sarcoidosis was made. PMID- 24403810 TI - Combined soft and hard tissue augmentation for a localized alveolar ridge defect. AB - Ideal alveolar ridge width and height allows placement of a natural appearing pontic, which provides maintenance of a plaque-free environment. The contour of a partially edentulous ridge should be thoroughly evaluated before a fixed partial denture is undertaken. Localized alveolar ridge defect refers to a volumetric deficit of the limited extent of bone and soft-tissue within the alveolar process. These ridge defects can be corrected by hard tissue and/or soft-tissue augmentation. A 30-year-old male patient was referred to the Department of Periodontology for correction of Seibert's Class III ridge defect in the lower anterior region. Granulation tissue/connective tissue present at the base of the defect was removed after elevation of full thickness flap. MucoMatrixX, an animal derived, collagen based soft-tissue graft was sutured to the labial flap and bone graft was placed into the defect. If a soft-tissue graft material could be used to replace the palatal grafts, then all the possible complications associated with donor site would be eliminated and above all periodontal plastic surgery and ridge augmentation would be better accepted by patients. PMID- 24403811 TI - Melanotic neuroectodermal tumor of infancy: A rare case report. AB - Melanotic neuroectodermal tumor of infancy (MNTI) is a relatively uncommon osteolytic-pigmented neoplasm that primarily affects the jaws of infants. The early onset and its rapid disfiguring spread necessitate early diagnosis. A 4 month-old male child reported with the complaint of swelling in the right back tooth region of the upper jaw, which rapidly increased in size causing disfigurement of the face. Radiographic examination showed a diffuse osteolytic radiolucent lesion in the right maxilla and displacement and dysmorphic changes in the developing primary tooth buds. Wide surgical excision was performed under general anesthesia. Histopathological report revealed characteristic large pigmented epitheloid cells (melanocyte like cells). The biphasic tumor cell population arranged in a background of fibrous connective tissue stroma is suggestive of MNTI involving the cancellous bone. Early diagnosis and management of such aggressive tumors precludes significant morbidity of the patient. PMID- 24403812 TI - One-piece implant in reduced edentulous space closure: A report of two cases. AB - Dental Implants have gained popularity over the years and are increasingly becoming the choice of treatment. Different clinical situations are often encountered where modifications have to be considered in order to achieve successful rehabilitation. One of the challenges faced includes non-availability of sufficient space for conventional implants. Here, we present 2 case reports of patients with over two year follow up using one piece implant. PMID- 24403813 TI - Juvenile psammomatoid ossifying fibroma: An unusual case report. AB - Ossifying fibromas are well-demarcated benign fibro-osseous tumors of craniofacial skeleton most often in the jaws. It has two types, conventional and juvenile ossifying fibroma (JOF). JOF is considered a separate entity from ossifying fibroma due to its locally aggressive behavior and tendency to occur at a young age. Two subtypes of JOF, i.e., juvenile psammomatoid ossifying fibroma (JPOF) and juvenile trabecular ossifying fibroma have been identified on the basis of histology 70% of the JPOF occur in the paranasal sinuses, 20% in the maxilla and only 10% in the mandible. Here, we report a case of JPOF in a 14-year old girl causing an asymptomatic expansile swelling in the right mandibular posterior region, which is a rare site for this tumor. PMID- 24403814 TI - Recurrent unicystic mural type ameloblastoma in a 9-year-old boy, 8 years follow up. AB - Unicystic ameloblastoma is not a rare odontogenic tumor in the pediatric population. A significant care should be given to unicystic ameloblastoma if it has mural invasions due to its local aggressiveness, high recurrence rates and radical management options as in conventional ameloblastoma. Fine needle aspiration (FNA) cytology is a rapid, non-traumatic diagnostic method that provides a required attention prior to surgery. We present an excisionsl biopsy proved FNA diagnosed mural type unicystic ameloblastoma in a 9-year-old child recurred as a solid ameloblastoma after 8 years. When distinctive features of ameloblastoma are known, an accurate diagnosis can be made by FNA cytology, in combination with clinicoradiological findings. This method gives benefit to the patients especially the younger ones both for the pre-operative surgical planning and the post-operative follow-up. PMID- 24403815 TI - Brands as Intentional Agents Framework: How Perceived Intentions and Ability Can Map Brand Perception. AB - Building on the Stereotype Content Model, this paper introduces and tests the Brands as Intentional Agents Framework. A growing body of research suggests that consumers have relationships with brands that resemble relations between people. We propose that consumers perceive brands in the same way they perceive people. This approach allows us to explore how social perception theories and processes can predict brand purchase interest and loyalty. Brands as Intentional Agents Framework is based on a well-established social perception approach: the Stereotype Content Model. Two studies support the Brands as Intentional Agents Framework prediction that consumers assess a brand's perceived intentions and ability and that these perceptions elicit distinct emotions and drive differential brand behaviors. The research shows that human social interaction relationships translate to consumer-brand interactions in ways that are useful to inform brand positioning and brand communications. PMID- 24403816 TI - Anterior-segment morphology and corneal biomechanical characteristics in pigmentary glaucoma. AB - PURPOSE: The aim of the study reported here was to evaluate characteristics of the anterior-segment via anterior-segment optical coherence tomography (AS-OCT) and corneal biomechanical properties using an ocular response analyzer and their changes by peripheral laser iridotomy (PI) in patients with pigmentary glaucoma (PG). MATERIALS AND METHODS: Seventeen eyes with PG were included consecutively. AS-OCT and ocular response analyzer measurements were taken before and 3 months after PI. Baseline morphology and change in morphology were analyzed by correlation and multiple linear regression analysis. The main parameters assessed were anterior-chamber (AC) angles and volume as well as corneal hysteresis (CH) and corneal resistance factor. RESULTS: AC angles were found to have decreased significantly in each quadrant after PI (P<0.001), with the highest effect seen in the temporal quadrant, which decreased from 57.0 degrees +/-9.6 degrees to 44.1 degrees +/-5.2 degrees (+/- standard deviation). Mean AC volume decreased significantly from 213.1+/-36.4 to 187.0+/-23.4 mm(3) (P<0.001). CH and corneal resistance factor did not change after PI. CH was found to correlate with the preoperative superior and inferior angle width (Spearman's rho 0.553 and 0.615, respectively, P<0.05). Biomechanical parameters showed no predictive value on the change of AC angles or volume. CONCLUSION: PI in eyes with PG results in a highly significant reduction in the AC angles and volume as visualized by AS-OCT, with the largest effect seen in the temporal quadrant. CH is strongly positively correlated with the superior and inferior preoperative AC angles, emphasizing the importance of the biomechanical properties of the cornea for glaucoma pathogenesis in PG, but corneal biomechanical properties cannot predict PI related AC changes. PMID- 24403818 TI - Phase III safety and efficacy study of long-term brinzolamide/timolol fixed combination in Japanese patients with open-angle glaucoma or ocular hypertension. AB - BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of a long-term, twice-daily brinzolamide 1%/timolol 0.5% fixed combination ophthalmic suspension (BRINZ/TIM-FC) in Japanese patients with open-angle glaucoma (primary open-angle, normal-tension, exfoliation, or pigmentary) or ocular hypertension. METHODS: This was a prospective, nonrandomized, multicenter, open-label, Phase III study of Japanese patients aged >=20 years with diagnoses of open-angle glaucoma or ocular hypertension. Patients were treated with topical BRINZ/TIM-FC twice daily for 52 weeks. The primary endpoint was mean reduction from baseline in intraocular pressure. Data were analyzed using repeated-measures analysis of variance and t-tests. Adverse events and ophthalmic, physiologic, and laboratory parameters were measured throughout the study as safety endpoints. A total of 126 patients (mean +/- SD age, 63+/-12 years) were enrolled, and 125 received BRINZ/TIM-FC. RESULTS: Mean intraocular pressure was significantly reduced from baseline at weeks 4 through 52, with changes ranging from -4.1 mmHg to -5.7 mmHg (P<0.0001, all time points). Adverse events related to BRINZ/TIM-FC treatment were observed in 22% of patients. No substantial changes from baseline were observed in ophthalmic, physiologic, or laboratory variables. CONCLUSION: Long-term, twice-daily BRINZ/TIM-FC therapy produced and maintained significant intraocular pressure reductions and was generally well tolerated in Japanese patients with open-angle glaucoma or ocular hypertension. PMID- 24403817 TI - Retinal angiomatous proliferation associated with risk alleles of ARMS2/HTRA1 gene polymorphisms in Japanese patients. AB - BACKGROUND: The purpose of this study was to investigate the association between ARMS2/HTRA1, CFH, and C3 gene polymorphisms and retinal angiomatous proliferation (RAP), an infrequent and severe form of exudative age-related macular degeneration, which is characterized by intraretinal neovascularization. METHODS: Diagnosis of RAP was based on fundus photographs, images of fluorescein and indocyanine green angiographies, and optical coherence tomography findings. Six single nucleotide polymorphisms (SNPs), A69S (rs10490924) in ARMS2, rs11200638 in HTRA1, I62V (rs800292) in CFH, Y402H (rs1061170) in CFH, R80G (rs2230199) in C3, and rs2241394 in C3, were genotyped in eight Japanese patients with RAP. RESULTS: The two SNPs in the ARMS2/HTRA1 were in complete linkage disequilibrium. The frequency of the risk T allele in ARMS2 (the risk A allele in HTRA1) was 93.8% in the RAP patients. The frequency of homozygosity for the risk genotype TT of ARMS2 (the risk genotype AA of HTRA1) was 87.5%. The frequency of the non-risk allele (A) of I62V was 100%. The frequencies of risk alleles of Y402H, R80G, and rs2241394 were 12.5%, 0%, and 18.8%, respectively. CONCLUSION: Our results suggest that the risk alleles of the ARMS2/HTRA1 SNPs may be associated with development of RAP and play a major role in the pathogenesis of intraretinal angiogenesis. PMID- 24403819 TI - Evaluation of clinical outcomes in patients with dry eye disease using lubricant eye drops containing polyethylene glycol or carboxymethylcellulose. AB - BACKGROUND: The purpose of this study was to compare changes in corneal staining in patients with dry eye after 6 weeks of treatment with Systane(r) Gel Drops or Refresh Liquigel(r) lubricant eye drops. METHODS: Patients aged >=18 years with a sodium fluorescein corneal staining sum score of >=3 in either eye and best corrected visual acuity of 0.6 logarithm of the minimum angle of resolution or better in each eye who were using a lubricant eye gel or ointment for dry eye were included in this randomized, parallel-group, multicenter, double-blind trial. Patients were randomized to four times daily Systane(r) Gel Drops (polyethylene glycol 400 0.4% and propylene glycol 0.3%) or Refresh LiquiGel(r) Drops (carboxymethylcellulose sodium 1%) for 6 weeks. The primary efficacy outcome was mean change from baseline to week 6 in sodium fluorescein corneal staining. Supportive efficacy outcomes included conjunctival staining, tear film break-up time, Patient Global Assessment of Improvement, Impact of Dry Eye on Everyday Life (IDEEL) Treatment Satisfaction/Treatment Bother Questionnaire, Single Symptom Comfort Scale, and Ocular Symptoms Questionnaire. The safety analysis comprised recording of adverse events. RESULTS: In total, 147 patients (Systane group, n=73; Refresh group, n=74; mean +/- standard deviation age, 57+/ 16 years) were enrolled and included in the safety and efficacy analyses. Corneal staining was significantly reduced from baseline to week 6 for Systane and Refresh (-3.4+/-2.5 and -2.5+/-2.6 units, respectively; P<0.0001, t-test), with a significantly greater improvement with Systane versus Refresh (P=0.0294). Results for conjunctival staining, tear film break-up time, and patient-reported outcome questionnaires were not statistically different between groups. No safety issues were identified; adverse events were reported by 19% of patients with Systane and 30% of patients with Refresh eye drops. CONCLUSION: Systane Gel Drops were associated with significantly better corneal staining scores versus Refresh Liquigel eye drops in patients with dry eye. Supportive efficacy outcomes were not significantly different between groups. Both treatments were well tolerated. PMID- 24403820 TI - Correlations between choroidal abnormalities, Lisch nodules, and age in patients with neurofibromatosis type 1. AB - To evaluate correlations between choroidal abnormalities, Lisch nodules, and age in patients with neurofibromatosis type 1 (NF1), we examined ten cases with NF1 using near-infrared reflectance imaging. Patients ranged in age from 4 to 39 years. The angle used for near-infrared reflectance imaging was 55 degrees . We counted the total number of choroidal abnormalities in an area within a 55 degrees angle centered on the fovea and the total number of Lisch nodules on the iris by slit-lamp examination. No positive correlation was found between the number of Lisch nodules and patient age (Spearman's rank correlation coefficient rho=0.117, P=0.7414). Choroidal abnormalities tended to increase with age (rho=0.6150), but this difference was not statistically significant (P=0.0650). A positive correlation was found between the number of choroidal abnormalities and Lisch nodules (rho=0.783, P=0.0267). In conclusion, choroidal abnormalities tend to increase with patient age and are correlated with the number of Lisch nodules. PMID- 24403821 TI - Development and characterization of a gastroretentive dosage form composed of chitosan and hydroxyethyl cellulose for alendronate. AB - In this study, alendronate, the most commonly used biphosphonate for treating osteoporosis, was formulated as gastroretentive dosage form (GRDF) tablets to enhance its oral bioavailability. GRDF tablets were characterized with the effects of different molecular weights (MWs) of chitosan (CS) and hydroxyethyl cellulose (HEC) at various ratios on swelling, floating, and physical integrity. The CS component was formed using various acids: acetic, lactic, malic, succinic, and citric, and a high viscosity grade of HEC was selected. The results demonstrated that the swelling ratios of the formulations comprising high MW CS were lower than those of low or medium MW CS when salts were formed with any countering acids except for acetic acid. The decreasing ranking of the swelling rates was: CS-citrate > CS-malate > CS-lactate > CS-succinate > CS-acetate. A negative correlation was found between the pKa of the respective countering acid and the swelling rate. The swelling rate was promoted if an acidic salt of CS with a lower water content was incorporated, while it became slower when tablet hardness was higher or the compression force to form tablets was increased. Although HEC did not contribute to swelling or floating, it played a role in maintaining structural integrity. A prolonged dissolution profile of alendronate GRDF tablets developed in this study was observed. PMID- 24403822 TI - Overview of clinical use and side effect profile of valsartan in Chinese hypertensive patients. AB - We reviewed the Chinese and English literature for the efficacy and safety data of valsartan monotherapy or combination therapy in Chinese hypertensive patients. According to the data of ten randomized controlled trials, valsartan monotherapy was as efficacious as another angiotensin receptor blocker or other classes of antihypertensive drugs, excepting the slightly inferior diastolic blood pressure lowering effect in comparison with calcium channel blockers. According to the data of six randomized controlled trials, valsartan combination, with hydrochlorothiazide, amlodipine, or nifedipine gastrointestinal therapeutic system, was more efficacious than monotherapy of valsartan, amlodipine, or nifedipine gastrointestinal therapeutic system. According to these trials, valsartan had an acceptable tolerability, regardless of whether it was used as monotherapy or in combination therapy. Nonetheless, several rare side effects have been reported, indicating that it should still be used with caution. This is of particular importance given that there are millions of hypertensive patients, worldwide, currently exposed to the drug. PMID- 24403824 TI - Application of rapid artificial cardiac pacing in thoracic endovascular aortic repair in aged patients. AB - OBJECTIVE: To compare the safety, efficacy, and impact on stent graft positioning between rapid artificial cardiac pacing (RACP), induced hypotension and sodium nitroprusside (SNP) induced hypotension during thoracic endovascular aortic repair (TEVAR) for Stanford B aortic dissection. METHODS: One hundred and sixty eight patients, who were diagnosed with Stanford B aortic dissection and who underwent selective TEVAR in Guangdong General Hospital and the People's Hospital of Baoan District, Shenzhen, People's Republic of China, were enrolled in this study. Patients were randomly divided into a RACP group (n=77) and a SNP group (n=91). During localization and deployment of the stent graft, hypotension was induced by RACP or intravenous SNP, according to randomization. Hemodynamics, landing precision (deviation from planned placement site), duration of procedure, renal function, neurocognitive function, and incidence of endoleaks and paraplegia/hemiplegia were compared. Except for methods of inducing hypotension, TEVAR was performed according to the same protocol in each group. RESULTS: RACP was successfully performed in all patients assigned to the RACP group. Compared with the SNP group, blood pressure was significantly lower (43+/-5 versus 81+/-6 mmHg, P=0.003) and the restoration time of blood pressure and the operation duration were significantly shorter (7+/-2 versus 451+/-87 seconds, P<0.001; 87+/ 15 versus 106+/-18 minutes, P<0.001, respectively) in the RACP group. Stent graft localization/deployment was more precise in the RACP group (2+/-1 versus 5+/-2 mm, P<0.001). Compared to baseline, there was no significant change after TEVAR in either group in regard to renal function, neurocognitive function, and incidence of endoleaks and paraplegia/hemiplegia. CONCLUSION: RACP can be safely applied to patients undergoing TEVAR for Stanford B dissection. RACP can shorten the operation duration and facilitate precise graft localization/deployment. PMID- 24403823 TI - Rituximab for the treatment of rheumatoid arthritis: an update. AB - Rituximab is a chimeric monoclonal antibody that targets the CD20 molecule expressed on the surface of B cells. It was first used in the treatment of non Hodgkin's lymphoma and later approved for the treatment of rheumatoid arthritis (RA) that does not respond adequately to disease-modifying antirheumatic drugs, including the anti-tumor-necrosis-factor (TNF) biologics. Sustained efficacy in RA can be achieved by repeated courses of rituximab. However, the optimal dose and retreatment schedule of rituximab in RA remains to be established. Seropositivity, complete B cell depletion shortly after treatment, and previous failure to no more than one anti-TNF agent are three factors associated with greater clinical benefits to rituximab. Infusion reaction to the first dose of rituximab occurs in approximately 25% of RA patients, and the incidence reduces with subsequent exposure. Immunogenicity to the chimeric compound occurs in 11% of RA patients, but this does not correlate with its efficacy in B cell depletion. Extended observation of randomized controlled trials in RA does not reveal a significant increase in the incidence of serious infections related to rituximab compared to placebo groups, and the infection rate remains static over time. Repeated treatment with rituximab is associated with hypogammaglobulinemia, which may increase the risk of serious, but rarely opportunistic, infections. Reactivation of occult hepatitis B infection has been reported in RA patients receiving rituximab, but no increase in the incidence of tuberculosis was observed. Screening for baseline serum immunoglobulin G level and hepatitis B status (including occult infection) is important, especially in Asian countries where hepatitis B infection is prevalent. The rare but fatal progressive multifocal leukoencephalopathy linked to the use of rituximab has to be noted. Postmarketing surveillance and registry data, particularly in Asia, are necessary to establish the long-term efficacy and safety of rituximab in the treatment of RA. PMID- 24403825 TI - Homocysteine is associated with plasma high-sensitivity cardiac troponin T levels in a community-dwelling population. AB - OBJECTIVES: Homocysteine (HCY) is associated with an increased risk for cardiovascular disease, possibly leading to myocardial damage. Cardiac troponin T (TnT), a marker of cardiomyocyte injury, can be detected by high-sensitivity TnT (hsTnT) assay. The current study investigated the relationship between plasma HCY and hsTnT levels in a community-based population. METHODS: We related plasma levels of hsTnT to HCY levels in 1,497 participants (mean age, 62.4 years; 629 men, 868 women) from a community-based population in Beijing, People's Republic of China. RESULTS: In multiple logistic regression models, serum HCY was associated with a higher likelihood of detectable hsTnT (odds ratio 1.5; 95% confidence interval 1.07-2.10; P=0.018). A subsequent subgroup analysis found that in subjects aged 65 years and older, the association between hsTnT levels and HCY levels was strengthened. The association between hsTnT and HCY was not present in the younger subgroup (<65 years old). CONCLUSION: Levels of serum HCY are associated with hsTnT levels in the elderly, indicating a relationship between HCY and subclinical myocardial damage. PMID- 24403826 TI - Incidence and risk of developing contrast-induced acute kidney injury following intravascular contrast administration in elderly patients. AB - BACKGROUND: The purpose of this meta-analysis was to evaluate the epidemiology of contrast-induced acute kidney injury (CI-AKI) in the elderly. METHODS: A literature review was undertaken to determine the incidence of CI-AKI in individuals receiving intravascular contrast medium in the hospital setting. RESULTS: Twenty-two studies with 186,455 patients were identified. The pooled incidence of CI-AKI was 13.6% in 67,831 patients older than 65 years of age (95% confidence interval [CI] 10.1-18.2, I(2) =0.496). The pooled odds ratio of CI-AKI in the elderly was 2.55 (95% CI 1.85-3.52, I(2) =0.34). The high incidence of CI AKI in the elderly was consistent across different administration route subgroups (intracoronary contrast medium group, 15.5% [95% CI 10.3-22.6]; intravenous contrast medium group, 12.4% [95% CI 8.0-18.8]). CONCLUSION: Elderly patients are at greater risk for developing CI-AKI. PMID- 24403827 TI - Improved antibacterial activity and biocompatibility on vancomycin-loaded TiO2 nanotubes: in vivo and in vitro studies. AB - The goal for current orthopedic implant research is to design implants that have not only good biocompatibility but also antibacterial properties. TiO2 nanotubes (NTs) were fabricated on the titanium surface through electrochemical anodization, which added new properties, such as enhanced biocompatibility and potential utility as drug nanoreservoirs. The aim of the present study was to investigate the antibacterial properties and biocompatibility of NTs loaded with vancomycin (NT-V), both in vitro and in vivo. Staphylococcus aureus was used to study the antibacterial properties of the NT-V. There were three study groups: the commercially pure titanium (Cp-Ti) group, the NT group (nonloaded vancomycin), and the NT-V group. We compared NT-V biocompatibility and antibacterial efficacy with those of the NT and Cp-Ti groups. Compared with Cp Ti, NT-V showed good antibacterial effect both in vitro and in vivo. Although the NTs reduced the surface bacterial adhesion in vitro, implant infection still developed in in vivo studies. Furthermore, the results also revealed that both NTs and NT-V showed good biocompatibility. Therefore, the NTs loaded with antibiotic might be potentially used for future orthopedic implants. PMID- 24403828 TI - Interaction between nanoparticles generated by zinc chloride treatment and oxidative responses in rat liver. AB - The aim of the present study was to investigate the interaction of zinc chloride (3 mg/kg, intraperitoneally [ip]) in rat liver in terms of the biosynthesis of nanoparticles. Zinc treatment increased zinc content in rat liver. Analysis of fluorescence revealed the presence of red fluorescence in the liver following zinc treatment. Interestingly, the co-exposure to zinc (3 mg/kg, ip) and selenium (0.20 mg/L, per os [by mouth]) led to a higher intensity of red fluorescence compared to zinc-treated rats. In addition, X-ray diffraction measurements carried out on liver fractions of zinc-treated rats point to the biosynthesis of zinc sulfide and/or selenide nanocomplexes at nearly 51.60 nm in size. Moreover, co-exposure led to nanocomplexes of about 72.60 nm in size. The interaction of zinc with other mineral elements (S, Se) generates several nanocomplexes, such as ZnS and/or ZnSe. The nanocomplex ZnX could interact directly with enzyme activity or indirectly by the disruption of mineral elements' bioavailability in cells. Subacute zinc or selenium treatment decreased malondialdehyde levels, indicating a drop in lipid peroxidation. In addition, antioxidant enzyme assays showed that treatment with zinc or co-treatment with zinc and selenium increased the activities of glutathione peroxidase, catalase, and superoxide dismutase. Consequently, zinc complexation with sulfur and/or selenium at nanoscale level could enhance antioxidative responses, which is correlated to the ratio of number of ZnX nanoparticles (X=sulfur or X=selenium) to malondialdehyde level in rat liver. PMID- 24403829 TI - An efficient Trojan delivery of tetrandrine by poly(N-vinylpyrrolidone)-block poly(epsilon-caprolactone) (PVP-b-PCL) nanoparticles shows enhanced apoptotic induction of lung cancer cells and inhibition of its migration and invasion. AB - Earlier studies have demonstrated the promising antitumor effect of tetrandrine (Tet) against a series of cancers. However, the poor solubility of Tet limits its application, while its hydrophobicity makes Tet a potential model drug for nanodelivery systems. We report on a simple way of preparing drug-loaded nanoparticles formed by amphiphilic poly(N-vinylpyrrolidone)-block-poly(epsilon caprolactone) (PVP-b-PCL) copolymers with Tet as a model drug. The mean diameters of Tet-loaded PVP-b-PCL nanoparticles (Tet-NPs) were between 110 nm and 125 nm with a negative zeta potential slightly below 0 mV. Tet was incorporated into PVP b-PCL nanoparticles with high loading efficiency. Different feeding ratios showed different influences on sizes, zeta potentials, and the drug loading efficiencies of Tet-NPs. An in vitro release study shows the sustained release pattern of Tet NPs. It is shown that the uptake of Tet-NPs is mainly mediated by the endocytosis of nanoparticles, which is more efficient than the filtration of free Tet. Further experiments including fluorescence activated cell sorting and Western blotting indicated that this Trojan strategy of delivering Tet in PVP-b-PCL nanoparticles via endocytosis leads to enhanced induction of apoptosis in the non small cell lung cancer cell A549 line; enhanced apoptosis is achieved by inhibiting the expression of anti-apoptotic Bcl-2 and Bcl-xL proteins. Moreover, Tet-NPs more efficiently inhibit the ability of cell migration and invasion than free Tet by down-regulating matrix metalloproteinases (MMP)-2 and MMP-9, as well as up-regulating tissue inhibitor of MMP-3 (TIMP-3). Therefore, data from this study not only confirms the potential of Tet in treating lung cancer but also offers an effective way of improving the anticancer efficiency of Tet by nanodrug delivery systems. PMID- 24403830 TI - Improving aqueous solubility and antitumor effects by nanosized gambogic acid mPEG2000 micelles. AB - The clinical application of gambogic acid, a natural component with promising antitumor activity, is limited due to its extremely poor aqueous solubility, short half-life in blood, and severe systemic toxicity. To solve these problems, an amphiphilic polymer-drug conjugate was prepared by attachment of low molecular weight (ie, 2 kDa) methoxy poly(ethylene glycol) methyl ether (mPEG) to gambogic acid (GA-mPEG2000) through an ester linkage and characterized by (1)H nuclear magnetic resonance. The GA-mPEG2000 conjugates self-assembled to form nanosized micelles, with mean diameters of less than 50 nm, and a very narrow particle size distribution. The properties of the GA-mPEG2000 micelles, including morphology, stability, molecular modeling, and drug release profile, were evaluated. MTT (3 (4,5-dimethylthiazo l-2-yl)-2,5 diphenyl tetrazolium bromide) tests demonstrated that the GA-mPEG2000 micelle formulation had obvious cytotoxicity to tumor cells and human umbilical vein endothelial cells. Further, GA-mPEG2000 micelles were effective in inhibiting tumor growth and prolonged survival in subcutaneous B16 F10 and C26 tumor models. Our findings suggest that GA-mPEG2000 micelles may have promising applications in tumor therapy. PMID- 24403831 TI - Greater fibroblast proliferation on an ultrasonicated ZnO/PVC nanocomposite material. AB - There has been a significant and growing concern over nosocomial medical device infections. Previous studies have demonstrated that embedding nanoparticles alone (specifically, zinc oxide [ZnO]) in conventional polymers (eg, polyvinyl chloride [PVC]) can decrease bacteria growth and may have the potential to prevent or disrupt bacterial processes that lead to infection. However, little to no studies have been conducted to determine mammalian cell functions on such a nanocomposite material. Clearly, for certain medical device applications, maintaining healthy mammalian cell functions while decreasing bacteria growth is imperative (yet uncommon). For this reason, in the presented study, ZnO nanoparticles of varying sizes (from 10 nm to >200 nm in diameter) and functionalization (including no functionalization to doping with aluminum oxide and functionalizing with a silane coupling agent KH550) were incorporated into PVC either with or without ultrasonication. Results of this study provided the first evidence of greater fibroblast density after 18 hours of culture on the smallest ZnO nanoparticle incorporated PVC samples with dispersion aided by ultrasonication. Specifically, the greatest amount of fibroblast proliferation was measured on ZnO nanoparticles functionalized with a silane coupling agent KH550; this sample exhibited the greatest dispersion of ZnO nanoparticles. Water droplet tests showed a general trend of decreased hydrophilicity when adding any of the ZnO nanoparticles to PVC, but an increase in hydrophilicity (albeit still below controls or pure PVC) when using ultrasonication to increase ZnO nanoparticle dispersion. Future studies will have to correlate this change in wettability to initial protein adsorption events that may explain fibroblast behavior. Mechanical tests also provided evidence of the ability to tailor mechanical properties of the ZnO/PVC nanocomposites through the use of the different ZnO nanoparticles. Coupled with previous antibacterial studies, the present study demonstrated that highly dispersed ZnO/PVC nanocomposite materials should be further studied for numerous medical device applications. PMID- 24403832 TI - Cytotoxicity and apoptosis induced by nanobacteria in human breast cancer cells. AB - BACKGROUND: The existing evidence that nanobacteria (NB) are closely associated with human disease is overwhelming. However, their potential toxicity against cancer cells has not yet been reported. The objective of this study was to investigate the cytotoxic effects of NB and nanohydroxyapatites (nHAPs) against human breast cancer cells and to elucidate the mechanisms of action underlying their cytotoxicity. METHODOLOGY/PRINCIPAL FINDINGS: NB were isolated from calcified placental tissue, and nHAPs were artificially synthesized. The viability of the MDA-MB-231 human breast cancer cell line was tested by using the Kit-8 cell counting kit assay. Apoptosis was examined by transmission electron microscopy and flow cytometry. The endocytosis of NB and nHAPs by MDA-MB-231 cells was initially confirmed by microscopy. Although both NB and nHAPs significantly decreased MDA-MB-231 cell viability and increased the population of apoptotic cells, NB were more potent than nHAPs. After 72 hours, NB also caused ultrastructural changes typical of apoptosis, such as chromatin condensation, nuclear fragmentation, nuclear dissolution, mitochondrial swelling, and the formation of apoptotic bodies. CONCLUSION/SIGNIFICANCE: In MDA-MB-231 human breast cancer cells, NB and nHAPs exerted cytotoxic effects that were associated with the induction of apoptosis. The effects exerted by NB were more potent than those induced by nHAPs. NB cytotoxicity probably emerged from toxic metabolites or protein components, rather than merely the hydroxyapatite shells. NB divided during culturing, and similar to cells undergoing binary fission, many NB particles were observed in culture by transmission electron microscopy, suggesting they are live microorganisms. PMID- 24403833 TI - Nanostructured lipid carrier-loaded hyaluronic acid microneedles for controlled dermal delivery of a lipophilic molecule. AB - Nanostructured lipid carriers (NLCs) were employed to formulate a lipophilic drug into hydrophilic polymeric microneedles (MNs). Hyaluronic acid (HA) was selected as a hydrophilic and bioerodible polymer to fabricate MNs, and nile red (NR) was used as a model lipophilic molecule. NR-loaded NLCs were consolidated into the HA based MNs to prepare NLC-loaded MNs (NLC-MNs). A dispersion of NLCs was prepared by high-pressure homogenization after dissolving NR in Labrafil and mixing with melted Compritol, resulting in 268 nm NLCs with a polydispersity index of 0.273. The NLC dispersion showed a controlled release of NR over 24 hours, following Hixson-Crowell's cube root law. After mixing the NLC dispersion with the HA solution, the drawing lithography method was used to fabricate NLC-MNs. The length, base diameter, and tip diameter of the NLC-MNs were approximately 350, 380, and 30 MUm, respectively. Fluorescence microscopic imaging of the NLC-MNs helped confirm that the NR-loaded NLCs were distributed evenly throughout the MNs. In a skin permeation study performed using a Franz diffusion cell with minipig dorsal skin, approximately 70% of NR was localized in the skin after 24 hour application of NLC-MNs. Confocal laser scanning microscopy (z-series) of the skin at different depths showed strong fluorescence intensity in the epidermal layer, which appeared to spread out radially with the passage of time. This study indicated that incorporation of drug-loaded NLCs into MNs could represent a promising strategy for controlled dermal delivery of lipophilic drugs. PMID- 24403834 TI - Anti-obesity efficacy of nanoemulsion oleoresin capsicum in obese rats fed a high fat diet. AB - PURPOSE: This study determined the effects of oleoresin capsicum (OC) and nanoemulsion OC (NOC) on obesity in obese rats fed a high-fat diet. METHODS: THE RATS WERE RANDOMLY SEPARATED INTO THREE GROUPS: a high-fat (HF) diet group, HF + OC diet group, and HF + NOC diet group. All groups were fed the diet and water ad libitum for 14 weeks. RESULTS: NOC reduced the body weight and adipose tissue mass, whereas OC did not. OC and NOC reduced mRNA levels of adipogenic genes, including peroxisome proliferator-activated receptor (PPAR)-gamma, sterol regulatory element-binding protein-1c, and fatty acid-binding protein in white adipose tissue. The mRNA levels of genes related to beta-oxidation or thermogenesis including PPAR-alpha, palmitoyltransferase-1alpha, and uncoupling protein-2 were increased by the OC and NOC relative to the HF group. Both OC and NOC clearly stimulated AMP-activated protein kinase (AMPK) activity. In particular, PPAR-alpha, palmitoyltransferase-1alpha, uncoupling protein-2 expression, and AMPK activity were significantly increased in the NOC group compared to in the OC group. NOC decreased glycerol-3-phosphate dehydrogenase activity whereas OC did not. CONCLUSION: From these results, NOC could be suggested as a potential anti-obesity agent in obese rats fed a HF diet. The effects of the NOC on obesity were associated with changes of multiple gene expression, activation of AMPK, and inhibition of glycerol-3-phosphate dehydrogenase in white adipose tissue. PMID- 24403835 TI - Relationship between alexithymia and coping strategies in patients with somatoform disorder. AB - PURPOSE: A multidimensional intervention integrating alexithymia, negative affect, and type of coping strategy is needed for the effective treatment of somatoform disorder; however, few studies have applied this approach to the three different dimensions of alexithymia in patients with somatoform disorder. The purpose of this study was to determine the relationship between type of coping strategy and three different dimensions of alexithymia expressed in patients. PATIENTS AND METHODS: A total of 196 patients with somatoform disorder completed the 20-item Toronto Alexithymia Scale, the Zung Self-Rating Depression Scale, the Spielberger State-Trait Anxiety Inventory, the Somatosensory Amplification Scale, and the Lazarus Stress Coping Inventory. The relationships between alexithymia (Toronto Alexithymia Scale - 20 score and subscales), demographic variables, and psychological inventory scores were analyzed using Pearson's correlation coefficients and stepwise multiple regression analysis. RESULTS: The mean Toronto Alexithymia Scale - 20 total score (56.1+/-10.57) was positively correlated with the number of physical symptoms as well as with psychopathology scores (Self Rating Depression Scale, State-Trait Anxiety Inventory trait, state, and Somatosensory Amplification Scale), but negatively correlated with planful problem solving, confrontive coping, seeking social support, and positive reappraisal coping scores. With respect to coping strategy, multiple regression analyses revealed that "difficulty in identifying feelings" was positively associated with an escape-avoidance strategy, "difficulty in describing feelings" was negatively associated with a seeking social support strategy, and "externally oriented thinking" was negatively associated with a confrontive coping strategy. CONCLUSION: Alexithymia was strongly associated with the number of somatic symptoms and negative affect. Patients with high "difficulty in describing feelings" tend to rely less on seeking social support, and patients with high "externally oriented thinking" tend to rely less on confrontive coping strategies. The coping skills intervention implemented should differ across individuals and should be based on the alexithymia dimension of each patient. PMID- 24403836 TI - Skin, fascias, and scars: symptoms and systemic connections. AB - Every element or cell in the human body produces substances that communicate and respond in an autocrine or paracrine mode, consequently affecting organs and structures that are seemingly far from each other. The same also applies to the skin. In fact, when the integrity of the skin has been altered, or when its healing process is disturbed, it becomes a source of symptoms that are not merely cutaneous. The skin is an organ, and similar to any other structure, it has different functions in addition to connections with the central and peripheral nervous system. This article examines pathological responses produced by scars, analyzing definitions and differences. At the same time, it considers the subcutaneous fascias, as this connective structure is altered when there is a discontinuous cutaneous surface. The consequence is an ample symptomatology, which is not limited to the body area where the scar is located, such as a postural or trigeminal disorder. PMID- 24403837 TI - Combination of neutrophil lymphocyte ratio and platelet lymphocyte ratio is a useful predictor of postoperative survival in patients with esophageal squamous cell carcinoma. AB - BACKGROUND: Recent studies have shown that the presence of systemic inflammation correlates with poor survival in various types of cancers. This study investigated the usefulness of a novel inflammation-based prognostic system, using the combination of neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR), collectively named the CNP, for predicting survival in patients with esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: THE CNP WAS CALCULATED ON THE BASIS OF DATA OBTAINED ON THE DAY OF ADMISSION: patients with both elevated NLR (>3.45) and PLR (>166.5) were allocated a score of 2, and patients showing one or neither were allocated a score of 1 or 0, respectively. RESULTS: The CNP was associated with tumor length (P<0.001), differentiation (P=0.021), depth of invasion (P<0.001), and nodal metastasis (P<0.001). No significant differences were found between the CNP and morbidity. However, significant differences were found between the CNP and mortality (P,0.001). The overall survival in the CNP 0, CNP 1, and CNP 2 groups were 63.4%, 50.0%, and 20.2%, respectively (CNP 0 versus CNP 1, P=0.014; CNP 1 versus CNP 2, P<0.001). Multivariate analyses showed that CNP was a significant predictor of overall survival. CNP 1-2 had a hazard ratio (HR) of 1.964 (95% confidence interval [CI]: 1.371-2.814, P<0.001) for overall survival. CNP (HR =1.964, P<0.001) is superior to NLR (HR =1.310, P=0.053) or PLR (HR =1.751, P<0.001) as a predictive factor. CONCLUSION: The CNP is considered a useful predictor of postoperative survival in patients with ESCC. The CNP is superior to NLR or PLR as a predictive factor in patients with ESCC. PMID- 24403838 TI - High expression of Sonic Hedgehog signaling pathway genes indicates a risk of recurrence of breast carcinoma. AB - BACKGROUND: Abnormal activation of the Sonic Hedgehog (SHH) signaling pathway contributing to carcinogenesis of some organs has been reported in the literature. We hypothesize that activation of the SHH pathway contributes to the recurrence of breast carcinoma. METHODS: Fifty consecutive patients with invasive breast carcinoma following curative resection were enrolled in this prospective study. The ratios of messenger RNA (mRNA) expression for Sonic Hedgehog (SHH), patched homolog-1 (PTCH-1), glioma-associated oncogene-1 (GLI-1), and smoothened (SMOH) were measured between breast carcinoma tissue and paired noncancerous breast tissue. These ratios were compared with their clinicopathologic characteristics. These factors and the mRNA ratios were compared between patients with recurrence and those without recurrence. RESULTS: The size of the invasive cancer correlated significantly with the ratio of SHH mRNA (P=0.001), that of PTCH-1 mRNA (P=0.005), and that of SMOH mRNA (P=0.021). Lymph node involvement correlated significantly with the ratio of SMOH mRNA (P=0.041). The correlation between Her-2 neu and the ratio of GLI-1 mRNA was statistically significant (P=0.012). Each ratio of mRNA of SHH, PTCH-1, GLI-1, and SMOH correlated significantly with cancer recurrence (P<0.001 for each). CONCLUSION: We suggest that high expression of SHH mRNA, PTCH-1 mRNA, GLI-1 mRNA, and SMOH mRNA in breast cancer tissue correlates with invasiveness and is a potential biomarker to predict postoperative recurrence. PMID- 24403839 TI - The long-term survival of a thymic carcinoma patient treated with S-1: a case report and literature review. AB - BACKGROUND: Thymic carcinoma is a rare neoplasm of the thymus. Systemic chemotherapy is an important therapeutic modality for thymic carcinoma. However, no standard chemotherapy for this carcinoma has yet been established. The usefulness of second-line or later-line chemotherapy has remained unclear. A case of relapsed thymic carcinoma that was successfully treated by S-1 as second-line chemotherapy is reported herein. CASE PRESENTATION: A 73-year-old man diagnosed as having thymic carcinoma was treated with three cycles of first-line chemotherapy with ADOC (cisplatin, doxorubicin, vincristine, and cyclophosphamide) and additional radiotherapy (50 Gy). Since his serum cytokeratin 19 fragment level increased suddenly after 3 months of stable disease, he was considered to have progressive disease, and was given S-1 as chemotherapy. Two months later, he had partial response, and the S-1 treatment has been continued since July 2009. Progression-free survival of greater than 4 years was obtained with S-1. CONCLUSION: A case of relapsed thymic carcinoma that was treated with S-1, and continues to show a long progression-free survival with good quality of life on treatment is described. S-1 might be an active agent against relapsed thymic carcinoma. PMID- 24403840 TI - High degree of duodenal inflammation in Nigerians with functional dyspepsia. AB - BACKGROUND: Functional dyspepsia (FD) is a heterogeneous disorder associated with diverse pathophysiological mechanisms, including immune activation and low-grade mucosal inflammation. Genetic factors, physiological functions, and environmental factors may determine the relative importance of various pathophysiological mechanisms. This study was designed to determine the histological alterations in the duodenal mucosa of Nigerian patients with FD. METHODS: Consecutive patients with dyspepsia seen over a 27-month period in two gastrointestinal endoscopy facilities in Enugu, South-East Nigeria were further evaluated with upper gastrointestinal endoscopy and duodenal mucosal biopsies if no lesion was found in the upper gastrointestinal tract. Patients with heartburn and/or regurgitation who did not have any dyspeptic symptoms and did not have any lesion in the upper gastrointestinal tract on endoscopy were presumed to have non-erosive reflux disease (NERD) and they served as controls. The control subjects also had duodenal biopsies. The histopathological findings in the cases and controls were compared. RESULTS: There were 68 patients with FD and 52 patients with NERD. The total inflammatory score was 242 in FD and 66 in NERD (Mann-Whitney U =1168, P=0.0011). Similarly, the scores for chronic inflammation, gastric metaplasia, neutrophilic activity, eosinophilic infiltration, and Helicobacter pylori were significantly higher in FD than NERD. CONCLUSION: Functional dyspepsia is associated with a high degree of inflammation in the duodenal mucosa. This may reflect the high prevalence of gastrointestinal infections in a tropical environment such as Nigeria. These findings may have therapeutic potential that further studies might elucidate. PMID- 24403843 TI - Antibiotics for the treatment of rheumatoid arthritis. AB - Antibiotic treatment for rheumatoid arthritis (RA) commenced in the 1930s with the use of sulfasalazine. Later, tetracyclines were successfully used for the treatment of RA. In double-blind and randomized studies, levofloxacin and macrolide antibiotics (including clarithromycin and roxithromycin) were also shown to be effective in the treatment of RA. There have been several reports in the literature indicating that periodontal pathogens are a possible cause of RA. Oral bacteria are one possible cause of RA. In this review, we aimed to investigate the effects of different antibiotics in RA treatment. PMID- 24403842 TI - Pathogenesis and management of postprandial hyperglycemia: role of incretin-based therapies. AB - Postprandial plasma glucose concentrations are an important contributor to glycemic control. There is evidence suggesting that postprandial hyperglycemia may be an independent risk factor for cardiovascular disease. Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents that predominantly reduce postprandial plasma glucose levels. DPP-4 inhibitors are associated with fewer gastrointestinal side effects than GLP-1 receptor agonists and are administered orally, unlike GLP-1 analogs, which are administered as subcutaneous injections. GLP-1 receptor agonists are somewhat more effective than DPP-4 inhibitors in reducing postprandial plasma glucose and are usually associated with significant weight loss. For these reasons, GLP-1 receptor agonists are generally preferred over DPP-4 inhibitors as part of combination treatment regimens in patients with glycated hemoglobin levels above 8.0%. This article reviews the pathogenesis of postprandial hyperglycemia, the mechanisms by which GLP-1 receptor agonists and DPP-4 inhibitors reduce postprandial plasma glucose concentrations, and the results of recent clinical trials (ie, published 2008 to October 2012) that evaluated the effects of these agents on postprandial plasma glucose levels when evaluated as monotherapy compared with placebo or as add-on therapy to metformin, a sulfonylurea, or insulin. Findings from recent clinical studies suggest that both GLP-1 receptor agonists and DPP-4 inhibitors could become valuable treatment options for optimizing glycemic control in patients unable to achieve glycated hemoglobin goals on basal insulin, with the added benefits of weight loss and a low risk of hypoglycemia. PMID- 24403841 TI - Overview of diagnostic/targeted treatment combinations in personalized medicine for breast cancer patients. AB - Breast cancer includes a body of molecularly distinct subgroups, characterized by different presentation, prognosis, and sensitivity to treatments. Significant advances in our understanding of the complex architecture of this pathology have been achieved in the last few decades, thanks to new biotechnologies that have recently come into the research field and the clinical practice, giving oncologists new instruments that are based on biomarkers and allowing them to set up a personalized approach for each individual patient. Here we review the main treatments available or in preclinical development, the biomolecular diagnostic and prognostic approaches that changed our perspective about breast cancer, giving an overview of targeted therapies that represent the current standard of care for these patients. Finally, we report some examples of how new technologies in clinical practice can set in motion the development of new drugs. PMID- 24403844 TI - Autopsy-certified maternal mortality at Ile-Ife, Nigeria. AB - AIM: Maternal mortality is a major health problem, especially in Nigeria, where accurate autopsy-based data on the prevalent causes are not readily available. The aim of this study was therefore to accurately determine the causes of maternal death as seen in a tertiary health facility in Nigeria. MATERIALS AND METHODS: This was a descriptive, retrospective review of the postmortem autopsy findings from cases of maternal death at the Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria over a 5-year period. Analyses were performed for differences in proportions using PEPI computer programs for epidemiologists (P is significant at <0.05). RESULTS: A total of 84 cases of maternal deaths were used for the study. Approximately 71.4% of the maternal deaths were due to direct causes and 28.6% were due to indirect causes. The mean age at the time of death was 27.9+/-7.5 years. Overall, the three leading causes of death were obstetric hemorrhage (30.9%), complications of abortion (23.8%), and nongenital (nonobstetric) infections (14.2%). Of the direct causes of maternal death, obstetric hemorrhage (43.3%) was the leading cause, with postpartum hemorrhage accounting for most (65.0%) of such deaths; other causes included complications of unsafe induced abortion (33.3%) and of labor (11.7%). Of the indirect causes, nongenital infections (50.0%), anemia (25.0%), and preexisting hypertension (20.8%) accounted for the majority of the maternal deaths. There was disparity between the clinical and autopsy diagnoses in 34 of the 84 cases (38.1%). CONCLUSION: The leading causes of maternal death in this study are similar to those in other developing countries. Autopsy is an invaluable tool in accurately determining the cause of maternal death. PMID- 24403845 TI - Sudden and rapid progression of lung affectation but stability in kidney function: a case report of anti-neutrophil cytoplasmic antibody-associated vasculitis. AB - We report the case of a patient with anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) who exhibited sudden progression of lung infiltration while maintaining stable kidney function. The 69-year-old man was diagnosed with AAV and renal insufficiency 4 years ago. Pulmonic affectation was detected in the right lower lobe of lung by a computed tomography (CT) scan. After beginning cyclophosphamide pulse therapy and sequential therapy with low-dose prednisone, he underwent a 4-year follow-up to detect changes in hemoglobin levels and serum creatinine levels, and had chest CT examinations. The CT scan and creatinine assay showed stable pulmonic fibrosis and kidney function. Although there was no increase of creatinine and detectable perinuclear ANCA, the patient suffered a pulmonary hemorrhage and levels of hemoglobin became progressive lower; the lung infiltration was found to be enlarged compared to the last examination the previous year. After immunosuppressive therapy for one week, the lung fibrosis was progressive, increased pulmonary hemorrhage occurred, and the patient died due to respiratory failure but not end-stage renal failure. PMID- 24403846 TI - Over-the-counter medication patterns in households in Sharjah, United Arab Emirates. AB - BACKGROUND: Self-medication and acquisition of over-the-counter (OTC) medications are emerging community health issues. Besides being a cheap alternative for treating common illnesses, the behavior entails serious ramifications, such as medication wastage, increasing pathogen resistance, and adverse drug reactions. The present study was conducted to explore the extent of OTC medications in households in Sharjah, United Arab Emirates (UAE), including native UAE and expatriate families. METHODS: The study employed a population-based, cross sectional, analytical study design. The study population included native and expatriate households residing in the Emirate of Sharjah, UAE. The snowball sampling technique was used, and the sample included a total of 335 households. RESULTS: Expatriate households acquired more OTC medications than did native households (adjusted odds ratio [aOR]=1.7). The demographic determinants for expatriate households were number of family members (aOR=1.6), age of children in the family (aOR=1.8), and annual income (aOR=0.5). Expatriate households purchased more OTC medication practices than did native households (aOR=2.2). In the statistical sense, expatriate household practices were buying medication upon relatives' advice (aOR=0.3), storage condition of medication (aOR=2.4), and disposal of expired medication (aOR=0.6). The highest percentages of OTC medications in native and expatriate households were those related to gastric and ear, nose, and throat illnesses. CONCLUSION: The presence of OTC medications in expatriate households was two-fold more common than in native households in Sharjah, UAE. There were significant associations for behaviors related to the reasons why OTC medications were purchased and stored within the household for both native and expatriate families. PMID- 24403847 TI - Improving plant functional groups for dynamic models of biodiversity: at the crossroads between functional and community ecology. AB - The pace of on-going climate change calls for reliable plant biodiversity scenarios. Traditional dynamic vegetation models use plant functional types that are summarized to such an extent that they become meaningless for biodiversity scenarios. Hybrid dynamic vegetation models of intermediate complexity (hybrid DVMs) have recently been developed to address this issue. These models, at the crossroads between phenomenological and process-based models, are able to involve an intermediate number of well-chosen plant functional groups (PFGs). The challenge is to build meaningful PFGs that are representative of plant biodiversity, and consistent with the parameters and processes of hybrid-DVMs. Here, we propose and test a framework based on few selected traits to define a limited number of PFGs, which are both representative of the diversity (functional and taxonomic) of the flora in the Ecrins National Park, and adapted to hybrid-DVMs. This new classification scheme, together with recent advances in vegetation modeling, constitutes a step forward for mechanistic biodiversity modeling. PMID- 24403848 TI - Genetics in diabetic retinopathy: current concepts and new insights. AB - There is emerging evidence which indicates the essential role of genetic factors in the development of diabetic retinopathy (DR). In this regard it should be highlighted that genetic factors account for 25-50% of the risk of developing DR. Therefore, the use of genetic analysis to identify those diabetic patients most prone to developing DR might be useful in designing a more individualized treatment. In this regard, there are three main research strategies: candidate gene studies, linkage studies and Genome-Wide Association Studies (GWAS). In the candidate gene approach, several genes encoding proteins closely related to DR development have been analyzed. The linkage studies analyze shared alleles among family members with DR under the assumption that these predispose to a more aggressive development of DR. Finally, Genome-Wide Association Studies (GWAS) are a new tool involving a massive evaluation of single nucleotide polymorphisms (SNP) in large samples. In this review the available information using these three methodologies is critically analyzed. A genetic approach in order to identify new candidates in the pathogenesis of DR would permit us to design more targeted therapeutic strategies in order to decrease this devastating complication of diabetes. Basic researchers, ophthalmologists, diabetologists and geneticists should work together in order to gain new insights into this issue. PMID- 24403850 TI - Molecular Population Genetics and Evolution of the Chagas' Disease Vector Triatoma infestans (Hemiptera: Reduviidae). AB - Triatoma infestans (Klug) is the main vector of Chagas' disease in the Southern Cone of Latin America between the latitudes 10 degrees S and 46 degrees S. The long-term effectiveness of the control campaigns is greatly dependent upon the vector population structure. Mitochondrial DNA (mtDNA) genes have been used in a number of T. infestans population genetic analyses. However, the maternally inherited markers as well as nuclear ribosomal DNA analyzed until the present exhibited low or limited levels of variation. Analyses based on microsatellite markers strongly supported the existence of some type of stratification in T. infestans populations and supported the hypothesis of vector population recovery from survivors of the insecticide-treated areas, highlighting the value of population genetic analyses in assessing the effectiveness of Chagas' disease vector control programmes. Although phylogeographic studies have generally suggested a Bolivian Andean origin of T. infestans, they recovered two reciprocal monophyletic groups of T. infestans and Bolivian populations who were not basal as expected for an ancestral group. In addition, a non-Andean origin could not be excluded by mtDNA genealogies that included sylvatic bugs from Gran Chaco. On the other side, mitochondrial and microsatellite markers supported the hypothesis of two independent migration events of colonization and secondary contacts in southern South America. Since the phylogenetic analyses remain inconclusive, more sequences, not only from mitochondrial genes but also from nuclear genes, need to be examined. PMID- 24403849 TI - Studies on the pathophysiology and genetic basis of migraine. AB - Migraine is a neurological disorder that affects the central nervous system causing painful attacks of headache. A genetic vulnerability and exposure to environmental triggers can influence the migraine phenotype. Migraine interferes in many facets of people's daily life including employment commitments and their ability to look after their families resulting in a reduced quality of life. Identification of the biological processes that underlie this relatively common affliction has been difficult because migraine does not have any clearly identifiable pathology or structural lesion detectable by current medical technology. Theories to explain the symptoms of migraine have focused on the physiological mechanisms involved in the various phases of headache and include the vascular and neurogenic theories. In relation to migraine pathophysiology the trigeminovascular system and cortical spreading depression have also been implicated with supporting evidence from imaging studies and animal models. The objective of current research is to better understand the pathways and mechanisms involved in causing pain and headache to be able to target interventions. The genetic component of migraine has been teased apart using linkage studies and both candidate gene and genome-wide association studies, in family and case control cohorts. Genomic regions that increase individual risk to migraine have been identified in neurological, vascular and hormonal pathways. This review discusses knowledge of the pathophysiology and genetic basis of migraine with the latest scientific evidence from genetic studies. PMID- 24403851 TI - Genome-wide Membrane Protein Structure Prediction. AB - Transmembrane proteins allow cells to extensively communicate with the external world in a very accurate and specific way. They form principal nodes in several signaling pathways and attract large interest in therapeutic intervention, as the majority pharmaceutical compounds target membrane proteins. Thus, according to the current genome annotation methods, a detailed structural/functional characterization at the protein level of each of the elements codified in the genome is also required. The extreme difficulty in obtaining high-resolution three-dimensional structures, calls for computational approaches. Here we review to which extent the efforts made in the last few years, combining the structural characterization of membrane proteins with protein bioinformatics techniques, could help describing membrane proteins at a genome-wide scale. In particular we analyze the use of comparative modeling techniques as a way of overcoming the lack of high-resolution three-dimensional structures in the human membrane proteome. PMID- 24403853 TI - RELATIONSHIPS BETWEEN MEN'S GENDER ATTITUDES AND FERTILITY: Response to Puur, et al.'s "Men's childbearing desires and views of the male role in Europe at the dawn of the 21st century", Demographic Research 19: 1883-1912. PMID- 24403852 TI - Comparative Genomics of X-linked Muscular Dystrophies: The Golden Retriever Model. AB - Duchenne muscular dystrophy (DMD) is a devastating disease that dramatically decreases the lifespan and abilities of affected young people. The primary molecular cause of the disease is the absence of functional dystrophin protein, which is critical to proper muscle function. Those with DMD vary in disease presentation and dystrophin mutation; the same causal mutation may be associated with drastically different levels of disease severity. Also contributing to this variation are the influences of additional modifying genes and/or changes in functional elements governing such modifiers. This genetic heterogeneity complicates the efficacy of treatment methods and to date medical interventions are limited to treating symptoms. Animal models of DMD have been instrumental in teasing out the intricacies of DMD disease and hold great promise for advancing knowledge of its variable presentation and treatment. This review addresses the utility of comparative genomics in elucidating the complex background behind phenotypic variation in a canine model of DMD, Golden Retriever muscular dystrophy (GRMD). This knowledge can be exploited in the development of improved, more personalized treatments for DMD patients, such as therapies that can be tailor-matched to the disease course and genomic background of individual patients. PMID- 24403854 TI - Supplementation of nicotinic acid with NAMPT inhibitors results in loss of in vivo efficacy in NAPRT1-deficient tumor models. AB - Nicotinamide adenine dinucleotide (NAD) is a metabolite essential for cell survival and generated de novo from tryptophan or recycled from nicotinamide (NAM) through the nicotinamide phosphoribosyltransferase (NAMPT)-dependent salvage pathway. Alternatively, nicotinic acid (NA) is metabolized to NAD through the nicotinic acid phosphoribosyltransferase domain containing 1 (NAPRT1) dependent salvage pathway. Tumor cells are more reliant on the NAMPT salvage pathway making this enzyme an attractive therapeutic target. Moreover, the therapeutic index of NAMPT inhibitors may be increased by in NAPRT-deficient tumors by NA supplementation as normal tissues may regenerate NAD through NAPRT1. To confirm the latter, we tested novel NAMPT inhibitors, GNE-617 and GNE-618, in cell culture- and patient-derived tumor models. While NA did not protect NAPRT1 deficient tumor cell lines from NAMPT inhibition in vitro, it rescued efficacy of GNE-617 and GNE-618 in cell culture- and patient-derived tumor xenografts in vivo. NA co-treatment increased NAD and NAM levels in NAPRT1-deficient tumors to levels that sustained growth in vivo. Furthermore, NAM co-administration with GNE 617 led to increased tumor NAD levels and rescued in vivo efficacy as well. Importantly, tumor xenografts remained NAPRT1-deficient in the presence of NA, indicating that the NAPRT1-dependent pathway is not reactivated. Protection of NAPRT1-deficient tumors in vivo may be due to increased circulating levels of metabolites generated by mouse liver, in response to NA or through competitive reactivation of NAMPT by NAM. Our results have important implications for the development of NAMPT inhibitors when considering NA co-treatment as a rescue strategy. PMID- 24403855 TI - Inflammatory factors of the tumor microenvironment induce plasticity in nontransformed breast epithelial cells: EMT, invasion, and collapse of normally organized breast textures. AB - Nontransformed breast epithelial cells that are adjacent to tumor cells are constantly exposed to tumor necrosis factor-alpha (TNFalpha) and interleukin 1beta (IL-1beta), two inflammatory cytokines identified as having pro-tumoral causative roles. We show that continuous stimulation of nontransformed breast epithelial cells by TNFalpha + IL-1beta for 2 to 3 weeks induced their spreading and epithelial-to-mesenchymal transition (EMT). The mechanistic bases for this slow induction of EMT by TNFalpha + IL-1beta are: 1) it took 2 to 3 weeks for the cytokines to induce the expression of the EMT activators Zeb1 and Snail; 2) although Twist has amplified the EMT-inducing activities of Zeb1 + Snail, its expression was reduced by TNFalpha + IL-1beta; however, the lack of Twist was compensated by prolonged stimulation with TNFalpha + IL-1beta that has potentiated the EMT-inducing activities of Zeb1 + Snail. Stimulation by TNFalpha + IL-1beta has induced the following dissemination-related properties in the nontransformed cells: 1) up-regulation of functional matrix metalloproteinases; 2) induction of migratory and invasive capabilities; 3) disruption of the normal phenotype of organized three-dimensional acini structures typically formed only by nontransformed breast cells and spreading of nontransformed cells out of such acini. Our findings suggest that TNFalpha + IL-1beta induce dissemination of nontransformed breast epithelial cells and their reseeding at the primary tumor site; if, then, such detached cells are exposed to transforming events, they may form secondary malignant focus and lead to disease recurrence. Thus, our study reveals novel pathways through which the inflammatory microenvironment may contribute to relapsed disease in breast cancer. PMID- 24403856 TI - Quantitative analysis of [11C]-erlotinib PET demonstrates specific binding for activating mutations of the EGFR kinase domain. AB - Activating mutations of the epidermal growth factor receptor (EGFR) occur in multiple tumor types, including non-small cell lung cancer (NSCLC) and malignant glioma, and have become targets for therapeutic intervention. The determination of EGFR mutation status using a noninvasive, molecular imaging approach has the potential for clinical utility. In this study, we investigated [(11)C]-erlotinib positron emission tomography (PET) imaging as a tool to identify activating mutations of EGFR in both glioma and NSCLC xenografts. Radiotracer specific binding was determined for high and low specific activity (SA) [(11)C]-erlotinib PET scans in mice bearing synchronous human cancer xenografts with different EGFR expression profiles (PC9, HCC827, U87, U87 DeltaEGFR, and SW620). Although xenograft immunohistochemistry demonstrated constitutive EGFR phosphorylation, PET scan analysis using the Simplified Reference Tissue Model showed that only kinase domain mutant NSCLC (HCC827 and PC9) had significantly greater binding potentials in high versus low SA scans. Xenografts with undetectable EGFR expression (SW620), possessing wild-type EGFR (U87), and expressing an activating extracellular domain mutation (U87 DeltaEGFR) were indistinguishable under both high and low SA scan conditions. The results suggest that [(11)C]-erlotinib is a promising radiotracer that could provide a novel clinical methodology for assessing EGFR and erlotinib interactions in patients with tumors that harbor EGFR-activating kinase domain mutations. PMID- 24403857 TI - Synthetic lethality screen identifies RPS6KA2 as modifier of epidermal growth factor receptor activity in pancreatic cancer. AB - Pancreatic cancer is characterized by a high degree of resistance to chemotherapy. Epidermal growth factor receptor (EGFR) inhibition using the small molecule inhibitor erlotinib was shown to provide a small survival benefit in a subgroup of patients. To identify kinases whose inhibition acts synergistically with erlotinib, we employed a kinome-wide small-interfering RNA (siRNA)-based loss-of-function screen in the presence of erlotinib. Of 779 tested kinases, we identified several targets whose inhibition acted synergistically lethal with EGFR inhibition by erlotinib, among them the S6 kinase ribosomal protein S6 kinase 2 (RPS6KA2)/ribosomal S6 kinase 3. Activated RPS6KA2 was expressed in approximately 40% of 123 human pancreatic cancer tissues. RPS6KA2 was shown to act downstream of EGFR/RAS/mitogen-activated protein kinase kinase (MEK)/extracellular-signal regulated kinase (ERK) signaling and was activated by EGF independently of the presence of KRAS mutations. Knockdown of RPS6KA2 by siRNA led to increased apoptosis only in the presence of erlotinib, whereas RPS6KA2 activation or overexpression rescued from erlotinib- and gemcitabine induced apoptosis. This effect was at least in part mediated by downstream activation of ribosomal protein S6. Genetic as well as pharmacological inhibition of RPS6KA2 by the inhibitor BI-D1870 acted synergistically with erlotinib. By applying this synergistic lethality screen using a kinome-wide RNA interference library approach, we identified RPS6KA2 as potential drug target whose inhibition synergistically enhanced the effect of erlotinib on tumor cell survival. This kinase therefore represents a promising drug candidate suitable for the development of novel inhibitors for pancreatic cancer therapy. PMID- 24403858 TI - N-Myc differentially regulates expression of MXI1 isoforms in neuroblastoma. AB - Amplification of the MYCN proto-oncogene is associated with a poor prognosis in patients with metastatic neuroblastoma (NB). MYCN encodes the N-Myc protein, a transcriptional regulator that dimerizes with the Max transcription factor, binds to E-box DNA sequences, and regulates genes involved in cell growth and apoptosis. Overexpression of N-Myc leads to transcriptional activation and an increase in NB cell proliferation. Mxi1, a member of the Myc family of transcriptional regulators, also binds to Max. However, Mxi1 is a transcriptional repressor and inhibits proliferation of NB cells, suggesting that Mxi1 functions as an N-Myc antagonist. Our laboratory previously identified Mxi1-0, an alternatively transcribed Mxi1 isoform. Mxi1-0 has properties distinct from those of Mxi1; in contrast to Mxi1, Mxi1-0 is unable to suppress c-Myc-dependent transcription. We now show that Mxi1-0 expression increases in response to MYCN overexpression in NB cells, with a positive correlation between MYCN and MXI1-0 RNA levels. We also show that N-Myc expression differentially regulates the MXI1 and MXI1-0 promoters: Increased MYCN expression suppresses MXI1 promoter activity while enhancing transcription through the MXI1-0 promoter. Finally, induction of Mxi1-0 leads to increased proliferation, whereas expression of Mxi1 inhibits cell growth, indicating differential roles for these two proteins. These data suggest that N-Myc differentially regulates the expression of MXI1 and MXI1-0 and can alter the balance between the two transcription factors. Furthermore, MXI1-0 appears to be a downstream target of MYCN-dependent signaling pathways and may contribute to N-Myc-dependent cell growth and proliferation. PMID- 24403859 TI - Tumor evolution and intratumor heterogeneity of an oropharyngeal squamous cell carcinoma revealed by whole-genome sequencing. AB - Head and neck squamous cell carcinoma (HNSCC) is characterized by significant genomic instability that could lead to clonal diversity. Intratumor clonal heterogeneity has been proposed as a major attribute underlying tumor evolution, progression, and resistance to chemotherapy and radiation. Understanding genetic heterogeneity could lead to treatments specific to resistant and metastatic tumor cells. To characterize the degree of intratumor genetic heterogeneity within a single tumor, we performed whole-genome sequencing on three separate regions of an human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma and two separate regions from one corresponding cervical lymph node metastasis. This approach achieved coverage of approximately 97.9% of the genome across all samples. In total, 5701 somatic point mutations (SPMs) and 4347 small somatic insertions and deletions (indels)were detected in at least one sample. Ninety-two percent of SPMs and 77% of indels were validated in a second set of samples adjacent to the discovery set. All five tumor samples shared 41% of SPMs, 57% of the 1805 genes with SPMs, and 34 of 55 cancer genes. The distribution of SPMs allowed phylogenetic reconstruction of this tumor's evolutionary pathway and showed that the metastatic samples arose as a late event. The degree of intratumor heterogeneity showed that a single biopsy may not represent the entire mutational landscape of HNSCC tumors. This approach may be used to further characterize intratumor heterogeneity in more patients, and their sample-to sample variations could reveal the evolutionary process of cancer cells, facilitate our understanding of tumorigenesis, and enable the development of novel targeted therapies. PMID- 24403860 TI - Regulation of metformin response by breast cancer associated gene 2. AB - Adenosine monophosphate-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis, has emerged as a promising molecular target in the prevention of breast cancer. Clinical trials using the United States Food and Drug Administration (FDA)-approved, AMPK-activating, antidiabetic drug metformin are promising in this regard, but the question of why metformin is protective for some women but not others still remains. Breast cancer associated gene 2 (BCA2/Rabring7/RNF115), a novel Really Interesting New Gene (RING) finger ubiquitin E3 ligase, is overexpressed in >50% of breast tumors. Herein, we report that BCA2 is an endogenous inhibitor of AMPK activation in breast cancer cells and that BCA2 inhibition increases the efficacy of metformin. BCA2 overexpression inhibited both basal and inducible Thr172 phosphorylation/activation of AMPKalpha1, while BCA2-specific small interfering RNA (siRNA) enhanced phosphorylated AMPKalpha1 (pAMPKalpha1). The AMPK-suppressive function of BCA2 requires its E3 ligase-specific RING domain, suggesting that BCA2 targets some protein controlling (de)phosphorylation of AMPKalpha1 for degradation. Activation of AMPK by metformin triggered a growth inhibitory signal but also increased BCA2 protein levels, which correlated with AKT activation and could be curbed by an AMPK inhibitor, suggesting a potential feedback mechanism from pAMPKalpha1 to pAkt to BCA2. Finally, BCA2 siRNA, or inhibition of its upstream stabilizing kinase AKT, increased the growth inhibitory effect of metformin in multiple breast cancer cell lines, supporting the conclusion that BCA2 weakens metformin's efficacy. Our data suggest that metformin in combination with a BCA2 inhibitor may be a more effective breast cancer treatment strategy than metformin alone. PMID- 24403861 TI - Combining molecular targeted drugs to inhibit both cancer cells and activated stromal cells in gastric cancer. AB - Recent studies have revealed that PDGF plays a role in promoting progressive tumor growth in several cancers, including gastric cancer. Cancer-associated fibroblasts, pericytes, and lymphatic endothelial cells in stroma express high levels of PDGF receptor (PDGF-R); cancer cells and vascular endothelial cells do not. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that increases the production of proteins that stimulate key cellular processes such as cell growth and proliferation, cell metabolism, and angiogenesis. In the present study, we examined the effects of PDGF-R tyrosine kinase inhibitor (nilotinib) and mTOR inhibitor (everolimus) on tumor stroma in an orthotopic nude mice model of human gastric cancer. Expression of PDGF-B and PDGF-Rbeta mRNAs was associated with stromal volume. Treatment with nilotinib did not suppress tumor growth but significantly decreased stromal reactivity, lymphatic invasion, lymphatic vessel area, and pericyte coverage of tumor microvessels. In contrast, treatment with everolimus decreased tumor growth and microvessel density but not stromal reactivity. Nilotinib and everolimus in combination reduced both the growth rate and stromal reaction. Target molecule-based inhibition of cancer stromal cell interaction appears promising as an effective antitumor therapy. PMID- 24403862 TI - Blockade of A2b adenosine receptor reduces tumor growth and immune suppression mediated by myeloid-derived suppressor cells in a mouse model of melanoma. AB - The A2b receptor (A2bR) belongs to the adenosine receptor family. Emerging evidence suggest that A2bR is implicated in tumor progression in some murine tumor models, but the therapeutic potential of targeting A2bR in melanoma has not been examined. This study first shows that melanoma-bearing mice treated with Bay 60-6583, a selective A2bR agonist, had increased melanoma growth. This effect was associated with higher levels of immune regulatory mediators interleukin-10 (IL 10) and monocyte chemoattractant protein 1 (MCP-1) and accumulation of tumor associated CD11b positive Gr1 positive cells (CD11b(+)Gr1(+)) myeloid-derived suppressor cells (MDSCs). Depletion of CD11b(+)Gr1(+) cells completely reversed the protumor activity of Bay 60-6583. Conversely, pharmacological blockade of A2bR with PSB1115 reversed immune suppression in the tumor microenvironment, leading to a significant melanoma growth delay. PSB1115 treatment reduced both levels of IL-10 and MCP-1 and CD11b(+)Gr1(+) cell number in melanoma lesions. These effects were associated with higher frequency of tumor-infiltrating CD8 positive (CD8(+)) T cells and natural killer T (NKT) cells and increased levels of T helper 1 (Th1)-like cytokines. Adoptive transfer of CD11b(+)Gr1(+) cells abrogated the antitumor activity of PSB1115. These data suggest that the antitumor activity of PSB1115 relies on its ability to lower accumulation of tumor-infiltrating MDSCs and restore an efficient antitumor T cell response. The antitumor effect of PSB1115 was not observed in melanoma-bearing nude mice. Furthermore, PSB1115 enhanced the antitumor efficacy of dacarbazine. These data indicate that A2bR antagonists such as PSB1115 should be investigated as adjuvants in the treatment of melanoma. PMID- 24403864 TI - The Development of Referential Communication and Autism Symptomatology in High Risk Infants. AB - Non-verbal referential communication is impaired in children with Autism Spectrum Disorders (ASD). However, the development of difficulties with referential communication in the younger siblings of children with ASD (High-Risk Siblings) and the degree to which early referential communication predicts later autism symptomatology-is not clear. We modeled the early developmental trajectories of three types of referential communication: responding to joint attention (RJA), initiating joint attention (IJA), and initiating behavioral requests (IBR) across 8, 10, 12, 15, and18 months of age in High-Risk Siblings (n = 40) and the infant siblings of children without ASD (Low-Risk Siblings; n = 21). Hierarchical Linear Modeling indicated that High-Risk Siblings exhibited lower levels of baseline RJA and IJA and a lower rate of linear change in IBR than Low-Risk Siblings. When the 10 High-Risk Siblings who received an ASD diagnosis were excluded from analyses, group differences in the development of referential communication remained significant only for RJA. Baseline levels of IJA were associated with later ASD symptomatology among High-Risk Siblings, suggesting that individual differences in referential communication development at 8 months may index early manifestations of ASD. PMID- 24403865 TI - Acculturation and Life Satisfaction Among Immigrant Mexican Adults. AB - The numbers of Mexican Americans living in the United States, many of whom are first generation immigrants, are increasing. The process of immigration and acculturation can be accompanied by stress, as an individual attempts to reconcile two potentially competing sets of norms and values and to navigate a new social terrain. However, the outcomes of studies investigating the relationship between levels of acculturation and well-being are mixed. To further investigate the dynamic of acculturation, this article will address the impact of acculturation and familismo, on reported life satisfaction and resilience among Mexican American adults living in the Southwest (N=307), the majority (89%) of which are immigrants. The findings indicate that bilingual individuals report significantly higher levels of life satisfaction and resilience than their Spanish-speaking counterparts do. Speaking primarily English only predicted higher levels of resilience but not life satisfaction. Implications for social work practice with Mexican American immigrants are discussed. PMID- 24403866 TI - Estimating Second Order Probability Beliefs from Subjective Survival Data. AB - Based on subjective survival probability questions in the Health and Retirement Study (HRS), we use an econometric model to estimate the determinants of individual-level uncertainty about personal longevity. This model is built around the modal response hypothesis (MRH), a mathematical expression of the idea that survey responses of 0%, 50%, or 100% to probability questions indicate a high level of uncertainty about the relevant probability. We show that subjective survival expectations in 2002 line up very well with realized mortality of the HRS respondents between 2002 and 2010. We show that the MRH model performs better than typically used models in the literature of subjective probabilities. Our model gives more accurate estimates of low probability events and it is able to predict the unusually high fraction of focal 0%, 50%, and 100% answers observed in many data sets on subjective probabilities. We show that subjects place too much weight on parents' age at death when forming expectations about their own longevity, whereas other covariates such as demographics, cognition, personality, subjective health, and health behavior are under weighted. We also find that less educated people, smokers, and women have less certain beliefs, and recent health shocks increase uncertainty about survival, too. PMID- 24403867 TI - Visual attention is not enough: Individual differences in statistical word referent learning in infants. AB - Recent evidence shows that infants can learn words and referents by aggregating ambiguous information across situations to discern the underlying word-referent mappings. Here, we use an individual difference approach to understand the role of different kinds of attentional processes in this learning: 12-and 14-month-old infants participated in a cross-situational word-referent learning task in which the learning trials were ordered to create local novelty effects, effects that should not alter the statistical evidence for the underlying correspondences. The main dependent measures were derived from frame-by-frame analyses of eye gaze direction. The fine- grained dynamics of looking behavior implicates different attentional processes that may compete with or support statistical learning. The discussion considers the role of attention in binding heard words to seen objects, individual differences in attention and vocabulary development, and the relation between macro-level theories of word learning and the micro-level dynamic processes that underlie learning. PMID- 24403868 TI - GLIMMPSE: Online Power Computation for Linear Models with and without a Baseline Covariate. AB - GLIMMPSE is a free, web-based software tool that calculates power and sample size for the general linear multivariate model with Gaussian errors (http://glimmpse.SampleSizeShop.org/). GLIMMPSE provides a user-friendly interface for the computation of power and sample size. We consider models with fixed predictors, and models with fixed predictors and a single Gaussian covariate. Validation experiments demonstrate that GLIMMPSE matches the accuracy of previously published results, and performs well against simulations. We provide several online tutorials based on research in head and neck cancer. The tutorials demonstrate the use of GLIMMPSE to calculate power and sample size. PMID- 24403869 TI - Generalized Redistribute-to-the-Right Algorithm: Application to the Analysis of Censored Cost Data. AB - Medical cost estimation is a challenging task when censoring of data is present. Although researchers have proposed methods for estimating mean costs, these are often derived from theory and are not always easy to understand. We provide an alternative method, based on a replace-from-the-right algorithm, for estimating mean costs more efficiently. We show that our estimator is equivalent to an existing one that is based on the inverse probability weighting principle and semiparametric efficiency theory. We also propose an alternative method for estimating the survival function of costs, based on the redistribute-to-the-right algorithm, that was originally used for explaining the Kaplan-Meier estimator. We show that this second proposed estimator is equivalent to a simple weighted survival estimator of costs. Finally, we develop a more efficient survival estimator of costs, using the same redistribute-to-the-right principle. This estimator is naturally monotone, more efficient than some existing survival estimators, and has a quite small bias in many realistic settings. We conduct numerical studies to examine the finite sample property of the survival estimators for costs, and show that our new estimator has small mean squared errors when the sample size is not too large. We apply both existing and new estimators to a data example from a randomized cardiovascular clinical trial. PMID- 24403863 TI - Cancer subclonal genetic architecture as a key to personalized medicine. AB - The future of personalized oncological therapy will likely rely on evidence-based medicine to integrate all of the available evidence to delineate the most efficacious treatment option for the patient. To undertake evidence-based medicine through use of targeted therapy regimens, identification of the specific underlying causative mutation(s) driving growth and progression of a patient's tumor is imperative. Although molecular subtyping is important for planning and treatment, intraclonal genetic diversity has been recently highlighted as having significant implications for biopsy-based prognosis. Overall, delineation of the clonal architecture of a patient's cancer and how this will impact on the selection of the most efficacious therapy remain a topic of intense interest. PMID- 24403870 TI - Role of wnt signaling in the control of adult hippocampal functioning in health and disease: therapeutic implications. AB - It is well recognized the role of the Wnt pathway in many developmental processes such as neuronal maturation, migration, neuronal connectivity and synaptic formation. Growing evidence is also demonstrating its function in the mature brain where is associated with modulation of axonal remodeling, dendrite outgrowth, synaptic activity, neurogenesis and behavioral plasticity. Proteins involved in Wnt signaling have been found expressed in the adult hippocampus suggesting that Wnt pathway plays a role in the hippocampal function through life. Indeed, Wnt ligands act locally to regulate neurogenesis, neuronal cell shape and pre- and postsynaptic assembly, events that are thought to underlie changes in synaptic function associated with long-term potentiation and with cognitive tasks such as learning and memory. Recent data have demonstrated the increased expression of the Wnt antagonist Dickkopf-1 (DKK1) in brains of Alzheimer's disease (AD) patients suggesting that dysfunction of Wnt signaling could also contribute to AD pathology. We review here evidence of Wnt-associated molecules expression linked to physiological and pathological hippocampal functioning in the adult brain. The basic aspects of Wnt related mechanisms underlying hippocampal plasticity as well as evidence of how hippocampal dysfunction may rely on Wnt dysregulation is analyzed. This information would provide some clues about the possible therapeutic targets for developing treatments for neurodegenerative diseases associated with aberrant brain plasticity. PMID- 24403871 TI - Role of presynaptic glutamate receptors in pain transmission at the spinal cord level. AB - Nociceptive primary afferents release glutamate, activating postsynaptic glutamate receptors on spinal cord dorsal horn neurons. Glutamate receptors, both ionotropic and metabotropic, are also expressed on presynaptic terminals, where they regulate neurotransmitter release. During the last two decades, a wide number of studies have characterized the properties of presynaptic glutamatergic receptors, particularly those expressed on primary afferent fibers. This review describes the subunit composition, distribution and function of presynaptic glutamate ionotropic (AMPA, NMDA, kainate) and metabotropic receptors expressed in rodent spinal cord dorsal horn. The role of presynaptic receptors in modulating nociceptive information in experimental models of acute and chronic pain will be also discussed. PMID- 24403872 TI - The effectiveness of treatments for cocaine dependence in schizophrenic patients: a systematic review. AB - OBJECTIVES: To evaluate and compare the effectiveness of available treatments for cocaine dependence in schizophrenic patients. METHOD: We searched articles published between May 2002 and June 2012 in the following databases: Scopus, Pubmed and Web of Knowledge. The key words utilised were "schizophrenia", "dementia praecox", "schizophrenic disorder", "cocaine related disorder", "cocaine abuse", "cocaine addiction", "cocaine dependence", "treatment", "therapeutic", and "drug therapy". SELECTION OF STUDIES AND DATA EXTRACTION: Original articles in English, Portuguese and Spanish were selected. Controlled, double-blind and open-label studies involving only human subjects were included in this review. DATA SYNTHESIS: We found studies on typical and atypical antipsychotics and one monoamine transporter antagonist. There were few indications of the effectiveness of atypical antipsychotic medications for the treatment of cocaine dependence in patients with schizophrenia. CONCLUSIONS: We suggest that further studies be conducted with atypical antipsychotic medicationsand greater methodological strictness, including using a placebo group in the studies, so that health professionals can determine the real effectiveness of this class of medication for the treatment of cocaine dependence in schizophrenic patients. PMID- 24403873 TI - Pyroglutamate-Modified Amyloid Beta Peptides: Emerging Targets for Alzheimer's Disease Immunotherapy. AB - Extracellular and intraneuronal accumulation of amyloid-beta (Abeta) peptide aggregates in the brain has been hypothesized to play an important role in the neuropathology of Alzheimer's Disease (AD). The main Abeta variants detected in the human brain are Abeta1-40 and Abeta1-42, however a significant proportion of AD brain Abeta consists also of N-terminal truncated species. Pyroglutamate modified Abeta peptides have been demonstrated to be the predominant components among all N-terminal truncated Abeta species in AD brains and represent highly desirable and abundant therapeutic targets. The current review describes the properties and localization of two pyroglutamate-modified Abeta peptides, AbetaN3(pE) and AbetaN11(pE), in the brain. The role of glutaminyl cyclase (QC) in the formation of these peptides is also addressed. In addition, two potential therapeutic strategies, the inhibition of QC and immunotherapy approaches, and clinical trials aimed to target these important pathological Abeta species are reviewed. PMID- 24403875 TI - Neurochemicals involved in medullary control of common carotid blood flow. AB - The common carotid artery (CCA) supplies intra- and extra-cranial vascular beds. An area in the medulla controlling CCA blood flow is defined as the dorsal facial area (DFA) by Kuo et al. in 1987. In the DFA, presynaptic nitrergic and/or glutamatergic fibers innervate preganglionic nitrergic and/or cholinergic neurons which give rise to the preganglionic fibers of the parasympathetic 7th and 9th cranial nerves. Released glutamate from presynaptic nitrergic and/or glutamatergic fibers can activate N-methyl-D-aspartate (NMDA) and alpha-amino-3 hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors on preganglionic nitrergic and/or cholinergic neurons. By modulating this glutamate release, several neurochemicals including serotonin, arginine, nitric oxide, nicotine, choline and ATP in the DFA regulate CCA blood flow. Understanding the neurochemical regulatory mechanisms can provide important insights of the physiological roles of the DFA, and may help develop therapeutic strategies for diseases involving CCA blood flow, such as migraine, hypertensive disease, Alzheimer's disease and cerebral ischemic stroke. PMID- 24403874 TI - The Molecular and Pharmacological Mechanisms of HIV-Related Neuropathic Pain. AB - Infection of the nervous system with the human immunodeficiency virus (HIV-1) can lead to cognitive, motor and sensory disorders. HIV-related sensory neuropathy (HIV-SN) mainly contains the HIV infection-related distal sensory polyneuropathy (DSP) and antiretroviral toxic neuropathies (ATN). The main pathological features that characterize DSP and ATN include retrograde ("dying back") axonal degeneration of long axons in distal regions of legs or arms, loss of unmyelinated fibers, and variable degree of macrophage infiltration in peripheral nerves and dorsal root ganglia (DRG). One of the most common complaints of HIV DSP is pain. Unfortunately, many conventional agents utilized as pharmacologic therapy for neuropathic pain are not effective for providing satisfactory analgesia in painful HIV-related distal sensory polyneuropathy, because the molecular mechanisms of the painful HIV-SDP are not clear in detail. The HIV envelope glycoprotein, gp120, appears to contribute to this painful neuropathy. Recently, preclinical studies have shown that glia activation in the spinal cord and DRG has become an attractive target for attenuating chronic pain. Cytokines/chemokines have been implicated in a variety of painful neurological diseases and in animal models of HIV-related neuropathic pain. Mitochondria injured by ATN and/or gp120 may be also involved in the development of HIV neuropathic pain. This review discusses the neurochemical and pharmacological mechanisms of HIV-related neuropathic pain based on the recent advance in the preclinical studies, providing insights into novel pharmacological targets for future therapy. PMID- 24403876 TI - MDMA (3,4-Methylenedioxymethamphetamine) Analogues as Tools to Characterize MDMA Like Effects: An Approach to Understand Entactogen Pharmacology. AB - Besides stimulants and hallucinogens, whose psychotropic effects are shared by many structurally related molecules exhibiting different efficacies and potencies in humans, the phenylisopropylamine MDMA (3,4-methylenedioxymethamphetamine, XTC, "Ecstasy") is the prototypical representative of a separate class of psychotropic substance, able to elicit the so-called entactogenic syndrome in healthy humans. This reversible altered state of consciousness, usually described as an "open mind state", may have relevant therapeutic applications, both in psychotherapy and as a pharmacological support in many neuropsychiatric disorders with a high rate of treatment failure. Nevertheless, a comprehensive and systematic exploration of the structure-activity relationships associated with entactogenic activity has remained incomplete and controversial, highlighting the possibility that MDMA might represent a pharmacological rarity in the field of psychotropics. As the latter is still an open question, the pharmacological characterization of MDMA analogues remains the logical strategy to attempt the elucidation of the structural requirements needed to elicit typical MDMA-like effects. Intriguingly, almost no experimental evidence supports the existence of actual MDMA analogues that truly resemble the whole pharmacological profile of MDMA, probably due to its complex (and partially not fully understood) mechanism of action that includes a disruption of monoaminergic neurotransmission. The present review presents a brief summary of the pharmacology of MDMA, followed by the evidence accumulated over the years regarding the characterization of classical structurally related MDMA analogues in different models and how this state of the art highlights the need to develop new and better MDMA analogues. PMID- 24403879 TI - A rare adrenal incidentaloma: adrenal schwannoma. AB - Adrenal schwannoma is an extremely uncommon cause of incidentaloma. It originates from neural sheath Schwann cells of the adrenal gland. We report the case of a left adrenal schwannoma incidentally discovered in a 32-year-old woman during examination of bloated feeling and stomach ache. The patient was incidentally found to have a left adrenal mass of 9 cm on abdominal ultrasonography. Computed tomography (CT) of the abdomen and [(18)F] fluorodeoxyglucose positron emission tomography (PET) were also performed. Metabolic evaluation was unremarkable. Due to the large size of the tumor, left adrenalectomy was performed. The postoperative course was uneventful. Histological examination established the diagnosis of schwannoma. This diagnosis was supported by immunohistochemistry of S-100 and vimentin positivity. In conclusion, adrenal schwannoma is an extremely rare entity and can grow considerably in size. The present case report emphasizes that clinicians should be aware of the possibility of retroperitoneal schwannoma. Total excision of benign schwannoma is associated with a favorable outcome. To our knowledge, there are case reports of schwannoma with CT and magnetic resonance imaging findings in the literature, although this is the first schwannoma case with PET-CT imaging. PMID- 24403878 TI - Breast reconstruction de novo by water-jet assisted autologous fat grafting--a retrospective study. AB - BACKGROUND: Autologous fat grafting has become a frequent, simple, reproducible and low-risk technique for revisional or partial breast reconstruction. The presented European multicenter study describes an optimized treatment and follow up protocol for the de novo breast reconstruction after total mastectomy by lipotransfer alone. METHODS: A retrospective European multicenter trial included 135 procedures on 28 (35 breasts) postmastectomy patients (mean 52.4 years). All women were treated with the water-jet assisted fat grafting method (BEAULITM) combined with additional procedures (NAC reconstruction, contralateral mastoplasty) and evaluated with at least 6 months follow-up (mean 2.6 years). Sonography or mammography, clinical examination, patient questionnaire (10-point Likert scale) and digital photographs were carried out. RESULTS: On average the patients received 4 to 6 procedures each with a single volume of 159 ml (+/-61 ml) over 21 months (range 9 months to 2.5 years). In total 1,020 ml (+/-515 ml) fat were grafted till a complete breast reconstruction was achieved. Irradiated patients needed a significantly higher volume than non-irradiated (p<0.041). Main treatment complications were liponecrosis (2.59%), infection (0.74%) and granuloma (0.74%). Patient satisfaction was overall high to very high (96%) and confirmed the good aesthetic results (68%) and the natural softness, contour and shape of the reconstructed breast. CONCLUSIONS: A complete breast reconstruction with large volume fat grafting is alternatively possible to standard techniques in selected cases. It takes at least 4 to 6 lipotransfers in the course of 2 years. Patients with prior radiotherapy may require even up to 8 sessions over nearly 3 years of treatment. PMID- 24403880 TI - A retroperitoneal bronchogenic cyst mimicking a pancreatic or adrenal mass. AB - Retroperitoneal location of bronchogenic cysts is extremely rare. Most commonly they are encountered in the posterior mediastinum. Bronchogenic cysts arise from developmental aberrations of the tracheobronchial tree in the early embryologic period. We report a 42-year-old female patient with a retroperitoneal bronchogenic cyst in the left adrenal region. She was admitted to our hospital with epigastric pain and subsequently underwent CT of the abdomen. The examination revealed a mass related to the left adrenal gland. Endocrine tests for adrenal hypersecretion were negative. Because of the uncertain entity, laparoscopic adrenalectomy was performed. Pathological examination revealed a bronchogenic cyst in proximity to an inconspicuous left adrenal gland. Although very rare, bronchogenic cysts should be considered in the differential diagnosis of retroperitoneal cystic lesions and surgical resection pursued for symptom resolution and to establish a definitive histology. PMID- 24403882 TI - Ameboma: a colon carcinoma-like lesion in a colonoscopy finding. AB - Ameboma is a rare complication of amebic colitis presenting as a mass of granulation tissue with peripheral fibrosis and a core of inflammation related to amebic chronic infection. The initial presentations are usually obstruction and low gastrointestinal bleeding. The most common sites are the ascending colon and the cecum. It may mimic colon carcinoma, Crohn's disease, carcinoma of the colon, non-Hodgkin's lymphoma, tuberculosis, fungal infection, AIDS-associated lymphoma and Kaposi's sarcoma in colonoscopy findings. The therapeutic strategy should be combined with antibiotics for invasive dysentery and eradication of luminal cysts. PMID- 24403881 TI - A Case of Adenocarcinoma of the Duodenum Arising from Brunner's Gland. AB - We report a rare case of adenocarcinoma of the duodenum arising from Brunner's gland. A 70-year-old man with a history of hypertension was referred to us with the complaint of abdominal discomfort. Upper gastrointestinal endoscopy revealed an irregular elevated mucosa and a submucosal tumor with delle in the duodenal bulb. Biopsy specimens revealed adenocarcinoma (the former) and hyperplasia (the latter). We could not agree with the patient about performing pancreaticoduodenectomy, so under the diagnosis of primary duodenal carcinoma, we performed resection of the bulbus and the antrum. Pathological examination showed that one of the tumors was consistent with normal Brunner's glands, Brunner's gland hyperplasia and adenocarcinoma arising from Brunner's glands. The patient's postoperative course was good, but 15 months after, he developed lymph node recurrence at the site of the pancreas head. Under the diagnosis of lymph node metastasis of duodenal cancer, we performed pancreaticoduodenectomy this time. Pathological examination confirmed our preoperative diagnosis. The patient remained well after the surgery for 2 years. PMID- 24403877 TI - Neurodevelopment in schizophrenia: the role of the wnt pathways. AB - OBJECTIVES: To review the role of Wnt pathways in the neurodevelopment of schizophrenia. METHODS: SYSTEMATIC PUBMED SEARCH, USING AS KEYWORDS ALL THE TERMS RELATED TO THE WNT PATHWAYS AND CROSSING THEM WITH EACH OF THE FOLLOWING AREAS: normal neurodevelopment and physiology, neurodevelopmental theory of schizophrenia, schizophrenia, and antipsychotic drug action. RESULTS: Neurodevelopmental, behavioural, genetic, and psychopharmacological data point to the possible involvement of Wnt systems, especially the canonical pathway, in the pathophysiology of schizophrenia and in the mechanism of antipsychotic drug action. The molecules most consistently found to be associated with abnormalities or in antipsychotic drug action are Akt1, glycogen synthase kinase3beta, and beta catenin. However, the extent to which they contribute to the pathophysiology of schizophrenia or to antipsychotic action remains to be established. CONCLUSIONS: The study of the involvement of Wnt pathway abnormalities in schizophrenia may help in understanding this multifaceted clinical entity; the development of Wnt related pharmacological targets must await the collection of more data. PMID- 24403883 TI - Repeated pancreatectomy for metachronous duodenal and pancreatic metastases of renal cell carcinoma. AB - A 50-year-old woman had undergone left nephrectomy for renal cell carcinoma 13 years previously. Ten years later, a solitary metastatic tumor had been detected in the pancreatic tail and she had undergone subsequent resection of the pancreatic tail and spleen. Three years after surgery, she was admitted to our hospital for severe anemia resulting from gastrointestinal tract bleeding. Esophagogastroduodenoscopy revealed a 3-cm solid tumor at the oral side of the papilla of Vater. Histology of the bioptic duodenal tissue revealed inflammatory granulation without malignancy. Computed tomography showed a well-contrasted hypervascular tumor in the descending portion of the duodenum. We diagnosed the patient with metachronous duodenal metastasis of renal cell carcinoma and performed a pancreaticoduodenectomy. An ulcerated polypoid mass was detected at the oral side of the papilla of Vater. Histology revealed clear cell carcinoma coated by granulation tissue across the surface of the tumor. Immunohistology demonstrated that the cells were positive for vimentin, CD10 and epithelial membrane antigen and negative for CK7. After a repeated pancreatectomy, the patient had no symptoms of gastrointestinal bleeding and maintained good glucose tolerance without insulin therapy because the remnant pancreas functioned well. In conclusion, for the diagnosis of patients who have previously undergone nephrectomy and present with gastrointestinal bleeding, the possibility of metastasis to the gastrointestinal tract, including the duodenum, should be considered. With respect to surgical treatment, the pancreas should be minimally resected to maintain a free surgical margin during the first surgery taking into account further metachronous metastasis to the duodenum and pancreas. PMID- 24403884 TI - Small-sized, flat-type invasive branch duct intraductal papillary mucinous neoplasm: a case report. AB - Recent improvements in diagnostic modalities are increasing the frequency of detection of small-sized branch duct intraductal papillary mucinous neoplasms (BD IPMNs). International consensus guidelines for IPMN recommend surveillance without immediate resection for small-sized (<3 cm) BD-IPMNs without malignant features on imaging. Our patient is the first to have undergone resection of a small-sized BD-IPMN containing invasive cancer, but without malignant features on imaging. We herein report a case involving a 70-year-old man with a small cystic lesion in the pancreas head detected by health screening ultrasonography. Detailed examination revealed that the cystic lesion was a BD-IPMN measuring about 2 cm, with no malignant features. However, cytological examination of the pancreatic juice showed atypical cells with high-grade dysplasia storing intracytoplasmic mucin, indicating malignant BD-IPMN. Pathological examination of the resected specimen showed a BD-IPMN measuring 16 mm with an associated invasive carcinoma that invaded the pancreatic parenchyma over a distance of 11 mm. In this patient, invasive cancer was present within a small BD-IPMN with no high-risk stigmata on imaging. Cytological examination of the pancreatic juice allowed for the detection of pancreatic cancer in such a small-sized IPMN. Although routine endoscopic retrograde cholangiopancreatography (ERCP) with cytology is not recommended in all patients with BD-IPMNs, ERCP may contribute to the detection of small pancreatic cancers in select cases. Accumulation of cases of pancreatic cancer within small BD-IPMNs may help establish the indications for ERCP with cytological examination for the purpose of early detection of small pancreatic cancer. PMID- 24403885 TI - Cauda equina syndrome secondary to complicated diverticulitis. AB - A 58-year-old woman presented to the emergency department with cauda equina syndrome and sepsis. The symptoms were attributed to a complicated episode of sigmoid diverticulitis. MRI showed that the diverticulitis had caused an intra abdominal fistula to a presacrally localized abscess expanding into the spinal canal, compressing the cauda equina nerves. Although Hartmann's procedure was performed, the neurological symptoms persisted, causing the patient to remain partially paraplegic. This case report illustrates that cauda equina syndrome is a condition that can also be caused by intra-abdominal pathology such as diverticulitis. PMID- 24403886 TI - Anastomotic Recurrence of Sigmoid Colon Cancer over Five Years after Surgery. AB - The incidence of anastomotic recurrence after curative resection of colorectal cancer is relatively low compared to that of other types of recurrence, such as hepatic, lung and local recurrence. However, almost all cases of anastomotic recurrence of colorectal cancer occur within 3 years after surgery. We experienced a rare case of anastomotic recurrence in whom colonoscopy revealed no signs of recurrence 3 years after surgery; however, anastomotic recurrence was detected over 5 years after surgery. A 60-year-old female with a history of surgery for cancer of the cecum in her forties underwent sigmoidectomy and right colectomy with D3 lymph node dissection for both stage IIA sigmoid colon cancer and stage IIA transverse colon cancer. Computed tomography and colonoscopy revealed no signs of recurrence 3 years after surgery; however, 5 years and 4 months after surgery, colonoscopy demonstrated surrounding flaring and swelling in the anastomotic area of the sigmoid colon, and a biopsy revealed an adenocarcinoma. Under the diagnosis of anastomotic recurrence over 5 years after surgery, lower anterior resection was performed. The patient has exhibited no other signs of recurrence in the 2 years since the last operation. PMID- 24403887 TI - Balloon against Jackhammer Disorder. AB - We describe a patient with dysphagia. The results of endoscopy, CT scan and echoendoscopy were normal. High-resolution manometry (HRM) showed esogastric junction dysfunction and hypercontractile peristaltic disorder. These HRM abnormalities completely disappeared after pneumatic esophageal dilatation. We discuss the treatment options and recovery of peristalsis after balloon dilatation. PMID- 24403888 TI - Eccrine porocarcinoma: clinical and pathological report of eight cases. AB - BACKGROUND: Eccrine porocarcinoma (EPC), a slow-growing carcinoma of the sweat gland, is a rare condition documented only in a small number of case series. Due to its rarity, guidelines and specific recommendations are not widely available. Accordingly, many dermatologists encounter difficulty in diagnosing and treating EPC. The aim of this study is to report the clinical and pathological features of EPC in order to contribute to the body of information currently available on the subject. PATIENTS AND METHODS: From 2003 to 2013, 8 Japanese patients were diagnosed with EPC at the Department of Dermatology in the Hachioji Medical Center of Tokyo Medical University. Patient data, including clinical manifestations, histopathological findings, immunohistochemical results, treatment method, and clinical course were collected and documented. RESULTS: The mean age of the patients (6 males and 2 females) was 72.6 years. The duration of the lesions ranged from 4 months to 5 years (mean: 3.5 years). All of the lesions clinically presented with erosive reddish nodules (mean size: 39.0 mm). Initial CT imaging revealed that 1 case had multiple distant metastases. Surgical resection was performed for all primary lesions and follow-up observations were available in all cases (mean: 10.9 months). One case with distal metastases underwent both radiation therapy and chemotherapy, but nevertheless succumbed to the disease. CONCLUSION: The EPC cases in our department presented a versatile clinical appearance and characteristic histopathological features. PMID- 24403889 TI - Tenosynovial giant cell tumor arising on the scapular region. AB - Tenosynovial giant cell tumor (TSGCT) is a benign soft tissue tumor arising from the synovial membrane that composes the lining of joints, tendons and bursae. TSGCT is a common tumor occurring in the hands and fingers, and also consecutively in the knees, ankles, feet and hips. It is rarely found in the scapular region. To the best of our knowledge, only 2 cases arising on the upper back have been reported. This report presents the case of a 44-year-old Japanese female with a TSGCT arising on her right scapular region. PMID- 24403890 TI - Fatal metastatic cutaneous squamous cell carcinoma evolving from a localized verrucous epidermal nevus. AB - A malignant transformation is known to occur in many nevi such as a sebaceous nevus or a basal cell nevus, but a verrucous epidermal nevus has only rarely been associated with neoplastic changes. Keratoacanthoma, multifocal papillary apocrine adenoma, multiple malignant eccrine poroma, basal cell carcinoma and cutaneous squamous cell carcinoma (CSCC) have all been reported to develop from a verrucous epidermal nevus. CSCC has also been reported to arise from other nevoid lesions like a nevus comedonicus, porokeratosis, a sebaceous nevus, an oral sponge nevus and an ichthyosiform nevus with CHILD syndrome. Here we report a case of progressive poorly differentiated CSCC arising from a localized verrucous epidermal nevus, which caused both spinal cord and brain metastasis. PMID- 24403891 TI - Disseminated superficial actinic porokeratosis on the face treated with imiquimod 5% cream. AB - Porokeratoses are a group of hereditary or acquired disorders characterized by annular lesions with an atrophic center and a prominent peripheral ridge. Pathologically, porokeratosis is characterized by the presence of abnormal clones of keratinocytes that form a column of parakeratotic cells, called the cornoid lamella. Fifteen percent of patients of disseminated superficial actinic porokeratosis (DSAP) have facial lesions; other regions like the extensor surface of extremities constitute the majority of reported cases. Exclusively facial lesions are probably less frequent. Rarely, actinic porokeratosis is confined to the nose only. Of reported porokeratosis cases, 7.5% have revealed a malignancy arising within the lesion. We present a case of facial sporadic DSAP that was treated with imiquimod 5% cream in conjunction with a regular sunscreen. Follow up of this case is important to rule out the possibility of malignant transformation of the lesions. PMID- 24403892 TI - Nodal Melanoma Metastasis under Infliximab Therapy in a Patient with Nevoid Melanoma First Misdiagnosed as Benign Nevus: A Potentially Dangerous Diagnostic Pitfall in the Era of Biologic Therapies. AB - We report the case of a 53-year-old Caucasian woman who developed nodal melanoma metastasis under infliximab therapy 2 years after the removal of a nevoid melanoma, which was initially misdiagnosed as a benign compound nevus. This case illustrates the potential link between tumor necrosis factor (TNF)-alpha inhibition and the reactivation of latent melanoma. Furthermore, this case highlights the need for a complete skin examination before using anti-TNF-alpha therapy to rule out atypical malignant lesions or melanomas that can easily be missed because of presentations such as nevoid melanoma. PMID- 24403893 TI - Facial pyoderma gangrenosum in senescence. AB - Clinically, pyoderma gangrenosum (PG) is characterized by a rapidly progressive, painful cutaneous ulcer with an irregular, violaceous and undermined border. PG occurs most frequently on the lower extremities and the trunk of middle-aged individuals. The face is only very rarely affected. We present an 89- and a 90 year-old patient, who developed a facial ulcer consistent with PG. PMID- 24403894 TI - Incidental finding of lamellar calcification of the falx cerebri leading to the diagnosis of gorlin-goltz syndrome. AB - Here, we report the case of an incidental finding of lamellar calcification of the falx cerebri in a routine computed tomography scan of the head after an accidental trauma. This lamellar calcification led to the diagnosis of Gorlin Goltz syndrome (GGS) in the patient and her daughter. Lamellar calcification of the falx cerebri is a pathognomonic feature of GGS. Our case report highlights the importance of a multidisciplinary diagnostic approach to GGS. PMID- 24403895 TI - PET-Negative Gastrointestinal Stromal Tumors. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal malignancy of the gastrointestinal tract. PET/CT is a common diagnostic tool and is also used for therapy monitoring. GISTs typically show strong (18)F fluorodeoxyglucose (FDG) uptake. Here we present two cases of GIST with unusually low/negative FDG uptake. FDG negativity does not preclude the diagnosis of a GIST. PMID- 24403896 TI - Male breast adenoid cystic carcinoma. AB - INTRODUCTION: Adenoid cystic carcinoma (ACC) of the breast is a rare condition, and cases in male patients are even less common. CASE: We describe a case of ACC of the breast with axillary lymph node metastasis, disseminated osteolytic bone metastasis and bone marrow involvement in a 41-year-old man. CONCLUSION: Male breast ACC is an extremely rare malignancy; there can be difficulty in obtaining a final diagnosis. We report this case because of its rarity. PMID- 24403897 TI - A case of severe ganciclovir-induced encephalopathy. AB - BACKGROUND: Ganciclovir, a drug against cytomegalovirus (CMV) infection, is generally well tolerated, but can cause neurotoxicity such as encephalopathy. Although ganciclovir-induced encephalopathy has been described in several reports, a literature search revealed that ganciclovir concentrations in the blood or cerebrospinal fluid were previously measured in only 3 patients with encephalopathy. Symptoms usually include confusion and disturbed consciousness, which mimic CMV encephalitis. Prompt and accurate diagnosis is thus sometimes difficult, and is derived solely from accumulated clinical information of definite cases, since ganciclovir concentrations, not routinely measured, become available after several days or a few weeks. CASE PRESENTATION: Here, we summarize clinical information of all patients with definite ganciclovir-induced encephalopathy including our own patient, who had severe symptoms, with the highest reported trough concentration of ganciclovir in the blood, and underwent therapeutic dialysis with complete recovery. CONCLUSION: Our summary of patients with definite encephalopathy could lead to prompt and accurate diagnoses. PMID- 24403898 TI - Intratarsal keratinous cyst - an emerging entity. AB - We report two cases of recurrent intratarsal keratinous cysts of the Meibomian gland, a recently described lesion thought to have been previously misdiagnosed. The correct diagnosis can be made based on histopathologic features alone, although expression of cytokeratin (CK) 5/6 in the cyst epithelium is a specific marker of these lesions. Recognition of these lesions, and distinguishing them from other intratarsal cysts that do not recur, is important to guide definitive therapy via full-thickness excision rather than simple incision and drainage. PMID- 24403899 TI - Retinal pigment epithelium tear after vitrectomy for vitreomacular traction syndrome in an eye with retinal angiomatous proliferation. AB - An 87-year-old Japanese man presented with retinal angiomatous proliferation (RAP) and a retinal pigment epithelium (RPE) detachment in his right eye. His decimal best-corrected visual acuity was 0.15 in the right eye, and optical coherence tomography (OCT) showed a vitreomacular adhesion in the right eye as well. After 3 monthly intravitreal injections of ranibizumab, the size and height of the RPE detachment was significantly reduced. The accumulated intra- and subretinal fluid also disappeared, but the vitreomacular traction remained. Pars plana vitrectomy was performed, and the posterior hyaloid was separated from the retina with a vitrectomy cutter without any intraoperative complications. Two months after the surgery, a large RPE tear was observed over the macular area. His visual acuity decreased to 0.06 and remained unchanged thereafter. We suggest that the small tear led to the larger RPE tear because vitreomacular traction was transmitted to the RPE through the fibrovascular tissue of the RAP during the creation of the hyaloid detachment. Because such an RPE tear has not been reported after vitrectomy for vitreomacular traction, surgeons need to pay special attention to this potential complication in eyes with vitreomacular traction and RAP. PMID- 24403900 TI - A case of acute posterior multifocal placoid pigment epitheliopathy demonstrating vogt-koyanagi-harada disease-like optical coherence tomography findings in the acute stage. AB - PURPOSE: We report a case of acute posterior multifocal placoid pigment epitheliopathy (APMPPE), which was difficult to differentiate from posterior pole type Vogt-Koyanagi-Harada (VKH) disease because the lesions were mainly located in the macula bilaterally. CASE REPORT: A 33-year-old man presented with rapid bilateral loss of vision. Fundoscopy revealed yellow-white subretinal lesions in the posterior pole of both eyes. Optical coherence tomography (OCT) revealed the presence of subretinal fluid with a subretinal septum. After initiation of systemic steroids, OCT revealed that the amount of subretinal fluid decreased immediately. However, vision loss was less responsive to the therapy, and OCT revealed partial reorganization of the inner segment/outer segment (IS/OS) line in the bilateral macular areas after therapy. DISCUSSION: In our case, the location of the macular lesions made it difficult to differentiate APMPPE from VKH disease by fluorescein angiography. OCT images showed VKH disease-like findings of serous retinal detachment with a subretinal septum. The outer nuclear layer disappeared and the IS/OS line in the affected area was disorganized in the acute stage of the disease. In this case, the rapid loss of vision was specific to the onset pattern of APMPPE, and the slow response to therapy was very different from the response typically observed in VKH disease. Thus, careful consideration of the clinical course is important for diagnosing APMPPE. PMID- 24403901 TI - Negative g-Force Ocular Trauma Caused by a Rapidly Spinning Carousel. AB - We present a case of a 10-year-old boy who presented with bilateral diffuse subconjunctival hemorrhages after spinning rapidly on a carousel attached to an electrical scooter. We present his clinical course and discuss the physics and pathophysiology of this unique mechanism of ocular trauma. PMID- 24403902 TI - Restoration of severely impaired eyesight in an adolescent with down syndrome and bilateral cataract in South Asia. AB - PURPOSE: To report the recovery of visual function after phacoemulsification in a 16-year-old adolescent with Down syndrome (DS) from Saharsa, India. METHODS: Interventional case report and short review of the pertinent literature. RESULTS: A 16-year-old South Asian male with DS and bilateral cataract underwent successful surgery in both eyes after considerable difficulty for his parents including cross-border travel from India into Nepal. After the operation, the patient responded to visual stimuli (e.g. movement of hands) that had eluded him prior to surgery, and thus the additional obstacle to social participation imposed by the impaired eyesight could be removed. CONCLUSIONS: The establishment of basic ophthalmological surgery in developing countries is feasible and can yield extraordinary benefits for individual patients. PMID- 24403903 TI - A daily glass of red wine and lifestyle changes do not affect arterial blood pressure and heart rate in patients with carotid arteriosclerosis after 4 and 20 weeks. AB - BACKGROUND: Regular consumption of small amounts of red wine improves blood lipids. However, there is concern whether this beneficial effect might be counterbalanced by an increase in blood pressure (BP) and heart rate (HR), which are risk factors for cerebro-cardiovascular disease. In particular, we studied whether regular consumption of red wine with and without lifestyle changes (LC; healthy diet and physical activity advice) results in an increase in BP and HR. METHODS: A prospective, unblinded randomized trial was performed in 108 patients (67% men) with carotid atherosclerosis documented by ultrasound, a mean BP of 122/79 mm Hg and a mean HR of 71 bpm at inclusion in the study. Sixty-eight percent were known and treated hypertensives. The mean 24-hour BP at baseline was 122/79 mm Hg. Half of the study participants, the control group, was seen by a nurse at baseline, after 4 and after 20 weeks, and was instructed not to change their eating and physical activity habits. In the other half, a dietician performed five sessions of 30 min each (at baseline, after 1 week and after 2, 3 and 4 weeks) giving advice on healthy eating based on a Mediterranean diet and physical exercise. The recommendations given were the following: 5 portions of fruit/vegetables per day, a diet low in absolute fat, a preference of vegetable oil (olive or rapeseed oil), whole-grain products, poultry, low-fat dairy products, 1 fat and 1 lean fish meal per week, reduced consumption of red meat, and avoidance of pork, ready-made meals, sugar and excessive salt intake. In addition, regular consumption of 1 bar of dark chocolate (25 g, >70% of cacao), 1 2 tomatoes, and 3-5 walnuts as well as at least 30 min of moderate daily physical activity were recommended. Within these two groups, half of the patients were randomized either to avoid alcohol completely or to drink 100 ml (women) or 200 ml of red wine (men) daily. RESULTS: Neither LC nor red wine had an effect on the mean systolic and diastolic 24-hour BP and HR after 4 and 20 weeks, as analyzed by general linear modeling. No difference was found for diurnal and nocturnal values. CONCLUSIONS: The possible beneficial effect of regular consumption of small amounts of red wine is not counterbalanced in the long term by an increase in the mean BP or HR in mainly normotensive and well-treated hypertensive patients with carotid atherosclerosis, neither in the patients given healthy lifestyle advice nor in those with a standard lifestyle. Yet, we remain cautious about actively advice patients to drink alcohol regularly given the well-known risks. PMID- 24403904 TI - Magnetic Resonance Imaging versus Computed Tomography in Transient Ischemic Attack and Minor Stroke: The More Upsilonou See the More You Know. AB - BACKGROUND: Magnetic resonance imaging (MRI) is proposed as the preferred imaging modality to investigate patients with transient ischemic attack (TIA). This is mainly based on a higher yield of small acute ischemic lesions; however, direct prospective comparisons are lacking. In this study, we aimed to directly compare the yield of acute ischemic lesions on MRI and computed tomography (CT) in the emergency diagnosis of suspected TIA or minor stroke. METHODS: Consecutive patients aged 18 years or older presenting with minor stroke (NIHSS <4) or high risk TIA and who were examined by a stroke neurologist within 24 h of symptom onset were prospectively enrolled in the CATCH study. Patients who had undergone both a baseline CT and an MRI within 24 h of symptom onset were included in this substudy. Baseline MRI and CT were interpreted independently to identify an acute ischemic lesion. The rates of acute ischemic lesions on CT and MRI were compared, and the volume of acute ischemic lesions was measured on MRI. In addition, the volume of acute ischemic lesions on MRI was compared between patients who had evidence of acute ischemia on CT and in those who did not. RESULTS: A total of 347 patients were included, 168 with TIAs, 147 with minor strokes and 32 with a final diagnosis of a mimic. Acute ischemic lesions were detected in 39% of TIAs by using MRI versus 8% by using CT (p < 0.0001) and in 86% of minor strokes by using MRI versus 18% by using CT (p < 0.0001). Compared to MRI, CT had a sensitivity of 20% and a specificity of 98% in identifying an acute ischemic lesion. The infarct volume on diffusion-weighted MRI was larger in cases where the CT also showed an acute ischemic lesion (median 5.07 ml, IQR 10) as compared to lesions seen only on MRI (median 0.68 ml, IQR 1.31, p < 0.0001). CONCLUSION: MRI is superior to CT in detecting the small ischemic lesions occurring after TIA and minor stroke. Since these lesions are clinically relevant, MRI should be the preferred imaging modality in this setting. PMID- 24403905 TI - Postpartum four-vessel cervical artery dissection. AB - A postpartum four-vessel cervical artery dissection with no stroke is reported. This transient vasculopathy took place in the autoimmune context of the HELLP syndrome combined with the reversible posterior leucoencephalopathy syndrome. Correlations between the clinical, radiological and biological entities are discussed. PMID- 24403906 TI - Context memory in Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease characterized by a gradual loss of memory. Specifically, context aspects of memory are impaired in AD. Our review sheds light on the neurocognitive mechanisms of this memory component that forms the core of episodic memory function. SUMMARY: Context recall, an element of episodic memory, refers to remembering the context in which an event has occurred, such as from whom or to whom information has been transmitted. KEY MESSAGES: Our review raises crucial questions. For example, (1) which context element is more prone to being forgotten in the disease? (2) How do AD patients fail to bind context features together? (3) May distinctiveness heuristic or decisions based on metacognitive expectations improve context retrieval in these patients? (4) How does cueing at retrieval enhance reinstating of encoding context in AD? By addressing these questions, our work contributes to the understanding of the memory deficits in AD. PMID- 24403907 TI - Evaluation of Anosognosia in Alzheimer's Disease Using the Symptoms of Early Dementia-11 Questionnaire (SED-11Q). AB - AIMS: The objective is to propose a brief method to evaluate anosognosia in Alzheimer's disease (AD) using the Symptoms of Early Dementia-11 Questionnaire (SED-11Q), a short informant-based screening questionnaire for identifying dementia. METHODS: The participants were 107 elderly individuals: 13 with a Clinical Dementia Rating (CDR) of 0.5, 73 with mild AD of CDR 1, and 21 with moderate AD of CDR 2. The patients and caregivers answered the SED-11Q independently, and the degree of discrepancy indicated the severity of anosognosia. RESULTS: THE SCORES WERE AS FOLLOWS: caregiver scores were 2.46 +/- 1.85 (mean +/- SD) in CDR 0.5, 6.36 +/- 3.02 in CDR 1, and 9.00 +/- 1.14 in CDR 2; patient scores were 2.00 +/- 1.78, 2.55 +/- 2.33, and 1.33 +/- 2.46, respectively. Discrepancy was 0.46 +/- 1.61, 3.81 +/- 3.95, and 7.67 +/- 2.87, respectively, and the caregiver assessments were significantly higher than the patient assessments in CDR 1 and CDR 2 (p < 0.001 in both groups). The SED-11Q for anosognosia was validated with the standardized Anosognosia Questionnaire for Dementia (AD-Q). The caregiver scores were moderately correlated with behavioral and psychological symptoms of dementia scores (r = 0.524), and the patient scores were moderately correlated with depression scores (r = 0.561). CONCLUSION: The SED-11Q serves a dual purpose: caregiver assessment is useful for the screening of dementia, and any discrepancy between the patient and the caregiver assessment is considered as an indication of the severity of anosognosia; this can be informative for caregivers and essential for successful care. PMID- 24403908 TI - Special care units and traditional care in dementia: relationship with behavior, cognition, functional status and quality of life - a review. AB - BACKGROUND: Special care facilities for patients with dementia gain increasing attention. However, an overview of studies examining the differences between care facilities with respect to their effects on behavior, cognition, functional status and quality of life is lacking. RESULTS: Our literature search resulted in 32 studies published until October 2012. Overall, patients with dementia who lived at special care units (SCUs) showed a significantly more challenging behavior, more agitation/aggression, more depression and anxiety, more cases of global cognitive impairment and a better psychosocial functioning. There was a tendency towards a better functional status in specialized care facilities, and a better quality of life was found in favor of the SCU group compared to the traditional nursing home (n-SCU) group. Longitudinal studies showed an increased number of neuropsychiatric cases, more patients displaying deteriorating behavior and resistance to care as well as less decline in activities of daily living (ADL) in the SCU group compared to the n-SCU group. Patients in small-scale, homelike SCUs showed more agitation and less ADL decline compared to SCU patients. CONCLUSION: This review shows that the patient characteristics in SCU and n-SCU settings and, to a minor extent, in SCU and small-scale, homelike SCU settings are different. Over time, there are differences between n-SCU, SCU and small-scale, homelike SCU facilities for some variables. PMID- 24403909 TI - Clinical utility of short social cognitive tests in early differentiation of behavioral variant frontotemporal dementia from Alzheimer's disease. AB - BACKGROUND: Traditional cognitive tests used in clinical practice may not be sensitive enough for the early differentiation of behavioral variant frontotemporal dementia (bvFTD) from Alzheimer's disease (AD). A growing body of literature has shown that deficits in various aspects of social cognition can be found in bvFTD. AIM: The objective of this study is to investigate whether short and easily administered tests of social cognition are useful in providing clinical information which might aid in the differentiation of bvFTD from AD in the early stages of bvFTD. METHODS: 11 patients diagnosed with bvFTD and 10 patients diagnosed with AD completed a neuropsychological assessment comprising global, executive and social cognitive tasks. RESULTS: Measures of global cognitive function showed no significant difference between the two groups, whereas even the short social cognitive measures (the Reading the Mind in the Eyes Test and the Emotion Hexagon) showed significant group differences, reflecting a poorer performance by the bvFTD group. CONCLUSION: Our results suggest that it may indeed be relevant to include short and easily administered measures of social cognition in the differential diagnosis of early bvFTD and AD. PMID- 24403910 TI - A comparison of systemic inflammation-based prognostic scores in patients on regular hemodialysis. AB - BACKGROUND/AIMS: Systemic inflammation-based prognostic scores have prognostic power in patients with cancer, independently of tumor stage and site. Although inflammatory status is associated with mortality in hemodialysis (HD) patients, it remains to be determined as to whether these composite scores are useful in predicting clinical outcomes. METHODS: We calculated the 6 prognostic scores [Glasgow prognostic score (GPS), modified GPS (mGPS), neutrophil-lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), prognostic index (PI) and prognostic nutritional index (PNI), which have been established as a useful scoring system in cancer patients. We enrolled 339 patients on regular HD (age: 64 +/- 13 years; time on HD: 129 +/- 114 months; males/females = 253/85) and followed them for 42 months. The area under the receiver-operating characteristics curve was used to determine which scoring system was more predictive of mortality. RESULTS: Elevated GPS, mGPS, NLR, PLR, PI and PNI were all associated with total mortality, independent of covariates. If GPS was raised, mGPS, NLR, PLR and PI were also predictive of all-cause mortality and/or hospitalization. GPS and PNI were associated with poor nutritional status. Using overall mortality as an endpoint, the area under the curve (AUC) was significant for a GPS of 0.701 (95% CI: 0.637-0.765; p < 0.01) and for a PNI of 0.616 (95% CI: 0.553-0.768; p = 0.01). However, AUC for hypoalbuminemia (<3.5 g/dl) was comparable to that of GPS (0.695, 95% CI: 0.632-0.759; p < 0.01). CONCLUSION: GPS, based on serum albumin and highly sensitive C-reactive protein, has the most prognostic power for mortality prediction among the prognostic scores in HD patients. However, as the determination of serum albumin reflects mortality similarly to GPS, other composite combinations are needed to provide additional clinical utility beyond that of albumin alone in HD patients. PMID- 24403911 TI - ALTERED BLOOD SPHINGOLIPIDOMICS AND ELEVATED PLASMA INFLAMMATORY CYTOKINES IN COMBAT VETERANS WITH POST-TRAUMATIC STRESS DISORDER. AB - Patients with post-traumatic stress disorder (PTSD) have greater risk of developing cardiovascular disease (CVD). While chronically elevated plasma cholesterol and pro-inflammatory cytokines levels increase CVD risk, several studies have shown that cholesterol reduction does not reduce CVD risk. Acid sphingomyelinase (ASMase) activation has been implicated in both CVD and major depressive disorder. We investigated plasma pro-inflammatory cytokine levels, ASMase activity, and changes in sphingolipids in PTSD patients compared to healthy controls. Levels of interleukin 6, interleukin 10, interferon-gamma and tumor necrosis factor-alpha were higher in PTSD patients than controls. Plasma ASMase activity and sphingosine 1-phosphate were higher in the PTSD group (1.6 fold and 2-fold, respectively; p<0.05). The results suggest that CVD risk factors in PTSD patients remain high despite cholesterol reduction. PMID- 24403912 TI - A Study of CC-Chemokine Receptor 5 (CCR5) Polymorphism on the Outcome of HCV Therapy in Egyptian Patients. AB - BACKGROUND: Chronic hepatitis C virus (HCV) infection is a globally serious public health issue. OBJECTIVES: In this study, we investigated CC chemokine receptor 5 (CCR5-59029) polymorphism which is considered an important component of the immune system in determining the outcome of HCV infection. Its critical role as a marker in response to interferon therapy of HCV infection is also investigated besides its effect on other clinical patient factors. PATIENTS AND METHODS: This study was conducted on 82 Egyptian patients with chronic Hepatitis C Virus (HCV) infection who received PEG-INF + Ribavirin treatment for 48 weeks. The study was also conducted on 50 healthy controls (with negative results for HCV antibody and RNA PCR). Full history of patients in this study was recorded. Clinical and histological examinations, qualitative HCV nested RT-PCR, quantitative real -time PCR, and genotyping of HCV RNA genome were performed. CCR5-59029 polymorphism with nucleotide substitution from G to A was amplified. The amplicons were digested with restriction endonuclease Bsp 1286I, and produced RFLPs of the CCR5 genotypes were determined. RESULTS: The present study showed a significant association between the functional SNP of CCR5 gene and the viral response to interferon in chronic HCV Egyptian patients. It was shown that the higher fibrosis stages (F2-F4) had significant association with nonresponse to treatment compared to the lower fibrosis stages (F0-F1) (95% confidence: 5.497 - 55.074, P = 0.0001). In addition, worse liver activity grade (A2-A3) had a very highly significant association with non-responder HCV patients compared to those with better liver activity grade (A1) (95% confidence: 2.242 - 20.974, P = 0.0007). Most importantly HCV patients with G allele had a high significant association with nonresponse to treatment, higher fibrosis stages and worse liver activity grades, while the A allele had a high significant association with sustained response, low fibrosis stages and relatively better liver activity grade (95% confidence: 3.347 - 15.036, P = 0.0001). CONCLUSIONS: SNPs within the CCR5 gene should be considered as an important factor used in combination with other host gene SNPs when developing a mathematical model for anticipating response to HCV therapy. PMID- 24403913 TI - Hyaluronic Acid: from biochemical characteristics to its clinical translation in assessment of liver fibrosis. AB - CONTEXT: Hyaluronic acid (HA) is a high molecular weight polysaccharide that is distributed in all bodily tissues and fluids. The liver is the most important organ involved in the synthesis and degradation of HA. Research has shown that liver cell injury can affect serum HA levels. In this review, authors aimed to describe the biochemical and physiological roles of this glycosaminoglycan and its changes in various liver diseases. EVIDENCE ACQUISITION: Liver fibrosis and in more severe form, cirrhosis are results of an imbalance between fibrogenesis and fibrinolysis. Liver biopsy is the gold standard to assess liver necro inflammatory injuries. This method is invasive and has some major side effects; therefore it is an unfavorable method for both physicians and patients. Now, a wide variety of noninvasive methods have been introduced based on evaluating serum level of different markers. They are safe, readily available, and more favorable. Serum HA levels are used by some researchers to assess stages of liver fibrosis. RESULTS: There are several scientific studies indicating HA as a biomarker for high score fibrosis and cirrhosis in various liver diseases alone or in algorithm models. It seems from various algorithm models that the use of HA as a major constituent has more diagnostic reliability and accuracy than the use of HA alone. CONCLUSIONS: Use of HA in an algorithm model, is an extra and valuable tool for assessing liver necro inflammatory injuries- in parallel with liver biopsy- but more comprehensive studies are needed to approve the use of HA as an appropriate clinical tool. PMID- 24403914 TI - Distribution of hepatitis C virus genotypes among patients with hepatitis C virus infection in hormozgan, iran. AB - BACKGROUND: More than 170 million people in the world are infected with Hepatitis C virus (HCV). Determination of HCV genotype before starting the treatment is required, because HCV genotype affects the course of treatment and drug dosage. OBJECTIVES: We aimed to evaluate HCV genotypes among patients with positive results for anti-HCV in Bandar Abbas from 2011 to 2012. PATIENTS AND METHODS: Five hundred and nine consecutive patients with established chronic HCV infection referred to Behavioral Diseases Consultation Center, Blood Transfusion and Center for Special Diseases from March 2011 to March 2012 were enrolled in this cross sectional study. Five mL of peripheral blood was taken from precipitants and viral RNA extracted after plasma separation. Hepatitis C virus RNA was detected by reverse transcriptase-nested polymerase chain reaction (RT-nested PCR) assay and then HCV genotypes analyzed using restriction fragment length polymorphism (RFLP) method. RESULTS: In overall, 509 patients enrolled to this study. The mean age of these patients was 38.87 +/- 9.55 years ranging from 1 to 90 years. Routs of transmission were: 238 (46.7%) inject of substance, 149 (29.3%) unknown rout, 62 (12.2%) blood transfusion, 50 (9.8%) sexual contact, and 10 (2%) mother to child. Frequency of HCV genotypes were: 316 (62.1%) 1a, 117 (23%) 1b, and 76 (14.9%) 3a. there was no significant association between HCV genotypes and gender, educational degree, risk factor of Hepatitis C, job, monthly income, HIV infection, Hepatitis B virus (HBV) infection, Intravenous drug injection, and underlying disease (P > 0.05). CONCLUSIONS: This results the same as many similar studies demonstrated that common HCV genotypes in Iranian patients were 1a, 3a and 1b, respectively. Patients with 1a and 1b genotypes have lower responses to interferon treatment, and it is reasonable to perform early screening to diagnose and determine HCV genotype for effective treatment and diagnose high-risk cases. PMID- 24403915 TI - Efficacy of Alfacalcidol on PEG-IFN/ Ribavirin Combination Therapy for Elderly Patients With Chronic Hepatitis C: A Pilot Study. AB - BACKGROUND: Serum vitamin D concentration is reported to show a decrease in older age. Patients with chronic hepatitis C (CHC) in Japan are older on average than those in Western countries. Moreover, the outcome of pegylated-interferon (PEG IFN)/ ribavirin therapy combined with vitamin D in elderly patients is unclear. OBJECTIVES: This pilot study explored the efficacy and safety of alfacalcidol as vitamin D source in PEG-IFN/ ribavirin combination therapy for elderly CHC patients infected with hepatitis C virus genotype 1b. PATIENTS AND METHODS: Consecutive twenty CHC patients aged >= 65 years were enrolled in this pilot study. Fifteen patients met the inclusion criteria and received PEG-IFN/ ribavirin therapy combined with alfacalcidol. Four-week lead-in of oral alfacalcidol was conducted, and it was subsequently and concurrently administered in PEG-IFN/ ribavirin combination therapy (vitamin D group). Age, gender, and IL28B genotype-matched patients, who received PEG-IFN/ ribavirin alone, were saved as control group (n = 15) to compare the treatment outcome with the vitamin D group. RESULTS: Subjects consisted of 14 males and 16 females, with a median age of 70 years (65-78). The serum 25 (OH) D3 concentration in females (20 ng/ml, 11-37) was significantly lower than males (27 ng/mL, 13-49) (P = 0.004). Sustained virological response (SVR) rates were 33.3% (5/15) in the control group and 80.0% (12/15) in the vitamin D group, respectively (P = 0.025). While no significant difference was shown in the (SVR) rate between the two groups among males (P = 0.592), in females the SVR rate was significantly higher in the vitamin D group (87.5%, 7/8) than the control group (25.0%, 2/8) (P = 0.041). The relapse rates in the groups with and without alfacalcidol were 7.7% (1/13) and 61.5% (8/13), respectively (P = 0.011). Interestingly, in females, the relapse in the control group was shown in 5 of 7 (71.4%), whereas in the vitamin D group the relapse rate was decreased (1/8, 12.5%) (P = 0.041). No specific adverse events were observed in the vitamin D group. CONCLUSIONS: PEG-IFN/ ribavirin combined with alfacalcidol may be effective and safe in elderly CHC patients. In particular, concomitant administration of alfacalcidol may lead to a reduced relapse rate, and consequently improving the SVR rate in elderly females. PMID- 24403916 TI - Dynamic Changes of Treg and Th17 Cells and Related Cytokines Closely Correlate With the Virological and Biochemical Response in Chronic Hepatitis B Patients Undergoing Nucleos(t)ide Analogues Treatment. AB - BACKGROUND: The restoration of HBV-specific T-cell response during antiviral therapy is associated with CD4+T-cell activity. Treg cells and Th17 cells are subtypes of CD4+T cell. However, it has remained unknown how the Treg and Th17 cells and their associated cytokines affect nucleos(t)ide analogues (NA) antiviral efficacy. OBJECTIVES: The aim of the present study was to provide a new insight to evaluate the NA antiviral therapy for patients with chronic hepatitis B (CHB). PATIENTS AND METHODS: Forty-four CHB patients hospitalized between July 2010 and August 2011 were enrolled in this study. They were received NA (entecavir, lamivudine and adefovir) treatment for 14.42 +/- 13.08 weeks, and the peripheral blood was collected. The frequencies of Treg and Th17 cells were detected by flow cytometric analysis, and the levels of IL-10, TGF-beta1, IL-17 and IL-23 were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: In complete and partial-responders, Treg cells frequencies and IL-10, TGF-beta1, IL 23 levels were all decreased significantly after NA therapy, while Th17 cells and the IL-17 levels were increased slightly. Treg/Th17 ratio was only dramatically declined in complete-responders. But there was no significant difference in non responders. Either HBV DNA decreased by at least 2 log copies /mL or ALT turned to normal level, Treg cells frequencies and IL-10, TGF-beta1, IL-23 levels were significantly reduced. Meanwhile, Treg cells were positively correlated with HBV DNA and ALT. CONCLUSIONS: The changes of Treg and Th17 cells and their associated cytokines were related to virological and biochemical responses. PMID- 24403917 TI - GB Virus C/Hepatitis G Virus Envelope Glycoprotein E2: Computational Molecular Features and Immunoinformatics Study. AB - INTRODUCTION: GB virus C (GBV-C) or hepatitis G virus (HGV) is an enveloped, RNA positive-stranded flavivirus-like particle. E2 envelope protein of GBV-C plays an important role in virus entry into the cytosol, genotyping and as a marker for diagnosing GBV-C infections. Also, there is discussion on relations between E2 protein and gp41 protein of HIV. The purposes of our study are to multi aspect molecular evaluation of GB virus C E2 protein from its characteristics, mutations, structures and antigenicity which would help to new directions for future researches. EVIDENCE ACQUISITION: Briefly, steps followed here were; retrieving reference sequences of E2 protein, entropy plot evaluation for finding the mutational /conservative regions, analyzing potential Glycosylation, Phosphorylation and Palmitoylation sites, prediction of primary, secondary and tertiary structures, then amino acid distributions and transmembrane topology, prediction of T and B cell epitopes, and finally visualization of epitopes and variations regions in 3D structure. RESULTS: Based on the entropy plot, 3 hypervariable regions (HVR) observed along E2 protein located in residues 133 135, 256-260 and 279-281. Analyzing primary structure of protein sequence revealed basic nature, instability, and low hydrophilicity of this protein. Transmembrane topology prediction showed that residues 257-270 presented outside, while residues 234- 256 and 271-293 were transmembrane regions. Just one N glycosylation site, 5 potential phosphorylated peptides and two palmitoylation were found. Secondary structure revealed that this protein has 6 alpha-helix, 12 beta-strand 17 Coil structures. Prediction of T-cell epitopes based on HLA A*02:01 showed that epitope NH3-LLLDFVFVL-COOH is the best antigen icepitope. Comparative analysis for consensus B-cell epitopes regarding transmembrane topology, based on physico-chemical and machine learning approaches revealed that residue 231- 296 (NH2- EARLVPLILLLLWWWVNQLAVLGLPAVEAAVAGEVFAGPALSWCLGLPVVSMILGLANLVLYFRWL-COOH) is most effective and probable B cell epitope for E2 protein. CONCLUSIONS: The comprehensive analysis of a protein with important roles has never been easy, and in case of E2 envelope glycoprotein of HGV, there is no much data on its molecular and immunological features, clinical significance and its pathogenic potential in hepatitis or any other GBV-C related diseases. So, results of the present study may explain some structural, physiological and immunological functions of this protein in GBV-C, as well as designing new diagnostic kits and besides, help to better understandingE2 protein characteristic and other members of Flavivirus family, especially HCV. PMID- 24403918 TI - Baseline prognostic factors and statistic model to predict early virological response in telbivudine-treated patients with chronic hepatitis B. AB - BACKGROUND: Hepatitis B virus (HBV) infection is still a worldwide disease, which may cause liver cirrhosis or even hepatocellular carcinoma. Telbivudine is a potent nucleoside analogue used in the treatment of chronic hepatitis B (CHB); however, drug resistance has remained a challenge. As early virological response can predict long-term efficacy of nucleotide analogue treatment, numerous studies have been conducted in this area. OBJECTIVES: The aim of this study was to establish baseline prognostic factors and a statistical model to predict early virological response in telbivudine-treated CHB patients. PATIENTS AND METHODS: One hundred and eight CHB patients without any experience of nucleotide analogue therapy were assigned to receive telbivudine (600 mg, once daily) for at least 24 weeks, and then were followed up every two weeks. Cox proportional hazard regression model analyses were employed to evaluate baseline variables, and further developing a statistical model to predict early virological response. RESULTS: Negative family history of HBV infection (P = 0.000235), baseline higher serum TBIL (P = 0.038714) and AST (P = 0.020684) concentrations, and lower level of HBV-DNA (P = 0.0034784) were identified to be associated with higher possibility of early virological response. A model was established based on these variables to calculate the risk scores (R) for CHB patients. R > -0.38 suggested early virological response to telbivudine. The model was validated among an independent set of 20 patients. CONCLUSIONS: Family history as well as baseline bilirubin, AST and HBV DNA levels can predict early virological response. The model provides a better tool for response prediction based on the four prognostic factors. PMID- 24403919 TI - Discovering the barriers to spread the usage of peripherally inserted central venous catheters in the neonatal intensive care units: A qualitative research. AB - BACKGROUND: By increasing the survival of immature newborns, intravenous access methods, used to provide intravenous therapy, became more important. More attention has been recently paid on peripherally inserted central venous catheters in newborns, although it is yet unknown in Iran. In this study, we tried to discover the barriers to spread the usage of peripherally inserted central venous catheters (PICC) in the neonatal intensive care units of hospitals affiliated to Isfahan University of Medical Sciences. MATERIALS AND METHODS: In this descriptive explorative qualitative research, conducted from December 2011 to April 2012 with purposeful sampling and snowball method, participants were selected from nurses and residents of neonatology and neonatal specialists working in Alzahra, Shahid Beheshty, and Amin hospitals, until data saturation occurred. Data were analyzed with thematic analysis proposed by Broun and Clarke in 2006. RESULTS: Data analysis yielded 175 initial codes, 12 sub-themes, and 3 main themes. The main themes included barriers related to procedure and maintenance, barriers related to persons providing care, and barriers related to management and planning. CONCLUSIONS: One of the major problems in premature newborns during hospitalization is long-term and safe intravascular access; therefore, more use of PICC is needed. A complete planning is also needed to eliminate barriers and to provide required catheters. Educating the personnel is also necessary. PMID- 24403920 TI - Comparison of vibro-acoustic stimulation and acupressure effects in nonstress test results and its parameters in pregnant women. AB - BACKGROUND: The primary goal of antenatal testing is to identify fetuses at risk of intrauterine neurologic injury or death so that these adverse outcomes can be prevented. We want to assess nonstress test (NST) results and some parameters before and after vibro-acoustic stimulation and acupressure. We did a randomized controlled clinical trial in Shahid-Beheshti Hospital in Isfahan in 2011. MATERIALS AND METHODS: A total of 64 pregnant women (32-36 weeks) in prenatal care unit were selected for vibro-acoustic stimulation (n = 32) and acupressure (n = 32) during the second NST. The statistical processing was performed by descriptive, paired t-test, analysis of variance (ANOVA), chi-square, and McNemar test through SPSS version 20. RESULTS: The mean baseline fetal heart rate (FHR) in vibro-acoustic and acupressure groups before and after stimulations did not differ significantly. The mean time of first acceleration in vibro-acoustic group was decreased after stimulations significantly, but in the acupressure group it did not differ statistically. The numbers of accelerations in both groups did not differ significantly before and after stimulation. The mean time of second acceleration in the vibro-acoustic group was 6.7 min before stimulation and 3.9 min after stimulation. This decrease was significant. The mean time of second acceleration after stimulation was lower than before significantly in the acupressure group. The frequency of reactive NST was same in both groups, before and after stimulation. CONCLUSION: Vibro-acoustic stimulation and acupressure of acupoint BL67 did not change FHR parameters but they could decrease the time of reactive result of NST. PMID- 24403921 TI - Nursing in Islamic thought: Reflection on application nursing metaparadigm concept: A philosophical inquiry. AB - BACKGROUND: Metaparadigm of nursing is one of the nursing discipline challenges of the present century, which should take into consideration the diversity of different cultures and viewpoints. MATERIALS AND METHODS: The purpose of this study is to evolve the concept of "nursing" (one of the concepts in nursing metaparadigm) on the basis of the Islamic scholars' view. In this philosophical inquiry, we sought to clarify the concept of nursing according to the ideas derived from the Islamic scholars' view. To achieve the research objectives, Islamic texts were studied and analyzed based on the criteria of concept anatomy (definition, attributes/characteristics, and boundaries). RESULTS: Based on Morse's criteria, with regard to Islamic thought, the concept of nursing in scientific literature is an immature concept. In Islamic viewpoint, human is a unique and integrated reality that implies a holistic paradigm in nursing theories. Since in Islamic thought human is described precisely and delicately, nursing concept can be delineated more clearly and can be helpful in enhancing and producing nursing clinical knowledge, nursing care, and nursing philosophy, specially clarifying holistic nursing. CONCLUSION: According to the criteria of concept anatomy, nursing is caring for and fulfilling the needs of patients, and it believes that nursing has a holistic paradigm and includes all of the dimensions and aspects of human beings. PMID- 24403922 TI - The effect of massage therapy on chemotherapy-induced nausea and vomiting in pediatric cancer. AB - BACKGROUND: Nausea and vomiting are the most common and unpleasant side effects of chemotherapy, and they may prevent successful treatment completion. Antiemetics not only cannot control nausea and vomiting completely but also have numerous side effects. So it is necessary to find other methods for a better control. This study aimed to assess the effect of massage therapy on chemotherapy induced nausea and vomiting in pediatric cancer. MATERIALS AND METHODS: In this randomized controlled clinical trial study, 70 patients (4-18 years of age) under chemotherapy were divided into two (massage therapy and control) groups randomly. In the massage group at 0.5 h and 24 h before and 24 h after chemotherapy, the patients were massaged (Swedish massage) for 20 min, respectively. All indices of nausea and vomiting (incidence, severity, time, and length) were assessed by Visual Analogue Scale (VAS) and BARF scales and other questionnaires and documented. RESULTS: The results of Mann-Whitney and chi-squire tests indicated that in the massage group, the incidence of nausea was 25.7%, the severity, length, and times of nausea were 20%, 54 min, and 0.35 times, respectively, and the severity and times of vomiting were 0.24 scores and 0.31 times lower than those of the control group (P < 0.05), respectively. But vomiting incidence in the two groups showed no significant difference (P = 0.192). CONCLUSIONS: Massage therapy reduced chemotherapy-induced nausea and vomiting. So, nurses can use it and educate it to the patients' families. Nurses, besides using it clinically, can provide instructions to families for involving them in the treatment process and they feel they are more efficate in care of their suffering children. PMID- 24403923 TI - Impact of guided reciprocal peer questioning on nursing students' self-esteem and learning. AB - BACKGROUND: Self-esteem is essential for clinical judgments. Nursing students in clinical environments should make a bridge between theoretical education and clinical function. This study was aimed to survey the effect of guided questioning in peer groups on nursing students' self-esteem and clinical learning. MATERIALS AND METHODS: In this quasi-experimental study, all nursing students in semester 4 (60) were selected. The autumn semester students (n = 28) were chosen as the control group, and the spring semester students (n = 32) as the experimental group. The experimental group underwent the course of cardiac medical surgical training by the Guided Reciprocal Peer Questioning. The control group was trained by lecture. After confirmation of the validity and reliability of tools including Rosenberg Self-esteem Scale and the researcher-made questionnaire, data were collected and analyzed by SPSS version 17.0. RESULTS: There was no significant difference concerning demographic and educational characteristics between the two groups. Mean score differences of self-esteem and learning were not significant before teaching, while they were significantly promoted after teaching in the experimental (P < 0.001) and control (P < 0.05) groups. Promotion in the experimental group was more considerable than in the control group. CONCLUSIONS: As revealed by the results, inquiry method, due to its more positive impact on self-esteem and students' learning, can be applied alone or in combination with the other methods. Conducting this study for other students and for theoretical courses is suggested. PMID- 24403924 TI - The effect of formative evaluation using "direct observation of procedural skills" (DOPS) method on the extent of learning practical skills among nursing students in the ICU. AB - BACKGROUND: Learning of clinical skills in the intensive care unit (ICU) is important for nursing students. Direct observation of procedural skills (DOPS)" is a modified objective method in the field of medical sciences, and we conducted this study with the aim of investigating the effect of evaluation using DOPS method on learning practical skills among nursing students in the ICU. MATERIALS AND METHODS: This semi-experimental study was conducted on 39 nursing students of the 7(th) semester (20 in the intervention group and 19 in the control group). First, the control group students spent their apprenticeship by the routine assessment method. The intervention group underwent formative evaluation using DOPS method in addition to the routine one. At the beginning and end of the period, skill levels of both groups in performing two optional procedures (arterial blood sampling and endotracheal suctioning) were evaluated using checklists, and each student's skill score was calculated in a range of 0-20. Period initiation and termination scores were considered as pre- and post-test values, respectively. RESULTS: The results showed no significant difference in pre-test scores between the two groups (P > 0.05), whereas the mean difference of post-test scores was significant for both procedures between the two groups (P < 0.001). Difference between the mean values of pre- and post-test scores of the two procedures for both intervention and control groups was significant (P < 0.001). CONCLUSION: Our findings indicate that DOPS formative assessment, more than the routine approach, increases arterial blood sampling and endotracheal suctioning skills in the ICU. Therefore, it is recommended that this method be used in other wards as well as for other skills. PMID- 24403925 TI - Burnout among nurses working in medical and educational centers in Shahrekord, Iran. AB - BACKGROUND: Nursing burnout is the main characteristic of job stress that is a delayed reaction to chronic stressful situations in the workplace which could affect nurses who do not have sufficient emotional energy to cope and communicate with different types of patients. There is also sometimes this belief that they do not have the required capabilities for their jobs. The aim of this study was the evaluation of burnout among nurses working in medical and educational centers in Shahrekord. MATERIALS AND METHODS: This descriptive study was performed on 340 nurses working in medical and educational centers in Shahrekord in 2009. Samples were selected using proportionate random sampling. Demographic information and the Maslach Burnout Inventory (MBI) were filled in for all nurses. RESULTS: Burnout was considerable among nurses. The results showed that 34.6, 28.8, and 95.7% of the nurses had emotional exhaustion (EE), high depersonalization (DP), and high reduced personal accomplishment (PA), respectively. The mean scores (+/- standard deviation) for EE, DP, and PA were 22.77 (12.44), 6.99 (6.23), and 32.20 (9.26), respectively. CONCLUSIONS: Our results showed that burnout was noticeable among nurses working in medical and educational centers in Shahrekord. Disproportionate relationship between the number of nurses, workload, and income was the most important factor affecting nursing burnout. Due to the importance of nursing in the health-care system, policy makers should adopt suitable strategies for increasing the satisfaction of nurses. PMID- 24403926 TI - The effect of intermittent local heat and cold on labor pain and child birth outcome. AB - BACKGROUND: Labor pain is one of the severest pains that cause many women request cesarean section for fear of pain. Thus, controlling labor pain is a major concern of maternity care. Nowadays, interest in non-pharmacological pain relief methods has been increased because of their lower side effects. The effects of discrete heat and cold on decreasing labor pain have been reported but there was no evaluation of the effects of simultaneous heat and cold. The aim of this study was to investigate the effect of intermittent heat and cold on pain severity and childbirth outcomes. MATERIALS AND METHODS: This study was a randomized controlled trial. Sixty-four nulliparous women with term, One fetus, and low-risk pregnancy were divided into the intervention (32 participants) and the control group (32 participants) by random allocation. Excluding criteria were: administration of pain relief drugs, skin disease in the field of intervention, fetal distress, bleeding, fever, and disagreement with participation in the study. Warm and cold packs were used intermittently on low back and lower abdomen during the first phase and on perineum during the second phase of labor. Pain intensity was assessed with Visual Analogue Scale. Descriptive statistic, chi square, and t-test were used for data analysis. RESULTS: There were no significant differences in demographic and midwifery characteristics and the baseline pain between two groups. The pain was significantly lower in intervention group during the first and second phases of labor. Duration of the first and third phases of labor was shorter in the case group. There were no significant differences in type of delivery, perineal laceration, oxytocin uptake, fetal heart rate, and APGAR between two groups. DISCUSSION: Local warming with intermittent cold pack can reduce labor pain without adverse effects on maternal and fetal outcomes. It is an inexpensive and simple method. CONCLUSION: Intermittent local heat and cold therapy is a no pharmalogical, safe and effective method to relief labor pain. PMID- 24403927 TI - Mothers' experience of having children with diabetes. AB - BACKGROUND: Diabetes is a major health problem, which has a wide prevalence in the world. There is no sign of its stopping, but it is increasing. Diabetes in children is three to four times more common than other childhood diseases. Diagnosis of diabetes for children causes emotional responses in parents and family members. Interventions for children with diabetes involve the family, child, and professionals including physicians, nurses, and nutritionist. Self care is difficult without direct parents' participation. According to studies, burden of diabetes for mothers is more than for fathers. This study aimed to explore mothers' experience of children with diabetes. MATERIALS AND METHODS: This is a qualitative content analysis. Study population was recruited through purposeful sampling. Eleven mothers who have a child with diabetes and referring to the "Glands and Metabolism Research Center" and "Al-Zahra Hospital" were selected. Participants were aged 28 to 42 years. Data gathering was done through deep interviews with participants in 2007 that was tape-recorded. Mean average of interviews was 45 minutes. Data analysis was done using conventional qualitative content analysis. RESULTS: Participants' experience was classified in the two main concepts including reaction at the time of diagnosis and disease consequences for mothers. CONCLUSION: Mothers of children with diabetes expressed some reactions at the time of diagnosis, which was mainly due to lack of information, and lack of attention to their needs at the time of diagnosis, especially it was due to the sudden diagnosis and lack of enough opportunities for mothers to accept the disease. The disease causes some consequences for mothers that affect their lives. Therefore, it is necessary to consider the needs of families of children with diabetes and to provide support and sufficient information about their child's illness for them. PMID- 24403928 TI - Nursing students' understanding of factors influencing ethical sensitivity: A qualitative study. AB - BACKGROUND: Ethical sensitivity is considered as a component of professional competency of nurses. Its effects on improvement of nurses' ethical performance and the therapeutic relationship between nurses and patients have been reported. However, very limited studies have evaluated ethical sensitivity. Since no previous Iranian research has been conducted in this regard, the present study aimed to review nursing students' understanding of effective factors on ethical sensitivity. MATERIALS AND METHODS: This qualitative study was performed in Kerman, Iran, during 2009. It used semi-structured individual interviews with eight MSc nursing students to assess their viewpoints. It also included two focus groups. Purposive sampling was continued until data saturation. Data were analyzed using manifest content analysis. RESULTS: The students' understanding of factors influencing ethical sensitivity were summarized in five main themes including individual and spiritual characteristics, education, mutual understanding, internal and external controls, and experience of an immoral act. CONCLUSIONS: The findings of this study create a unique framework for sensitization of nurses in professional performance. The application of these factors in human resource management is reinforcement of positive aspects and decrease in negative aspects, in education can use for educational objectives setting, and in research can designing studies based on this framework and making related tools. It is noteworthy that presented classification was influenced by students themselves and mentioned to a kind of learning activity by them. PMID- 24403929 TI - The relationship between occupational stress and dysmenorrhea in midwives employed at public and private hospitals and health care centers in Iran (Mashhad) in the years 2010 and 2011. AB - BACKGROUND: According to the biopsychosocial model, menstrual symptoms are caused not only by a combination of biological factors such as hormonal disorders and lifestyle, but also by psychological and social factors such as working environment. This study aimed to determine the relation between occupational stress and dysmenorrhea in Iranian midwives. MATERIALS AND METHODS: This prospective correlational study was performed on 150 midwives at public and private hospitals and health care centers of Mashhad, Iran. The subjects were selected through two-stage cluster sampling during 2010-2011. At the beginning of the study, participants completed questionnaires containing demographic information, work circumstances, the 21-item Depression, Anxiety, and Stress Scale, and the Job Content Questionnaire. They then completed the short form of daily Menstrual Distress Questionnaire during three consecutive menstrual cycles. Independent Student's t-test, one-way analysis of variance, Kruskal-Wallis, Mann Whitney, and chi-square tests, correlation coefficients, and linear regression analysis were used to analyze the data collected data in SPSS11.5. RESULTS: Dysmenorrhea was observed in 63.3% of the participants. Among these individuals, 15.7%, 45.2%, and 38.9% had mild, moderate, and severe symptoms, respectively. Moreover, 59.3% of the studied midwives had severe occupational stress. There was a significant positive correlation between occupational stress and severity of dysmenorrhea (P = 0.002, r = 0.82). CONCLUSIONS: Occupational stress is associated with increased risk of severe dysmenorrhea. This finding can be used to guide preventive measures to eliminate or decrease occupational stress and dysmenorrhea among Iranian midwives. However, identification of sources of occupational stress and related workloads is necessary. PMID- 24403930 TI - Factors concerning the attitudes of married women toward family planning in Aydupsilonn, Turkey: A cross-sectional study. AB - BACKGROUND: Because of unemployment and inadequate education and health services, high rate of maternal and infant mortalities, a rapidly growing population is a serious problem in Turkey. Social values and attitudes of women might be effective in using modern family planning methods. Our aim in this study was to evaluate the factors concerning the attitudes of married women toward family planning. MATERIALS AND METHODS: Four hundred and twenty-seven women were randomly selected among 29,874 women and included in this cross-sectional study. The study was conducted between June 2008 and September 2008, and included married women between 15 and 49 years of age, living in the provincial centre of Aydin, a city in western Turkey. The study data were obtained using a questionnaire and the Family Planning Attitude Scale. RESULTS: Of the women participating in the study, 60.4% used modern methods and 26.0% used conventional methods. These variables included, in a descending order of contribution to the model's power, having a college degree, being a primary school graduate, the longest period of rural life, use of conventional methods, discussing with one's spouse issues about family planning, and age and high perception of income level. CONCLUSIONS: Reorganization of family planning services by giving priority to women living in rural areas with low income and education level and conventional contraception method use could contribute to positive attitudes toward family planning. Including their spouses to this reorganization may enhance the impact. PMID- 24403931 TI - Effect of watching a movie on family members' anxiety level during their relatives' surgery. AB - BACKGROUND: Surgery is a stressful condition for both patient and family members. This anxiety may interfere with the adequate family functioning and in providing positive support for the patient. Thus, specialized assessment and interventions to reduce anxiety level of family members are essential. The aim of this study was to assess the effect of watching movie on anxiety level of family members during their relatives' surgery. MATERIALS AND METHODS: This was a before-after trial study conducted in Alzahra Medical Center, Isfahan, Iran. Between February 2010 and November 2010, 164 eligible family members in the surgical waiting room who met the inclusion criteria entered in the study. Before and after watching movie, the anxiety level was evaluated using the State-Trait Anxiety Inventory (STAI). Chi-squares, ANOVA and paired-t test were used for analysis using the Statistical Package for Social Sciences (SPSS, Version 14) for Microsoft Windows. RESULTS: The study population were 164 people, of whom 87 (53%) were female and 77 (47%) were male. The mean age of participants was 36.6 (SD: 8.4) years ranging from 18 to 67 years. After watching movie, the mean STAI score reached from 46.06 (SD: 9.26) to 39.15 (SD: 11.81) and this difference was statistically significant (p = 0.003). CONCLUSIONS: The results of this study indicated that watching movie could reduce family members' anxiety during surgery. The findings suggested that movie might be a simple and cost-effective tool to help family members to manage anxiety during surgery of their relatives. PMID- 24403932 TI - Teamwork improvement in emergency trauma departments. AB - BACKGROUND: Interprofessional teamwork is considered as the key to improve the quality of patient management in critical settings such as trauma emergency departments, but it is not fully conceptualized in these areas to guide practice. The aim of this article is to explore interprofessional teamwork and its improvement strategies in trauma emergency departments. MATERIALS AND METHODS: Participants of this qualitative study consisted of 11 nurses and 6 supervisors recruited from the emergency departments of a newly established trauma center using purposive sampling. Data were generated using two focus group and six in depth individual interviews, and analyzed using qualitative content analysis. RESULTS: Interprofessional teamwork attributes and improvement strategies were emerged in three main themes related to team, context, and goal. These were categorized as the effective presence of team members, role definition in team framework, managerial and physical context, effective patient management, and overcoming competing goals. CONCLUSIONS: Interprofessional teamwork in trauma emergency departments is explained as interdependence of team, context, and goal; so, it may be improved by strengthening these themes. The findings also provide a basis to evaluate, teach, and do research on teamwork. PMID- 24403933 TI - A descriptive study of perceived stress among the North Indian nursing undergraduate students. AB - BACKGROUND: In recent years, there is a growing appreciation of the stresses involved in nursing training. It is important for nursing educators to know the prevalence of psychological distress and psychological well-being among nursing students. The present study aimed to assess perceived stress in the undergraduate students studying in a nursing college located in North India. MATERIALS AND METHODS: The present cross-sectional study was carried out at College of Nursing, Maharishi Markandeshwar University, Haryana, in the month of August 2011 using pretested self-administered questionnaire. Perceived stress score was measured using perceived stress scale (PSS). RESULTS: The mean perceived stress score of all 282 students was 28.67 (SD = 5.32), with a median of 26 (IQR = 22-34). Female students had more perceived stress score (31.33) than male students (26.01). The maximum mean perceived stress score (29.66) was observed in 2(nd) year students, and the least mean perceived stress score (26.28) was found in 3rd year students. CONCLUSION: The present study indicates high levels of psychological disturbance among nursing undergraduate students in the middle phase of the course. Hence, there is an urgent need to take measures by the authorities to reduce stress among the nursing students. PMID- 24403934 TI - Determining job satisfaction of nurses working in hospitals of Iran: A systematic review and meta-analysis. AB - BACKGROUND: Employees feeling and attitude to their job has a significant role on their performance. Present study sought to investigate documents related to nurses job satisfaction, using systematic review and meta-analysis to estimate nurses job satisfaction in Iran. MATERIALS AND METHODS: Papers on nurses job satisfaction were identified by searching different data bases using appropriate key words. Seventeen studies were extracted using inclusuion criteria. Data were analyzed using Meta-analysis command in STATA 11. RESULTS: Considerable hetrogenecity is apparent in results of nurses job satisfaction studies. Although, according to random effect model, nurses total job satisfaction was estimated at 46.3 (CI: 32.1-60.4), this was estimated at 51.9 (CI = 51.1-52.8) using fixed effect model. Additionally, a reverse relationship was observed between nurses overall job satisfaction and their age. CONCLUSION: Nurses' job satisfaction in Iran is at a good level compared with other countries. The more satisfied the nurses are with their working conditions, the less is their intention to leave their job. Dissatisfaction is associated with higher resignment and turnover, paying deep attention to efficient factors on nurses dissatisfaction and trying to overcome them is important to improve nurses' working conditions. PMID- 24403935 TI - Lived experiences of pediatric oncology nurses in Iran. AB - BACKGROUND: Caring is a valuable task. The staff in any profession that involves patients' fear, anxiety, pain, and suffering may experience similar feelings. As a professional group, oncology nurses deal with patients and their relatives and caregivers under very stressful conditions. They encounter pain, suffering, and death as a part of their daily life. A number of studies have evaluated the experiences of pediatric oncology nurses in other countries. Therefore, conducting a survey about the experiences of Iranian nurses of caring for children with cancer can reveal their demands, stress, and limitations. MATERIALS AND METHODS: In a qualitative research, in-depth, unstructured individual interviews with open-ended questions were conducted to evaluate the experiences of pediatric oncology nurses in a hospital in a metropolitan city of Iran. The subjects all consented to participate and had at least one year of working experience in the ward. Content analysis was performed to analyze the data. RESULTS: The lived experiences of pediatric oncology nurses were categorized in five main themes. These themes included attachment, supportive care, trying to repress feelings, feeling of helplessness, and the need to be supported. CONCLUSIONS: According to these results, nurses who provide care for children with cancer require support. This research also highlighted the roles, limitations, and needs of nurses in pediatric oncology wards. PMID- 24403936 TI - Comparison of the effectiveness of combination of fennel extract/vitamin E with ibuprofen on the pain intensity in students with primary dysmenorrhea. AB - BACKGROUND: Dysmenorrhea is a common gynecologic disorder affecting as many as 60% of menstruating women. In the United States, work absenteeism due to dysmenorrhea is estimated to be 600 million work hours per year, and the economic consequences are estimated at $2 billion per year; therefore, it is a public problem nowadays. AIM: The purpose of this study was to compare the effects of combination of fennel extract/vitamin E with ibuprofen on the intensity of pain in primary dysmenorrhea among the students of Tabriz city in 2007-2009. MATERIALS AND METHODS: This study was done by using double-blinded quasi-experimental research method. After taking the required licenses from ethics committee, 68 students from Medical and Tabriz universities, who were living in the dormitory, suffering from primary dysmenorrhea, and were eligible for the study, were randomly divided into two groups of 34 students each (the two groups used combination of fennel extract/vitamin E and ibuprofen cross-over form in the 2 months). We used Visual Analogue Scale (VAS) tool for ranking the intensity of the pain. Data analysis was done by using SPSS Ver. 14. RESULTS: The mean of peak pain intensity in the first, second, third, sixth, and forty-eighth hours in the group that had used combination of fennel extract/vitamin E was lower than the group that had used ibuprofen, and statistical differences were observed between the two groups in the first and second hours; combination of fennel extract/vitamin E was more effective than ibuprofen in the first hour (P < 0.03) and second hour (P < 0.04). CONCLUSION: Combination of fennel extract/vitamin E is effective on decreasing the intensity of pain of primary dysmenorrhea, and it is advised to those who cannot use chemical drugs. PMID- 24403937 TI - Relationship between adequacy of prenatal care utilization index and pregnancy outcomes. AB - BACKGROUND: Prenatal care is a comprehensive antepartum care program involving a coordinated approach to medical care and psychosocial support that is optimally offered before conception. Inadequate care during pregnancy can lead to undesirable outcomes, including preterm labor and low birth weight. One of these new, accurate, and comprehensive indicator measurements is adequacy of prenatal care utilization index. This study aimed to assess the adequacy of care and its relationship with preterm labor and low birth weight. MATERIALS AND METHODS: This analytic historical cohort study was performed on 420 mothers who referred to health centers in Sari during 2010. Data were collected by interviews and questionnaires. Based on the adequacy of prenatal care utilization, this care was classified into four groups: intensive, adequate, intermediate, and inadequate. Data were analyzed using chi-square test, analysis of variance (ANOVA), Spearman correlation coefficient, and relative risk (RR). RESULTS: Of the 420 mothers who were studied, inadequate care was observed in 151 (36%) cases, which was the highest percentage of care. There was a significant relationship between the adequacy of prenatal care utilization and preterm labor and low birth weight (for both P < 0.05). Performing inadequate care, the rate of preterm labor was RR = 1.36 times and the rate of low birth weight was RR = 1.08 times more than in adequate and intensive care. CONCLUSION: According to the programs that reduced the number of referrals of pregnant mothers (standardization protocol for mothers in Iran), this study confirms the efficacy of adequacy of prenatal care on reducing preterm labor and low birth weight. This study emphasizes on minimum care performance and the importance of conducting further studies to assess the relationship between quantities of care and other outcomes. PMID- 24403938 TI - The role of nurse practitioners in health sector reform in Iran (2011). AB - BACKGROUND: Most countries use educated nurses called "nurse practitioners" (NPs) besides the family physicians for diagnosis, treatment, and specifically health education of the family. The main goal of this study was to redefine the role of NPs for better use of their capabilities in the so-called "family physician reform" in Iran. MATERIALS AND METHODS: This is a qualitative and comparative study carried out in three stages (triangulation method) in 2011. In the first stage, we conducted a literature review to design a conceptual framework. The second stage was a comparative study on four countries. In this study, we focused on the role of NPs, which in turn helped to redefine this role in the health sector reform of Iran. In the third stage, two expert panels were involved and the suggested roles were confirmed. RESULTS: In the United States, NPs are licensed by the state in which they practice and have a national board certification. In Canada, nurses involved in clinics should participate in specific training course of diagnosis and management of health care after registration. In Austria, nurses in Nursing homes and maternity do some of the medical procedures under the supervision of the physicians. In the United Kingdom, NPs increasingly substitute for GPs in the care of minor illness and routine management of chronic diseases. CONCLUSIONS: There is still debate in nursing and medical circles about what the focus of the NP roles should be. In Iran, whereas a noticeable reform toward "family physician" is ongoing, redefining the nurses' role is essential. They can perform more active roles in associating with GPs in the clinics of family physicians, both in urban and rural areas, even with higher degrees of autonomy. PMID- 24403939 TI - The effectiveness of risk management program on pediatric nurses' medication error. AB - BACKGROUND: Medication therapy is one of the most complex and high-risk clinical processes that nurses deal with. Medication error is the most common type of error that brings about damage and death to patients, especially pediatric ones. However, these errors are preventable. Identifying and preventing undesirable events leading to medication errors are the main risk management activities. The aim of this study was to investigate the effectiveness of a risk management program on the pediatric nurses' medication error rate. MATERIALS AND METHODS: This study is a quasi-experimental one with a comparison group. In this study, 200 nurses were recruited from two main pediatric hospitals in Tehran. In the experimental hospital, we applied the risk management program for a period of 6 months. Nurses of the control hospital did the hospital routine schedule. A pre- and post-test was performed to measure the frequency of the medication error events. SPSS software, t-test, and regression analysis were used for data analysis. RESULTS: After the intervention, the medication error rate of nurses at the experimental hospital was significantly lower (P < 0.001) and the error reporting rate was higher (P < 0.007) compared to before the intervention and also in comparison to the nurses of the control hospital. CONCLUSIONS: Based on the results of this study and taking into account the high-risk nature of the medical environment, applying the quality-control programs such as risk management can effectively prevent the occurrence of the hospital undesirable events. Nursing mangers can reduce the medication error rate by applying risk management programs. However, this program cannot succeed without nurses' cooperation. PMID- 24403940 TI - The effect of aquatic exercises on primary dysmenorrhoea in nonathlete girls. AB - BACKGROUND: Primary dysmenorrhoea without any specific pelvic disease is one of the common complaints in women's medicine. The general purpose of this research is to define the effects of 12-week aquatic exercises on nonathletic girls' primary dysmenorrhoea. MATERIALS AND METHODS: This quasi-experimental was conducted on 40 nonathletic girls aged 18-25 years. Data gathering tools were: Evaluation form of primary dysmenorrhoea and the pain evaluation tool based on the McGill standard pain questionnaire completed before and after the intervention in 3 months (first, second, and third run). Then, 20 subjects were assigned to aquatic exercise group and the other 20 to control group. The subjects in experimental group did aquatic exercise for three sessions a week for 60 minutes for 12 weeks between two menstruations. Kruskal - Wallis and one way analysis of variance (ANOVA) tests were used to analyze the data. RESULTS: The results of this research indicated that severity and duration of pain decreased after 12 weeks of aquatic exercises. Comparison of the two groups showed a significant difference in pain intensity based on visual analogue scale (VAS) scale after these exercises (first, second, and third runs). Present pain intensity (PPI) scale after these exercises (second and third runs) showed a significant difference. Comparison of the two groups showed a significant difference in length of pain after these exercises (third run). CONCLUSIONS: Totally, the findings of the present study showed that 12-week regular aquatic exercises are effective on decrease of the severity of the symptoms of primary dysmenorrhoea. PMID- 24403941 TI - The outcomes of health care process in Iran's rural society. AB - BACKGROUND: Health care systems in rural areas face numerous challenges in meeting the community's needs and adequate attention has not been paid to this problem. The aim of this study was to describe the outcomes of health care process in rural society. MATERIALS AND METHODS: Twenty-six participants including twenty-one rural health care providers and five clients were selected according to purposive sampling. The data were collected via semi-structured individual interviews and a mini focus group. Data were analyzed by using qualitative content analysis based on methods described by Granheme and Landman. RESULTS: Data analysis eventually led to formation of one category of inefficiency in health care process in rural society including subcategories such as arbitrary self-therapy, slow care process, dissatisfaction with the care process, superficial caring, job stress and burn out of caregivers, and ineffective caring relationship. CONCLUSION: Outcomes in health care in rural society of Iran represents inefficiency of the current health care process. These outcomes are related to the cultural and social context of rural communities and the structure of the health system. These outcomes in health care in the rural society of Iran represent impairment of the current health care process. The necessity of modifying the existing care trend with new models designed to improve the health care process is felt. PMID- 24403942 TI - Effects of nurses' practice of a sedation protocol on sedation and consciousness levels of patients on mechanical ventilation. AB - BACKGROUND: Providing high-quality care in the intensive care units (ICUs) is a major goal of every medical system. Nurses play a crucial role in achieving this goal. One of the most important responsibilities of nurses is sedation and pain control of patients. The present study tried to assess the effect of nurses' practice of a sedation protocol on sedation and consciousness levels and the doses of sedatives and analgesics in the ICU patients. MATERIALS AND METHODS: This clinical trial was conducted on 132 ICU patients on mechanical ventilation. The patients were randomly allocated to two groups. While the control group received the ICU's routine care, the intervention group was sedated by ICU nurses based on Jacob's modified sedation protocol. The subjects' sedation and consciousness levels were evaluated by the Richmond Agitation Sedation Scale (RASS) and the Glasgow Coma Scale (GCS), respectively. Doses of administered midazolam and morphine were also recorded. RESULTS: The mean RASS score of the intervention group was closer to the ideal range (-1 to +1), compared to the control group (-0.95 +/- 0.3 vs. -1.88 +/- 0.4). Consciousness level of the control group was lower than that of the intervention group (8.4 +/- 0.4 vs. 8.8 +/- 0.4). Finally, higher doses of midazolam and morphine were administered in the control group than in the intervention group. CONCLUSION: As nurses are in constant contact with the ICU patients, their practice of a sedation protocol can result in better sedation and pain control in the patients and reduce the administered doses of sedatives and analgesics. PMID- 24403943 TI - Developing an instrument to measure the influential factors on career choice among Iranian nursing students. AB - BACKGROUND: Understanding why the graduates from the high schools choose nursing is essential for the health policy makers in each country and Iran is not an exception. The aim of this study was to develop an instrument measuring the influential factors on career choice among Iranian nursing students. MATERIALS AND METHODS: This methodological study employed both qualitative and quantitative approaches. In the first phase of the study, the items were generated for the instrument. These items were drawn from a relevant literature review along with taking a poll of experts' opinions. Then the psychometric properties of instrument were measured using content validity, face validity, and construct (exploratory factor analysis) validity as well as its reliability. RESULTS: Initially, a 35-item instrument was developed. In the second phase, a scale-level content validity index of 0.90 was obtained for the instrument. The factor structure of the inventory was identified by undertaking a principal component analysis in a sample of 139 nursing students. Three factors were extracted with a total variance account of 42.03%. Reliability was demonstrated with Cronbach's alpha coefficient of 0.77 for the entire scale. Consistency of the instrument was established with test - retest reliability with an interval of 2 weeks (intra cluster correlation = 0.94, P < 0.001). Wilcoxon signed-rank test demonstrated no significant differences between the test - retest scores (P > 0.05). CONCLUSION: It seems a culturally sensitive instrument with a satisfactory level of validity and reliability has some implications for policy makers in nursing education. PMID- 24403944 TI - Association between menstruation signs and anxiety, depression, and stress in school girls in Mashhad in 2011-2012. AB - BACKGROUND: Menstruation signs are among the most common disorders in adolescents and are influenced by various environmental and psychosocial factors. This study aimed to define the association between menstruation signs and anxiety, depression, and stress in school girls in Mashhad in 2011-2012. MATERIALS AND METHODS: This was a cross-sectional study on 407 high school girls in Mashhad who were selected through two-step random sampling. The students completed a questionnaire concerning demographic characteristics, menstruation, Depression, Anxiety, and Stress Scale of 21 questions (DASS-21), and menstruation signs in three phases of their menstruation. Data were analyzed by the statistical tests of Pearson correlation coefficient, Student's t-test, one-way analysis of variance (ANOVA), and regression through SPSS version 14. RESULTS: Based on the findings, 74% of the subjects reported pre-menstruation signs, 94% reported signs during bleeding, and 40.8% reported post-menstruation signs. About 44.3% of the subjects had anxiety, 45.5% had depression, and 47.2% had stress. In addition, Pearson correlation coefficient test showed a significant positive correlation between menstruation signs and depression, anxiety, and stress (P < 0.05). CONCLUSION: With regard to the association between menstruation signs and psycho cognitive variables, prevention and treatment of these disorders by the authorities of education and training and the Ministry of Health are essential. PMID- 24403945 TI - A grounded theory approach to understand the process of decision making on fertility control methods in urban society of Mashhad, Iran. AB - BACKGROUND: More than 30% of pregnancies in Iran are unintended and most of them happen among the women who use various contraceptive methods. Results of Integrated Monitoring and Evaluation System (IMES) showed that the rate of innovative contraceptive use in Mashhad has been 41.5%-57% in different urban areas. This study was conducted to explore the process of making decision toward using family planning methods in women of reproductive age in urban society of Mashhad, Iran. MATERIALS AND METHODS: In this grounded theory study, semi structured interviews were conducted with 45 purposefully selected participants including 28 women and 17 key informants including family health providers and managers, and participants' mothers and husbands, who lived in urban society of Mashhad, Iran, in 2011-2012. Participants' recruitment continued until data saturation occurred. Data were analyzed using Strauss and Corbin's mode of analysis through constant comparative method, applying levels of open, axial, and selective coding with MAXqda software. Study rigor was confirmed through prolonged engagement, member check, expert debriefing, and thick description of the data. RESULTS: The core category of "caring the comprehensive health of my family," which emerged from the data, described the process of couples' decision making toward using family planning methods in this study. Other developed categories which were presented into a theoretical scheme consisted of 1) shaping the ideas of fertility control, 2) developing cognition about the fertility control methods, 3) appraising available choices and choosing the most appropriate one, 4) managing the course of using methods, and 5) realizing the fertility intentions. CONCLUSION: It is important that family planning providers understand the motivations, perceptions, and knowledge of women about contraceptive methods in their contextual situation, which illustrates their mode of interaction in the arenas of family planning decision making. PMID- 24403946 TI - Effects of anxiety reduction training on physiological indices and serum cortisol levels before elective surgery. AB - BACKGROUND: Patients awaiting surgery typically experience significant physical and psychological stress. Vital signs and serum cortisol level are altered in response to anxiety. The aim of this study was to assess the effects of preoperative education on physiological indices and cortisol level of female patients undergoing elective surgeries. MATERIALS AND METHODS: In this single blinded randomized controlled trial, 60 women undergoing gynecological elective surgeries in Kowsar Hospital (Qazvin, Iran) were randomly assigned to either control or intervention group. The patients of the intervention group were assessed based on the nursing process after admission. Subjects with anxiety, inadequate awareness, and fear received necessary training on anxiety reduction techniques. The control group merely received routine care. A questionnaire including demographic characteristics, baseline and preoperative vital signs, and serum cortisol level was completed for all subjects. Data were analyzed by descriptive and inferential statistics (Fisher's exact test, paired and independent t-tests, and Mann-Whitney U test) in SPSS17. P values less than 0.05 were considered significant. RESULTS: The two groups were homogeneous in terms of age (P = 0.20), marital status (P = 0.50), education (P = 0.10), employment status (P = 0.13), and admission history (P = 0.30). There were no significant differences in baseline vital signs between the intervention and control groups. Before surgery, the mean values of vital signs increased in both the groups. However, the increments were less in the experimental group than in the control group. Serum cortisol levels were also lower in the experimental group compared to the control group (P < 0.01). CONCLUSIONS: Education based on the nursing process is a non-pharmaceutical and effective method to minimize changes in vital signs and decrease serum cortisol level in patients undergoing gynecological elective surgeries. PMID- 24403947 TI - Effect of self-efficacy enhancement program on self-care behaviors in chronic obstructive pulmonary disease. AB - BACKGROUND: Given the importance of the chronic obstructive pulmonary disease (COPD) and role of different factors in self-care behaviors of COPD patients, this study was conducted to determine the effect of self-efficacy program on self care behaviors of COPD patients. MATERIALS AND METHODS: In this semi-experimental study, 62 COPD patients were recruited in which 31 subjects were in control group and 31 were in experimental group. Subjects were selected based on purposive sampling from Imam Hospital affiliated to the Urmia University of Medical Sciences, Iran, in 2011. Two valid and reliable questionnaires were filled after completing informed consent form. A month later, and after implementing the planned intervention, the questionnaires were completed by the subjects again. RESULTS: The mean standard deviation of age were 64.1 (9.1) years in the control group and 65.2 (8.0) years in the experimental group. There was a statistically significant difference between self-efficacy state before and after intervention. Self-care scores in the experimental group were significantly higher after intervention (t = 25.18, P < 0.0001). CONCLUSIONS: Given the high potency of self efficacy factors on self-care behaviors of the COPD patients, enhancement of self efficacy in these patients can be very effective in disease control, prevention of complications, reduction of hospitalization costs, and improve their quality of life. Hence, it is suggested that in empowerment programs of these patients, special emphasis will put on the strengthening of their self-efficacy. PMID- 24403948 TI - Development and evaluation of a nutritional health program for adolescents. AB - BACKGROUND: Unhealthy nutritional behaviors are a threat to adolescents. In this regard, we compared different training methods through a participatory interventional study. MATERIALS AND METHODS: Through proportional random selection, 1823 female students were selected from 15 middle schools of Tehran. Following 2 years of intervention, nutritional habits of three different interventional groups were assessed. RESULTS: Eating breakfast was significantly higher in the trained groups, and the use of weight loss diets was lower in them than in the control group. Also, satisfactory consumption of various kinds of nutrients in the trained groups was more than in the control group. CONCLUSION: Participatory health training, especially through parents, leads to adolescence nutritional health promotion. PMID- 24403949 TI - Adequacy of fine-needle aspiration specimens for human papillomavirus infection molecular testing in head and neck squamous cell carcinoma. AB - BACKGROUND: Head and neck squamous cell carcinoma is often associated with human papillomavirus (HPV) infection. Positive HPV status has been associated with increased response to treatment and improved prognosis in terms of recurrence free and overall survival. In certain instances, diagnosis is performed through fine-needle aspiration of lymph nodes with metastatic carcinoma, often demonstrating extensive tumor necrosis. We evaluated the effect of tumor necrosis on deoxyribonucleic acid (DNA) adequacy for HPV molecular testing. MATERIALS AND METHODS: Retrospective review of the pathology files at our institution identified cases of squamous cell carcinoma (SCC) diagnosed by fine-needle aspiration (FNA) on which HPV DNA molecular testing was performed. The cases were classified according to percent tumor necrosis into three categories (<10% necrosis, 10-70% necrosis and >70% necrosis) and the percentage of cases with adequate HPV DNA for molecular testing in each of the categories was compared. When available, p16 immunohistochemistry performed on the cases was compared with HPV status by molecular testing. RESULTS: A total of 70 cases from 67 patients were included in the study. Adequate DNA for molecular HPV testing was obtained from samples of 47 cases (67%) while samples from 23 cases (33%) were inadequate for molecular testing. Of the adequate samples, 36 (77%) were positive and 11 (23%) were negative for high-risk HPV. Adequate DNA for testing was obtained in 22 out of 33 cases showing no necrosis (67%), 10 out of 16 cases showing partial necrosis (63%) and in 13 out of 17 cases showing extensive necrosis (76%). CONCLUSION: Our study found that HPV molecular testing is not influenced by percent tumor necrosis or method by which FNA was performed. We believe that a portion of the FNA specimen obtained from head and neck lesions diagnosed as SCC during the rapid on-site evaluation should be sent for HPV DNA testing, independent of the amount of tumor necrosis, thus guaranteeing availability of specimen for HPV testing. PMID- 24403950 TI - Protein extraction from methanol fixed paraffin embedded tissue blocks: A new possibility using cell blocks. AB - BACKGROUND: Methanol fixed and paraffin embedded (MFPE) cellblocks are an essential cytology preparation. However, MFPE cellblocks often contain limited material and their relatively small size has caused them to be overlooked in biomarker discovery. Advances in the field of molecular biotechnology have made it possible to extract proteins from formalin fixed and paraffin embedded (FFPE) tissue blocks. In contrast, there are no established methods for extracting proteins from MFPE cellblocks. We investigated commonly available CHAPS (3-[(3 cholamidopropyl) dimethylammonio]-1-propanesulfonate) buffer, as well as two commercially available Qiagen((r)) kits and compared their effectiveness on MFPE tissue for protein yields. MATERIALS AND METHODS: MFPE blocks were made by CellientTM automated system using human tissue specimens from normal and malignant specimens collected in ThinPrepTM Vials. Protein was extracted from Cellient-methanol fixed and paraffin embedded blocks with CHAPS buffer method as well as FFPE and Mammalian Qiagen((r)) kits. RESULTS: Comparison of protein yields demonstrated the effectiveness of various protein extraction methods on MFPE cellblocks. CONCLUSION: In the current era of minimally invasive techniques to obtain minimal amount of tissue for diagnostic and prognostic purposes, the use of commercial and lab made buffer on low weight MFPE scrapings obtained by Cellient((r)) processor opens new possibilities for protein biomarker research. PMID- 24403951 TI - Pre-analytic steps for molecular testing on thyroid fine-needle aspirations: The goal of good results. AB - Fine-needle aspiration cytology (FNAC) represents a valid alternative to biopsy in a variety of clinical settings mainly based on its simplicity and less invasive clinical approach. In some cases, morphology evaluation alone is not sufficient to manage the patients, so that the application of ancillary techniques can contribute to diagnosis, prognosis and prediction of tumor behavior. These techniques include polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), in situ PCR, direct Sequencing, microarrays and proteomic methodologies. Although several recent experiences underline the superior value of deoxyribonucleic acid (DNA) quality mainly for advanced genomic high throughput platforms, very scant literature studied the role of the pre analytical or analytical phases. Despite the high specificity of molecular techniques as a support for diagnosis, there is a need for an increased standardization of pre-analytical/analytical steps such as providing appropriate clinical history, proper collection of laboratory specimens and proper preparation of samples, adequate fixative/reagent concentrations and technical equipments. All these requirements are crucial according to the results from 42 American laboratories, which reported 0.33% of significant molecular errors with 60% of them in the pre-analytical phase. The most common error is to forget that cytological preparation requires specific molecular variables, which are different from histological specimens. Cytological samples offer the advantage of a well preserved DNA, readily extractable and reasonably stable (from 6 months to 5 years) avoiding pitfalls due to formalin-fixation. Freshly prepared, unstained direct, alcohol-fixed papanicolaou, air-dried diff-quick smears are all suitable for DNA extraction and preservation. In the specific field of thyroid FNAC, molecular analysis has been supported by the growing evidence that papillary thyroid carcinoma (PTC), the most common thyroid cancer, frequently is a diploid lesion and can display non-overlapping mutations of the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) in 46% to 70%, cases, ret proto-oncogene (RET) in 3 to 85% and Rat Sarcoma oncogene (RAS) in 0-21% cases. Recently, several cytological papers demonstrated that the combination of morphology and molecular analysis can increase the diagnostic accuracy allowing more precise prediction of malignancy regardless of the diagnostic categories. In conclusion, the correct use of the pre-analytical-analytical steps might lead to optimal results on cytology and empower the prognostic value of molecular techniques as strong indicators of cancer for their high specificity and positive predictive value. PMID- 24403952 TI - In Sickness and in Health: a Literature Review about Function of Social Support within Anxiety and Heart Disease Association. AB - A narrative review of the major evidence concerning the relationship between anxiety, social support and cardiac disease was conducted. Literature demonstrates that a strict relationship between anxiety, social support and cardiac disease outcomes subsists. However, the function of social support within anxiety and heart disease association remains unclear and needs to further researches to be established. Moreover evidence suggests that it's the quality of close relationships to play an important role in affecting psychological and physiological health status. The main components that the literature suggests for a better quality of social support and close relationship, and the main assessment measure are presented. Evidence about cardiac rehabilitation programs and the need to assess and intervene on psychological and psychosocial factors is discussed. PMID- 24403953 TI - Effect of surgical clipping versus endovascular coiling on recovery from oculomotor nerve palsy in patients with posterior communicating artery aneurysms: A retrospective comparative study and meta-analysis. AB - BACKGROUND: Oculomotor nerve palsy (OMNP) is a well-recognized complication of posterior communicating artery (PCOM) aneurysms. Only a few comparative studies have assessed the effect of clipping versus coiling on recovery from OMNP in PCOM aneurysms. A retrospective review and meta-analysis was conducted to assess the relationship between PCOM aneurysm treatment and OMNP. MATERIALS AND METHODS: Medical records of all patients presenting between January 2000 and February 2013 with intracranial aneurysm were searched. All patients with OMNP secondary to PCOM aneurysm were included for analysis. Patients undergoing surgical clipping or endovascular coiling were compared with respect to complete resolution of OMNP after aneurysm surgery (i.e., primary outcome). A meta-analysis of published studies of OMNP associated with PCOM aneurysm was performed after a MEDLINE search. RESULTS: Seventeen patients with OMNP secondary to PCOM aneurysms met the inclusion criteria. Surgical clipping (seven of eight patients, or 87.5%) resulted in greater complete resolution of OMNP compared with endovascular coiling (four of nine patients, or 44.4%), P = 0.13. A meta-analysis of similar studies revealed that complete resolution of OMNP was more commonly associated with surgical clipping (36 of 43 patients, or 83.7%) than with endovascular coiling (29 of 55 patients, or 52.7%), yielding an adjusted odds ratio (OR) of 6.04 [confidence interval (CI) =1.88-19.45, P = 0.003]. Multivariate analysis found that the degree of pre-operative OMNP (OR = 0.07, CI = 0.02-0.28, P = 0.001) and surgical clipping (OR = 6.37, CI = 1.73-23.42, P = 0.005) were significant factors that affected the complete recovery of OMNP. CONCLUSION: Complete recovery of OMNP with PCOM aneurysms is more commonly associated with surgical clipping than with endovascular coiling. Also, the degree of pre operative OMNP and the treatment modality are significant factors that affect the complete recovery of OMNP. PMID- 24403954 TI - Optimal invasive key-hole neurosurgery with a miniaturized 3D chip on the tip: Microendoscopic device. AB - OBJECTIVE: The goal of the performed study was to evaluate the possibility of a three-dimensional endoscope to become a combined microscope-endoscope device in one. We analyzed the ergonomy of the device, the implementation into the surgical workflow, the image quality, and the future perspectives such devices could have for the next generation of neurosurgeons. MATERIALS AND METHODS: Within 6 months, 22 patients (10 male, 12 female, 20-65 age) underwent surgery in neuroaxis using the new 3D-microendoscope (ME). The new 3D-ME has (a) the ability to visualize the surgical field from out- to inside with all advantages offered by a microscope, and in the same moment, (b) its design is like a small diameter endoscope that allows stereoscopic views extracorporal, intracorporal, and panoramic "para-side" of the lesion. RESULTS: In general, transcranial 3D "microendoscopy" was performed in all patients with high-resolution 3D quality. No severe complications were observed intra- or postoperatively. With the addition of depth perception, the anatomic structures were well seen and observed. CONCLUSION: The 3D-microendoscopy is a very promising surgical concept associated with new technological developments. The surgeon is able to switch to a modern visualization instrument reaching the most optimal surgical approach without compromising safety, effectiveness, and visual information. PMID- 24403955 TI - Cisternostomy: Replacing the age old decompressive hemicraniectomy? AB - BACKROUND: Practical scenario in trauma neurosurgery comes with multiple challenges and limitations. It accounts for the maximum mortality in neurosurgery and yet the developing countries are still ill-equipped even for an emergency set up for primary management of traumatic brain injuries. The evolution of modern neurosurgical techniques in traumatic brain injury has been ongoing for the last two centuries. However, it has always been a challenge to obtain a satisfactory clinical outcome, especially those following severe traumatic brain injuries. Other than the well-established procedures such as decompressive hemicraniectomy and those for acute and or chronic subdural hematomas and depressed skull fractures, contusions etcetera newer avenues for development of surgical techniques where indicated have been minimal. We are advocating a replacement for decompressive hemicranictomy, which would have the same indications as decompressive hemicraniectomy. The results of this procedure has been compared with the results of decompressive hemicraniectomy done in our institution and elsewhere and has been proven beyond doubts to be superior to decompressive hemicraniectomy. This procedure is elegant and can replace decompressive hemicraniectomy because of low morbidity and mortality. However, there is a steep learning curve and the microscope has to be used. MATERIALS AND METHODS: Based on the clinical experience and observation of acute neurosurgical service in tertiary medical centers in a developing country, the procedure of cisternostomy in the management of trauma neurosurgery have been elucidated in the current study. The study proposes to apply the principles of microvascular surgery and skull base surgery in selected cases of severe traumatic brain injuries, thus replacing decompressive hemicraniectomy as the primary modality of treatment for indicated cases. CONCLUSION: Extensive opening of cisterns making use of skull base techniques to approach them in a swollen brain is a better option to decompressive hemicraniectomy for the same indications. PMID- 24403956 TI - Recurrent lumbar disc herniation: A prospective comparative study of three surgical management procedures. AB - CONTEXT: The optimal surgical treatment of recurrent lumbar disc herniation is controversial. AIM: To compare prospectively the clinical outcomes of surgical treatment of recurrent lumbar disc herniation by three different methods; discectomy alone, discectomy with transforaminal lumbar interbody fusion (TLIF), and diecectomy with posterolateral fusion (PLF), regardless of the postoperative radiological findings. STUDY DESIGN: This is a prospective, randomized, comparative study. MATERIALS AND METHODS: This is a prospective, randomized, comparative study on 45 patients with first time recurrent lumbar disc herniation. Patients were evaluated clinically by using the criteria of the Japanese Orthopedic Association's evaluation system for low back pain syndrome (JOA score). The patients were classified into three groups: Group A; patients who had revision discectomy alone, group B; patients who had revision discectomy with TLIF, and group C; patients who had revision discectomy with PLF. The mean follow-up period was 37 (+/-7.85 STD) months. RESULTS: The mean overall recovery rate was 87.2% (+/-19.26 STD) and the satisfactory rate was 88.9%. Comparison between the three groups showed no significant difference with regard to the mean total postoperative JOA score, recovery rate, and satisfactory rate. However, the postoperative low back pain was significantly higher in group A than that of group B and C. Two patients in group A required further revision surgery. The incidences of dural tear and postoperative neurological deficit were higher in group A. The intraoperative blood loss and length of operation were significantly less in group A. The total cost of the procedure was significantly different between the three groups, being least in group A and highest in group B. There was no significant difference between the three groups with regard to the length of postoperative hospital stay. CONCLUSION: Revision discectomy is effective in patients with recurrent lumbar disc herniation. Fusion with revision discectomy improves the postoperative low back pain, decreases the intraoperative risk of dural tear or neural damage and decreases the postoperative incidence of mechanical instability or re-recurrence. TLIF and PLF have comparable results when used with revision discectomy, but PLF has significantly less total cost than TLIF. PMID- 24403957 TI - Success rate of endoscopic third ventriculostomy in infants below six months of age with congenital obstructive hydrocephalus (a preliminary study of eight cases). AB - AIM: In this study, we were assessing the outcome of Endoscopic Third Ventriculostomy (ETV) in infants below six months of age in cases of congenital obstructive hydrocephalus. MATERIALS AND METHODS: The study was done prospectively on eight cases of obstructive hydrocephalus in infants younger than six months of age to assess the success rate of ETV as a primary treatment for hydrocephalus in this age group; in cases of evident failure, a ventriculo peritoneal (VP) shunt was applied. RESULTS: Despite eliminating the factors suggested as causes of ETV failure in infants below six months; the type, as with the communicating hydrocephalus, the thickness of the third ventricular floor, history of previous intracranial hemorrhage or central nervous system infection, still the success rate did not exceed 12.5%. CONCLUSIONS: The complication rate following ETV was low in comparison to the high frequency (20-80%) and seriousness of the possible postoperative complications following VP shunt with a significant decrease in the quality of patients' lives. Hence the decision-making as well as the parental counselling were in a trial to estimate the ETV success or the need to perform a shunt in the treatment of obstructive hydrocephalus. PMID- 24403958 TI - Percutaneous pedicle screw placement in the thoracic spine: A cadaveric study. AB - STUDY DESIGN: A cadaveric study to determine the accuracy of percutaneous screw placement in the thoracic spine using standard fluoroscopic guidance. SUMMARY OF BACKGROUND DATA: While use of percutaneous pedicle screws in the lumbar spine has increased rapidly, its acceptance in the thoracic spine has been slower. As indications for pedicle screw fixation increase in the thoracic spine so will the need to perform accurate and safe placement of percutaneous screws with or without image navigation. To date, no study has determined the accuracy of percutaneous thoracic pedicle screw placement without use of stereotactic imaging guidance. MATERIALS AND METHODS: Eighty-six thoracic pedicle screw placements were performed in four cadaveric thoracic spines from T1 to T12. At each level, Ferguson anterior-posterior fluoroscopy was used to localize the pedicle and define the entry point. Screw placement was attempted unless the borders of the pedicle could not be delineated solely using intraoperative fluoroscopic guidance. The cadavers were assessed using pre- and postprocedural computed tomography (CT) scans as well as dissected and visually inspected in order to determine the medial breach rate. RESULTS: Ninety pedicles were attempted and 86 screws were placed. CT analysis of screw placement accuracy revealed that only one screw (1.2%) breached the medial aspect of the pedicle by more than 2 mm. A total of four screws (4.7%) were found to have breached medially by visual inspection (three Grade 1 and one Grade 2). One (1.2%) lateral breach was greater than 2 mm and no screw violated the neural foramen. The correlation coefficient of pedicle screw violations and pedicle diameter was found to be 0.96. CONCLUSIONS: This cadaveric study shows that percutaneous pedicle screw placement can be performed in the thoracic spine without a significant increase in the pedicle breach rate as compared with standard open techniques. A small percentage (4.4%) of pedicles, especially high in the thoracic spine, may not be safely visualized. PMID- 24403959 TI - Demographic and clinical profile of patients with brain metastases: A retrospective study. AB - CONTEXT: Brain metastases are the most common type of intracranial neoplasm, with the total number outnumbering primary brain tumors by a ratio of 10:1 and occur in about 25% of cancer patients. However, controversies exist regarding demographic and clinical profile of brain metastases. AIMS: The purpose of this study was to analyze retrospectively the demographic and clinical profile of patients with brain metastases. SETTINGS AND DESIGN: Retrospective, single institutional study. MATERIALS AND METHODS: A retrospective study of 72 patients with brain metastasis was carried out from November 2010 to October 2012. The data pertaining to these patients was entered in a standardized case record form. These include History; clinical examination and other investigations including computed tomography/magnetic resonance imaging scan of the brain. STATISTICAL ANALYSIS: A statistical analysis was performed on the data collected using the MedCalc version 11. RESULTS: Brain metastases were more common in male and occur in 6(th) decade of life mostly. There was no relationship of occupation or socio economic status with the incidence of brain metastases. Carcinoma lung was the most common primary giving rise to brain metastases followed by breast. Adenocarcinoma accounts for most common histology of the primary that give rise to metastases. Multiple metastases were more common than the single group. Supratentorial lesions were more common than infratentorial lesions. Among them, parietal lobe was the most common site of involvement. CONCLUSIONS: The present study highlights that the incidence of brain metastasis is common in elderly population and mostly due to primary lung. Adenocarcinoma was the most common histology of primary. Majority of lesions has been observed at parietal lobe. PMID- 24403960 TI - Hemorrhagic colloid cyst: Case report and review of the literature. AB - Colloid cysts are cystic lesions located at the anterior part of third ventricle, close to foramen of Monro and contain colloid material. Hemorrhage in a colloid cyst is very rare. On literature review, we found only six cases of hemorrgic colloid cyst; among them, four were diagnosed at postmortem examination. We report a rare case of a hemorrhagic colloid cyst in a young lady who presented with sudden onset severe headache and vomiting. Computed tomography (CT) scan showed isodense lesion located at foramen of Monro with hyperdense areas suggestive of hemorrhage with foraminal obstruction. The lesion was not enhancing on contrast. Magnetic resonance imaging (MRI) brain revealed a well-defined cystic mass lesion located at the foramen of Monro which was hyperintense on T1 and hypointense on T2-weighted images. Excision of the colloid cyst was performed which revealed hemorrhagic clot instead of colloid material. Histopathological examination revealed a colloid cyst with hemorrhage. We believe that this is the first such reported case of successful clinical outcome following early diagnosis and excision of a hemorrhagic colloid cyst in an adult. PMID- 24403961 TI - Grave's disease with transverse and sigmoid sinus thrombosis needing surgical intervention. AB - Thrombosis of venous sinuses associated with thyrotoxicosis is rare, and isolated transverse and sigmoid sinus thrombosis is rarer and reported only once previously. We present a case of Graves disease, who suffered unilateral sigmoid and transverse sinus thrombosis with intracranial hemorrhage. A 42-year-old female, a diagnosed case of Graves disease, presented to us with headache, drowsiness, and hemiparesis. Computed Tomography revealed a large right temporo parieto-occipital venous infarct. The patient needed surgical intervention in the form of decompressive craniotomy following which she improved, and on follow-up is having no deficits. Thrombophilia profile showed a low Protein S and Anti thrombin III (AT III) levels. Deranged thrombophilia profile in combination with the hypercoagulable state in thyrotoxicosis, most likely precipitated the thrombotic event. Timely surgical intervention can be offered in selective cases with a good clinical outcome. PMID- 24403962 TI - Large primary intraorbital hydatid cyst in elderly. AB - We report a case of solitary, primary intraorbital hydatid cyst in a elderly female aged 80 years who presented with nontender, nonpulsatile proptosis of left eye with diminution of vision. MRI scan of the head and the orbits, revealed a retro-bulbar cyst. Surgical excision was performed by employing a lateral orbitotomy approach. Histopathology report confirmed hydatid cyst. PMID- 24403963 TI - Atlanto-axial dislocation associated with anomalous single vertebral artery and agenesis of unilateral internal carotid artery. AB - We report a case of an anomalous single midline vertebral artery (VA) in a case of atlanto-axial dislocation (AAD). The left VA coursed in the midline at craniovertebral junction as there was no right VA. The left internal carotid artery was also not formed. This was a case report of a 34-year-old male patient who presented with features of high cervical myelopathy. On evaluation, he had fixed AAD. There was inadvertent intra-operative VA injury, which was sealed to control the brisk bleeding to require stenting ultimately. Patient did not survive and expired after 5 days due to brain edema secondary to compromised anomalous intracranial circulation. PMID- 24403964 TI - Unruptured anterior communicating artery aneurysms presenting with seizure: Report of three cases and review of literature. AB - Aneurysms generally present with bleed and epileptogenic aneurysms are rare. Unruptured epilpetogenic anterior communicating artery aneurysms are extremely rare and anecdotal. We present three patients with unruptured anterior communicating artery aneurysms who presented with seizures and were surgically managed. Seizure might be related to the large size, presence of thrombus, microbleeds and surrounding gliosis. We suggest that large thrombosed anterior communicating artery aneurysms should be considered in the differential diagnosis of patients presenting with late onset of seizure and having a suprasellar lesion on imaging. Surgical clipping offers a fair chance of seizure freedom in selected patients. PMID- 24403965 TI - Armoured brain of unknown etiology. AB - Armoured brain is a rare condition where dense calcification occurs over the brain. It can result in mass effect and raised intracranial pressure. Most often, it happens due to trauma, subdural effusion, infection, or after VP shunt. There is controversy in its treatment. Most published literature does not support removing the calcification. We describe a rare case of idiopathic chronic calcified subdural hematoma with relatively short history which was successfully treated by microsurgical removal of calcification over the brain. This resulted in complete expansion of the brain with relief in symptoms. PMID- 24403966 TI - The causal representation of outpatients with Crohn's disease: is there a link between psychological distress and clinical disease activity? AB - OBJECTIVES: Because of the fluctuating and occasional character of Crohn's disease (CD), patients have to cope with a changeable condition of health. Personal perceived control is known to be an important element of adaptation to their medical condition. The objectives of this work are to determine if perceived personal control is predictive of the clinical activity of the disease and of psychological distress (depression, anxiety). METHODS: The Hospital Anxiety Depression Scale (HADS), the causal dimension scale and the Clinical Global Impression (CGI; assessing perceived severity) were administered to 160 patients affected by Crohn's disease. Indicators of inflammation (CRP), disease duration and clinical activity of the disease were also asessed. RESULTS: Globally, CD patients perceive their disease as being personally neither controllable nor uncontrollable. Whereas psychological distress is significantly higher when the disease is active, the relationship between the variables appears complex. The feeling of personal control is explained by the clinical activity of the disease (p=.0001) and by the perception that CD is unstable (p<.00001) and globally impacts the life of patients (p=.001). Nevertheless perception of personal control does not explain the clinical activity of the disease. Finally, psychological distress is explained by the perception that the medical team is unable to control the disease (p=.00001) and by the global consequences of the disease on life (p<.005). CONCLUSIONS: Psychological treatments should take these dimensions into account so as to improve the well-being and medical conditions of patients. PMID- 24403967 TI - Manual for the psychotherapeutic treatment of acute and post-traumatic stress disorders following multiple shocks from implantable cardioverter defibrillator (ICD). AB - BACKGROUND: In view of the increasing number of implanted cardioverter defibrillators (ICD), the number of people suffering from so-called "multiple ICD shocks" is also increasing. The delivery of more than five shocks (appropriate or inappropriate) in 12 months or three or more shocks (so called multiple shocks) in a short time period (24 hours) leads to an increasing number of patients suffering from severe psychological distress (anxiety disorder, panic disorder, adjustment disorder, post-traumatic stress disorder). Untreated persons show chronic disease processes and a low rate of spontaneous remission and have an increased morbidity and mortality. Few papers have been published concerning the psychotherapeutic treatment for these patients. OBJECTIVE: The aim of this study is to develop a psychotherapeutic treatment for patients with a post-traumatic stress disorder or adjustment disorder after multiple ICD shocks. DESIGN: Explorative feasibility study: Treatment of 22 patients as a natural design without randomisation and without control group. The period of recruitment was three years, from March 2007 to March 2010. The study consisted of two phases: in the first phase (pilot study) we tested different components and dosages of psychotherapeutic treatments. The final intervention programme is presented in this paper. In the second phase (follow-up study) we assessed the residual post traumatic stress symptoms in these ICD patients. The time between treatment and follow-up measurement was 12 to 30 months. POPULATION: Thirty-one patients were assigned to the Department of Psychocardiology after multiple shocks. The sample consisted of 22 patients who had a post-traumatic stress disorder or an adjustment disorder and were willing and able to participate. They were invited for psychological treatment. 18 of them could be included into the follow-up study. METHODS: After the clinical assessment at the beginning and at the end of the inpatient treatment a post-treatment assessment with questionnaires followed. In this follow-up measurement, minimum 12 months after inpatient treatment, posttraumatic stress was assessed using the "Impact of Event Scale" (IES-R). SETTING: Inpatient treatment in a large Heart and Thorax Centre with a Department of Psychocardiology (Kerckhoff Heart Centre). RESULTS: From the 18 patients in the follow-up study no one reported complaints of PTSD. 15 of them reported a high or even a very high decrease of anxiety and avoidance behaviour. CONCLUSIONS: The fist step of the treatment development seems to be successful. It shows encouraging results with an acceptable dosage. The second step of our work is in process now: we evaluate the treatment manual within other clinical institutions and a higher number of psychotherapists. This leads in the consequence to a controlled and randomised comparison study. PMID- 24403968 TI - Letter from the editor. PMID- 24403970 TI - Management of patients with risk factors. AB - This review addresses concomitant diseases and risk factors in patients treated for diseases of the ears, nose and throat in outpatient and hospital services. Besides heart disease, lung disease, liver disease and kidney disease, this article also covers disorders of coagulation (including therapy with new oral anticoagulants) and electrolyte imbalance. Special attention is paid to the prophylaxis, diagnosis and treatment of perioperative delirium. It is also intended to help optimise the preparation for surgical procedures and pharmacotherapy during the hospital stay. PMID- 24403971 TI - Hazards and risks in oncology: radiation oncology. AB - Adverse effects and hazards which have their origin from radiation using conventional techniques like 3-D conformal radiotherapy and total radiation doses are well known. However little is known about the sprectum of especially late toxicity after radiation using new technologies like intensity modulated radiotherapy (IMRT) combined with novel target volume and dose concepts. Since IMRT allows for selective protection of the large salivary glands this technique improves the intermediate term quality of life and is the standard of care despite many details need further prospective evaluation. Combining cytotoxic drugs and radiotherapy yield improved survival in well-defined high risk patients. However morbidity and mortality of these protocols are high and deserve special expertise and supportive therapy. EGF-receptor antibodies have gained well defined indications, albeit specific toxicities in combination with irradiation deserve prospective studies and special attention. PMID- 24403969 TI - Diagnostic and therapeutic pitfalls in benign vocal fold diseases. AB - More than half of patients presenting with hoarseness show benign vocal fold changes. The clinician should be familiar with the anatomy, physiology and functional aspects of voice disorders and also the modern diagnostic and therapeutic possibilities in order to ensure an optimal and patient specific management. This review article focuses on the diagnostic and therapeutic limitations and difficulties of treatment of benign vocal fold tumors, the management and prevention of scarred vocal folds and the issue of unilateral vocal fold paresis. PMID- 24403972 TI - Surgical errors and risks - the head and neck cancer patient. AB - Head and neck surgery is one of the basic principles of head and neck cancer therapy. Surgical errors and malpractice can have fatal consequences for the treated patients. It can lead to functional impairment and has impact in future chances for disease related survival. There are many risks for head and neck surgeons that can cause errors and malpractice. To avoid surgical mistakes, thorough preoperative management of patients is mandatory. As there are ensuring operability, cautious evaluation of preoperative diagnostics and operative planning. Moreover knowledge of anatomical structures of the head and neck, of the medical studies and data as well as qualification in modern surgical techniques and the surgeons ability for critical self assessment are basic and important prerequisites for head and neck surgeons in order to make out risks and to prevent from mistakes. Additionally it is important to have profound knowledge in nutrition management of cancer patients, wound healing and to realize and to be able to deal with complications, when they occur. Despite all precaution and surgical care, errors and mistakes cannot always be avoided. For that it is important to be able to deal with mistakes and to establish an appropriate and clear communication and management for such events. The manuscript comments on recognition and prevention of risks and mistakes in the preoperative, operative and postoperative phase of head and neck cancer surgery. PMID- 24403975 TI - Aesthetic rhinoplasty plus brow, eyelid and conchal surgery: pitfalls - complications - prevention. AB - Within the last years aesthetic surgery enjoys greater popularity and acceptance. One of the most frequently asked operations has been the aesthetic rhinoplasty. Hardly any other field of surgery is exposed to such a critical analysis than aesthetic rhinoplasty because the results are so obvious. According to the "International Society of Aesthetic Surgery" (ISAPS) over 980,000 cosmetic rhinoplasties have been performed in 2010. This corresponds to 10.4% of all registered aesthetic procedures worldwide. Complications can not be eliminated in such a large number of nasal operations. Five to 15% of all patients re-consult a doctor for a revision because they are much dissatisfied with their final rhinoplasty result. Findings of the tip followed by functional problems and irregularities of the nasal dorsum are named most frequently. The responsible rhinosurgeon has to take into account all anatomical and physiological details and to consider ethical and psychological aspects in the pre-selection and postoperative care of the patient. Aesthetic surgeons should be acquainted with terms and definitions like body image, dysmorphophobia or Thersites complex. Acronyms, like "SIMON" or "SYLVIA", support the physician additionally to analyze and assess the patient. The following article describes the most frequent faults, complications and pitfalls after aesthetic rhinoplasty listed by the anatomical structure. Results will be analyzed and strategies and techniques will be suggested to correct the faults and to prevent them in the future. Furthermore psychologic, social and psychiatric aspects will be discussed and handling with aesthetic patients explained. PMID- 24403978 TI - Errors and pitfalls: Briefing and accusation of medical malpractice - the second victim. AB - In June 2012, the German Medical Association (Bundesarztekammer) published the statistics of medical malpractice for 2011 (published at http://www.bundesaerztekammer.de). Still ENT-specific accusations of medical malpractice are by far the fewest in the field of hospitals and actually even in the outpatient context. Clearly most of the unforeseen incidents still occur in the disciplines of trauma surgery and orthopedics. In total, however, an increasing number of errors in treatment can be noticed on the multidisciplinary level: in 25.5% of the registered cases, an error in treatment was found to be the origin of damage to health justifying a claim for compensation of the patient. In the year before, it was only 24.7%. The reasons may be manifold, but the medical system itself certainly plays a major role in this context: the recent developments related to health policy lead to a continuous economisation of medical care. Rationing and limited remuneration more and more result in the fact that therapeutic decision are not exclusively made for the benefit of the patient but that they are oriented at economic or bureaucratic aspects. Thus, in the long term, practising medicine undergoes a change. According to the SS 1, 3 of the professional code of conduct for doctors (Musterberufsordnung fur Arzte; MBO-A) medical practice as liberal profession is principally incompatible with the pursuit of profit, however, even doctors have to earn money which more and more makes him play the role of a businessman. Lack of personnel and staff savings lead to excessive workloads of physicians, caregivers, and nurses, which also favour errors. The quality and even the confidential relationship between doctor and patient, which is important for the treatment success, are necessarily affected by the cost pressure. The victims in this context are not only the patients but also the physicians find themselves in the continuous conflict between ethical requirements of their profession and the actual requirements of the realities in the healthcare field. But also the technical and scientific progress bear new risks beside the therapeutic successes, further especially bigger hospitals require high efforts regarding organisation favouring errors in cases of deficiencies. Even the increasing juridification of the medicine that is expected to achieve a provisional highlight with the planned law of patients' rights leads to an important focus on the quality of medical care (see also [1]). The explicit legal regulation of patients' rights, which have never been out of question up to now, confirms the impression of patients who have to be protected from their doctors. This development favours a natural mistrust in the quality of the treatment and the desire of legal verification in cases of treatment failures. A totally perfect and error-free treatment, however, will never occur. Already this fact leads to the obligation to do everything possible to reduce the risk to an absolute minimum. The risks that might arise from a relation of treatment are manifold. Not only may the patient undergo risks that arise in particular from lacking or insufficient briefing, complications, or medical malpractice. Also the doctor has to fear legal consequences if he does not stick clearly to the increasing requirements that jurisdiction and legislation impose - not least by the planned law of patients' rights. In the following, the basic principles and particularities will be described that apply for the patients' briefing. Further the different types of medical malpractice will be explained in relation to the resulting procedural consequences. Finally some current problematic fields will be described with regard to other possible liabilities or responsibilities of physicians in hospitals or doctor's offices. PMID- 24403977 TI - Safe patient care - safety culture and risk management in otorhinolaryngology. AB - Safety culture is positioned at the heart of an organization's vulnerability to error because of its role in framing organizational awareness to risk and in providing and sustaining effective strategies of risk management. Safety related attitudes of leadership and management play a crucial role in the development of a mature safety culture ("top-down process"). A type marker for organizational culture and thus a predictor for an organization's maturity in respect to safety is information flow and in particular an organization's general way of coping with information that suggests anomaly. As all values and beliefs, relationships, learning, and other aspects of organizational safety culture are about sharing and processing information, safety culture has been termed "informed culture". An informed culture is free of blame and open for information provided by incidents. "Incident reporting systems" are the backbone of a reporting culture, where good information flow is likely to support and encourage other kinds of cooperative behavior, such as problem solving, innovation, and inter-departmental bridging. Another facet of an informed culture is the free flow of information during perioperative patient care. The World Health Organization's safe surgery checklist" is the most prevalent example of a standardized information exchange aimed at preventing patient harm due to information deficit. In routine tasks mandatory standard operating procedures have gained widespread acceptance in guaranteeing the highest possible process quality. Technical and non-technical skills of healthcare professionals are the decisive human resource for an efficient and safe delivery of patient care and the avoidance of errors. The systematic enhancement of staff qualification by providing training opportunities can be a major investment in patient safety. In recent years several otorhinolaryngology departments have started to incorporate stimulation based team trainings into their curriculum. PMID- 24403973 TI - Surgery of the ear and the lateral skull base: pitfalls and complications. AB - Surgery of the ear and the lateral skull base is a fascinating, yet challenging field in otorhinolaryngology. A thorough knowledge of the associated complications and pitfalls is indispensable for the surgeon, not only to provide the best possible care to his patients, but also to further improve his surgical skills. Following a summary about general aspects in pre-, intra-and postoperative care of patients with disorders of the ear/lateral skull base, this article covers the most common pitfalls and complications in stapes surgery, cochlear implantation and surgery of vestibular schwannomas and jugulotympanal paragangliomas. Based on these exemplary procedures, basic "dos and don'ts" of skull base surgery are explained, which the reader can easily transfer to other disorders. Special emphasis is laid on functional aspects, such as hearing, balance and facial nerve function. Furthermore, the topics of infection, bleeding, skull base defects, quality of life and indication for revision surgery are discussed. An open communication about complications and pitfalls in ear/lateral skull base surgery among surgeons is a prerequisite for the further advancement of this fascinating field in ENT surgery. This article is meant to be a contribution to this process. PMID- 24403980 TI - Cat-scratch disease in adult hospitalized for prolonged-Fever associated with multiple lymphadenopathies and weight loss. AB - We report a 19-year-old patient with a Cat-scratch disease presenting three months continuous alteration of the general condition, including prolonged-fever, anorexia, asthenia, weight loss associated with adenitis and multiple thoracic abdominal adenopathies, leukocytosis with neutrophil polynuclear predominance, and increased of C-reactive protein. The serologies of toxoplasmosis, infectious mononucleosis, human immunodeficiency virus, Brucellosis, Bartonellosis and the tuberculosis research by tuberculin reaction test and Ziehl acid-alcohol resistant bacilli direct examination were negatives. The cytomegalovirus and Epstein-Barr virus serologies were positives only for immunoglobulin-G. The Bartonella henselae diagnosis was made with the analysis of histopathological specimens. The clinical and biological symptoms regressed following eight weeks of azithromycin's treatment. According to this observation, the cat-scratch disease should be considered in differential diagnosis of patients presenting prolonged-fever associated with multiple lymphadenopathies and weight loss. The azithromycin would be an alternative therapeutic issue for this pathology in case of confirmed efficacy by studies in a large patient population. PMID- 24403979 TI - Advantages and limitations of ribosomal RNA PCR and DNA sequencing for identification of bacteria in cardiac valves of danish patients. AB - Studies on the value of culture-independent molecular identification of bacteria in cardiac valves are mostly restricted to comparing agreement of identification to what is obtained by culture to the number of identified bacteria in culture negative cases. However, evaluation of the usefulness of direct molecular identification should also address weaknesses, their relevance in the given setting, and possible improvements. In this study cardiac valves from 56 Danish patients referred for surgery for infective endocarditis were analysed by microscopy and culture as well as by PCR targeting part of the bacterial 16S rRNA gene followed by DNA sequencing of the PCR product. PCR and DNA sequencing identified significant bacteria in 49 samples from 43 patients, including five out of 13 culture-negative cases. No rare, exotic, or intracellular bacteria were identified. There was a general agreement between bacterial identity obtained by ribosomal PCR and DNA sequencing from the valves and bacterial isolates from blood culture. However, DNA sequencing of the 16S rRNA gene did not discriminate well among non-haemolytic streptococci, especially within the Streptococcus mitis group. Ribosomal PCR with subsequent DNA sequencing is an efficient and reliable method of identifying the cause of IE, but exact species identification of some of the most common causes, i.e. non-haemolytic streptococci, may be improved with other molecular methods. PMID- 24403981 TI - Validating emergency department vital signs using a data quality engine for data warehouse. AB - BACKGROUND: Vital signs in our emergency department information system were entered into free-text fields for heart rate, respiratory rate, blood pressure, temperature and oxygen saturation. OBJECTIVE: We sought to convert these text entries into a more useful form, for research and QA purposes, upon entry into a data warehouse. METHODS: We derived a series of rules and assigned quality scores to the transformed values, conforming to physiologic parameters for vital signs across the age range and spectrum of illness seen in the emergency department. RESULTS: Validating these entries revealed that 98% of free-text data had perfect quality scores, conforming to established vital sign parameters. Average vital signs varied as expected by age. Degradations in quality scores were most commonly attributed logging temperature in Fahrenheit instead of Celsius; vital signs with this error could still be transformed for use. Errors occurred more frequently during periods of high triage, though error rates did not correlate with triage volume. CONCLUSIONS: In developing a method for importing free-text vital sign data from our emergency department information system, we now have a data warehouse with a broad array of quality-checked vital signs, permitting analysis and correlation with demographics and outcomes. PMID- 24403982 TI - Limitations of Adenoviral Vector-Mediated Delivery of Gold Nanoparticles to Tumors for Hyperthermia Induction. AB - Novel combinatorial treatment strategies are desired to achieve tumor eradication. In this regard, nanotechnology and gene therapy hold the potential to expand the available tumor treatment options. In particular, gold nanoparticles (AuNPs) have been utilized for hyperthermic tumor cell ablation. Similarly, adenoviral (Ad) vectors have been utilized for targeting, imaging, and cancer gene therapy. Thus, to combine AuNP-mediated hyperthermia with Ad vector based gene therapy, we have previously coupled AuNPs to Ad vectors. Herein we tested the capability of these AuNP-coupled Ad vectors for hyperthermic tumor cell ablation. Towards this end, we compared absorption characteristics of different sized AuNPs and determined that in our system 20 nm diameter AuNPs are suitable for laser induced hyperthermic tumor cell killing. In addition, we observed that AuNPs outside and inside the cell contribute differentially towards hyperthermia induction. Unfortunately, due to the limitation of delivery of required amounts of AuNPs to cells, we observed that AuNP-coupled Ad vectors are unable to kill tumor cells via hyperthermia. However, with future technological advances, it may become possible to realize the potential of the multifunctional AuNP-coupled Ad vector system for simultaneous targeting, imaging, and combined hyperthermia and gene therapy of tumors. PMID- 24403976 TI - Malpractice claims and unintentional outcome of tonsil surgery and other standard procedures in otorhinolaryngology. AB - BACKGROUND: Septoplasty, tonsillectomy (with and without adenoidectomy) and cervical lymph node excision are amongst the most common 50 inpatient operations in Germany. Intracapsular tonsillectomies (i.e. tonsillotomies) are increasingly performed. The aim of this study was to evaluate technical traps and pitfalls as well as alleged medical malpractice associated with tonsillectomy (TE), adenoidectomy (AE), tonsillotomy (TT), septoplasty (SP) and cervical lymph node excision (LN). METHODS: A questionnaire was sent to the Regional Medical Conciliation Boards, Medical Services of the Health Insurance Companies (MDK) and Regional Institutes of Forensic Medicine in Germany to collect anonymized cases of complications following TE, TT, AE, LN and SP. The results were discussed in the light of the contemporary medical literature and published trials and verdicts in Germany. RESULTS: The response rate of our survey was 55.9%. The Institutes of Forensic Medicine contributed nine cases, 49 cases were submitted by the Regional Conciliation Boards and none by MDK. All forensic cases were associated with exsanguinations following tonsillectomy including two children (5 and 8 years of age) and seven adults (aged 20 to 69 years). The fatal post tonsillectomy hemorrhage (PTH) had occurred 8.7 days on average; four patients experienced the bleeding episode at home (day 5, 8, 9 and 17, respectively). Repeated episodes of bleeding requiring surgical intervention had occurred in 6 patients. Three Conciliation Boards submitted decicions associated with TT (1), AE (4), LN (3), SP (16) and TE (25). Cases with lethal outcome were not registered. Only three of the 49 cases were assessed as surgical malpractice (6.1%) including lesion of the spinal accessory nerve, wrong indication for TE and dental lesion after insertion of the mouth gag. The review of the medico legal literature yielded 71 published verdicts after AE and TE (29), LN (28) and SP (14) of which 37 resulted in compensation of malpractice after LN (16; 57%), TE (10; 37%), SP (8; 57%) and AE (2; 100%). There were 16 cases of PTH amongst 27 trials after TE resulting either in death (5) or apallic syndrome (5). Bleeding complications had occurred on the day of surgery in only 2 patients. 16 trials were based on malpractice claims following SP encompassing lack of informed consent (6), anosmia (4), septal perforation (2), frontobasal injury (2) and dry nose (2). Trials after LN procedures were associated exclusively with a lesion of the spinal accessory nerve (28), including lack of informed consent in 19 cases. 49 cases (69%) were decided for the defendant, 22 (31%) were decided for the plaintiff with monetary compensation in 7 of 29 AE/TE-trials, 9 of 28 LN-trials and 6 of 14 SP-trials. Lack of informed consent was not registered for AE/TE but LN (11) and SP (2). CONCLUSION: Complicated cases following TE, TT, ATE, SP and LN are not systematically collected in Germany. It can be assumed, that not every complicated case is published in the medical literature or law journals and therefore not obtainable for scientific research. Alleged medical malpracice is proven for less than 6% before trial stage. Approximately half of all cases result in a plaintiff verdict or settlement at court. Proper documentation of a thourough counselling, examination, indication, informed consent and follow-up assists the surgeon in litigation. An adequate complication management of PTH is essential, including instructions for the patients/parents, instructions for the medical staff and readily available surgical instruments. Successful outcome of life-threatening PTH is widely based on a proper airway management in an interdisciplinary approach. Electrosurgical tonsillectomy techniques were repeatedly labeled as a risk factor for bleeding complications following TE. Institutions should analyse the individual PTH rate on a yearly basis. Contradictory expert opinions and verdicts of the courts concerning spinal accesory nerve lesions following LN are due to a lack of a surgical standard. PMID- 24403983 TI - Moderate Recurrent Hypoglycemia Markedly Impairs Set-Shifting Ability in a Rodent Model: Cognitive and Neurochemical Effects. AB - Recurrent hypoglycemia (RH) is the major complication of intensive insulin treatment for diabetes mellitus. Of particular concern is the perceived potential for long-term impact of RH on cognition. Because diabetic patients have been reported to have deficits in mental flexibility and judgment, both generally considered to be mediated predominantly by the prefrontal cortex, the purpose of the present study was to determine whether RH would affect prefrontal cortex function. Medial prefrontal cortex (mPFC)-mediated set-shifting ability was tested in male Sprague-Dawley rats using a maze-based, food-reward Set-Shift task analogous to the Wisconsin card-sorting task. The performance measure was the number of trials to criterion on both day 1 (initial rule-learning) and day 2 (set-shifting in response to a changed contingency). In vivo microdialysis was used to measure mPFC extracellular glucose, lactate, pyruvate, glutamate, and dopamine. Post-mortem measures within the mPFC included glucose transporter 3 (GluT3) and c-Fos. RH animals had enhanced performance on day 1, consistent with previous work that showed RH to improve subsequent hippocampal function when euglycemic. The key finding of the present work is that RH led to impaired set shifting performance on day 2, suggesting impairment in e.g. mental flexibility. Consistent with this finding, RH animals show decreased mPFC glycolysis on day 2 compared to controls. Our data show that RH can lead to subsequent impaired judgment, accompanied by reduced prefrontal cortex function. The findings suggest a potential underlying mechanism for the impaired judgment seen in diabetic patients. PMID- 24403984 TI - An integrated microfluidic device for rapid serodiagnosis of amebiasis. AB - A microfluidic device was successfully fabricated for the rapid serodiagnosis of amebiasis. A micro bead-based immunoassay was fabricated within integrated microfluidic chip to detect the antibody to Entamoeba histolytica in serum samples. In this assay, a recombinant fragment of C terminus of intermediate subunit of galactose and N-acetyl-D-galactosamine-inhibitable lectin of Entamoeba histolytica (C-Igl, aa 603-1088) has been utilized instead of the crude antigen. This device was validated with serum samples from patients with amebiasis and showed great sensitivity. The serodiagnosis can be completed within 20 min with 2 MUl sample consumption. The device can be applied for the rapid and cheap diagnosis of other infectious disease, especially for the developing countries with very limited medical facilities. PMID- 24403974 TI - Danger points, complications and medico-legal aspects in endoscopic sinus surgery. AB - Endoscopic endonasal sinus surgery represents the overall accepted type of surgical treatment for chronic rhinosinusitis. Notwithstanding raised and still evolving quality standards, surgeons performing routine endoscopic interventions are faced with minor complications in 5% and major complications in 0.5-1%. A comprehensive review on all minor and major complications of endoscopic surgery of the paranasal sinuses and also on the anterior skull base is presented listing the actual scientific literature. The pathogenesis, signs and symptoms of each complication are reviewed and therapeutic regimens are discussed in detail relating to actual publication references. Potential medico-legal aspects are explicated and recent algorithms of avoidance are mentioned taking into account options in surgical training and education. PMID- 24403985 TI - Separation of tumor cells with dielectrophoresis-based microfluidic chip. AB - The present work demonstrates the use of a dielectrophoretic lab-on-a-chip device in effectively separating different cancer cells of epithelial origin for application in circulating tumor cell (CTC) identification. This study uses dielectrophoresis (DEP) to distinguish and separate MCF-7 human breast cancer cells from HCT-116 colorectal cancer cells. The DEP responses for each cell type were measured against AC electrical frequency changes in solutions of varying conductivities. Increasing the conductivity of the suspension directly correlated with an increasing frequency value for the first cross-over (no DEP force) point in the DEP spectra. Differences in the cross-over frequency for each cell type were leveraged to determine a frequency at which the two types of cell could be separated through DEP forces. Under a particular medium conductivity, different types of cells could have different DEP behaviors in a very narrow AC frequency band, demonstrating a high specificity of DEP. Using a microfluidic DEP sorter with optically transparent electrodes, MCF-7 and HCT-116 cells were successfully separated from each other under a 3.2 MHz frequency in a 0.1X PBS solution. Further experiments were conducted to characterize the separation efficiency (enrichment factor) by changing experimental parameters (AC frequency, voltage, and flow rate). This work has shown the high specificity of the described DEP cell sorter for distinguishing cells with similar characteristics for potential diagnostic applications through CTC enrichment. PMID- 24403986 TI - Sequentially pulsed fluid delivery to establish soluble gradients within a scalable microfluidic chamber array. AB - This work presents a microfluidic chamber array that generates soluble gradients using sequentially pulsed fluid delivery (SPFD). SPFD produces stable gradients by delivering flow pulses to either side of a chamber. The pulses on each side contain different signal concentrations, and they alternate in sequence, providing the driving force to establish a gradient via diffusion. The device, herein, is significant because it demonstrates the potential to simultaneously meet four important needs that can accelerate and enhance the study of cellular responses to signal gradients. These needs are (i) a scalable chamber array, (ii) low complexity fabrication, (iii) a non-shearing microenvironment, and (iv) gradients with low (near zero) background concentrations. The ability to meet all four needs distinguishes the SPFD device from flow-based and diffusion-based designs, which can only achieve a subset of such needs. Gradients are characterized using fluorescence measurements, which reveal the ability to change the curvature of concentration profiles by simple adjustments to pulsing sequence and flow rate. Preliminary experiments with MDA-MB-231 cancer cells demonstrate cell viability and indicate migrational and morphological responses to a fetal bovine serum gradient. Improved and expanded versions of this technology could form the basis of high-throughput screening tools to study cell migration, development, and cancer. PMID- 24403987 TI - Empirical chemosensitivity testing in a spheroid model of ovarian cancer using a microfluidics-based multiplex platform. AB - The use of biomarkers to infer drug response in patients is being actively pursued, yet significant challenges with this approach, including the complicated interconnection of pathways, have limited its application. Direct empirical testing of tumor sensitivity would arguably provide a more reliable predictive value, although it has garnered little attention largely due to the technical difficulties associated with this approach. We hypothesize that the application of recently developed microtechnologies, coupled to more complex 3-dimensional cell cultures, could provide a model to address some of these issues. As a proof of concept, we developed a microfluidic device where spheroids of the serous epithelial ovarian cancer cell line TOV112D are entrapped and assayed for their chemoresponse to carboplatin and paclitaxel, two therapeutic agents routinely used for the treatment of ovarian cancer. In order to index the chemoresponse, we analyzed the spatiotemporal evolution of the mortality fraction, as judged by vital dyes and confocal microscopy, within spheroids subjected to different drug concentrations and treatment durations inside the microfluidic device. To reflect microenvironment effects, we tested the effect of exogenous extracellular matrix and serum supplementation during spheroid formation on their chemotherapeutic response. Spheroids displayed augmented chemoresistance in comparison to monolayer culturing. This resistance was further increased by the simultaneous presence of both extracellular matrix and high serum concentration during spheroid formation. Following exposure to chemotherapeutics, cell death profiles were not uniform throughout the spheroid. The highest cell death fraction was found at the center of the spheroid and the lowest at the periphery. Collectively, the results demonstrate the validity of the approach, and provide the basis for further investigation of chemotherapeutic responses in ovarian cancer using microfluidics technology. In the future, such microdevices could provide the framework to assay drug sensitivity in a timeframe suitable for clinical decision making. PMID- 24403988 TI - Probing the mechanical properties of brain cancer cells using a microfluidic cell squeezer device. AB - Despite being invasive within surrounding brain tissues and the central nervous system, little is known about the mechanical properties of brain tumor cells in comparison with benign cells. Here, we present the first measurements of the peak pressure drop due to the passage of benign and cancerous brain cells through confined microchannels in a "microfluidic cell squeezer" device, as well as the elongation, speed, and entry time of the cells in confined channels. We find that cancerous and benign brain cells cannot be differentiated based on speeds or elongation. We have found that the entry time into a narrow constriction is a more sensitive indicator of the differences between malignant and healthy glial cells than pressure drops. Importantly, we also find that brain tumor cells take a longer time to squeeze through a constriction and migrate more slowly than benign cells in two dimensional wound healing assays. Based on these observations, we arrive at the surprising conclusion that the prevailing notion of extraneural cancer cells being more mechanically compliant than benign cells may not apply to brain cancer cells. PMID- 24403989 TI - Antibody-independent isolation of circulating tumor cells by continuous-flow dielectrophoresis. AB - Circulating tumor cells (CTCs) are prognostic markers for the recurrence of cancer and may carry molecular information relevant to cancer diagnosis. Dielectrophoresis (DEP) has been proposed as a molecular marker-independent approach for isolating CTCs from blood and has been shown to be broadly applicable to different types of cancers. However, existing batch-mode microfluidic DEP methods have been unable to process 10 ml clinical blood specimens rapidly enough. To achieve the required processing rates of 10(6) nucleated cells/min, we describe a continuous flow microfluidic processing chamber into which the peripheral blood mononuclear cell fraction of a clinical specimen is slowly injected, deionized by diffusion, and then subjected to a balance of DEP, sedimentation and hydrodynamic lift forces. These forces cause tumor cells to be transported close to the floor of the chamber, while blood cells are carried about three cell diameters above them. The tumor cells are isolated by skimming them from the bottom of the chamber while the blood cells flow to waste. The principles, design, and modeling of the continuous-flow system are presented. To illustrate operation of the technology, we demonstrate the isolation of circulating colon tumor cells from clinical specimens and verify the tumor origin of these cells by molecular analysis. PMID- 24403990 TI - Dielectrophoresis has broad applicability to marker-free isolation of tumor cells from blood by microfluidic systems. AB - The number of circulating tumor cells (CTCs) found in blood is known to be a prognostic marker for recurrence of primary tumors, however, most current methods for isolating CTCs rely on cell surface markers that are not universally expressed by CTCs. Dielectrophoresis (DEP) can discriminate and manipulate cancer cells in microfluidic systems and has been proposed as a molecular marker independent approach for isolating CTCs from blood. To investigate the potential applicability of DEP to different cancer types, the dielectric and density properties of the NCI-60 panel of tumor cell types have been measured by dielectrophoretic field-flow fractionation (DEP-FFF) and compared with like properties of the subpopulations of normal peripheral blood cells. We show that all of the NCI-60 cell types, regardless of tissue of origin, exhibit dielectric properties that facilitate their isolation from blood by DEP. Cell types derived from solid tumors that grew in adherent cultures exhibited dielectric properties that were strikingly different from those of peripheral blood cell subpopulations while leukemia-derived lines that grew in non-adherent cultures exhibited dielectric properties that were closer to those of peripheral blood cell types. Our results suggest that DEP methods have wide applicability for the surface marker independent isolation of viable CTCs from blood as well as for the concentration of leukemia cells from blood. PMID- 24403991 TI - Investigating dielectric properties of different stages of syngeneic murine ovarian cancer cells. AB - In this study, the electrical properties of four different stages of mouse ovarian surface epithelial (MOSE) cells were investigated using contactless dielectrophoresis (cDEP). This study expands the work from our previous report describing for the first time the crossover frequency and cell specific membrane capacitance of different stages of cancer cells that are derived from the same cell line. The specific membrane capacitance increased as the stage of malignancy advanced from 15.39 +/- 1.54 mF m(-2) for a non-malignant benign stage to 26.42 +/- 1.22 mF m(-2) for the most aggressive stage. These differences could be the result of morphological variations due to changes in the cytoskeleton structure, specifically the decrease of the level of actin filaments in the cytoskeleton structure of the transformed MOSE cells. Studying the electrical properties of MOSE cells provides important information as a first step to develop cancer treatment techniques which could partially reverse the cytoskeleton disorganization of malignant cells to a morphology more similar to that of benign cells. PMID- 24403992 TI - Label-free isolation of circulating tumor cells in microfluidic devices: Current research and perspectives. AB - This review will cover the recent advances in label-free approaches to isolate and manipulate circulating tumor cells (CTCs). In essence, label-free approaches do not rely on antibodies or biological markers for labeling the cells of interest, but enrich them using the differential physical properties intrinsic to cancer and blood cells. We will discuss technologies that isolate cells based on their biomechanical and electrical properties. Label-free approaches to analyze CTCs have been recently invoked as a valid alternative to "marker-based" techniques, because classical epithelial and tumor markers are lost on some CTC populations and there is no comprehensive phenotypic definition for CTCs. We will highlight the advantages and drawbacks of these technologies and the status on their implementation in the clinics. PMID- 24403994 TI - A pillar-based microfilter for isolation of white blood cells on elastomeric substrate. AB - Our goal is to design, fabricate, and characterize a pillar-based microfluidic device for size-based separation of human blood cells on an elastomeric substrate with application in the low-cost rapid prototyping of lab-chip devices. The single inlet single outlet device is using parallel U-shape arrays of pillars with cutoff size of 5.5 MUm for trapping white blood cells (WBCs) in a pillar chamber with internal dead-volume of less than 1.0 MUl. The microstructures are designed to limit the elastomeric deformation against fluid pressures. Numerical analysis showed that at maximum pressure loss of 15 kPa which is lower than the device conformal bonding strength, the pillar elastomeric deformation is less than 5% for flow rates of up to 1.0 ml min(-1). Molding technique was employed for device prototyping using polyurethane methacrylate (PUMA) resin and polydimethylsiloxane (PDMS) mold. Characterization of the dual-layer device with beads and blood samples is performed. Tests with blood injection showed that ~18% 25% of WBCs are trapped and ~84%-89% of red blood cells (RBCs) are passed at flow rates of 15-50 MUl min(-1) with a slight decrease of WBCs trap and improve of the RBCs pass at higher flow rates. Similar results were obtained by separation of mixed microspheres of different size injected at flow rates of up to 400 MUl min( 1). Tests with blood samples stained by fluorescent gel demonstrated that the WBCs are accumulated in the arrays of pillars that later end up to blockage of the device. Filtration results of using elastomeric substrate present a good consistency with the trend of separation efficiencies of the similar silicon based filters. PMID- 24403995 TI - Production rate and diameter analysis of spherical monodisperse microbubbles from two-dimensional, expanding-nozzle flow-focusing microfluidic devices. AB - Flow-focusing microfluidic devices (FFMDs) can produce microbubbles (MBs) with precisely controlled diameters and a narrow size distribution. In this paper, poly-dimethyl-siloxane based, rectangular-nozzle, two-dimensional (2-D) planar, expanding-nozzle FFMDs were characterized using a high speed camera to determine the production rate and diameter of Tween 20 (2% v/v) stabilized MBs. The effect of gas pressure and liquid flow rate on MB production rate and diameter was analyzed in order to develop a relationship between FFMD input parameters and MB production. MB generation was observed to transition through five regimes at a constant gas pressure and increasing liquid flow rate. Each MB generation event (i.e., break-off to break-off) was further separated into two characteristic phases: bubbling and waiting. The duration of the bubbling phase was linearly related to the liquid flow rate, while the duration of the waiting phase was related to both liquid flow rate and gas pressure. The MB production rate was found to be inversely proportional to the sum of the bubbling and waiting times, while the diameter was found to be proportional to the product of the gas pressure and bubbling time. PMID- 24403996 TI - Design criteria for developing low-resource magnetic bead assays using surface tension valves. AB - Many assays for biological sample processing and diagnostics are not suitable for use in settings that lack laboratory resources. We have recently described a simple, self-contained format based on magnetic beads for extracting infectious disease biomarkers from complex biological samples, which significantly reduces the time, expertise, and infrastructure required. This self-contained format has the potential to facilitate the application of other laboratory-based sample processing assays in low-resource settings. The technology is enabled by immiscible fluid barriers, or surface tension valves, which stably separate adjacent processing solutions within millimeter-diameter tubing and simultaneously permit the transit of magnetic beads across the interfaces. In this report, we identify the physical parameters of the materials that maximize fluid stability and bead transport and minimize solution carryover. We found that fluid stability is maximized with <=0.8 mm i.d. tubing, valve fluids of similar density to the adjacent solutions, and tubing with <=20 dyn/cm surface energy. Maximizing bead transport was achieved using >=2.4 mm i.d. tubing, mineral oil valve fluid, and a mass of 1-3 mg beads. The amount of solution carryover across a surface tension valve was minimized using <=0.2 mg of beads, tubing with <=20 dyn/cm surface energy, and air separators. The most favorable parameter space for valve stability and bead transport was identified by combining our experimental results into a single plot using two dimensionless numbers. A strategy is presented for developing additional self-contained assays based on magnetic beads and surface tension valves for low-resource diagnostic applications. PMID- 24403993 TI - Perspective: Flicking with flow: Can microfluidics revolutionize the cancer research? AB - According to the World Health Organization, cancer is one of the leading causes of death worldwide. Cancer research, in its all facets, is truly interdisciplinary in nature, cutting across the fields of fundamental and applied sciences, as well as biomedical engineering. In recent years, microfluidics has been applied successfully in cancer research. There remain, however, many elusive features of this disease, where microfluidic systems could throw new lights. In addition, some inherent features of microfluidic systems remain unexploited in cancer research. In this article, we first briefly review the advancement of microfluidics in cancer biology. We then describe the biophysical aspects of cancer and outline how microfluidic system could be useful in developing a deeper understanding on the underlying mechanisms. We next illustrate the effects of the confined environment of microchannel on cellular dynamics and argue that the tissue microconfinement could be a crucial facet in tumor development. Lastly, we attempt to highlight some of the most important problems in cancer biology, to inspire next level of microfluidic applications in cancer research. PMID- 24403997 TI - Continual collection and re-separation of circulating tumor cells from blood using multi-stage multi-orifice flow fractionation. AB - Circulating tumor cells (CTCs) are highly correlated with the invasive behavior of cancer; as such, the ability to isolate and quantify CTCs is of great biomedical importance. This research presents a multi-stage multi-orifice flow fractionation (MS-MOFF) device formed by combining three single-stage multi orifice segments designed for separating breast cancer cells from blood. The structure and dimensions of the MS-MOFF were determined by hydrodynamic principles to have consistent Reynolds numbers (Re) at each multi-orifice segment. From this device, we achieved improved separation efficiency by collecting and re-separating non-selected target cells in comparison with the single-stage multi-orifice flow fractionation (SS-MOFF). The recovery of breast cancer cells increased from 88.8% to greater than 98.9% through the multi-stage multi-orifice segments. This device can be utilized to isolate rare cells from human blood, such as CTCs, in a label-free manner solely through the use of hydrodynamic forces. PMID- 24403998 TI - Experimental validation of numerical study on thermoelectric-based heating in an integrated centrifugal microfluidic platform for polymerase chain reaction amplification. AB - A comprehensive study involving numerical analysis and experimental validation of temperature transients within a microchamber was performed for thermocycling operation in an integrated centrifugal microfluidic platform for polymerase chain reaction (PCR) amplification. Controlled heating and cooling of biological samples are essential processes in many sample preparation and detection steps for micro-total analysis systems. Specifically, the PCR process relies on highly controllable and uniform heating of nucleic acid samples for successful and efficient amplification. In these miniaturized systems, the heating process is often performed more rapidly, making the temperature control more difficult, and adding complexity to the integrated hardware system. To gain further insight into the complex temperature profiles within the PCR microchamber, numerical simulations using computational fluid dynamics and computational heat transfer were performed. The designed integrated centrifugal microfluidics platform utilizes thermoelectrics for ice-valving and thermocycling for PCR amplification. Embedded micro-thermocouples were used to record the static and dynamic thermal responses in the experiments. The data collected was subsequently used for computational validation of the numerical predictions for the system response during thermocycling, and these simulations were found to be in agreement with the experimental data to within ~97%. When thermal contact resistance values were incorporated in the simulations, the numerical predictions were found to be in agreement with the experimental data to within ~99.9%. This in-depth numerical modeling and experimental validation of a complex single-sided heating platform provide insights into hardware and system design for multi-layered polymer microfluidic systems. In addition, the biological capability along with the practical feasibility of the integrated system is demonstrated by successfully performing PCR amplification of a Group B Streptococcus gene. PMID- 24403999 TI - Paper pump for passive and programmable transport. AB - In microfluidic systems, a pump for fluid-driving is often necessary. To keep the size of microfluidic systems small, a pump that is small in size, light-weight and needs no external power source is advantageous. In this work, we present a passive, simple, ultra-low-cost, and easily controlled pumping method based on capillary action of paper that pumps fluid through conventional polymer-based microfluidic channels with steady flow rate. By using inexpensive cutting tools, paper can be shaped and placed at the outlet port of a conventional microfluidic channel, providing a wide range of pumping rates. A theoretical model was developed to describe the pumping mechanism and aid in the design of paper pumps. As we show, paper pumps can provide steady flow rates from 0.3 MUl/s to 1.7 MUl/s and can be cascaded to achieve programmable flow-rate tuning during the pumping process. We also successfully demonstrate transport of the most common biofluids (urine, serum, and blood). With these capabilities, the paper pump has the potential to become a powerful fluid-driving approach that will benefit the fielding of microfluidic systems for point-of-care applications. PMID- 24404000 TI - Cell-free protein expression systems in microdroplets: Stabilization of interdroplet bilayers. AB - Cell-free protein expression with bacterial lysates has been demonstrated to produce soluble proteins in microdroplets. However, droplet assays with expressed membrane proteins require the presence of a lipid bilayer. A bilayer can be formed in between lipid-coated aqueous droplets by bringing these into contact by electrokinetic manipulation in a continuous oil phase, but it is not known whether such interdroplet bilayers are compatible with high concentrations of biomolecules. In this study, we have characterized the lifetime and the structural integrity of interdroplet bilayers by measuring the bilayer current in the presence of three different commercial cell-free expression mixtures and their individual components. Samples of pure proteins and of a polymer were included for comparison. It is shown that complete expression mixtures reduce the bilayer lifetime to several minutes or less, and that this is mainly due to the lysate fraction itself. The fraction that contains the molecules for metabolic energy generation does not reduce the bilayer lifetime but does give rise to current steps that are indicative of lipid packing defects. Gel electrophoresis confirmed that proteins are only present at significant amounts in the lysate fractions and, when supplied separately, in the T7 enzyme mixture. Interestingly, it was also found that pure-protein and pure-polymer solutions perturb the interdroplet bilayer at higher concentrations; 10% (w/v) polyethylene glycol 8000 (PEG 8000) and 3 mM lysozyme induce large bilayer currents without a reduction in bilayer lifetime, whereas 3 mM albumin causes rapid bilayer failure. It can, therefore, be concluded that the high protein content of the lysates and the presence of PEG polymer, a typical lysate supplement, compromise the structural integrity of interdroplet bilayers. However, we established that the addition of lipid vesicles to the cell-free expression mixture stabilizes the interdroplet bilayer, allowing the exposure of interdroplet bilayers to cell-free expression solutions. Given that cell-free expressed membrane proteins can insert in lipid bilayers, we envisage that microdroplet technology may be extended to the study of in situ expressed membrane receptors and ion channels. PMID- 24404001 TI - Stretching DNA by electric field and flow field in microfluidic devices: An experimental validation to the devices designed with computer simulations. AB - We examined the performance of three microfluidic devices for stretching DNA. The first device is a microchannel with a contraction, and the remaining two are the modifications to the first. The modified designs were made with the help of computer simulations [C. C. Hsieh and T. H. Lin, Biomicrofluidics 5(4), 044106 (2011) and C. C. Hsieh, T. H. Lin, and C. D. Huang, Biomicrofluidics 6, 044105 (2012)] and they were optimized for operating with electric field. In our experiments, we first used DC electric field to stretch DNA. However, the experimental results were not even in qualitative agreement with our simulations. More detailed investigation revealed that DNA molecules adopt a globular conformation in high DC field and therefore become more difficult to stretch. Owing to the similarity between flow field and electric field, we turned to use flow field to stretch DNA with the same devices. The evolution patterns of DNA conformation in flow field were found qualitatively the same as our prediction based on electric field. We analyzed the maximum values, the evolution and the distributions of DNA extension at different Deborah number in each device. We found that the shear and the hydrodynamic interaction have significant influence on the performance of the devices. PMID- 24404002 TI - Enrichment of live unlabelled cardiomyocytes from heterogeneous cell populations using manipulation of cell settling velocity by magnetic field. AB - The majority of available cardiomyocyte markers are intercellular proteins, limiting our ability to enrich live cardiomyocytes from heterogeneous cell preparations in the absence of genetic labeling. Here, we describe enrichment of live cardiomyocytes from the hearts of adult mice in a label-free microfluidic approach. The separation device consisted of a vertical column (15 mm long, 700 MUm diameter), placed between permanent magnets resulting in a field strength of 1.23 T. To concentrate the field at the column wall, the column was wrapped with 69 MUm diameter nickel wire. Before passing the cells through the column, the cardiomyocytes in the cell suspension had been rendered paramagnetic by treatment of the adult mouse heart cell preparation with sodium nitrite (2.5 mM) for 20 min on ice. The cell suspension was loaded into the vertical column from the top and upon settling, the non-myocytes were removed by the upward flow from the column. The cardiomyocytes were then collected from the column by applying a higher flow rate (144 MUl/min). We found that by applying a separation flow rate of 4.2 MUl/min in the first step, we can enrich live adult cardiomyocytes to 93% +/- 2% in a label-free manner. The cardiomyocytes maintained viability immediately after separation and upon 24 h in culture. PMID- 24404003 TI - Electrokinetic trapping and surface enhanced Raman scattering detection of biomolecules using optofluidic device integrated with a microneedles array. AB - In this study, microneedles which possess sharp tips were utilized to trap and detect the biomolecules. Owing to the large curvature, the tips of the microneedles created a substantially high gradient of electric field under the non-uniform electric field which served as not only the trapping sites but also the substrate for surface enhanced Raman scattering (SERS). Separation of polystyrene microparticles with different sizes and two kinds of biomolecules (Staphylococcus aureus (S. aureus) and the red blood cells (RBCs)) were demonstrated. Moreover, in situ detection of S. aureus was performed immediately after separation was completed. The results showed that, after 15 s of sample collection, the Raman signals of S. aureus were detected and greatly enhanced through SERS effect. PMID- 24404004 TI - Optimization of microfluidic microsphere-trap arrays. AB - Microarray devices are powerful for detecting and analyzing biological targets. However, the potential of these devices may not be fully realized due to the lack of optimization of their design and implementation. In this work, we consider a microsphere-trap array device by employing microfluidic techniques and a hydrodynamic trapping mechanism. We design a novel geometric structure of the trap array in the device, and develop a comprehensive and robust framework to optimize the values of the geometric parameters to maximize the microsphere arrays' packing density. We also simultaneously optimize multiple criteria, such as efficiently immobilizing a single microsphere in each trap, effectively eliminating fluidic errors such as channel clogging and multiple microspheres in a single trap, minimizing errors in subsequent imaging experiments, and easily recovering targets. We use finite element simulations to validate the trapping mechanism of the device, and to study the effects of the optimization geometric parameters. We further perform microsphere-trapping experiments using the optimized device and a device with randomly selected geometric parameters, which we denote as the un-optimized device. These experiments demonstrate easy control of the transportation and manipulation of the microspheres in the optimized device. They also show that the optimized device greatly outperforms the un optimized device by increasing the packing density by a factor of two, improving the microsphere trapping efficiency from 58% to 99%, and reducing fluidic errors from 48% to a negligible level (less than 1%). The optimization framework lays the foundation for the future goal of developing a modular, reliable, efficient, and inexpensive lab-on-a-chip system. PMID- 24404006 TI - Review of microfluidic microbioreactor technology for high-throughput submerged microbiological cultivation. AB - Microbial fermentation process development is pursuing a high production yield. This requires a high throughput screening and optimization of the microbial strains, which is nowadays commonly achieved by applying slow and labor-intensive submerged cultivation in shake flasks or microtiter plates. These methods are also limited towards end-point measurements, low analytical data output, and control over the fermentation process. These drawbacks could be overcome by means of scaled-down microfluidic microbioreactors (MUBR) that allow for online control over cultivation data and automation, hence reducing cost and time. This review goes beyond previous work not only by providing a detailed update on the current MUBR fabrication techniques but also the operation and control of MUBRs is compared to large scale fermentation reactors. PMID- 24404005 TI - Hydrodynamic mechanisms of cell and particle trapping in microfluidics. AB - Focusing and sorting cells and particles utilizing microfluidic phenomena have been flourishing areas of development in recent years. These processes are largely beneficial in biomedical applications and fundamental studies of cell biology as they provide cost-effective and point-of-care miniaturized diagnostic devices and rare cell enrichment techniques. Due to inherent problems of isolation methods based on the biomarkers and antigens, separation approaches exploiting physical characteristics of cells of interest, such as size, deformability, and electric and magnetic properties, have gained currency in many medical assays. Here, we present an overview of the cell/particle sorting techniques by harnessing intrinsic hydrodynamic effects in microchannels. Our emphasis is on the underlying fluid dynamical mechanisms causing cross stream migration of objects in shear and vortical flows. We also highlight the advantages and drawbacks of each method in terms of throughput, separation efficiency, and cell viability. Finally, we discuss the future research areas for extending the scope of hydrodynamic mechanisms and exploring new physical directions for microfluidic applications. PMID- 24404007 TI - Differential electronic detector to monitor apoptosis using dielectrophoresis induced translation of flowing cells (dielectrophoresis cytometry). AB - The instrument described here is an all-electronic dielectrophoresis (DEP) cytometer sensitive to changes in polarizability of single cells. The important novel feature of this work is the differential electrode array that allows independent detection and actuation of single cells within a short section ([Formula: see text]) of the microfluidic channel. DEP actuation modifies the altitude of the cells flowing between two altitude detection sites in proportion to cell polarizability; changes in altitude smaller than 0.25 MUm can be detected electronically. Analysis of individual experimental signatures allows us to make a simple connection between the Clausius-Mossotti factor (CMF) and the amount of vertical cell deflection during actuation. This results in an all-electronic, label-free differential detector that monitors changes in physiological properties of the living cells and can be fully automated and miniaturized in order to be used in various online and offline probes and point-of-care medical applications. High sensitivity of the DEP cytometer facilitates observations of delicate changes in cell polarization that occur at the onset of apoptosis. We illustrate the application of this concept on a population of Chinese hamster ovary (CHO) cells that were followed in their rapid transition from a healthy viable to an early apoptotic state. DEP cytometer viability estimates closely match an Annexin V assay (an early apoptosis marker) on the same population of cells. PMID- 24404008 TI - A negative-pressure-driven microfluidic chip for the rapid detection of a bladder cancer biomarker in urine using bead-based enzyme-linked immunosorbent assay. AB - This paper describes an integrated microfluidic chip that is capable of rapidly and quantitatively measuring the concentration of a bladder cancer biomarker, apolipoprotein A1, in urine samples. All of the microfluidic components, including the fluid transport system, the micro-valve, and the micro-mixer, were driven by negative pressure, which simplifies the use of the chip and facilitates commercialization. Magnetic beads were used as a solid support for the primary antibody, which captured apolipoprotein A1 in patients' urine. Because of the three-dimensional structure of the magnetic beads, the concentration range of the target that could be detected was as high as 2000 ng ml(-1). Because this concentration is 100 times higher than that quantifiable using a 96-well plate with the same enzyme-linked immunosorbent assay (ELISA) kit, the dilution of the patient's urine can be avoided or greatly reduced. The limit of detection was determined to be approximately 10 ng ml(-1), which is lower than the cutoff value for diagnosing bladder cancer (11.16 ng ml(-1)). When the values measured using the microfluidic chip were compared with those measured using conventional ELISA using a 96-well plate for five patients, the deviations were 0.9%, 6.8%, 9.4%, 1.8%, and 5.8%. The entire measurement time is 6-fold faster than that of conventional ELISA. This microfluidic device shows significant potential for point-of-care applications. PMID- 24404009 TI - A numerical study on distributions during cryoprotectant loading caused by laminar flow in a microchannel. AB - In this work, we conduct a computational study on the loading of cryoprotective agents into cells in preparation for cryopreservation. The advantages of microfluidics in cryopreserving cells include control of fluid flow parameters for reliable cryoprotectant loading and reproducible streamlined processing of samples. A 0.25 m long, three inlet T-junction microchannel serves as an idealized environment for this process. The flow field and concentration distribution are determined from a computational fluid dynamics study and cells are tracked as inert particles in a Lagrangian frame. These particles are not confined to streamlines but can migrate laterally due to the Segre-Sildeberg effect for particles in a shear flow. During this tracking, the local concentration field surrounding the cell is monitored. This data are used as input into the Kedem-Katchalsky equations to numerically study passive solute transport across the cell membrane. As a result of the laminar flow, each cell has a unique pathline in the flow field resulting in different residence times and a unique external concentration field along its path. However, in most previous studies, the effect of a spatially varying concentration field on the transport across the cell membrane is ignored. The dynamics of this process are investigated for a population of cells released from the inlet. Using dimensional analysis, we find a governing parameter alpha, which is the ratio of the time scale for membrane transport to the average residence time in the channel. For [Formula: see text], cryoprotectant loading is completed to within 5% of the target concentration for all of the cells. However, for [Formula: see text], we find the population of cells does not achieve complete loading and there is a distribution of intracellular cryoprotective agent concentration amongst the population. Further increasing alpha beyond a value of 2 leads to negligible cryoprotectant loading. These simulations on populations of cells may lead to improved microfluidic cryopreservation protocols where more consistent cryoprotective agent loading and freezing can be achieved, thus increasing cell survival. PMID- 24404010 TI - Reconfigurable microfluidics combined with antibody microarrays for enhanced detection of T-cell secreted cytokines. AB - Cytokines are small proteins secreted by leukocytes in blood in response to infections, thus offering valuable diagnostic information. Given that the same cytokines may be produced by different leukocyte subsets in blood, it is beneficial to connect production of cytokines to specific cell types. In this paper, we describe integration of antibody (Ab) microarrays into a microfluidic device to enable enhanced cytokine detection. The Ab arrays contain spots specific to cell-surface antigens as well as anti-cytokine detection spots. Infusion of blood into a microfluidic device results in the capture of specific leukocytes (CD4 T-cells) and is followed by detection of secreted cytokines on the neighboring Ab spots using sandwich immunoassay. The enhancement of cytokine signal comes from leveraging the concept of reconfigurable microfluidics. A three layer polydimethylsiloxane microfluidic device is fabricated so as to contain six microchambers (1 mm * 1 mm * 30 MUm) in the ceiling of the device. Once the T cell capture is complete, the device is reconfigured by withdrawing liquid from the channel, causing the chambers to collapse onto Ab arrays and enclose cell/anti-cytokine spots within a 30 nl volume. In a set of proof-of-concept experiments, we demonstrate that ~90% pure CD4 T-cells can be captured inside the device and that signals for three important T-cell secreted cytokines, tissue necrosis factor-alpha, interferon-gamma, and interleukin-2, may be enhanced by 2 to 3 folds through the use of reconfigurable microfluidics. PMID- 24404011 TI - High-throughput particle manipulation by hydrodynamic, electrokinetic, and dielectrophoretic effects in an integrated microfluidic chip. AB - Integrating different steps on a chip for cell manipulations and sample preparation is of foremost importance to fully take advantage of microfluidic possibilities, and therefore make tests faster, cheaper and more accurate. We demonstrated particle manipulation in an integrated microfluidic device by applying hydrodynamic, electroosmotic (EO), electrophoretic (EP), and dielectrophoretic (DEP) forces. The process involves generation of fluid flow by pressure difference, particle trapping by DEP force, and particle redirect by EO and EP forces. Both DC and AC signals were applied, taking advantages of DC EP, EO and AC DEP for on-chip particle manipulation. Since different types of particles respond differently to these signals, variations of DC and AC signals are capable to handle complex and highly variable colloidal and biological samples. The proposed technique can operate in a high-throughput manner with thirteen independent channels in radial directions for enrichment and separation in microfluidic chip. We evaluated our approach by collecting Polystyrene particles, yeast cells, and E. coli bacteria, which respond differently to electric field gradient. Live and dead yeast cells were separated successfully, validating the capability of our device to separate highly similar cells. Our results showed that this technique could achieve fast pre-concentration of colloidal particles and cells and separation of cells depending on their vitality. Hydrodynamic, DC electrophoretic and DC electroosmotic forces were used together instead of syringe pump to achieve sufficient fluid flow and particle mobility for particle trapping and sorting. By eliminating bulky mechanical pumps, this new technique has wide applications for in situ detection and analysis. PMID- 24404012 TI - Efficient sample preparation in immuno-matrix-assisted laser desorption/ionization mass spectrometry using acoustic trapping. AB - Acoustic trapping of minute bead amounts against fluid flow allows for easy automation of multiple assay steps, using a convenient aspirate/dispense format. Here, a method based on acoustic trapping that allows sample preparation for immuno-matrix-assisted laser desorption/ionization mass spectrometry using only half a million 2.8 MUm antibody covered beads is presented. The acoustic trapping is done in 200 * 2000 MUm(2) glass capillaries and provides highly efficient binding and washing conditions, as shown by complete removal of detergents and sample processing times of 5-10 min. The versatility of the method is demonstrated using an antibody against Angiotensin I (Ang I), a peptide hormone involved in hypotension. Using this model system, the acoustic trapping was efficient in enriching Angiotensin at 400 pM spiked in plasma samples. PMID- 24404013 TI - Block-and-break generation of microdroplets with fixed volume. AB - We introduce a novel type of droplet generator that produces droplets of a volume set by the geometry of the droplet generator and not by the flow rates of the liquids. The generator consists of a classic T-junction with a bypass channel. This bypass directs the continuous fluid around the forming droplets, so that they can fill the space between the inlet of the dispersed phase and the exit of the bypass without breaking. Once filled, the dispersed phase blocks the exit of the bypass and is squeezed by the continuous fluid and broken off from the junction. We demonstrate the fixed-volume droplet generator for (i) the formation of monodisperse droplets from a source of varying flow rates, (ii) the formation of monodisperse droplets containing a gradation of solute concentration, and (iii) the parallel production of monodisperse droplets. PMID- 24404014 TI - Alternating current-dielectrophoresis driven on-chip collection and chaining of green microalgae in freshwaters. AB - The capability of the AC dielectrophoresis (DEP) for on-chip capture and chaining of microalgae suspended in freshwaters was evaluated. The effects of freshwater composition as well as the electric field voltage, frequency, and duration, on the dielectrophoretic response of microalga Chlamydomonas reinhardtii were characterized systematically. Highest efficiency of cell alignment in one dimensional arrays, determined by the percentage of cells in chain and the chain length, was obtained at AC-field of 20 V mm(-1) and 1 kHz applied for 600 s. The DEP response and cell alignment of C. reinhardtii in water sampled from lake, pond, and river, as well as model media were affected by the chemical composition of the media. In the model media, the efficiency of DEP chaining was negatively correlated to the conductivity of the cell suspensions, being higher in suspensions with low conductivity. The cells suspended in freshwaters, however, showed anomalously high chaining at long exposure times. High concentrations of nitrate and dissolved organic matter decrease cell chaining efficiency, while phosphate and citrate concentrations increase it and favor formation of longer chains. Importantly, the application of AC-field had no effect on algal autofluorescence, cell membrane damage, or oxidative stress damages in C. reinhardtii. PMID- 24404015 TI - A capillary dielectrophoretic chip for real-time blood cell separation from a drop of whole blood. AB - This study proposes a capillary dielectrophoretic chip to separate blood cells from a drop of whole blood (approximately 1 MUl) sample using negative dielectrophoretic force. The separating efficiency was evaluated by analyzing the image before and after dielectrophoretic force manipulation. Blood samples with various hematocrits (10%-60%) were tested with varied separating voltages and chip designs. In this study, a chip with 50 MUm gap design achieved a separation efficiency of approximately 90% within 30 s when the hematocrit was in the range of 10%-50%. Furthermore, glucose concentration was electrochemically measured by separating electrodes following manipulation. The current response increased significantly (8.8-fold) after blood cell separation, which was attributed not only to the blood cell separation but also to sample disturbance by the dielectrophoretic force. PMID- 24404016 TI - Single cell rheometry with a microfluidic constriction: Quantitative control of friction and fluid leaks between cell and channel walls. AB - We report how cell rheology measurements can be performed by monitoring the deformation of a cell in a microfluidic constriction, provided that friction and fluid leaks effects between the cell and the walls of the microchannels are correctly taken into account. Indeed, the mismatch between the rounded shapes of cells and the angular cross-section of standard microfluidic channels hampers efficient obstruction of the channel by an incoming cell. Moreover, friction forces between a cell and channels walls have never been characterized. Both effects impede a quantitative determination of forces experienced by cells in a constriction. Our study is based on a new microfluidic device composed of two successive constrictions, combined with optical interference microscopy measurements to characterize the contact zone between the cell and the walls of the channel. A cell squeezed in a first constriction obstructs most of the channel cross-section, which strongly limits leaks around cells. The rheological properties of the cell are subsequently probed during its entry in a second narrower constriction. The pressure force is determined from the pressure drop across the device, the cell velocity, and the width of the gutters formed between the cell and the corners of the channel. The additional friction force, which has never been analyzed for moving and constrained cells before, is found to involve both hydrodynamic lubrication and surface forces. This friction results in the existence of a threshold for moving the cells and leads to a non-linear behavior at low velocity. The friction force can nevertheless be assessed in the linear regime. Finally, an apparent viscosity of single cells can be estimated from a numerical prediction of the viscous dissipation induced by a small step in the channel. A preliminary application of our method yields an apparent loss modulus on the order of 100 Pa s for leukocytes THP-1 cells, in agreement with the literature data. PMID- 24404017 TI - Protein sensing by nanofluidic crystal and its signal enhancement. AB - Nanofluidics has a unique property that ionic conductance across a nanometer sized confined space is strongly affected by the space surface charge density, which can be utilized to construct electrical read-out biosensor. Based on this principle, this work demonstrated a novel protein sensor along with a sandwich signal enhancement approach. Nanoparticles with designed aptamer onside are assembled in a suspended micropore to form a 3-dimensional network of nanometer sized interstices, named as nanofluidic crystal hereafter, as the basic sensing unit. Proteins captured by aptamers will change the surface charge density of nanoparticles and thereby can be detected by monitoring the ionic conductance across this nanofluidic crystal. Another aptamer can further enlarge the variations of the surface charge density by forming a sandwich structure (capturing aptamer/protein/signal enhancement aptamer) and the read-out conductance as well. The preliminary experimental results indicated that human alpha-thrombin was successfully detected by the corresponding aptamer modified nanofluidic crystal with the limit of detection of 5 nM (0.18 MUg/ml) and the read-out signal was enhanced up to 3 folds by using another thrombin aptamer. Being easy to graft probe, facile and low-cost to prepare the nano-device, and having an electrical read-out, the present nanofluidic crystal scheme is a promising and universal strategy for protein sensing. PMID- 24404018 TI - Development of vertical SU-8 microtubes integrated with dissolvable tips for transdermal drug delivery. AB - Polymer-based microneedles have drawn much attention in the transdermal drug delivery resulting from their flexibility and biocompatibility. Traditional fabrication approach deploys various kinds of molds to create sharp tips at the end of needles for the penetration purpose. This approach is usually time consuming and expensive. In this study, we developed an innovative fabrication process to make biocompatible SU-8 microtubes integrated with biodissolvable maltose tips as novel microneedles for the transdermal drug delivery applications. These microneedles can easily penetrate the skin's outer barrier represented by the stratum corneum (SC) layer. The drug delivery device of mironeedles array with 1000 MUm spacing between adjacent microneedles is proven to be able to penetrate porcine cadaver skins successfully. The maximum loading force on the individual microneedle can be as large as 7.36 +/- 0.48N. After 9 min of the penetration, all the maltose tips are dissolved in the tissue. Drugs can be further delivered via these open biocompatible SU-8 microtubes in a continuous flow manner. The permeation patterns caused by the solution containing Rhodamine 110 at different depths from skin surface were characterized via a confocal microscope. It shows successful implementation of the microneedle function for fabricated devices. PMID- 24404019 TI - A fluorescence based method for the quantification of surface functional groups in closed micro- and nanofluidic channels. AB - Surface analysis is critical for the validation of microfluidic surface modifications for biology, chemistry, and physics applications. However, until now quantitative analytical methods have mostly been focused on open surfaces. Here, we present a new fluorescence imaging method to directly measure the surface coverage of functional groups inside assembled microchannels over a wide dynamic range. A key advance of our work is the elimination of self-quenching to obtain a linear signal even with a high density of functional groups. This method is applied to image the density and monitor the stability of vapor deposited silane layers in bonded silicon/glass micro- and nanochannels. PMID- 24404020 TI - Ionic current devices-Recent progress in the merging of electronic, microfluidic, and biomimetic structures. AB - We review the recent progress in the emerging area of devices and circuits operating on the basis of ionic currents. These devices operate at the intersection of electrochemistry, electronics, and microfluidics, and their potential applications are inspired by essential biological processes such as neural transmission. Ionic current rectification has been demonstrated in diode like devices containing electrolyte solutions, hydrogel, or hydrated nanofilms. More complex functions have been realized in ionic current based transistors, solar cells, and switching memory devices. Microfluidic channels and networks-an intrinsic component of the ionic devices-could play the role of wires and circuits in conventional electronics. PMID- 24404021 TI - A hybrid microfluidic platform for cell-based assays via diffusive and convective trans-membrane perfusion. AB - We present a novel 3D hybrid assembly of a polymer microfluidic chip with polycarbonate track-etched membrane (PCTEM) enabling membrane-supported cell culture. Two chip designs have been developed to establish either diffusive or convective reagent delivery using the integrated PCTEM. While it is well suited to a range of cell-based assays, we specifically employ this platform for the screening of a common antitumor chemotoxic agent (mitomycin C - MMC) on the HL60 myeloid leukemia cell line. The toxic activity of MMC is based on the generation of severe DNA damage in the cells. Using either mode of operation, the HL60 cells were cultured on-chip before, during, and after exposure to MMC at concentrations ranging from 0 to 50 MUM. Cell viability was analysed off-chip by the trypan blue dye exclusion assay. The results of the on-chip viability assay were found to be consistent with those obtained off-chip and indicated ca. 40% cell survival at MMC concentration of 50 MUM. The catalogue of capabilities of the here described cell assay platform comprises of (i) the culturing of cells either under shear free conditions or under induced through-membrane flows, (ii) the tight time control of the reagent exposure, (iii) the straightforward assembly of devices, (iv) the flexibility on the choice of the membrane, and, prospectively, (v) the amenability for large-scale parallelization. PMID- 24404022 TI - Viscoelasticity of blood and viscoelastic blood analogues for use in polydymethylsiloxane in vitro models of the circulatory system. AB - The non-Newtonian properties of blood are of great importance since they are closely related with incident cardiovascular diseases. A good understanding of the hemodynamics through the main vessels of the human circulatory system is thus fundamental in the detection and especially in the treatment of these diseases. Very often such studies take place in vitro for convenience and better flow control and these generally require blood analogue solutions that not only adequately mimic the viscoelastic properties of blood but also minimize undesirable optical distortions arising from vessel curvature that could interfere in flow visualizations or particle image velocimetry measurements. In this work, we present the viscoelastic moduli of whole human blood obtained by means of passive microrheology experiments. These results and existing shear and extensional rheological data for whole human blood in the literature enabled us to develop solutions with rheological behavior analogous to real whole blood and with a refractive index suited for PDMS (polydymethylsiloxane) micro- and milli channels. In addition, these blood analogues can be modified in order to obtain a larger range of refractive indices from 1.38 to 1.43 to match the refractive index of several materials other than PDMS. PMID- 24404023 TI - Simulation of single DNA molecule stretching and immobilization in a de-wetting two-phase flow over micropillar-patterned surface. AB - We investigate single DNA stretching dynamics in a de-wetting flow over micropillars using Brownian dynamics simulation. The Brownian dynamics simulation is coupled with transient flow field computation through a numerical particle tracking algorithm. The droplet formation on the top of the micropillar during the de-wetting process creates a flow pattern that allows DNA to stretch across the micropillars. It is found that DNA nanowire forms if DNA molecules could extend across the stagnation point inside the connecting water filament before its breakup. It also shows that DNA locates closer to the top wall of the micropillar has higher chance to enter the flow pattern of droplet formation and thus has higher chance to be stretched across the micropillars. Our simulation tool has the potential to become a design tool for DNA manipulation in complex biomicrofluidic devices. PMID- 24404024 TI - Continuous flowing micro-reactor for aqueous reaction at temperature higher than 100 degrees C. AB - Some aqueous reactions in biological or chemical fields are accomplished at a high temperature. When the reaction temperature is higher than 100 degrees C, an autoclave reactor is usually required to elevate the boiling point of the water by creating a high-pressure environment in a closed system. This work presented an alternative continuous flowing microfluidic solution for aqueous reaction with a reaction temperature higher than 100 degrees C. The pressure regulating function was successfully fulfilled by a small microchannel based on a delicate hydrodynamic design. Combined with micro heater and temperature sensor that integrated in a single chip by utilizing silicon-based microfabrication techniques, this pressure regulating microchannel generated a high-pressure/high temperature environment in the upstream reaction zone when the reagents continuously flow through the chip. As a preliminary demonstration, thermal digestion of aqueous total phosphorus sample was achieved in this continuous flowing micro-reactor at a working pressure of 990 kPa (under the working flow rate of 20 nl/s) along with a reaction temperature of 145 degrees C. This continuous flowing microfluidic solution for high-temperature reaction may find applications in various micro total analysis systems. PMID- 24404025 TI - Direct detection of cancer biomarkers in blood using a "place n play" modular polydimethylsiloxane pump. AB - Cancer biomarkers have significant potential as reliable tools for the early detection of the disease and for monitoring its recurrence. However, most current methods for biomarker detection have technical difficulties (such as sample preparation and specific detector requirements) which limit their application in point of care diagnostics. We developed an extremely simple, power-free microfluidic system for direct detection of cancer biomarkers in microliter volumes of whole blood. CEA and CYFRA21-1 were chosen as model cancer biomarkers. The system automatically extracted blood plasma from less than 3 MUl of whole blood and performed a multiplex sample-to-answer assay (nano-ELISA (enzyme-linked immunosorbent assay) technique) without the use of external power or extra components. By taking advantage of the nano-ELISA technique, this microfluidic system detected CEA at a concentration of 50 pg/ml and CYFRA21-1 at a concentration of 60 pg/ml within 60 min. The combination of PnP polydimethylsiloxane (PDMS) pump and nano-ELISA technique in a single microchip system shows great promise for the detection of cancer biomarkers in a drop of blood. PMID- 24404026 TI - A microfluidic chip for direct and rapid trapping of white blood cells from whole blood. AB - Blood analysis plays a major role in medical and science applications and white blood cells (WBCs) are an important target of analysis. We proposed an integrated microfluidic chip for direct and rapid trapping WBCs from whole blood. The microfluidic chip consists of two basic functional units: a winding channel to mix and arrays of two-layer trapping structures to trap WBCs. Red blood cells (RBCs) were eliminated through moving the winding channel and then WBCs were trapped by the arrays of trapping structures. We fabricated the PDMS (polydimethylsiloxane) chip using soft lithography and determined the critical flow velocities of tartrazine and brilliant blue water mixing and whole blood and red blood cell lysis buffer mixing in the winding channel. They are 0.25 MUl/min and 0.05 MUl/min, respectively. The critical flow velocity of the whole blood and red blood cell lysis buffer is lower due to larger volume of the RBCs and higher kinematic viscosity of the whole blood. The time taken for complete lysis of whole blood was about 85 s under the flow velocity 0.05 MUl/min. The RBCs were lysed completely by mixing and the WBCs were trapped by the trapping structures. The chip trapped about 2.0 * 10(3) from 3.3 * 10(3) WBCs. PMID- 24404027 TI - Numerical modeling of DNA-chip hybridization with chaotic advection. AB - We present numerical simulations of DNA-chip hybridization, both in the "static" and "dynamical" cases. In the static case, transport of free targets is limited by molecular diffusion; in the dynamical case, an efficient mixing is achieved by chaotic advection, with a periodic protocol using pumps in a rectangular chamber. This protocol has been shown to achieve rapid and homogeneous mixing. We suppose in our model that all free targets are identical; the chip has different spots on which the probes are fixed, also all identical, and complementary to the targets. The reaction model is an infinite sink potential of width dh , i.e., a target is captured as soon as it comes close enough to a probe, at a distance lower than dh . Our results prove that mixing with chaotic advection enables much more rapid hybridization than the static case. We show and explain why the potential width dh does not play an important role in the final results, and we discuss the role of molecular diffusion. We also recover realistic reaction rates in the static case. PMID- 24404028 TI - Microfluidic device for trapping and monitoring three dimensional multicell spheroids using electrical impedance spectroscopy. AB - In this paper, we report the design, fabrication, and testing of a lab-on-a-chip based microfluidic device for application of trapping and measuring the dielectric properties of microtumors over time using electrical impedance spectroscopy (EIS). Microelectromechanical system (MEMS) techniques were used to embed opposing electrodes onto the top and bottom surfaces of a microfluidic channel fabricated using Pyrex substrate, chrome gold, SU-8, and polydimethylsiloxane. Differing concentrations of cell culture medium, differing sized polystyrene beads, and MCF-7 microtumor spheroids were used to validate the designs ability to detect background conductivity changes and dielectric particle diameter changes between electrodes. The observed changes in cell medium concentrations demonstrated a linear relation to extracted solution resistance (Rs), while polystyrene beads and multicell spheroids induced changes in magnitude consistent with diameter increase. This design permits optical correlation between electrical measurements and EIS spectra. PMID- 24404029 TI - Spatially gradated segregation and recovery of circulating tumor cells from peripheral blood of cancer patients. AB - For cancer patients, the enumeration of rare circulating tumor cells (CTCs) in peripheral blood is a strong prognostic indicator of the severity of the cancer; for the general population, the capture of CTCs is needed for use as a clinical tool for cancer screening, early detection, and treatment assessment. Here, we present a fast, high-purity (~90%) and high-efficiency (>90%) method for the segregation and undamaged recovery of CTCs using a spatially gradated microfluidic chip. Further, by lysing the red blood cells we achieved not only a significant reduction in the overall processing time but also mitigated the blood clogging problem commonly encountered in microfluidic-based CTC isolation systems. To clinically validate the chip, we employed it to detect and capture CTCs from 10 liver cancer patients. Positive CTC enumeration was observed in all the blood samples, and the readings ranged from a low of 1-2 CTCs (1 patient) to a high of >20 CTCs (2 patients) with the balance having 3-20 CTCs per 3-ml blood sample. The work here indicates that our system can be developed for use in cancer screening, metastatic assessment, and chemotherapeutic response and for pharmacological and genetic evaluation of single CTCs. PMID- 24404030 TI - Two dimensional barcode-inspired automatic analysis for arrayed microfluidic immunoassays. AB - The usability of many high-throughput lab-on-a-chip devices in point-of-care applications is currently limited by the manual data acquisition and analysis process, which are labor intensive and time consuming. Based on our original design in the biochemical reactions, we proposed here a universal approach to perform automatic, fast, and robust analysis for high-throughput array-based microfluidic immunoassays. Inspired by two-dimensional (2D) barcodes, we incorporated asymmetric function patterns into a microfluidic array. These function patterns provide quantitative information on the characteristic dimensions of the microfluidic array, as well as mark its orientation and origin of coordinates. We used a computer program to perform automatic analysis for a high-throughput antigen/antibody interaction experiment in 10 s, which was more than 500 times faster than conventional manual processing. Our method is broadly applicable to many other microchannel-based immunoassays. PMID- 24404031 TI - The effect of the surface functionalization and the electrolyte concentration on the electrical conductance of silica nanochannels. AB - It is known that the conductance of nanochannels as a function of electrolyte concentration deviates from a linearly proportional relationship and approaches a value independent of the concentration as the electrolyte concentration is lowered. Most of the proposed models account for this behavior by considering a constant surface charge density and an ideal electrolyte solution. However, at low electrolyte concentrations, the ideal electrolyte approximation is no longer valid because the ions that result from the atmospheric carbon dioxide dissolution in water dominate the ionic concentration. In this paper, arrays of silica nanochannels were electrically characterized via conductance measurements. The conductance at low salt concentrations is modeled by a variable surface charge model that accounts for all ionic species in solution. This model was used to determine the variable surface charge of the bare silica nanochannels as well as of chemically modified nanochannels. The model correctly predicted the variation of the nanochannel conductance observed after silane (aminopropyldimethylethoxysilane) functionalization and single-strand DNA immobilization. Finally, pH modification of bulk KCl solutions was employed as an alternative method of changing the surface charge of silica nanochannels. Surface charge calculated from conductance measurements performed at different bulk pH values confirmed that the surface charge of the silica nanochannel walls is sensitive to the H(+) concentration. PMID- 24404032 TI - Parallel generation of uniform fine droplets at hundreds of kilohertz in a flow focusing module. AB - Droplet-based microfluidic systems enable a variety of biomedical applications from point-of-care diagnostics with third world implications, to targeted therapeutics alongside medical ultrasound, to molecular screening and genetic testing. Though these systems maintain the key advantage of precise control of the size and composition of the droplet as compared to conventional methods of production, the low rates at which droplets are produced limits translation beyond the laboratory setting. As well, previous attempts to scale up shear-based microfluidic systems focused on increasing the volumetric throughput and formed large droplets, negating many practical applications of emulsions such as site specific therapeutics. We present the operation of a parallel module with eight flow-focusing orifices in the dripping regime of droplet formation for the generation of uniform fine droplets at rates in the hundreds of kilohertz. Elevating the capillary number to access dripping, generation of monodisperse droplets of liquid perfluoropentane in the parallel module exceeded 3.69 * 10(5) droplets per second, or 1.33 * 10(9) droplets per hour, at a mean diameter of 9.8 MUm. Our microfluidic method offers a novel means to amass uniform fine droplets in practical amounts, for instance, to satisfy clinical needs, with the potential for modification to form massive amounts of more complex droplets. PMID- 24404033 TI - Lattice Boltzmann numerical simulation and experimental research of dynamic flow in an expansion-contraction microchannel. AB - This paper applies the lattice Boltzmann method (LBM) to a 3D simulation of micro flows in an expansion-contraction microchannel. We investigate the flow field under various inlet flow rates and cavity structures, and then systematically study the flow features of the vortex and Dean flow in this channel. Vortex formation analysis demonstrates that there is no observable vortex generated when the inlet flow rate is low enough. As the inlet flow rate increases, a small vortex first appears near the inlet, and then this vortex region will keep expanding until it fully occupies the cavity. A smaller cavity width may result in a larger vortex but the vortex is less influenced by cavity length. The Dean flow features at the outlet become more apparent with increasing inlet flow rate and more recirculation regions can be observed in the cross-section under over high inlet flow rate. In order to support the simulation results, some experimental processes are conducted successfully. It validates that the applied model can accurately characterize the flow in the microchannel. Results of simulations and experiments in this paper provide insights into the design and operation of microfluidic systems for particle/cell manipulation. PMID- 24404034 TI - Highly selective biomechanical separation of cancer cells from leukocytes using microfluidic ratchets and hydrodynamic concentrator. AB - The separation of cells based on their biomechanical properties, such as size and deformability, is important in applications such as the identification of circulating tumor cells, where morphological differences can be used to distinguish target cancer cells from contaminant leukocytes. Existing filtration based separation processes are limited in their selectivity and their ability to extract the separated cells because of clogging in the filter microstructures. We present a cell separation device consisting of a hydrodynamic concentrator and a microfluidic ratchet mechanism operating in tandem. The hydrodynamic concentrator removes the majority of the fluid and a fraction of leukocytes based on size, while the microfluidic ratchet mechanism separates cancer cells from leukocytes based on a combination of size and deformability. The irreversible ratcheting process enables highly selective separation and robust extraction of separated cells. Using cancer cells spiked into leukocyte suspensions, the complete system demonstrated a yield of 97%, while enriching the concentration of target cancer cells 3000 fold relative to the concentration of leukocytes. PMID- 24404035 TI - Microarray of non-connected gold pads used as high density electric traps for parallelized pairing and fusion of cells. AB - Cell fusion consists of inducing the formation of a hybridoma cell containing the genetic properties of the progenitor cells. Such an operation is usually performed chemically or electrically. The latter method, named electrofusion, is considered as having a strong potential, due to its efficiency and non-toxicity, but deserves further investigations prior to being applicable for key applications like antibody production and cancer immunotherapy. Indeed, to envision such applications, a high amount of hybrid cells is needed. In this context, we present in this paper a device for massive cell pairing and electrofusion, using a microarray of non-connected conductive pads. The electrofusion chamber--or channel--exposes cells to an inhomogeneous electric field, caused by the pads array, enabling the trapping and pairing of cells with dielectrophoresis (DEP) forces prior to electrofusion. Compared to a mechanical trapping, such electric trapping is fully reversible (on/off handling). The DEP force is contactless and thus eases the release of the produced hybridoma. Moreover, the absence of wire connections on the pads permits the high density trapping and electrofusion of cells. In this paper, the electric field mapping, the effect of metallic pads thickness, and the transmembrane potential of cells are studied based on a numerical model to optimize the device. Electric calculations and experiments were conducted to evaluate the trapping force. The structure was finally validated for cell pairing and electrofusion of arrays of cells. We believe that our approach of fully electric trapping with a simple structure is a promising method for massive production of electrofused hybridoma. PMID- 24404036 TI - Sample preconcentration inside sessile droplets using electrowetting. AB - Electrowetting with alternate voltage (AC) creates azimuthal flow vortices inside sessile droplets. These flow vortices can be controlled by introducing pinning sites at the contact line. When the frequency of the applied AC voltage is gradually ramped from a few hundreds of hertz to a few tens of kilohertz the azimuthal flow vortices contract and move towards the contact line near the pinning site. Dispersed particles in the liquid are collected in the center of these vortices leading to an increase in the local particle concentration by up to more than one order of magnitude. We provide a qualitative explanation for symmetry of the flow patterns within the drops and discuss possible scenarios explaining the particle collection and preconcentration. PMID- 24404037 TI - Isotachophoresis with emulsions. AB - An experimental study on isotachophoresis (ITP) in which an emulsion is used as leading electrolyte (LE) is reported. The study aims at giving an overview about the transport and flow phenomena occurring in that context. Generally, it is observed that the oil droplets initially dispersed in the LE are collected at the ITP transition zone and advected along with it. The detailed behavior at the transition zone depends on whether or not surfactants (polyvinylpyrrolidon, PVP) are added to the electrolytes. In a system without surfactants, coalescence is observed between the droplets collected at the ITP transition zone. After having achieved a certain size, the droplets merge with the channel walls, leaving an oil film behind. In systems with PVP, coalescence is largely suppressed and no merging of droplets with the channel walls is observed. Instead, at the ITP transition zone, a droplet agglomerate of increasing size is formed. In the initial stages of the ITP experiments, two counter rotating vortices are formed inside the terminating electrolyte. The vortex formation is qualitatively explained based on a hydrodynamic instability triggered by fluctuations of the number density of oil droplets. PMID- 24404038 TI - Coplanar electrowetting-induced stirring as a tool to manipulate biological samples in lubricated digital microfluidics. Impact of ambient phase on drop internal flow pattern. AB - Oscillating electrowetting on dielectrics (EWOD) with coplanar electrodes is investigated in this paper as a way to provide efficient stirring within a drop with biological content. A supporting model inspired from Ko et al. [Appl. Phys. Lett. 94, 194102 (2009)] is proposed allowing to interpret oscillating EWOD induced drop internal flow as the result of a current streaming along the drop surface deformed by capillary waves. Current streaming behaves essentially as a surface flow generator and the momentum it sustains within the (viscous) drop is even more significant as the surface to volume ratio is small. With the circular electrode pair considered in this paper, oscillating EWOD sustains toroidal vortical flows when the experiments are conducted with aqueous drops in air as ambient phase. But when oil is used as ambient phase, it is demonstrated that the presence of an electrode gap is responsible for a change in drop shape: a pinch off at the electrode gap yields a peanut-shaped drop and a symmetry break-up of the EWOD-induced flow pattern. Viscosity of oil is also responsible for promoting an efficient damping of the capillary waves which populate the surface of the actuated drop. As a result, the capillary network switches from one standing wave to two superimposed traveling waves of different mechanical energy, provided that actuation frequency is large enough, for instance, as large as the one commonly used in electrowetting applications (f ~ 500 Hz and beyond). Special emphasis is put on stirring of biological samples. As a typical application, it is demonstrated how beads or cell clusters can be focused under flow either at mid height of the drop or near the wetting plane, depending on how the nature of the capillary waves is (standing or traveling), and therefore, depending on the actuation frequency (150 Hz-1 KHz). PMID- 24404039 TI - Microfluidic trapping of giant unilamellar vesicles to study transport through a membrane pore. AB - We present a microfluidic platform able to trap single GUVs in parallel. GUVs are used as model membranes across many fields of biophysics including lipid rafts, membrane fusion, and nanotubes. While their creation is relatively facile, handling and addressing single vesicles remains challenging. The PDMS microchip used herein contains 60 chambers, each with posts able to passively capture single GUVs without compromising their integrity. The design allows for circular valves to be lowered from the channel ceiling to isolate the vesicles from rest of the channel network. GUVs containing calcein were trapped and by rapidly opening the valves, the membrane pore protein alpha-hemolysin (alphaHL) was introduced to the membrane. Confocal microscopy revealed the kinetics of the small molecule efflux for different protein concentrations. This microfluidic approach greatly improves the number of experiments possible and can be applied to a wide range of biophysical applications. PMID- 24404040 TI - Label-free viscosity measurement of complex fluids using reversal flow switching manipulation in a microfluidic channel. AB - The accurate viscosity measurement of complex fluids is essential for characterizing fluidic behaviors in blood vessels and in microfluidic channels of lab-on-a-chip devices. A microfluidic platform that accurately identifies biophysical properties of blood can be used as a promising tool for the early detections of cardiovascular and microcirculation diseases. In this study, a flow switching phenomenon depending on hydrodynamic balancing in a microfluidic channel was adopted to conduct viscosity measurement of complex fluids with label free operation. A microfluidic device for demonstrating this proposed method was designed to have two inlets for supplying the test and reference fluids, two side channels in parallel, and a junction channel connected to the midpoint of the two side channels. According to this proposed method, viscosities of various fluids with different phases (aqueous, oil, and blood) in relation to that of reference fluid were accurately determined by measuring the switching flow-rate ratio between the test and reference fluids, when a reverse flow of the test or reference fluid occurs in the junction channel. An analytical viscosity formula was derived to measure the viscosity of a test fluid in relation to that of the corresponding reference fluid using a discrete circuit model for the microfluidic device. The experimental analysis for evaluating the effects of various parameters on the performance of the proposed method revealed that the fluidic resistance ratio ( R J L / R L , fluidic resistance in the junction channel ( R J L ) to fluidic resistance in the side channel ( R L )) strongly affects the measurement accuracy. The microfluidic device with smaller R J L / R L values is helpful to measure accurately the viscosity of the test fluid. The proposed method accurately measured the viscosities of various fluids, including single phase (Glycerin and plasma) and oil-water phase (oil vs. deionized water) fluids, compared with conventional methods. The proposed method was also successfully applied to measure viscosities of blood with varying hematocrits, chemically fixed RBCS, and channel sizes. Based on these experimental results, the proposed method can be effectively used to measure the viscosities of various fluids easily, without any fluorescent labeling and tedious calibration procedures. PMID- 24404041 TI - Microfluidic platform for isolating nucleic acid targets using sequence specific hybridization. AB - The separation of target nucleic acid sequences from biological samples has emerged as a significant process in today's diagnostics and detection strategies. In addition to the possible clinical applications, the fundamental understanding of target and sequence specific hybridization on surface modified magnetic beads is of high value. In this paper, we describe a novel microfluidic platform that utilizes a mobile magnetic field in static microfluidic channels, where single stranded DNA (ssDNA) molecules are isolated via nucleic acid hybridization. We first established efficient isolation of biotinylated capture probe (BP) using streptavidin-coated magnetic beads. Subsequently, we investigated the hybridization of target ssDNA with BP bound to beads and explained these hybridization kinetics using a dual-species kinetic model. The number of hybridized target ssDNA molecules was determined to be about 6.5 times less than that of BP on the bead surface, due to steric hindrance effects. The hybridization of target ssDNA with non-complementary BP bound to bead was also examined, and non-specific hybridization was found to be insignificant. Finally, we demonstrated highly efficient capture and isolation of target ssDNA in the presence of non-target ssDNA, where as low as 1% target ssDNA can be detected from mixture. The microfluidic method described in this paper is significantly relevant and is broadly applicable, especially towards point-of-care biological diagnostic platforms that require binding and separation of known target biomolecules, such as RNA, ssDNA, or protein. PMID- 24404042 TI - Poly(vinyl alcohol)-heparin biosynthetic microspheres produced by microfluidics and ultraviolet photopolymerisation. AB - Biosynthetic microspheres have the potential to address some of the limitations in cell microencapsulation; however, the generation of biosynthetic hydrogel microspheres has not been investigated or applied to cell encapsulation. Droplet microfluidics has the potential to produce more uniform microspheres under conditions compatible with cell encapsulation. Therefore, the aim of this study was to understand the effect of process parameters on biosynthetic microsphere formation, size, and morphology with a co-flow microfluidic method. Poly(vinyl alcohol) (PVA), a synthetic hydrogel and heparin, a glycosaminoglycan were chosen as the hydrogels for this study. A capillary-based microfluidic droplet generation device was used, and by varying the flow rates of both the polymer and oil phases, the viscosity of the continuous oil phase, and the interfacial surface tension, monodisperse spheres were produced from ~200 to 800 MUm. The size and morphology were unaffected by the addition of heparin. The modulus of spheres was 397 and 335 kPa for PVA and PVA/heparin, respectively, and this was not different from the bulk gel modulus (312 and 365 for PVA and PVA/heparin, respectively). Mammalian cells encapsulated in the spheres had over 90% viability after 24 h in both PVA and PVA/heparin microspheres. After 28 days, viability was still over 90% for PVA-heparin spheres and was significantly higher than in PVA only spheres. The use of biosynthetic hydrogels with microfluidic and UV polymerisation methods offers an improved approach to long-term cell encapsulation. PMID- 24404043 TI - Selective dynamic concentration of peptides at poles of cation-selective nanoporous granules. AB - The authors exposed a non-equilibrium dynamic counterion and coion analyte concentration to an AC electric field to selectively concentrate peptides at the poles of a cation-selective granule. The counterion polarization results from the focusing of the electric field show a discontinuous drop in the intra-granule counterion electromigration flux at the pole. The coion concentration polarization is due to the combined external convective and electromigration fluxes toward the pole that neutralize the accumulating counterions. Because the electromigration mobility of the peptide anion analyte depends on the pH, the authors determined a 20 000-fold high concentration factor for a near-neutral pH of 6.0 to 7.7. Because the peptide is protonated at the acidic pole and its absolute charge ranges from -0.3 to -1.9, the concentration factor scales exponentially with the absolute charge, thus allowing extremely selective concentrations of various peptides, which is demonstrated by fluorescein isothiocyanate tagged angiotensin I (pI ~ 5.8) and Texas red tagged avidin (pI ~ 10.5). This dynamic concentration effect can substantially enhance the sensitivity of bio-assays. PMID- 24404044 TI - Field tested milliliter-scale blood filtration device for point-of-care applications. AB - In this paper, we present a low cost and equipment-free blood filtration device capable of producing plasma from blood samples with mL-scale capacity and demonstrate its clinical application for hepatitis B diagnosis. We report the results of in-field testing of the device with 0.8-1 ml of undiluted, anticoagulated human whole blood samples from patients at the National Hospital for Tropical Diseases in Hanoi, Vietnam. Blood cell counts demonstrate that the device is capable of filtering out 99.9% of red and 96.9% of white blood cells, and the plasma collected from the device contains lower red blood cell counts than plasma obtained from a centrifuge. Biochemistry and immunology testing establish the suitability of the device as a sample preparation unit for testing alanine transaminase (ALT), aspartate transaminase (AST), urea, hepatitis B "e" antigen (HBeAg), hepatitis B "e" antibody (HBe Ab), and hepatitis B surface antibody (HBs Ab). The device provides a simple and practical front-end sample processing method for point-of-care microfluidic diagnostics, enabling sufficient volumes for multiplexed downstream tests. PMID- 24404045 TI - Adding reagent to droplets with controlled rupture of encapsulated double emulsions. AB - We present a method to add reagent to microfluidic droplets by enveloping them as a double emulsions in reagent-filled droplets and then rupturing them with an electric field. When the double emulsions rupture, they release their contents into the enveloping droplets, ensuring mixing with reagent while limiting cross droplet contamination. PMID- 24404046 TI - Effects of non-Newtonian power law rheology on mass transport of a neutral solute for electro-osmotic flow in a porous microtube. AB - Mass transport of a neutral solute for a power law fluid in a porous microtube under electro-osmotic flow regime is characterized in this study. Combined electro-osmotic and pressure driven flow is conducted herein. An analytical solution of concentration profile within mass transfer boundary layer is derived from the first principle. The solute transport through the porous wall is also coupled with the electro-osmotic flow to predict the solute concentration in the permeate stream. The effects of non-Newtonian rheology and the operating conditions on the permeation rate and permeate solute concentration are analyzed in detail. Both cases of assisting (electro-osmotic and poiseulle flow are in same direction) and opposing flow (the individual flows are in opposite direction) cases are taken care of. Enhancement of Sherwood due to electro osmotic flow for a non-porous conduit is also quantified. Effects if non Newtonian rheology on Sherwood number enhancement are observed. PMID- 24404047 TI - Label-free electronic probing of nucleic acids and proteins at the nanoscale using the nanoneedle biosensor. AB - Detection of proteins and nucleic acids is dominantly performed using optical fluorescence based techniques, which are more costly and timely than electrical detection due to the need for expensive and bulky optical equipment and the process of fluorescent tagging. In this paper, we discuss our study of the electrical properties of nucleic acids and proteins at the nanoscale using a nanoelectronic probe we have developed, which we refer to as the Nanoneedle biosensor. The nanoneedle consists of four thin film layers: a conductive layer at the bottom acting as an electrode, an oxide layer on top, and another conductive layer on top of that, with a protective oxide above. The presence of proteins and nucleic acids near the tip results in a decrease in impedance across the sensing electrodes. There are three basic mechanisms behind the electrical response of DNA and protein molecules in solution under an applied alternating electrical field. The first change stems from modulation of the relative permittivity at the interface. The second mechanism is the formation and relaxation of the induced dipole moment. The third mechanism is the tunneling of electrons through the biomolecules. The results presented in this paper can be extended to develop low cost point-of-care diagnostic assays for the clinical setting. PMID- 24404048 TI - Simulation of malaria-infected red blood cells in microfluidic channels: Passage and blockage. AB - Malaria-infected red blood cells (iRBCs) become less deformable with the progression of infection and tend to occlude microcapillaries. This process has been investigated in vitro using microfluidic channels. The objective of this paper is to provide a quantitative basis for interpreting the experimental observations of iRBC occlusion of microfluidic channels. Using a particle-based model for the iRBC, we simulate the traverse of iRBCs through a converging microfluidic channel and explore the progressive loss of cell deformability due to three factors: the stiffening of the membrane, the reduction of the cell's surface-volume ratio, and the growing solid parasites inside the cell. When examined individually, each factor tends to hinder the passage of the iRBC and lengthen the transit time. Moreover, at sufficient magnitude, each may lead to obstruction of narrow microfluidic channels. We then integrate the three factors into a series of simulations that mimic the development of malaria infection through the ring, trophozoite, and schizont stages. These simulations successfully reproduce the experimental observation that with progression of infection, the iRBC transitions from passage to blockage in larger and larger channels. The numerical results suggest a scheme for quantifying iRBC rigidification through microfluidic measurements of the critical pressure required for passage. PMID- 24404049 TI - High-throughput inertial particle focusing in a curved microchannel: Insights into the flow-rate regulation mechanism and process model. AB - In this work, we design and fabricate a miniaturized spiral-shaped microchannel device which can be used for high-throughput particle/cell ordering, enrichment, and purification. To probe into the flow rate regulation mechanism, an experimental investigation is carried out on the focusing behaviors of particles with significantly different sizes in this device. A complete picture of the focusing position shifting process is unfolded to clarify the confusing results obtained from flow regimes with different dominant forces in past research. Specifically, with the increase of the flow rate, particles are observed to first move towards the inner wall under the dominant inertial migration, then stabilize at a specific position and finally shift away from the inner wall due to the alternation of the dominant force. Novel phenomena of focusing instability, co focusing, and focusing position interchange of differently sized particles are also observed and investigated. Based on the obtained experimental data, we develop and validate, for the first time, a five-stage model of the particle focusing process with increasing flow rate for interpreting particle behaviors in terms of the competition between inertial lift and Dean drag forces. These new experimental findings and the proposed process model provide an important supplement to the existing mechanism of inertial particle flow and enable more flexible and precise particle manipulation. Additionally, we examine the focusing behaviors of bioparticles with a polydisperse size distribution to validate the explored mechanisms and thus help realize efficient enrichment and purification of these particles. PMID- 24404050 TI - Fabrication of uniform multi-compartment particles using microfludic electrospray technology for cell co-culture studies. AB - In this work, we demonstrate a robust and reliable approach to fabricate multi compartment particles for cell co-culture studies. By taking advantage of the laminar flow within our microfluidic nozzle, multiple parallel streams of liquids flow towards the nozzle without significant mixing. Afterwards, the multiple parallel streams merge into a single stream, which is sprayed into air, forming monodisperse droplets under an electric field with a high field strength. The resultant multi-compartment droplets are subsequently cross-linked in a calcium chloride solution to form calcium alginate micro-particles with multiple compartments. Each compartment of the particles can be used for encapsulating different types of cells or biological cell factors. These hydrogel particles with cross-linked alginate chains show similarity in the physical and mechanical environment as the extracellular matrix of biological cells. Thus, the multi compartment particles provide a promising platform for cell studies and co culture of different cells. In our study, cells are encapsulated in the multi compartment particles and the viability of cells is quantified using a fluorescence microscope after the cells are stained for a live/dead assay. The high cell viability after encapsulation indicates the cytocompatibility and feasibility of our technique. Our multi-compartment particles have great potential as a platform for studying cell-cell interactions as well as interactions of cells with extracellular factors. PMID- 24404051 TI - Microfluidic rectifier based on poly(dimethylsiloxane) membrane and its application to a micropump. AB - A microfluidic rectifier incorporating an obstructed microchannel and a PDMS membrane is proposed. During forward flow, the membrane deflects in the upward direction; thereby allowing the fluid to pass over the obstacle. Conversely, during reverse flow, the membrane seals against the obstacle, thereby closing the channel and preventing flow. It is shown that the proposed device can operate over a wide pressure range by increasing or decreasing the membrane thickness as required. A microfluidic pump is realized by integrating the rectifier with a simple stepper motor mechanism. The experimental results show that the pump can achieve a vertical left height of more than 2 m. Moreover, it is shown that a maximum flow rate of 6.3 ml/min can be obtained given a membrane thickness of 200 MUm and a motor velocity of 80 rpm. In other words, the proposed microfluidic rectifier not only provides an effective means of preventing reverse flow but also permits the realization of a highly efficient microfluidic pump. PMID- 24404052 TI - Vortex-aided inertial microfluidic device for continuous particle separation with high size-selectivity, efficiency, and purity. AB - In this paper, we report an inertial microfluidic device with simple geometry for continuous extraction of large particles with high size-selectivity (<2 MUm), high efficiency (~90%), and high purity (>90%). The design takes advantage of a high-aspect-ratio microchannel to inertially equilibrate cells and symmetric chambers for microvortex-aided cell extraction. A side outlet in each chamber continuously siphons larger particles, while the smaller particles or cells exit through the main outlet. The design has several advantages, including simple design, small footprint, ease of paralleling and cascading, one-step operation, and continuous separation with ultra-selectivity, high efficiency and purity. The described approach is applied to manipulating cells and particles for ultra selective separation, quickly and effectively extracting larger sizes from the main flow, with broad applications in cell separations. PMID- 24404053 TI - Sorting of circulating tumor cells (MV3-melanoma) and red blood cells using non inertial lift. AB - We demonstrate the method of non-inertial lift induced cell sorting (NILICS), a continuous, passive, and label-free cell sorting approach in a simple single layer microfluidic device at low Reynolds number flow conditions. In the experiments, we exploit the non-inertial lift effect to sort circulating MV3 melanoma cells from red blood cell suspensions at different hematocrits as high as 9%. We analyze the separation process and the influence of hematocrit and volume flow rates. We achieve sorting efficiencies for MV3-cells up to EMV3 = 100% at Hct = 9% and demonstrate cell viability by recultivation of the sorted cells. PMID- 24404054 TI - Three dimensional microfluidics with embedded microball lenses for parallel and high throughput multicolor fluorescence detection. AB - We report a 3D microfluidic device with 32 detection channels and 64 sheath flow channels and embedded microball lens array for high throughput multicolor fluorescence detection. A throughput of 358 400 cells/s has been accomplished. This device is realized by utilizing solid immersion micro ball lens arrays for high sensitivity and parallel fluorescence detection. High refractive index micro ball lenses (n = 2.1) are embedded underneath PDMS channels close to cell detection zones in channels. This design permits patterning high N.A. micro ball lenses in a compact fashion for parallel fluorescence detection on a small footprint device. This device also utilizes 3D microfluidic fabrication to address fluid routing issues in two-dimensional parallel sheath focusing and allows simultaneous pumping of 32 sample channels and 64 sheath flow channels with only two inlets. PMID- 24404055 TI - A droplet-based novel approach for viable and low volume consumption surface plasmon resonance bio-sensing inside a polydimethylsiloxane microchip. AB - Over the course of last two decades, surface plasmon resonance (SPR) has emerged as a viable candidate for label-free detection and characterization for a large pool of biological interactions, ranging from hybridization of oligonucleotides to high throughput drug-screening. Conventional SPR bio-sensing involves a step response method where the SPR sensorgram in response to a switched sequential flow of analyte and buffer is plotted in real-time and fitted to an exponential curve to extract the associative and dissociative reaction rates. Such measurement schemes involve continuous flow conditions where a substantial reagent volume is consumed and is subject to dispersive mixing at flow switching zones. In this paper, we demonstrate a new plug-train SPR technique in a microfluidic chip that separates and singulates solvent plugs in analyte and buffer by an immiscible air phase. Bio-samples are first discretized within plug droplets with volumes in order of few hundred nanoliters or less followed by pressure-driven transport onto SPR sensing sites of this hydrophobically modified SPR microdevise. The kinetic constants ka and kd for a model protein-small molecule interaction pair are extracted from a plug-train signal and are shown to be in reasonable agreement with our previous reports. PMID- 24404056 TI - Bistability in droplet traffic at asymmetric microfluidic junctions. AB - We present the first experimental demonstration of confined microfluidic droplets acting as discrete negative resistors, wherein the effective hydrodynamic resistance to flow in a microchannel is reduced by the presence of a droplet. The implications of this hitherto unexplored regime in the traffic of droplets in microfluidic networks are highlighted by demonstrating bistable filtering into either arm of symmetric and asymmetric microfluidic loops, and programming oscillatory droplet routing therein. PMID- 24404057 TI - Circulating but not immobilized N-deglycosylated von Willebrand factor increases platelet adhesion under flow conditions. AB - The role of von Willebrand factor (VWF) as a shear stress activated platelet adhesive has been related to a coiled-elongated shape conformation. The forces dominating this transition have been suggested to be controlled by the proteins polymeric architecture. However, the fact that 20% of VWF molecular weight originates from glycan moieties has so far been neglected in these calculations. In this study, we present a systematic experimental investigation on the role of N-glycosylation for VWF mediated platelet adhesion under flow. A microfluidic flow chamber with a stenotic compartment that allows one to mimic various physiological flow conditions was designed for the efficient analysis of the adhesion spectrum. Surprisingly, we found an increase in platelet adhesion with elevated shear rate, both qualitatively and quantitatively fully conserved when N deglycosylated VWF (N-deg-VWF) instead of VWF was immobilized in the microfluidic channel. This has been demonstrated consistently over four orders of magnitude in shear rate. In contrast, when N-deg-VWF was added to the supernatant, an increase in adhesion rate by a factor of two was detected compared to the addition of wild type VWF. It appears that once immobilized, the role of glycans is at least modified if not-as found here for the case of adhesion-negated. These findings strengthen the physical impact of the circulating polymer on shear dependent platelet adhesion events. At present, there is no theoretical explanation for an increase in platelet adhesion to VWF in the absence of its N-glycans. However, our data indicate that the effective solubility of the protein and hence its shape or conformation may be altered by the degree of glycosylation and is therefore a good candidate for modifying the forces required to uncoil this biopolymer. PMID- 24404058 TI - A standalone perfusion platform for drug testing and target validation in micro vessel networks. AB - Studying the effects of pharmacological agents on human endothelium includes the routine use of cell monolayers cultivated in multi-well plates. This configuration fails to recapitulate the complex architecture of vascular networks in vivo and does not capture the relationship between shear stress (i.e. flow) experienced by the cells and dose of the applied pharmacological agents. Microfluidic platforms have been applied extensively to create vascular systems in vitro; however, they rely on bulky external hardware to operate, which hinders the wide application of microfluidic chips by non-microfluidic experts. Here, we have developed a standalone perfusion platform where multiple devices were perfused at a time with a single miniaturized peristaltic pump. Using the platform, multiple micro-vessel networks, that contained three levels of branching structures, were created by culturing endothelial cells within circular micro-channel networks mimicking the geometrical configuration of natural blood vessels. To demonstrate the feasibility of our platform for drug testing and validation assays, a drug induced nitric oxide assay was performed on the engineered micro-vessel network using a panel of vaso-active drugs (acetylcholine, phenylephrine, atorvastatin, and sildenafil), showing both flow and drug dose dependent responses. The interactive effects between flow and drug dose for sildenafil could not be captured by a simple straight rectangular channel coated with endothelial cells, but it was captured in a more physiological branching circular network. A monocyte adhesion assay was also demonstrated with and without stimulation by an inflammatory cytokine, tumor necrosis factor-alpha. PMID- 24404059 TI - Discrimination between the human prostate normal cell and cancer cell by using a novel electrical impedance spectroscopy controlling the cross-sectional area of a microfluidic channel. AB - The prostate biopsy method shows a high false negative result because the suspicious tissue considered as cancer is not confirmed during tissue sampling. Thus, repeated biopsy procedures and diagnostic errors in relation to prostate cancer frequently occur. The purpose of this research is to enhance the prostate cancer detection rate by using microfluidic electrical impedance spectroscopy (MUEIS), which allows real-time measurement of the electrical impedance of a single human prostate normal cell and cancer cell. The MUEIS was equipped with a movable flexible membrane, which is operated by pneumatic pressure to capture the single cell on the surface of sensing electrodes. The forced tight contact between the cell and electrodes makes it possible to measure the electrical characteristics of the cell with a high sensitivity. The MUEIS discriminates well between normal human prostate cells (RWPE-1) and cancer cells (PC-3) at 8.7 kHz based on the electrical signal responses of the cells. The average difference rates of admittance magnitude and susceptance are 54.55% and 54.59%, respectively. The developed MUEIS also shows high repeatability, which was verified by a deionized water test conducted before and after each cell assay; the maximum variance of both the impedance and admittance at 8.7 kHz was as small as 9.48%. PMID- 24404060 TI - A multichannel acoustically driven microfluidic chip to study particle-cell interactions. AB - Microfluidic devices have emerged as important tools for experimental physiology. They allow to study the effects of hydrodynamic flow on physiological and pathophysiological processes, e.g., in the circulatory system of the body. Such dynamic in vitro test systems are essential in order to address fundamental problems in drug delivery and targeted imaging, such as the binding of particles to cells under flow. In the present work an acoustically driven microfluidic platform is presented in which four miniature flow channels can be operated in parallel at distinct flow velocities with only slight inter-experimental variations. The device can accommodate various channel architectures and is fully compatible with cell culture as well as microscopy. Moreover, the flow channels can be readily separated from the surface acoustic wave pumps and subsequently channel-associated luminescence, absorbance, and/or fluorescence can be determined with a standard microplate reader. In order to create artificial blood vessels, different coatings were evaluated for the cultivation of endothelial cells in the microchannels. It was found that 0.01% fibronectin is the most suitable coating for growth of endothelial monolayers. Finally, the microfluidic system was used to study the binding of 1 MUm polystyrene microspheres to three different types of endothelial cell monolayers (HUVEC, HUVECtert, HMEC-1) at different average shear rates. It demonstrated that average shear rates between 0.5 s(-1) and 2.25 s(-1) exert no significant effect on cytoadhesion of particles to all three types of endothelial monolayers. In conclusion, the multichannel microfluidic platform is a promising device to study the impact of hydrodynamic forces on cell physiology and binding of drug carriers to endothelium. PMID- 24404061 TI - Microfluidic fabrication of polymeric core-shell microspheres for controlled release applications. AB - We report a facile and robust microfluidic method to fabricate polymeric core shell microspheres as delivery vehicles for biomedical applications. The characteristics of core-shell microspheres can be precisely and easily tuned by manipulating the microfluidic double emulsion templates. The addition of a shell can significantly improve the versatility as well as functionality of these microspheres as delivery vehicles. We demonstrate that the nature of the shell material plays an important role in the properties of the core-shell delivery vehicles. The release kinetics is significantly influenced by the material of the shell and other characteristics such as the thickness. For example, by adding a poly(lactic-co-glycolic acid) (PLGA) shell to an alginate core, the encapsulation efficiency is enhanced and undesired leakage of hydrophilic actives is prevented. By contrast, adding an alginate shell to PLGA core can lead to a reduction of the initial release rate, thus extending the release period of hydrophobic actives. Microfluidic fabrication enables the generation of precisely controlled core shell microspheres with a narrow size distribution, which enables the investigation of the relationship between the release kinetics of these microspheres and their characteristics. The approach of using core-shell particles as delivery vehicles creates new opportunities to customize the release kinetics of active ingredients. PMID- 24404062 TI - Circadian rhythms in Neurospora crassa on a polydimethylsiloxane microfluidic device for real-time gas perturbations. AB - Racetubes, a conventional system employing hollow glass tubes, are typically used for monitoring circadian rhythms from the model filamentous fungus, Neurospora crassa. However, a major technical limitation in using a conventional system is that racetubes are not amenable for real-time gas perturbations. In this work, we demonstrate a simple microfluidic device combined with real-time gas perturbations for monitoring circadian rhythms in Neurospora crassa using bioluminescence assays. The developed platform is a useful toolbox for investigating molecular responses under various gas conditions for Neurospora and can also be applied to other microorganisms. PMID- 24404063 TI - Bio-electrospraying of human mesenchymal stem cells: An alternative for tissue engineering. AB - Bio-electrospraying (BES) is a technique used for the processing of cells and can be applied to tissue engineering. The association of BES with scaffold production techniques has been shown to be an interesting strategy for the production of biomaterials with cells homogeneously distributed in the entire structure. Various studies have evaluated the effects of BES on different cell types. However, until the present moment, no studies have evaluated the impact of BES time on mesenchymal stem cells (MSC). Therefore, the aim of this work was to standardise the different parameters of BES (voltage, flow rate, and distance of the needle from the collecting plate) in relation to cell viability and then to evaluate the impact of BES time in relation to viability, proliferation, DNA damage, maintenance of plasticity and the immunophenotypic profile of MSC. Using 15 kV voltage, 0.46 ml/h flow rate and 4 cm distance, it was possible to form a stable and continuous jet of BES without causing a significant reduction in cell viability. Time periods between 15 and 60 min of BES did not cause alterations of viability, proliferation, plasticity, and immunophenotypic profile of the MSC. Time periods above 30 min of BES resulted in DNA damage; however, the DNA was able to repair itself within five hours. These results indicate that bio electrospraying is an adequate technique for processing MSC which can be safely applied to tissue engineering and regenerative medicine. PMID- 24404064 TI - Continuous separation of blood cells in spiral microfluidic devices. AB - Blood cell sorting is critical to sample preparation for both clinical diagnosis and therapeutic research. The spiral inertial microfluidic devices can achieve label-free, continuous separation of cell mixtures with high throughput and efficiency. The devices utilize hydrodynamic forces acting on cells within laminar flow, coupled with rotational Dean drag due to curvilinear microchannel geometry. Here, we report on optimized Archimedean spiral devices to achieve cell separation in less than 8 cm of downstream focusing length. These improved devices are small in size (<1 in.(2)), exhibit high separation efficiency (~95%), and high throughput with rates up to 1 * 10(6) cells per minute. These device concepts offer a path towards possible development of a lab-on-chip for point-of care blood analysis with high efficiency, low cost, and reduced analysis time. PMID- 24404065 TI - Deformation properties between fluid and periodic circular obstacles in polydimethylsiloxane microchannels: Experimental and numerical investigations under various conditions. AB - Understanding the mechanical properties of optically transparent polydimethylsiloxane (PDMS) microchannels was essential to the design of polymer based microdevices. In this experiment, PDMS microchannels were filled with a 100 MUM solution of rhodamine 6G dye at very low Reynolds numbers (~10(-3)). The deformation of PDMS microchannels created by pressure-driven flow was investigated by fluorescence microscopy and quantified the deformation by the linear relationship between dye layer thickness and intensity. A line scan across the channel determined the microchannel deformation at several channel positions. Scaling analysis widely used to justify PDMS bulging approximation was allowed when the applied flow rate was as high as 2.0 MUl/min. The three physical parameters (i.e., flow rate, PDMS wall thickness, and mixing ratio) and the design parameter (i.e., channel aspect ratio = channel height/channel width) were considered as critical parameters and provided the different features of pressure distributions within polymer-based microchannel devices. The investigations of the four parameters performed on flexible materials were carried out by comparison of experiment and finite element method (FEM) results. The measured Young's modulus from PDMS tensile test specimens at various circumstances provided reliable results for the finite element method. A thin channel wall, less cross-linker, high flow rate, and low aspect ratio microchannel were inclined to have a significant PDMS bulging. Among them, various mixing ratios related to material property and aspect ratios were one of the significant factors to determine PDMS bulging properties. The measured deformations were larger than the numerical simulation but were within corresponding values predicted by the finite element method in most cases. PMID- 24404066 TI - Three-phase slug flow in microchips can provide beneficial reaction conditions for enzyme liquid-liquid reactions. AB - Here, we introduce a solution to low stability of a two-phase slug flow with a chemical reaction occurring at the phase interface in a microfluidic reactor where substantial merging of individual reacting slugs results in the loss of uniformity of the flow. We create a three-phase slug flow by introducing a third fluid phase into the originally two-phase liquid-liquid slug flow, which generates small two-phase liquid slugs separated by gas phase. Introduction of the third phase into our system efficiently prevents merging of slugs and provides beneficial reaction conditions, such as uniform flow pattern along the whole reaction capillary, interfacial area with good reproducibility, and intensive water-oil interface renewal. We tested the three-phase flow on an enzyme hydrolysis of soybean oil and compared the reaction conversion with those from unstable two-phase slug flows. We experimentally confirmed that the three phase slug flow arrangement provides conversions and pressure drops comparable or even better with two-phase liquid-liquid arrangements. PMID- 24404067 TI - Hydrodynamic particle focusing design using fluid-particle interaction. AB - For passive sheathless particles focusing in microfluidics, the equilibrium positions of particles are typically controlled by micro channels with a V-shaped obstacle array (VOA). The design of the obstacles is mainly based on the distribution of flow streamlines without considering the existence of particles. We report an experimentally verified particle trajectory simulation using the arbitrary Lagrangian-Eulerian (ALE) fluid-particle interaction method. The particle trajectory which is strongly influenced by the interaction between the particle and channel wall is systematically analyzed. The numerical experiments show that the streamline is a good approximation of particle trajectory only when the particle locates on the center of the channel in depth. As the advantage of fluid-particle interaction method is achieved at a high computational cost and the streamline analysis is complex, a heuristic dimensionless design objective based on the Faxen's law is proposed to optimize the VOA devices. The optimized performance of particle focusing is verified via the experiments and ALE method. PMID- 24404068 TI - Influence of hydrodynamics on the growth kinetics of glass-adhering Pseudomonas putida cells through a parallel plate flow chamber. AB - The objective of this work was to investigate the influence of hydrodynamics on the growth kinetics of surface-adhering Pseudomonas putida cells. The results showed in particular that under non substrate-limiting conditions, the early step of bacterial apparent growth rate is lower than those measured with suspended cells. Contrary to previously cited authors which explain this behavior to the different adhesive properties of the "daughter"-cells (which makes more probable the detachment of these daughter-cells), in our experimental conditions, that explanation does not hold and we show a clear dependence of growth kinetics with flow conditions, due to the formation of boundary layer concentration at low Reynolds number. These results revealed that using Monod law in the modeling of biofilm growth in fixed-biomass processes should be performed with care. PMID- 24404069 TI - On-chip magnetophoretic isolation of CD4 + T cells from blood. AB - This paper presents the design, fabrication, and testing of a magnetophoretic bioseparation chip for the rapid isolation and concentration of CD4 + T cells from the peripheral blood. In a departure from conventional magnetic separation techniques, this microfluidic-based bioseperation device has several unique features, including locally engineered magnetic field gradients and a continuous flow with a buffer switching scheme to improve the performance of the separation process. Additionally, the chip is capable of processing significantly smaller sample volumes than conventional methods and sample losses are eliminated due to decreased handling. Furthermore, the possibility of sample-to-sample contamination is reduced with the disposable format. The overall dimensions of the device were 22 mm by 60 mm by 1 mm, approximately the size of a standard microscope slide. The results indicate a cell purity of greater than 95% at a sample flow rate of 50 ml/h and a cell recovery of 81% at a sample flow rate of 10 ml/h. The cell purity was found to increase with increasing the sample flow rate. However, the cell recovery decreases with an increase in the flow rate. A parametric study was also performed to investigate the effects of channel height, substrate thickness, magnetic bead size, and number of beads per cell on the cell separation performance. PMID- 24404070 TI - Rare cell isolation and profiling on a hybrid magnetic/size-sorting chip. AB - We present a hybrid magnetic/size-sorting (HMSS) chip for isolation and molecular analyses of circulating tumor cells (CTCs). The chip employs both negative and positive cell selection in order to provide high throughput, unbiased CTC enrichment. Specifically, the system utilizes a self-assembled magnet to generate high magnetic forces and a weir-style structure for cell sorting. The resulting device thus can perform multiple functions, including magnetic depletion, size selective cell capture, and on-chip molecular staining. With such capacities, the HMSS device allowed one-step CTC isolation and single cell detection from whole blood, tested with spiked cancer cells. The system further facilitated the study of individual CTCs for heterogeneity in molecular marker expression. PMID- 24404071 TI - Finite element simulations of hydrodynamic trapping in microfluidic particle-trap array systems. AB - Computational fluid dynamic (CFD) simulation is a powerful tool in the design and implementation of microfluidic systems, especially for systems that involve hydrodynamic behavior of objects such as functionalized microspheres, biological cells, or biopolymers in complex structures. In this work, we investigate hydrodynamic trapping of microspheres in a novel microfluidic particle-trap array device by finite element simulations. The accuracy of the time-dependent simulation of a microsphere's motion towards the traps is validated by our experimental results. Based on the simulation, we study the fluid velocity field, pressure field, and force and stress on the microsphere in the device. We further explore the trap array's geometric parameters and critical fluid velocity, which affect the microsphere's hydrodynamic trapping. The information is valuable for designing microfluidic devices and guiding experimental operation. Besides, we provide guidelines on the simulation set-up and release an openly available implementation of our simulation in one of the popular FEM softwares, COMSOL Multiphysics. Researchers may tailor the model to simulate similar microfluidic systems that may accommodate a variety of structured particles. Therefore, the simulation will be of particular interest to biomedical research involving cell or bead transport and migration, blood flow within microvessels, and drug delivery. PMID- 24404072 TI - Implementation of tetra-poly(ethylene glycol) hydrogel with high mechanical strength into microfluidic device technology. AB - Hydrogels have several excellent characteristics suitable for biomedical use such as softness, biological inertness and solute permeability. Hence, integrating hydrogels into microfluidic devices is a promising approach for providing additional functions such as biocompatibility and porosity, to microfluidic devices. However, the poor mechanical strength of hydrogels has severely limited device design and fabrication. A tetra-poly(ethylene glycol) (tetra-PEG) hydrogel synthesized recently has high mechanical strength and is expected to overcome such a limitation. In this research, we have comprehensively studied the implementation of tetra-PEG gel into microfluidic device technology. First, the fabrication of tetra-PEG gel/PDMS hybrid microchannels was established by developing a simple and robust bonding technique. Second, some fundamental features of tetra-PEG gel/PDMS hybrid microchannels, particularly fluid flow and mass transfer, were studied. Finally, to demonstrate the unique application of tetra-PEG-gel-integrated microfluidic devices, the generation of patterned chemical modulation with the maximum concentration gradient: 10% per 20 MUm in a hydrogel was performed. The techniques developed in this study are expected to provide fundamental and beneficial methods of developing various microfluidic devices for life science and biomedical applications. PMID- 24404073 TI - Human red blood cell behavior under homogeneous extensional flow in a hyperbolic shaped microchannel. AB - It is well known that certain pathological conditions result in a decrease of red blood cells (RBCs) deformability and subsequently can significantly alter the blood flow in microcirculation, which may block capillaries and cause ischemia in the tissues. Microfluidic systems able to obtain reliable quantitative measurements of RBC deformability hold the key to understand and diagnose RBC related diseases. In this work, a microfluidic system composed of a microchannel with a hyperbolic-shaped contraction followed by a sudden expansion is presented. We provide a detailed quantitative description of the degree of deformation of human RBCs under a controlled homogeneous extensional flow field. We measured the deformation index (DI) as well as the velocity of the RBCs travelling along the centerline of the channel for four different flow rates and analyze the impact of the particle Reynolds number. The results show that human RBC deformation tends to reach a plateau value in the region of constant extensional rate, the value of which depends on the extension rate. Additionally, we observe that the presence of a sudden expansion downstream of the hyperbolic contraction modifies the spatial distribution of cells and substantially increases the cell free layer (CFL) downstream of the expansion plane similarly to what is seen in other expansion flows. Beyond a certain value of flow rate, there is only a weak effect of inlet flow rates on the enhancement of the downstream CFL. These in vitro experiments show the potential of using microfluidic systems with hyperbolic shaped microchannels both for the separation of the RBCs from plasma and to assess changes in RBC deformability in physiological and pathological situations for clinical purposes. However, the selection of the geometry and the identification of the most suitable region to evaluate the changes on the RBC deformability under extensional flows are crucial if microfluidics is to be used as an in vitro clinical methodology to detect circulatory diseases. PMID- 24404074 TI - A microfluidic device for simultaneous measurement of viscosity and flow rate of blood in a complex fluidic network. AB - Blood viscosity has been considered as one of important biophysical parameters for effectively monitoring variations in physiological and pathological conditions of circulatory disorders. Standard previous methods make it difficult to evaluate variations of blood viscosity under cardiopulmonary bypass procedures or hemodialysis. In this study, we proposed a unique microfluidic device for simultaneously measuring viscosity and flow rate of whole blood circulating in a complex fluidic network including a rat, a reservoir, a pinch valve, and a peristaltic pump. To demonstrate the proposed method, a twin-shaped microfluidic device, which is composed of two half-circular chambers, two side channels with multiple indicating channels, and one bridge channel, was carefully designed. Based on the microfluidic device, three sequential flow controls were applied to identify viscosity and flow rate of blood, with label-free and sensorless detection. The half-circular chamber was employed to achieve mechanical membrane compliance for flow stabilization in the microfluidic device. To quantify the effect of flow stabilization on flow fluctuations, a formula of pulsation index (PI) was analytically derived using a discrete fluidic circuit model. Using the PI formula, the time constant contributed by the half-circular chamber is estimated to be 8 s. Furthermore, flow fluctuations resulting from the peristaltic pumps are completely removed, especially under periodic flow conditions within short periods (T < 10 s). For performance demonstrations, the proposed method was applied to evaluate blood viscosity with respect to varying flow rate conditions [(a) known blood flow rate via a syringe pump, (b) unknown blood flow rate via a peristaltic pump]. As a result, the flow rate and viscosity of blood can be simultaneously measured with satisfactory accuracy. In addition, the proposed method was successfully applied to identify the viscosity of rat blood, which circulates in a complex fluidic network. These observations confirm that the proposed method can be used for simultaneous measurement of viscosity and flow rate of whole blood circulating in the complex fluid network, with sensorless and label-free detection. Furthermore, the proposed method will be used in evaluating variations in the viscosity of human blood during cardiopulmonary bypass procedures or hemodialysis. PMID- 24404075 TI - Inducing self-rotation of cells with natural and artificial melanin in a linearly polarized alternating current electric field. AB - The phenomenon of self-rotation observed in naturally and artificially pigmented cells under an applied linearly polarized alternating current (non-rotating) electrical field has been investigated. The repeatable and controllable rotation speeds of the cells were quantified and their dependence on dielectrophoretic parameters such as frequency, voltage, and waveform was studied. Moreover, the rotation behavior of the pigmented cells with different melanin content was compared to quantify the correlation between self-rotation and the presence of melanin. Most importantly, macrophages, which did not originally rotate in the applied non-rotating electric field, began to exhibit self-rotation that was very similar to that of the pigmented cells, after ingesting foreign particles (e.g., synthetic melanin or latex beads). We envision the discovery presented in this paper will enable the development of a rapid, non-intrusive, and automated process to obtain the electrical conductivities and permittivities of cellular membrane and cytoplasm in the near future. PMID- 24404076 TI - Accurate dispensing system for single oocytes using air ejection. AB - In this study, we propose a new approach to increase the success rate of single oocyte dispensing and investigate the subsequent viability of the dispensed oocytes. We used a pair of capacitance sensors placed in a microfluidic chip to detect the oocyte, and custom-designed a special buffer zone in the microchannel to decelerate the flow velocity and reduce the hydraulic pressure acting on the oocyte. In the buffer zone, a semicircular bay, formed by equally spaced micro pillars, is used to stop the oocyte at the dispensing nozzle hole. Finally, the oocyte is ejected by airflow to the culture array. The novel feature of the developed microfluidic system is that the extraordinary improvement in success rate is accompanied by a lack of change in oocyte survival rate (as assessed by a comparison of survival rates before and after the dispensing procedure). By using this device, we achieved a highly accurate single-oocyte dispensing process with a success rate of 100%. The oocyte survival rate is approximately 70%, regardless of whether or not the oocyte is dispensed. The newly proposed system has the advantages of high operation speed and potential usage for two-dimensional micropatterning. PMID- 24404077 TI - Manufacturing and wetting low-cost microfluidic cell separation devices. AB - Deterministic lateral displacement (DLD) is a microfluidic size-based particle separation or filter technology with applications in cell separation and enrichment. Currently, there are no cost-effective manufacturing methods for this promising microfluidic technology. In this fabrication paper, however, we develop a simple, yet robust protocol for thermoplastic DLD devices using regulatory approved materials and biocompatible methods. The final standalone device allowed for volumetric flow rates of 660 MUl min(-1) while reducing the manufacturing time to <1 h. Optical profilometry and image analysis were employed to assess manufacturing accuracy and precision; the average replicated post height was 0.48% less than the average post height on the master mold and the average replicated array pitch was 1.1% less than the original design with replicated posts heights of 62.1 +/- 5.1 MUm (mean +/- 6 standard deviations) and replicated array pitches of 35.6 +/- 0.31 MUm. PMID- 24404078 TI - A novel MU-fluidic whole blood coagulation assay based on Rayleigh surface acoustic waves as a point-of-care method to detect anticoagulants. AB - A universal coagulation test that reliably detects prolonged coagulation time in patients, irrespective of the anticoagulant administered, has not been available to date. An easily miniaturised, novel MU-fluidic universal coagulation test employing surface acoustic waves (SAW) is presented here. SAW was employed to instantly mix and recalcify 6 MUl citrated whole blood and image correlation analysis was used to quantify clot formation kinetics. The detection of clinically relevant anticoagulant dosing with old anticoagulants (unfractionated heparin, argatroban) and new anticoagulants (dabigatran, rivaroxaban) has been tested and compared to standard plasma coagulation assays. The applicability of this novel method has been confirmed in a small patient population. Coagulation was dose-proportionally prolonged with heparin, argatroban, dabigatran, and rivaroxaban, comparable to standard tests. Aspirin and clopidogrel did not interfere with the SAW-induced clotting time (SAW-CT), whereas the strong GPIIb/IIIa-inhibitor abciximab did interfere. Preliminary clinical data prove the suitability of the SAW-CT in patients being treated with warfarin, rivaroxaban, or dabigatran. The system principally allows assessment of whole blood coagulation in humans in a point-of-care setting. This method could be used in stroke units, emergency vehicles, general and intensive care wards, as well as for laboratory and home testing of coagulation. PMID- 24404122 TI - Prevalence and causes of prescribing errors: the PRescribing Outcomes for Trainee Doctors Engaged in Clinical Training (PROTECT) study. AB - OBJECTIVES: Study objectives were to investigate the prevalence and causes of prescribing errors amongst foundation doctors (i.e. junior doctors in their first (F1) or second (F2) year of post-graduate training), describe their knowledge and experience of prescribing errors, and explore their self-efficacy (i.e. confidence) in prescribing. METHOD: A three-part mixed-methods design was used, comprising: prospective observational study; semi-structured interviews and cross sectional survey. All doctors prescribing in eight purposively selected hospitals in Scotland participated. All foundation doctors throughout Scotland participated in the survey. The number of prescribing errors per patient, doctor, ward and hospital, perceived causes of errors and a measure of doctors' self-efficacy were established. RESULTS: 4710 patient charts and 44,726 prescribed medicines were reviewed. There were 3364 errors, affecting 1700 (36.1%) charts (overall error rate: 7.5%; F1:7.4%; F2:8.6%; consultants:6.3%). Higher error rates were associated with : teaching hospitals (p<0.001), surgical (p = <0.001) or mixed wards (0.008) rather thanmedical ward, higher patient turnover wards (p<0.001), a greater number of prescribed medicines (p<0.001) and the months December and June (p<0.001). One hundred errors were discussed in 40 interviews. Error causation was multi-factorial; work environment and team factors were particularly noted. Of 548 completed questionnaires (national response rate of 35.4%), 508 (92.7% of respondents) reported errors, most of which (328 (64.6%) did not reach the patient. Pressure from other staff, workload and interruptions were cited as the main causes of errors. Foundation year 2 doctors reported greater confidence than year 1 doctors in deciding the most appropriate medication regimen. CONCLUSIONS: Prescribing errors are frequent and of complex causation. Foundation doctors made more errors than other doctors, but undertook the majority of prescribing, making them a key target for intervention. Contributing causes included work environment, team, task, individual and patient factors. Further work is needed to develop and assess interventions that address these. PMID- 24404123 TI - Gated F-18 FDG PET for assessment of left ventricular volumes and ejection fraction using QGS and 4D-MSPECT in patients with heart failure: a comparison with cardiac MRI. AB - PURPOSE: Ventricular function is a powerful predictor of survival in patients with heart failure (HF). However, studies characterizing gated F-18 FDG PET for the assessment of the cardiac function are rare. The aim of this study was to prospectively compare gated F-18 FDG PET and cardiac MRI for the assessment of ventricular volume and ejection fraction (EF) in patients with HF. METHODS: Eighty-nine patients with diagnosed HF who underwent both gated F-18 FDG PET/CT and cardiac MRI within 3 days were included in the analysis. Left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV), and EF were obtained from gated F-18 FDG PET/CT using the Quantitative Gated SPECT (QGS) and 4D-MSPECT software. RESULTS: LV EDV and LV ESV measured by QGS were significantly lower than those measured by cardiac MRI (both P<0.0001). In contrast, the corresponding values for LV EDV for 4D-MSPECT were comparable, and LV ESV was underestimated with borderline significance compared with cardiac MRI (P = 0.047). LV EF measured by QGS and cardiac MRI showed no significant differences, whereas the corresponding values for 4D-MSPECT were lower than for cardiac MRI (P<0.0001). The correlations of LV EDV, LV ESV, and LV EF between gated F-18 FDG PET/CT and cardiac MRI were excellent for both QGS (r = 0.92, 0.92, and 0.76, respectively) and 4D-MSPECT (r = 0.93, 0.94, and 0.75, respectively). However, Bland-Altman analysis revealed a significant systemic error, where LV EDV ( 27.9+/-37.0 mL) and ESV (-18.6+/-33.8 mL) were underestimated by QGS. CONCLUSION: Despite the observation that gated F-18 FDG PET/CT were well correlated with cardiac MRI for assessing LV function, variation was observed between the two imaging modalities, and so these imaging techniques should not be used interchangeably. PMID- 24404124 TI - Integrating remote sensing and GIS for prediction of winter wheat (Triticum aestivum) protein contents in Linfen (Shanxi), China. AB - In this study, relationships between normalized difference vegetation index (NDVI) and plant (winter wheat) nitrogen content (PNC) and between PNC and grain protein content (GPC) were investigated using multi-temporal moderate-resolution imaging spectroradiometer (MODIS) data at the different stages of winter wheat in Linfen (Shanxi, P. R. China). The anticipating model for GPC of winter wheat was also established by the approach of NDVI at the different stages of winter wheat. The results showed that the spectrum models of PNC passed F test. The NDVI4.14 regression effect of PNC model of irrigated winter wheat was the best, and that in dry land was NDVI4.30. The PNC of irrigated and dry land winter wheat were significantly (P<0.01) and positively correlated to GPC. Both of protein spectral anticipating model of irrigated and dry land winter wheat passed a significance test (P<0.01). Multiple anticipating models (MAM) were established by NDVI from two periods of irrigated and dry land winter wheat and PNC to link GPC anticipating model. The coefficient of determination R(2) (R) of MAM was greater than that of the other two single-factor models. The relative root mean square error (RRMSE) and relative error (RE) of MAM were lower than those of the other two single-factor models. Therefore, test effects of multiple proteins anticipating model were better than those of single-factor models. The application of multiple anticipating models for predication of protein content (PC) of irrigated and dry land winter wheat was more accurate and reliable. The regionalization analysis of GPC was performed using inverse distance weighted function of GIS, which is likely to provide the scientific basis for the reasonable winter wheat planting in Linfen city, China. PMID- 24404125 TI - Metabotropic glutamate receptor-1 contributes to progression in triple negative breast cancer. AB - TNBC is an aggressive breast cancer subtype that does not express hormone receptors (estrogen and progesterone receptors, ER and PR) or amplified human epidermal growth factor receptor type 2 (HER2), and there currently exist no targeted therapies effective against it. Consequently, finding new molecular targets in triple negative breast cancer (TNBC) is critical to improving patient outcomes. Previously, we have detected the expression of metabotropic glutamate receptor-1 (gene: GRM1; protein: mGluR1) in TNBC and observed that targeting glutamatergic signaling inhibits TNBC growth both in vitro and in vivo. In this study, we explored how mGluR1 contributes to TNBC progression, using the isogenic MCF10 progression series, which models breast carcinogenesis from nontransformed epithelium to malignant basal-like breast cancer. We observed that mGluR1 is expressed in human breast cancer and that in MCF10A cells, which model nontransformed mammary epithelium, but not in MCF10AT1 cells, which model atypical ductal hyperplasia, mGluR1 overexpression results in increased proliferation, anchorage-independent growth, and invasiveness. In contrast, mGluR1 knockdown results in a decrease in these activities in malignant MCF10CA1d cells. Similarly, pharmacologic inhibition of glutamatergic signaling in MCF10CA1d cells results in a decrease in proliferation and anchorage-independent growth. Finally, transduction of MCF10AT1 cells, which express c-Ha-ras, using a lentiviral construct expressing GRM1 results in transformation to carcinoma in 90% of resultant xenografts. We conclude that mGluR1 cooperates with other factors in hyperplastic mammary epithelium to contribute to TNBC progression and therefore propose that glutamatergic signaling represents a promising new molecular target for TNBC therapy. PMID- 24404126 TI - STAT3 oligonucleotide inhibits tumor angiogenesis in preclinical models of squamous cell carcinoma. AB - PURPOSE: Signal transducer and activator of transcription 3 (STAT3) has shown to play a critical role in head and neck squamous cell carcinoma (HNSCC) and we have recently completed clinical trials of STAT3 decoy oligonucleotide in patients with recurrent or metastatic HNSCC. However, there is limited understanding of the role of STAT3 in modulating other aspects of tumorigenesis such as angiogenesis. In this study, we aimed to examine the effects of STAT3 decoy oligonucleotide on tumor angiogenesis. EXPERIMENTAL DESIGN: A STAT3 decoy oligonucleotide and small interfering RNA (siRNA) were used to inhibit STAT3 in endothelial cells in vitro and in vivo. The biochemical effects of STAT3 inhibition were examined in conjunction with the consequences on proliferation, migration, apoptotic staining, and tubule formation. Additionally, we assessed the effects of STAT3 inhibition on tumor angiogenesis using murine xenograft models. RESULTS: STAT3 decoy oligonucleotide decreased proliferation, induces apoptosis, decreased migration, and decreased tubule formation of endothelial cells in vitro. The STAT3 decoy oligonucleotide also inhibited tumor angiogenesis in murine tumor xenografts. Lastly, our data suggest that the antiangiogenic effects of STAT3 decoy oligonucleotide were mediatedthrough the inhibition of both STAT3 and STAT1. CONCLUSIONS: The STAT3 decoy oligonucleotidewas found to be an effective antiangiogenic agent, which is likely to contribute to the overall antitumor effects of this agent in solid tumors.Taken together with the previously demonstrated antitumor activity of this agent, STAT3 decoy oligonucleotide represents a promising single agent approach to targeting both the tumor and vascular compartments in various malignancies. PMID- 24404127 TI - Tie2 signaling cooperates with TNF to promote the pro-inflammatory activation of human macrophages independently of macrophage functional phenotype. AB - Angiopoietin (Ang) -1 and -2 and their receptor Tie2 play critical roles in regulating angiogenic processes during development, homeostasis, tumorigenesis, inflammation and tissue repair. Tie2 signaling is best characterized in endothelial cells, but a subset of human and murine circulating monocytes/macrophages essential to solid tumor formation express Tie2 and display immunosuppressive properties consistent with M2 macrophage polarization. However, we have recently shown that Tie2 is strongly activated in pro-inflammatory macrophages present in rheumatoid arthritis patient synovial tissue. Here we examined the relationship between Tie2 expression and function during human macrophage polarization. Tie2 expression was observed under all polarization conditions, but was highest in IFN-gamma and IL-10 -differentiated macrophages. While TNF enhanced expression of a common restricted set of genes involved in angiogenesis and inflammation in GM-CSF, IFN-gamma and IL-10 -differentiated macrophages, expression of multiple chemokines and cytokines, including CXCL3, CXCL5, CXCL8, IL6, and IL12B was further augmented in the presence of Ang-1 and Ang-2, via Tie2 activation of JAK/STAT signaling. Conditioned medium from macrophages stimulated with Ang-1 or Ang-2 in combination with TNF, sustained monocyte recruitment. Our findings suggest a general role for Tie2 in cooperatively promoting the inflammatory activation of macrophages, independently of polarization conditions. PMID- 24404128 TI - Guillain-Barre syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccines: a multinational self-controlled case series in Europe. AB - BACKGROUND: The risk of Guillain-Barre syndrome (GBS) following the United States' 1976 swine flu vaccination campaign in the USA led to enhanced active surveillance during the pandemic influenza (A(H1N1)pdm09) immunization campaign. This study aimed to estimate the risk of GBS following influenza A(H1N1)pdm09 vaccination. METHODS: A self-controlled case series (SCCS) analysis was performed in Denmark, Finland, France, Netherlands, Norway, Sweden, and the United Kingdom. Information was collected according to a common protocol and standardised procedures. Cases classified at levels 1-4a of the Brighton Collaboration case definition were included. The risk window was 42 days starting the day after vaccination. Conditional Poisson regression and pooled random effects models estimated adjusted relative incidences (RI). Pseudo likelihood and vaccinated only methods addressed the potential contraindication for vaccination following GBS. RESULTS: Three hundred and three (303) GBS and Miller Fisher syndrome cases were included. Ninety-nine (99) were exposed to A(H1N1)pdm09 vaccination, which was most frequently adjuvanted (Pandemrix and Focetria). The unadjusted pooled RI for A(H1N1)pdm09 vaccination and GBS was 3.5 (95% Confidence Interval (CI): 2.2 5.5), based on all countries. This lowered to 2.0 (95% CI: 1.2-3.1) after adjustment for calendartime and to 1.9 (95% CI: 1.1-3.2) when we accounted for contra-indications. In a subset (Netherlands, Norway, and United Kingdom) we further adjusted for other confounders and there the RI decreased from 1.7 (adjusted for calendar month) to 1.4 (95% CI: 0.7-2.8), which is the main finding. CONCLUSION: This study illustrates the potential of conducting European collaborative vaccine safety studies. The main, fully adjusted analysis, showed that the RI of GBS was not significantly elevated after influenza A(H1N1)pdm09 vaccination (RI = 1.4 (95% CI: 0.7-2.8). Based on the upper limits of the pooled estimate we can rule out with 95% certainty that the number of excess GBS cases after influenza A(H1N1)pdm09 vaccination would be more than 3 per million vaccinated. PMID- 24404129 TI - A new method to improve the clinical evaluation of cystic fibrosis patients by mucus viscoelastic properties. AB - In cystic fibrosis (CF) patients airways mucus shows an increased viscoelasticity due to the concentration of high molecular weight components. Such mucus thickening eventually leads to bacterial overgrowth and prevents mucus clearance. The altered rheological behavior of mucus results in chronic lung infection and inflammation, which causes most of the cases of morbidity and mortality, although the cystic fibrosis complications affect other organs as well. Here, we present a quantitative study on the correlation between cystic fibrosis mucus viscoelasticity and patients clinical status. In particular, a new diagnostic parameter based on the correlation between CF sputum viscoelastic properties and the severity of the disease, expressed in terms of FEV1 and bacterial colonization, was developed. By using principal component analysis, we show that the types of colonization and FEV1 classes are significantly correlated to the elastic modulus, and that the latter can be used for CF severity classification with a high predictive efficiency (88%). The data presented here show that the elastic modulus of airways mucus, given the high predictive efficiency, could be used as a new clinical parameter in the prognostic evaluation of cystic fibrosis. PMID- 24404130 TI - Histology verification demonstrates that biospectroscopy analysis of cervical cytology identifies underlying disease more accurately than conventional screening: removing the confounder of discordance. AB - BACKGROUND: Subjective visual assessment of cervical cytology is flawed, and this can manifest itself by inter- and intra-observer variability resulting ultimately in the degree of discordance in the grading categorisation of samples in screening vs. representative histology. Biospectroscopy methods have been suggested as sensor-based tools that can deliver objective assessments of cytology. However, studies to date have been apparently flawed by a corresponding lack of diagnostic efficiency when samples have previously been classed using cytology screening. This raises the question as to whether categorisation of cervical cytology based on imperfect conventional screening reduces the diagnostic accuracy of biospectroscopy approaches; are these latter methods more accurate and diagnose underlying disease? The purpose of this study was to compare the objective accuracy of infrared (IR) spectroscopy of cervical cytology samples using conventional cytology vs. histology-based categorisation. METHODS: Within a typical clinical setting, a total of n = 322 liquid-based cytology samples were collected immediately before biopsy. Of these, it was possible to acquire subsequent histology for n = 154. Cytology samples were categorised according to conventional screening methods and subsequently interrogated employing attenuated total reflection Fourier-transform IR (ATR-FTIR) spectroscopy. IR spectra were pre-processed and analysed using linear discriminant analysis. Dunn's test was applied to identify the differences in spectra. Within the diagnostic categories, histology allowed us to determine the comparative efficiency of conventional screening vs. biospectroscopy to correctly identify either true atypia or underlying disease. RESULTS: Conventional cytology based screening results in poor sensitivity and specificity. IR spectra derived from cervical cytology do not appear to discriminate in a diagnostic fashion when categories were based on conventional screening. Scores plots of IR spectra exhibit marked crossover of spectral points between different cytological categories. Although, significant differences between spectral bands in different categories are noted, crossover samples point to the potential for poor specificity and hampers the development of biospectroscopy as a diagnostic tool. However, when histology-based categories are used to conduct analyses, the scores plot of IR spectra exhibit markedly better segregation. CONCLUSIONS: Histology demonstrates that ATR-FTIR spectroscopy of liquid-based cytology identifies the presence of underlying atypia or disease missed in conventional cytology screening. This study points to an urgent need for a future biospectroscopy study where categories are based on such histology. It will allow for the validation of this approach as a screening tool. PMID- 24404131 TI - Microfluidic thrombosis under multiple shear rates and antiplatelet therapy doses. AB - The mainstay of treatment for thrombosis, the formation of occlusive platelet aggregates that often lead to heart attack and stroke, is antiplatelet therapy. Antiplatelet therapy dosing and resistance are poorly understood, leading to potential incorrect and ineffective dosing. Shear rate is also suspected to play a major role in thrombosis, but instrumentation to measure its influence has been limited by flow conditions, agonist use, and non-systematic and/or non quantitative studies. In this work we measured occlusion times and thrombus detachment for a range of initial shear rates (500, 1500, 4000, and 10000 s(-1)) and therapy concentrations (0-2.4 uM for eptifibatide, 0-2 mM for acetyl salicylic acid (ASA), 3.5-40 Units/L for heparin) using a microfluidic device. We also measured complete blood counts (CBC) and platelet activity using whole blood impedance aggregometry. Effects of shear rate and dose were analyzed using general linear models, logistic regressions, and Cox proportional hazards models. Shear rates have significant effects on thrombosis/dose-response curves for all tested therapies. ASA has little effect on high shear occlusion times, even at very high doses (up to 20 times the recommended dose). Under ASA therapy, thrombi formed at high shear rates were 4 times more prone to detachment compared to those formed under control conditions. Eptifibatide reduced occlusion when controlling for shear rate and its efficacy increased with dose concentration. In contrast, the hazard of occlusion from ASA was several orders of magnitude higher than that of eptifibatide. Our results show similar dose efficacy to our low shear measurements using whole blood aggregometry. This quantitative and statistically validated study of the effects of a wide range of shear rate and antiplatelet therapy doses on occlusive thrombosis contributes to more accurate understanding of thrombosis and to models for optimizing patient treatment. PMID- 24404132 TI - Association of ABCC2 -24C>T polymorphism with high-dose methotrexate plasma concentrations and toxicities in childhood acute lymphoblastic leukemia. AB - Methotrexate (MTX) is a key agent for the treatment of childhood acute lymphoblastic leukemia (ALL). Increased MTX plasma concentrations are associated with a higher risk of adverse drug effects. ATP-binding cassette subfamily C member 2 (ABCC2) is important for excretion of MTX and its toxic metabolite. The ABCC2 -24C>T polymorphism (rs717620) reportedly contributes to variability of MTX kinetics. In the present study, we assessed the association between the ABCC2 24C>T polymorphism and methotrexate (MTX) toxicities in childhood ALL patients treated with high-dose MTX. A total of 112 Han Chinese ALL patients were treated with high-dose MTX according to the ALL-Berlin-Frankfurt-Muenster 2000 protocol. Our results showed that presence of the -24T allele in ABCC2 gene led to significantly higher MTX plasma concentrations at 48 hours after the start of infusion, which would strengthen over repeated MTX infusion. The -24T allele in ABCC2 gene was significantly associated with higher risks of high-grade hematologic (leucopenia, anemia, and thrombocytopenia) and non-hematologic (gastrointestinal and mucosal damage/oral mucositis) MTX toxicities. This study provides the first evidence that the -24T allele in ABCC2 gene is associated with the severity of MTX toxicities, which add fresh insights into clinical application of high-dose MTX and individualization of MTX treatment. PMID- 24404133 TI - Labour-efficient in vitro lymphocyte population tracking and fate prediction using automation and manual review. AB - Interest in cell heterogeneity and differentiation has recently led to increased use of time-lapse microscopy. Previous studies have shown that cell fate may be determined well in advance of the event. We used a mixture of automation and manual review of time-lapse live cell imaging to track the positions, contours, divisions, deaths and lineage of 44 B-lymphocyte founders and their 631 progeny in vitro over a period of 108 hours. Using this data to train a Support Vector Machine classifier, we were retrospectively able to predict the fates of individual lymphocytes with more than 90% accuracy, using only time-lapse imaging captured prior to mitosis or death of 90% of all cells. The motivation for this paper is to explore the impact of labour-efficient assistive software tools that allow larger and more ambitious live-cell time-lapse microscopy studies. After training on this data, we show that machine learning methods can be used for realtime prediction of individual cell fates. These techniques could lead to realtime cell culture segregation for purposes such as phenotype screening. We were able to produce a large volume of data with less effort than previously reported, due to the image processing, computer vision, tracking and human computer interaction tools used. We describe the workflow of the software assisted experiments and the graphical interfaces that were needed. To validate our results we used our methods to reproduce a variety of published data about lymphocyte populations and behaviour. We also make all our data publicly available, including a large quantity of lymphocyte spatio-temporal dynamics and related lineage information. PMID- 24404134 TI - Effect of dorsal and ventral hippocampal lesions on contextual fear conditioning and unconditioned defensive behavior induced by electrical stimulation of the dorsal periaqueductal gray. AB - The dorsal (DH) and ventral (VH) subregions of the hippocampus are involved in contextual fear conditioning. However, it is still unknown whether these two brain areas also play a role in defensive behavior induced by electrical stimulation of the dorsal periaqueductal gray (dPAG). In the present study, rats were implanted with electrodes into the dPAG to determine freezing and escape response thresholds after sham or bilateral electrolytic lesions of the DH or VH. The duration of freezing behavior that outlasted electrical stimulation of the dPAG was also measured. The next day, these animals were subjected to contextual fear conditioning using footshock as an unconditioned stimulus. Electrolytic lesions of the DH and VH impaired contextual fear conditioning. Only VH lesions disrupted conditioned freezing immediately after footshock and increased the thresholds of aversive freezing and escape responses to dPAG electrical stimulation. Neither DH nor VH lesions disrupted post-dPAG stimulation freezing. These results indicate that the VH but not DH plays an important role in aversively defensive behavior induced by dPAG electrical stimulation. Interpretations of these findings should be made with caution because of the fact that a non-fiber-sparing lesion method was employed. PMID- 24404135 TI - Role of SOX2 in the etiology of embryonal carcinoma, based on analysis of the NCCIT and NT2 cell lines. AB - The transcription factor SOX2, associated with amongst others OCT3/4, is essential for maintenance of pluripotency and self-renewal of embryonic stem cells. SOX2 is highly expressed in embryonal carcinoma (EC), the stem cell component of malignant nonseminomatous germ cell tumors, referred to as germ cell cancer (GCC). In fact, OCT3/4 together with SOX2 is an informative diagnostic tool for EC in a clinical setting. Several studies support the hypothesis that SOX2 is a relevant oncogenic factor in various cancers and recently, SOX2 has been suggested as a putative therapeutic target for early stage EC. We demonstrate the presence of genomic amplification of SOX2 in an EC cell line, NCCIT, using array comparative genome hybridization and fluorescence in situ hybridization. Down-regulation of SOX2 by targeted siRNA provokes NCCIT cells towards apoptosis, while inhibition of OCT3/4 expression induced differentiation, with retained SOX2 levels. Mice pluripotent xenografts from NCCIT (N-NCCIT and N2 NCCIT) show a consistent SOX2 expression, in spite of loss of the expression of OCT3/4, and differentiation, with retained presence of genomic amplification. No SOX2 amplification has been identified in primary pure and mixed EC in vivo patient samples so far. The data presented in this study are based on a single EC cell line with a SOX2 amplification, with NT2 as control EC cell line, showing no profound induction of apoptosis upon SOX2 downregulation. The findings are of relevance to identify mechanisms involved in the pathogenesis of EC tumors, and support the model of SOX2-oncogene dependency of EC, which however, does not exclude induction of differentiation. This finding is likely related to the presence of wild type p53 in GCC, resulting in expression of downstream target genes, amongst others miR-34a, miR-145 and SOX2, associated to the unique sensitivity of GCC to DNA damaging agents. PMID- 24404136 TI - Clinical classification of cancer cachexia: phenotypic correlates in human skeletal muscle. AB - BACKGROUND: Cachexia affects the majority of patients with advanced cancer and is associated with a reduction in treatment tolerance, response to therapy, and duration of survival. One impediment towards the effective treatment of cachexia is a validated classification system. METHODS: 41 patients with resectable upper gastrointestinal (GI) or pancreatic cancer underwent characterisation for cachexia based on weight-loss (WL) and/or low muscularity (LM). Four diagnostic criteria were used >5%WL, >10%WL, LM, and LM+>2%WL. All patients underwent biopsy of the rectus muscle. Analysis included immunohistochemistry for fibre size and type, protein and nucleic acid concentration, Western blots for markers of autophagy, SMAD signalling, and inflammation. FINDINGS: Compared with non cachectic cancer patients, patients with LM or LM+>2%WL, mean muscle fibre diameter was reduced by about 25% (p = 0.02 and p = 0.001 respectively). No significant difference in fibre diameter was observed if patients had WL alone. Regardless of classification, there was no difference in fibre number or proportion of fibre type across all myosin heavy chain isoforms. Mean muscle protein content was reduced and the ratio of RNA/DNA decreased in patients with either >5%WL or LM+>2%WL. Compared with non-cachectic patients, SMAD3 protein levels were increased in patients with >5%WL (p = 0.022) and with >10%WL, beclin (p = 0.05) and ATG5 (p = 0.01) protein levels were increased. There were no differences in phospho-NFkB or phospho-STAT3 levels across any of the groups. CONCLUSION: Muscle fibre size, biochemical composition and pathway phenotype can vary according to whether the diagnostic criteria for cachexia are based on weight loss alone, a measure of low muscularity alone or a combination of the two. For intervention trials where the primary end-point is a change in muscle mass or function, use of combined diagnostic criteria may allow identification of a more homogeneous patient cohort, reduce the sample size required and enhance the time scale within which trials can be conducted. PMID- 24404137 TI - Pediatric obesity and vitamin D deficiency: a proteomic approach identifies multimeric adiponectin as a key link between these conditions. AB - Key circulating molecules that link vitamin D (VD) to pediatric obesity and its co-morbidities remain unclear. Using a proteomic approach, our objective was to identify key molecules in obese children dichotomized according to 25OH-vitamin D (25OHD) levels. A total of 42 obese children (M/F = 18/24) were divided according to their 25OHD3 levels into 25OHD3 deficient (VDD; n = 18; 25OHD<15 ng/ml) or normal subjects (NVD; n = 24; >30 ng/ml). Plasma proteomic analyses by two dimensional (2D)-electrophoresis were performed at baseline in all subjects. VDD subjects underwent a 12mo treatment with 3000 IU vitamin D3 once a week to confirm the proteomic analyses. The proteomic analyses identified 53 "spots" that differed between VDD and NVD (p<0.05), amongst which adiponectin was identified. Adiponectin was selected for confirmational studies due to its tight association with obesity and diabetes mellitus. Western Immunoblot (WIB) analyses of 2D-gels demonstrated a downregulation of adiponectin in VDD subjects, which was confirmed in the plasma from VDD with respect to NVD subjects (p<0.035) and increased following 12mo vitamin D3 supplementation in VDD subjects (p<0.02). High molecular weight (HMW) adiponectin, a surrogate indicator of insulin sensitivity, was significantly lower in VDD subjects (p<0.02) and improved with vitamin D3 supplementation (p<0.042). A direct effect in vitro of 1alpha,25-(OH)2D3 on adipocyte adiponectin synthesis was demonstrated, with adiponectin and its multimeric forms upregulated, even at low pharmacological doses (10(-9) M) of 1alpha,25-(OH)2D3. This upregulation was paralleled by the adiponectin interactive protein, DsbA-L, suggesting that the VD regulation of adiponectin involves post-transciptional events. Using a proteomic approach, multimeric adiponectin has been identified as a key plasma protein that links VDD to pediatric obesity. PMID- 24404138 TI - Estimation of the HIV basic reproduction number in rural south west Uganda: 1991 2008. AB - BACKGROUND: The basic reproduction number, [Formula: see text], is one of the many measures of the epidemic potential of an infection in a population. We estimate HIV [Formula: see text] over 18 years in a rural population in Uganda, examine method-specific differences in estimated [Formula: see text], and estimate behavioural changes that would reduce [Formula: see text] below one. METHODS: Data on HIV natural history and infectiousness were collated from literature. Data on new sexual partner count were available from a rural clinical cohort in Uganda over 1991-2008. [Formula: see text] was estimated using six methods. Behavioural changes required to reduce [Formula: see text] below one were calculated. RESULTS: Reported number of new partners per year was 0 to 16 (women) and 0 to 80 (men). When proportionate sexual mixing was assumed, the different methods yielded comparable [Formula: see text] estimates. Assuming totally assortative mixing led to increased [Formula: see text] estimates in the high sexual activity class while all estimates in the low-activity class were below one. Using the "effective" partner change rate introduced by Anderson and colleagues resulted in [Formula: see text] estimates all above one except in the lowest sexual activity class. [Formula: see text] could be reduced below one if: (a) medium risk individuals reduce their partner acquisition rate by 70% and higher risk individuals reduce their partner acquisition rate by 93%, or (b) higher risk individuals reduce the partner acquisition rate by 95%. CONCLUSIONS: The estimated [Formula: see text] depended strongly on the method used. Ignoring variation in sexual activity leads to an underestimation of [Formula: see text]. Relying on behaviour change alone to eradicate HIV may require unrealistically large reductions in risk behaviour, even though for a small proportion of the population. To control HIV, complementary prevention strategies such as male circumcision and HIV treatment services need rapid scale up. PMID- 24404139 TI - Celecoxib ameliorates non-alcoholic steatohepatitis in type 2 diabetic rats via suppression of the non-canonical Wnt signaling pathway expression. AB - Our aim was to test whether pharmacological inhibition of cycloxygenase-2 (COX-2) reverses non-alcoholic steatohepatitis (NASH) in type 2 diabetes mellitus (T2DM) rats via suppression of the non-canonical Wnt signaling pathway expression. Twenty-four male Sprague-Dawley rats were randomly distributed to two groups and were fed with a high fat and sucrose (HF-HS) diet or a normal chow diet, respectively. After four weeks, rats fed with a HF-HS diet were made diabetic with low-dose streptozotocin. At the 9(th) week the diabetic rats fed with a HF HS diet or the non-diabetic rats fed with a normal chow diet were further divided into two subgroups treated with vehicle or celecoxib (a selective COX-2 inhibitor, 10 mg/Kg/day, gavage) for the last 4 weeks, respectively. At the end of the 12(th) week, rats were anesthetized. NASH was assessed by histology. Related cytokine expression was measured at both the protein and gene levels through immunohistochemistry (IHC), Western blot and real-time PCR. T2DM rats fed with a HF-HS diet developed steatohepatitis and insulin resistance associated with elevated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), insulin levels and the non-alcoholic fatty liver disease (NAFLD) activity score (NAS). The expression of Wnt5a, JNK1, NF-kappaB p65, and COX-2 were all significantly increased in the T2DM-NASH group compared with the control and control-cele group. Hepatic injury was improved by celecoxib in T2DM-NASH-Cele group indicated by reduced serum ALT and AST levels and hepatic inflammation was reduced by celecoxib showed by histology and the NAFLD activity score (NAS). Serum related metabolic parameters, HOMA-IR and insulin sensitivity index were all improved by celecoxib. The expression of Wnt5a, JNK1, NF-kappaB p65, and COX 2 expression were all suppressed by celecoxib in T2DM-NASH-Cele group. The results of the present study indicated that celecoxib ameliorated NASH in T2DM rats via suppression of the non-canonical Wnt5a/JNK1 signaling pathway expression. PMID- 24404140 TI - A dual TLR agonist adjuvant enhances the immunogenicity and protective efficacy of the tuberculosis vaccine antigen ID93. AB - With over eight million cases of tuberculosis each year there is a pressing need for the development of new vaccines against Mycobacterium tuberculosis. Subunit vaccines consisting of recombinant proteins are an attractive vaccine approach due to their inherent safety compared to attenuated live vaccines and the uniformity of manufacture. Addition of properly formulated TLR agonist-containing adjuvants to recombinant protein vaccines enhances the antigen-specific CD4(+) T cell response characterized by IFN-gamma and TNF, both of which are critical for the control of TB. We have developed a clinical stage vaccine candidate consisting of a recombinant fusion protein ID93 adjuvanted with the TLR4 agonist GLA-SE. Here we examine whether ID93+GLA-SE can be improved by the addition of a second TLR agonist. Addition of CpG containing DNA to ID93+GLA-SE enhanced the magnitude of the multi-functional TH1 response against ID93 characterized by co production of IFN-gamma, TNF, and IL-2. Addition of CpG also improved the protective efficacy of ID93+GLA-SE. Finally we demonstrate that this adjuvant synergy between GLA and CpG is independent of TRIF signaling, whereas TRIF is necessary for the adjuvant activity of GLA-SE in the absence of CpG. PMID- 24404141 TI - Both alpha1- and alpha2-adrenoceptors in the insular cortex are involved in the cardiovascular responses to acute restraint stress in rats. AB - The insular cortex (IC) is a limbic structure involved in cardiovascular responses observed during aversive threats. However, the specific neurotransmitter mediating IC control of cardiovascular adjustments to stress is yet unknown. Therefore, in the present study we investigated the role of local IC adrenoceptors in the cardiovascular responses elicited by acute restraint stress in rats. Bilateral microinjection of different doses (0.3, 5, 10 and 15 nmol/100 nl) of the selective alpha1-adrenoceptor antagonist WB4101 into the IC reduced both the arterial pressure and heart rate increases elicited by restraint stress. However, local IC treatment with different doses (0.3, 5, 10 and 15 nmol/100 nl) of the selective alpha2-adrenoceptor antagonist RX821002 reduced restraint-evoked tachycardia without affecting the pressor response. The present findings are the first direct evidence showing the involvement of IC adrenoceptors in cardiovascular adjustments observed during aversive threats. Our findings indicate that IC noradrenergic neurotransmission acting through activation of both alpha1- and alpha2-adrenoceptors has a facilitatory influence on pressor response to acute restraint stress. Moreover, IC alpha1-adrenoceptors also play a facilitatory role on restraint-evoked tachycardiac response. PMID- 24404142 TI - Rational design of a new Trypanosoma rangeli trans-sialidase for efficient sialylation of glycans. AB - This paper reports rational engineering of Trypanosoma rangeli sialidase to develop an effective enzyme for a potentially important type of reactivity: production of sialylated prebiotic glycans. The Trypanosoma cruzi trans-sialidase and the homologous T. rangeli sialidase has previously been used to investigate the structural requirements for trans-sialidase activity. We observed that the T. cruzi trans-sialidase has a seven-amino-acid motif (197-203) at the border of the substrate binding cleft. The motif differs substantially in chemical properties and substitution probability from the homologous sialidase, and we hypothesised that this motif is important for trans-sialidase activity. The 197-203 motif is strongly positively charged with a marked change in hydrogen bond donor capacity as compared to the sialidase. To investigate the role of this motif, we expressed and characterised a T. rangeli sialidase mutant, Tr13. Conditions for efficient trans-sialylation were determined, and Tr13's acceptor specificity demonstrated promiscuity with respect to the acceptor molecule enabling sialylation of glycans containing terminal galactose and glucose and even monomers of glucose and fucose. Sialic acid is important in association with human milk oligosaccharides, and Tr13 was shown to sialylate a number of established and potential prebiotics. Initial evaluation of prebiotic potential using pure cultures demonstrated, albeit not selectively, growth of Bifidobacteria. Since the 197-203 motif stands out in the native trans-sialidase, is markedly different from the wild-type sialidase compared to previous mutants, and is shown here to confer efficient and broad trans-sialidase activity, we suggest that this motif can serve as a framework for future optimization of trans-sialylation towards prebiotic production. PMID- 24404143 TI - Rapamycin ameliorates inflammation and fibrosis in the early phase of cirrhotic portal hypertension in rats through inhibition of mTORC1 but not mTORC2. AB - OBJECTIVE: Hepatic stellate cells (HSCs) transdifferentiation and subsequent inflammation are important pathological processes involved in the formation of cirrhotic portal hypertension. This study characterizes the pathogenetic mechanisms leading to cholestatic liver fibrosis and portal hypertension, and focuses on mammalian target of rapamycin (mTOR) pathway as a potential modulator in the early phase of cirrhotic portal hypertension. METHODS: Early cirrhotic portal hypertension was induced by bile duct ligation (BDL) for three weeks. One week after operation, sham-operated (SHAM) and BDL rats received rapamycin (2 mg/kg/day) by intraperitoneal injection for fourteen days. Vehicle-treated SHAM and BDL rats served as controls. Fibrosis, inflammation, and portal pressure were evaluated by histology, morphometry, and hemodynamics. Expressions of pro fibrogenic and pro-inflammatory genes in liver were measured by RT-PCR; alpha smooth muscle actin (alpha-SMA) and antigen Ki67 were detected by immunohistochemistry; expressions of AKT/mTOR signaling molecules, extracellular signal-regulated kinase 1/2 (ERK1/2), p-ERK1/2, and interleukin-1 beta (IL-1beta) were assessed by western blot. RESULTS: The AKT/mTOR signaling pathway was markedly activated in the early phase of cirrhotic portal hypertension induced by BDL in rats. mTOR blockade by rapamycin profoundly improved liver function by limiting inflammation, fibrosis and portal pressure. Rapamycin significantly inhibited the expressions of phosphorylated 70KD ribosomal protein S6 kinase (p P70S6K) and phosphorylated ribosomal protein S6 (p-S6) but not p-AKT Ser473 relative to their total proteins in BDL-Ra rats. Those results suggested that mTOR Complex 1 (mTORC1) rather than mTORC2 was inhibited by rapamycin. Interestingly, we also found that the level of p-ERK1/2 to ERK1/2 was significantly increased in BDL rats, which was little affected by rapamycin. CONCLUSIONS: The AKT/mTOR signaling pathway played an important role in the early phase of cirrhotic portal hypertension in rats, which could be a potential target for therapeutic intervention in the early phase of such pathophysiological progress. PMID- 24404144 TI - Human mammospheres secrete hormone-regulated active extracellular vesicles. AB - Breast cancer is a leading cause of cancer-associated death worldwide. One of the most important prognostic factors for survival is the early detection of the disease. Recent studies indicate that extracellular vesicles may provide diagnostic information for cancer management. We demonstrate the secretion of extracellular vesicles by primary breast epithelial cells enriched for stem/progenitor cells cultured as mammospheres, in non-adherent conditions. Using a proteomic approach we identified proteins contained in these vesicles whose expression is affected by hormonal changes in the cellular environment. In addition, we showed that these vesicles are capable of promoting changes in expression levels of genes involved in epithelial-mesenchymal transition and stem cell markers. Our findings suggest that secreted extracellular vesicles could represent potential diagnostic and/or prognostic markers for breast cancer and support a role for extracellular vesicles in cancer progression. PMID- 24404145 TI - Computational modeling of 3D tumor growth and angiogenesis for chemotherapy evaluation. AB - Solid tumors develop abnormally at spatial and temporal scales, giving rise to biophysical barriers that impact anti-tumor chemotherapy. This may increase the expenditure and time for conventional drug pharmacokinetic and pharmacodynamic studies. In order to facilitate drug discovery, we propose a mathematical model that couples three-dimensional tumor growth and angiogenesis to simulate tumor progression for chemotherapy evaluation. This application-oriented model incorporates complex dynamical processes including cell- and vascular-mediated interstitial pressure, mass transport, angiogenesis, cell proliferation, and vessel maturation to model tumor progression through multiple stages including tumor initiation, avascular growth, and transition from avascular to vascular growth. Compared to pure mechanistic models, the proposed empirical methods are not only easy to conduct but can provide realistic predictions and calculations. A series of computational simulations were conducted to demonstrate the advantages of the proposed comprehensive model. The computational simulation results suggest that solid tumor geometry is related to the interstitial pressure, such that tumors with high interstitial pressure are more likely to develop dendritic structures than those with low interstitial pressure. PMID- 24404147 TI - DEC1 coordinates with HDAC8 to differentially regulate TAp73 and DeltaNp73 expression. AB - P73, a member of the p53 family, plays a critical role in neural development and tumorigenesis. Due to the usage of two different promoters, p73 is expressed as two major isoforms, TAp73 and DeltaNp73, often with opposing functions. Here, we reported that transcriptional factor DEC1, a target of the p53 family, exerts a distinct control of TAp73 and DeltaNp73 expression. In particular, we showed that DEC1 was able to increase TAp73 expression via transcriptional activation of the TAp73 promoter. By contrast, Np73 transcription was inhibited by DEC1 via transcriptional repression of the DeltaNp73 promoter. To further explore the underlying mechanism, we showed that DEC1 was unable to increase TAp73 expression in the absence of HDAC8, suggesting that HDAC8 is required for DEC1 to enhance TAp73 expression. Furthermore, we found that DEC1 was able to interact with HDAC8 and recruit HDAC8 to the TAp73, but not the DeltaNp73, promoter. Together, our data provide evidence that DEC1 and HDAC8 in differentially regulate TAp73 and DeltaNp73 expression, suggesting that this regulation may lay a foundation for a therapeutic strategy to enhance the chemosensitivity of tumor cells. PMID- 24404146 TI - Macrophages mediate a switch between canonical and non-canonical Wnt pathways in canine mammary tumors. AB - OBJECTIVE: According to the current hypothesis, tumor-associated macrophages (TAMs) are "corrupted" by cancer cells and subsequently facilitate, rather than inhibit, tumor metastasis. Because the molecular mechanisms of cancer cell-TAM interactions are complicated and controversial we aimed to better define this phenomenon. METHODS AND RESULTS: Using microRNA microarrays, Real-time qPCR and Western blot we showed that co-culture of canine mammary tumor cells with TAMs or treatment with macrophage-conditioned medium inhibited the canonical Wnt pathway and activated the non-canonical Wnt pathway in tumor cells. We also showed that co-culture of TAMs with tumor cells increased expression of canonical Wnt inhibitors in TAMs. Subsequently, we demonstrated macrophage-induced invasive growth patterns and epithelial-mesenchymal transition of tumor cells. Validation of these results in canine mammary carcinoma tissues (n = 50) and xenograft tumors indicated the activation of non-canonical and canonical Wnt pathways in metastatic tumors and non-metastatic malignancies, respectively. Activation of non-canonical Wnt pathway correlated with number of TAMs. CONCLUSIONS: We demonstrated that TAMs mediate a "switch" between canonical and non-canonical Wnt signaling pathways in canine mammary tumors, leading to increased tumor invasion and metastasis. Interestingly, similar changes in neoplastic cells were observed in the presence of macrophage-conditioned medium or live macrophages. These observations indicate that rather than being "corrupted" by cancer cells, TAMs constitutively secrete canonical Wnt inhibitors that decrease tumor proliferation and development, but as a side effect, they induce the non-canonical Wnt pathway, which leads to tumor metastasis. These data challenge the conventional understanding of TAM-cancer cell interactions. PMID- 24404148 TI - Is health aid reaching the poor? Analysis of household data from aid recipient countries. AB - OBJECTIVE: To determine the extent to which the narrowing of child mortality across wealth gradients has been related to foreign aid to the health sector in low- and middle-income countries. METHODS: Mortality and wealth data on 989,901 under-5 children from 957,674 households in 49 aid recipient countries in Africa, Asia, South America, and the Caribbean between 1993 and 2012 were used in the analysis. Declines in under-5 mortality in the four poorest wealth quantiles were compared to the decline among the wealthiest at varying levels of health aid per capita using fixed effects multivariable regression models and controlling for maternal education, urbanization, and domestic spending on health among recipient countries. RESULTS: Each additional dollar in total health aid per capita was associated with 5.7 fewer deaths per 10,000 child-years among children in the poorest relative to the wealthiest households (p<0.001). This was also true when measured in percent declines (1.90% faster decline in under-5 mortality among the poorest compared with the wealthiest with each dollar in total health aid, p = 0.008). The association was stronger when using health aid specifically for malaria than total health aid, 12.60% faster decline among the poorest compared with the wealthiest with each dollar in malaria aid, p = 0.001. CONCLUSIONS: Foreign aid to the health sector is preferentially related to reductions in under 5 mortality among the poorest compared with the wealthiest. Health aid addressing malaria, which imposes a disproportionate burden among the poor, may explain the observed effect. PMID- 24404149 TI - Analysis of HIV-1 protease gene reveals frequent multiple infections followed by recombination among drug treated individuals living in Sao Paulo and Santos, Brazil. AB - The present study investigated the prevalence of HIV-1 multiple infections in a population composed by 47 patients under HAART failure and enrolled at the National DST/AIDS, Program, Ministry of Health, Brazil.Detection of multiple infections was done using a previously published RFLP assay for the HIV-1 protease gene, which is able of distinguishing between infections caused by a single or multiple HIV-1 subtypes. Samples with multiple infections were cloned, and sequence data submitted to phylogenetic analysis. We were able to identify 17 HIV-1 multiple infections out of 47 samples. Multiple infections were mostly composed by a mixture of recombinant viruses (94%), with only one case in which protease gene pure subtypes B and F were recovered. This is the first study that reports the prevalence of multiple infections and intersubtype recombinants in a population undergoing HAART in Brazil. Based on the data there was a steep increase of multiple infections after the introduction of the combined antiretroviral therapy in Brazil. Cases of multiple infections may be associated with HIV-1 genetic diversity through recombination allowing for the generation of viruses showing a combination of resistance mutations. PMID- 24404150 TI - Local plasticity of dendritic excitability can be autonomous of synaptic plasticity and regulated by activity-based phosphorylation of Kv4.2. AB - While plasticity is typically associated with persistent modifications of synaptic strengths, recent studies indicated that modulations of dendritic excitability may form the other part of the engram and dynamically affect computational processing and output of neuronal circuits. However it remains unknown whether modulation of dendritic excitability is controlled by synaptic changes or whether it can be distinct from them. Here we report the first observation of the induction of a persistent plastic decrease in dendritic excitability decoupled from synaptic stimulation, which is localized and purely activity-based. In rats this local plasticity decrease is conferred by CamKII mediated phosphorylation of A-type potassium channels upon interaction of a back propagating action potential (bAP) with dendritic depolarization. PMID- 24404151 TI - Diagnostic value of urinary kidney injury molecule 1 for acute kidney injury: a meta-analysis. AB - BACKGROUND: Urinary Kidney Injury Molecule 1 (KIM-1) is a proximal tubular injury biomarker for early detection of acute kidney injury (AKI), with variable performance characteristics depending on clinical and population settings. METHODS: Meta-analysis was performed to assess the diagnostic value of urinary KIM-1 in AKI. Relevant studies were searched from MEDLINE, EMBASE, Pubmed, Elsevier Science Direct, Scopus, Web of Science, Google Scholar and Cochrane Library. Meta-analysis methods were used to pool sensitivity and specificity and to construct summary receiver operating characteristic (SROC) curves. RESULTS: A total of 2979 patients from 11 eligible studies were enrolled in the analysis. Five prospective cohorts, two cross-sectional and four case-control studies were identified for meta-analysis. The estimated sensitivity of urinary KIM-1 for the diagnosis of AKI was 74.0% (95% CI, 61.0%-84.0%), and specificity was 86.0% (95% CI, 74.0%-93.0%). The SROC analysis showed an area under the curve of 0.86(0.83 0.89). Subgroup analysis suggested that population settings and detection time were the key factors affecting the efficiency of KIM-1 for AKI diagnosis. LIMITATION: Various population settings, different definition of AKI and Serum creatinine level used as the standard might have influence on AKI diagnosis. The relatively small number of studies and heterogeneity between them also affected the evaluation. CONCLUSION: Urinary KIM-1 may be a promising biomarker for early detection of AKI with considerable predictive value, especially for cardiac surgery patients, and its potential value needs to be validated in large studies and across a broader scope of clinical settings. PMID- 24404152 TI - Disturbing miR-182 and -381 inhibits BRD7 transcription and glioma growth by directly targeting LRRC4. AB - Inactivated LRRC4 has been clinically detected in gliomas, and promoter hypermethylation has been implicated as the mechanism of inactivation in some of those tumors. Our previous researches indicated that LRRC4 is a target gene of miR-381, the interaction of miR-381 and LRRC4 is involved in glioma growth. In this study, we demonstrate that LRRC4 is a target gene of the other microRNA, miR 182. We found that the high expression of miR-182 and miR-381 in gliomas are involved in pathological malignant progression. The silencing of miR-182 and miR 381 inhibited the proliferation in vitro and growth of glioma cell with in vivo magnetic resonance imaging by intracranial transplanted tumor model in rats. We also demonstrated that BRD7, a transcriptional cofactor for p53, is highly expressed and negatively correlated with LRRC4 expression in gliomas. Disturbing miR-182 and miR-381 affected transcriptional regulation of the BRD7 gene. This finding was verified by ectopic overexpression of LRRC4 or restoration of endogenous LRRC4 expression by treatment with the DNA demethylating agent 5-Aza dC. Taken together, miR-182 and miR-381 may be a useful therapeutic target for treatment of glioma. PMID- 24404153 TI - Discovery of tumor markers for gastric cancer by proteomics. AB - Gastric cancer (GC) has a high rate of morbidity and mortality among various cancers worldwide. The development of noninvasive diagnostic methods or technologies for tracking the occurrence of GC is urgent, and searching reliable biomarkers is considered.This study intended to directly discover differential biomarkers from GC tissues by two-dimension-differential gel electrophoresis (2D DIGE), and further validate protein expression by western blotting (WB) and immunohistochemistry (IHC).Pairs of GC tissues (gastric cancer tissues and the adjacent normal tissues) obtained from surgery was investigated for 2D-DIEG.Five proteins wereconfirmed by WB and IHC, including glucose-regulated protein 78 (GRP78), glutathione s-transferase pi (GSTpi), apolipoprotein AI (ApoAI), alpha-1 antitrypsin (A1AT) and gastrokine-1 (GKN-1). Among the results, GRP78, GSTpi and A1ATwere significantlyup-regulated and down-regulated respectively in gastric cancer patients. Moreover, GRP78 and ApoAI were correlated with A1AT for protein expressions.This study presumes these proteins could be candidates of reliable biomarkers for gastric cancer. PMID- 24404154 TI - Copy number variation of the beta-defensin genes in europeans: no supporting evidence for association with lung function, chronic obstructive pulmonary disease or asthma. AB - Lung function measures are heritable, predict mortality and are relevant in diagnosis of chronic obstructive pulmonary disease (COPD). COPD and asthma are diseases of the airways with major public health impacts and each have a heritable component. Genome-wide association studies of SNPs have revealed novel genetic associations with both diseases but only account for a small proportion of the heritability. Complex copy number variation may account for some of the missing heritability. A well-characterised genomic region of complex copy number variation contains beta-defensin genes (DEFB103, DEFB104 and DEFB4), which have a role in the innate immune response. Previous studies have implicated these and related genes as being associated with asthma or COPD. We hypothesised that copy number variation of these genes may play a role in lung function in the general population and in COPD and asthma risk. We undertook copy number typing of this locus in 1149 adult and 689 children using a paralogue ratio test and investigated association with COPD, asthma and lung function. Replication of findings was assessed in a larger independent sample of COPD cases and smoking controls. We found evidence for an association of beta-defensin copy number with COPD in the adult cohort (OR = 1.4, 95%CI:1.02-1.92, P = 0.039) but this finding, and findings from a previous study, were not replicated in a larger follow-up sample(OR = 0.89, 95%CI:0.72-1.07, P = 0.217). No robust evidence of association with asthma in children was observed. We found no evidence for association between beta-defensin copy number and lung function in the general populations. Our findings suggest that previous reports of association of beta-defensin copy number with COPD should be viewed with caution. Suboptimal measurement of copy number can lead to spurious associations. Further beta-defensin copy number measurement in larger sample sizes of COPD cases and children with asthma are needed. PMID- 24404155 TI - Do we need to detect isoniazid resistance in addition to rifampicin resistance in diagnostic tests for tuberculosis? AB - BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is resistant to both rifampicin (RIF) and isoniazid (INH). Whereas many TB diagnostics detect RIF resistance, few detect INH-monoresistance, which is common and may increase risk of acquired MDR-TB. Whether inclusion of INH-resistance in a first-line rapid test for TB would have an important impact on MDR-TB rates remains uncertain. METHODS: WE DEVELOPED A TRANSMISSION MODEL TO EVALUATE THREE TESTS IN A POPULATION SIMILAR TO THAT OF INDIA: a rapid molecular test for TB, the same test plus RIF-resistance detection ("TB+RIF"), and detection of RIF and INH-resistance ("TB+RIF/INH"). Our primary outcome was the prevalence of INH-resistant and MDR TB at ten years. RESULTS: Compared to the TB test alone and assuming treatment of all diagnosed MDR cases, the TB+RIF test reduced the prevalence of MDR-TB among all TB cases from 5.5% to 3.8% (30.6% reduction, 95% uncertainty range, UR: 17 54%). Despite using liberal assumptions about the impact of INH-monoresistance on treatment outcomes and MDR-TB acquisition, expansion from TB+RIF to TB+RIF/INH lowered this prevalence only from 3.8% to 3.6% further (4% reduction, 95% UR: 3 7%) and INH-monoresistant TB from 15.8% to 15.1% (4% reduction, 95% UR: (-8) 19%). CONCLUSION: When added to a rapid test for TB plus RIF-resistance, detection of INH-resistance has minimal impact on transmission of TB, MDR-TB, and INH-monoresistant TB. PMID- 24404156 TI - Influence of prior exercise on VO2 kinetics subsequent exhaustive rowing performance. AB - Prior exercise has the potential to enhance subsequent performance by accelerating the oxygen uptake (VO2) kinetics. The present study investigated the effects of two different intensities of prior exercise on pulmonary VO2 kinetics and exercise time during subsequent exhaustive rowing exercise. It was hypothesized that in prior heavy, but not prior moderate exercise condition, overall VO2 kinetics would be faster and the VO2 primary amplitude would be higher, leading to longer exercise time at VO2max. Six subjects (mean +/- SD; age: 22.9+/-4.5 yr; height: 181.2+/-7.1 cm and body mass: 75.5+/-3.4 kg) completed square-wave transitions to 100% of VO2max from three different conditions: without prior exercise, with prior moderate and heavy exercise. VO2 was measured using a telemetric portable gas analyser (K4b(2), Cosmed, Rome, Italy) and the data were modelled using either mono or double exponential fittings. The use of prior moderate exercise resulted in a faster VO2 pulmonary kinetics response (tau1 = 13.41+/-3.96 s), an improved performance in the time to exhaustion (238.8+/-50.2 s) and similar blood lactate concentrations ([La(-)]) values (11.8+/-1.7 mmol.L(-1)) compared to the condition without prior exercise (16.0+/-5.56 s, 215.3+/-60.1 s and 10.7+/-1.2 mmol.L(-1), for tau1, time sustained at VO2max and [La(-)], respectively). Performance of prior heavy exercise, although useful in accelerating the VO2 pulmonary kinetics response during a subsequent time to exhaustion exercise (tau1 = 9.18+/-1.60 s), resulted in a shorter time sustained at VO2max (155.5+/-46.0 s), while [La(-)] was similar (13.5+/-1.7 mmol.L(-1)) compared to the other two conditions. Although both prior moderate and heavy exercise resulted in a faster pulmonary VO2 kinetics response, only prior moderate exercise lead to improved rowing performance. PMID- 24404158 TI - In situ investigation the photolysis of the PAHs adsorbed on mangrove leaf surfaces by synchronous solid surface fluorimetry. AB - An established synchronous solid surface fluorimetry (S-SSF) was utilized for in situ study the photolysis processes of anthracene (An) and pyrene (Py) adsorbed on the leaf surfaces of Kandelia obovata seedlings (Ko) and Aegiceras corniculata (L.) Blanco seedlings (Ac). Experimental results demonstrated that the photolysis of An and Py adsorbed on the leaf surfaces of two mangrove species under the laboratory conditions, followed first-order kinetics with their photolysis rates in the order of Ac>Ko. In addition, with the same amount of substances, the photolysis rate of An adsorbed on the same mangrove leaf surfaces was much faster than the adsorbed Py. In order to investigate further, the photolysis processes of An and Py in water were also studied for comparison. And the photolysis of An and Py in water also followed first-order kinetics. Moreover, for the same initial amount, the photolysis rate of the PAH in water was faster than that adsorbed on the leaf surfaces of two mangrove species. Therefore, photochemical behaviors of PAHs were dependent not only on their molecular structures but also the physical-chemical properties of the substrates on which they are adsorbed. PMID- 24404157 TI - Autonomic cardiovascular responses in acclimatized lowlanders on prolonged stay at high altitude: a longitudinal follow up study. AB - Acute exposure to hypobaric hypoxia at high altitude is reported to cause sympathetic dominance that may contribute to the pathophysiology of high altitude illnesses. The effect of prolonged stay at high altitude on autonomic functions, however, remains to be explored. Thus, the present study aimed at investigating the effect of high altitude on autonomic neural control of cardiovascular responses by monitoring heart rate variability (HRV) during chronic hypobaric hypoxia. Baseline electrocardiography (ECG) data was acquired from the volunteers at mean sea level (MSL) (<250 m) in Rajasthan. Following induction of the study population to high altitude (4500-4800 m) in Ladakh region, ECG data was acquired from the volunteers after 6 months (ALL 6) and 18 months of induction (ALL 18). Out of 159 volunteers who underwent complete investigation during acquisition of baseline data, we have only included the data of 104 volunteers who constantly stayed at high altitude for 18 months to complete the final follow up after 18 months. HRV parameters, physiological indices and biochemical changes in serum were investigated. Our results show sympathetic hyperactivation along with compromise in parasympathetic activity in ALL 6 and ALL 18 when compared to baseline data. Reduction of sympathetic activity and increased parasympathetic response was however observed in ALL 18 when compared to ALL 6. Our findings suggest that autonomic response is regulated by two distinct mechanisms in the ALL 6 and ALL 18. While the autonomic alterations in the ALL 6 group could be attributed to increased sympathetic activity resulting from increased plasma catecholamine concentration, the sympathetic activity in ALL 18 group is associated with increased concentration of serum coronary risk factors and elevated homocysteine. These findings have important clinical implications in assessment of susceptibility to cardio-vascular risks in acclimatized lowlanders staying for prolonged duration at high altitude. PMID- 24404159 TI - Regional impact of climate on Japanese encephalitis in areas located near the three gorges dam. AB - BACKGROUND: In this study, we aim to identify key climatic factors that are associated with the transmission of Japanese encephalitis virus in areas located near the Three Gorges Dam, between 1997 and 2008. METHODS: We identified three geographical regions of Chongqing, based on their distance from the Three Gorges Dam. Collectively, the three regions consisted of 12 districts from which study information was collected. Zero-Inflated Poisson Regression models were run to identify key climatic factors of the transmission of Japanese encephalitis virus for both the whole study area and for each individual region; linear regression models were conducted to examine the fluctuation of climatic variables over time during the construction of the Three Gorges Dam. RESULTS: Between 1997 and 2008, the incidence of Japanese encephalitis decreased throughout the entire city of Chongqing, with noticeable variations taking place in 2000, 2001 and 2006. The eastern region, which is closest to the Three Gorges Dam, suffered the highest incidence of Japanese encephalitis, while the western region experienced the lowest incidence. Linear regression models revealed that there were seasonal fluctuations of climatic variables during this period. Zero-Inflated Poisson Regression models indicated a significant positive association between temperature (with a lag of 1 and 3 months) and Japanese encephalitis incidence, and a significant negative association between rainfall (with a lag of 0 and 4 months) and Japanese encephalitis incidence. CONCLUSION: The spatial and temporal trends of Japanese encephalitis incidence that occurred in the City of Chongqing were associated with temperature and rainfall. Seasonal fluctuations of climatic variables during this period were also observed. Additional studies that focus on long-term data collection are needed to validate the findings of this study and to further explore the effects of the Three Gorges Dam on Japanese encephalitis and other related diseases. PMID- 24404160 TI - Proactive and reactive processes in the medial frontal cortex: an electrophysiological study. AB - The posterior medial frontal cortex (pMFC) is known to be involved in adaptive goal-directed behavior, but its specific function is not yet clear. Most theories have proposed that the pMFC monitors performance in a reactive manner only, but it is possible that the pMFC also contributes to performance monitoring in a proactive manner. To date, the evidence for proactive pMFC activity is equivocal. Here, we investigated pMFC activity before, during and after the performance of a challenging motor task. Participants navigated a cursor through narrow and wide mazes in randomly intermixed trials. On each trial, participants saw previews of the actual maze display prior to gaining control of the cursor. Event-related potentials (ERPs) to the preview displays were compared to ERPs elicited by no-go signals and errors. Compared to the wider maze, the preview display for the more challenging narrow maze elicited a medial-frontal negativity (MFN) similar to the ERP components elicited by no-go signals and errors. Like these known ERP components, the preview-elicited MFN appeared to be generated from a source in pMFC. This is consistent with the hypothesis that the pMFC participates in adaptive behavior whenever there is a need for increased effort to maintain successful task performance. PMID- 24404161 TI - HRES-1/Rab4 promotes the formation of LC3(+) autophagosomes and the accumulation of mitochondria during autophagy. AB - HRES-1/Rab4 is a small GTPase that regulates endocytic recycling. It has been colocalized to mitochondria and the mechanistic target of rapamycin (mTOR), a suppressor of autophagy. Since the autophagosomal membrane component microtubule associated protein light chain 3 (LC3) is derived from mitochondria, we investigated the impact of HRES-1/Rab4 on the formation of LC3(+) autophagosomes, their colocalization with HRES-1/Rab4 and mitochondria, and the retention of mitochondria during autophagy induced by starvation and rapamycin. HRES-1/Rab4 exhibited minimal baseline colocalization with LC3, which was enhanced 22-fold upon starvation or 6-fold upon rapamycin treatment. Colocalization of HRES-1/Rab4 with mitochondria was increased >2-fold by starvation or rapamycin. HRES-1/Rab4 overexpression promoted the colocalization of mitochondria with LC3 upon starvation or rapamycin treatment. A dominant-negative mutant, HRES-1/Rab4(S27N) had reduced colocalization with LC3 and mitochondria upon starvation but not rapamycin treatment. A constitutively active mutant, HRES-1/Rab4(Q72L) showed diminished colocalization with LC3 but promoted the partitioning of mitochondria with LC3 upon starvation or rapamycin treatment. Phosphorylation-resistant mutant HRES-1/Rab4(S204Q) showed diminished colocalization with LC3 but increased partitioning to mitochondria. A newly discovered C-terminally truncated native isoform, HRES-1/Rab4(1-121), showed enhanced localization to LC3 and mitochondria without starvation or rapamycin treatment. HRES-1/Rab4(1-121) increased the formation of LC3(+) autophagosomes in resting cells, while other isoforms promoted autophagosome formation upon starvation. HRES-1/Rab4, HRES-1/Rab4(1 121), HRES-1/Rab4(Q72L) and HRES-1/Rab4(S204Q) promoted the accumulation of mitochondria during starvation. The specificity of HRES-1/Rab4-mediated mitochondrial accumulation is indicated by its abrogation by dominant-negative HRES-1/Rab4(S27N) mutation. The formation of interconnected mitochondrial tubular networks was markedly enhanced by HRES-1/Rab4(Q72L) upon starvation, which may contribute to the retention of mitochondria during autophagy. The present study thus indicates that HRES-1/Rab4 regulates autophagy through promoting the formation of LC3(+) autophagosomes and the preservation of mitochondria. PMID- 24404162 TI - Reduction of VLDL secretion decreases cholesterol excretion in niemann-pick C1 like 1 hepatic transgenic mice. AB - An effective way to reduce LDL cholesterol, the primary risk factor of atherosclerotic cardiovascular disease, is to increase cholesterol excretion from the body. Our group and others have recently found that cholesterol excretion can be facilitated by both hepatobiliary and transintestinal pathways. However, the lipoprotein that moves cholesterol through the plasma to the small intestine for transintestinal cholesterol efflux (TICE) is unknown. To test the hypothesis that hepatic very low-density lipoproteins (VLDL) support TICE, antisense oligonucleotides (ASO) were used to knockdown hepatic expression of microsomal triglyceride transfer protein (MTP), which is necessary for VLDL assembly. While maintained on a high cholesterol diet, Niemann-Pick C1-like 1 hepatic transgenic (L1Tg) mice, which predominantly excrete cholesterol via TICE, and wild type (WT) littermates were treated with control ASO or MTP ASO. In both WT and L1Tg mice, MTP ASO decreased VLDL triglyceride (TG) and cholesterol secretion. Regardless of treatment, L1Tg mice had reduced biliary cholesterol compared to WT mice. However, only L1Tg mice treated with MTP ASO had reduced fecal cholesterol excretion. Based upon these findings, we conclude that VLDL or a byproduct such as LDL can move cholesterol from the liver to the small intestine for TICE. PMID- 24404163 TI - Visual hierarchical processing and lateralization of cognitive functions through domestic chicks' eyes. AB - Hierarchical stimuli have proven effective for investigating principles of visual organization in humans. A large body of evidence suggests that the analysis of the global forms precedes the analysis of the local forms in our species. Studies on lateralization also indicate that analytic and holistic encoding strategies are separated between the two hemispheres of the brain. This raises the question of whether precedence effects may reflect the activation of lateralized functions within the brain. Non-human animals have perceptual organization and functional lateralization that are comparable to that of humans. Here we trained the domestic chick in a concurrent discrimination task involving hierarchical stimuli. Then, we evaluated the animals for analytic and holistic encoding strategies in a series of transformational tests by relying on a monocular occlusion technique. A local precedence emerged in both the left and the right hemisphere, adding further evidence in favour of analytic processing in non-human animals. PMID- 24404164 TI - Green tea and one of its constituents, Epigallocatechine-3-gallate, are potent inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1. AB - The microsomal enzyme 11beta-hydroxysteroid deydrogenase type 1 (11beta-HSD1) catalyzes the interconversion of glucocorticoid receptor-inert cortisone to receptor- active cortisol, thereby acting as an intracellular switch for regulating the access of glucocorticoid hormones to the glucocorticoid receptor. There is strong evidence for an important aetiological role of 11beta-HSD1 in various metabolic disorders including insulin resistance, diabetes type 2, hypertension, dyslipidemia and obesity. Hence, modulation of 11beta-HSD1 activity with selective inhibitors is being pursued as a new therapeutic approach for the treatment of the metabolic syndrome. Since tea has been associated with health benefits for thousands of years, we sought to elucidate the active principle in tea with regard to diabetes type 2 prevention. Several teas and tea specific polyphenolic compounds were tested for their possible inhibition of cortisone reduction with human liver microsomes and purified human 11beta-HSD1. Indeed we found that tea extracts inhibited 11beta-HSD1 mediated cortisone reduction, where green tea exhibited the highest inhibitory potency with an IC50 value of 3.749 mg dried tea leaves per ml. Consequently, major polyphenolic compounds from green tea, in particular catechins were tested with the same systems. (-) Epigallocatechin gallate (EGCG) revealed the highest inhibition of 11beta-HSD1 activity (reduction: IC50 = 57.99 uM; oxidation: IC50 = 131.2 uM). Detailed kinetic studies indicate a direct competition mode of EGCG, with substrate and/or cofactor binding. Inhibition constants of EGCG on cortisone reduction were Ki = 22.68 uM for microsomes and Ki = 18.74 uM for purified 11beta-HSD1. In silicio docking studies support the view that EGCG binds directly to the active site of 11beta-HSD1 by forming a hydrogen bond with Lys187 of the catalytic triade. Our study is the first to provide evidence that the health benefits of green tea and its polyphenolic compounds may be attributed to an inhibition of the cortisol producing enzyme 11beta-HSD1. PMID- 24404165 TI - Mining rare associations between biological ontologies. AB - The constantly increasing volume and complexity of available biological data requires new methods for their management and analysis. An important challenge is the integration of information from different sources in order to discover possible hidden relations between already known data. In this paper we introduce a data mining approach which relates biological ontologies by mining cross and intra-ontology pairwise generalized association rules. Its advantage is sensitivity to rare associations, for these are important for biologists. We propose a new class of interestingness measures designed for hierarchically organized rules. These measures allow one to select the most important rules and to take into account rare cases. They favor rules with an actual interestingness value that exceeds the expected value. The latter is calculated taking into account the parent rule. We demonstrate this approach by applying it to the analysis of data from Gene Ontology and GPCR databases. Our objective is to discover interesting relations between two different ontologies or parts of a single ontology. The association rules that are thus discovered can provide the user with new knowledge about underlying biological processes or help improve annotation consistency. The obtained results show that produced rules represent meaningful and quite reliable associations. PMID- 24404166 TI - Radiofrequency ablation versus hepatic resection for small hepatocellular carcinomas: a meta-analysis of randomized and nonrandomized controlled trials. AB - OBJECTIVES: To evaluate the efficacy and safety of radiofrequency ablation (RFA) versus hepatic resection (HR) for early hepatocellular carcinoma (HCC) meeting the Milan criteria. METHODS: A meta-analysis was conducted, and PubMed, Web of Science, the Cochrane Library, CBM, CNKI and VIP databases were systematically searched through November 2012 for randomized and nonrandomized controlled trials (RCTs and NRCTs). The Cochrane Collaboration's tool and modified MINORS score were applied to assess the quality of RCTs and NRCTs, respectively. The GRADE approach was employed to evaluate the strength of evidence. RESULTS: Three RCTs and twenty-five NRCTs were included. Among 11,873 patients involved, 6,094 patients were treated with RFA, and 5,779 with HR. The pooled results of RCTs demonstrated no significant difference between groups for 1- and 3-year overall survival (OS), recurrence-free survival (RFS) and disease-free survival (DFS) (p>0.05). The 5-year OS (Relative Risk, RR 0.72, 95% CI 0.60 to 0.88) and RFS (RR 0.56, 95% CI 0.40 to 0.78) were lower with RFA than with HR. The 3- and 5-year recurrences with RFA were higher than with HR (RR 1.48, 95% CI 1.14 to 1.94, and RR 1.52, 95% CI 1.18 to 1.97, respectively), but 1-year recurrence and in hospital mortality showed no significant differences between groups (p>0.05). The complication rate (RR 0.18, 95% CI 0.06 to 0.53) was lower and hospital stays (Mean difference -8.77, 95% CI -10.36 to -7.18) were shorter with RFA than with HR. The pooled results of NRCTs showed that the RFA group had lower 1-, 3- and 5 year OS, RFS and DFS, and higher recurrence than the HR group (p<0.05). But for patients with very early stage HCC, RFA was comparable to HR for OS and recurrence. CONCLUSION: The effectiveness of RFA is comparable to HR, with fewer complications but higher recurrence, especially for very early HCC patients. PMID- 24404167 TI - The molecular detection and clinical significance of ALK rearrangement in selected advanced non-small cell lung cancer: ALK expression provides insights into ALK targeted therapy. AB - BACKGROUND: This study aimed to elucidate clinical significance of anaplastic lymphoma kinase (ALK) rearrangement in selected advanced non-small cell lung cancer (NSCLC), to compare the application of different ALK detection methods, and especially evaluate a possible association between ALK expression and clinical outcomes in crizotinib-treated patients. METHODS: ALK status was assessed by fluorescent in situ hybridization (FISH), immunohistochemistry (IHC) and quantitative RT-PCR (qRT-PCR) in 173 selected advanced NSCLC patients. Clinicopathologic data, genotype status and survival outcomes were analyzed. Moreover, the association of ALK expression with clinical outcomes was evaluated in ALK FISH-positive crizotinib-treated patients including two patients with concurrent epidermal growth factor receptor (EGFR) mutation. RESULTS: The positivity detection rate of ALK rearrangement by FISH, IHC and qRT-PCR was 35.5% (59/166), 35.7% (61/171), and 27.9% (34/122), respectively. ALK rearrangement was observed predominantly in young patients, never or light smokers, and adenocarcinomas, especially with signet ring cell features and poor differentiation. Median progression-free survival (PFS) of crizotinib-treated patients was 7.6 months. The overall survival (OS) of these patients was longer compared with that of crizotinib-naive or wild-type cohorts, but there was no significant difference in OS compared with patients with EGFR mutation. ALK expression did not associate with PFS; but, when ALK expression was analyzed as a dichotomous variable, moderate and strong ALK expression had a decreased risk of death (P = 0.026). The two patients with concomitant EGFR and ALK alterations showed difference in ALK expression, response to EGFR and ALK inhibitors, and overall survival. CONCLUSIONS: Selective enrichment according to clinicopathologic features in NSCLC patients could highly improve the positivity detection rate of ALK rearrangement for ALK-targeted therapy. IHC could provide more clues for clinical trial design and therapeutic strategies for ALK-positive NSCLC patients including patients with double genetic aberration of ALK and EGFR. PMID- 24404169 TI - Unveiling the conservation biogeography of a data-deficient endangered bird species under climate change. AB - It remains a challenge to identify the geographical patterns and underlying environmental associations of species with unique ecological niches and distinct behaviors. This in turn hinders our understanding of the ecology as well as effective conservation management of threatened species. The white-eared night heron (Gorsachius magnificus) is a non-migratory nocturnal bird species that has a patchy distribution in the mountainous forests of East Asia. It is currently categorized as "Endangered" on the IUCN Red List, primarily due to its restricted range and fragmented habitat. To improve our knowledge of the biogeography and conservation of this species, we modeled the geographical pattern of its suitable habitat and evaluated the potential impacts of climate change using ecological niche modeling with a maximum entropy approach implemented in Maxent. Our results indicated that the amount of suitable habitat in all of East Asia was about 130 000 km(2), which can be spatially subdivided into several mountain ranges in southern and southwestern China and northern Vietnam. The extent of suitable habitat range may shrink by more than 35% under a predicted changing climate when assuming the most pessimistic condition of dispersal, while some more suitable habitat would be available if the heron could disperse unrestrainedly. The significant future changes in habitat suitability suggested for Gorsachius magnificus urge caution in any downgrading of Red List status that may be considered. Our results also discern potentially suitable areas for future survey efforts on new populations. Overall, this study demonstrates that ecological niche modeling offers an important tool for evaluating the habitat suitability and potential impacts of climate change on an enigmatic and endangered species based on limited presence data. PMID- 24404168 TI - T cells detect intracellular DNA but fail to induce type I IFN responses: implications for restriction of HIV replication. AB - HIV infects key cell types of the immune system, most notably macrophages and CD4+ T cells. Whereas macrophages represent an important viral reservoir, activated CD4+ T cells are the most permissive cell types supporting high levels of viral replication. In recent years, it has been appreciated that the innate immune system plays an important role in controlling HIV replication, e.g. via interferon (IFN)-inducible restriction factors. Moreover, innate immune responses are involved in driving chronic immune activation and the pathogenesis of progressive immunodeficiency. Several pattern recognition receptors detecting HIV have been reported, including Toll-like receptor 7 and Retinoic-inducible gene-I, which detects viral RNA. Here we report that human primary T cells fail to induce strong IFN responses, despite the fact that this cell type does express key molecules involved in DNA signaling pathways. We demonstrate that the DNA sensor IFI16 migrates to sites of foreign DNA localization in the cytoplasm and recruits the signaling molecules stimulator of IFN genes and Tank-binding kinase, but this does not result in expression of IFN and IFN-stimulated genes. Importantly, we show that cytosolic DNA fails to affect HIV replication. However, exogenous treatment of activated T cells with type I IFN has the capacity to induce expression of IFN-stimulated genes and suppress HIV replication. Our data suggest the existence of an impaired DNA signaling machinery in T cells, which may prevent this cell type from activating cell-autonomous anti-HIV responses. This phenomenon could contribute to the high permissiveness of CD4+ T cells for HIV-1. PMID- 24404170 TI - Targeting of GFP-Cre to the mouse Cyp11a1 locus both drives cre recombinase expression in steroidogenic cells and permits generation of Cyp11a1 knock out mice. AB - To permit conditional gene targeting of floxed alleles in steroidogenic cell types we have generated a transgenic mouse line that expresses Cre Recombinase under the regulation of the endogenous Cytochrome P450 side chain cleavage enzyme (Cyp11a1) promoter. Mice Carrying the Cyp11a1-GC (GFP-Cre) allele express Cre Recombinase in fetal adrenal and testis, and adrenal cortex, testicular Leydig cells (and a small proportion of Sertoli cells), theca cells of the ovary, and the hindbrain in postnatal life. Circulating testosterone concentration is unchanged in Cyp11(+/GC) males, suggesting steroidogenesis is unaffected by loss of one allele of Cyp11a1, mice are grossly normal, and Cre Recombinase functions to recombine floxed alleles of both a YFP reporter gene and the Androgen Receptor (AR) in steroidogenic cells of the testis, ovary, adrenal and hindbrain. Additionally, when bred to homozygosity (Cyp11a1(GC/GC) ), knock-in of GFP-Cre to the endogenous Cyp11a1 locus results in a novel mouse model lacking endogenous Cyp11a1 (P450-SCC) function. This unique dual-purpose model has utility both for those wishing to conditionally target genes within steroidogenic cell types and for studies requiring mice lacking endogenous steroid hormone production. PMID- 24404171 TI - A higher frequency of circulating IL-22(+)CD4(+) T cells in Chinese patients with newly diagnosed Hashimoto's thyroiditis. AB - BACKGROUND: IL-22 and IL-17A are implicated in the pathogenesis of autoimmune diseases. However, the role of IL-22(+) and IL-17A(+) CD4(+) T cells in the pathogenesis of Hashimoto's thyroiditis (HT) is not fully understood. This study investigates serum IL-22 and IL-17A levels and determines the frequency of circulating IL-22(+) CD4(+) T cells in HT patients to understand their roles in the pathogenesis of HT. METHODS: The levels of serum IL-22, IL-17A and IFN-gamma and the frequency of circulating IL-22(+)CD4(+) and IL-17A(+)CD4(+) T cells in 17 HT patients and 17 healthy controls (HC) were determined by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. The levels of serum free triiodothyronine (FT4), free thyroxine (FT3), thyroid stimulating hormone (TSH), anti-thyroid peroxidase (TPO) and anti-thyroglobulin antibodies (TgAb) by chemiluminescent enzyme immunoassay and radioimmunoassay. RESULTS: The percentages of circulating IL-22(+)CD4(+) and IL-17(+)CD4(+) T cells (p<0.0001, p<0.0001) and the levels of serum IL-22, IL-17A and IFN-gamma (p<0.0001, p<0.0001, p = 0.0210) in the HT patients were significantly higher than that in the HC. The percentages of IL-22(+)CD4(+) T cells were positively correlated with Th17 cells (r = 0.8815, p<0.0001) and IL-17A(+)IL-22(+)CD4(+) T cells (r = 0.8914, p<0.0001), but were negatively correlated with Th1 cells (r = -0.6110, p<0.0092) in the HT patients. The percentages of Th22 cells, Th17 cells and IL 17A(+)IL-22(+)CD4(+) T cells were negatively correlated with the levels of serum TSH in the HT patients (r = -0.8402, p<0.0001; r = -0.8589, p<0.0001; r = -0.8289 p<0.0001, respectively). CONCLUSIONS: A higher frequency of circulating IL 22(+)CD4(+) and IL-17A(+)CD4(+) T cells may be associated with the development of HT in Chinese patients. PMID- 24404172 TI - Silymarin induces insulin resistance through an increase of phosphatase and tensin homolog in Wistar rats. AB - BACKGROUND AND AIMS: Phosphatase and tensin homolog (PTEN) is a phosphoinositide phosphatase that regulates crucial cellular functions, including insulin signaling, lipid and glucose metabolism, as well as survival and apoptosis. Silymarin is the active ingredient in milk thistle and exerts numerous effects through the activation of PTEN. However, the effect of silymarin on the development of insulin resistance remains unknown. METHODS: Wistar rats fed fructose-rich chow or normal chow were administered oral silymarin to identify the development of insulin resistance using the homeostasis model assessment of insulin resistance and hyperinsulinemic- euglycemic clamping. Changes in PTEN expression in skeletal muscle and liver were compared using western blotting analysis. Further investigation was performed in L6 cells to check the expression of PTEN and insulin-related signals. PTEN deletion in L6 cells was achieved by small interfering ribonucleic acid transfection. RESULTS: Oral administration of silymarin at a dose of 200 mg/kg once daily induced insulin resistance in normal rats and enhanced insulin resistance in fructose-rich chow-fed rats. An increase of PTEN expression was observed in the skeletal muscle and liver of rats with insulin resistance. A decrease in the phosphorylation of Akt in L6 myotube cells, which was maintained in a high-glucose condition, was also observed. Treatment with silymarin aggravated high-glucose-induced insulin resistance. Deletion of PTEN in L6 cells reversed silymarin-induced impaired insulin signaling and glucose uptake. CONCLUSIONS: Silymarin has the ability to disrupt insulin signaling through increased PTEN expression. Therefore, silymarin should be used carefully in type-2 diabetic patients. PMID- 24404173 TI - ClassyFlu: classification of influenza A viruses with Discriminatively trained profile-HMMs. AB - Accurate and rapid characterization of influenza A virus (IAV) hemagglutinin (HA) and neuraminidase (NA) sequences with respect to subtype and clade is at the basis of extended diagnostic services and implicit to molecular epidemiologic studies. ClassyFlu is a new tool and web service for the classification of IAV sequences of the HA and NA gene into subtypes and phylogenetic clades using discriminatively trained profile hidden Markov models (HMMs), one for each subtype or clade. ClassyFlu merely requires as input unaligned, full-length or partial HA or NA DNA sequences. It enables rapid and highly accurate assignment of HA sequences to subtypes H1-H17 but particularly focusses on the finer grained assignment of sequences of highly pathogenic avian influenza viruses of subtype H5N1 according to the cladistics proposed by the H5N1 Evolution Working Group. NA sequences are classified into subtypes N1-N10. ClassyFlu was compared to semiautomatic classification approaches using BLAST and phylogenetics and additionally for H5 sequences to the new "Highly Pathogenic H5N1 Clade Classification Tool" (IRD-CT) proposed by the Influenza Research Database. Our results show that both web tools (ClassyFlu and IRD-CT), although based on different methods, are nearly equivalent in performance and both are more accurate and faster than semiautomatic classification. A retraining of ClassyFlu to altered cladistics as well as an extension of ClassyFlu to other IAV genome segments or fragments thereof is undemanding. This is exemplified by unambiguous assignment to a distinct cluster within subtype H7 of sequences of H7N9 viruses which emerged in China early in 2013 and caused more than 130 human infections. http://bioinf.uni-greifswald.de/ClassyFlu is a free web service. For local execution, the ClassyFlu source code in PERL is freely available. PMID- 24404174 TI - The role of the st313-td gene in virulence of Salmonella Typhimurium ST313. AB - Multidrug-resistant Salmonella enterica serovar Typhimurium ST313 has emerged in sub-Saharan Africa causing severe infections in humans. Therefore, it has been speculated that this specific sequence type, ST313, carries factors associated with increased pathogenicity. We assessed the role in virulence of a gene with a yet unknown function, st313-td, detected in ST313 through comparative genomics. Additionally, the structure of the genomic island ST313-GI, harbouring the gene was determined. The gene st313-td was cloned into wild type S. Typhimurium 4/74 (4/74-C) as well as knocked out in S. Typhimurium ST313 02-03/002 (Deltast313-td) followed by complementation (02-03/002-C). Deltast313-td was less virulent in mice following i.p. challenge than the wild type and this phenotype could be partly complemented in trans, indicating that st313-td plays a role during systemic infection. The gene st313-td was shown not to affect invasion of cultured epithelial cells, while the absence of the gene significantly affects uptake and intracellular survival within macrophages. The gene st313-td was proven to be strongly associated to invasiveness, harboured by 92.5% of S. Typhimurium blood isolates (n = 82) and 100% of S. Dublin strains (n = 50) analysed. On the contrary, S. Typhimurium isolates of animal and food origin (n = 82) did not carry st313-td. Six human, non-blood isolates of S. Typhimurium from Belarus, China and Nepal harboured the gene and belonged to sequence types ST398 and ST19. Our data showed a global presence of the st313-td gene and in other sequence types than ST313. The gene st313-td was shown to be expressed during logarithmic phase of growth in 14 selected Salmonella strains carrying the gene. This study reveals that st313-td plays a role in S. Typhimurium ST313 pathogenesis and adds another chapter to understanding of the virulence of S. Typhimurium and in particular of the emerging sequence type ST313. PMID- 24404175 TI - Phyllostomid bat occurrence in successional stages of neotropical dry forests. AB - Tropical dry forests (TDFs) are highly endangered tropical ecosystems being replaced by a complex mosaic of patches of different successional stages, agricultural fields and pasturelands. In this context, it is urgent to understand how taxa playing critical ecosystem roles respond to habitat modification. Because Phyllostomid bats provide important ecosystem services (e.g. facilitate gene flow among plant populations and promote forest regeneration), in this study we aimed to identify potential patterns on their response to TDF transformation in sites representing four different successional stages (initial, early, intermediate and late) in three Neotropical regions: Mexico, Venezuela and Brazil. We evaluated bat occurrence at the species, ensemble (abundance) and assemblage level (species richness and composition, guild composition). We also evaluated how bat occurrence was modulated by the marked seasonality of TDFs. In general, we found high seasonal and regional specificities in phyllostomid occurrence, driven by specificities at species and guild levels. For example, highest frugivore abundance occurred in the early stage of the moistest TDF, while highest nectarivore abundance occurred in the same stage of the driest TDF. The high regional specificity of phyllostomid responses could arise from: (1) the distinctive environmental conditions of each region, (2) the specific behavior and ecological requirements of the regional bat species, (3) the composition, structure and phenological patterns of plant assemblages in the different stages, and (4) the regional landscape composition and configuration. We conclude that, in tropical seasonal environments, it is imperative to perform long-term studies considering seasonal variations in environmental conditions and plant phenology, as well as the role of landscape attributes. This approach will allow us to identify potential patterns in bat responses to habitat modification, which constitute an invaluable tool for not only bat biodiversity conservation but also for the conservation of the key ecological processes they provide. PMID- 24404176 TI - Cognitive reserve in young and old healthy subjects: differences and similarities in a testing-the-limits paradigm with DSST. AB - Cognitive reserve (CR) is understood as capacity to cope with challenging conditions, e.g. after brain injury or in states of brain dysfunction, or age related cognitive decline. CR in elderly subjects has attracted much research interest, but differences between healthy older and younger subjects have not been addressed in detail hitherto. Usually, one-time standard individual assessments are used to characterise CR. Here we observe CR as individual improvement in cognitive performance (gain) in a complex testing-the-limits paradigm, the digit symbol substitution test (DSST), with 10 repeated measurements, in 140 younger (20-30 yrs) and 140 older (57-74 yrs) healthy subjects. In addition, we assessed attention, memory and executive function, and mood and personality traits as potential influence factors for CR. We found that both, younger and older subjects showed significant gains, which were significantly correlated with speed of information processing, verbal short-term memory and visual problem solving in the older group only. Gender, personality traits and mood did not significantly influence gains in either group. Surprisingly about half of the older subjects performed at the level of the younger group, suggesting that interindividual differences in CR are possibly age independent. We propose that these findings may also be understood as indication that one-time standard individual measurements do not allow assessment of CR, and that the use of DSST in a testing-the-limits paradigm is a valuable assessment method for CR in young and elderly subjects. PMID- 24404177 TI - What cues do ungulates use to assess predation risk in dense temperate forests? AB - Anti-predator responses by ungulates can be based on habitat features or on the near-imminent threat of predators. In dense forest, cues that ungulates use to assess predation risk likely differ from half-open landscapes, as scent relative to sight is predicted to be more important. We studied, in the Bialowieza Primeval Forest (Poland), whether perceived predation risk in red deer (Cervus elaphus) and wild boar (Sus scrofa) is related to habitat visibility or olfactory cues of a predator. We used camera traps in two different set-ups to record undisturbed ungulate behavior and fresh wolf (Canis lupus) scats as olfactory cue. Habitat visibility at fixed locations in deciduous old growth forest affected neither vigilance levels nor visitation rate and cumulative visitation time of both ungulate species. However, red deer showed a more than two-fold increase of vigilance level from 22% of the time present on control plots to 46% on experimental plots containing one wolf scat. Higher vigilance came at the expense of time spent foraging, which decreased from 32% to 12% while exposed to the wolf scat. These behavioral changes were most pronounced during the first week of the experiment but continuous monitoring of the plots suggested that they might last for several weeks. Wild boar did not show behavioral responses indicating higher perceived predation risk. Visitation rate and cumulative visitation time were not affected by the presence of a wolf scat in both ungulate species. The current study showed that perceived predation risk in red deer and wild boar is not related to habitat visibility in a dense forest ecosystem. However, olfactory cues of wolves affected foraging behavior of their preferred prey species red deer. We showed that odor of wolves in an ecologically equivalent dose is sufficient to create fine-scale risk factors for red deer. PMID- 24404178 TI - Experimental comparison of the high-speed imaging performance of an EM-CCD and sCMOS camera in a dynamic live-cell imaging test case. AB - The study of living cells may require advanced imaging techniques to track weak and rapidly changing signals. Fundamental to this need is the recent advancement in camera technology. Two camera types, specifically sCMOS and EM-CCD, promise both high signal-to-noise and high speed (>100 fps), leaving researchers with a critical decision when determining the best technology for their application. In this article, we compare two cameras using a live-cell imaging test case in which small changes in cellular fluorescence must be rapidly detected with high spatial resolution. The EM-CCD maintained an advantage of being able to acquire discernible images with a lower number of photons due to its EM-enhancement. However, if high-resolution images at speeds approaching or exceeding 1000 fps are desired, the flexibility of the full-frame imaging capabilities of sCMOS is superior. PMID- 24404180 TI - Binocular combination of second-order stimuli. AB - Phase information is a fundamental aspect of visual stimuli. However, the nature of the binocular combination of stimuli defined by modulations in contrast, so called second-order stimuli, is presently not clear. To address this issue, we measured binocular combination for first- (luminance modulated) and second-order (contrast modulated) stimuli using a binocular phase combination paradigm in seven normal adults. We found that the binocular perceived phase of second-order gratings depends on the interocular signal ratio as has been previously shown for their first order counterparts; the interocular signal ratios when the two eyes were balanced was close to 1 in both first- and second-order phase combinations. However, second-order combination is more linear than previously found for first order combination. Furthermore, binocular combination of second-order stimuli was similar regardless of whether the carriers in the two eyes were correlated, anti correlated, or uncorrelated. This suggests that, in normal adults, the binocular phase combination of second-order stimuli occurs after the monocular extracting of the second-order modulations. The sensory balance associated with this second order combination can be obtained from binocular phase combination measurements. PMID- 24404181 TI - An image encryption algorithm utilizing julia sets and hilbert curves. AB - Image encryption is an important and effective technique to protect image security. In this paper, a novel image encryption algorithm combining Julia sets and Hilbert curves is proposed. The algorithm utilizes Julia sets' parameters to generate a random sequence as the initial keys and gets the final encryption keys by scrambling the initial keys through the Hilbert curve. The final cipher image is obtained by modulo arithmetic and diffuse operation. In this method, it needs only a few parameters for the key generation, which greatly reduces the storage space. Moreover, because of the Julia sets' properties, such as infiniteness and chaotic characteristics, the keys have high sensitivity even to a tiny perturbation. The experimental results indicate that the algorithm has large key space, good statistical property, high sensitivity for the keys, and effective resistance to the chosen-plaintext attack. PMID- 24404179 TI - ADAM10 negatively regulates neuronal differentiation during spinal cord development. AB - Members of the ADAM (a disintegrin and metalloprotease) family are involved in embryogenesis and tissue formation via their proteolytic function, cell-cell and cell-matrix interactions. ADAM10 is expressed temporally and spatially in the developing chicken spinal cord, but its function remains elusive. In the present study, we address this question by electroporating ADAM10 specific morpholino antisense oligonucleotides (ADAM10-mo) or dominant-negative ADAM10 (dn-ADAM10) plasmid into the developing chicken spinal cord as well as by in vitro cell culture investigation. Our results show that downregulation of ADAM10 drives precocious differentiation of neural progenitor cells and radial glial cells, resulting in an increase of neurons in the developing spinal cord, even in the prospective ventricular zone. Remarkably, overexpression of the dn-ADAM10 plasmid mutated in the metalloprotease domain (dn-ADAM10-me) mimics the phenotype as found by the ADAM10-mo transfection. Furthermore, in vitro experiments on cultured cells demonstrate that downregulation of ADAM10 decreases the amount of the cleaved intracellular part of Notch1 receptor and its target, and increases the number of betaIII-tubulin-positive cells during neural progenitor cell differentiation. Taken together, our data suggest that ADAM10 negatively regulates neuronal differentiation, possibly via its proteolytic effect on the Notch signaling during development of the spinal cord. PMID- 24404182 TI - SHOOT GROWTH1 maintains Arabidopsis epigenomes by regulating IBM1. AB - Maintaining correct DNA and histone methylation patterns is essential for the development of all eukaryotes. In Arabidopsis, we identified SHOOT GROWTH1 (SG1), a novel protein involved in the control of gene methylation. SG1 contains both a Bromo-Adjacent Homology (BAH) domain found in several chromatin regulators and an RNA-Recognition Motif (RRM). The sg1 mutations are associated with drastic pleiotropic phenotypes. The mutants degenerate after few generations and are similar to mutants of the histone demethylase INCREASE IN BONSAI METHYLATION1 (IBM1). A methylome analysis of sg1 mutants revealed a large number of gene bodies hypermethylated in the cytosine CHG context, associated with an increase in di-methylation of lysine 9 on histone H3 tail (H3K9me2), an epigenetic mark normally found in silenced transposons. The sg1 phenotype is suppressed by mutations in genes encoding the DNA methyltransferase CHROMOMETHYLASE3 (CMT3) or the histone methyltransferase KRYPTONITE (KYP), indicating that SG1 functions antagonistically to CMT3 or KYP. We further show that the IBM1 transcript is not correctly processed in sg1, and that the functional IBM1 transcript complements sg1. Altogether, our results suggest a function for SG1 in the maintenance of genome integrity by regulating IBM1. PMID- 24404183 TI - Isolation and characterization of three cassava elongation factor 1 alpha (MeEF1A) promoters. AB - In plant genetic engineering, the identification of gene promoters leading to particular expression patterns is crucial for the development of new genetically modified plant generations. This research was conducted in order to isolate and characterize several new promoters from cassava (Manihot esculenta Crantz) elongation factor 1 alpha (EF1A) gene family.Three promoters MeEF1A3, MeEF1A5 and MeEF1A6 were successfully isolated [corrected]. Sequence analyses showed that all of the promoters contain three conserved putative cis-acting elements which are located upstream of the transcription start site. These elements are included a TEF1, a TELO and TATA boxes. In addition, all of the promoters also have the 5'UTR intron but with a different lengths. These promoters were constructed translationally with gusA reporter gene (promoter::gusA fusion) in pBI-121 binary vector to build a new binary vector using Overlap Extension PCR Cloning (OEPC) technique. Transient expression assay that was done by using agroinfiltration method was used to show functionality of these promoters. Qualitative and quantitative analysis from GUS assay showed that these promoters were functional and conferred a specific activity in tobacco seedlings (Nicotiana tabacum), tomato fruits (Solanum lycopersicum) and banana fruits (Musa acuminata). We hypothesized that MeEF1A6 could be categorized as a constitutive promoter because it was able to drive the gene expression in all transformed tissue described in here and also comparable to CaMV35S. On the other hand, MeEF1A3 drove specific expression in the aerial parts of seedlings such as hypocotyl and cotyledon thus MeEF1A5 drove specific expression in fruit tissue. The results obtained from transient analysis showed that these promoters had a distinct activity although they came from same gene family. The DNA sequences identified here are new promoters potentially use for genetic engineering in cassava or other plants. PMID- 24404184 TI - Rab27a is essential for the formation of neutrophil extracellular traps (NETs) in neutrophil-like differentiated HL60 cells. AB - Neutrophils play a crucial role in host defence. In response to a variety of inflammatory stimulation, they form neutrophil extracellular traps (NETs). NETs are extracellular structures composed of chromatin fibers decorated with antimicrobial proteins and developing studies indicate that NETs contribute to extracellular microbial killing. While the intracellular signaling pathways that regulate NET formation remain largely unknown, there is growing evidence that generation of reactive oxygen species (ROS) is a key event for NET formation. The Rab family small GTPase Rab27a is an important component of the secretory machinery of azurophilic granules in neutrophils. However, the precise mechanism of NET formation and whether or not Rab27a contributes to this process are unknown. Using neutrophil-like differentiated HL60 cells, we show here that Rab27a plays an essential role in both phorbol myristate acetate (PMA)- and Candida albicans-induced NET formation by regulating ROS production. Rab27a knockdown inhibited ROS-positive phagosome formation during complement-mediated phagocytosis. To investigate the role of Rab27a in neutrophil function in detail, both primary human neutrophils and neutrophil-like differentiated HL60 cells were treated with PMA, and NET formation process was assessed by measurement of release of histone H3 into the medium, citrullination of the arginine in position 3 of histone H4 and chase of the nuclear change of the living cells in the co existence of both cell-permeable and -impermeable nuclear indicators. PMA-induced NET formation occured sequentially in both neutrophil-like differentiated HL60 cells and primary neutrophils, and Rab27a-knockdown clearly inhibited NET formation in association with reduced ROS production. We also found that serum treated Candida albicans triggers NET formation in a ROS-dependent manner, and that Rab27a-knockdown inhibits this process as well. Our findings demonstrate that Rab27a plays an important role in NET formation induced by both Candida albicans infection and PMA treatment by regulating ROS production. PMID- 24404185 TI - Altered spontaneous brain activity in patients with Parkinson's disease accompanied by depressive symptoms, as revealed by regional homogeneity and functional connectivity in the prefrontal-limbic system. AB - As patients with Parkinson's disease (PD) are at high risk for comorbid depression, it is hypothesized that these two diseases are sharing common pathogenic pathways. Using regional homogeneity (ReHo) and functional connectivity approaches, we characterized human regional brain activity at resting state to examine specific brain networks in patients with PD and those with PD and depression (PDD). This study comprised 41 PD human patients and 25 normal human subjects. The patients completed the Hamilton Depression Rating Scale and were further divided into two groups: patients with depressive symptoms and non-depressed PD patients (nD-PD). Compared with the non-depressed patients, those with depressive symptoms exhibited significantly increased regional activity in the left middle frontal gyrus and right inferior frontal gyrus, and decreased ReHo in the left amygdala and bilateral lingual gyrus. Brain network connectivity analysis revealed decreased functional connectivity within the prefrontal-limbic system and increased functional connectivity in the prefrontal cortex and lingual gyrus in PDD compared with the nD-PD group. In summary, the findings showed regional brain activity alterations and disruption of the mood regulation network in PDD patients. The pathogenesis of PDD may be attributed to abnormal neural activity in multiple brain regions. PMID- 24404186 TI - C/EBPalpha is dispensable for the ontogeny of PD-1+ CD4+ memory T cells but restricts their expansion in an age-dependent manner. AB - Ageing and cancer is often associated with altered T cell distributions and this phenomenon has been suggested to be the main driver in the development of immunosenescence. Memory phenotype PD-1+ CD4+ T cells accumulate with age and during leukemic development, and they might account for the attenuated T cell response in elderly or diseased individuals. The transcription factor C/EBPalpha has been suggested to be responsible for the accumulation as well as for the senescent features of these cells including impaired TCR signaling and decreased proliferation. Thus modulating the activity of C/EBPalpha could potentially target PD-1+ CD4+ T cells and consequently, impede the development of immunosenescence. To exploit this possibility we tested the importance of C/EBPalpha for the development of age-dependent PD-1+ CD4+ T cells as well as its role in the accumulation of PD-1+ CD4+ T cells during leukemic progression. In contrast to earlier suggestions, we find that loss of C/EBPalpha expression in the lymphoid compartment led to an increase of PD-1+ CD4+ T cells specifically in old mice, suggesting that C/EBPalpha repress the accumulation of these cells in elderly by inhibiting their proliferation. Furthermore, C/EBPalpha-deficiency in the lymphoid compartment had no effect on leukemic development and did not affect the accumulation of PD-1+ CD4+ T cells. Thus, in addition to contradict earlier suggestions of a role for C/EBPalpha in immunosenescence, these findings efficiently discard the potential of using C/EBPalpha as a target for the alleviation of ageing/cancer-associated immunosenescence. PMID- 24404187 TI - The importance of the regional species pool, ecological species traits and local habitat conditions for the colonization of restored river reaches by fish. AB - It is commonly assumed that the colonization of restored river reaches by fish depends on the regional species pools; however, quantifications of the relationship between the composition of the regional species pool and restoration outcome are lacking. We analyzed data from 18 German river restoration projects and adjacent river reaches constituting the regional species pools of the restored reaches. We found that the ability of statistical models to describe the fish assemblages established in the restored reaches was greater when these models were based on 'biotic' variables relating to the regional species pool and the ecological traits of species rather than on 'abiotic' variables relating to the hydromorphological habitat structure of the restored habitats and descriptors of the restoration projects. For species presence in restored reaches, 'biotic' variables explained 34% of variability, with the occurrence rate of a species in the regional species pool being the most important variable, while 'abiotic' variables explained only the negligible amount of 2% of variability. For fish density in restored reaches, about twice the amount of variability was explained by 'biotic' (38%) compared to 'abiotic' (21%) variables, with species density in the regional species pool being most important. These results indicate that the colonization of restored river reaches by fish is largely determined by the assemblages in the surrounding species pool. Knowledge of species presence and abundance in the regional species pool can be used to estimate the likelihood of fish species becoming established in restored reaches. PMID- 24404188 TI - Development of a multiplexed bead-based suspension array for the detection and discrimination of pospiviroid plant pathogens. AB - Efficient and reliable diagnostic tools for the routine indexing and certification of clean propagating material are essential for the management of pospiviroid diseases in horticultural crops. This study describes the development of a true multiplexed diagnostic method for the detection and identification of all nine currently recognized pospiviroid species in one assay using Luminex bead based suspension array technology. In addition, a new data-driven, statistical method is presented for establishing thresholds for positivity for individual assays within multiplexed arrays. When applied to the multiplexed array data generated in this study, the new method was shown to have better control of false positives and false negative results than two other commonly used approaches for setting thresholds. The 11-plex Luminex MagPlex-TAG pospiviroid array described here has a unique hierarchical assay design, incorporating a near-universal assay in addition to nine species-specific assays, and a co-amplified plant internal control assay for quality assurance purposes. All assays of the multiplexed array were shown to be 100% specific, sensitive and reproducible. The multiplexed array described herein is robust, easy to use, displays unambiguous results and has strong potential for use in routine pospiviroid indexing to improve disease management strategies. PMID- 24404189 TI - Proliferation and survival signaling from both Jak2-V617F and Lyn involving GSK3 and mTOR/p70S6K/4EBP1 in PVTL-1 cell line newly established from acute myeloid leukemia transformed from polycythemia vera. AB - The gain of function mutation JAK2-V617F is very frequently found in myeloproliferative neoplasms (MPNs) and is strongly implicated in pathogenesis of these and other hematological malignancies. Here we report establishment of a new leukemia cell line, PVTL-1, homozygous for JAK2-V617F from a 73-year-old female patient with acute myeloid leukemia (AML) transformed from MPN. PVTL-1 is positive for CD7, CD13, CD33, CD34, CD117, HLA-DR, and MPO, and has complex karyotypic abnormalities, 44,XX,-5q,-7,-8,add(11)(p11.2),add(11)(q23),-16,+21, 22,+mar1. Sequence analysis of JAK2 revealed only the mutated allele coding for Jak2-V617F. Proliferation of PVTL-1 was inhibited and apoptosis was induced by the pan-Jak inhibitor Jak inhibitor-1 (JakI-1) or dasatinib, which inhibits the Src family kinases as well as BCR/ABL. Consistently, the Src family kinase Lyn was constitutively activated with phosphorylation of Y396 in the activation loop, which was inhibited by dasatinib but not by JakI-1. Further analyses with JakI-1 and dasatinib indicated that Jak2-V617F phosphorylated STAT5 and SHP2 while Lyn phosphorylated SHP1, SHP2, Gab-2, c-Cbl, and CrkL to induce the SHP2/Gab2 and c Cbl/CrkL complex formation. In addition, JakI-1 and dasatinib inactivated the mTOR/p70S6K/4EBP1 pathway and reduced the inhibitory phosphorylation of GSK3 in PVTL-1 cells, which correlated with their effects on proliferation and survival of these cells. Furthermore, inhibition of GSK3 by its inhibitor SB216763 mitigated apoptosis induced by dasatinib but not by JakI-1. Together, these data suggest that apoptosis may be suppressed in PVTL-1 cells through inactivation of GSK3 by Lyn as well as Jak2-V617F and additionally through activation of STAT5 by Jak2-V617F. It is also speculated that activation of the mTOR/p70S6K/4EBP1 pathway may mediate proliferation signaling from Jak2-V617F and Lyn. PVTL-1 cells may provide a valuable model system to elucidate the molecular mechanisms involved in evolution of Jak2-V617F-expressing MPN to AML and to develop novel therapies against this intractable condition. PMID- 24404190 TI - Accuracy of microRNA discovery pipelines in non-model organisms using closely related species genomes. AB - Mapping small reads to genome reference is an essential and more common approach to identify microRNAs (miRNAs) in an organism. Using closely related species genomes as proxy references can facilitate miRNA expression studies in non-model species that their genomes are not available. However, the level of error this introduces is mostly unknown, as this is the result of evolutionary distance between the proxy reference and the species of interest. To evaluate the accuracy of miRNA discovery pipelines in non-model organisms, small RNA library data from a mosquito, Aedes aegypti, were mapped to three well annotated insect genomes as proxy references using miRanalyzer with two strict and loose mapping criteria. In addition, another web-based miRNA discovery pipeline (DSAP) was used as a control for program performance. Using miRanalyzer, more than 80% reduction was observed in the number of mapped reads using strict criterion when proxy genome references were used; however, only 20% reduction was recorded for mapped reads to other species known mature miRNA datasets. Except a few changes in ranking, mapping criteria did not make any significant differences in the profile of the most abundant miRNAs in A. aegypti when its original or a proxy genome was used as reference. However, more variation was observed in miRNA ranking profile when DSAP was used as analysing tool. Overall, the results also suggested that using a proxy reference did not change the most abundant miRNAs' differential expression profiles when infected or non-infected libraries were compared. However, usage of a proxy reference could provide about 67% of the original outcome from more extremely up- or down-regulated miRNA profiles. Although using closely related species genome incurred some losses in the number of miRNAs, the most abundant miRNAs along with their differential expression profile would be acceptable based on the sensitivity level of each project. PMID- 24404191 TI - Exploring physical and chemical factors influencing the properties of recombinant prion protein and the real-time quaking-induced conversion (RT-QuIC) assay. AB - Real-time quaking-induced conversion (RT-QuIC), a highly specific and sensitive assay able to detect low levels of the disease-inducing isoform of the prion protein (PrP(d)) in brain tissue biopsies and cerebral spinal fluid, has great potential to become a method for diagnosing prion disease ante mortem. In order to standardize the assay method for routine analysis, an understanding of how physical and chemical factors affect the stability of the recombinant prion protein (rPrP) substrate and the RT-QuIC assay's sensitivity, specificity, and reproducibility is required. In this study, using sporadic Creutzfeldt-Jakob Disease brain homogenate to seed the reactions and an in vitro-expressed recombinant prion protein, hamster rPrP, as the substrate, the following factors affecting the RT-QuIC assay were examined: salt and substrate concentrations, substrate storage, and pH. Results demonstrated that both the generation of the quality and quantities of rPrP substrate critical to the reaction, as well as the RT-QuIC reaction itself required strict adherence to specific physical and chemical conditions. Once optimized, the RT-QuIC assay was confirmed to be a very specific and sensitive assay method for sCJD detection. Findings in this study indicate that further optimization and standardization of RT-QuIC assay is required before it can be adopted as a routine diagnostic test. PMID- 24404192 TI - Reproducible biofilm cultivation of chemostat-grown Escherichia coli and investigation of bacterial adhesion on biomaterials using a non-constant-depth film fermenter. AB - Biomaterials-associated infections are primarily initiated by the adhesion of microorganisms on the biomaterial surfaces and subsequent biofilm formation. Understanding the fundamental microbial adhesion mechanisms and biofilm development is crucial for developing strategies to prevent such infections. Suitable in vitro systems for biofilm cultivation and bacterial adhesion at controllable, constant and reproducible conditions are indispensable. This study aimed (i) to modify the previously described constant-depth film fermenter for the reproducible cultivation of biofilms at non-depth-restricted, constant and low shear conditions and (ii) to use this system to elucidate bacterial adhesion kinetics on different biomaterials, focusing on biomaterials surface nanoroughness and hydrophobicity. Chemostat-grown Escherichia coli were used for biofilm cultivation on titanium oxide and investigating bacterial adhesion over time on titanium oxide, poly(styrene), poly(tetrafluoroethylene) and glass. Using chemostat-grown microbial cells (single-species continuous culture) minimized variations between the biofilms cultivated during different experimental runs. Bacterial adhesion on biomaterials comprised an initial lag-phase I followed by a fast adhesion phase II and a phase of saturation III. With increasing biomaterials surface nanoroughness and increasing hydrophobicity, adhesion rates increased during phases I and II. The influence of materials surface hydrophobicity seemed to exceed that of nanoroughness during the lag-phase I, whereas it was vice versa during adhesion phase II. This study introduces the non constant-depth film fermenter in combination with a chemostat culture to allow for a controlled approach to reproducibly cultivate biofilms and to investigate bacterial adhesion kinetics at constant and low shear conditions. The findings will support developing and adequate testing of biomaterials surface modifications eventually preventing biomaterial-associated infections. PMID- 24404193 TI - Similar mechanisms underlie the detection of horizontal and vertical disparity corrugations. AB - Our aim was to compare sensitivity for horizontal and vertical disparity corrugations and to resolve whether these stimuli are processed by similar or radically different underlying mechanisms. We measure global disparity sensitivity as a function of carrier spatial frequency for equi-detectable carriers and found a similar optimal carrier relationship for vertical and horizontal stimuli. Sensitivity as a function of corrugation spatial frequency for stimuli of comparable spatial summation and composed of optimal, equi detectable narrowband carriers did not significantly differ for vertical and horizontal stimuli. A small anisotropy was revealed when fixed, high contrast broadband carriers were used. In a separate discrimination-at-threshold experiment, multiple mechanisms of similar tuning were revealed to underlie the detection of both vertical and horizontal disparity corrugations. We conclude that the processing of the horizontal and vertical disparity corrugations occurs along similar lines. PMID- 24404195 TI - The heterozygote superiority hypothesis for polymorphic color vision is not supported by long-term fitness data from wild neotropical monkeys. AB - The leading explanatory model for the widespread occurrence of color vision polymorphism in Neotropical primates is the heterozygote superiority hypothesis, which postulates that trichromatic individuals have a fitness advantage over other phenotypes because redgreen chromatic discrimination is useful for foraging, social signaling, or predator detection. Alternative explanatory models predict that dichromatic and trichromatic phenotypes are each suited to distinct tasks. To conclusively evaluate these models, one must determine whether proposed visual advantages translate into differential fitness of trichromatic and dichromatic individuals. We tested whether color vision phenotype is a significant predictor of female fitness in a population of wild capuchins, using longterm 26 years survival and fertility data. We found no advantage to trichromats over dichromats for three fitness measures fertility rates, offspring survival and maternal survival. This finding suggests that a selective mechanism other than heterozygote advantage is operating to maintain the color vision polymorphism. We propose that attention be directed to field testing the alternative mechanisms of balancing selection proposed to explain opsin polymorphism nichedivergence, frequencydependence and mutual benefit of association. This is the first indepth, longterm study examining the effects of color vision variation on survival and reproductive success in a naturallyoccurring population of primates. PMID- 24404196 TI - Bigger helpers in the ant Cataglyphis bombycina: increased worker polymorphism or novel soldier caste? AB - INTRODUCTION: The mechanisms by which development favors or constrains the evolution of new phenotypes are incompletely understood. Polyphenic species may benefit from developmental plasticity not only regarding ecological advantages, but also potential for evolutionary diversification. For instance, the repeated evolution of novel castes in ants may have been facilitated by the existence of alternative queen and worker castes and their respective developmental programs. MATERIAL AND METHODS: Cataglyphis bombycina is exceptional in its genus because winged queens and size-polymorphic workers occur together with bigger individuals having saber-shaped mandibles. We measured seven body parts in more than 150 individuals to perform a morphometric analysis and assess the developmental origin of this novel phenotype. RESULTS: Adults with saber-shaped mandibles differ from both workers and queens regarding the size of most body parts. Their relative growth rates are identical to workers for some pairs of body parts, and identical to queens for other pairs of body parts; critical sizes differ in all cases. CONCLUSIONS: Big individuals are a third caste, i.e. soldiers, not major workers. Novel traits such as elongated mandibles are combined with a mix of queen and worker growth rates. We also reveal the existence of a dimorphism in the queen caste (microgynes and macrogynes). We discuss how novel phenotypes can evolve more readily in the context of an existing polyphenism. Both morphological traits and growth rules from existing queen and worker castes can be recombined, hence mosaic phenotypes are more likely to be viable. In C. bombycina, such a mosaic phenotype appears to function both for defense (saber-shaped mandibles) and fat storage (big abdomen). Recycling of developmental programs may have contributed to the morphological diversity and ecological success of ants. PMID- 24404194 TI - Distinct cyclosporin a doses are required to enhance bone formation induced by cyclic and rest-inserted loading in the senescent skeleton. AB - Age-related decline in periosteal adaptation negatively impacts the ability to utilize exercise to enhance bone mass and strength in the elderly. We recently observed that in senescent animals subject to cyclically applied loading, supplementation with Cyclosporin A (CsA) substantially enhanced the periosteal bone formation rates to levels observed in young animals. We therefore speculated that if the CsA supplement could enhance bone response to a variety of types of mechanical stimuli, this approach could readily provide the means to expand the range of mild stimuli that are robustly osteogenic at senescence. Here, we specifically hypothesized that a given CsA supplement would enhance bone formation induced in the senescent skeleton by both cyclic (1-Hz) and rest inserted loading (wherein a 10-s unloaded rest interval is inserted between each load cycle). To examine this hypothesis, the right tibiae of senescent female C57BL/6 mice (22 Mo) were subjected to cyclic or rest-inserted loading supplemented with CsA at 3.0 mg/kg. As previously, we initially found that while the periosteal bone formation rate (p.BFR) induced by cyclic loading was enhanced when supplemented with 3.0 mg/kg CsA (by 140%), the response to rest-inserted loading was not augmented at this CsA dosage. In follow-up experiments, we observed that while a 30-fold lower CsA dosage (0.1 mg/kg) significantly enhanced p.BFR induced by rest-inserted loading (by 102%), it was ineffective as a supplement with cyclic loading. Additional experiments and statistical analysis confirmed that the dose-response relations were significantly different for cyclic versus rest-inserted loading, only because the two stimuli required distinct CsA dosages for efficacy. While not anticipated a priori, clarifying the complexity underlying the observed interaction between CsA dosage and loading type holds potential for insight into how bone response to a broad range of mechanical stimuli may be substantially enhanced in the senescent skeleton. PMID- 24404198 TI - Sortilin expression is essential for pro-nerve growth factor-induced apoptosis of rat vascular smooth muscle cells. AB - BACKGROUND: Sortilin, a member of the Vps10p-domain receptor family, has been demonstrated a key regulator in mediating cellular response to pro-neurotrophins. In the present study, we investigated the role of sortilin in the apoptotic pathway of vascular smooth muscle cells. METHODS AND PRINCIPAL FINDINGS: Immunohistochemistry revealed that sortilin was barely detectable in human and rat normal young vessels, while its expression was increased in human fibroatheromatous plaques. Sortilin immunodetection was also marked in the neointima of the rat aorta fifteen days after ballooning.In vitro, rat aortic intimal cells expressed higher sortilin levels than normal media SMCs; sortilin was distributed in the cytoplasm and in correspondence of the cell membrane. After 48 h, pro-nerve growth factor (proNGF) induced the strong dose-dependent increase of intimal cell apoptosis and the accumulation of sortilin protein. ProNGF was a more potent apoptotic inducer than equimolar or even higher concentration of NGF, whereas brain derived neutrotrophic factor was ineffective. Targeted interfering RNA-mediated sortilin reduction counteracted proNGF-induced apoptosis without affecting p75(NTR) expression. ProNGF-induced apoptosis was associated to NF-kappaB down-regulation and bax increase. Inhibition of NF-kappaB activity increased intimal cell apoptosis that did not further increase with the addition of proNGF. CONCLUSIONS: Our results indicate that sortilin expression characterizes human atheromatous lesions and rat aortic post-injury neointima, and suggest that sortilin represents an important regulator of proNGF-induced SMC apoptosis and arterial remodeling. PMID- 24404199 TI - Workplace social capital and mental health among Chinese employees: a multi level, cross-sectional study. AB - BACKGROUND: Whereas the majority of previous research on social capital and health has been on residential neighborhoods and communities, the evidence remains sparse on workplace social capital. To address this gap in the literature, we examined the association between workplace social capital and health status among Chinese employees in a large, multi-level, cross-sectional study. METHODS: By employing a two-stage stratified random sampling procedure, 2,796 employees were identified from 35 workplaces in Shanghai during March to November 2012. Workplace social capital was assessed using a validated and psychometrically tested eight-item measure, and the Chinese language version of the WHO-Five Well-Being Index (WHO-5) was used to assess mental health. Control variables included sex, age, marital status, education level, occupation status, smoking status, physical activity, and job stress. Multilevel logistic regression analysis was conducted to explore whether individual- and workplace-level social capital was associated with mental health status. RESULTS: In total, 34.9% of workers reported poor mental health (WHO-5<13). After controlling for individual level socio-demographic and lifestyle variables, compared to workers with the highest quartile of personal social capital, workers with the third, second, and lowest quartiles exhibited 1.39 to 3.54 times greater odds of poor mental health, 1.39 (95% CI: 1.10-1.75), 1.85 (95% CI: 1.38-2.46) and 3.54 (95% CI: 2.73-4.59), respectively. Corresponding odds ratios for workplace-level social capital were 0.95 (95% CI: 0.61-1.49), 1.14 (95% CI: 0.72-1.81) and 1.63 (95% CI: 1.05-2.53) for the third, second, and lowest quartiles, respectively. CONCLUSIONS: Higher workplace social capital is associated with lower odds of poor mental health among Chinese employees. Promoting social capital at the workplace may contribute to enhancing employees' mental health in China. PMID- 24404197 TI - Upregulation of APP, ADAM10 and ADAM17 in the denervated mouse dentate gyrus. AB - The disintegrin and metalloproteinases ADAM10 and ADAM17 are regarded as the most important alpha-secretases involved in the physiological processing of amyloid precursor protein (APP) in brain. Since it has been suggested that processing of APP by alpha-secretases could be involved in the reorganization of the brain following injury, we studied mRNA expression of the two alpha-secretases Adam10 and Adam17, the beta-secretase Bace1, and the App-gene family (App, Aplp1, Aplp2) in the dentate gyrus of the mouse following entorhinal denervation. Using laser microdissection, tissue was harvested from the outer molecular layer and the granule cell layer of the denervated dentate gyrus. Expression levels of candidate genes were assessed using Affymetrix GeneChip Mouse Gene 1.0 ST arrays and reverse transcription-quantitative PCR, revealing an upregulation of Adam10 mRNA and Adam17 mRNA in the denervated outer molecular layer and an upregulation of Adam10 mRNA and App mRNA in the dentate granule cell layer. Immunolabeling for ADAM10 or ADAM17 in combination with markers for astro- and microglia revealed an increased labeling of ADAM10 and ADAM17 in the denervated outer molecular layer that was associated with reactive astrocytes but not with microglia. Collectively, these data show that denervation affects the expression level of APP and its two most important alpha-secretases. This suggests that APP processing could be shifted towards the non-amyloidogenic pathway in denervated areas of the brain and, thus, towards the formation of neuroprotective APP cleavage products, such as APPsalpha. PMID- 24404200 TI - Pattern association and consolidation emerges from connectivity properties between cortex and hippocampus. AB - The basic structure of the cortico-hippocampal system is highly conserved across mammalian species. Comparatively few hippocampal neurons can represent and address a multitude of cortical patterns, establish associations between cortical patterns and consolidate these associations in the cortex. In this study, we investigate how elementary anatomical properties in the cortex-hippocampus loop along with synaptic plasticity contribute to these functions. Specifically, we focus on the high degree of connectivity between cortex and hippocampus leading to converging and diverging forward and backward projections and heterogenous synaptic transmission delays that result from the detached location of the hippocampus and its multiple loops. We found that in a model incorporating these concepts, each cortical pattern can evoke a unique spatio-temporal spiking pattern in hippocampal neurons. This hippocampal response facilitates a reliable disambiguation of learned associations and a bridging of a time interval larger than the time window of spike-timing dependent plasticity in the cortex. Moreover, we found that repeated retrieval of a stored association leads to a compression of the interval between cue presentation and retrieval of the associated pattern from the cortex. Neither a high degree of connectivity nor heterogenous synaptic delays alone is sufficient for this behavior. We conclude that basic anatomical properties between cortex and hippocampus implement mechanisms for representing and consolidating temporal information. Since our model reveals the observed functions for a range of parameters, we suggest that these functions are robust to evolutionary changes consistent with the preserved function of the hippocampal loop across different species. PMID- 24404201 TI - Tumor necrosis factor-a polymorphisms and colorectal cancer risk: a meta analysis. AB - BACKGROUND AND OBJECTIVES: Tumor necrosis factor-alpha (TNF-a) was related to inflammation and involved in the development of colorectal cancer. Polymorphisms located in TNF-a promoter region, such as 308G/A and 238G/A, could affect the risk of various types of cancer by regulating TNF-a production. In this study, a meta-analysis was performed to investigate the association between common polymorphisms of TNF-a promoter region and colorectal cancer susceptibility. METHODS: Searching of several databases was performed for all publications on the association between TNF-a polymorphisms and colorectal cancer. Summary odds ratios (ORs) with their 95% confidence intervals (95% CIs) were calculated using random-effects models. Stratified analyses based on ethnicity and control population source were also conducted. RESULTS: Overall, TNF-a 308A polymorphism showed a significant association with increased risk of colorectal cancer in worldwide populations under homozygote comparison [AA vs. GG, OR (95% CI) = 1.46 (1.07-1.97)] other than heterozygote comparison [AG vs. GG, OR (95% CI) = 1.05 (0.93-1.19)]. TNF-a 238A was not associated with colorectal cancer risk under homozygote or heterozygote comparisons. In stratified analysis, significant association was observed only in Western populations [AA vs. GG, OR (95% CI) = 1.39 (1.01-1.91)] other than in Eastern populations under homozygote comparison. No significant difference was observed between population-based subgroup and hospital-based subgroup. CONCLUSIONS: TNF-a 308A was moderately associated with an increased risk of colorectal cancer in Western populations, and TNF-a 238A polymorphism was not significantly associated with colorectal cancer risk. PMID- 24404202 TI - Functional expression of Rat Nav1.6 voltage-gated sodium channels in HEK293 cells: modulation by the auxiliary beta1 subunit. AB - The Nav1.6 voltage-gated sodium channel alpha subunit isoform is abundantly expressed in the adult rat brain. To assess the functional modulation of Nav1.6 channels by the auxiliary beta1 subunit we expressed the rat Nav1.6 sodium channel alpha subunit by stable transformation in HEK293 cells either alone or in combination with the rat beta1 subunit and assessed the properties of the reconstituted channels by recording sodium currents using the whole-cell patch clamp technique. Coexpression with the beta1 subunit accelerated the inactivation of sodium currents and shifted the voltage dependence of channel activation and steady-state fast inactivation by approximately 5-7 mV in the direction of depolarization. By contrast the beta1 subunit had no effect on the stability of sodium currents following repeated depolarizations at high frequencies. Our results define modulatory effects of the beta1 subunit on the properties of rat Nav1.6-mediated sodium currents reconstituted in HEK293 cells that differ from effects measured previously in the Xenopus oocyte expression system. We also identify differences in the kinetic and gating properties of the rat Nav1.6 channel expressed in the absence of the beta1 subunit compared to the properties of the orthologous mouse and human channels expressed in this system. PMID- 24404203 TI - AtEXP2 is involved in seed germination and abiotic stress response in Arabidopsis. AB - Expansins are cell wall proteins that promote cell wall loosening by inducing pH dependent cell wall extension and stress relaxation. Expansins are required in a series of physiological developmental processes in higher plants such as seed germination. Here we identified an Arabidopsis expansin gene AtEXPA2 that is exclusively expressed in germinating seeds and the mutant shows delayed germination, suggesting that AtEXP2 is involved in controlling seed germination. Exogenous GA application increased the expression level of AtEXP2 during seed germination, while ABA application had no effect on AtEXP2 expression. Furthermore, the analysis of DELLA mutants show that RGL1, RGL2, RGA, GAI are all involved in repressing AtEXP2 expression, and RGL1 plays the most dominant role in controlling AtEXP2 expression. In stress response, exp2 mutant shows higher sensitivity than wild type in seed germination, while overexpression lines of AtEXP2 are less sensitive to salt stress and osmotic stress, exhibiting enhanced tolerance to stress treatment. Collectively, our results suggest that AtEXP2 is involved in the GA-mediated seed germination and confers salt stress and osmotic stress tolerance in Arabidopsis. PMID- 24404204 TI - The potential role of As-sumo-1 in the embryonic diapause process and early embryo development of Artemia sinica. AB - During embryonic development of Artemia sinica, environmental stresses induce the embryo diapause phenomenon, required to resist apoptosis and regulate cell cycle activity. The small ubiquitin-related modifier-1 (SUMO), a reversible post translational protein modifier, plays an important role in embryo development. SUMO regulates multiple cellular processes, including development and other biological processes. The molecular mechanism of diapause, diapause termination and the role of As-sumo-1 in this processes and in early embryo development of Artemia sinica still remains unknown. In this study, the complete cDNA sequences of the sumo-1 homolog, sumo ligase homolog, caspase-1 homolog and cyclin B homolog from Artemia sinica were cloned. The mRNA expression patterns of As-sumo 1, sumo ligase, caspase-1, cyclin B and the location of As-sumo-1 were investigated. SUMO-1, p53, Mdm2, Caspase-1, Cyclin B and Cyclin E proteins were analyzed during different developmental stages of the embryo of A. sinica. Small interfering RNA (siRNA) was used to verify the function of sumo-1 in A. sinica. The full-length cDNA of As-sumo-1 was 476 bp, encoding a 92 amino acid protein. The As-caspases-1 cDNA was 966 bp, encoding a 245 amino-acid protein. The As-sumo ligase cDNA was 1556 bp encoding, a 343 amino acid protein, and the cyclin B cDNA was 739 bp, encoding a 133 amino acid protein. The expressions of As-sumo-1, As caspase-1 and As-cyclin B were highest at the 10 h stage of embryonic development, and As-sumo ligase showed its highest expression at 0 h. The expression of As-SUMO-1 showed no tissue or organ specificity. Western blotting showed high expression of As-SUMO-1, p53, Mdm2, Caspase-1, Cyclin B and Cyclin E at the 10 h stage. The siRNA caused abnormal development of the embryo, with increased malformation and mortality. As-SUMO-1 is a crucial regulation and modification protein resumption of embryonic diapause and early embryo development of A. sinica. PMID- 24404206 TI - Influence of deforestation, logging, and fire on malaria in the Brazilian Amazon. AB - Malaria is a significant public health threat in the Brazilian Amazon. Previous research has shown that deforestation creates breeding sites for the main malaria vector in Brazil, Anopheles darlingi, but the influence of selective logging, forest fires, and road construction on malaria risk has not been assessed. To understand these impacts, we constructed a negative binomial model of malaria counts at the municipality level controlling for human population and social and environmental risk factors. Both paved and unpaved roadways and fire zones in a municipality increased malaria risk. Within the timber production states where 90% of deforestation has occurred, compared with areas without selective logging, municipalities where 0-7% of the remaining forests were selectively logged had the highest malaria risk (1.72, 95% CI 1.18-2.51), and areas with higher rates of selective logging had the lowest risk (0.39, 95% CI 0.23-0.67). We show that roads, forest fires, and selective logging are previously unrecognized risk factors for malaria in the Brazilian Amazon and highlight the need for regulation and monitoring of sub-canopy forest disturbance. PMID- 24404207 TI - Sequential bilateral central retinal vein occlusions in a cystic fibrosis patient with hyperhomocysteinemia and hypergamma-globulinemia. AB - PURPOSE: To report a case of sequential bilateral central retinal vein occlusions in a cystic fibrosis patient with hyperhomocysteinemia and hypergamma globulinemia over 6 years of follow up. METHODS: Observational case report of one patient. RESULTS: A 31 year-old male with a history of cystic fibrosis presented with a central retinal vein occlusion (CRVO) in his left eye, followed by a CRVO in his right eye 4 years later. His medical workup was significant for elevated levels of homocysteine and gamma-globulins, which coincided with initiation of intravenous immunoglobulin (IVIG) proceeding his second CRVO. CONCLUSIONS: We describe a case of sequential bilateral central retinal vein occlusions in a cystic fibrosis patient with hyperhomocysteinemia and hypergamma-globulinemia over 6 years of follow up and discuss the important role of these risk factors in retinal venous occlusive disease. PMID- 24404205 TI - Curcumin chemosensitizes 5-fluorouracil resistant MMR-deficient human colon cancer cells in high density cultures. AB - OBJECTIVE: Treatment of colorectal cancer (CRC) remains a clinical challenge, as more than 15% of patients are resistant to 5-Fluorouracil (5-FU)-based chemotherapeutic regimens, and tumor recurrence rates can be as high as 50-60%. Cancer stem cells (CSC) are capable of surviving conventional chemotherapies that permits regeneration of original tumors. Therefore, we investigated the effectiveness of 5-FU and plant polyphenol (curcumin) in context of DNA mismatch repair (MMR) status and CSC activity in 3D cultures of CRC cells. METHODS: High density 3D cultures of CRC cell lines HCT116, HCT116+ch3 (complemented with chromosome 3) and their corresponding isogenic 5-FU-chemo-resistant derivative clones (HCT116R, HCT116+ch3R) were treated with 5-FU either without or with curcumin in time- and dose-dependent assays. RESULTS: Pre-treatment with curcumin significantly enhanced the effect of 5-FU on HCT116R and HCR116+ch3R cells, in contrast to 5-FU alone as evidenced by increased disintegration of colonospheres, enhanced apoptosis and by inhibiting their growth. Curcumin and/or 5-FU strongly affected MMR-deficient CRC cells in high density cultures, however MMR-proficient CRC cells were more sensitive. These effects of curcumin in enhancing chemosensitivity to 5-FU were further supported by its ability to effectively suppress CSC pools as evidenced by decreased number of CSC marker positive cells, highlighting the suitability of this 3D culture model for evaluating CSC marker expression in a close to vivo setting. CONCLUSION: Our results illustrate novel and previously unrecognized effects of curcumin in enhancing chemosensitization to 5-FU-based chemotherapy on DNA MMR-deficient and their chemo-resistant counterparts by targeting the CSC sub-population. (246 words in abstract). PMID- 24404208 TI - DISTORTION-OPTIMAL SELF-CALIBRATING PARALLEL MRI BY BLIND INTERPOLATION IN SUBSAMPLED FILTER BANKS. AB - Self-calibrating k-space-based image reconstruction in parallel MRI interpolates the subsampled multi-channel data to a fully sampled Nyquist grid in k-space. Adopting a filter bank interpolation framework, we provide a new formulation of the associated inverse problem and develop the theory for blind identification of the interpolant filters. The developed method is applied to imaging scenarios where high effective acceleration is desired and is shown to be capable of reconstructing artifact-free images with minimal amount of calibration data - hence, achieving high effective accelerations. Simulation and in-vivo results indicate that improved image quality, and thus greater scan time reductions compared to the state-of-the-art method of GRAPPA can be achieved. PMID- 24404209 TI - A Milestone in the Milestones Movement: the JGME Milestones Supplement. PMID- 24404211 TI - Internal medicine milestones. PMID- 24404210 TI - Emergency medicine milestones. PMID- 24404212 TI - Neurological surgery milestones. PMID- 24404213 TI - Orthopaedic surgery milestones. PMID- 24404214 TI - Pediatrics milestones. PMID- 24404215 TI - Diagnostic radiology milestones. PMID- 24404216 TI - Urology milestones. PMID- 24404217 TI - Tracing the steps of survey design: a graduate medical education research example. PMID- 24404218 TI - Competency-based education, entrustable professional activities, and the power of language. PMID- 24404219 TI - Behavioral specification of the entrustment process. PMID- 24404220 TI - To play or not to play: leveraging video in medical education. AB - While video is a powerful teaching and learning tool because it can influence knowledge, skills, and attitude formation effectively and reach learners with various learning and communication styles, there are pedagogical, technical, and copyright considerations. Instructors must know sources of appropriate videos, select effective video segments, apply various strategies for incorporating video triggers into the overall educational process, refine the message, overcome technological obstacles, and comply with copyright laws. One might ask, "Is using video triggers to improve your teaching worth it?" "Yes!" Numerous studies demonstrate that using video in many medical education settings supports and enhances learning and offers a bigger advantage in contrast with traditional methods. PMID- 24404221 TI - A narrative review of surgical resident duty hour limits: where do we go from here? AB - BACKGROUND: Resident duty hour limits have been a point of debate among educators, administrators, and policymakers alike since the Libby Zion case in 1984. Advocates for duty hour limits in the surgical subspecialties cite improvements in patient safety, whereas opponents claim that limiting resident duty hours jeopardizes resident education and preparedness for independent surgical practice. METHODS: Using orthopaedic surgery as an example, we describe the historical context of the implementation of the duty hour standards, provide a review of the literature presenting data that both supports and refutes continued restrictions, and outline suggestions for policy going forward that prioritize patient safety while maintaining an enhanced environment for resident education. RESULTS: Although patient safety markers have improved in some studies since the implementation of duty hour limits, it is unclear whether this is due to changes in residency training or external factors. The literature is mixed regarding academic performance and trainee readiness during and after residency. CONCLUSION: Although excessive duty hours and resident fatigue may have historically contributed to errors in the delivery of patient care, those are certainly not the only concerns. An overall "culture of safety," which includes pinpointing systematic improvements, identifying potential sources of error, raising performance standards and safety expectations, and implementing multiple layers of protection against medical errors, can continue to augment safety barriers and improve patient care. This can be achieved within a more flexible educational environment that protects resident education and ensures optimal training for the next generation of physicians and surgeons. PMID- 24404222 TI - Interns' experiences of disruptive behavior in an academic medical center. AB - BACKGROUND: The first year of graduate medical education is an important period in the professional development of physicians. Disruptive behavior interferes with safe and effective clinical practice. OBJECTIVE: To determine the frequency and nature of disruptive behavior perceived by interns and attending physicians in a teaching hospital environment. METHOD: All 516 interns at Partners HealthCare (Boston, MA) during the 2010 and 2011 academic years were eligible to complete an anonymous questionnaire. A convenience nonrandom sample of 40 attending physicians also participated. RESULTS: A total of 394 of 516 eligible interns (76.4%) participated. Attendings and interns each reported that their team members generally behaved professionally (87.5% versus 80.4%, respectively). A significantly greater proportion of attendings than interns felt respected at work (90.0% versus 71.5% respectively; P = .01). Disruptive behavior was experienced by 93% of interns; 54% reported that they experienced it once a month or more. Interns reported disruptive behavior significantly more frequently than attending physicians, including increased reports of condescending behavior (odds ratio [OR], 5.46 for interns compared with attendings; P < .001), exclusion from decision making (OR, 6.97; P < .001), and berating (OR, 4.84; P = .02). Inappropriate jokes, abusive language, and gender bias were also reported, and they were not significantly more frequent among interns than attending physicians. Interns most frequently identified nurses as the source of disruption, and were significantly more likely than faculty to identify nurses as the source of disruptive behavior (OR, 10.40; P < .001). Attendings reported other physicians as the most frequent source of disruption. CONCLUSIONS: Although interns generally feel respected at work, they frequently experience disruptive behavior. Interns described more disruptive behaviors than a convenience sample of attending physicians at our institution. PMID- 24404223 TI - Recent family medicine residency graduates' perceptions of resident duty hour restrictions. AB - BACKGROUND: Resident duty hour limits, new requirements for supervision, and an enhanced focus on patient safety have shown mixed effects on resident quality of life, patient safety, and resident competency. Few studies have assessed how recent graduates feel these changes have affected their education. OBJECTIVE: We assessed recent graduates' perceptions about the effects of duty hour and supervision requirements on their education. METHODS: We conducted a cross sectional survey of graduates from South Carolina Area Health Education Consortium-affiliated family medicine residency programs from 2005 to 2009 by using logistic regression to determine associations between participant characteristics and survey responses. RESULTS: Graduates (N = 136) completed the survey with a 51.3% response rate. Nearly all (96%) reported that residency prepared them for their current work hours; 97% reported they felt adequately supervised; 81% worked fewer hours in practice than in residency; 20% believed the limits had restricted their clinical experience; and 3% felt duty hour limits were more important than supervision. Graduates who practiced in a mid-sized communities were more likely to report duty hour limits restricted their clinical experience than individuals practicing in communities of <10 000 (OR = 6.30; 95% CI, 1.38-28.72). CONCLUSIONS: Most graduates who responded to the survey felt supervision was equally or more important than limits on resident duty hours. However, 20% of respondents felt that the duty hour standards limited their education. The duty hour and supervision requirements challenge educators to ensure quality education. PMID- 24404224 TI - The effect of a patient- and family-centered care curriculum on pediatrics residents' patient-centeredness. AB - BACKGROUND: Patient- and family-centered care (PFCC) approaches to care are important in enhancing the patient-centeredness of the health care experience, yet little is known about the effectiveness of formal approaches for teaching patient-centeredness in residency. INTERVENTION: We developed and implemented a PFCC curriculum and assessed its impact on residents' self-perceptions of patient centered behavior and practices. METHODS: We used a quasi-experimental, nonrandomized approach with a pretest-posttest design. An experimental group of 24 interns filled out the Patient Practitioner Orientation Scale (PPOS) before residency, and a control group of 18 graduating residents who had not been exposed to a PFCC curriculum also completed the PPOS. After 2 years of residency and exposure to a PFCC curriculum, interns in the experimental group repeated the PPOS. We compared mean total and subscale PPOS scores. RESULTS: There was no difference in baseline total or subscale PPOS scores between the experimental and control group. The mean total PPOS score for the experimental group after exposure to the curriculum was 4.55 (P = .45), reflecting no change in patient centeredness. The 17 female interns in the intervention group were more patient centered (4.8 +/- 0.36) than the 6 male interns (4.2 +/- 0.38) (P = .005), scoring significantly higher (4.6 +/- 0.39 versus 4.0 +/- 0.38) in the sharing domain (P = .001). CONCLUSION: Interns' exposure to a PFCC curriculum did not result in a change in their perceived patient-centeredness. Most pediatrics residents at our children's hospital perceive themselves as patient and family centered at the start of residency and remain so throughout. PMID- 24404225 TI - Increasing Faculty Attendance at Emergency Medicine Resident Conferences: Does CME Credit Make a Difference? AB - BACKGROUND: Faculty involvement in resident teaching events is beneficial to resident education, yet evidence about the factors that promote faculty attendance at resident didactic conferences is limited. OBJECTIVE: To determine whether offering continuing medical education (CME) credits would result in an increase in faculty attendance at weekly emergency medicine conferences and whether faculty would report the availability of CME credit as a motivating factor. METHODS: Our prospective, multi-site, observational study of 5 emergency medicine residency programs collected information on the number of faculty members present at CME and non-CME lectures for 9 months and collected information from faculty on factors influencing decisions to attend resident educational events and from residents on factors influencing their learning experience. RESULTS: Lectures offering CME credit on average were attended by 5 additional faculty members per hour, compared with conferences that did not offer CME credit (95% confidence interval [CI], 3.9-6.1; P < .001). Faculty reported their desire to "participate in resident education" was the most influential factor prompting them to attend lectures, followed by "explore current trends in emergency medicine" and the lecture's "specific topic." Faculty also reported that "clinical/administrative duties" and "family responsibilities" negatively affected their ability to attend. Residents reported that the most important positive factor influencing their conference experience was "lectures given by faculty." CONCLUSIONS: Although faculty reported that CME credit was not an important factor in their decision to attend resident conferences, offering CME credit resulted in significant increases in faculty attendance. Residents reported that "lectures given by faculty" and "faculty attendance" positively affected their learning experience. PMID- 24404226 TI - Essential facets of competence that enable trust in graduates: a delphi study among physician educators in the Netherlands. AB - BACKGROUND: There is a need for valid methods to assess the readiness for clinical practice of recently graduated physicians. To develop these methods, it is relevant to know the general features of trainees' performance that facilitate supervisors' trust in their ability to perform critical clinical tasks. OBJECTIVE: To discover such essential facets of competence (FOCs), based on the opinion of experienced physician educators. METHODS: We conducted a Delphi study, consisting of 2 rounds, among 18 experienced physician educators in the Netherlands. Mean, standard deviation, level of agreement, and skewness were calculated for the importance of FOCs for making entrustment decisions. The study yielded a list of 25 FOCs. RESULTS: In the first round, means were between 6.50 and 7.00 on a 7-point Likert scale (SD, 0.42-2.18); in the second round, means ranged from 5.45 to 6.90 (SD, 0.3-2.02). The level of agreement was high for 92% of the FOCs in the first round and 100% of the FOCs in the second round. CONCLUSIONS: Our Delphi study found consensus among experts about FOCs that are important for clinical entrustment decisions. PMID- 24404227 TI - Identifying entrustable professional activities in internal medicine training. AB - BACKGROUND: Entrustable professional activities (EPAs) can form the foundation of competency-based assessment in medical training, focused on performance of discipline-specific core clinical activities. OBJECTIVE: To identify EPAs for the Internal Medicine (IM) Educational Milestones to operationalize competency-based assessment of residents using EPAs. METHODS: We used a modified Delphi approach to conduct a 2-step cross-sectional survey of IM educators at a 3-hospital IM residency program; residents also completed a survey. Participants rated the importance and appropriate year of training to reach competence for 30 proposed IM EPAs. Content validity indices identified essential EPAs. We conducted independent sample t tests to determine IM educator-resident agreement and calculated effect sizes. Finally, we determined the effect of different physician roles on ratings. RESULTS: Thirty-six IM educators participated; 22 completed both surveys. Twelve residents participated. Seventeen EPAs had a content validity index of 100%; 10 additional EPAs exceeded 80%. Educators and residents rated the importance of 27 of 30 EPAs similarly. Residents felt that 10 EPAs could be met at least 1 year earlier than educators had specified. CONCLUSIONS: Internal medicine educators had a stable opinion of EPAs developed through this study, and residents generally agreed. Using this approach, programs could identify EPAs for resident evaluation, building on the initial list created via our study. PMID- 24404228 TI - Remediation in the context of the competencies: a survey of pediatrics residency program directors. AB - BACKGROUND: The 6 competencies defined by the Accreditation Council for Graduate Medical Education provide the framework of assessment for trainees in the US graduate medical education system, but few studies have investigated their impact on remediation. METHODS: We obtained data via an anonymous online survey of pediatrics residency program directors. For the purposes of the survey, remediation was defined as "any form of additional training, supervision, or assistance above that required for a typical resident." Respondents were asked to quantify 3 groups of residents: (1) residents requiring remediation; (2) residents whose training was extended for remediation purposes; and (3) residents whose training was terminated owing to issues related to remediation. For each group, the proportion of residents with deficiencies in each of the 6 competencies was calculated. RESULTS: In all 3 groups, deficiencies in medical knowledge and patient care were most common; deficiencies in professionalism and communication were moderately common; and deficiencies in systems-based practice and practice-based learning and improvement were least common. Residents whose training was terminated were more likely to have deficiencies in multiple competencies. CONCLUSION: Although medical knowledge and patient care are reported most frequently, deficiencies in any of the 6 competencies can lead to the need for remediation in pediatrics residents. Residents who are terminated are more likely to have deficits in multiple competencies. It will be critical to develop and refine tools to measure achievement in all 6 competencies as the graduate medical education community may be moving further toward individualized training schedules and competency-based, rather than time-based, training. PMID- 24404229 TI - Evaluating nonphysician staff members' self-perceived ability to provide multisource evaluations of residents. AB - BACKGROUND: Multisource evaluations of residents offer valuable feedback, yet there is little evidence on the best way to collect these data from a range of health care professionals. OBJECTIVE: This study evaluated nonphysician staff members' ability to assess internal medicine residents' performance and behavior, and explored whether staff members differed in their perceived ability to participate in resident evaluations. METHODS: We distributed an anonymous survey to nurses, medical assistants, and administrative staff at 6 internal medicine residency continuity clinics. Differences between nurses and other staff members' perceived ability to evaluate resident behavior were examined using independent t tests. RESULTS: The survey response rate was 82% (61 of 74). A total of 55 respondents (90%) reported that it was important for them to evaluate residents. Participants reported being able to evaluate professional behaviors very well (62% [36 of 58] on the domain of respect to staff; 61% [36 of 59] on attire; and 54% [32 of 59] on communication). Individuals without a clinical background reported being uncomfortable evaluating medical knowledge (60%; 24 of 40) and judgment (55%; 22 of 40), whereas nurses reported being more comfortable evaluating these competencies. Respondents reported that the biggest barrier to evaluation was limited contact (86%; 48 of 56), and a significant amount of feedback was given verbally rather than on written evaluations. CONCLUSIONS: Nonphysician staff members agree it is important to evaluate residents, and they are most comfortable providing feedback on professional behaviors. A significant amount of feedback is provided verbally but not necessarily captured in a formal written evaluation process. PMID- 24404230 TI - Impact of an anesthesiology rotation on subsequent endotracheal intubation success. AB - BACKGROUND: Endotracheal intubation (ETI) is an essential skill that emergency medicine residents learn throughout their training. OBJECTIVE: To evaluate the effect of implementing a postgraduate year (PGY)-1 anesthesiology rotation on ETI success in the emergency department during PGY-2. METHODS: Residents in the study group completed a 4-week PGY-1 anesthesiology rotation. During the first 6 months of PGY-2, we compared ETI performance of the study group with a control group who did not experience a PGY-1 anesthesiology rotation. Data recorded included date, level of training, first- and second-attempt success, rescue devices used, major adverse events, and intubation scenario. A Pearson chi(2) test was used to compare first-attempt success, overall success (<=2 attempts), and adverse events rates between the 2 groups. RESULTS: Overall success rate for the study groups was 95.7% (111 of 116), compared with 94.5% (137 of 145) for the controls (P = 66). First-attempt success for the study group was 78.4% (91 of 116), compared with 83.4% (121 of 145) for the control group; this was not statistically significant (P = .30). Observed major and minor adverse events were similar: 19.0% for the study group (22 of 116) versus 24.8% (36 of 145) for the control group (P = .26). CONCLUSIONS: The addition of an anesthesiology rotation to the PGY-1 curriculum did not have a significant effect on ETI success or the rate of adverse events during the first 6 months of PGY-2. First-attempt overall success and adverse events of our PGY-2 study group were consistent with previously published studies. PMID- 24404231 TI - Optimizing the implementation of practice improvement modules in training: lessons from educators. AB - BACKGROUND: The American Board of Internal Medicine approved the use of Practice Improvement Modules (PIMs) to help training programs teach and assess practice based learning and improvement (PBLI) and systems-based practice (SBP). METHODS: We surveyed individuals who ordered a PIM in a residency or fellowship training program between June 2006 and August 2009. The 43 programs that volunteered to participate completed a 30-minute anonymous online survey. RESULTS: Program directors or associate program directors led the PIM process in 30 programs (70%). Trainees' degrees of involvement in PIMs were highly variable between programs, and several respondents felt that trainees were either not sufficiently engaged or not engaged with enough consistency. The most common activity for trainee involvement was data collection through patient surveys or chart review, although only 17 programs (40%) provided protected time for this activity. Few trainees participated in higher level activities such as data analysis or identification for areas of improvement or were given leadership roles; yet most respondents reported that completing the PIM helped trainees learn basic principles of QI and develop competence in PBLI and SBP and that PIM completion improved the program's ability to develop QI initiatives and resulted in program or institutional improvements, including sustainable improvement in patient care. Most respondents reported that the outcome warranted the effort to complete PIMs. CONCLUSIONS: PIMs may be a valuable but underused educational experience for trainees as well as training programs. Focusing on particular themes and facets of PIMs may facilitate implementation. PMID- 24404232 TI - Pediatrics Residents' Perspectives on Family-Centered Rounds: A Qualitative Study at 2 Children's Hospitals. AB - BACKGROUND: Many academic hospitals have incorporated family-centered rounds, yet little is known about pediatrics residents' perspectives on the educational impact of these rounds. OBJECTIVE: To identify pediatrics residents' knowledge, attitudes, and beliefs about family-centered rounds, including perceived benefits and barriers. METHODS: We conducted focus groups of residents exposed to family centered rounds at 2 university-affiliated, freestanding children's hospitals. Focus group data were analyzed using grounded theory. RESULTS: A total of 24 residents participated in 4 focus groups. Residents reported that family-centered rounds enhance education by increasing patient encounters and improving physical exam skills, direct observation, real-time feedback, and attending role modeling; improve parent satisfaction, interpersonal and communication skills, and safety; and reduce length of stay. Physical constraints (large teams and small rooms), lack of uniform approaches to family-centered rounds, variable attending teaching styles, and specific conditions (child abuse, patients on isolation) were cited barriers. CONCLUSIONS: Pediatrics residents report that well-conducted family centered rounds improve their education and the quality of patient care, including parent satisfaction, communication with families, and patients' length of stay. Standardizing family-centered rounds and reducing attending variability in teaching style might further enhance residents' educational experiences. PMID- 24404233 TI - Assessing the utility of procedural training for pediatrics residents in general pediatric practice. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) recommends that residents gain broad procedural competence in pediatrics training. There is little recent information regarding practice patterns after graduation. OBJECTIVE: We analyzed reported procedures performed in actual practice by graduates of a general pediatrics residency program. METHODS: We conducted an online survey from April 2007 to April 2011 of graduates of a single pediatrics program from a large children's hospital. Eligible participants completed general pediatrics residency training between 1992 and 2006. Graduates were asked about the adequacy of their training for each procedure, as well as the frequency of commonly performed procedures in their practice. As the primary analysis, procedures were divided into emergent and urgent procedures. RESULTS: Our response rate was 54% (209 of 387). General pediatricians rarely performed emergent procedures, such as endotracheal intubation, intraosseous line placement, thoracostomy, and thoracentesis. Instead, they more commonly performed urgent procedures, such as laceration repair, fracture or dislocation care, bladder catheterization, foreign body removal, and incision and drainage of simple abscesses. Statistically significant differences existed between emergent and urgent procedures (P < .001). CONCLUSIONS: In a single, large, urban, pediatrics residency, 15 years of graduates who practiced general pediatrics after graduation reported they rarely performed emergent procedures, such as endotracheal intubation, but more often performed urgent procedures, such as laceration repair. These results may have implications for ACGME recommendations regarding the amount and type of procedural training required for general pediatrics residents. PMID- 24404234 TI - Current Practice in End-of-Residency Handoffs: A Survey of Internal Medicine Pediatrics Program Directors. AB - BACKGROUND: End-of-residency outpatient handoffs affect at least 1 million patients per year, yet there is no consensus on best practices. OBJECTIVE: To explore the use of formal systems for end-of-residency clinic handoffs in internal medicine-pediatrics residency (Med-Peds) programs, and their associated categorical internal medicine and pediatrics programs. METHODS: We surveyed Med Peds program directors about their programs' system for handing off ambulatory continuity patients. RESULTS: Our response rate was 85% (67 of 79 programs). Thirty-one programs (46%) reported having a system for end-of-residency handoffs. Of the 30 that offered detailed information, 22 (73%) formally introduced the program to residents, 12 (40%) standardized the handoff, and 14 (47%) used multiple methods for information exchange, with the electronic health record and oral transfer of information (15 of 30, 50%) the most common. Six programs (20%) indicated they did not offer residents protected time to complete end-of residency handoffs, and 13 programs (43%) did not identify a specific postgraduate year level for residents to whom patients were handed off. Programs were more likely to have a system for end-of-residency handoffs if another categorical program at their institution also had one (P < .001). CONCLUSIONS: Fewer than half of responding Med-Peds programs have outpatient handoff systems in place. Inclusion of end-of-residency handoff information in the electronic health record may represent a best practice that has the potential of enhancing continuity and safety of care for patients in resident continuity clinics. PMID- 24404235 TI - Educational milestone development in the first 7 specialties to enter the next accreditation system. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) Outcome Project introduced 6 general competencies relevant to medical practice but fell short of its goal to create a robust assessment system that would allow program accreditation based on outcomes. In response, the ACGME, the specialty boards, and other stakeholders collaborated to develop educational milestones, observable steps in residents' professional development that describe progress from entry to graduation and beyond. OBJECTIVES: We summarize the development of the milestones, focusing on 7 specialties, moving to the next accreditation system in July 2013, and offer evidence of their validity. METHODS: Specialty workgroups with broad representation used a 5-level developmental framework and incorporated information from literature reviews, specialty curricula, dialogue with constituents, and pilot testing. RESULTS: The workgroups produced richly diverse sets of milestones that reflect the community's consideration of attributes of competence relevant to practice in the given specialty. Both their development process and the milestones themselves establish a validity argument, when contemporary views of validity for complex performance assessment are used. CONCLUSIONS: Initial evidence for validity emerges from the development processes and the resulting milestones. Further advancing a validity argument will require research on the use of milestone data in resident assessment and program accreditation. PMID- 24404237 TI - Entrustable professional activities in family medicine. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education Outcome Project intended to move residency education toward assessing and documenting resident competence in 6 dimensions of performance important to the practice of medicine. Although the project defined a set of general attributes of a good physician, it did not define the actual activities that a competent physician performs in practice in the given specialty. These descriptions have been called entrustable professional activities (EPAs). OBJECTIVE: We sought to develop a list of EPAs for ambulatory practice in family medicine to guide curriculum development and resident assessment. METHODS: We developed an initial list of EPAs over the course of 3 years, and we refined it further by obtaining the opinion of experts using a Delphi Process. The experts participating in this study were recruited from 2 groups of family medicine leaders: organizers and participants in the Preparing the Personal Physician for Practice initiative, and members of the Society of Teachers of Family Medicine Task Force on Competency Assessment. The experts participated in 2 rounds of anonymous, Internet-based surveys. RESULTS: A total of 22 experts participated, and 21 experts participated in both rounds of the Delphi Process. The Delphi Process reduced the number of competency areas from 91 to 76 areas, with 3 additional competency areas added in round 1. CONCLUSIONS: This list of EPAs developed through our Delphi process can be used as a starting point for family medicine residency programs interested in moving toward a competency-based approach to resident education and assessment. PMID- 24404236 TI - Fatigue optimization scheduling in graduate medical education: reducing fatigue and improving patient safety. AB - BACKGROUND: Medical error is a major cause of preventable morbidity and mortality. Resident fatigue is likely to be a significant contributor. OBJECTIVES: We calculated and compared predicted fatigue impairment in surgical residents on varying schedules by using the validated Sleep, Activity, Fatigue, and Task Effectiveness model and Fatigue Avoidance Scheduling Tool; we identified specific times of day and rotations during which residents were most affected, instituted countermeasures, and measured the predicted response. METHODS: We compared 4 scheduling patterns: day shift, trauma shift, night shift, and prework hour restriction Q3 call (or every-third-night call). The dependent variables were mean daily effectiveness while at work and the percentage of time residents worked with critical fatigue impairment (defined as an effectiveness score of less than 70 correlated with an increased risk for error and a blood alcohol content of 0.08). Fatigue countermeasures (ie, a 30-minute nap, eliminating 24 hour shifts) were applied to rotations with significant impairment to determine impairment plasticity. RESULTS: CALCULATED MEAN EFFECTIVENESS SCORES AND PERCENTAGE OF TIME SPENT IMPAIRED AT WORK WERE AS FOLLOWS: day shift, 90.3, 0%; trauma shift, 82.0, 7.5%; prework hour restriction Q3 call shift, 80.7, 23%; and night shift, 68.0, 50% (P < .001). Fatigue optimization countermeasures for night shift rotation improved mean daily effectiveness to 87.1 with only 1.9% of time working while impaired (P < .001). CONCLUSIONS: There is a significant potential for fatigue impairment in residents, with work schedule a significant factor. Once targeted, fatigue impairment may be minimized with specific countermeasures. Fatigue optimization tools provide data for targeted scheduling interventions, which reduce fatigue and may mitigate medical error. PMID- 24404238 TI - An experiential community orientation to improve knowledge and assess resident attitudes toward poor patients. AB - BACKGROUND: Future physicians may not be prepared for the challenges of caring for the growing population of poor patients in this country. Given the potential for a socioeconomic "gulf" between physicians and patients and the lack of curricula that address the specific needs of poor patients, resident knowledge about caring for this underserved population is low. INTERVENTION: We created a 2 day Resident Academy orientation, before the start of residency training, to improve community knowledge and address resident attitudes toward poor patients through team-based experiential activities. We collected demographic and satisfaction data through anonymous presurvey and postsurvey t tests, and descriptive analysis of the quantitative data were conducted. Qualitative comments from open-ended questions were reviewed, coded, and divided into themes. We also offer information on the cost and replicability of the Academy. RESULTS: Residents rated most components of the Academy as "very good" or "excellent." Satisfaction scores were higher among residents in primary care training programs than among residents in nonprimary care programs for most Academy elements. Qualitative data demonstrated an overall positive effect on resident knowledge and attitudes about community resource availability for underserved patients, and the challenges of poor patients to access high-quality health care. CONCLUSIONS: The Resident Academy orientation improved knowledge and attitudes of new residents before the start of residency, and residents were satisfied with the experience. The commitment of institutional leaders is essential for success. PMID- 24404239 TI - Preparing Interns for Anesthesiology Residency Training: Development and Assessment of the Successful Transition to Anesthesia Residency Training (START) E-Learning Curriculum. AB - BACKGROUND: The transition from internship to residency training may be a stressful time for interns, particularly if it involves a change among programs or institutions after completing a preliminary year. OBJECTIVE: We explored whether an e-learning curriculum would increase interns' preparedness for the transition to the first year of clinical anesthesiology training and reduce stress by improving confidence and perceived competence in performing professional responsibilities. INTERVENTION: We tested a 10-month e-learning program, Successful Transition to Anesthesia Residency Training (START), as a longitudinal intervention to increase interns' self-perceived preparedness to begin anesthesiology residency training in a prospective, observational study and assessed acceptance and sustainability. After a needs assessment, we administered the START modules to 22 interns, once a month, using an integrated learning management and lecture-capture system. We surveyed interns' self-assessed preparedness to begin anesthesiology residency before and after completing the START modules. Interns from the prior year's class, who did not participate in the online curriculum, served as controls. RESULTS: After participation in the START intervention, self-assessed preparedness to begin residency improved by 72% (P = .02). Interns also felt more connected to, and had improved positive feelings toward, their new residency program and institution. CONCLUSION: Participation in our novel 10-month e-learning curriculum and virtual mentorship program improved interns' impression of their residency program and significantly increased interns' subjective assessment of their preparedness to begin anesthesiology residency. This e-learning concept could be more broadly applied and useful to other residency programs. PMID- 24404240 TI - Operationalizing the internal medicine milestones-an early status report. AB - BACKGROUND: The internal medicine milestones were developed to advance outcomes based residency training and will play an important role in the next accreditation system. INNOVATION: As an element of our program's participation in the internal medicine educational innovations project, we implemented a milestones-based evaluation process in our general medicine and pulmonary critical care rotations on July 1, 2010. MEASURES: Outcomes assessed included survey-rated acceptability to participating faculty, residents, and clinical competency committee members. RESULTS: Faculty and residents agreed that the milestones promoted a common understanding of what knowledge, skills, and attitudes should be displayed at particular points in residents' professional development and enhanced evaluators' ability to provide specific performance feedback. Most residents and faculty members agreed that the milestones promoted fairness and uniformity in the evaluation process. Clinical competency committee members agreed the milestones improved the quality of information available for deliberations and resulted in more uniform promotion standards. Faculty rated the use of too many milestones per form/tool at a mean of 7.3 (where 1 was minimally problematic, and 10 was maximally problematic) and the potential for evaluator fatigue (mean, 8.2) as the most significant challenges to the use of milestones. Eight of 12 faculty members would recommend milestones in other programs; 4 were uncertain. CONCLUSIONS: Despite logistical challenges, educators and trainees found that milestones promoted a common understanding of what knowledge, skills and attitudes should be displayed at particular stages of training; permitted greater specificity in performance feedback; and enhanced uniformity and fairness in promotion decisions. PMID- 24404241 TI - Education and training of referring physicians decreases at-home call demand. AB - BACKGROUND: Excessive, sometimes unnecessary consultation challenges the ophthalmology resident's ability to obtain adequate rest and personal time while taking at-home calls. Basic training of nonophthalmologists in assessing and treating common ophthalmic emergencies offers a potential solution to this problem by providing primary caregivers the knowledge base, tools, and confidence to manage them independently. OBJECTIVE: We measured ophthalmic consultation requests at a large teaching institution and the impact of an educational intervention on the number and type of requests. METHODS: During a 31-day period in 2009 all requests for urgent ophthalmic consultation were logged and characterized by reason, urgency, and source of the call. A 3-part educational intervention was targeted to residents and attending physicians in the departments of emergency medicine (half-day lecture and practice), anesthesiology (grand rounds lecture), and otolaryngology (guidelines for traumatic orbital fractures). Six months later we conducted a 26-day call log to evaluate the impact. RESULTS: Pre intervention, we received 63 total and 56 after-hours calls for urgent ophthalmic consultation as compared to 39 total and 35 after-hours calls post intervention. Ophthalmology residents reported seeing more urgent and fewer nonessential consultations in the postintervention period, and there was greater agreement between calling physicians' initial diagnosis and consulting physicians' final diagnosis. No adverse patient outcomes occurred as a result of the change in practices. CONCLUSION: Basic education of nonophthalmologists in ophthalmic diagnostic and treatment concepts, through relatively brief educational interventions, was associated with a decrease in total consultation requests and more appropriate consultations in this pilot study at a single institution. PMID- 24404242 TI - Pilot Study of iPad Incorporation Into Graduate Medical Education. AB - BACKGROUND: Increased documentation and charting requirements are challenging for residents, given duty hour limits. Use of mobile electronic devices may help residents complete these tasks efficiently. OBJECTIVE: To collect initial data on usage rates, information technology (IT) support requirements, and resident use of iPads during training. METHODS: In this pilot study, we provided 12 residents/fellows from various specialties at the University of Virginia with an iPad with IT support. The system used a virtual private network with access to the institution's electronic health record. Participants were allowed to develop their own methods and systems for personalized iPad use, and after 9 months they provided data on the utility of the iPad. Feedback from the IT team also was obtained. RESULTS: Average iPad use was 2.1 h/d (range, 0.5-6 h/d). The average self-reported reduction in administrative work due to the iPad was 2.7 h/wk (range, 0-9 h/wk). A total of 75% (9 of 12) of the users would recommend universal adoption among residents and fellows. More than 90% (11 of 12) of users reported the iPad would improve communication for coordination of care. A total of 68% (8 of 12) of users reported that an iPad facilitated their activities as educators of medical students and junior residents. Residents cited slow data entry into the electronic health record and hospital areas lacking Wi-Fi connectivity as potential drawbacks to iPad use. The IT team reported minimal support time for device setup, maintenance, and upgrades, and limited security risks. CONCLUSIONS: The iPad may contribute to increased clinical efficiency, reduced hours spent on administrative tasks, and enhanced educational opportunities for residents, with minimal IT support. PMID- 24404243 TI - Effect of a multidisciplinary-assisted resident diabetes clinic on resident knowledge and patient outcomes. AB - BACKGROUND: Despite the rising prevalence of diabetes, there is a paucity of diabetes curricula in residency training. The multidisciplinary diabetes team approach is underused in residency education. OBJECTIVE: To assess the feasibility of an innovative multidisciplinary resident diabetes clinic (MRDC) in enhancing (1) resident diabetes knowledge via a Diabetes Awareness Questionnaire, and (2) subsequent process and patient outcomes in patients with diabetes via a Diabetes Practice Behavior Checklist. METHODS: From October 2008 to February 2010, 14 internal medicine residents managed patients with uncontrolled diabetes in a weekly half-day MRDC for 1 month (total 4-5 half-day sessions/resident), with a collaborative team of internists, diabetes educators, an endocrinologist, and a pharmacist. The curriculum included didactic sessions, required readings, and patient-specific case discussions. A 20-question Diabetes Awareness Questionnaire was administered to each resident prerotation and postrotation. Records of 47 patients with diabetes in the residents' own continuity clinics (not the MRDC) were audited 6 months before and after the MRDC for Diabetes Practice Behavior Checklist measures (glycated hemoglobin, blood pressure, low density lipoprotein cholesterol, retinal referral, foot exam, microalbumin screen). Pre-MRDC and post-MRDC data were compared via paired t test. RESULTS: The MRDC residents exhibited a modest increase in mean (SD) scores on the Diabetes Awareness Questionnaire (before, 8.2 [2.8]; after, 10.9 [2.8]; P = .02) and a modest mean (SD) performance increase in overall process outcomes from the Diabetes Practice Behavior Checklist (before, 74% [18%]; after, 84% [18%]; P = .004). No improvements occurred in patient outcomes. CONCLUSIONS: Multidisciplinary diabetes teaching may be useful in fostering certain resident knowledge and performance measures but may not alter clinical outcomes. Further large-scale, longitudinal studies are needed to understand the effect of our curriculum on residents' diabetes knowledge and future practice behavior. PMID- 24404244 TI - Brief educational intervention improves content of intern handovers. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education requires residency programs to ensure safe patient handovers and to document resident competency in handover communication, yet there are few evidence-based curricula teaching resident handover skills. OBJECTIVE: We assessed the immediate and sustained impact of a brief educational intervention on pediatrics intern handover skills. METHODS: Interns at a freestanding children's hospital participated in an intervention that included a 1-hour educational workshop on components of high-quality handovers, as well as implementation of a standardized handover format. The format, SAFETIPS, includes patient information, current diagnosis and assessment, patient acuity, a focused plan, a baseline exam, a to do list, anticipatory guidance, and potential pointers and pitfalls. Important communication behaviors, such as paraphrasing key information, were addressed. Quality of intern handovers was evaluated using a simulated encounter 2 weeks before, 2 weeks after, and 7 months after the workshop. Two trained, blinded, independent observers scored the videotaped encounters. RESULTS: All 27 interns rotating at the Children's Hospital consented to participate in the study, and 20 attended the workshop. We included all participant data in the analysis, regardless of workshop attendance. Following the intervention, intern reporting of patient acuity improved from 13% to 92% (P < .001), and gains were maintained 7 months later. Rates of key communication behaviors, such as paraphrasing critical information, did not improve. CONCLUSIONS: A brief educational workshop promoting standardized handovers improved the inclusion of essential information during intern handovers, and these improvements were sustained over time. The intervention did not improve key communication behaviors. PMID- 24404245 TI - Workshop preparation and presentation: a valuable form of scholarship for the clinician-educator. PMID- 24404246 TI - Nuts and bolts of entrustable professional activities. PMID- 24404247 TI - SUPERB Safety: Improving Supervision for Medical Specialty Residents. PMID- 24404248 TI - Rise of the Cyborgs: Residents With Smartphones, iPads, and Androids. PMID- 24404249 TI - Poverty, health, and graduate medical education. PMID- 24404250 TI - Skill Retention After Simulation-based Education. PMID- 24404251 TI - Inclination to hate. PMID- 24404253 TI - Top reviewers 2012. PMID- 24404252 TI - Improving site visit reports for high-performing residency programs without citations. PMID- 24404254 TI - It's Not All in Your Head: Viewing Graduate Medical Education Through the Lens of Situated Cognition. PMID- 24404255 TI - How do you define high-quality education research? PMID- 24404256 TI - Turned off and burned out: what will it take for "front-line" medicine to tune back in? PMID- 24404257 TI - Training Tomorrow's Comprehensive Primary Care Internists: A Way Forward for Internal Medicine Education. PMID- 24404258 TI - Length of training debate in family medicine: idealism versus realism? AB - How long a resident must train to achieve competency is an ongoing debate in medicine. For family medicine, there is an Accreditation Council for Graduate Medical Education (ACGME)-approved proposal to examine the benefits of lengthening family medicine training from 3 to 4 years. The rationale for adding another year of residency in family medicine has included the following: (1) overcoming the effect of the duty hour limits in further reducing educational opportunities, (2) reversing the growing number of first-time takers of the American Board of Family Medicine primary board who fail to pass the exam, (3) enhancing the family medicine training experience by "decompressing" the ever growing number of Residency Review Committee requirements to maintain accreditation, and (4) improving the overall quality of family medicine graduates. PMID- 24404259 TI - Restructuring graduate medical education to meet the health care needs of emirati citizens. AB - Many nations are struggling with the design, implementation, and ongoing improvement of health care systems to meet the needs of their citizens. In the United Arab Emirates, a small nation with vast wealth, the lives of average citizens have evolved from a harsh, nomadic existence to enjoyment of the comforts of modern life. Substantial progress has been made in the provision of education, housing, health, employment, and other forms of social advancement. Having covered these basic needs, the government of Abu Dhabi, United Arab Emirates, is responding to the challenge of developing a comprehensive health system to serve the needs of its citizens, including restructuring the nation's graduate medical education (GME) system. We describe how Abu Dhabi is establishing GME policies and infrastructure to develop and support a comprehensive health care system, while also being responsive to population health needs. We review recent progress in developing a systematic approach for developing GME infrastructure in this small emirate, and discuss how the process of designing a GME system to meet the needs of Emirati citizens has benefited from the experience of "Western" nations. We also examine the challenges we encountered in this process and the solutions adopted, adapted, or specifically developed to meet local needs. We conclude by highlighting how our experience "at the GME drawing board" reflects the challenges encountered by scholars, administrators, and policymakers in nations around the world as they seek to coordinate health care and GME resources to ensure care for populations. PMID- 24404260 TI - A more ambitious agenda for medical education research. PMID- 24404261 TI - Update in internal medicine residency education: a review of the literature in 2010 and 2011. AB - BACKGROUND: Evidence-based practice in education requires high-quality evidence, and many in the medical education community have called for an improvement in the methodological quality of education research. OBJECTIVE: Our aim was to use a valid measure of medical education research quality to highlight the methodological quality of research publications and provide an overview of the recent internal medicine (IM) residency literature. METHODS: We searched MEDLINE and PreMEDLINE to identify English-language articles published in the United States and Canada between January 1, 2010, and December 31, 2011, focusing on IM residency education. Study quality was assessed using the Medical Education Research Study Quality Instrument (MERSQI), which has demonstrated reliability and validity. Qualitative articles were excluded. Articles were ranked by quality score, and the top 25% were examined for common themes, and 2 articles within each theme were selected for in-depth presentation. RESULTS: The search identified 731 abstracts of which 223 articles met our inclusion criteria. The mean (+/-SD) MERSQI score of the 223 studies included in the review was 11.07 (+/ 2.48). Quality scores were highest for data analysis (2.70) and lowest for study design (1.41) and validity (1.29). The themes identified included resident well being, duty hours and resident workload, career decisions and gender, simulation medicine, and patient-centered outcomes. CONCLUSIONS: Our review provides an overview of the IM medical education literature for 2010-2011, highlighting 5 themes of interest to the medical education community. Study design and validity are 2 areas where improvements in methodological quality are needed, and authors should consider these when designing research protocols. PMID- 24404262 TI - A review of the medical education literature for graduate medical education teachers. AB - BACKGROUND: A rapidly evolving body of literature in medical education can impact the practice of clinical educators in graduate medical education. OBJECTIVE: To aggregate studies published in the medical education literature in 2011 to provide teachers in general internal medicine with an overview of the current, relevant medical education literature. REVIEW: We systematically searched major medical education journals and the general clinical literature for medical education studies with sound design and relevance to the educational practice of graduate medical education teachers. We chose 12 studies, grouped into themes, using a consensus method, and critiqued these studies. RESULTS: Four themes emerged. They encompass (1) learner assessment, (2) duty hour limits and teaching in the inpatient setting, (3) innovations in teaching, and (4) learner distress. With each article we also present recommendations for how readers may use them as resources to update their clinical teaching. While we sought to identify the studies with the highest quality and greatest relevance to educators, limitation of the studies selected include their single-site and small sample nature, and the frequent lack of objective measures of outcomes. These limitations are shared with the larger body of medical education literature. CONCLUSIONS: The themes and the recommendations for how to incorporate this information into clinical teaching have the potential to inform the educational practice of general internist educators as well as that of teachers in other specialties. PMID- 24404263 TI - Review of influential articles in surgical education: 2002-2012. AB - BACKGROUND: Exploring the trends in surgical education research offers insight into concerns, developments, and questions researchers are exploring that are relevant to teaching and learning in surgical specialties. OBJECTIVE: We conducted a review of the surgical education literature published between 2002 and 2012. The purpose was 2-fold: to provide an overview of the most frequently cited articles in the field of surgical education during the last decade and to describe the study designs and themes featured in these articles. METHODS: Articles were identified through Web of Science by using "surgical education" and "English language" as search terms. Using a feature in Web of Science, we tracked the number of citations of any publication. Of the 800 articles produced by the initial search, we initially selected 23 articles with 45 or more citations, and ultimately chose the 20 articles that were most frequently cited for our analysis. RESULTS: Analysis of the most frequently cited articles published in US journals between the years 2002-2012 identified 7 research themes and presented them in order of frequency with which they appear: use of simulation, issues in student/resident assessment, specialty choice, patient safety, team training, clinical competence assessment, and teaching the clinical sciences, with surgical simulation being the central theme. Researchers primarily used descriptive methods. CONCLUSIONS: Popular themes in surgical education research illuminate the information needs of surgical educators as well as topics of high interest to the surgical community. PMID- 24404264 TI - Cultural competency training requirements in graduate medical education. AB - BACKGROUND: Cultural competency is an important skill that prepares physicians to care for patients from diverse backgrounds. OBJECTIVE: We reviewed Accreditation Council for Graduate Medical Education (ACGME) program requirements and relevant documents from the ACGME website to evaluate competency requirements across specialties. METHODS: The program requirements for each specialty and its subspecialties were reviewed from December 2011 through February 2012. The review focused on the 3 competency domains relevant to culturally competent care: professionalism, interpersonal and communication skills, and patient care. Specialty and subspecialty requirements were assigned a score between 0 and 3 (from least specific to most specific). Given the lack of a standardized cultural competence rating system, the scoring was based on explicit mention of specific keywords. RESULTS: A majority of program requirements fell into the low- or no specificity score (1 or 0). This included 21 core specialties (leading to primary board certification) program requirements (78%) and 101 subspecialty program requirements (79%). For all specialties, cultural competency elements did not gravitate toward any particular competency domain. Four of 5 primary care program requirements (pediatrics, obstetrics-gynecology, family medicine, and psychiatry) acquired the high-specificity score of 3, in comparison to only 1 of 22 specialty care program requirements (physical medicine and rehabilitation). CONCLUSIONS: The degree of specificity, as judged by use of keywords in 3 competency domains, in ACGME requirements regarding cultural competency is highly variable across specialties and subspecialties. Greater specificity in requirements is expected to benefit the acquisition of cultural competency in residents, but this has not been empirically tested. PMID- 24404265 TI - Nature and impact of interruptions on clinical workflow of medical residents in the inpatient setting. AB - BACKGROUND: Medical officers (trainees) in their first to third postgraduate years (PGY-1-3s) work in complex, busy environments, performing tasks that require concentration and application of learned skills. There are frequently competing demands, and being paged is among the most common. OBJECTIVE: We quantified and described the effect of interruptions that paging created on the clinical workflow of PGY-1-3s during ward duties. METHODS: This prospective study was conducted at 2 teaching hospitals in Sydney, Australia. Medical students were recruited as observers to log interruptions of PGY-1-3s' workflow arising from pages from other members of the hospital team. RESULTS: Forty-two pairs consisting of a PGY-1-3 trainee and an observer were recruited, with 24 proceeding to data collection. Nursing was the most frequent source of pages (47%); other medical staff accounted for 16% of pages, allied health for 12%, and others for 24% (with pharmacy the most common). Pages commonly involved direct patient care (46%), followed by medication issues (21%). Tasks interrupted by pages encompassed direct patient care (37%), indirect patient care (15%), and documentation (12%). Only 27% of pages were assessed as appropriate and urgent, while 58% were considered appropriate but not urgent, and 16% were not appropriate. Only 38% of pages were judged to be clinically more important than the task they interrupted. CONCLUSIONS: Pages frequently interrupted direct patient care activities for PGY-1-3 trainees, and a significant proportion of pages were identified as either not requiring immediate attention or not appropriate, resulting in potentially avoidable interruptions to clinical workflow. Alternate means of alerting trainees to nonurgent tasks may reduce interruptions and facilitate patient care. PMID- 24404266 TI - Enablers of and barriers to abortion training. AB - BACKGROUND: Since the legalization of abortion services in the United States, provision of abortions has remained a controversial issue of high political interest. Routine abortion training is not offered at all obstetrics and gynecology (Ob-Gyn) training programs, despite a specific training requirement by the Accreditation Council for Graduate Medical Education. Previous studies that described Ob-Gyn programs with routine abortion training either examined associations by using national surveys of program directors or described the experience of a single program. OBJECTIVE: We set out to identify enablers of and barriers to Ob-Gyn abortion training in the context of a New York City political initiative, in order to better understand how to improve abortion training at other sites. METHODS: We conducted in-depth qualitative interviews with 22 stakeholders from 7 New York City public hospitals and focus group interviews with 62 current residents at 6 sites. RESULTS: Enablers of abortion training included program location, high-capacity services, faculty commitment to abortion training, external programmatic support, and resident interest. Barriers to abortion training included lack of leadership continuity, leadership conflict, lack of second-trimester abortion services, difficulty obtaining mifepristone, optional rather than routine training, and antiabortion values of hospital personnel. CONCLUSIONS: Supportive leadership, faculty commitment, and external programmatic support appear to be key elements for establishing routine abortion training at Ob-Gyn residency training programs. PMID- 24404267 TI - Training at a faith-based institution matters for obstetrics and gynecology residents: results from a regional survey. AB - BACKGROUND: Prior data suggest that opportunities in family planning training may be limited during obstetrics and gynecology (Ob-Gyn) residency training, particularly at faith-based institutions with moral and ethical constraints, although this aspect of the Ob-Gyn curriculum has not been formally studied to date. OBJECTIVES: We compared Ob-Gyn residents' self-rated competency and intentions to provide family planning procedures at faith-based versus those of residents at non-faith-based programs. METHODS: We surveyed residents at all 20 Ob-Gyn programs in Illinois, Indiana, Iowa, and Wisconsin from 2008 to 2009. Residents were queried about current skills and future plans to perform family planning procedures. We examined associations based on program and residents' personal characteristics and performed multivariable logistic regression analysis. RESULTS: A total of 232 of 340 residents (68%) from 17 programs (85%) returned surveys. Seven programs were faith-based. Residents from non-faith-based programs were more likely to be completely satisfied with family planning training (odds ratio [OR] = 3.4, 95% confidence limit [CI], 1.9-6.2) and to report they "understand and can perform on own" most procedures. Most residents, regardless of program type, planned to provide all surveyed family planning services. CONCLUSIONS: Despite similar intentions to provide family planning procedures after graduation, residents at faith-based training programs were less satisfied with their family planning training and rate their ability to perform family planning services lower than residents at non-faith-based training programs. PMID- 24404268 TI - Validation of an Evidence-Based Medicine Critically Appraised Topic Presentation Evaluation Tool (EBM C-PET). AB - BACKGROUND: Competence in evidence-based medicine (EBM) is an important clinical skill. Pediatrics residents are expected to acquire competence in EBM during their education, yet few validated tools exist to assess residents' EBM skills. OBJECTIVE: We sought to develop a reliable tool to evaluate residents' EBM skills in the critical appraisal of a research article, the development of a written EBM critically appraised topic (CAT) synopsis, and a presentation of the findings to colleagues. METHODS: Instrument development used a modified Delphi technique. We defined the skills to be assessed while reviewing (1) a written CAT synopsis and (2) a resident's EBM presentation. We defined skill levels for each item using the Dreyfus and Dreyfus model of skill development and created behavioral anchors using a frame-of-reference training technique to describe performance for each skill level. We evaluated the assessment instrument's psychometric properties, including internal consistency and interrater reliability. RESULTS: The EBM Critically Appraised Topic Presentation Evaluation Tool (EBM C-PET) is composed of 14 items that assess residents' EBM and global presentation skills. Resident presentations (N = 27) and the corresponding written CAT synopses were evaluated using the EBM C-PET. The EBM C-PET had excellent internal consistency (Cronbach alpha = 0.94). Intraclass correlation coefficients were used to assess interrater reliability. Intraclass correlation coefficients for individual items ranged from 0.31 to 0.74; the average intraclass correlation coefficients for the 14 items was 0.67. CONCLUSIONS: We identified essential components of an assessment tool for an EBM CAT synopsis and presentation with excellent internal consistency and a good level of interrater reliability across 3 different institutions. The EBM C-PET is a reliable tool to document resident competence in higher-level EBM skills. PMID- 24404269 TI - Burnout, coping, and spirituality among internal medicine resident physicians. AB - BACKGROUND: Burnout in physicians is common, and studies show a prevalence of 30% to 78%. Identifying constructive coping strategies and personal characteristics that protect residents against burnout may be helpful for reducing errors and improving physician satisfaction. OBJECTIVE: We explored the complex relationships between burnout, behaviors, emotional coping, and spirituality among internal medicine and internal medicine-pediatrics residents. METHODS: We anonymously surveyed 173 internal medicine and medicine-pediatrics residents to explore burnout, coping, and spiritual attitudes. We used 3 validated survey instruments: the Maslach Burnout Inventory, the Carver Coping Orientation to Problems Experienced (COPE) Inventory, and the Hatch Spiritual Involvement and Beliefs Scale (SIBS). RESULTS: A total of 108 (63%) residents participated, with 31 (28%) reporting burnout. Residents who employed strategies of acceptance, active coping, and positive reframing had lower emotional exhaustion and depersonalization (all, P < .03). Residents who reported denial or disengagement had higher emotional exhaustion and depersonalization scores. Personal accomplishment was positively correlated with the SIBS total score (r = +.28, P = .003), as well as the internal/fluid domain (r = +.32, P = .001), existential axes (r = +.32, P = .001), and humility/personal application domain (r = +.23, P = .02). The humility/personal application domain also was negatively correlated with emotional exhaustion (r = -.20, P = .04) and depersonalization (r = -.25, P = .009). No activity or demographic factor affected any burnout domain. CONCLUSIONS: Burnout is a heterogeneous syndrome that affects many residents. We identified a range of emotional and spiritual coping strategies that may have protective benefit. PMID- 24404270 TI - Relationship between performance on child and adolescent psychiatry in-training and certification examinations. AB - BACKGROUND: Studies across a range of specialties have consistently yielded positive associations between performance on in-training examinations and board certification examinations, supporting the use of the in-training examination as a valuable formative feedback tool for residents and residency programs. That association to date, however, has not been tested in child and adolescent psychiatry residents. OBJECTIVE: This is the first study to explore the relationship between performance on the American College of Psychiatrists' Child Psychiatry Resident In-Training Examination (CHILD PRITE) and subsequent performance on the American Board of Psychiatry and Neurology's (ABPN) subspecialty multiple-choice examination (Part I) in child and adolescent psychiatry (CAP). METHODS: Pearson correlation coefficients were used to examine the relationship between performance on the CHILD PRITE and the CAP Part I examination for 342 fellows. RESULTS: Second-year CAP fellows performed significantly better on the CHILD PRITE than did the first-year fellows. The correlation between the CHILD PRITE total score and the CAP Part I examination total score was .41 (P = .01) for first-year CAP fellows; it was .52 (P = .01) for second-year CAP fellows. CONCLUSIONS: The significant correlations between scores on the 2 tests show they assess the same achievement domain. This supports the use of the CHILD PRITE as a valid measure of medical knowledge and formative feedback tool in child and adolescent psychiatry. PMID- 24404271 TI - Attrition rates between residents in obstetrics and gynecology and other clinical specialties, 2000-2009. AB - BACKGROUND: As resident attrition disrupts educational and workload balance and reduces the number of graduating physicians to care for patients, an ongoing goal of graduate medical education programs is to retain residents. OBJECTIVE: We compared annual rates of resident attrition in obstetrics and gynecology (Ob-Gyn) with other clinical specialties of similar or larger size during a recent 10-year period, and explored the reasons for resident attrition. METHODS: In this observational study, we analyzed annual data from the American Medical Association Graduate Medical Education Census between academic years 2000 and 2009 for residents who entered Ob-Gyn and other core clinical specialties. Our primary outcome was the trend in averaged annual attrition rates. RESULTS: The average annual attrition was 196 +/- 12 (SD) residents, representing 4.2% +/- 0.5% of all Ob-Gyn residents. Rates of attrition were consistently higher among men (5.3%) and international medical school graduates (7.6%). The annual rate of attrition was similar to that for other clinical specialties (mean: 4.0%; range: from 1.5% in emergency medicine to 7.9% in psychiatry). The attrition rates for Ob-Gyn residents were relatively stable for the 10-year period (range: 3.6% in 2008 to 5.1% in 2006). Common reasons for attrition were transition to another specialty (30.0%), withdrawal/dismissal (28.2%), transfer to another Ob-Gyn program (25.4%), and leave of absence (2.2%). These proportions remained fairly constant during this 10-year period. CONCLUSIONS: The average annual attrition rate of residents in Ob-Gyn was 4.2%, comparable to most other core clinical specialties. PMID- 24404272 TI - Statistical literacy of obstetrics-gynecology residents. AB - BACKGROUND: Residents' ability to interpret statistics is important for scholarly pursuits and understanding evidence-based medicine. Yet there is limited research assessing residents' statistical literacy and their training in statistics. METHODS: In 2011 we surveyed US obstetrics-gynecology residents participating in the Council for Resident Education in Obstetrics and Gynecology In-Training Examination about their statistical literacy and statistical literacy training. RESULTS: Our response rate was 95% (4713 of 4961). About two-thirds (2980 of 4713) of the residents rated their statistical literacy training as adequate. Female respondents were more likely to rate their statistical literacy training poorly, with 25% (897 of 3575) indicating inadequate literacy compared with 17% (141 of 806) of the male respondents (P < .001). Respondents performed poorly on 2 statistical literacy questions, with only 26% (1222 of 4713) correctly answering a positive predictive value question and 42% (1989 of 4173) correctly defining a P value. A total of 51% (2391 of 4713) of respondents reported receiving statistical literacy training through a journal club, 29% (1359 of 4713) said they had informal training, 15% (711 of 4713) said that they had statistical literacy training as part of a course, and 11% (527 of 4713) said that they had no training. CONCLUSIONS: The findings suggest that statistical literacy training for residents could still be improved. A total of 37% (1743 of 4713) of obstetrics-gynecology residents have received no formal statistical literacy training in residency. Fewer residents answered the 2 statistical literacy questions correctly compared with previous studies. PMID- 24404273 TI - The relationship between the american board of anesthesiology part 1 certification examination and the United States medical licensing examination. AB - BACKGROUND: The graduate medical education community uses results from the United States Medical Licensing Examination (USMLE) to inform decisions about individuals' readiness for postgraduate training. OBJECTIVE: We sought to determine the relationship between performance on the USMLE and the American Board of Anesthesiology (ABA) Part 1 Certification Examination using a national sample of examinees, and we considered the relationship in the context of undergraduate medical education location and examination content. METHODS: Approximately 7800 individuals met inclusion criteria. The relationships between USMLE scores and ABA Part 1 pass rates were examined, and predictions for the strength of the relationship between USMLE content areas and ABA performance were compared with observed relationships. RESULTS: Pearson correlations between ABA Part 1 scores and USMLE Steps 1, 2 (clinical knowledge), and 3 scores for first taker US/Canadian graduates were .59, .56, and .53, respectively. A clear relationship was demonstrated between USMLE scores and pass rates on ABA Part 1, and content experts were able to successfully predict the USMLE content categories that would least or most likely relate to ABA Part 1 scores. CONCLUSIONS: The analysis provided evidence on a national scale that results from the USMLE and the ABA Part 1 were correlated and that success on the latter examination was associated with level of USMLE performance. Both testing programs have been successful in conceptualizing many of the knowledge areas of interest and in developing test content to reflect those areas. PMID- 24404274 TI - Teaching cost-conscious medicine: impact of a simple educational intervention on appropriate abdominal imaging at a community-based teaching hospital. AB - BACKGROUND: Rising costs pose a major threat to US health care. Residency programs are being asked to teach residents how to provide cost-conscious medical care. METHODS: An educational intervention incorporating the American College of Radiology appropriateness criteria with lectures on cost-consciousness and on the actual hospital charges for abdominal imaging was implemented for residents at Scripps Mercy Hospital in San Diego, CA. We hypothesized that residents would order fewer abdominal imaging examinations for patients with complaints of abdominal pain after the intervention. We analyzed the type and number of abdominal imaging studies completed for patients admitted to the inpatient teaching service with primary abdominal complaints for 18 months before (738 patients) and 12 months following the intervention (632 patients). RESULTS: There was a significant reduction in mean abdominal computed tomography (CT) scans per patient (1.7-1.4 studies per patient, P < .001) and total abdominal radiology studies per patient (3.1-2.7 studies per patient, P = .02) following the intervention. The avoidance of charges solely due to the reduction in abdominal CT scans following the intervention was $129 per patient or $81,528 in total. CONCLUSIONS: A simple educational intervention appeared to change the radiologic test-ordering behavior of internal medicine residents. Widespread adoption of similar interventions by residency programs could result in significant savings for the health care system. PMID- 24404275 TI - Using a learning coach to develop family medicine residents' goal-setting and reflection skills. AB - BACKGROUND: Self-directed learning (SDL) skills, such as self-reflection and goal setting, facilitate learning throughout a physician's career. Yet, residents do not often formally engage in these activities during residency. INTERVENTION: To develop resident SDL skills, we created a learning coach role for a junior faculty member to meet with second-year residents monthly to set learning goals and promote reflection. METHODS: The study was conducted from 2008-2010 at the Brown Family Medicine Residency in Pawtucket, Rhode Island. During individual monthly meetings with the learning coach, residents entered their learning goals and reflections into an electronic portfolio. A mixed-methods evaluation, including coach's ratings of goal setting and reflection, coach's meeting notes, portfolio entries, and resident interviews, was used to assess progress in residents' SDL abilities. RESULTS: Coach ratings of 25 residents' goal-setting ability increased from a mean of 1.9 to 4.6 (P < .001); ratings of reflective capacity increased from a mean of 2.0 to 4.7 (P < .001) during each year. Resident portfolio entries showed a range of domains for goal setting and reflection. Resident interviews demonstrated progressive independence in setting goals and appreciation of the value of reflection for personal development. CONCLUSIONS: Introducing a learning coach, use of a portfolio, and providing protected time for self-reflected learning allowed residents to develop SDL skills at their own pace. The learning coach model may be applicable to other residency programs in developing resident lifelong learning skills. PMID- 24404276 TI - The stanford anesthesia faculty teaching scholars program: summary of faculty development, projects, and outcomes. AB - BACKGROUND: The Stanford Anesthesia Teaching Scholars Program was launched in 2007 to further pedagogic training of faculty and improve residency education. OBJECTIVES: The goals of this article are to describe the program intervention and improvements made based on participant feedback, summarize the characteristics of the faculty enrolled and projects undertaken, and report on program outcomes tracked to date. INTERVENTION: THE TEACHING SCHOLARS PROGRAM HOUSED WITHIN THE DEPARTMENT OF ANESTHESIA SUPPORTS FACULTY IN THESE AREAS: (1) attending education-related meetings; (2) engaging in a monthly seminar on core topics paired with independent study reading; and (3) undertaking a project to improve resident education. Structured interviews with all graduates (n = 19; 47% women) were conducted using a pilot-tested questionnaire. RESULTS: A total of 15 of 19 Scholars (79%) were instructors/assistant professors. Sixteen Scholars (84%) attended an off-site education meeting. The Scholars pursued a variety of projects, including curriculum (53%), teaching (26%), administration (11%), assessment (5%), and advising/mentoring (5%). Projects were fully completed by 13 of 19 participants (68%), and 12 of 19 projects (63%) are currently integrated into the residency. Completed projects were published/presented at conferences by 4 of 13 participants (31%), and education grants were received by 3 of 19 participants (16%). CONCLUSIONS: This is the first description of a faculty development (education) program in an anesthesiology department. The program has been well accepted by participants and resulted in increased educational products, some of which have become a permanent part of the residency curriculum. This educational innovation can be replicated in other departments of anesthesiology provided that funding is available for faculty time and meeting expenses. PMID- 24404277 TI - The writing retreat: a high-yield clinical faculty development opportunity in academic writing. AB - BACKGROUND: The need for consistent academic productivity challenges junior clinician-scholars, who often lack the aptitude to ensure efficient production of manuscripts. INTERVENTION: To solve this problem, an academic division of a major medical center developed an off-site writing retreat. The purpose of the retreat was not to teach writing skills, but to offer senior mentor assistance with a focus on the elements of manuscript writing. METHODS: The retreat paired senior faculty members with junior staff. Senior faculty identified manuscript topics and provided real-time writing and editing supervision. Team-building exercises, midcourse corrections, and debriefing interviews were built into the retreat. The number of manuscripts and grant proposals generated during the 2008-2011 retreats was recorded, and the program was evaluated by using unstructured debriefing interviews. RESULTS: An average of 6 to 7 faculty members and fellows participated in each retreat. During the past 4 years, participants produced an average of 3 grant proposals and 7 manuscripts per retreat. After the writing retreat, each fellow and junior faculty member produced an average of 4 scholarly products per year, compared to fewer than 2 for prior years' retreats. Participant feedback indicated the success of the retreat resulted from protected time, direct mentorship by the scholars involved, and pairing of authors, which allows for rapid production of manuscripts and accelerated the editing process. More than 80% of mentors returned each year to participate. CONCLUSIONS: The writing retreat is a feasible, effective strategy to increase scholarship among faculty, acceptable to mentees and mentors, and sustainable over time. PMID- 24404278 TI - Sustainability and effectiveness of a quality improvement project to improve handoffs to night float residents in an internal medicine residency program. AB - BACKGROUND: Handoff is the process in which patient care is transitioned from one provider to another. In teaching hospitals, handoffs are frequent, and resident duty hour restrictions have increased the use of night float staff. To date, few studies have focused on long-term sustainability and effectiveness of a handoff quality improvement project. OBJECTIVE: The objective of our resident-driven quality improvement project was to evaluate the effectiveness and sustainability of a standardized template for handoff quality in a community hospital internal medicine program. METHODS: We used a multistep continuous quality improvement approach. Problems in the handoff process were identified through process mapping and anonymous needs assessment of the residents. A group of residents and faculty identified problems during biweekly discussions, created a standardized template, and adopted a new handoff process. We audited handoffs and surveyed residents at 3 and 9 months after implementation to assess effectiveness and sustainability. RESULTS: Before the intervention, only 40% of residents reported regular morning handoff. Using the standardized template, statistically significant, sustained improvements were seen in morning handoff frequency (59% preintervention, 90% at 3 months, 89% at 9 months), along with decreases in unreported overnight events (84% preintervention, 58% at 3 months, 50% at 9 months) and uncertainty about decisions because of poor handoffs (72% preintervention, 49% at 3 months, 37% at 9 months). Statistically significant decreases in missed content (69%-46%) and copy-and-paste behavior (78%-38%) at 3 months were not sustained. CONCLUSIONS: We demonstrated sustained improvements in unreported events and uncertainty caused by poor handoffs. Initial improvements in missed content and copy-and-paste behavior that were not sustained suggest a need for ongoing reinforcement and monitoring of handoff quality. PMID- 24404279 TI - Use of a Geriatric Quality Initiative to Educate Internal Medicine Residents about Delirium and Its Risk Factors. AB - BACKGROUND: Delirium is a common and debilitating complication of inpatient care for many older adults, yet internal medicine residents often do not recognize delirium or its risk factors. Integrating geriatric education (eg, delirium recognition) with inpatient quality improvement (QI) is not well tested. METHODS: We developed an educational pilot program within an ongoing hospital-wide geriatric QI initiative (Global Risk Assessment and Careplan for the Elderly Acute Care [GRACE-AC]). GRACE-AC modifies the inpatient computerized provider order entry system to meet the needs of vulnerable older adults and uses a bedside care checklist to identify patients with possible delirium and promote delirium prevention by checking on the need for "tethers" (intravenous fluids, Foley catheters, and telemetry). Residents were assessed before and after each inpatient rotation by using anonymous electronic surveys. RESULTS: A total of 167 eligible residents (91%) completed prerotation surveys, and 102 (56%) residents completed postrotation surveys. All but the first rotating resident group received a standardized 2-minute educational in-service orientation. In a comparison of postrotation responses before and after implementation of the in service, the proportion of residents who reported improvement in their ability to recall which patients had tethers increased from 17% to 52% for intravenous fluids (P = .004), 28% to 75% for Foley catheters (P < .001), and 21% to 50% for telemetry (P = .02). Comparing pre- and postrotation surveys, the proportion of correct responses to questions on haloperidol dosing and the characteristics of delirium increased from 26% to 76% and 31% to 63%, respectively (both P < .001). CONCLUSIONS: Our pilot program demonstrated that inpatient geriatric QI initiatives can be successfully merged with a brief educational curriculum. PMID- 24404280 TI - Financial Implications of Different Interpretations of ACGME Anesthesiology Program Requirements for Rotations in the Operating Room. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) standards for resident education in anesthesiology mandate required rotations including rotations inside the operating room (OR). When residents complete rotations outside the OR, other providers must be used to maintain the OR's clinical productivity. OBJECTIVE: WE QUANTIFIED AND COMPARED THE COSTS OF REPLACING RESIDENTS BY USING TWO DIFFERENT WORKING PATTERNS THAT ARE COMPLIANT WITH THE ACGME ANESTHESIOLOGY PROGRAM REQUIREMENTS: (1) the minimum amount of time in the OR, and (2) working the maximum amount of time permitted in the OR. METHODS: We calculated resident replacement costs over a 36-month residency period in both a minimum and maximum OR time model. We used a range of Certified Registered Nurse Anesthetist (CRNA) pay scales determined by a local market analysis for cost comparisons. RESULTS: Depending on CRNA pay rates, the cost differentials to replace a resident in the OR between the minimum and maximum OR time models ranged from $236,000 to $581,876, assuming a 50-hour resident work week, and $373,400 to $931,001, assuming an 80-hour resident work week. This cost was per resident over the entire 3 years of their residency. CONCLUSIONS: Varying the amount of time residents work in the OR (as allowed under ACGME program requirements) has significant financial implications over a 36-month anesthesiology residency. The larger the residency, the more significant will be the impact on the department and sponsoring institution. PMID- 24404281 TI - Constructing a Novel Simple LEEP Training Model. AB - BACKGROUND: Duty hour restrictions and enhanced focus on patient safety have prompted the development of new instruction models for practice of surgical techniques outside the operating room, including models for teaching loop electrosurgical excisional procedure (LEEP), a common procedure that gynecology residents perform to diagnose and manage cervical disease. OBJECTIVE: We sought to develop an inexpensive and reusable training model for guided practice opportunities that will improve gynecology residents' LEEP technique. METHODS: Polyvinyl chloride, foam, and a polish sausage are used to simulate the basic anatomy of the vagina and cervix. A 2-in-diameter polyvinyl chloride pipe and high-density foam are used to create a realistic representation with the sausage simulating the cervix. An electrosurgical pad is attached to the sausage and a standard operating room electrosurgical generator is used. RESULTS: After a brief lecture and demonstration of the LEEP procedure, gynecology residents are positioned at individual stations. Use of 2 to 3 instructors allows for the provision of directions and feedback to residents as they perform the simulated LEEP. During the last 6 years, this model has continued to improve residents' confidence and skills with the procedure. CONCLUSIONS: An anatomically accurate LEEP model can not only improve resident knowledge, skills, and confidence, but also improve quality and patient safety. This training model allows residents to refine their surgical skills through guided practice and instructors to monitor performance before residents to perform the procedure on patients. PMID- 24404282 TI - PEARLs of Wisdom: Impact of a New Block Conference on Pediatrics Resident Attendance, Satisfaction, and Learning. AB - BACKGROUND: Resident attendance and participation at didactic conferences is often limited owing to time demands. In 2010, University of Wisconsin-Madison pediatrics residency eliminated all noon conferences and implemented a new block format, PEARL (Pediatric Education and Active Resident Learning). OBJECTIVE: The purpose of this study was to assess whether changes in a conference structure improved resident attendance, distractibility, satisfaction, perception of clinical relevance, and connection. METHODS: Pediatrics residents were surveyed to compare experiences in 2 different conference structures: a traditional noon conference and an interactive case-based PEARL conference. Pediatrics residents from the 2008-2010 classes were surveyed about noon conference experiences and 2009-2011 classes were surveyed about PEARL conference experiences. RESULTS: Participants included 32 residents in the 2010 presurvey and 36 in the 2011 postsurvey. All measures of attendance, distractibility, and satisfaction showed positive changes. For example, the average proportion of conferences attended was 73% with noon conferences and 98% with PEARL (P = .001). However, measures of perceived clinical relevance and resident participation did not change significantly. For example, on average 47% of residents reported contributing comments in a noon conference, whereas 56% of residents reported contributing in a block conference (P = .199). CONCLUSIONS: PEARL conference significantly improved resident attendance, lowered distractibility, and improved resident satisfaction. However, these structural changes did not lead to changes in perceived clinical relevance of information learned or resident participation. Further content changes or faculty teaching strategies should be considered. PMID- 24404283 TI - Resident education in free clinics: an internal medicine continuity clinic experience. AB - BACKGROUND: Most internal medicine (IM) residency programs provide ambulatory training in academic medical centers. Community-based ambulatory training has been suggested to improve ambulatory and primary care education. Free clinics offer another potential training setting, but there have been few reports about the experience of IM residents in free clinics. OBJECTIVE: We assessed the feasibility and acceptability of inclusion of an ambulatory rotation in a free clinic and IM residency curriculum and the advantages of the free clinic setting over the traditional ambulatory clinic model. METHODS: In 2010, the University of Chicago Internal Medicine Residency Program partnered with a free clinic in order to establish a community-based continuity clinic experience. To assess the feasibility of this innovation, 16 residents were surveyed 9 months after implementation of the clinic to determine satisfaction, perceived preparation to address common medical conditions, and attitudes toward the underserved care population. A subset of these responses was compared to responses from residents in the traditional clinic model. RESULTS: Residents in the free clinic rotation were more satisfied and perceived they were more prepared to work in low-resource settings and reported similar levels of preparation regarding common outpatient conditions than residents in a traditional continuity clinic format. They reported increased future likelihood of working in an underserved clinic. CONCLUSIONS: Our exploratory study suggests free clinics may be an effective platform for community-based continuity clinic training. PMID- 24404284 TI - Intraoperative assessment of residents. PMID- 24404285 TI - Improving Written Sign-Outs Through Education and Structured Audit: The UPDATED Approach. PMID- 24404286 TI - Interruptions to clinical work: how frequent is too frequent? PMID- 24404287 TI - Statistical illiteracy in residents: what they do not learn today will hurt their patients tomorrow. PMID- 24404288 TI - Scholarly mentorship and publication: an innovative approach for female psychiatry residents. PMID- 24404289 TI - Integrative medicine in residency education: the need to consider costs and returns. PMID- 24404290 TI - Toward a humanistic learning environment: addressing resident mistreatment. PMID- 24404292 TI - Culture Shock: A Canadian Fellow Lands at the VA. PMID- 24404291 TI - A modern day paradox: service versus education. PMID- 24404293 TI - Testing a site visit approach for the next accreditation system. PMID- 24404294 TI - What Do Our Respondents Think We're Asking? Using Cognitive Interviewing to Improve Medical Education Surveys. PMID- 24404295 TI - So you want to write? Practices that work. PMID- 24404296 TI - Patient-centered care or patient data-centered care: a tale of 2 admissions. PMID- 24404297 TI - The case for on-site child care in residency training and afterward. PMID- 24404298 TI - Compliance and falsification of duty hours: reports from residents and program directors. PMID- 24404299 TI - Morning report: can an established medical education tradition be validated? AB - BACKGROUND: Morning report is accepted as an essential component of residency education throughout different parts of the world. OBJECTIVE: To review the evidence of the educational value, purpose, methods, and outcomes of morning report. METHODS: A literature search of PubMed, Ovid, and the Cochrane Library for English-language studies published between January 1, 1966, and October 31, 2011, was performed. We searched for keywords and Medical Subject Heading terms related to medical education, methods, attitudes, and outcomes in regard to "morning report." Title and abstract review, followed by a full-text review by 3 authors, was performed to identify all pertinent articles. RESULTS: We identified 71 citations; 40 articles were original studies and 31 were commentaries, editorials, or review articles; 56 studies (79%) originated from internal medicine residency programs; 6 studies (8%) focused on ambulatory morning report; and 63 (89%) originated from the United States. Identified studies varied in objectives, methods, and outcome measures, and were not suitable for meta analysis. Main outcome measures were resident satisfaction, faculty satisfaction, preparation for professional examinations, use of evidence-based medicine, clinical effects on patient care, adverse event detection, and utilization of a curriculum in case selection. CONCLUSIONS: Morning report has heterogeneous purposes, methods, and settings. As an educational tool, morning report is challenging to define, its outcome is difficult to measure, and this precludes firm conclusions about its contribution to resident education or patient care. Residency programs should tailor morning report to meet their own unique educational objectives and needs. PMID- 24404300 TI - "Best practice" for patient-centered communication: a narrative review. AB - BACKGROUND: Communicating with patients has long been identified as an important physician competency. More recently, there is a growing consensus regarding the components that define physician-patient communication. There continues to be emphasis on both the need to teach and to assess the communication skills of physicians. OBJECTIVE: This narrative review aims to summarize the work that has been conducted in physician-patient communication that supports the efficacy of good communications skills. This work may also help to define the physician patient communication skills that need to be taught and assessed. RESULTS: A review of the literature shows it contains impressive evidence supporting positive associations between physician communication behaviors and positive patient outcomes, such as patient recall, patient understanding, and patient adherence to therapy. There is a consensus about what constitutes "best practice" for physician communication in medical encounters: (1) fostering the relationship, (2) gathering information, (3) providing information, (4) making decisions, (5) responding to emotions, and (6) enabling disease- and treatment related behavior. CONCLUSIONS: Evidence supports the importance of communication skills as a dimension of physician competence. Effort to enhance teaching of communication skills to medical trainees likely will require significant changes in instruction at undergraduate and graduate levels, as well as changes in assessing the developing communication skills of physicians. An added critical dimension is faculty understanding of the importance of communication skills, and their commitment to helping trainees develop those skills. PMID- 24404301 TI - Internal medicine postgraduate training and assessment of patient handoff skills. AB - BACKGROUND: Effective communication during patient care transitions is essential for high-quality patient care. OBJECTIVE: The purpose of this study was (1) to objectively assess patient handoff skills of internal medicine residents, and (2) to evaluate correlations between clinical experience and patient handoff skill self-assessment with directly observed skill. METHODS: We studied simulated patient handoffs in postgraduate year (PGY)-1 and PGY-2 residents between July 2011 and September 2011, using a standardized scenario in an observed structured handoff exam (OSHE). Our design was a posttest-only, with nonequivalent groups. Assessment used a previously published checklist for evaluating handoff skills. Residents were asked about clinical experience with patient handoffs and about their self-confidence in performing a patient handoff independently. We evaluated between-group differences on OSHE checklist performance, patient handoff experience, and self-confidence and used multiple regression analyses to assess the association between performance, experience, and confidence. RESULTS: Forty seven PGY-1 residents and 38 PGY-2 residents completed the study. Interrater reliability was substantial (intraclass correlation = 0.68). There was no significant difference in OSHE performance by PGY-1 residents (mean = 79%, SD = 4.6) and PGY-2 residents (mean = 82%; SD = 7.6; P = .07). The PGY-2 residents were significantly more experienced (P < .001) and confident (P < .001) than PGY-1 residents were, yet clinical experience and self-confidence did not significantly predict OSHE performance. CONCLUSIONS: Clinical experience and self assessment do not predict skills in simulated patient handoffs, and residents with substantial clinical experience still benefit from further skills development. PMID- 24404302 TI - Pediatrics residents' preparedness for neonatal resuscitation assessed using high fidelity simulation. AB - BACKGROUND: Pediatrics residents are expected to demonstrate preparedness for neonatal resuscitation, yet research has shown gaps in residents' readiness to perform this skill. OBJECTIVE: To evaluate procedural skills and team performance of pediatrics residents during neonatal resuscitation (NR) using a high-fidelity mannequin, and to assess residents' confidence in their NR skills before and after training. METHODS: Two teams of residents (all had completed NR program training) participated in 2 separate, 90-minute sessions (2 to 3 weeks apart) in an off-site delivery room during their neonatal intensive care rotation. Residents' confidence in assisting and leading NR was surveyed before each session. Teams participated in a scenario (adapted from the NR program), which required 5 skills (positive pressure ventilation, chest compressions, endotracheal intubation, umbilical vein catheterization, and epinephrine administration). Video recording was used for debriefing and scoring. Skills were scored for technique and timeliness, and team behaviors were scored for communication, management, and leadership. RESULTS: Twenty-six residents (11 teams) completed 2 paired sessions. Self-confidence scores increased between the 2 sessions but were not correlated with performance. Gaps in procedural skill performance were observed, and timeliness for most skills did not meet expectations. Significant improvement in team communication was noted. CONCLUSIONS: Important gaps in procedural skill performance, particularly timeliness, were detected by NR simulation training; residents' improvements in self-confidence did not reflect gains in actual performance. Their relative unpreparedness for NR (despite prior certification) highlights the need for deliberate practice and specific team training before and during neonatal intensive care delivery room rotations. PMID- 24404303 TI - Overweight physicians during residency: a cross-sectional and longitudinal study. AB - BACKGROUND: Resident physicians are at risk for increasing weight status given their changes in environment, resources, and stress level. OBJECTIVE: To describe body mass index (BMI), blood pressure, eating habits, and physical activity during postgraduate training and to compare the findings to data for nationally matched controls. METHODS: This was a combined cross-sectional study and longitudinal cohort, with a comparison to matched controls in 2 academic hospital centers in the eastern and western United States. BMI and blood pressure were objectively measured, and an eating and exercise habits recall was obtained for 375 enrolled medical and surgical residents (93 longitudinally) at the onset of each postgraduate year (PGY) in 2006, 2007, and 2008. RESULTS: Nearly half (43%) of overweight residents described themselves as normal weight. Residents were more likely to be overweight (BMI >=25) at the beginning of PGY-3 than at the beginning of PGY-1 (49% versus 30%; odds ratio 2.26; 95% confidence interval 1.19 4.28). The average BMI of residents at PGY-1 was lower than that of their matched controls, but the magnitude of this difference decreased with increasing PGY (P = .02). CONCLUSIONS: Overweight status is underacknowledged by overweight residents and increases by PGY of training. These changes differ significantly from that of controls and may affect overweight physicians' long-term health. PMID- 24404304 TI - Validation of the colorado psychiatry evidence-based medicine test. AB - BACKGROUND: Evidence-based medicine (EBM) has become an important part of residency education, yet many EBM curricula lack a valid and standardized tool to identify learners' prior knowledge and assess progress. OBJECTIVE: We developed an EBM examination in psychiatry to measure our effectiveness in teaching comprehensive EBM to residents. METHODS: We developed a psychiatry EBM test using the validated EBM Fresno Test of Competence for family medicine. The test consists of case scenarios with open-ended questions. We also developed a scoring rubric and obtained reliability with multiple raters. Fifty-seven residents provided test data after completing 3, 6, 25, or 31 EBM sessions. The number of sessions for each resident was based on their length of training in our program. RESULTS: The examination had strong interrater reliability, internal reliability, and item discrimination. Many residents showed significant improvement on their examination scores when data were compared from tests taken before and after a sequence of teaching sessions. Also, a threshold for the level of expert on the examination was established using test data from 5 EBM teacher-experts. CONCLUSIONS: We successfully developed a valid and reliable EBM examination for use with psychiatry residents to measure essential EBM skills as part of a larger project to encourage EBM practice for residents in routine patient care. The test provides information on residents' knowledge in EBM from entry level concepts through expert performance. It can be used to place incoming residents in appropriate levels of an EBM curriculum and to monitor the effectiveness of EBM instruction. PMID- 24404305 TI - Reporting for duty during mass casualty events: a survey of factors influencing emergency medicine physicians. AB - BACKGROUND: Academic medical centers play a major role in disaster response, and residents frequently serve as key resources in these situations. Studies examining health care professionals' willingness to report for duty in mass casualty situations have varying response rates, and studies of emergency medicine (EM) residents' willingness to report for duty in disaster events and factors that affect these responses are lacking. OBJECTIVE: We sought to determine EM resident and faculty willingness to report for duty during 4 disaster scenarios (natural, explosive, nuclear, and communicable), to identify factors that affect willingness to work, and to assess opinions regarding disciplinary action for physicians unwilling to work in a disaster situation. METHODS: We surveyed residents and faculty at 7 US teaching institutions with accredited EM residency programs between April and November 2010. RESULTS: A total of 229 faculty and 259 residents responded (overall response rate, 75.4%). Willingness to report for duty ranged from 54.1% for faculty in a natural disaster to 94.2% for residents in a nonnuclear explosive disaster. The 3 most important factors influencing disaster response were concern for the safety of the family, belief in the physician's duty to provide care, and availability of protective equipment. Faculty and residents recommended minimal or no disciplinary action for individuals unwilling to work, except in the infectious disease scenario. CONCLUSIONS: Most EM residents and faculty indicated they would report for duty. Residents and faculty responses were similar in all but 1 scenario. Disciplinary action for individuals unwilling to work generally was not recommended. PMID- 24404307 TI - Early feedback on the use of the internal medicine reporting milestones in assessment of resident performance. AB - BACKGROUND: The educational milestones were designed as a criterion-based framework for assessing resident progression on the 6 Accreditation Council for Graduate Medical Education competencies. OBJECTIVE: We obtained feedback on, and assessed the construct validity and perceived feasibility and utility of, draft Internal Medicine Milestones for Patient Care and Systems-Based Practice. METHODS: All participants in our mixed-methods study were members of competency committees in internal medicine residency programs. An initial survey assessed participant and program demographics; focus groups obtained feedback on the draft milestones and explored their perceived utility in resident assessment, and an exit survey elicited input on the value of the draft milestones in resident assessment. Surveys were tabulated using descriptive statistics. Conventional content analysis method was used to assess the focus group data. RESULTS: Thirty four participants from 17 programs completed surveys and participated in 1 of 6 focus groups. Overall, the milestones were perceived as useful in formative and summative assessment of residents. Participants raised concerns about the length and complexity of some draft milestones and suggested specific changes. The focus groups also identified a need for faculty development. In the exit survey, most participants agreed that the Patient Care and Systems-Based Practice Milestones would help competency committees assess trainee progress toward independent practice. CONCLUSIONS: Draft reporting milestones for 2 competencies demonstrated significant construct validity in both the content and response process and the perceived utility for the assessment of resident performance. To ensure success, additional feedback from the internal medicine community and faculty development will be necessary. PMID- 24404306 TI - Self-reported subjective workload of on-call interns. AB - BACKGROUND: Workload has traditionally been measured by using surrogates, such as number of patients admitted or census, but these may not fully represent the complex concept of workload. OBJECTIVE: We measured self-reported subjective workload of interns and explored the relationship between subjective workload and possible predictors of it. METHODS: Trained research assistants observed internal medicine interns on call on a general medicine service. Approximately once an hour, the research assistants recorded the self-reported subjective workload of the interns by using Borg's Self-Perceived Exertion Scale, a 6 to 20 scale, and also recorded their own perceptions of the intern's workload. Research assistants continuously recorded the tasks performed by the interns. Interns were surveyed before and after the observation to obtain demographic and census data. RESULTS: Our sample included 25 interns, with a mean age of 28.6 years (SD, 2.4 years). Mean self-reported subjective workload was 12.0 (SD, 2.4). Mean self-reported subjective workload was significantly correlated with intern age (r = 0.49, P < .05), but not with team or intern census, number of admissions, or number of patients cross-covered. Self-reported subjective workload in the period after sign-out was significantly higher than in the period before and during sign-out (P < .001). CONCLUSIONS: Self-reported subjective workload was not associated with traditional measures of workload. However, receiving sign-out and assuming the care of cross-coverage patients may be related to higher subjective workload in interns. Given the patient safety implications of workload, it is important that the medical education community have tools to evaluate workload and identify contributors to it. PMID- 24404308 TI - Toward defining and measuring social accountability in graduate medical education: a stakeholder study. AB - BACKGROUND: Since 1965, Medicare has publically financed graduate medical education (GME) in the United States. Given public financing, various advisory groups have argued that GME should be more socially accountable. Several efforts are underway to develop accountability measures for GME that could be tied to Medicare payments, but it is not clear how to measure or even define social accountability. OBJECTIVE: We explored how GME stakeholders perceive, define, and measure social accountability. METHODS: Through purposive and snowball sampling, we completed semistructured interviews with 18 GME stakeholders from GME training sites, government agencies, and health care organizations. We analyzed interview field notes and audiorecordings using a flexible, iterative, qualitative group process to identify themes. RESULTS: THREE THEMES EMERGED IN REGARDS TO DEFINING SOCIAL ACCOUNTABILITY: (1) creating a diverse physician workforce to address regional needs and primary care and specialty shortages; (2) ensuring quality in training and care to best serve patients; and (3) providing service to surrounding communities and the general public. All but 1 stakeholder believed GME institutions have a responsibility to be socially accountable. Reported barriers to achieving social accountability included training time constraints, financial limitations, and institutional resistance. Suggestions for measuring social accountability included reviewing graduates' specialties and practice locations, evaluating curricular content, and reviewing program services to surrounding communities. CONCLUSIONS: Most stakeholders endorsed the concept of social accountability in GME, suggesting definitions and possible measures that could inform policy makers calls for increased accountability despite recognized barriers. PMID- 24404309 TI - The ACGME Duty Hour Standards and Board Certification Examination Performance Trends in Surgical Specialties. AB - BACKGROUND: Duty hour limitations initiated by the Accreditation Council for Graduate Medical Education (ACGME) in 2003 could improve resident education in surgical specialties. OBJECTIVE: The purpose of this study was to evaluate national surgical board examination performance and its relationship to the ACGME duty hour standards. METHODS: In this retrospective cohort study, electronically published website content was evaluated for examination statistics for the 10 surgical boards in the American Board of Medical Specialties. To evaluate examination trends over time, we performed simple linear regression. We also performed interrupted time series analyses, using segmented logistic regression. The secondary analyses consisted of a chi(2) test of passing and failing examinees before and after 2003. All statistics used alpha = .05. RESULTS: There were 8 of 10 (80%) surgical boards with examinations that met inclusion criteria and a total of 72 482 unique examination results. Of the 16 examinations evaluated (50% written, 50% oral), 13 (81%) had either significant pass rate trends on regression analyses and/or a significant pre-post pass rate surrounding the initiation of the ACGME duty hour standards in 2003 in the secondary analysis (P < .05). CONCLUSIONS: There are both increasing examination pass rates and some downward trends in examination performance on surgical board examinations since the initiation of the ACGME duty hour standards in 2003. The etiology of these trends is unclear, but trends are important to know for individual examinees, residency training programs, and surgical boards. PMID- 24404310 TI - Retention of critical care skills after simulation-based mastery learning. AB - BACKGROUND: Whether cognitive and patient care skills attained during simulation based mastery learning (SBML) are retained is largely unknown. OBJECTIVE: We studied retention of intensive care unit (ICU) clinical skills after an SBML boot camp experience. METHODS: Forty-seven postgraduate year (PGY)-1 residents completed SBML intervention designed to increase procedural, communication, and patient care skills. The intervention included ICU skills such as ventilator and hemodynamic parameter management. Residents were required to meet or exceed a minimum passing score (MPS) on a clinical skills examination before starting actual patient care. Skill retention was assessed in 42 residents who rotated in the medical ICU. Residents received a standardized 15-minute booster teaching session reviewing key concepts during the first week of the rotation. During the fourth week of their rotation, PGY-1 residents completed a clinical skills examination at the bedside of an actual ICU patient. Group mean examination scores and the proportion of subjects who met or exceeded the MPS at each testing occasion were compared. RESULTS: Residents scored a mean 90% (SD = 6.5%) on the simulated skills examination immediately after training. Residents retained skills obtained through SBML as the mean score at bedside follow-up testing was 89% (SD = 8.9%, P = .36). Thirty-seven of 42 (88%) PGY-1 residents met or exceeded the MPS at follow-up. CONCLUSION: SBML leads to substantial retention of critical care knowledge, and patient care skills PGY-1 boot camp is a highly efficient and effective model that can be administered at the beginning of the academic year. PMID- 24404311 TI - Focused Board Intervention (FBI): A Remediation Program for Written Board Preparation and the Medical Knowledge Core Competency. AB - BACKGROUND: Residents deemed at risk for low performance on standardized examinations require focused attention and remediation. OBJECTIVE: To determine whether a remediation program for residents identified as at risk for failure on the Emergency Medicine (EM) Written Board Examination is associated with improved outcomes. INTERVENTION: All residents in 8 classes of an EM 1-3 program were assessed using the In-Training Examination. Residents enrolled in the Focused Board Intervention (FBI) remediation program based on an absolute score on the EM 3 examination of <70% or a score more than 1 SD below the national mean on the EM 1 or 2 examination. Individualized education plans (IEPs) were created for residents in the FBI program, combining self-study audio review lectures with short-answer examinations. The association between first-time pass rate for the American Board of Emergency Medicine (ABEM) Written Qualifying Examination (WQE) and completion of all IEPs was examined using the chi(2) test. RESULTS: Of the 64 residents graduating and sitting for the ABEM examination between 2000 and 2008, 26 (41%) were eligible for the program. Of these, 10 (38%) residents were compliant and had a first-time pass rate of 100%. The control group (12 residents who matched criteria but graduated before the FBI program was in place and 4 who were enrolled but failed to complete the program) had a 44% pass rate (7 of 16), which was significantly lower (chi(2) = 8.6, P = .003). CONCLUSIONS: The probability of passing the ABEM WQE on the first attempt was improved through the completion of a structured IEP. PMID- 24404312 TI - Teaching resident physicians chronic disease management: simulating a 10-year longitudinal clinical experience with a standardized dementia patient and caregiver. AB - BACKGROUND: Education for all physicians should include specialty-specific geriatrics-related and chronic disease-related topics. OBJECTIVE: We describe the development, implementation, and evaluation of a chronic disease/geriatric medicine curriculum designed to teach Accreditation Council for Graduate Medical Education core competencies and geriatric medicine competencies to residents by using longitudinal encounters with a standardized dementia patient and her caregiver daughter. INTERVENTION: Over 3 half-day sessions, the unfolding standardized patient (SP) case portrays the progressive course of dementia and simulates a 10-year longitudinal clinical experience between residents and a patient with dementia and her daughter. A total of 134 residents participated in the University of Cincinnati-based curriculum during 2007-2010, 72% of whom were from internal medicine (79) or family medicine (17) residency programs. Seventy five percent of participants (100) said they intended to provide primary care to older adults in future practice, yet 54% (73) had little or no experience providing medical care to older adults with dementia. RESULTS: Significant improvements in resident proficiency were observed for all self-reported skill items. SPs' evaluations revealed that residents' use of patient-centered language and professionalism significantly improved over the 3 weekly visits. Nearly all participants agreed that the experience enhanced clinical competency in the care of older adults and rated the program as "excellent" or "above average" compared to other learning activities. CONCLUSIONS: Residents found this SP-based curriculum using a longitudinal dementia case realistic and valuable. Residents improved in both self-perceived knowledge of dementia and the use of patient centered language and professionalism. PMID- 24404313 TI - Use of portfolios for assessment of resident teaching skills. AB - BACKGROUND: Portfolios are effective instruments for assessment of teaching skills among professional teachers and have recently been adapted in medical education. However, scoring rubrics are needed to effectively guide assessors. INTERVENTION: Portfolio assessors reviewed and made assessment comments about the resident-as-teacher sections of 11 internal medicine residents' electronic portfolios and discussed their assessments in an assessor group discussion. We performed qualitative analyses of written and oral comments. Major themes were identified, and member checking and triangulation with the literature was performed to evaluate the trustworthiness of the qualitative analysis. RESULTS: Three faculty educators reviewed and commented on 241 uploaded e-portfolio documents accompanying reflections. Three major themes were identified: Application of Teaching Skills, Presentation Skills, and Insights as a Teacher. Themes and subthemes matched closely to several components of the conceptual framework of effective presentations formulated in Glassick standards for scholarly work, as well as themes found in assessments of professional teachers' portfolios. CONCLUSIONS: Assessments of portfolios by experienced faculty educators appear to be useful for identifying many important facets of formal teaching presentations and may be useful for creation of a scoring rubric. PMID- 24404314 TI - Successful efforts to increase diversity in a cardiology fellowship training program. AB - BACKGROUND: A large volume of literature has documented racial disparities in the delivery of cardiovascular care in the United States and that decreased access to procedures and undertreatment lead to worse outcomes. A lack of diversity among physicians is considered to be a major contributor. The fellowship training program in cardiovascular medicine at The Ohio State University Medical Center had never trained a fellow from a minority group underrepresented in medicine (URM) before 2007. INTERVENTION: In 2005, the fellowship made it a priority to recruit and match URM candidates in an effort to address the community's lack of diversity and disparities in cardiovascular care. METHODS: Program leaders revised the recruitment process, making diversity a high priority. Faculty met with members of diverse residency programs during visits to other institutions, the focus of interview day was changed to highlight mentorship, additional targeted postinterview communications reached out to highly competitive applicants, and a regular mentoring program was constructed to allow meaningful interaction with URM faculty and fellows. RESULTS: Since these changes were implemented, the program has successfully matched a URM fellow for 5 consecutive years. Such candidates currently make up 4 of 16 total trainees (25%) in the fellowship in cardiovascular medicine. CONCLUSIONS: The cardiovascular medicine fellowship training program at The Ohio State University was able to revise recruitment to attract competitive URM applicants as part of a concerted effort. Other educational programs facing similar challenges may be able to learn from the university's experiences. PMID- 24404315 TI - "If you build it, they will come": attitudes of medical residents and fellows about seeking services in a resident wellness program. AB - BACKGROUND: High rates of burnout and distress in resident physicians suggest a significant number would benefit from counseling. INTERVENTION: A resident wellness program (RWP) was designed to lower known barriers limiting resident access to services. METHODS: In 2011, medical residents and fellows were surveyed and logistic regression analyses were conducted to identify demographic and training program differences in perceived barriers and willingness to access the RWP. RESULTS: Of the 88% of trainees who knew about the RWP, 87% indicated they would be very likely or somewhat likely to seek out services. Time remained the biggest barrier for residents to getting help. Being male (odds ratio [OR] = 0.54, 95% confidence interval [CI] 0.34-0.84) or an ethnic/racial minority (OR = 0.49, 95% CI 0.28-0.85) was associated with greater unwillingness to seek counseling. Reluctance to access the RWP was associated with concerns about helpfulness, confidentiality, being unable to take a break, and stigma. Women (OR = 1.60, 95% CI 1.06-2.42) and primary care residents (OR = 1.58, 95% CI 0.98 2.54) were more likely to be concerned about taking a break. Men were more likely to question the helpfulness of counseling (OR = 0.55, 95% CI 0.36-0.85). CONCLUSIONS: The RWP removed barriers of cost and knowledge about counseling services. More educational outreach is needed to address sex and ethnic differences about RWP utilization and attitudes in medical culture about a physician's right to address personal health care needs. PMID- 24404316 TI - Feasibility and acceptability of a structured curriculum in teaching procedural and basic diagnostic ultrasound skills to internal medicine residents. AB - BACKGROUND: Point-of-care ultrasound has emerged as a powerful diagnostic tool and is also being increasingly used by clinicians to guide procedures. Many current and future internists desire training, yet no formal, multiple application, program-wide teaching interventions have been described. INTERVENTION: We describe a structured 30-hour ultrasound training course in diagnostic and procedural ultrasound implemented during intern orientation. Internal medicine interns learned basic ultrasound physics and machine skills; focused cardiac, great vessel, pulmonary, and abdominal ultrasound diagnostic examinations; and procedural applications. RESULTS: In postcourse testing, learners demonstrated the ability to acquire images, had significantly increased knowledge scores (P < .001), and demonstrated good performance on practical scenarios designed to test abilities in image acquisition, interpretation, and incorporation into medical decision making. In the postcourse survey, learners strongly agreed (4.6 of 5.0) that ultrasound skills would be valuable during residency and in their careers. CONCLUSIONS: A structured ultrasound course can increase knowledge and can result in learners who have skills in image acquisition, interpretation, and integration in management. Future work will focus on refining and improving these skills to allow these learners to be entrusted with the use of ultrasound independently for patient care decisions. PMID- 24404317 TI - Point-of-Care Ultrasound in Internal Medicine: A National Survey of Educational Leadership. AB - BACKGROUND: Ultrasound is a valuable tool in the safe performance of an increasing number of procedures. It has additionally emerged as a powerful instrument for point-of-care assessment by offering internists an opportunity to extend their traditional physical examination. OBJECTIVE: This study explored how internal medicine (IM) educators perceive the use of ultrasound for procedures and point-of-care assessments, the extent to which curricula for teaching IM residents ultrasound skills exist, and perceived barriers to teaching its use. METHODS: In February 2012, we administered a 27-question survey to all members of the Association of Program Directors in Internal Medicine, eliciting their opinions about the use of point-of-care ultrasound. RESULTS: Of 2200 surveys distributed electronically, 234 were returned (a 11% response rate), including 167 by program directors or assistant program directors. Respondents highly rated the usefulness of ultrasound for central-line placement, thoracentesis, paracentesis, and diagnosis of pleural effusions. Evaluation of vena cava and heart, and placement of radial artery catheters received somewhat lower usefulness scores. Forty-five respondents (25%) reported having formal curricula to teach point-of-care ultrasound, and 46 respondents without current ultrasound programs were planning to initiate them in the next 12 months. Potential barriers to teaching and use of ultrasound included the time and cost to train faculty, the cost of ultrasound machines, and the time required to train residents. CONCLUSIONS: Educational leaders in IM view point-of-care ultrasound as a valuable tool in diagnosis and procedures, and many residency programs are teaching these skills to their learners. PMID- 24404318 TI - Using skype as an alternative for residency selection interviews. AB - BACKGROUND: Residency interviews can place significant time and financial burdens on applicants. OBJECTIVE: To determine whether the use of Skype as a screening tool during interview season in a family medicine residency is cost-effective and time-efficient for the applicant and the residency program. METHODS: We surveyed 2 groups of medical students during interviews for our family medicine program. Thirty-two students were interviewed via our face-to-face, traditional interview (TI) process, and 10 students, the second group, who did not meet the program's standard interview selection criteria for TI, underwent our Skype interview (SI) process. RESULTS: Using an unpaired t test, we found that the applicants' costs of an SI were significantly less than a TI, $566 (95% confidence interval [CI] $784-$349, P < .001). Direct cash savings plus indirect salary savings to the program were $5,864, with a time savings of 7 interview days. Three of the applicants who were participants in the SI limb of the study were in our final rank order list. CONCLUSIONS: For interviewing in family medicine residencies, use of Skype may be a cost-effective and time-efficient screening tool for both the applicant and the program. Alternate uses of SI may include the time sensitive, postmatch Supplemental Offer and Acceptance Program. PMID- 24404319 TI - A novel survey tool to assess pulmonary and critical care fellows' attitudes regarding acquiring teaching skills during fellowship training. AB - BACKGROUND: Important components of fellowship training include learning teaching skills and career development. Pulmonary and critical care medicine (PCCM) fellows' opinions of the importance of developing teaching skills and interest in careers in medical education have not been previously described, and there are no tools to assess interest in acquiring teaching skills. OBJECTIVE: We describe the development and initial psychometric validation of a survey tool to assess trainees' attitudes toward and interest in acquiring teaching skills. METHODS: A survey tool to assess attitudes toward teaching and medical education skills was designed and psychometrically characterized. We then anonymously surveyed fellows in 1 PCCM program to assess their perceptions of and attitudes regarding acquiring teaching skills. RESULTS: The survey tool demonstrated acceptable psychometric properties. The survey showed that most fellows felt that acquiring teaching skills was "very important," and nearly half reported being "interested" or "very interested" in pursuing careers as medical educators. However, fellows disagreed with the feedback they received from attending physicians with regard to their teaching abilities (10% disagreed with feedback at the beginning of the year, 36% disagreed at the end of the year; P = .03). CONCLUSIONS: Our survey demonstrates acceptable psychometric properties and performance characteristics in a single-site study of PCCM fellows during 1 academic year. Fellows are interested in improving their teaching skills but do not know how to become better teachers. Added research in multiple settings should explore the generalizability of our findings. PMID- 24404320 TI - A Curriculum to Improve Residents' End-of-Life Communication and Pain Management Skills During Pediatrics Intensive Care Rotation: Pilot Study. AB - BACKGROUND: Research suggests pediatrics practitioners lack confidence and skills in the end-of-life (EOL) care. OBJECTIVE: This pilot study explored the impact of a curriculum designed to prepare future pediatricians to manage pain and provide comfort for children and infants with life-threatening conditions and to be more confident and competent in their EOL discussions with families. METHODS: Participants included 8 postgraduate year (PGY)-2 residents in the study group and 9 PGY-3 residents in a control group. The EOL curriculum included 4, 1-hour sessions consisting of didactic lectures, videos, and small-group, interactive discussions. Topics included discussing EOL with families, withdrawal of care, and pain assessment and management. Curriculum evaluation used an objective structured clinical examination (OSCE), self-assessment confidence and competency questionnaire, and a follow-up survey 18 months after the intervention. RESULTS: The OSCE showed no statistically significant differences between PGY-2 versus PGY 3 residents in discussing EOL issues with family (mean = 48.3 [PGY-2] versus 41.0 [PGY-3]), managing withdrawal of care (mean = 20.9 [PGY-2] versus 18.91 [PGY-3]), and managing adolescent pain (mean = 30.97 [PGY-2] versus 29.27 [PGY 3]). The self-assessment confidence and competency scores improved significantly after the intervention for both PGY-2 residents (0.62 versus 0.86, P < .01) and PGY-3 residents (0.61 versus 0.85, P < .01). CONCLUSIONS: An EOL curriculum for PGY-2 pediatrics residents delivered during the intensive care unit rotation is feasible and may be effective. Residents reported the curriculum was useful in their practice. PMID- 24404321 TI - Assessing interpersonal communications skills: the use of standardized patients in graduate medical education. PMID- 24404322 TI - Teaching and assessing critical reasoning through the use of entrustment. PMID- 24404323 TI - Weighing in on residents' body mass index: a teachable moment for physicians and patients alike? PMID- 24404324 TI - Physician willingness to respond to disasters: what can we learn? PMID- 24404325 TI - Diversity by design. PMID- 24404326 TI - Mixed messages: ambivalence among specialist providers regarding optimal communication practices. PMID- 24404327 TI - Next accreditation system: the need for separate evaluators. PMID- 24404329 TI - Consult courtesy. PMID- 24404328 TI - American physician in Japan: teaching out of context. PMID- 24404330 TI - Initial Tests of the ACGME Self Study. PMID- 24404331 TI - Intercellular Lipid Mediators and GPCR Drug Discovery. AB - G-protein-coupled receptors (GPCR) are the largest superfamily of receptors responsible for signaling between cells and tissues, and because they play important physiological roles in homeostasis, they are major drug targets. New technologies have been developed for the identification of new ligands, new GPCR functions, and for drug discovery purposes. In particular, intercellular lipid mediators, such as, lysophosphatidic acid and sphingosine 1-phosphate have attracted much attention for drug discovery and this has resulted in the development of fingolimod (FTY-720) and AM095. The discovery of new intercellular lipid mediators and their GPCRs are discussed from the perspective of drug development. Lipid GPCRs for lysophospholipids, including lysophosphatidylserine, lysophosphatidylinositol, lysophosphatidylcholine, free fatty acids, fatty acid derivatives, and other lipid mediators are reviewed. PMID- 24404332 TI - Nucleic Acid aptamers: new methods for selection, stabilization, and application in biomedical science. AB - The adoption of oligonucleotide aptamer is well on the rise, serving an ever increasing demand for versatility in biomedical field. Through the SELEX (Systematic Evolution of Ligands by EXponential enrichment), aptamer that can bind to specific target with high affinity and specificity can be obtained. Aptamers are single-stranded nucleic acid molecules that can fold into complex threedimensional structures, forming binding pockets and clefts for the specific recognition and tight binding of any given molecular target. Recently, aptamers have attracted much attention because they not only have all of the advantages of antibodies, but also have unique merits such as thermal stability, ease of synthesis, reversibility, and little immunogenicity. The advent of novel technologies is revolutionizing aptamer applications. Aptamers can be easily modified by various chemical reactions to introduce functional groups and/or nucleotide extensions. They can also be conjugated to therapeutic molecules such as drugs, drug containing carriers, toxins, or photosensitizers. Here, we discuss new SELEX strategies and stabilization methods as well as applications in drug delivery and molecular imaging. PMID- 24404333 TI - Emodin Isolated from Polygoni cuspidati Radix Inhibits TNF-alpha and IL-6 Release by Blockading NF-kappaB and MAP Kinase Pathways in Mast Cells Stimulated with PMA Plus A23187. AB - Emodin, a naturally occurring anthraquinone derivative isolated from Polygoni cuspidati radix, has several beneficial pharmacologic effects, which include anti cancer, anti-diabetic, and anti-inflammatory activities. In this study, the authors examined the effect of emodin on the production of proinflammatory cytokines, such as, tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, in mouse bone marrow-derived mast cells (BMMCs) stimulated with phorbol 12-myristate 13-acetate (PMA) plus the calcium ionophore A23187. To investigate the mechanism responsible for the regulation of pro-inflammatory cytokine production by emodin, the authors assessed its effects on the activations of transcriptional factor nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinases (MAPKs). Emodin attenuated the nuclear translocation of (NF)-kappaB p65 and its DNA binding activity by reducing the phosphorylation and degradation of IkappaBalpha and the phosphorylation of IkappaB kinase B (IKK). Furthermore, emodin dose dependently attenuated the phosphorylations of MAPKs, such as, extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAP kinase, and the stress-activated protein kinases (SAPK)/c-Jun-N-terminal kinase (JNK). Taken together, the findings of this study suggest that the anti-inflammatory effects of emodin on PMA plus A23187-stimulated BMMCs are mediated via the inhibition of NF-kappaB activation and of the MAPK pathway. PMID- 24404334 TI - The Longevity Properties of 1,2,3,4,6-Penta-O-Galloyl-beta-D-Glucose from Curcuma longa in Caenorhabditis elegans. AB - Here in this study, we isolated 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG) from Curcuma longa L. and elucidated the lifespanextending effect of PGG using Caenorhabditis elegans model system. In the present study, PGG demonstrated potent lifespan extension of worms under normal culture condition. Then, we determined the protective effects of PGG on the stress conditions such as thermal and oxidative stress. In the case of heat stress, PGG-treated worms exhibited enhanced survival rate, compared to control worms. In addition, PGG-fed worms lived longer than control worms under oxidative stress induced by paraquat. To verify the possible mechanism of PGG-mediated increased lifespan and stress resistance of worms, we investigated whether PGG might alter superoxide dismutase (SOD) activities and intracellular ROS levels. Our results showed that PGG was able to elevate SOD activities of worms and reduce intracellular ROS accumulation in a dose-dependent manner. PMID- 24404335 TI - A ROCK Inhibitor Blocks the Inhibitory Effect of Chondroitin Sulfate Proteoglycan on Morphological Changes of Mesenchymal Stromal/Stem Cells into Neuron-Like Cells. AB - Chondroitin sulfate proteoglycan (CSPG) inhibits neurite outgrowth of various neuronal cell types, and CSPG-associated inhibition of neurite outgrowth is mediated by the Rho/ROCK pathway. Mesenchymal stromal/stem cells (MSCs) have the potential to differentiate into neuron-like cells under specific conditions and have been shown to differentiate into neuron-like cells by co-treatment with the ROCK inhibitor Y27632 and the hypoxia condition mimicking agent CoCl2. In this study, we addressed the hypothesis that a ROCK inhibitor might be beneficial to regenerate neurons during stem cell therapy by preventing transplanted MSCs from inhibition by CSPG in damaged tissues. Indeed, dose-dependent inhibition by CSPG pretreatment was observed during morphological changes of Wharton's jelly-derived MSCs (WJ-MSCs) induced by Y27632 alone. The formation of neurite-like structures was significantly inhibited when WJ-MSCs were pre-treated with CSPG before induction under Y27632 plus CoCl2 conditions, and pretreatment with a protein kinase C inhibitor reversed such inhibition. However, CSPG treatment resulted in no significant inhibition of the WJ-MSC morphological changes into neuron-like cells after initiating induction by Y27632 plus CoCl2. No marked changes were detected in expression levels of neuronal markers induced by Y27632 plus CoCl2 upon CSPG treatment. CSPG also blocked the morphological changes of human bone marrow-derived MSCs into neuron-like cells under other neuronal induction condition without the ROCK inhibitor, and Y27632 pre-treatment blocked the inhibitory effect of CSPG. These results suggest that a ROCK inhibitor can be efficiently used in stem cell therapy for neuronal induction by avoiding hindrance from CSPG. PMID- 24404336 TI - Neuroprotective Effects of a Butanol Fraction of Rosa hybrida Petals in a Middle Cerebral Artery Occlusion Model. AB - The neuroprotective effects of a butanol fraction of white rose petal extract (WRPE-BF) were investigated in a middle cerebral artery occlusion (MCAO) model. Seven week-old male rats were orally administered WRPE-BF for 2 weeks and subjected to MCAO for 2 h, followed by reperfusion. Twenty-four h later, MCAO induced behavioral dysfunctions were markedly improved in a dose-dependent manner by pretreatment with WRPE-BF. Moreover, higher dose of WRPE-BF not only decreased infarction area but also effectively reduced astrogliosis. The expression of inducible nitric oxide synthase, cyclooxygenase-2, and glial fibrillary acidic protein in MCAO model were markedly inhibited by WRPE-BF treatment. Notably, WRPE BF decreased nitric oxide and malondialdehyde levels in the striatum and subventricular zone of stroke-challenged brains. These data suggested that WRPE BF may exert its neuroprotective effects via anti-oxidative and anti-inflammatory activities against ischemia-reperfusion brain injury and could be a good candidate as a therapeutic target for ischemic stroke. PMID- 24404337 TI - Inhibitory Effects of Eucommia ulmoides Oliv. Bark on Scopolamine-Induced Learning and Memory Deficits in Mice. AB - Eucommia ulmoides Oliv. Bark (EUE) is commonly used for the treatment of hypertension, rheumatoid arthritis, lumbago, and ischialgia as well as to promote longevity. In this study, we tested the effects of EUE aqueous extract in graded doses to protect and enhance cognition in scopolamine-induced learning and memory impairments in mice. EUE significantly improved the impairment of short-term or working memory induced by scopolamine in the Y-maze and significantly reversed learning and memory deficits in mice as measured by the passive avoidance and Morris water maze tests. One day after the last trial session of the Morris water maze test (probe trial session), EUE dramatically increased the latency time in the target quadrant in a dose-dependent manner. Furthermore, EUE significantly inhibited acetylcholinesterase (AChE) and thiobarbituric acid reactive substance (TBARS) activities in the hippocampus and frontal cortex in a dose-dependent manner. EUE also markedly increased brain-derived neurotrophic factor (BDNF) and phosphorylation of cAMP element binding protein (CREB) in the hippocampus of scopolamine-induced mice. Based on these findings, we suggest that EUE may be useful for the treatment of cognitive deficits, and that the beneficial effects of EUE are mediated, in part, by cholinergic signaling enhancement and/or protection. PMID- 24404338 TI - Direct Analysis in Real Time Mass Spectrometry (DART-MS) Analysis of Skin Metabolome Changes in the Ultraviolet B-Induced Mice. AB - Ultraviolet (UV) radiation is a major environmental factor that leads to acute and chronic reactions in the human skin. UV exposure induces wrinkle formation, DNA damage, and generation of reactive oxygen species (ROS). Most mechanistic studies of skin physiology and pharmacology related with UV-irradiated skin have focused on proteins and their related gene expression or single- targeted small molecules. The present study identified and analyzed the alteration of skin metabolites following UVB irradiation and topical retinyl palmitate (RP, 5%) treatment in hairless mice using direct analysis in real time (DART) time-of flight mass spectrometry (TOF-MS) with multivariate analysis. Under the negative ion mode, the DART ion source successfully ionized various fatty acids including palmitoleic and linolenic acid. From DART-TOF-MS fingerprints measured in positive mode, the prominent dehydrated ion peak (m/z: 369, M+H-H2O) of cholesterol was characterized in all three groups. In positive mode, the discrimination among three groups was much clearer than that in negative mode by using multivariate analysis of orthogonal partial-least squares-discriminant analysis (OPLS-DA). DART-TOF-MS can ionize various small organic molecules in living tissues and is an efficient alternative analytical tool for acquiring full chemical fingerprints from living tissues without requiring sample preparation. DART-MS measurement of skin tissue with multivariate analysis proved to be a powerful method to discriminate between experimental groups and to find biomarkers for various experiment models in skin dermatological research. PMID- 24404339 TI - Impact of High Fat Diet-induced Obesity on the Plasma Levels of Monoamine Neurotransmitters in C57BL/6 Mice. AB - Obesity is one of the most serious health problems in developed countries. It negatively affects diverse aspects of human wellbeing. Of these, a relationship between obesity and depression is widely recognized but biomarkers for assessment of obesityassociated mood changes in animal obesity models are rarely known. Here we explored the link between obesity and the plasma levels of monoamine neurotransmitters involved in mood control using a sensitive UPLC/MSMS technique in high fat diet (HFD)- induced obesity model in male C57BL/6 mice to explore the potential utility of plasma tests for obesity-associated mood change. HFD (60% of total calories, 8 weeks) induced significantly higher weight gains in body (+37.8%) and fat tissue (+306%) in male C57BL/6 mice. Bioanalysis of serotonin, dopamine and norepinephrine in plasma at 8 weeks of HFD revealed that serotonin decreased significantly in the obese mice when compared to normal diet-fed mice (2.7 +/- 0.6 vs 4.3 +/- 2.0 ng/ml, N=8). Notably, a negative correlation was found between the levels of serotonin and body weight gains. Furthermore, principal component analysis (PCA) with the individual levels of neurotransmitters revealed that plasma levels of dopamine and serotonin could apparently differentiate the obese mice from lean ones. Our study demonstrated that blood plasma levels of neurotransmitters can be employed to evaluate the mood changes associated with obesity and more importantly, provided an important clue for understanding of the relationship between obesity and mood disorders. PMID- 24404340 TI - Cell motility is decreased in macrophages activated by cancer cell-conditioned medium. AB - Macrophages play a role in innate immune responses to various foreign antigens. Many products from primary tumors influence the activation and transmigration of macrophages. Here, we investigated a migration of macrophages stimulated with cancer cell culture-conditioned medium (CM). Macrophage activation by treatment with CM of B16F10 cells were judged by the increase in protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2). The location where macrophages were at 4 h-incubation with control medium or CM was different from where they were at 5 h-incubation in culture dish. Percentage of superimposed macrophages at every 1 h interval was gradually increased by CM treatment as compared to control. Total coverage of migrated track expressed in coordinates was smaller and total distance of migration was shorter in CM-treated macrophages than that in control. Rac1 activity in CM-treated macrophages was also decreased as compared to that in control. When macrophages were treated with CM in the presence of dexamethasone (Dex), an increase in COX2 protein levels, and a decrease in Rac1 activity and total coverage of migration were reversed. In the meanwhile, biphasic changes were detected by Dex treatment in section distance of migration at each time interval, which was more decreased at early time and then increased at later time. Taken together, data demonstrate that macrophage motility could be reduced in accordance with activation in response to cancer cell products. It suggests that macrophage motility could be a novel marker to monitor cancer-associated inflammatory diseases and the efficacy of anti-inflammatory agents. PMID- 24404341 TI - Evaluation of Luminescent P450 Analysis for Directed Evolution of Human CYP4A11. AB - Cytochrome P450 4A11 (CYP4A11) is a fatty acid hydroxylase enzyme expressed in human liver. It catalyzes not only the hydroxylation of saturated and unsaturated fatty acids, but the conversion of arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a regulator of blood pressure. In this study, we performed a directed evolution analysis of CYP4A11 using the luminogenic assay system. A random mutant library of CYP4A11, in which mutations were made throughout the entire coding region, was screened with luciferase activity to detect the demethylation of luciferin-4A (2-[6-methoxyquinolin-2-yl]-4,5-dihydrothiazole-4 carboxylic acid) of CYP4A11 mutants in Escherichia coli. Consecutive rounds of random mutagenesis and screening yielded three improved CYP4A11 mutants, CP2600 (A24T/T263A), CP2601 (T263A), and CP2616 (A24T/T263A/V430E) with ~3-fold increase in whole cells and >10-fold increase in purified proteins on the luminescence assay. However, the steady state kinetic analysis for lauric acid hydroxylation showed the significant reductions in enzymatic activities in all three mutants. A mutant, CP2600, showed a 51% decrease in catalytic efficiency (k cat/K m) for lauric acid hydroxylation mainly due to an increase in K m. CP2601 and CP2616 showed much greater reductions (>75%) in the catalytic efficiency due to both a decrease in k cat and an increase in K m. These decreased catalytic activities of CP2601 and CP2616 can be partially attributed to the changes in substrate affinities. These results suggest that the enzymatic activities of CYP4A11 mutants selected from directed evolution using a luminogenic P450 substrate may not demonstrate a direct correlation with the hydroxylation activities of lauric acid. PMID- 24404343 TI - Alterations in Circulating Adhesion Molecules in Acute Myocardial Infarction before and after Thrombolysis with Streptokinase. AB - INTRODUCTION: The role of adhesion molecules in the development and progression of coronary atherosclerosis is inevitable. It is not clear yet whether these molecules increase or decrease in level after thrombolytic therapy. This study was designed to compare concentrations of soluble forms of adhesion molecules in patients with acute myocardial infarction before and after reperfusion by thrombolysis with streptokinase (SK). METHODS: In this study, in 40 patients with acute myocardial infarction who were admitted in our Emergency Department undergoing thrombolysis with SK, plasma concentrations of six adhesion molecules [soluble L-selectin, P-selectin, E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and platelet endothelial cell adhesion molecule-1 (PECAM-1)] were measured by enzyme linked immunosorbent assay (ELISA), before and 3 hours after intervention. RESULTS: While soluble E selectin and PECAM-1 concentrations did not differ within the 3 hours after interventions (P> 0.05), the level of P-selectin, L-selectin, ICAM-1, VCAM-1 were significantly reduced after thrombolysis with SK (P< 0.05). CONCLUSION: Adhesion molecules which mediate the interactions in leukocyte endothelium vary in levels after reperfusion with SK. It was shown that 4 out of 6 adhesion molecules significantly reduced after thrombolysis with SK. PMID- 24404342 TI - Does the effect of supervised cardiac rehabilitation programs on body fat distribution remained long time? AB - INTRODUCTION: An increased accumulation of fat in the intra-abdominal cavity is highly correlated with adverse coronary risk profiles. Cardiac rehabilitation (CR) produces a host of health benefits related to modifiable cardiovascular risk factors. Further research is needed to define better program for weight loss and risk improvement in coronary patients. The aim of this study was to determine the effect of supervised and unsupervised cardiac rehabilitation program on body composition and body fat distribution in a population with coronary artery disease. METHODS: The study investigated 167 patients with coronary artery disease (73% males; mean age = 52.67±9.11 years) before and after a supervised protocol cardiac rehabilitation program, and 12-months later. Target variables included body fat distribution indices (waist and hip circumference and waist to hip ratio), weight and body mass index. RESULTS: Weight, waist circumference, waist to hip ratio and body mass index significantly decreased with 2 month supervised program (P<0.001), but hip circumference was not significantly changed. Males improved to a greater extent than the female patients. All of measurements relatively returned to baseline at the end of program (after 12 months). CONCLUSION: Supervised cardiac rehabilitation program results in improvements in body composition and body fat distribution. The effects of non-supervised program were minimal and the program needed to be reviewed. PMID- 24404344 TI - Arterial lactate level changes in first day after cardiac operation. AB - Lactate level is an important index for predicting cardiac events. There are some debates about time and type of sampling for defining of its prognostic values. To assess the prognostic importance of arterial lactate level in patients after cardiac surgery with regarding to operation factors serial arterial lactate levels during and after surgery was measured up to 24 hours, these data were processed by T-independent test and chi-square, P less than 0.01 was significant. 31 patients entered to study, high persistent arterial lactate level (1.5-4 mmol/L) can be seen in most patients (80%) during operation which returned to normal level (<1.5 mmol/L) up to12(th) hours post operation in 75% of cases. Persistent high level (>4 mmol/L) will occur unusually at 24(th) hour but can be associated with poor prognosis. Serial measurement of serum lactate level can be helpful for our management quality and very highly persistent arterial lactate level (>4 mmol/lit) up to 24 hours after operation will increase mortality rate in operated patients for congenital heart disease. PMID- 24404345 TI - Warming Endotracheal Tube in Blind Nasotracheal Intubation throughout Maxillofacial Surgeries. AB - INTRODUCTION: Blind nasotracheal intubation is an intubation method without observation of glottis that is used when the orotracheal intubation is difficult or impossible. One of the methods to minimize trauma to the nasal cavity is to soften the endotracheal tube through warming. Our aim in this study was to evaluate endotracheal intubation using endotracheal tubes softened by hot water at 50 °C and to compare the patients in terms of success rate and complications. METHODS: 60 patients with ASA Class I and II scheduled to undergo elective jaw and mouth surgeries under general anesthesia were recruited. RESULTS: success rate for Blind nasotracheal intubation in the control group was 70% vs. 83.3% in the study group. Although the success rate in the study group was higher than the control group, this difference was not statistically significant. The most frequent position of nasotracheal intubation tube was tracheal followed by esophageal and anterior positions, respectively. CONCLUSION: In conclusion, our study showed that using an endotracheal tube softened by warm water could reduce the incidence and severity of epistaxis during blind nasotracheal intubation; however it could not facilitate blind nasotracheal intubation. PMID- 24404346 TI - Molecular diagnosis of bacterial infective endocarditis in tabriz, azerbaijan. AB - INTRODUCTION: The aim of this study was to analyze a PCR based approach for detection of infective endocarditis in Azerbaijan. METHODS: Ten aortic valves, 8 mitral valves and 2 tricuspid valves, were analyzed for the presence of bacterial infective endocarditis using Gram staining, culture and PCR methods. RESULTS: Of the 20 valves, 5 and 4 cases were positive by Gram staining and culture assay, respectively. Bacterial DNA was positive in 12 of the 20 valves (60%) by broad spectrum PCR. Direct sequencing for species identification was possible in 10 cases. CONCLUSION: PCR and direct molecular identification of the etiological agents responsible for infective endocarditis may enable specific treatment to begin at an earlier phase of the disease. PMID- 24404347 TI - Evaluation of the prevalence and risk factors of delirium in cardiac surgery ICU. AB - INTRODUCTION: Delirium is defined as an acute cognitive disorder presenting with fluctuation in cognition, apathy and non-organized thinking. It may increase morbidity, mortality, ICU stay and cost. In patients who underwent heart surgery delirium may increase post-operative complications such as respiratory insufficiency, sternum instability and need to re-operation of the sternum. The aim of this study was to evaluate the prevalence and risk factors of delirium in patients admitted to cardiac surgery. MATERIALS AND METHODS: 18 years or older patients who had undergone cardiac surgeries and stayed for more than 24 hours in ICU following surgery were recruited. All subjects were assessed for signs & symptoms of delirium using CAM-ICU and its risk factors. All data were analyzed by SPSS 16 at the end of the study. RESULTS: The prevalence of delirium in these patients was 23.5% (47 patients). The mean age of patients with delirium was more than other patients (P=0.001). The Incidence of delirium in the patients with cardiopulmonary bypass surgery (CPB) was higher than the patients without CPB (P=0.01). The Incidence of delirium in the patients with Atrial fibrillation was higher than patients without it (P=0.002). The Incidence of delirium in the patients with CVA history was higher than the patients without CVA history (P=0.032). The mean time of mechanical ventilation in the delirious patients was more than other patients (P=0.01). CONCLUSION: Older Age, CPB, history of CVA, Atrial Fibrillation, and prolonged mechanical ventilation are considered as the risk factors of delirium in cardiac surgery patients. PMID- 24404348 TI - Factors influencing mortality after bioprosthetic valve replacement; a midterm outcome. AB - INTRODUCTION: Although valve repair is applied routinely nowadays, particularly for mitral regurgitation (MR) or tricuspid regurgitation (TR), valve replacement using prosthetic valves is also common especially in adults. Unfortunately the valve with ideal hemodynamic performance and long-term durability without increasing the risk of bleeding due to long-term anticoagulant therapy has not been introduced. Therefore, patients and physicians must choose either bioprosthetic or mechanical valves. Currently, there is an increasing clinical trend of using bioprosthetic valves instead of mechanical valves even in young patients apparently because of their advantages. METHODS: Seventy patients undergone valvular replacement using bioprosthetic valves were evaluated by ECG and Echocardiography to assess the rhythm and ejection fracture. Mean follow-up time was 33 months (min 9, max 92). RESULTS: Mortality rate was 25.9% (n=18) within 8 years of follow-up. Statistical analysis showed a significant relation between atrial fibrillation rhythm and mortality (P=0.02). Morbidities occurred in 30 patients (42.8%). Significant statistical relation was found between the morbidities and age over 65 years old (P=0.005). In follow-up period, 4 cases (5.7%) underwent re-operation due to global valve dysfunction. CONCLUSION: Our study shows that using biprosthetic valve could reduce the risk of morbidity occurrence in patient who needs valve replacement. However, if medical treatments fail, patients should be referred for surgery. This would reduce the risk of mortality because of lower incident of complications such as atrial fibrillation and morbidities due to younger patients' population. PMID- 24404349 TI - Effects of emotional stimuli on cardiovascular responses in patients with essential hypertension based on brain/behavioral systems. AB - INTRODUCTION: Effects of emotional stimuli on hemodynamics in patients with essential hypertension based on brain/behavioral systems have not been studied broadly. METHODS: Eighty five essential hypertensive male patients who had completed Carver-White BIS/BAS scale were enrolled to the study. Later, 25 BIS and 25 BAS patients were selected and their blood pressure and heart rate were recorded prior to stimuli induction. Participants were then exposed to stressor pictures. After that, 15 minutes of relaxation and cognitive tasks were performed. Finally, the participants were exposed to pleasant pictures. The blood pressure and heart rate were recorded after presenting of 2 stimuli. RESULTS: Our study showed that BIS patients achieved higher scores in diastolic blood pressure and heart rate in comparison with BAS patients after presenting stressful stimuli. Also, BAS patients achieved lower scores in systolic blood pressure and heart rate in comparison with BIS patients after presenting pleasant stimuli. CONCLUSION: In summary, BIS patients experience negative emotions more than BAS patients. Therefore, the role of induced mood states is important in relation to physical health. PMID- 24404350 TI - Universal glove and gown use for healthcare workers: what is the role of visitors? PMID- 24404351 TI - Unusual clinical presentation of a giant left ventricle hydatid cyst. AB - A 39-year-old woman was hospitalized in our center due to chest and left shoulder pain. Having a history of tamponade and tuberculosis, she was under treatment for the previous two months. Echocardiography, chest CT and MRI documented intramyocardial and pericardial hydatid cyst which was later confirmed by further pathological studies. Later, the cyst was removed surgically. PMID- 24404352 TI - Pediatric guillain-barre syndrome and autonomic dysfunction. PMID- 24404353 TI - Reply: pediatric guillain-barre syndrome and autonomic dysfunction. PMID- 24404354 TI - Can Barker's Hypothesis Explain the Observed Different Trends of Mortality from Atherosclerotic Cardiovascular Disease in Western Europe? PMID- 24404355 TI - Vinca alkaloids. AB - Vinca alkaloids are a subset of drugs obtained from the Madagascar periwinkle plant. They are naturally extracted from the pink periwinkle plant, Catharanthus roseus G. Don and have a hypoglycemic as well as cytotoxic effects. They have been used to treat diabetes, high blood pressure and have been used as disinfectants. The vinca alkaloids are also important for being cancer fighters. There are four major vinca alkaloids in clinical use: Vinblastine (VBL), vinorelbine (VRL), vincristine (VCR) and vindesine (VDS). VCR, VBL and VRL have been approved for use in the United States. Vinflunine is also a new synthetic vinca alkaloid, which has been approved in Europe for the treatment of second line transitional cell carcinoma of the urothelium is being developed for other malignancies. Vinca alkaloids are the second-most-used class of cancer drugs and will stay among the original cancer therapies. Different researches and studies for new vinca alkaloid applications will be carried out in this regard. PMID- 24404356 TI - Effects of training course on occupational exposure to bloodborne pathogens: a controlled interventional study. AB - BACKGROUND: One of the serious occupational concerns in health care workers (HCWs) is exposure to blood/body fluids that can transmit blood borne pathogens such as human immunodeficiency virus and hepatitis B and C viruses. We are reporting the effects of training course and surveillance on the rate of needle stick injuries (NSIs) among HCWs at an educational hospital in Iran. AIMS: To evaluate the effects of training course on the rate of NSIs and its reporting. METHODS: We selected two hospitals (A&B) based on their similarities in wards and facilities then asked the managers of these two hospitals to participate in our study. We established a new occupational health center and conducted a training course at hospital A on 2010 and compared it with control group (hospital B). The data from 2009 to 2011 was collected, analyzed to compare pre and post intervention rates. RESULTS: DURING STUDY PERIOD NURSES SUSTAINED THE HIGHEST NUMBER OF INJURIES (HOSPITAL A: n=80; 66.1% and hospital B: n=64; 35.4%). The incidence rate of NSIs in hospital A was 7.16 NSI/100FTE/YEAR before the intervention which was increased to 12.06 after the intervention. In hospital B this rate was 6.05 during three years. CONCLUSIONS: The study revealed remarkable increase in the incidence rate of NSIs after the intervention. This is being achieved by meticulous surveillance, training course and improving awareness. PMID- 24404357 TI - Comparing Three Methods of Co-culture of Retinal Pigment Epithelium with Progenitor Cells Derived Human Embryonic Stem Cells. AB - BACKGROUND: Close interaction between retinal pigment epithelium (RPE) and photoreceptors plays an essential role in visual function. The objective of this study is to determine the effects of RPE cells in the differentiation of progenitor derived human embryonic stem cells (hESC) into retinal cells; we developed in vitro co-culture models and compare these models to investigate in which model the expression of photoreceptor markers is superior. It seems the effects of RPE cells on differentiation of retinal progenitor cells (RPCs) through the cell-to-cell contact or with the use of insert and compare of these methods has not been reported yet. METHODS: Initially, retinal progenitors (RPs) were differentiated from hESC. After isolation of RPE sheet from rabbit eyes, demonstrated these cells maintains the integrity and feature after 2 weeks. Next, we examined the induction of photoreceptors by the co-culture of RPE through insert in 1 week and 2 weeks (indirect) or without insert by the cell-to-cell contact (direct). The differentiation of retinal cells was verified by protein and gene expression in these three methods. The adherent cells were morphologically examined using phase contrast microscopy and characterized by immunofluorescent staining and reverse transcription.polymerase chain reaction (RT-PCR). RESULTS: Evaluation of immunostaining showed that hESC, highly (>80%) can be directed to the RPs fate. Upon co-culture of RPCs with RPE sheet using insert for 2 weeks or by the cell-to-cell contact, these cells differentiated to neural retina and expressed photoreceptor-specific markers. However, in direct co culture, some mature photoreceptor markers like arrestin expressed in compare with indirect co-culture. CONCLUSIONS: The expression of late photoreceptor marker could be improved when RPE cells seeded on RPCs in compare with the use of insert. PMID- 24404358 TI - Ethnicity Modifies the Additive Effects of Anxiety and Drug Use Disorders on Suicidal Ideation among Black Adults in the United States. AB - BACKGROUND: This study aimed to test if ethnicity moderates the additive effects of lifetime psychiatric disorders on serious suicidal thoughts among a nationally representative sample of Black adults in the United States. METHODS: For this study, we used data of 5,181 Black adults (3,570 African Americans and 1,621 Caribbean Blacks) who participated in the National Survey of American Life, 2001 2003. Five lifetime psychiatric disorders (i.e., major depressive disorder, general anxiety disorder, post-traumatic stress disorder, alcohol abuse disorder, and drug abuse) were considered as the independent variables. Lifetime serious suicidal ideation was considered as the dependent variable. Logistic regressions were used to determine if ethnicity modifies the effects of each psychiatric disorder on serious suicide ideation. Ethnicity was conceptualized as the possible moderator and socio-demographics (i.e., age, gender, education level, employment, marital status and country region) were control variables. RESULTS: Among African Americans, major depressive disorder, general anxiety disorder, post-traumatic stress disorder and alcohol abuse disorder were associated with higher odds of suicidal thoughts. Among Caribbean Blacks, major depressive disorder and drug abuse disorder were associated with higher odds of suicidal thoughts. In the pooled sample, there was a significant interaction between ethnicity and anxiety disorder and a marginally significant interaction between ethnicity and drug abuse. CONCLUSIONS: Based on our study, suicidality due to psychiatric disorders among Black adults in the United States may depend on ethnicity. General anxiety disorder seems to be a more important risk factor for suicidal ideation among African Americans while drug abuse may contribute more to the risk of suicidal thoughts among Caribbean Blacks. PMID- 24404359 TI - Comparing the preventive effect of 2 percent topical lidocaine and intravenous atropine on oculocardiac reflex in ophthalmological surgeries under general anesthesia. AB - BACKGROUND: The current study aimed to determine preventive effect of 2 percent topical xylocaine on oculocardiac reflex in ophthalmological surgeries except strabismus, including retinal detachment and vitrectomy with scleral buckling under general anesthesia. METHODS: A randomized controlled clinical trial was carried out on 150 patients aged 18-90 years undergoing ophthalmological surgeries under general anesthesia. Samples randomly divided into the experimental group (received four drops of 2 percent topical xylocaine instilled in desired eye) and control group (received 0.5 mg atropine sulfate injection). Systolic, diastolic and mean arterial blood pressure of patients and baseline heart rate were recorded. They were compared regarding the incidence of bradycardia, heart rate less than 60 beats/minute, hypotension and blood pressure less than 90 mm/Hg. Data were analyzed by Statistical Package for the Social Sciences software version 20 using Chi-square and ANOVA. RESULTS: The difference between two groups was not statistically significant regarding demographic and basic variables. The incidence of bradycardia in both groups was respectively (90.7 percent vs. 17.3 percent), heart rate less than 60 beats/minute (40 percent vs. 13.3 percent), hypotension (76 percent vs. 32 percent) and blood pressure less than 90 mmHg was (28 percent vs. 8 percent). Accordingly, the differences between both groups were statistically significant (P > 0.001). CONCLUSIONS: The preventive impact of topical xylocaine upon oculocardiac reflex in ophthalmological surgeries such as retinal detachment and vitrectomy with scleral buckling under general anesthesia was less effective than that of atropine injection. Therefore, to avoid this reflex in high-risk patients, injecting atropine would be safer. PMID- 24404360 TI - Does Carotid Intima-media Thickness have Relationship with Polycystic Ovary Syndrome? AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder associated with cardiovascular disease (CVD) risk factors and metabolic disturbances and a genetically heterogeneous disease. Intima-media thickness (IMT) is an indicator of atherosclerosis. This study aimed to determine the relation between IMT and PCOS in women. METHODS: This cross-sectional study was performed on 44 PCOS patients and 44 healthy women. Data collection included lipid profiles, blood pressure, waist circumference, body mass index (BMI), and common and internal IMT of carotid artery which were measured in studied subjects. IMT was measured by a radiologist using a linear 12 MHz ultrasound probe (LOGIC S6, GE) in carotid setting. RESULTS: IMT of common carotid artery (56.8 +/- 7.6 in cases versus 49.8 +/- 7.3 in controls), internal carotid artery (56.9 +/- 6.03 in cases versus 49.6 +/- 6.9 in controls), and both common and internal carotid artery (56.6 +/- 6.7 in cases versus 49.7 +/- 6.9 in controls) were significantly higher in PCOS patients than healthy women (P < 0.001). CONCLUSIONS: In summary, results demonstrated that carotid artery thickness as a risk for premature atherosclerosis in patients with PCOS is higher than healthy subjects. And hence care and monitoring of PCOS women with these risk factors sounds to be important and necessary. PMID- 24404361 TI - Thyroid Function Test in Pre-term Neonates During the First Five Weeks of Life. AB - BACKGROUND: Congenital hypothyroidism (CHT) is one of the most common congenital endocrinal disorders. The prevalence of CHT is estimated about 1 in 3,000 newborns. The prevalence, etiology and associated disorders of abnormal thyroid screening tests are reported in different ranges. In this study, we assessed the pre-term newborns for CHT and associated factors that influence thyroid function. METHODS: One hundred newborns with the gestational age fewer than 35 weeks were investigated. Baseline serum thyroid stimulating hormone (TSH) and free thyroxin (FT4) levels were measured during the first 5 days of life and were repeated during the first 5 weeks. We analyzed the effects of demographic factors and the presence of respiratory distress syndrome on the alteration of thyroid function tests during the first 5 weeks of life. RESULTS: The mean gestational age (GA) at delivery was 32.35i1.97 (range 28 to 35) weeks. CHT was observed in 13(13%) preterm infants. GA was the only factor which affect the FT4 changes over the two weeks follow-up (P < 0.001, b: -2.783, Power: 70.2%) although the differences between baseline and follow-up amount of TSH were not significantly influenced by GA (P = 0.062, power: 46%). However, the adjusted TSH and FT4 serum level changes during follow-up were significantly different between two groups (between CHT and normal, P = 0.006, 0.000, respectively). CONCLUSIONS: It seems that thyroid function tests should be repeated in preterm infants, especially for patients with lower gestational age, to confirm the diagnosis of CHT. Also, CHT should be considered among the newborns that are affected by RDS. PMID- 24404362 TI - Psychometric properties of the persian version of the multidimensional scale of perceived social support in iran. AB - BACKGROUND: Social support is a complex and multifaceted construct. Thus, It is important that a given social support scale be theoretically grounded and its purview clearly defined. The purpose of this study was to examine the reliability, validity and factor structure of the Iranian version of the Multidimensional Scale of Perceived Social Support (MSPSS). METHODS: The sample study included 176 consecutive myocardial infarction (MI) patients admitted to the coronary care unit (CCU) ward of nine hospitals in Isfahan, Iran, and 71 consecutive subjects from the general population. They all filled out the final Iranian version of the MSPSS and also 71 participants filled out the MSPSS twice over a 2-month period. Factor analysis, Cronbach's alpha coefficient and Pearson's correlation coefficient correlation were used to analyze data. RESULTS: Factor analysis of the scores of the patient and healthy samples yielded a three factor structure, including family, friends and significant others. The percentage of variance explained by the three factors in the patient sample and healthy sample were 77.87% and 78.55%, respectively. Cronbach's alpha coefficient has been found to be 0.84 for the scale and 0.90, 0.93 and 0.85, respectively, for the friends, significant others and family subscales from the patient sample, and 0.92 for the scale and 0.89, 0.92 and 0.87, respectively, for the friends, significant others and family subscales from the healthy sample. Test-retest stability over a 2-month period yielded 0.84 for the scale and 0.73, 0.78 and 0.84, respectively, for the friends, significant others and family subscales from the healthy sample. CONCLUSIONS: The findings proved the three-factor structure of the Iranian version of the MSPSS and indicated that the Iranian version of the MSPSS is a reliable, valid and acceptable measure of perceived social support. PMID- 24404363 TI - Comparing the Effects of Group and Home-based Physical Activity on Mental Health in the Elderly. AB - BACKGROUND: The present study focuses on comparing the effects of home-based (HB) and group-based (GB) physical activity on mental health in a sample of older adults in Shahr-e-kord. METHODS: In this quasi-experimental study, a twice-weekly physical activity program for 2 months was provided either individually at home or in a group format for 181 people who were divided into two groups (HB and GB). The outcome, mental health, was measured with the 28-item General Health Questionnaire (GHQ-28). RESULTS: Mental health status improved after participation in the physical activity program. The decrease in GHQ-28 total score in GB group, 3 months after intervention, was 3.61 +/- 2.28 (P < 0.001). In HB group, this reduction was 1.20 +/- 2.32 during the same period (P < 0.001). The difference of these "before-after differences" between the two groups in the GHQ-28 and all its subscales was statistically significant (P < 0.001). Also, the effects of GB physical activity on mental health compared with HB physical activity, adjusted for related baseline variables, were significant. CONCLUSIONS: These findings reveal the probable effects of GB rather than HB physical activity on mental health among the elderly. PMID- 24404364 TI - Cigarette, Water-pipe, and Medwakh Smoking Prevalence Among Applicants to Abu Dhabi's Pre-marital Screening Program, 2011. AB - BACKGROUND: This study assesses self-reported tobacco use prevalence (cigarette, water-pipe, and medwakh) among applicants to Abu Dhabi's Premarital Screening program during 2011. METHODS: Premarital Screening data reported to the Health Authority - Abu Dhabi from April to December 2011 were utilized to estimate tobacco use prevalence among applicants. Smoking prevalence was examined by nationality, age group and gender. RESULTS: Overall, 24.7% of Premarital Screening Program applicants were current smokers; 11.5% smoked cigarettes, 5.9% smoked medwakh (hand-held pipe), 4.8% smoked water-pipe and 2.5% smoked a combination (more than one type). Men (19.2%) were more likely than women (3.5%) to be current cigarette smokers. Women were much less likely to smoke medwakh (0.1%) than men (11.5%), with male UAE Nationals having the highest medwakh smoking prevalence (16.1%). The overall prevalence of water-pipe smoking was 6.8% among men and 2.8% for women with the highest water-pipe smoking prevalence (10.2%) among Arab expatriate men. CONCLUSIONS: Variations in tobacco use prevalence among Premarital Screening Program applicants reflect preferences for different modes of tobacco consumption by nationality, age group and gender. Enforcement of tobacco control laws, including implementation of clean indoor air laws and tobacco tax increases, and targeted health education programs are required to reduce tobacco consumption and concomitant tobacco-related morbidity and mortality. PMID- 24404365 TI - Out of pocket payment for obstetrical complications: a cost analysis study in iran. AB - BACKGROUND: This study was conducted to determine the total expenditure and out of pocket payment on pregnancy complications in Tehran, the capital of Iran. METHODS: A cross-sectional study conducted on 1172 patients who admitted in two general teaching referral Hospitals in Tehran. In this study, we calculated total and out of pocket inpatient costs for seven pregnancy complications including preeclampsia, intrauterine growth restriction (IUGR), abortion, ante-partum hemorrhage, preterm delivery, premature rupture of membranes and post-dated pregnancy. We used descriptive analysis and analysis of variance test to compare these pregnancy complications. RESULTS: The average duration of hospitalization was 3.28 days and the number of visits by physicians for a patient was 9.79 on average. The average total cost for these pregnancy complications was 735.22 Unites States Dollars (USD) (standard deviation [SD] = 650.53). The average out of packet share was 277.08 USD (SD = 350.74), which was 37.69% of total expenditure. IUGR with payment of 398.76 USD (SD = 418.54) (52.06% of total expenditure) had the greatest amount of out of pocket expenditure in all complications. While, abortion had the minimum out of pocket amount that was 148.77 USD (SD = 244.05). CONCLUSIONS: Obstetrics complications had no catastrophic effect on families, but IUGR cost was about 30% of monthly household non-food costs in Tehran so more financial protection plans and insurances are recommended for these patients. PMID- 24404366 TI - An algorithm of smoking stages assessment in adolescents: a validation study using the latent class analysis model. AB - BACKGROUND: Notwithstanding the importance of smoking stages evaluation in adolescents, there is not an appropriate instrument for its measurement. This study aims to introduce an appropriate instrument for measurement of smoking stages in adolescents and to examine its validity using latent class analysis (LCA) model. METHODS: We designed an algorithm to measure the smoking stages. The relevancy and clarity of the algorithm was examined by experts and lay experts. We assessed the reliability of our algorithm using test-retest method. Moreover, using the LCA, we studied the validity of the stages measured by the designed algorithm in 4903 students (ages 14-19), who were randomly selected from grade 10 high school students in Tabriz (North-West of Iran). RESULTS: The algorithm content validity indicates high relevancy and clarity percentages. Intra-class correlation of 0.929 was found in the assessment of the reliability of smoking stages (9 stages) in 154 students within a two-week interval. The LCA model revealed nine interpretable classes (G(2) = 0.051, df = 1, P = 0.821) for the measurement of smoking stages. Examination of the smoking cessation stages in a sample of 218 students in the cessation stage demonstrated that the results for five classes could be interpreted (G(2) = 0.001, df = 1, P = 0.975). CONCLUSIONS: The results suggested that this algorithm is clear, valid, and reliable. PMID- 24404367 TI - The Study Protocol of Women's Education to Create Smoke-free Home on the Basis of Family Ties in Isfahan, Iran. AB - BACKGROUND: Tobacco smoke is the leading cause of preventable death world-wide. Unfortunately, the risk is not limited to smokers. It is dangerous for non smokers particularly women, kids and elderly. Despite the remarkable reduction of tobacco exposure in public places, it is still continuing at homes as the most common places. Interventions to create a smoke-free home are needed, but little is known about them. The aim of this study is to explain the field randomized controlled trial that is designed to examine the role of non-smoker women to create a smoke-free home through establishing complete agreement on ban smoking at home. METHODS: In this field randomized controlled trial, the effectiveness of women's education will be evaluated in primary health-care centers. A total of 136 non-smoker women who exposed to second-hand smoke by their husbands at home will be included (68 intervention/non-intervention group). The intervention arm will receive an educational package including a consultation visit individually, a peer group session, a booklet, a "no smoking" sign. The primary outcome is the frequency of smoke-free home (no exposure to second-hand smoke at home). Mediator outcomes include a complete agreement to ban smoking at home, second-hand smoke exposure rate and self-assertiveness rate. All measurements will be conducted on baseline, 1 and 3 months after intervention. CONCLUSIONS: Outcomes will present the effects of implementing multi-component women's education intervention program to ban smoking at home. If the effectiveness of the trial is confirmed, it will be suggested to merge this package to routine care in primary health-care centers. PMID- 24404368 TI - Prevention of renal damage by treating hyperuricemia. AB - Nephrolithiasis, obstructive renal failure, essential hypertension, and chronic tubulointerstitial nephritis have been considered as the renal complications of hyperuricemia. Massive proteinuria has been rarely reported as the primary manifestation of increased serum uric acid. This is the report of a child presented with proteinuira, hypertension, and glomerular scelrosis secondary to hypouricosuric hyperuricemia, who was treated by uric acid lowering management. PMID- 24404369 TI - Primary perianal tuberculosis in a diabetic patient. AB - Primary perianal tuberculosis is a rare form of extra pulmonary tuberculosis. We present a case of perianal tuberculosis without any pulmonary or gastrointestinal involvement in a diabetic patient. Histopathological examination of perianal lesion demonstrated loose granulomas and positive staining for Erlich-Ziehl Neelsen (EZN) stain. PMID- 24404370 TI - The significance of the psychosocial factors influence in pathogenesis of cardiovascular disease. AB - BACKGROUND: Cardiovascular diseases (CVD) are the leading cause of death in the world today. Risk factors are those factors that influence the development of CVD. Risk factors can be divided into materialistic (genetic predisposition, smoking, alcohol) and non-materialistic (psychosocial factors). Our goal is to note the role of the health system, to emphasize the importance of psychosocial factors in the pathogenesis of CVD, explain the relationship between psychosocial factors and other risk factors, stress the importance of prevention through the provision of management of the cardiovascular system (CVS) diseases. METHODS: A DESCRIPTIVE ANALYSIS WAS PERFORMED ON SCIENTIFIC STUDIES IN SEVERAL PUBLISHED ARTICLES IN JOURNALS ON CVS: Public Health Reviews, CVD, European Heart Journal, Materia Socio Medica and other indexed journals that publish articles on CVS. RESULTS AND CONCLUSIONS: THE IMPORTANCE AND ROLE OF THE HEALTH SYSTEM IN THE EARLY DETECTION, DIAGNOSIS, THERAPY AND CVS DISEASE PREVENTION IS PRESENTED THROUGH THREE THEMATIC AREAS: (a) The incidence and prevalence of CVS diseases; (b) treatment of CVS diseases and (c) promotion of health in patients with CVS disease and those the risk of their occurrence. Health promotion is the most important aspect of the health system monitoring. Health promotion is adequately implemented ifthe management ofCVD is proper. The main objectives of CVD management are: Preventing or delaying the occurrence of CVD, reducing the number and severity of worsening and complications of CVD. Management Includes: Individual and family, the health system and the community. Materialistic and non materialistic risk factors together contribute to the development of CVD. PMID- 24404371 TI - Application of PHEL - 'Public Health Epidemiological Logic' of Public Health Intervention and Public Health Impact. AB - There is a growing tendency where medicalization of public health through mass therapeutics and secondary preventive measures are being substituted for primary preventive activity. Scaled-up mass therapeutic intervention in the community is being confused with public health intervention. The objective of this paper is to provide a broad public health and epidemiological criteria for public health intervention and public health impact. PMID- 24404372 TI - Social problem solving ability predicts mental health among undergraduate students. AB - BACKGROUND: The main objective of this study was predicting student's mental health using social problem solving- ability. METHODS: In this correlational. descriptive study, 369 (208 female and 161 male) from, Mazandaran University of Medical Science were selected through stratified random sampling method. In order to collect the data, the social problem solving inventory-revised and general health questionnaire were used. Data were analyzed through SPSS-19, Pearson's correlation, t test, and stepwise regression analysis. RESULTS: Data analysis showed significant relationship between social problem solving ability and mental health (P < 0.01). Social problem solving ability was significantly associated with the somatic symptoms, anxiety and insomnia, social dysfunction and severe depression (P < 0.01). CONCLUSIONS: The results of our study demonstrated that there is a significant correlation between social problem solving ability and mental health. PMID- 24404373 TI - Exploring the impact of public health measures in prevention and control of oral cancer. PMID- 24404374 TI - Carbonium vs. carbenium ion-like transition state geometries for carbocation cyclization - how strain associated with bridging affects 5-exo vs. 6-endo selectivity. AB - Quantum chemical calculations are used to explore the origins of regioselectivity for proton-, Pt(II)- and Pd(II)-promoted cyclizations of 1,5-hexadienes, 5 aminoalkenes, and allylic acetimidates. The strain associated with achieving carbonium ion-like transition state geometries is shown to be a key factor in controlling 5-exo vs. 6-endo selectivity. PMID- 24404375 TI - Special Review: Accelerating fracture repair in humans: a reading of old experiments and recent clinical trials. AB - Based on their mode of action and preclinical data, one would expect bisphosphonates to improve the healing of fractures in cancellous bone, and bone morphogenetic proteins (BMPs) to reduce the risk of non-union in severe shaft fractures. Parathyreoid hormone (PTH) can be expected to accelerate fracture healing in general. The clinical data in support of this is meager. Stimulation of cancellous bone healing and strength by bisphosphonates has been inadvertently shown in the context of implant fixation, but not convincingly in fractures per se. The clinical BMP literature is confusing, and the chance of ever demonstrating reduced numbers of non-union are small, due to power issues. Still, acceleration of 'normal' healing may be possible, but largely remains to show. For PTH, the two available clinical trials both show accelerated healing, but none of them is flawless, and there is a need for better studies. PMID- 24404376 TI - Regulation of postnatal bone homeostasis by TGFbeta. AB - Perhaps more so than any other tissue, bone has pivotal mechanical and biological functions. Underlying the ability of bone to execute these functions, whether providing structural support or preserving mineral homeostasis, is the dynamic remodeling of bone matrix. Cells within bone integrate multiple stimuli to balance the deposition and resorption of bone matrix. Transforming growth factor beta (TGFbeta) uniquely coordinates bone cell activity to maintain bone homeostasis. TGFbeta regulates the differentiation and function of both osteoblasts and osteoclasts, from lineage recruitment to terminal differentiation, to balance bone formation and resorption. TGFbeta calibrates the synthesis and material quality of bone matrix and bone's responsiveness to applied mechanical loads. Therefore, by coupling the activity of bone forming and resorbing cells, and by sensing, responding to and defining physical cues, TGFbeta integrates physical and biochemical stimuli to maintain bone homeostasis. Disruption of TGFbeta signaling has significant consequences on bone mass and quality. Alternatively, TGFbeta is a powerful lever that has the potential to yield therapeutic benefit in cases where bone homeostasis needs to be recalibrated. PMID- 24404377 TI - Nanomolecular changes in trabeculae due to bisphosphonate therapy. PMID- 24404378 TI - Tissue flaps and their use in open tibial fractures: a complex picture. PMID- 24404379 TI - APC gene copy number significantly associated with bone mineral density in humans. PMID- 24404380 TI - Osterix and Runx2 cooperate to induce expression of the Col1a1 promoter. PMID- 24404381 TI - Dye-Sensitized Nanostructured Crystalline Mesoporous Tin-doped Indium Oxide Films with Tunable Thickness for Photoelectrochemical Applications. AB - A simple route towards nanostructured mesoporous Indium-Tin Oxide (templated nano ITO) electrodes exhibiting both high conductivities and optimized bicontinuous pore-solid network is reported. The ITO films are first produced as an X-ray amorphous, high surface area material, by adapting recently established template directed sol-gel methods using Sn(IV) and In(III) salts. Carefully controlled temperature/atmosphere treatments convert the as-synthesized ITO films into nano crystalline coatings with the cubic bixbyite structure. Specially, a multi layered synthesis was successfully undertaken for tuning the film thickness. In order to evaluate the performances of templated nano-ITO as an electrode substrate for photoelectrochemical applications, photoelectrodes were prepared by covalent grafting of a redox-active dye, the complex [Ru(bpy)2(4,4'-(CH2PO3H2)2 bpy)]Cl21 (bpy=bipyridine). Surface coverage was shown to increase with the film thickness, from 0.7 * 10-9 mol.cm-2 (one layer, 45 nm) to 3.5 * 10-9 mol.cm-2 (ten layers, 470 nm), the latter value being ~ 100 times larger than that for commercially available planar ITO. In the presence of an electron mediator, photocurrents up to 50 MUA.cm-2 have been measured under visible light irradiation, demonstrating the potential of this new templated nano-ITO preparation for the construction of efficient photoelectrochemical devices. PMID- 24404382 TI - Extracorporeal membrane oxygenation. AB - Extracorporeal membrane oxygenation (ECMO) is an advanced form of life support technology whereby venous blood is oxygenated outside of the body and returned to the patient. ECMO was initially used as last-resort rescue therapy for patients with severe respiratory failure. Over the last four decades, it has developed into a safe, standard therapy for newborns with progressive cardiorespiratory failure, as a resuscitation therapy after cardiac arrest, and in combination with other treatments such as hypothermia and various blood filtration therapies. ECMO has also become routine for children and adults with all forms of cardiogenic shock and is also routine in early graft failure after transplantation. The one area of ongoing debate is the role of ECMO in adults with hypoxemic respiratory failure. As ECMO equipment becomes safer, earlier use improves patient outcomes. Several modifications of the two basic venovenous and venoarterial ECMO systems are now occurring, as are many minor variations in cannulation strategies and systems of care for patients receiving ECMO. The indications and situations in which ECMO have been tried continue to change, and ECMO for sub-acute and chronic illnesses is now commonplace, as is the use of ECMO in patients with clinical problems previously regarded as contraindications, such as sepsis, malignancy, and immunosuppression. PMID- 24404383 TI - Autism genes keep turning up chromatin. AB - Autism-spectrum disorders (ASD) are complex genetic disorders collectively characterized by impaired social interactions and language as well as repetitive and restrictive behaviors. Of the hundreds of genes implicated in ASD, those encoding proteins acting at neuronal synapses have been most characterized by candidate gene studies. However, recent unbiased genome-wide analyses have turned up a multitude of novel candidate genes encoding nuclear factors implicated in chromatin remodeling, histone demethylation, histone variants, and the recognition of DNA methylation. Furthermore, the chromatin landscape of the human genome has been shown to influence the location of de novo mutations observed in ASD as well as the landscape of DNA methylation underlying neurodevelopmental and synaptic processes. Understanding the interactions of nuclear chromatin proteins and DNA with signal transduction pathways and environmental influences in the developing brain will be critical to understanding the relevance of these ASD candidate genes and continued uncovering of the "roots" of autism etiology. PMID- 24404384 TI - Influence of Age and Nutritional Status on Flight Performance of the Asian Tiger Mosquito Aedes albopictus (Diptera: Culicidae). AB - The Asian tiger mosquito, Aedes albopictus, is a competent vector for arboviruses and recently was implicated as the vector of the first autochthonous cases of dengue and chikungunya in southern Europe. The objective of this study was to analyze the flight performance of female Ae. albopictus of different ages that were starved, sugar-fed, or sugar-fed and blood-fed, using flight mills. After three days of starvation post emergence, females flew an average distance of 0.7 +/- 0.5 km in 1.9 +/- 1.5 h during a 16 h trial period, whereas sugar- or sugar- and blood-fed females of this age covered a significantly higher distance of around 3 km with a mean total flight time of around 6 h. The age of females (up to four weeks) had no effect on performance. The average of maximal continuous flight segments of sugar-fed (2.14 +/- 0.69 h) and blood-fed (3.17 +/- 0.82 h) females was distinctly higher than of starved females (0.38 +/- 0.15 h) of which most flyers (83%) performed maximal flight segments that lasted no longer than 0.5 h. Overall, the results for the laboratory monitored flight performance of Ae. albopictus confirm their ability to disperse a few kilometres between breeding site and host. PMID- 24404385 TI - Embarking on a new journey with the allergy, asthma & immunology research. PMID- 24404386 TI - The efficacy of glucocorticoid on macrolide resistant Mycoplasma pneumonia in children. PMID- 24404387 TI - Histamine-releasing factor and immunoglobulins in asthma and allergy. AB - Factors that can induce the release of histamine from basophils have been studied for more than 30 years. A protein termed histamine-releasing factor (HRF) was purified and molecularly cloned in 1995. HRF can stimulate histamine release and IL-4 and IL-13 production from IgE-sensitized basophils and mast cells. HRF-like activities were found in bodily fluids during the late phase of allergic reactions, implicating HRF in allergic diseases. However, definitive evidence for the role of HRF in allergic diseases has remained elusive. On the other hand, we found effects of monomeric IgE on the survival and activation of mast cells without the involvement of a specific antigen, as well as heterogeneity of IgEs in their ability to cause such effects. The latter property of IgE molecules seemed to be similar to the heterogeneity of IgEs in their ability to prime basophils in response to HRF. This similarity led to our recent finding that ~30% of IgE molecules can bind to HRF via their Fab interactions with two binding sites within the HRF molecule. The use of peptide inhibitors that block HRF-IgE interactions revealed an essential role of HRF to promote skin hypersensitivity and airway inflammation. This review summarizes this and more recent findings and provides a perspective on how they impact our understanding of allergy pathogenesis and potentially change the treatment of allergic diseases. PMID- 24404388 TI - Molecular genetic mechanisms of chronic urticaria. AB - Chronic urticaria (CU) is a common allergic skin disease that requires long-term pharmacological treatment. Some patients with severe CU suffer a poor quality of life. Although the pathogenic mechanisms of CU are not clearly understood, several groups have suggested that genetic mechanisms are involved in various CU cohorts. To further understand the molecular genetic mechanisms of CU, we summarize recent genetic data in this review. Although a few HLA alleles were suggested to be candidate markers in different ethnic groups, further replication studies that apply the recent classification are needed. Genetic polymorphisms in histamine-related genes, including FcepsilonRI and HNMT, were suggested to be involved in mast cell activation and histamine metabolism. Several genetic polymorphisms of leukotriene-related genes, such as ALOX5, LTC4S, and the PGE2 receptor gene PTGER4, were suggested to be involved in leukotriene overproduction, a pathogenic mechanism. Further investigations using candidate gene approaches and genome-wide association studies (GWAS) will provide new insights into the molecular genetic mechanisms of CU, which will provide new marker genes for differentiation of CU phenotypes and identification of potential therapeutic targets. PMID- 24404389 TI - Effects of Methylprednisolone Pulse Therapy on Refractory Mycoplasma pneumoniae Pneumonia in Children. AB - PURPOSE: Mycoplasma pneumoniae (M. pneumoniae) is one of the most common causes of community-acquired pneumonia in children. The clinical course is typically self-limited and benign; however, rare cases of severe pneumonia can develop despite appropriate antibiotic therapy. We studied the effects of methylprednisolone pulse therapy on severe refractory M. pneumoniae pneumonia in children. METHODS: The clinical effects of methylprednisolone therapy were evaluated retrospectively in 12 children with severe refractory M. pneumoniae pneumonia, which was diagnosed serologically. All patients developed respiratory distress, high fever, and initial lobar pneumonic consolidation based on radiological findings. All clinical symptoms deteriorated despite appropriate antibiotic therapy. Thus, children were treated with intravenous methylprednisolone pulse therapy in addition to antibiotics. RESULTS: The average febrile period before admission was 4.9+/-1.7 days, and fever persisted in all children until steroid administration. Methylprednisolone pulse therapy (30 mg/kg) was given 5.4+/-2.5 days after admission. After methylprednisolone pulse therapy, clinical symptoms improved in all patients without adverse events. The fever subsided 0-2 h after initiation of corticosteroid therapy. The abnormal radiological findings resolved within 2.6+/-1.3 days, and the high C-reactive protein levels (6.7+/-5.9 mg/dL) on admission decreased to 1.3+/-1.7 mg/dL within 3.0+/-1.1 days after starting corticosteroid therapy. CONCLUSIONS: Three-day methylprednisolone pulse therapy could be applied to treatment of refractory M. pneumoniae pneumonia despite appropriate antibiotic therapy and appeared to be efficacious and well-tolerated. PMID- 24404390 TI - Fractional exhaled nitric oxide and impulse oscillometry in children with allergic rhinitis. AB - PURPOSE: Airway inflammation, bronchial hyper-responsiveness (BHR), and bronchodilator response (BDR) are representative characteristics of asthma. Because allergic rhinitis (AR) is a risk factor for asthma development, we evaluated these 3 characteristics in AR using measurement of fractional exhaled nitric oxide (FeNO), a methacholine challenge test (MCT), and impulse oscillometry (IOS). METHODS: This study included 112 children with asthma (asthma group), 196 children with AR (AR group), and 32 control subjects (control group). We compared pulmonary function parameters and FeNO levels among the 3 groups. The AR group was subdivided into 2 categories: the AR group with BHR and the AR group without, and again pulmonary function and FeNO levels were compared between the 2 subgroups. RESULTS: FeNO levels were more increased in the AR and asthma groups than in the control group; within the AR group, FeNO was higher in the AR group with BHR than in the AR group without. The BDR was more increased in the AR group than in the control group when percent changes in reactance at 5 Hz (Delta X5) and reactance area (Delta AX) were compared. In the AR group, however, there was no difference in Delta X5 and Delta AX between the AR group with BHR and the AR group without. CONCLUSIONS: Reversible airway obstruction on IOS and elevated FeNO levels were observed in children with AR. Because elevated FeNO levels can indicate airway inflammation and because chronic inflammation may lead to BHR, FeNO levels may be associated with BHR in AR. IOS can be a useful tool for detecting lower airway involvement of AR independent of BHR assessed in the MCT. PMID- 24404391 TI - Can Fecal Calprotectin Level Be Used as a Markers of Inflammation in the Diagnosis and Follow-Up of Cow's Milk Protein Allergy? AB - PURPOSE: Calprotectin is a cytosolic protein with immunomodulatory, antimicrobial, and antiproliferative actions. The concentration of calprotectin increases in infection, inflammation, and malignancy. We determined if calprotectin can be used as a marker for the diagnosis and follow-up of bowel inflammation in cow's milk protein allergy (CMPA). METHODS: In total, 32 patients newly diagnosed with CMPA were included (24 IgE-mediated, 8 non-IgE-mediated). In all subjects, a complete blood count, total IgE, cow's milk-specific IgE, and fecal calprotectin (FC) were assessed before and after a cow's milk protein (CMP) elimination diet was started. The results were compared with those of 39 healthy children. RESULTS: The mean FC value before the CMP elimination diet was 516+/ 311 ug/g in the 32 patients with CMPA and 296+/-94 ug/g in the control group (P=0.011). The mean FC value after the diet in these patients was 254+/-169 ug/g, which was significantly different from the mean value before the CMP elimination diet (P<0.001). When we compared FC levels before the CMP elimination diet in the IgE-mediated group with the control group, we found no significant statistical difference (P=0.142). The mean FC value before the CMP elimination diet was 886+/ 278 ug/g in the non-IgE-mediated group and 296+/-94 ug/g in the control group; this difference was statistically significant (P<0.001). In the IgE-mediated and non-IgE-mediated groups, FC values after CMP elimination diet were 218+/-90 ug/g and 359+/-288 ug/g, respectively, and FC values before CMP elimination diet were 392+/-209 ug/g and 886+/-278 ug/g, respectively; these differences were statistically significant (P=0.001 and P=0.025, respectively). CONCLUSIONS: FC levels may be a useful marker for follow-up treatment and recurrence determination in CMPA. PMID- 24404392 TI - Eosinophilic airway inflammation and airway hyperresponsiveness according to aeroallergen sensitization pattern in patients with lower airway symptoms. AB - PURPOSE: Sensitization to specific allergens may be important in the development of allergic airway inflammation and airway hyperresponsiveness (AHR). We evaluated the effect of specific aeroallergen sensitization on eosinophilic airway inflammation and AHR. METHODS: We reviewed retrospectively the clinical data of subjects who underwent skin prick tests to aeroallergens, induced sputum analysis, and methacholine bronchial provocation tests to evaluate lower airway symptoms as well as analyzed the associations between the pattern of aeroallergen sensitization and sputum eosinophilia or AHR. RESULTS: Of the 1,202 subjects be enrolled, 534 (44.4%) were sensitized to at least one aeroallergen in skin tests. AHR was demonstrated in 23.5% and sputum eosinophilia in 38.8%. Sputum eosinophilia was significantly associated with sensitization to perennial allergens (OR, 1.9; 95% CI, 1.4-2.5), house dust mite (OR, 1.7; 95% CI, 1.3-2.3), dog (OR, 1.9; 95% CI, 1.1-3.3), and cat (OR, 2.1; 95% CI, 1.4-3.4). AHR was associated with sensitization to perennial allergens (OR, 2.7; 95% CI, 2.0-3.7), house dust mite (OR, 2.2; 95% CI, 1.6 3.2), Alternaria (OR, 2.3; 95% CI, 1.2 4.7), and cat (OR, 2.7; 95% CI, 1.7-4.3). Sensitization to more perennial allergens increased the risk for sputum eosinophilia and AHR. There was no relationship with individual seasonal allergens. CONCLUSION: The development of airway eosinophilic inflammation and AHR in an adult Korean population was associated with sensitization to perennial allergens rather than seasonal allergens. PMID- 24404393 TI - Variability of offending allergens of allergic rhinitis according to age: optimization of skin prick test allergens. AB - PURPOSE: This study evaluates offending allergens in patients with allergic rhinitis (AR) according to age that establish a minimal panel for skin prick test (SPT) allergens required to identify if a patient is sensitized. METHODS: We retrospectively analyzed SPT results according to age to determine the minimum test battery panel necessary to screen at least 93%-95% of AR patients. Allergic skin tests (common airborne indoor and outdoor allergens) were performed on 7,182 patients from January 2007 to June 2011. All patients were classified into 9 groups according to age; subsequently, we investigated offending allergens by age group. RESULTS: A total of 5,032 (70.1%) patients were found sensitized to at least one of the 55 aeroallergen extracts tested. The annual ranking of offending allergens was not significantly different from each other over the past 5 years. House dust mites (HDM) were the most prevalent allergens ranked from first to third for all 5 years. The allergens in the minimum test panel differed slightly among all age groups; in addition, the types of sensitized allergen sources were more diverse in the older versus younger age group. HDM covered a larger proportion of the sensitized allergens in the younger age group versus the older age group. Testing with 5 allergens (Dermatophagoides farinae, Tetranychus urticae, oak, mugwort and cockroach) adequately identified over 90% of the sensitized patients. CONCLUSIONS: A SPT with around 5-7 allergens adequately detected most of the sensitization in the majority of the age groups in Korea. However, this study suggests that physicians perform the SPT with appropriately selected allergens in each age category for the screening of AR. PMID- 24404394 TI - Gene-Gene Interaction Between CCR3 and Eotaxin Genes: The Relationship With Blood Eosinophilia in Asthma. AB - PURPOSE: Eosinophils function as an effector cell in the development of asthma and allergic disease. Eotaxins are cytokines that promote pulmonary eosinophilia via the receptor CCR3. Single-nucleotide polymorphisms (SNPs) in CCR3 and eotaxin genes are associated with asthma. In this study, genetic interactions among SNPs of several eotaxin genes and CCR3 were assessed and their relationship with blood eosinophilia in asthma was examined. METHODS: A total of 533 asthmatics were enrolled in this study. Asthmatics with eosinophilia (>0.5*10(9)/L) were compared with those without eosinophilia (<=0.5*10(9)/L). Chi-square tests were used to compare SNP frequencies. Two different models were used to evaluate gene-gene interactions: logistic regression and generalized multifactor dimensionality reduction (GMDR). RESULTS: EOT2+304C>A (29L>I) was significantly associated with 3 of the 4 CCR3 SNPs among asthmatics with eosinophilia (P=0.037-0.009). EOT2+304C>A (29L>I) and the CCR3 SNPs were also significantly associated with blood eosinophilia in an interaction model constructed by logistic regression (P=0.0087). GMDR analysis showed that the combination of EOT2+304C>A (29L>I) and CCR3-174C>T was the best model (accuracy=0.536, P=0.005, CVC 9/10). CONCLUSIONS: The epistatic influence of CCR3 on eotaxin gene variants indicates that these variants may be candidate markers for eosinophilia in asthma. PMID- 24404395 TI - Bioactive lysophosphatidylcholine 16:0 and 18:0 are elevated in lungs of asthmatic subjects. AB - PURPOSE: Asthma is a chronic inflammatory disease of the airways, and is associated with upregulation of phospholipase A2 (PLA2), the enzyme that hydrolyzes phosphatidylcholine, producing lysophosphatidylcholine (LPC) and free fatty acids. LPC is a lipid mediator with known pro-inflammatory and pro atherogenic properties, and is believed to be a critical factor in cardiovascular diseases. We postulate that asthmatic subjects have an elevated content of LPC in the lung lining fluids. METHODS: Eight non-asthmatic controls and seven asthmatic subjects were recruited for broncho-alveolar lavage fluids (BALF) collection for analysis of LPC by high performance liquid chromatography-tandem mass spectrometry. RESULTS: LPC16:0 and LPC18:0 were significantly elevated in the BALF of asthmatics with impaired lung function characteristic of moderate asthma, but not mild asthma. The increased LPC content in BALF was accompanied by increased PLA2 activity. Furthermore, qRT-PCR analysis of the BALF cell fraction indicated increased secretory PLA2-X (sPLA2-X). CONCLUSIONS: The increased LPC content in the lung lining fluids is a potential critical lipid mediator in the initiation and/or progression of airway epithelial injury in asthma. PMID- 24404396 TI - Stimulated bronchial epithelial cells release bioactive lysophosphatidylcholine 16:0, 18:0, and 18:1. AB - PURPOSE: In human subjects and animal models with acute and chronic lung injury, the bioactive lysophosphatidylcholine (LPC) is elevated in lung lining fluids. The increased LPC can promote an inflammatory microenvironment resulting in lung injury. Furthermore, pathological lung conditions are associated with upregulated phospholipase A2 (PLA2), the predominant enzyme producing LPC in tissues by hydrolysis of phosphatidylcholine. However, the lung cell populations responsible for increases of LPC have yet to be systematically characterized. The goal was to investigate the LPC generation by bronchial epithelial cells in response to pathological mediators and determine the major LPC species produced. METHODS: Primary human bronchial epithelial cells (NHBE) were challenged by vascular endothelial growth factor (VEGF) for 1 or 6 h, and condition medium and cells collected for quantification of predominant LPC species by high performance liquid chromatography-tandem mass spectrometry (LC-MS-MS). The cells were analyzed by quantitative reverse transcriptase polymerase chain reaction (qRT PCR) for PLA2. The direct effects of LPC in inducing inflammatory activities on NHBE were assessed by transepithelial resistance as well as expression of interleukin-8 (IL-8) and matrix metalloproteinase-1 (MMP-1). RESULTS: VEGF stimulation of NHBE for 1 or 6 h, significantly increased concentrations of LPC16:0, LPC18:0, and LPC18:1 in condition medium compared to control. The sPLA2 selective inhibitor (oleyloxyethyl phosphorylcholine) inhibited the VEGF-induced release of LPC16:0 and LPC18:1 and PLA2 activity. In contrast, NHBE stimulated with TNF did not induce LPC release. VEGF did not increase mRNA of PLA2 subtypes sPLA2-X, sPLA2-XIIa, cPLA2-IVa, and iPLA2-VI. Exogenous LPC treatment increased expression of IL-8 and MMP-1, and reduced the transepithelial resistance in NHBE. CONCLUSIONS: Our findings indicate that VEGF-stimulated bronchial epithelial cells are a key source of extracellular LPCs, which can function as an autocrine mediator with potential to induce airway epithelial inflammatory injury. PMID- 24404397 TI - A Quantitative Study of Airway Changes on Micro-CT in a Mouse Asthma Model: Comparison With Histopathological Findings. AB - PURPOSE: To evaluate airway changes in ovalbumin-induced asthmatic mice in terms of postmortem micro-CT images and pathological findings. METHODS: Asthma was induced in mice by intraperitoneal injection and nasal instillation of ovalbumin aluminium hydroxide into mice (experimental group, n=6), and another group of mice received intraperitoneal injection and nasal instillation of distilled phosphate-buffered saline (control group, n=6). Bronchial lumen area was measured in the main bronchial lumen of the distal third bronchial branch level (6 parts per each mouse) on axial scans of Micro-CT, using a Lucion's smart pen (semi automated) and a curve pen (manual). Bronchial wall thickness was obtained in 4 sections (2 levels on either side) after the third bronchial branch by measuring the diameter which was perpendicular to the longitudinal axis of the main bronchus on curved Multi-planar reconstruction (MPR) images. Histologic slides were obtained from the lesion that was matched with its CT images, and bronchial wall thicknesses were determined. RESULTS: The mean bronchial lumen area was 0.196+/-0.072 mm(2) in the experimental group and 0.243+/-0.116 mm(2) in the control group; the difference was significant. Bronchial wall thickness on micro CT images (mean, 0.119+/-0.01 vs. 0.108+/-0.013 mm) and in pathological specimens (mean, 0.066+/-0.011 vs. 0.041+/-0.009 mm) were thicker in the experimental group than in the control group; bronchial wall thickness on micro-CT images correlated well with pathological thickness (for the experimental group, r=0.712; for the control group, r=0.46). The thick bronchial wall in the experimental group demonstrated submucosal hypertrophy along with goblet cell hyperplasia and smooth muscle hyperplasia. CONCLUSIONS: The results of this study suggest that asthma may induce thickening of bronchial wall and narrowing of the lumen area on micro CT images and that these results may significantly correlate with pathological findings. PMID- 24404398 TI - A novel synthetic mycolic Acid inhibits bronchial hyperresponsiveness and allergic inflammation in a mouse model of asthma. AB - PURPOSE: Recognition of microbes is important to trigger the innate immune system. Mycolic acid (MA) is a component of the cell walls of mycobacteria such as Mycobacterium bovis Bacillus Calmette-Guerin. MA has immunogenic properties, which may modulate the innate and adaptive immune response. This study aimed to investigate whether a novel synthetic MA (sMA) inhibits allergic inflammatory responses in a mouse model of asthma. METHODS: BALB/c mice were injected intraperitoneally with sMA followed by sensitization and challenge with ovalbumin (OVA). Mice were examined for bronchial hyperresponsiveness (BHR), the influx of inflammatory cells into the lung tissues, histopathological changes in the lungs and CD4(+)CD25(+)Foxp3(+) T cells in the spleen, and examined the response after the depleting regulatory T cells (Tregs) with an anti-CD25mAb. RESULTS: Treatment of mice with sMA suppressed the asthmatic response, including BHR, bronchoalveolar inflammation, and pulmonary eosinophilic inflammation. Anti CD25mAb treatment abrogated the suppressive effects of sMA in this mouse model of asthma and totally depleted CD4(+)CD25(+)Foxp3(+) T cells in the spleen. CONCLUSIONS: sMA attenuated allergic inflammation in a mouse model of asthma, which might be related with CD4(+)CD25(+)Foxp3(+) T cell. PMID- 24404399 TI - Autologous immunoglobulin therapy in patients with severe recalcitrant atopic dermatitis: a preliminary report. AB - The management of severe recalcitrant atopic dermatitis (AD) is a challenging issue for clinicians and patients. We hypothesized that repeated intramuscular injections of autologous immunoglobulin (autologous immunoglobulin therapy: AIGT) might induce clinical improvements in patients with AD by stimulation of the active immune response to antigen-binding-site of pathogenic antibodies. We tried AIGT in 3 adult patients with severe recalcitrant AD whose clinical conditions could not be effectively controlled by medical treatments (including oral cyclosporine) for more than 2 years. Autologous immunoglobulin was purified from the autologous plasma by affinity chromatography using Protein A. The patients were treated by an intramuscular injection of 50 mg of autologous immunoglobulin twice a week for 4 weeks. A clinical severity score of AD (SCORAD value) showed a decrease greater than 30% at 8 weeks after the initiation of AIGT compared with the baseline before the initiation of AIGT in all 3 patients with severe recalcitrant AD. No significant side effects from treatment were observed. Further studies with larger numbers of patients are required to evaluate the clinical usefulness of AIGT for AD. PMID- 24404400 TI - A Case of Codeine Induced Anaphylaxis via Oral Route. AB - Codeine is widely prescribed in clinical settings for the relief of pain and non productive coughs. Common adverse drug reactions to codeine include constipation, euphoria, nausea, and drowsiness. However, there have been few reports of serious adverse reactions after codeine ingestion in adults. Here, we present a case of severe anaphylaxis after oral ingestion of a therapeutic dose of codeine. A 30 year-old Korean woman complained of the sudden onset of dyspnea, urticaria, chest tightness, and dizziness 10 minutes after taking a 10-mg dose of codeine to treat a chronic cough following a viral infection. She had previously experienced episodes of asthma exacerbation following upper respiratory infections, and had non-atopic rhinitis and a food allergy to seafood. A skin prick test showed a positive response to 1-10 mg/mL of codeine extract, with a mean wheal size of 3.5 mm, while negative results were obtained in 3 healthy adult controls. A basophil histamine release test showed a notable dose-dependent increase in histamine following serial incubations with codeine phosphate, while there were minimal changes in the healthy controls. Following a CYP2D6 genotype analysis, the patient was found to have the CYP2D6*1/*10 allele, indicating she was an intermediate metabolizer. An open label oral challenge test was positive. To the best of our knowledge, this is the first report of a patient presenting with severe anaphylaxis after the ingestion of a therapeutic dose of codeine, which may be mediated by the direct release of histamine by basophils following exposure to codeine. PMID- 24404401 TI - A case of idiopathic hypereosinophilic syndrome presenting with acute respiratory distress syndrome. AB - Although idiopathic hypereosinophilic syndrome(IHES) commonly involves the lung, it is rarely associated with acute respiratory distress syndrome (ARDS). Here we describe a case of IHES presented in conjunction with ARDS. A 37-year-old male visited the emergency department at Samsung Medical Center, Seoul, Korea, with a chief complaint of dyspnea. Blood tests showed profound peripheral eosinophilia and thrombocytopenia. Patchy areas of consolidation with ground-glass opacity were noticed in both lower lung zones on chest radiography. Rapid progression of dyspnea and hypoxia despite supplement of oxygen necessitated the use of mechanical ventilation. Eosinophilic airway inflammation was subsequently confirmed by bronchoalveolar lavage, leading to a diagnosis of IHES. High-dose corticosteroids were administered, resulting in a dramatic clinical response. PMID- 24404402 TI - Microsurgical anatomy of the transsylvian translimen insula approach to the mediobasal temporal lobe: Technical considerations and case illustration. AB - BACKGROUND: Various vascular, neoplastic, and epileptogenic pathologies occur in the mediobasal temporal region. A transsylvian translimen insula (TTI) approach can be used as an alternative to temporal transcortical approach to the mediobasal temporal region. The aim of this study was to demonstrate the surgical anatomy of the TTI approach, including the gyral, sulcal, and vascular anatomy in and around the limen insula. The use of this approach is illustrated in the resection of a complex arteriovenous malformation. METHODS: The TTI approach to the mediobasal temporal region was performed on three silicone-injected cadaveric heads. The gyral, sulcal, and arterial anatomy of the limen insula was studied in six formalin-fixed injected hemispheres. RESULTS: The TTI approach provided access to the anterior and middle segments of the mediobasal temporal lobe region as well as allowing access to temporal horn of the lateral ventricle. Using this approach we were able to successfully resect an arteriovenous malformation of the dominant medial temporal lobe. CONCLUSION: The TTI approach provides a viable surgical route to the region of mediobasal temporal lobe region. This approach offers an advantage over the temporal transcortical route in that there is less risk of damage to optic radiations and speech area in the dominant hemisphere. PMID- 24404403 TI - Beneficial actions of the anti-inflammatory dimethyl fumarate in glioblastomas. AB - BACKGROUND: Dimethylfumarate (DMF), a drug used in the treatment of psoriasis and multiple sclerosis, has been shown to limit the growth of melanoma cells. The ability of DMF to inhibit the Rel protein has been used to explain the antioncogenic properties of this drug. Studies analyzing the effect of DMF in gliomas are limited. Therefore, we investigated the potential antitumor effects of DMF by assessing its effects on proliferation, cell death, and differentiation in gliomas in several glioma models. METHODS: Mouse glioma Gl261, human glioblastoma A172 and human glioblastoma cells from patients were exposed to DMF at therapeutic concentrations (100 MUM) and supratherapeutic concentrations (300 MUM) and studies to assess proliferation, cellular lysis, and differentiation undertaken. The 5-bromo-2'-deoxyuridine (BRDU) proliferation assay and lactate dehydrogenase LDH cell lysis assay were used. Immunocytochemistry was used to assess differentiation: CD133 (stem cell marker), Nestin (progenitor marker), Sox2 (progenitor marker), beta-tubulin III (neuronal marker), glial fibrillary acidic protein (astrocytic marker), and myelin basic protein (oligodendrocytic marker). We also assessed cellular expression of nuclear factor kappa B (NF kappaB) via immunocytochemistry. RESULTS: Proliferation significantly decreased and tumor cell lysis significantly increased in all tumor cell lines after exposure to DMF. The human glioblastoma cells expressed the Neuronal Stem Cell marker CD133, Progenitor Cell markers, Neuronal and Astrocytic Cell Markers in vitro. When exposed to DMF, a drastic decline in CD133 expression was observed in addition to a decrease in the expression of NF-kappaB. CONCLUSION: DMF appears to have a promising role in the treatment of malignant brain neoplasms. DMF reduced proliferation rate, generated cell lysis, decreased the expression of NF-kappaB, and restricted the growth of CD133 cells in gliomas. This suggests that DMF may be considered for further antitumor studies, and provide a new treatment modality for brain tumors. PMID- 24404404 TI - Long segment spinal epidural extramedullary hematopoiesis. AB - BACKGROUND: Extramedullary hematopoiesis is defined as the formation of blood cells outside the bone marrow. It is a common manifestation of many chronic hemolytic anemias, and typically involves the liver, spleen, and lymph nodes. Only rarely is the spinal epidural space involved. METHODS: We describe a 25-year old male, known to have thalassemia intermedia, who presented with a 1-month history of stiffness and weakness in both lower extremities. On physical examination, he had palpable splenomegaly accompanied by spinal tenderness at the D5 level, weakness in both lower extremities, hyperactive bilateral Patellar and Achilles reflexes with bilateral Babinski responses, and a graded sensory loss to pin appreciation below D5. RESULTS: The magnetic resonance (MR) study revealed a posterior, isointense and soft tissue epidural mass extending from D2 to D12 on both the T1- and T2-weighted images. These findings were consistent with the diagnosis of "red marrow," and long-segment spinal epidural extramedullary hematopoiesis. CONCLUSIONS: Although extramedullary hematopoiesis is rarely encountered within the spinal canal, it should be considered among the differential diagnoses when a posterior compressive thoracic lesion contributes to myelopathy in a patient with a history of thalassemia intermedia and the accompanying chronic hemolytic anemia. PMID- 24404406 TI - SlopMap: a software application tool for quick and flexible identification of similar sequences using exact k-mer matching. AB - With the advent of Next-Generation (NG) sequencing, it has become possible to sequence a entire genomes quickly and inexpensively. However, in some experiments one only needs to extract and assembly a portion of the sequence reads, for example when performing transcriptome studies, sequencing mitochondrial genomes, or characterizing exomes. With the raw DNA-library of a complete genome it would appear to be a trivial problem to identify reads of interest. But it is not always easy to incorporate well-known tools such as BLAST, BLAT, Bowtie, and SOAP directly into a bioinformatics pipelines before the assembly stage, either due to incompatibility with the assembler's file inputs, or because it is desirable to incorporate information that must be extracted separately. For example, in order to incorporate flowgrams from a Roche 454 sequencer into the Newbler assembler it is necessary to first extract them from the original SFF files. We present SlopMap, a bioinformatics software utility that allows quickly identification similar to the provided reference reads from either Roche 454 or Illumnia DNA library. With simple and intuitive command-line interface along with file output formats compatible to assembly programs, SlopMap can be directly embedded to biological data processing pipeline without any additional programming work. In addition, SlopMap preserves flowgram information needed for Roche 454 assembler. PMID- 24404405 TI - Gradient Boosting as a SNP Filter: an Evaluation Using Simulated and Hair Morphology Data. AB - Typically, genome-wide association studies consist of regressing the phenotype on each SNP separately using an additive genetic model. Although statistical models for recessive, dominant, SNP-SNP, or SNP-environment interactions exist, the testing burden makes an evaluation of all possible effects impractical for genome wide data. We advocate a two-step approach where the first step consists of a filter that is sensitive to different types of SNP main and interactions effects. The aim is to substantially reduce the number of SNPs such that more specific modeling becomes feasible in a second step. We provide an evaluation of a statistical learning method called "gradient boosting machine" (GBM) that can be used as a filter. GBM does not require an a priori specification of a genetic model, and permits inclusion of large numbers of covariates. GBM can therefore be used to explore multiple GxE interactions, which would not be feasible within the parametric framework used in GWAS. We show in a simulation that GBM performs well even under conditions favorable to the standard additive regression model commonly used in GWAS, and is sensitive to the detection of interaction effects even if one of the interacting variables has a zero main effect. The latter would not be detected in GWAS. Our evaluation is accompanied by an analysis of empirical data concerning hair morphology. We estimate the phenotypic variance explained by increasing numbers of highest ranked SNPs, and show that it is sufficient to select 10K-20K SNPs in the first step of a two-step approach. PMID- 24404407 TI - Differential effects of binge drinking on learning and memory in emerging adults. AB - Alterations in memory function due to alcohol exposure have been observed in both animal models and human populations. The human literature on neurocognitive consequences of binge alcohol use in emerging adults has not systematically investigated its potential negative impacts on visuospatial memory. For instance, these impacts have not yet been assessed using a human analogue of the Morris Water Maze Task (WMT), a key memory measure in the animal literature. Accordingly, this study compared performance between emerging adult binge drinkers (BD, n=22) and age- and sex-matched light drinkers (LD, n=29) using the Morris WMT, as well as verbal memory using the California Verbal Learning Test (CVLT). Emerging adult BD demonstrated worse performance on verbal learning and memory relative to LD. However, no significant group differences were observed on spatial learning and memory. Furthermore, no sex differences or interactions with drinking status were observed on either memory domain. These data suggest that in emerging adults who are at a heightened risk for alcohol abuse disorders, but who do not yet meet diagnostic criteria, verbal learning is uniquely impacted by the neurotoxic effects of binge drinking, whereas spatial learning is relatively spared between bouts of intoxication. PMID- 24404409 TI - Intrauterine volvulus of terminal ileum without malrotation. AB - Neonatal terminal ileum volvulus in the absence of malrotation has never been reported before in English literature. However, another similar rare entity known as neonatal primary segmental volvulus without malrotation has been reported before. Volvulus, in general, is an extreme emergency and cases not diagnosed in time lead to death. The main diagnosis is based on radiological features seen on imaging. We present a case of volvulus of terminal ileum that was diagnosed and surgically treated at age of 15 h ensuring the newborn survived. The definitive diagnosis was based mainly on ultrasonographic findings. PMID- 24404408 TI - Project nGage: Network Supported HIV Care Engagement for Younger Black Men Who Have Sex with Men and Transgender Persons. AB - BACKGROUND: Young Black men who have sex with men and transgender persons (YBMSMT) aged 13-29 carry the nation's highest burden of new HIV infections. Studies indicate that YBMSMT have poor retention in care, which is associated with reduced medication adherence and increased virologic failure. OBJECTIVE: Project nGage is a randomized controlled (RCT) trial evaluating the feasibility and preliminary efficacy of a brief, dyadic intervention designed to promote adherence to HIV primary care in safety-net clinics. Network visualization is used to identify and engage a support confidant (SC) from participants' social networks. A social work interventionist then meets with the SC and SC-participant dyad to activate and maintain HIV-specific social support. METHODS: Project nGage is operating in two phases. In Phase I, the Team refined study protocols based on pilot testing. In Phase II, 94 HIV infected YBMSMT ages 16-29 will be recruited, enrolled and randomly assigned to receive Project nGage or treatment as usual (TAU). The primary outcome is appointment attendance; the secondary outcomes are medication adherence and viral load. RESULTS: Implementation challenges include coordinating sites, managing dyadic intervention logistics, and recruiting non adherent patients or those who have fallen out of care. The team continues to address implementation issues as the study progresses. CONCLUSIONS: Project nGage is addressing a gap in HIV care-related research by focusing on supportive relationships as a mechanism through which to promote retention in care. Pending study results, a larger RCT would compare the relative effectiveness of the Project nGage intervention versus TAU over 18 to 24 months. PMID- 24404410 TI - Vena caval anomalies. AB - Anomalous vena cavae can have significant implications for procedures on the right side of the heart. We report a rare anatomical configuration in a 44-year old female, which to the best of our knowledge, is the first report of such an association. She had a bicuspid aortic valve in conjunction with a persistent left superior vena cava (PLSVC) draining into the coronary sinus, and a left sided inferior vena cava (IVC) draining into a left superior vena cava via the hemiazygos vein. Comprehensive assessment of these anomalies is crucial given the widespread use of invasive cardiac procedures. PMID- 24404411 TI - Malignant mesenchymal renal tumor: a rare case of primary renal fibrosarcoma. AB - Malignant mesenchymal neoplasms of kidney constitute a rare group of tumors. Primary fibrosarcoma of kidney is an extremely rare subtype of primary malignant mesenchymal renal neoplasms. An elderly female presented with a gradually increasing abdominal lump and mild abdominal discomfort. On cross-sectional imaging, the lesion showed features suggestive of an atypical renal mass not conforming to either ball or bean type growth pattern. The mass was surgically removed and on histopathological and immunohistological investigations diagnosed to be primary renal fibrosarcoma. PMID- 24404412 TI - Diffusion Tensor Imaging of the Kidneys: Influence of b-Value and Number of Encoding Directions on Image Quality and Diffusion Tensor Parameters. AB - OBJECTIVES: The purpose of this study was to evaluate to which degree investment of acquisition time in more encoding directions leads to better image quality (IQ) and what influence the number of encoding directions and the choice of b values have on renal diffusion tensor imaging (DTI) parameters. MATERIAL AND METHODS: Eight healthy volunteers (32.3 y +/- 5.1 y) consented to an examination in a 1.5T whole-body MR scanner. Coronal DTI data sets of the kidneys were acquired with systematic variation of b-values (50, 150, 300, 500, and 700 s/mm(2)) and number of diffusion-encoding directions (6, 15, and 32) using a respiratory-triggered echo-planar sequence (TR/TE 1500 ms/67 ms, matrix size 128 * 128). Additionally, two data sets with more than two b-values were acquired (0, 150, and 300 s/mm(2) and all six b-values). Parametrical maps were calculated on a pixel-by-pixel basis. Image quality was determined with a reader score. RESULTS: Best IQ was visually assessed for images acquired with 15 and 32 encoding directions, whereas images acquired with six directions had significantly lower IQ ratings. Image quality, fractional anisotropy, and mean diffusivity only varied insignificantly for b-values between 300 and 500 s/mm(2). In the renal medulla fractional anisotropy (FA) values between 0.43 and 0.46 and mean diffusivity (MD) values between 1.8-2.1 * 10(-3) mm(2)/s were observed. In the renal cortex, the corresponding ranges were 0.24-0.25 (FA) and 2.2-2.8 * 10( 3) mm(2)/s (MD). Including b-values below 300 s/mm(2), notably higher MD values were observed, while FA remained constant. Susceptibility artifacts were more prominent in FA maps than in MD maps. CONCLUSION: In DTI of the kidneys at 1.5T, the best compromise between acquisition time and resulting image quality seems the application of 15 encoding directions with b-values between 300 and 500 s/mm(2). Including lower b-values allows for assessment of fast diffusing spin components. PMID- 24404413 TI - Radiological imaging findings of a case with vertebral osteoid osteoma leading to brachial neuralgia. AB - Osteoid osteoma is a small, benign osteoblastic tumor consisting of a highly vascularized nidus of connective tissue surrounded by sclerotic bone. Three quarters of osteoid osteomas are located in the long bones, and only 7-12% in the vertebral column. The classical clinical presentation of spinal osteoid osteoma is that of painful scoliosis. Other clinical features include nerve root irritation and night pain. Osteoid osteoma has characteristic computed tomography (CT) findings. Because magnetic resonance imaging (MRI) findings of the osteoid osteomas causing intense perinidal edema can be confusing, these patients should be evaluated with clinical findings and other imaging techniques. In this study, we present X-ray, CT, and MRI findings of a case with osteoid osteoma located in thoracic 1 vertebra left lamina and transverse process junction leading to brachial neuralgia symptoms. PMID- 24404414 TI - Computed tomography findings of an unusual maxillary sinus mass: brown tumor due to tertiary hyperparathyroidism. AB - Brown tumor is a non-neoplastic bone lesion that develops secondary to hyperparathyroidism and it is very rare in the maxillofacial region. We report the case of a 59-year-old man who presented with pain and a swelling in the left cheek. Computed tomography (CT) demonstrated an expansile and radioluscent lesion in the left maxillary sinus. Incisional biopsy was performed, and the diagnosis was Brown tumor. Brown tumor must be considered in the differential diagnosis of expansile lesions of maxillary sinus. PMID- 24404415 TI - Giant renal angiomyolipoma: unusual cause of huge abdominal mass. AB - We present the imaging and histopathological characteristics of a giant renal angiomyolipoma (AML) in a 49-year-old female patient, who presented with bloating sensation in the abdomen and a steadily increasing abdominal girth for about 3 years. Contrast enhanced computed tomography (CECT) scan films of abdomen revealed that a large fat containing tumor had replaced the left kidney while displacing the rest of the abdominal contents toward the other side of the midline. Intraoperatively the left kidney was completely replaced by a fat containing tumor. The recovered surgical specimen measured 39 cm * 25 cm * 9 cm and weighed 7500 g. Histopathological investigation with immuno-histochemical staining of the specimen with hydroxy beta-methylbutyric acid-45 confirmed this lesion as AML. CECT scan of the head did not show any lesion suggestive of tuberous sclerosis. The giant tumor of the present case is the heaviest AML in both syndromic and sporadic categories and largest by dimensions as sporadic AML ever reported in the literature. PMID- 24404416 TI - Foreign gene recruitment to the fatty acid biosynthesis pathway in diatoms. AB - Diatoms are highly successful marine and freshwater algae that contribute up to 20% of global carbon fixation. These species are leading candidates for biofuel production owing to ease of culturing and high fatty acid content. To assist in strain improvement and downstream applications for potential use as a biofuel, it is important to understand the evolution of lipid biosynthesis in diatoms. The evolutionary history of diatoms is however complicated by likely multiple endosymbioses involving the capture of foreign cells and horizontal gene transfer into the host genome. Using a phylogenomic approach, we assessed the evolutionary history of 12 diatom genes putatively encoding functions related to lipid biosynthesis. We found evidence of gene transfer likely from a green algal source for seven of these genes, with the remaining showing either vertical inheritance or evolutionary histories too complicated to interpret given current genome data. The functions of horizontally transferred genes encompass all aspects of lipid biosynthesis (initiation, biosynthesis, and desaturation of fatty acids) as well as fatty acid elongation, and are not restricted to plastid-targeted proteins. Our findings demonstrate that the transfer, duplication, and subfunctionalization of genes were key steps in the evolution of lipid biosynthesis in diatoms and other photosynthetic eukaryotes. This target pathway for biofuel research is highly chimeric and surprisingly, our results suggest that research done on related genes in green algae may have application to diatom models. PMID- 24404417 TI - Chromosome mapping of retrotransposable elements Rex1 and Rex3 in Leporinus Spix, 1829 species (Characiformes: Anostomidae) and its relationships among heterochromatic segments and W sex chromosome. AB - The family Anostomidae is an interesting model for studies of repetitive elements, mainly because of the presence of high numbers of heterochromatic segments related to a peculiar system of female heterogamety, which is restricted to a few species of Leporinus genus. Thus, cytogenetic mapping of the retrotransposable elements Rex1, Rex3, and Rex6 was performed in six Leporinus species, to elucidate the genomic organization of this genus. The sequencing of the Rex1 and Rex3 elements detected different base pair compositions in these elements among species, whereas the Rex6 element was not identified in the genomes of these species. FISH analysis using Rex1 detected different distribution patterns, L. elongatus, L. macrocephalus, and L. obtusidens had clusters in the terminal regions, whereas the signals were dispersed throughout all of the chromosomes with some signals in the terminal position in other species. The Rex3 signals were found mainly in the terminal positions in all the chromosomes of all species. The W chromosomes of L. elongatus, L. macrocephalus, and L. obtusidens contained the Rex1 and Rex3 signal in an interstitial position. These results suggest the emergence of different activity levels for these elements during the evolution of the species analyzed. Despite the conserved karyotype macrostructure species Leporinus often discussed, our results show some variation in hybridization patterns, particularly between the species with specific patterns in their sex chromosomes and species without this differentiated system. PMID- 24404418 TI - Substance Use Attenuates Physiological Responses Associated With PTSD among Individuals with Co-Morbid PTSD and SUDs. AB - Posttraumatic stress disorder (PTSD) is often conceptualized from a fear conditioning perspective given individuals with PTSD demonstrate a reduced ability to inhibit fear even under safe conditions as compared to those without PTSD. The self-medication hypothesis suggests that individuals with PTSD often develop substance use disorders (SUDs) as an attempt to mitigate trauma-related distressing emotions. This investigation examined this hypothesis in a sample 214 participants, of which 81 did not meet criteria for either PTSD or SUDs (No diagnosis Control group); 33 met criteria for lifetime PTSD, but not SUDs (PTSD only group); 54 met criteria for lifetime SUDs, but not PTSD (SUDs only group); and 46 met lifetime criteria for both disorders (PTSD+SUDs group). PTSD was assessed using the modified PTSD Symptoms Scale (mPSS), SUDs were assessed using the Structured Clinical Interview for DSM-IV-TR (SCID). The startle magnitude was assessed using electromyography (EMG) of the eyeblink muscle in response to an acoustic startle probe. Fear-potentiated startle (FPS) was analyzed by comparing startle magnitude at baseline to startle during a fear conditioned stimulus. Results showed that PTSD significantly increased startle responses. However, there was a significant effect of SUDs on fear-potentiated startle to the danger signal, in that those who met criteria for SUDs had reduced fear compared to those who did not. The individuals who had co-morbid PTSD and SUDs did not differ from the Control group. Findings indicate that SUDs may attenuate exaggerated fear responses associated with PTSD. Consistent with the self-medication hypothesis, results suggest that substance use may co-occur with PTSD because it reduces heightened fear load and may allow normalized function in traumatized individuals. PMID- 24404419 TI - Nonconscious processing and a novel target for schizophrenia research. AB - Analysis of the pattern of altered cognition observed in schizophrenia provides better insight into neurocognitive deficits. It reveals a potential novel target for schizophrenia research. To understand this target we reviewed the findings of neuroimaging studies on implicit [nonconscious] memory. These studies have consistently reported attenuated activity in the area V3A of the extrastriate cortex during retrieval of studied items. It was suggested that the attenuation limits the pool of information available for further cognitive processing. Therefore, if V3A is functionally damaged, individuals will have access to a larger pool of information for cognitive processing. Since cognitive tasks that are not dependent on attention [attention independent] process a larger pool of information more efficiently, performance in these tasks is likely to improve after V3A is damaged. Conversely, tasks that are dependent on attentional resources are more efficient in processing smaller pool of information. Performance in these tasks therefore is expected to deteriorate if a large pool of information is made available following V3A damage. A review of cognitive performance in schizophrenia suggests that patients perform at above normal level in attention independent priming tasks and perform at subnormal level in attention dependent episodic and working memory tasks. These findings indicate possible impairment of V3A activity. It could therefore be a potentially important unstudied target for schizophrenia research, particularly because a number of investigators have reported that the activity in this area is altered in schizophrenia. PMID- 24404420 TI - Replenish the source within: Rescuing tumor-infiltrating lymphocytes by double checkpoint blockade. AB - We have recently reported that the PD-1 and CTLA4 signaling pathways are active in both effector and regulatory T cells, causing profound immune dysfunctions in the tumor microenvironment. In line with this notion, the dual blockade of PD-1- and CTLA4-conveyed signals may exert robust therapeutic effects. Here, we discuss the mechanisms possibly underlying such a synergic interaction. PMID- 24404421 TI - A new role for NFkappaB in immunosurveillance and its implications for cancer immunotherapy. AB - The activation of NFkappaB in the tumor microenvironment is associated with inflammatory responses that promote disease progression. We have recently found that the activation of NFkappaB in the tumor also regulates T cell-mediated immune responses, hence actively participating in cancer immunosurveillance. These findings call for reassessment of the function of NFkappaB within neoplastic lesions and open novel perspectives for anticancer immunotherapy. PMID- 24404422 TI - The TLR7 agonist imiquimod as an adjuvant for radiotherapy-elicited in situ vaccination against breast cancer. AB - Radiotherapy can convert malignant cells into an in situ anticancer vaccine, but is often inadequate at generating sufficient pro-inflammatory signals to optimally activate innate and adaptive immune responses. Topical imiquimod is a powerful pro-inflammatory agent with clinical activity against superficial skin cancers. These two modalities appear to complement each other, hence achieving local and systemic tumor control. PMID- 24404423 TI - Retargeting NK-92 cells by means of CD19- and CD20-specific chimeric antigen receptors compares favorably with antibody-dependent cellular cytotoxicity. AB - Multiple natural killer (NK) cell-based anticancer therapies are currently under development. Here, we compare the efficiency of genetically modified NK-92 cells expressing chimeric antigen receptors (CARs) at killing NK cell-resistant B lymphoid leukemia cells to the antibody-dependent cell-mediated cytotoxicity (ADCC) of NK-92 cells expressing a high affinity variant of the IgG Fc receptor (FcgammaRIII). First, we compared in vitro the abilities of NK-92 cells expressing CD20-targeting CARs to kill primary chronic lymphocytic leukemia (CLL) cells derived from 9 patients with active, untreated disease to the cytotoxicity of NK-92 cells expressing FcgammaRIII combined with either of the anti-CD20 monoclonal antibodies (mAbs) rituximab or ofatumumab. We found that CAR expressing NK-92 cells effectively kill NK cell-resistant primary CLL cells and that such a cytotoxic response is significantly stronger than that resulting from ADCC. For studying CAR-expressing NK cell-based immunotherapy in vivo, we established xenograft mouse models of residual leukemia using the human BCR-ABL1+ cell lines SUP-B15 (CD19+CD20-) and TMD-5 (CD19+CD20+), two acute lymphoblastic leukemia (ALL) lines that are resistant to parental NK-92 cells. Intravenous injection of NK-92 cells expressing CD19-targeting CARs eliminated SUP-B15 cells, whereas they had no such effect on TMD-5 cells. However, the intrafemoral injection of NK-92 cells expressing CD19-targeting CAR resulted in the depletion of TMD-5 cells from the bone marrow environment. Comparative studies in which NK 92 cells expressing either CD19- or CD20-targeting CARs were directly injected into subcutaneous CD19+CD20+ Daudi lymphoma xenografts revealed that CD20 targeting CAR is superior to its CD19-specific counterpart in controlling local tumor growth. In summary, we show here that CAR-expressing NK-92 cells can be functionally superior to ADCC (as mediated by anti-CD20 mAbs) in the elimination of primary CLL cells. Moreover, we provide data demonstrating that the systemic administration of CAR-expressing NK-92 cells can control lymphoblastic leukemia in immunocompromised mice. Our results also suggest that the direct injection of CAR-expressing NK-92 cells to neoplastic lesions could be an effective treatment modality against lymphoma. PMID- 24404424 TI - Immunogenic cell death in radiation therapy. PMID- 24404425 TI - Immune response to mutant neo-antigens: Cancer's lessons for aging. AB - Extending observations on the immunogenicity of neo-antigens that arise in the course of oncogenesis and tumor progression, we suggest that somatic mutations affecting normal tissues also lead to generation of new epitopes. We hypothesize that, at least under inflammatory conditions, immune responses against such neo antigens may lead to the elimination or functional impairment of normal cells, thus contributing to aging. PMID- 24404426 TI - Tumor-derived lactate and myeloid-derived suppressor cells: Linking metabolism to cancer immunology. AB - Many malignant cells produce increased amounts of lactate, which promotes the development of myeloid-derived suppressor cells (MDSCs). MDSCs, lactate, and a low pH in the tumor microenvironment inhibit the function of natural killer (NK) cells and T lymphocytes, hence allowing for disease progression. Ketogenic diets can deplete tumor-bearing animals from MDSCs and regulatory T cells, thereby improving their immunological profile. PMID- 24404427 TI - The IL-15-based superagonist ALT-803 promotes the antigen-independent conversion of memory CD8+ T cells into innate-like effector cells with antitumor activity. AB - ALT-803, an interleukin-15-based superagonist, induces memory CD8+ T cells to proliferate, upregulate receptors involved in innate immunity, secrete interferon gamma and acquire the ability to kill malignant cells in the absence of antigenic stimulation. Thus, ALT-803 can promote the expansion and activation of memory CD8+ T cells while converting them into innate immune effector cells that exhibit robust antineoplastic activity. PMID- 24404428 TI - Dendritic cell-based vaccines: Shining the spotlight on signal 3. AB - Dendritic cell (DC)-based anticancer vaccines have yielded disappointing results in a multitude of clinical trials. New data suggest that the clinical efficacy of DC-based vaccines may be dependent on the paracrine production of interleukin-12 in the course of antigen presentation and the consequent development of therapeutic Type 1 CD8+ T-cell immunity. PMID- 24404430 TI - Preventing surgery-induced NK cell dysfunction and cancer metastases with influenza vaccination. AB - Surgical resection is the mainstay of treatment for solid tumors, but the postoperative period is uniquely inclined to the formation of metastases, largely due to the suppression of natural killer (NK) cells. We found that preoperative influenza vaccination prevents postoperative NK-cell dysfunction, attenuating tumor dissemination in murine models and promoting the activation of NK cells in cancer patients. PMID- 24404429 TI - The interplay between regulatory T cells and metabolism in immune regulation. AB - Regulatory T cells (Tregs) are crucial for peripheral tolerance and are intimately involved in immunological diseases and cancer. Recent studies have highlighted a key role for Tregs in metabolic disorders, for instance as they accumulate in the adipose tissue to protect against obesity-related inflammation and insulin resistance. Conversely, the generation and immunosuppressive functions of Tregs are influenced by both systemic and cellular metabolism. The nutritional status as well as metabolic cues such as those provided by leptin impinge upon the proliferation of Tregs. In addition, the mTOR-dependent lipid metabolism has a crucial role in programming the activity of Tregs under steady state conditions as well as upon activation. This review discusses the intricate interaction between Tregs and metabolism, focusing on the roles of Tregs in systemic and local metabolic circuitries as well as on the regulation of Treg abundance and function by metabolic signals. PMID- 24404431 TI - Gender differences in the development of uremic cardiomyopathy following partial nephrectomy: Role of progesterone. AB - Gender difference has been suggested as a risk factor for developing cardiovascular and renal diseases in humans and experimental animals. As a major sex hormone, progesterone was reported to compete with cardiotonic steroid binding to Na/K-ATPase. Our previous publication demonstrated that cardiotonic steroids (e.g., marinobufagenin) play an important role in the development of experimental uremic cardiomyopathy. We also observed that the putative mineralocorticoid antagonists, spironolactone and its major metabolite canrenone, antagonize binding of cardiotonic steroids to Na/K-ATPase in a competitive manner and also ameliorate experimental uremic cardiomyopathy induced by partial nephrectomy. In the following studies, we noted that progesterone displayed competitive inhibition of cardiotonic steroid binding to Na/K-ATPase and partially inhibited collagen synthesis induced by marinobufagenin in cultured cardiac fibroblasts. Therefore, we sought to examine whether female rats displayed less uremic cardiomyopathy than male rats when subjected to partial nephrectomy. Although partial nephrectomy caused the induction of smaller increases in blood pressure of female rats, they appeared to be similarly susceptible to cardiac remodeling induced by partial nephrectomy in terms of hypertrophy and fibrosis as age-matched male rats. The possible explanations for our findings are therefore discussed. PMID- 24404432 TI - Topical Corticosteroids in the Management of Bacterial Keratitis. AB - Bacterial keratitis can cause significant morbidity from ulceration of the cornea and the resultant scarring. The use of steroids to decrease these complications is controversial with arguments for and against their use. The SCUT (Steroids for Corneal Ulcers Trial) was initiated in 2006 to definitively determine whether steroids in bacterial keratitis were beneficial or harmful. While the SCUT showed no benefit or harm overall, subgroup analyses showed that larger, more central ulcers with very poor initial visual acuity may benefit. On the other hand, Nocardia ulcers that were treated with steroids had worse outcomes. The study did have some limitations as the patient population was not typical for bacterial keratitis in the United States, and there were some criticisms of the therapeutic approach so the question is still not definitively answered. PMID- 24404433 TI - Using Community Data to Test the Discriminate Validity of Ethnic/Racial Group IATs. AB - The present study used a multi-method, multi-measure, multi-group approach to investigate the discriminant validity of prejudice-related IATs. Community members from three ethnic/racial groups in the U.S. completed IATs and explicit measures of attitudes toward African Americans and Latinos, with Whites used as the comparison group. The results of this study provided strong support for the discriminant validity of the IATs by showing, (a) expected patterns of variation among the three participant groups that were unique to each IAT, (b) unique relations between responses on each IAT and corresponding (same-group) explicit measures of prejudice, and (c) invariance across the three participant groups in the degree to which the attitude measures loaded on two latent factors, indicating distinct attitudes toward African Americans and Latinos. PMID- 24404434 TI - A H2-evolving photocathode based on direct sensitization of MoS3 with an organic photovoltaic cell. AB - An organic solar cell based on a poly-3-hexylthiophene (P3HT): phenyl-C61-butyric acid (PCBM) bulk hetero-junction was directly coupled with molybdenum sulfide resulting in the design of a new type of photocathode for the production of hydrogen. Both the light-harvesting system and the catalyst were deposited by low cost solution-processed methods, i.e. spin coating and spray coating respectively. Spray-coated MoS3 films are catalytically active in strongly acidic aqueous solutions with the best efficiencies for thicknesses of 40 to 90 nm. The photocathodes display photocurrents higher than reference samples, without catalyst or without coupling with a solar cell. Analysis by gas chromatography confirms the light-induced hydrogen evolution. The addition of titanium dioxide in the MoS3 film enhances electron transport and collection within thick films and therefore the performance of the photocathode. PMID- 24404435 TI - Muscle function and omega-3 fatty acids in the prediction of lean body mass after breast cancer treatment. AB - BACKGROUND: Decreased lean body mass (LBM) is common in breast cancer survivors yet currently there is a lack of information regarding the determinants of LBM after treatment, in particular, the effect of physical activity and dietary factors, such as long-chain omega-3 fatty acids (LCn-3) on LBM and LBM function. This cross-sectional study explored associations of LBM and function with LCn-3 intake, dietary intake, inflammation, quality of life (QOL) and physical fitness in breast cancer survivors to improve clinical considerations when addressing body composition change. METHODS: Forty-nine women who had completed treatment (surgery, radiation and/or chemotherapy) were assessed for body composition (BODPOD), LCn-3 content of erythrocytes, C-reactive protein (CRP), QOL, dietary intake, objective physical activity, 1-min push-ups, 1-min sit-stand, sub-maximal treadmill (TM) test, and handgrip strength. RESULTS: After adjustment for age, LBM was associated with push-ups (r = 0.343, p = 0.000), stage reached on treadmill (StageTM) (r = 0.302, 0.001), % time spent >= moderate activity (Mod + Vig) (r = 0.228, p = 0.024). No associations were seen between anthropometric values and any treatment, diagnostic and demographical variables. Body mass, push ups and StageTM accounted for 76.4% of the variability in LBM (adjusted r-square: 0.764, p = 0.000). After adjustment docosahexanoic acid (DHA) was positively associated with push-ups (beta=0.399, p = 0.001), eicosapentanoic acid (EPA) was negatively associated with squats (r = -0.268, p = 0.041), with no other significant interactions found between LCn-3 and physical activity for LBM or LBM function. CONCLUSION: This is the first investigation to report that a higher weight adjusted LBM is associated with higher estimated aerobic fitness and ability to perform push-ups in breast cancer survivors. Potential LCn-3 and physical activity interactions on LBM require further exploration. PMID- 24404436 TI - Mutant LV(476-7)AA of A-subunit of Enterococcus hirae V1-ATPase: High affinity of A3B3 complex to DF axis and low ATPase activity. AB - Vacuolar ATPase (V-ATPase) of Enterococcus hirae is composed of a soluble functional domain V1 (A3B3DF) and an integral membrane domain Vo (ac), where V1 and Vo domains are connected by a central stalk, composed of D-, F-, and d subunits; and two peripheral stalks (E- and G-subunits). We identified 120 interacting residues of A3B3 heterohexamer with D-subunit in DF heterodimer in the crystal structures of A3B3 and A3B3DF. In our previous study, we reported 10 mutants of E. hirae V1-ATPase, which showed lower binding affinities of DF with A3B3 complex leading to higher initial specific ATPase activities compared to the wild-type. In this study, we identified a mutation of A-subunit (LV(476-7)AA) at its C-terminal domain resulting in the A3B3 complex with higher binding affinities for wild-type or mutant DF heterodimers and lower initial ATPase activities compared to the wild-type A3B3 complex, consistent with our previous proposal of reciprocal relationship between the ATPase activity and the protein protein binding affinity of DF axis to the A3B3 catalytic domain of E. hirae V ATPase. These observations suggest that the binding of DF axis at the contact region of A3B3 rotary ring is relevant to its rotation activity. PMID- 24404437 TI - How to explain exercise-induced phenotype from molecular data: rethink and reconstruction based on AMPK and mTOR signaling. AB - During endurance and resistance exercise training, AMPK and mTOR signaling were known as selective pathways implicating the differentiation of exercise-induced phenotype in skeletal muscle. Among the previous studies, however, the differences in exercise protocol, the individuality and the genetic heterogeneity within species make it difficult to reach a consistent conclusion in the roles of AMPK and mTOR signaling. In this review, we aim not to reanalyze the previous articles and present the research progress of AMPK and mTOR signaling in exercise, but to propose an abstract general hypothesis for exercise-induced phenotype. Generally, exercise- induced skeletal muscle phenotype is independent of one and a few genes, proteins and signaling pathways. Convergent adaptation will better summarize the specificity of skeletal muscle phenotype in response to a single mode of exercise. Backward adaptation will open a new concept to illustrate the process of exercise-induced adaptation, such as mitochondrial quality control and muscle mass homeostasis. PMID- 24404438 TI - Stability and prognostic value of Slug, Sox9 and Sox10 expression in breast cancers treated with neoadjuvant chemotherapy. AB - BACKGROUND: Expression of transcription-factors as Slug and Sox9 was recently described to determine mammary stem-cell state. Sox10 was previously shown to be present also in breast cancer. Protein overexpression of Slug, Sox9 and Sox10 were associated with poor overall survival and with triple-negative phenotype in breast cancer. In this study we tested the stability of Slug, Sox9 and Sox10 expression during chemotherapy and addressed their prognostic role of in neoadjuvant treated primary breast-cancer and their correlation to pathological response and overall survival. METHODS: We analyzed immunohistochemical expression of Slug, Sox9 and Sox10 in tissue microarrays of 96 breast cancers prior to and after neoadjuvant chemotherapy. Expression was evaluated in invasive tumor cells and in tumor stroma and scored as 0, 1+, 2+ 3+. Expression-profile prior to and after chemotherapy was correlated to overall survival (Kaplan Meier) and with established clinico-pathological parameter. RESULTS: Sox9, Sox10 and Slug were expressed in 82-96% of the tumor cells prior to chemotherapy. Slug was expressed in 97% of the cases in tumor stroma before therapy. Change in expression-profile after chemotherapy occurred only in Slug expression in tumor cells (decreased from 82 to 51%, p = 0.0001, Fisher's exact test). The other markers showed no significant change after chemotherapy. Stromal Sox9 expression (0 to 2+) correlated to better overall survival after chemotherapy (p = 0.004) and reached almost statistical significance prior to chemotherapy (p = 0.065). There was no correlation between Sox9 and hormone-receptor expression. In multivariate-analysis, the stromal Sox9 expression after chemotherapy proved to be an independent and better prognostic marker than hormone-receptor status. Other clinico-pathological parameter (as HER2-status or pathological-stage) showed no correlation to the analyzed markers. CONCLUSION: Strong stromal Sox9 expression in breast cancer after chemotherapy was found to bear negative prognostic information and was associated with shortened overall survival. Slug expression was significantly changed (reduced) in samples after neoadjuvant chemotherapy. PMID- 24404439 TI - The role of culture-gene coevolution in morality judgment: examining the interplay between tightness-looseness and allelic variation of the serotonin transporter gene. AB - This research provides novel insights into the evolutionary basis of cultural norm development and maintenance. We yield evidence for a unique culture-gene coevolutionary model between ecological threat, allelic frequency of the serotonin transporter polymorphism (5-HTTLPR), cultural tightness-looseness-the strength of norms and tolerance for deviance from norms-and moral justifiability. As hypothesized, the results across 21 nations show that: (a) propensity for ecological threat correlates with short (S) allele frequency in the 5-HTTLPR, (b) allelic frequency in the 5-HTTLPR and vulnerability to ecological threat both correlate with cultural tightness-looseness, (c) susceptibility to ecological threat predicts tightness-looseness via the mediation of S allele carriers, and (d) frequency of S allele carriers predicts justifiability of morally relevant behavior via tightness-looseness. This research highlights the importance of studying the interplay between environmental, genetic, and cultural factors underlying contemporary differences in social behavior and presents an empirical framework for future research. PMID- 24404440 TI - A Computational Framework for High-Throughput Isotopic Natural Abundance Correction of Omics-Level Ultra-High Resolution FT-MS Datasets. AB - New metabolomics applications of ultra-high resolution and accuracy mass spectrometry can provide thousands of detectable isotopologues, with the number of potentially detectable isotopologues increasing exponentially with the number of stable isotopes used in newer isotope tracing methods like stable isotope resolved metabolomics (SIRM) experiments. This huge increase in usable data requires software capable of correcting the large number of isotopologue peaks resulting from SIRM experiments in a timely manner. We describe the design of a new algorithm and software system capable of handling these high volumes of data, while including quality control methods for maintaining data quality. We validate this new algorithm against a previous single isotope correction algorithm in a two-step cross-validation. Next, we demonstrate the algorithm and correct for the effects of natural abundance for both (13)C and (15)N isotopes on a set of raw isotopologue intensities of UDP-N-acetyl-D-glucosamine derived from a (13)C/(15)N tracing experiment. Finally, we demonstrate the algorithm on a full omics-level dataset. PMID- 24404441 TI - Research perspectives: gold nanoparticles in cancer theranostics. AB - High recurrence rates after surgical resection remain a formidable challenge in many cancers. Although chemo- and/or radiotherapy are often applied following surgery to prevent tumor relapse, these treatments are generally accompanied by serious side effects and challenges in their delivery that limit their effectiveness. Gold nanoparticles (AuNPs), which possess unique physicochemical properties, have the potential to enhance the efficacy of these conventional treatment modalities. In this review, we briefly describe the current state of AuNP research in the area of cancer theranostics. Recent studies have investigated AuNPs' use as photothermal converters, drug carriers, radiosensitizers, and imaging probes in a wide range of applications for cancer diagnosis and therapy. AuNPs have promise in minimally invasive thermal ablation therapy, diagnostic imaging, intraoperative tumor margin delineation, and multimodal anticancer therapy. The successful translation of AuNPs into the clinic will have significant impact on the care of cancer patients using image guided, minimally invasive approaches. PMID- 24404442 TI - Theranostics and contrast-agents for medical imaging: a pharmaceutical company viewpoint. PMID- 24404443 TI - Atherosclerotic plaque inflammation quantification using dynamic contrast enhanced (DCE) MRI. AB - Inflammation plays an important role in atherosclerosis. Given the increasing interest in using in-vivo imaging methods to study the physiology and treatment effects in atherosclerosis, noninvasive intraplaque inflammation quantitative method is needed. Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) has been proposed and validated to quantitatively characterize atherosclerotic plaque inflammation. Recent studies have optimized the imaging protocol, pharmacokinetic modeling techniques. All of these technical advances further promoted DCE-MRI to clinical investigations in plaque risk assessment and therapeutic response monitor. Although larger clinical studies are still needed, DCE-MRI has been proven to be a promising tool to reveal more about intraplaque inflammation by in vivo quantitative inflammation imaging. PMID- 24404444 TI - Ternary hybrid nanocomposites for gene delivery and magnetic resonance imaging of hepatocellular carcinoma cells. AB - This paper describes comparative studies in magnetic resonance imaging (MRI) and gene deliveries toward hepatocellular carcinoma (HCC) HepG2 cells with ternary composites that consist of superparamagnetic iron oxide (SPIO) nanoparticles (NPs) (8-10 nm) with deferoxamine coating, circular plasmid DNA (~4 kb) equipped with green fluorescent probe, and branched polyethylenimine (PEI) (25 kDa, PDI 2.5). The packaging of the ternary complexes has been characterized by agarose gel retardation assay. By tuning the PEI/NP ratios and with a fixed DNA amount, different ternary composites have been employed for NP/gene transfection towards HepG2 cells, which have been characterized by in vitro MRI and green fluorescence protein (GFP) fluorescence. PMID- 24404445 TI - Further exploration of MRI techniques for liver T1rho quantification. AB - With biliary duct ligation and CCl4 induced rat liver fibrosis models, recent studies showed that MR T1rho imaging is able to detect liver fibrosis, and the degree of fibrosis is correlated with the degree of elevation of the T1rho measurements, suggesting liver T1rho quantification may play an important role for liver fibrosis early detection and grading. It has also been reported it is feasible to obtain consistent liver T1rho measurement for human subjects at 3 Tesla (3 T), and preliminary clinical data suggest liver T1rho is increased in patients with cirrhosis. In these previous studies, T1rho imaging was used with the rotary-echo spin-lock pulse for T1rho preparation, and number of signal averaging (NSA) was 2. Due to the presence of inhomogeneous B0 field, artifacts may occur in the acquired T1rho-weighted images. The method described by Dixon et al. (Magn Reson Med 1996;36:90-4), which is a hard RF pulse with 135 degrees flip angle and same RF phase as the spin-locking RF pulse is inserted right before and after the spin-locking RF pulse, has been proposed to reduce sensitivity to B0 field inhomogeneity in T1rho imaging. In this study, we compared the images scanned by rotary-echo spin-lock pulse method (sequence 1) and the pulse modified according to Dixon method (sequence 2). When the artifacts occurred in T1rho images, we repeated the same scan until satisfactory. We accepted images if artifact in liver was less than 10% of liver area by visual estimation. When NSA =2, the breath-holding duration for data acquisition of one slice scanning was 8 sec due to a delay time of 6,000 ms for magnetization restoration. If NSA =1, the duration was shortened to be 2 sec. In previous studies, manual region of interest (ROI) analysis of T1rho map was used. In this current study, histogram analysis was also applied to evaluate liver T1rho value on T1rho maps. MRI data acquisition was performed on a 3 T clinical scanner. There were 29 subjects with 61 examinations obtained. Liver T1rho values obtained by sequence 1 (NSA =2) and sequence 2 (NSA =2) showed similar values, i.e., 43.1+/-2.1 ms (range: 38.6-48.0 ms, n=40 scans) vs. 43.5+/-2.5 ms (range: 39.0 47.7 ms, ?n=12 scans, P=0.74) respectively. For the six volunteers scanned with both sequences in one session, the intraclass correlation coefficient (ICC) was 0.939. Overall, the success rate of obtaining satisfactory images per acquisition was slightly over 50% for both sequence 1 and sequence 2. Satisfactory images can usually be obtained by asking the volunteer subjects to better hold their breath. However, sequence 2 did not increase the scan success rate. For the nine subjects scanned by sequence 2 with both NSA =2 and NSA =1 during one session, the ICC was 0.274, demonstrated poor agreement. T1rho measurement by ROI method and histogram had an ICC of 0.901 (P>0.05), demonstrated very good agreement. We conclude that by including 135 degrees flip angle before and after the spin-locking RF pulse, the rate of artifacts occurring did not decrease. On the other hand, sequence 1 and sequence 2 measured similar T1rho value in healthy liver. While reducing the breath-holding duration significantly, NSA =1 did not offer satisfactory signal to-noise ratio. Histogram measurement can be adopted for future studies. PMID- 24404446 TI - Imaging of solitary pulmonary nodule-a clinical review. AB - Current widespread use of cross-sectional imaging has led to exponential rise in detection of solitary pulmonary nodules (SPNs). Whilst large numbers of these are benign 'incidentalomas', lung cancers presenting as SPNs are often early disease, which have good prognosis. Therefore, there is rising demand and expectation for more accurate, non-invasive, diagnostic tests to characterize SPNs, aiming to avoid missed or delayed diagnosis of lung cancer. There are wide differential diagnoses of benign and malignant lesions that manifest as SPNs. On conventional imaging, the morphological features supporting benignity include stable small nodule size, smooth demarcated margins, and calcifications. Lack of significant contrast enhancement is also more suggestive of benign nodules. With improved understanding of tumor biology, for instance neo-vascularization and increased vascular permeability, imaging techniques such as dynamic contrast-enhanced computed tomography (CT) provide details on contrast uptake and wash-out kinetics, which is more closely reflecting the physiological and pathological phenomena. Positron emission tomography (PET) using 18fluorine-fluoro deoxyglucose ((18)F-FDG) is a well-established functional imaging technique, for which one of the most common indications is differentiating between benign and malignant SPNs. Combined PET-CT integrates the anatomical, morphological and metabolic aspects in a single examination, improving overall diagnostic accuracy. Semi-quantitative analysis in FDG-PET imaging is based on measurement of maximum standardized uptake values (SUVmax). SUVmax analysis may become more useful as an assessment of tumor biology in future risk stratification models for cancers. Dual-time point FDG-PET imaging, dual-energy CT, perfusion CT, magnetic resonance (MR) imaging using dynamic contrast enhancement or diffusion-weighted imaging (DWI) techniques, are among the growing armamentarium for diagnostic imaging of SPNs. Provided there is no unacceptably high procedural or operative risk, tissue diagnosis by resection or percutaneous biopsy of SPN should be advocated in those patients identified as at moderate or high risk of malignancy, based on clinical stratification. PMID- 24404447 TI - Comparison of the results of computerized tomographic and diffusion-weighted magnetic resonance imaging techniques in inflammatory bowel diseases. AB - AIM: To compare the findings obtained by computerised tomography (CT) enterography, which uses oral neutral contrast material and non-contrasted diffusion-weighted magnetic resonance imaging (DW-MRI) technique and reveal the diagnostic value of DW-MRI in patients with inflammatory bowel diseases. METHODS: Patients with established or clinically suspect diagnosis of inflammatory bowel disease were included in the study. CT enterography and DW-MRI obtained from the patients were evaluated by a radiologist blinded to the endoscopic and/or histopathological results. Duodenum, jejunum, ileal loops, ascending, transverse, descending colon, sigmoid colon and rectum were evaluated in that order as for general imaging quality, luminal distension and adequate visualization of the intestinal wall. Image qualities of neutral contrast CT-enterography and DW-MRI were compared. RESULTS: The study included 31 patients. Based on statistical analyses, the best correlation between the results of CT-enterography and diffusion-weighted imaging (DWI) were observed in the evaluation of transverse colon, ileum and duodenum in order of decreasing frequency and with an almost perfect compatibility. Radiological findings of sigmoid colon, jejunum and descending colon were completely compatible. However, a moderate degree of compatibility was estimated between radiological findings of rectum and cecum. CONCLUSIONS: Though conventional enteroclysis is the gold standard method among radiological imaging techniques used for the evaluation of inflammatory small intestinal abnormalities, CT enterography and DW-MRI are alternative methods that can be used effectively to obtain useful information. PMID- 24404448 TI - Primary intraosseous Kaposi's sarcoma of the maxilla in AIDS: a case report. AB - In China, Kaposi's sarcoma (KS) is very rare. However, KS does occur as one of the complications in patients with acquired immunodeficiency syndrome (AIDS). Usually AIDS-related KS involves the lymph nodes, the skin and gastrointestinal tract. Intraosseous KS have been reported but it is very rare. We report a case of primary intraosseous KS of the maxilla in an AIDS patient, proven by pathology findings and showed multiple metastasis by positron emission tomography and computed tomography (PET/CT). To our knowledge, this is the first report of primary intraosseous KS of the maxilla in an AIDS patient in China. PMID- 24404449 TI - Classic pneumatosis intestinalis and hepatic portal venous gas in setting of severe abdominal aorta atherosclerosis. AB - An 86-year-old man with extensive past medical history was referred to Emergency Department for evaluation of dehydration, hyperkalemia and worsening of mental status. In physical examination, abdomen was distended and tender with no bowel sounds. Abdominal computed tomographic imaging revealed pneumatosis intestinalis (PI) and hepatic portal venous gas (HPVG) in presence of severe atherosclerotic calcification of abdominal aorta. PMID- 24404450 TI - Concurrent central odontogenic fibroma (WHO Type) and traumatic bone cyst: report of a rare case. PMID- 24404451 TI - MRI of adrenal lymphangioma: a case report. PMID- 24404452 TI - What's New in Critical Illness and Injury Science? The ongoing debate on the optimal resuscitative fluid and monitoring parameters. PMID- 24404453 TI - Ventilator-Associated Pneumonia: When to hold the breath? AB - Ventilator-associated pneumonia (VAP) is the most common infection in mechanically ventilated patients, and carries the highest mortality. An early diagnosis and definitive management not only reduces the overall mortality, but also brings down the burden of health care to the patient by reducing the cost, length of Intensive Care Unit (ICU) stay, duration of mechanical ventilation, and so on. Out of the various scoring systems, the Clinical Pulmonary Infection Score (CPIS) calculation for VAP has a good sensitivity (72%) and specificity (85%) and the targeted antibiotic therapy in the appropriate dosage is found to be more beneficial than empirical treatment. Although controversies persist on several issues, preventive strategies like head elevation by 30 degrees, cuff pressure monitoring, avoidance of sedatives and muscle relaxants, and so on, have been found to reduce the occurrence of VAP. PMID- 24404454 TI - Hepatobiliary diseases during pregnancy and their management: An update. AB - Liver diseases in pregnancy although rare but they can seriously affect mother and fetus. Signs and symptoms are often not specific and consist of jaundice, nausea, vomiting, and abdominal pain. Although any type of liver disease can develop during pregnancy or pregnancy may occur in a patient already having chronic liver disease. All liver diseases with pregnancy can lead to increased maternal and fetal morbidity and mortality. It is difficult to identify features of liver disease in pregnant women because of physiological changes. Physiological changes of normal pregnancy can be confounding with that of sign and symptoms of liver diseases. Telangiectasia or spider angiomas, palmar erythema, increased alkaline phosphatase due to placental secretion, hypoalbuminemia due to hemodilution. These normal alterations mimic physiological changes in patients with decompensated chronic liver disease. Besides all these pathological changes however, blood flow to the liver remains constant and the liver usually remains impalpable during pregnancy. The diagnosis of liver disease in pregnancy is challenging and relies on laboratory investigations. The underlying disorder can have a significant effect on morbidity and mortality in both mother and fetus, and a diagnostic workup should be initiated promptly. If we see the spectrum of liver disease in pregnancy, in mild form there occur increase in liver enzymes to severe form, where liver failure affecting the entire system or maternal mortality and morbidity. It can not only complicate mother's life but also poses burden of life of fetus to growth restriction. Most of the times termination is only answer to save life of mother but sometimes early detection of diseases, preventive measures and available active treatment is helpful for both of the life. Extreme vigilance in recognizing physical and laboratory abnormalities in pregnancy is a prerequisite for an accurate diagnosis. This could lead to a timely intervention and successful outcome. PMID- 24404455 TI - Contemporary issues in the management of abnormal placentation during pregnancy in developing nations: An Indian perspective. AB - The gap between the developed and developing nations with regards to maternal mortality and morbidity may have narrowed but still a lot of dedicated work is required to bridge these differences. Obstetrical haemorrhage is the leading cause of maternal deaths in these developing nations especially in India. The most common causes of this fatal haemorrhage are the placental abnormalities which rarely get detected before delivery. Numerous factors have been incremental in the causation of this abnormal placental implantation with resultant complications. The present article is an attempt to review possible predictors of abnormal placental implantation. Also, a genuine attempt has been made to enumerate possible measures to identify the predictors of abnormal placentation during early pregnancy and their suitable prevention and management. PMID- 24404456 TI - Pattern of non-fatal injuries in road traffic crashes in a hilly area: A study from Shimla, North India. AB - RESEARCH QUESTION: What are the various injuries in road traffic crash cases? OBJECTIVES: To study various non-fatal injuries in road traffic crash cases. STUDY DESIGN: Hospital based Descriptive study. STUDY POPULATION: The study population comprised of 401 consecutive cases of non- fatal injuries involved in road traffic crashes and reported at Indira Gandhi Medical College hospital, Shimla. STUDY PERIOD: 1(st) June 2005 to 31(st) May 2006. STUDY VARIABLES: Demographic characteristics of the victims, pattern of injuries and hospital stay of the victims. Types of crashes, time, day and month of crashes, vehicles involved in crashes, use of protective gear etc. STATISTICAL ANALYSIS: Percentages, Proportions. RESULTS: 73% of the injured victims were young between 20-49yrs, male to female ratio being 5.3:1. Employees (34.7%) and occupants of transport vehicles (45.9%) constituted the maximum number of the victims. Major injuries (fractures and abd. injuries) were reported in 53.4% of the victims and fractures of lower limb were the commonest of the injuries (26.3%). Use of seat belt was found to be alarmingly low (14.3%) amongst the four- wheeler users and its non-use was found to be significantly associated with the major injuries. Helmet was used by 36 cases (66.7%) out of total of 54 users of motorized two wheelers at the time of crash. Human error was the most reported cause of crash (82%) and the most common mode of crash was skidding and/rolling down (55%).23.1% of the drivers were reported to have consumed alcohol at the time of crash. PMID- 24404457 TI - Comparison of heparin dosing based on actual body weight in non-obese, obese and morbidly obese critically ill patients. AB - BACKGROUND: Obesity is endemic in the United States and obese patients are at increased risk of thromboembolism but little data are available for dosing unfractionated heparin (UFH). We evaluated the relationship between obesity and UFH efficacy during critical illness by examining UFH infusions in non-obese, obese, and morbidly obese critically ill patients. MATERIALS AND METHODS: Retrospective review of UFH infusions in non-obese, obese, and morbidly obese critically ill patients. Heparin was initiated without a bolus at 16 units/kg/h or 12 units/kg/h in obese and morbidly obese patients. Demographics, UFH dosage/therapy duration, laboratory values, and bleeding events were reviewed for patients receiving UFH for >24 h. Steady state (SS) was defined as the dosage that resulted in three consecutive activated partial thromboplastin times (aPTT) within target range. RESULTS: Sixty-two patients were analyzed including 21 non obese (mean body mass index (BMI) 24.2 +/- 2.3); 21 obese (BMI 34.1 +/- 3.1); and 20 morbidly obese (mean BMI 55.3 +/- 13.7). Patients had otherwise similar demographics. Although 92% had at least one therapeutic aPTT, only 55% of patients reached SS. Six patients developed minor bleeding, but no major hemorrhagic complications. The dosing of heparin based on actual body weight (units/kg/h) and time to first therapeutic aPTT was similar between groups, but dose was statistically higher at steady state in the non-obese (16.3 +/- 5.3 non obese, 11.6 +/- 5.5 obese and 11.1 +/- 1.2 obese, P = 0.01) with similar times to steady state. CONCLUSIONS: Dosing of UFH in morbidly obese and obese critically ill patients based on actual body weight and a reduced initial dose was associated with similar time to first therapeutic aPTT and steady state. PMID- 24404458 TI - Limiting intensive care therapy in dying critically Ill patients: Experience from a tertiary care center in United Arab Emirates. AB - BACKGROUND: Limitations of life-support interventions, by either withholding or withdrawing support, are integrated parts of intensive care unit (ICU) activities and are ethically acceptable. The end-of-life legal aspects and practices in United Arab Emirates ICUs are rarely mentioned in the medical literature. The objective of this study was to examine the current practice of limiting futile life-sustaining therapies in our ICU, modalities for implementing of these decisions, and documentations in dying critically ill patients. MATERIALS AND METHODS: This was a retrospective observational study conducted at our ICU. We studied all ICU patients who died from September 2008 to February 2009. Patients' baseline demo-graphics, past medical problems, diagnosis on admission to ICU, and decision to withhold, withdraw and their modalities were collected. METHODS: This was a retrospective observational study conducted at our ICU. We studied all ICU patients who died from September 2008 to February 2009. Patients' baseline demo graphics, past medical problems, diagnosis on admission to ICU, and decision to withhold, withdraw and their modalities were collected. RESULTS: The electronic medical records of 67 patients were reviewed. The commonest method of limiting therapy was no escalation 53.6%. Interventions were withheld in 41.5%. "Do not resuscitate" order was documented in only 16.3%. The commonest method of documenting limitation of therapy was discussion with the family and documenting the prognosis and futility of additional therapy (73.3%). Patients who died early (<48 hrs) compared to patients who died late (>48 hrs) of ICU admission received terminal cardiopulmonary resuscitation more frequently (P < 0.007), had less frequent prognosis documentation (P < 0.009), and had more vasopressors administered (P < 0.006). CONCLUSION: Withholding therapy after discussion with the family was the preferred mode of limiting therapy in a dying patient. PMID- 24404459 TI - Evaluation of the efficacy of simplified Fencl-Stewart equation in analyzing the changes in acid base status following resuscitation with two different fluids. AB - BACKGROUND: Metabolic acid-base disorders in critically ill patients may not be identified by base excess (BE) approach. Anion gap method can detect approximately 1/3 hidden "gap acidosis". In such conditions, when adjusted for hypoalbuminemia, Fencl-Stewart's approach can reliably detect the hidden abnormal anions. AIM: Evaluate the efficacy of simplified Fencl-Stewart equation in identifying the changes in acid-base status of sepsis patients following resuscitation with two different fluids. SETTINGS AND DESIGN: Intensive care unit, randomized, prospective, interventional study. MATERIALS AND METHODS: Three hundred adult patients of both sexes presenting with abdominal sepsis, requiring fluid resuscitation were randomly assigned into normal saline (NS) and Ringer's lactate (RL) group, each comprising of 150 patients. 20 ml/kg of NS or RL were administered over a period of 30 min. The changes in the acid-base status were calculated applying the simplified Fencl-Stewart equation and was compared with the measured values obtained through arterial blood gas. STATISTICAL METHODS: Paired t-test for intra-group while unpaired t-test for inter-group comparison. RESULTS: Blood pH and standard BE decreased and the serum Na(+) and Cl(-) level increased significantly in NS group. The serum albumin level significantly decreased in both the groups. Sodium chloride effect on BE significantly increased in NS group. Albumin effect on BE significantly increased in both the groups. Unmeasured ion effect on BE did not significantly change in both the groups. Measured standard BE level was significantly less as compared to unmeasured anion effect on BE, in both the groups. CONCLUSION: Simplified Fencl Stewart equation is effective in identifying a mixed acid-base disorder, which otherwise would remain undetected. PMID- 24404460 TI - Masochistic habits in a child patient: A case report and its management. AB - This is a case report of diagnosis and management of masochistic habits, a special type of mechanical trauma to the gingival tissue known as self-inflicted lesions, also termed as gingivitis artefacta. Self-inflicted injuries can be premeditated, accidental, or can also result from an uncommon habit. The purpose of this article is to review clinical findings in a 6-year-old female patient who had a habit of left forearm sucking since birth and also presented with a nail biting habit which caused a gingival stripping on the left buccal surface of maxillary first and second deciduous molars. A full-arm sleeve was advised to be used for habit breaking, selective grinding of cusps was done of lower left first and second deciduous molars, and also topical anesthetic gel was prescribed. PMID- 24404461 TI - Repeated snake bite for recreation: Mechanisms and implications. AB - Snake venom use for recreational purposes has been documented earlier. Willfully subjecting oneself to repeated lethal snake bite as a source of getting relieved of stress and recreation observed in two healthy software engineers, without any underlying psychiatric ailments or comorbidities along with probable mechanisms, are reported. Emergency physicians and practitioners have to be aware of novel methods of exposure to snake venom so as to recognize such cases and treat them accordingly. PMID- 24404462 TI - Candidiasis: An unusual cause of persistent high-grade fever in mid-pregnancy. AB - Pyrexia can be extremely threatening during the normal progression of pregnancy if it occurs during the early phase of gestation as compared to the latter half of pregnancy. The degree of temperature rise, stage of pregnancy, and duration of the underlying illness are the important determinants for the outcome of pregnancy. Fever, resulting from the intrauterine infections, can be extremely hazardous for the newborn. Any history of fever (>24 h) during pregnancy mandate a complete clinical examination and thorough investigations. We report successful management of a rare case of prolonged high-grade pyrexia with unusual cause during mid-pregnancy. PMID- 24404463 TI - A brain-dead pregnant woman with prolonged somatic support and successful neonatal outcome: A grand rounds case with a detailed review of literature and ethical considerations. AB - There are increased reports in the medical literature of brain death during pregnancy. In these rare cases, the decision was either to consider discontinuing homeostatic support and mechanical ventilation with an understanding that the fetus then will also die, or to continue full support in an attempt to prolong pregnancy for the purpose of maintaining the fetus alive until maturity. We report the first case in the United Arab Emirates and in literature of somatic support that extended up to 110 days with the successful delivery of a viable fetus. A 35-year-old woman suffered intracranial hemorrhage during the 16(th) week of pregnancy that lead to brain death despite maximal surgical and medical management. Upon confirmation of this diagnosis, the patient received full ventilatory and homeostatic support required to prolong gestation and improve the survival prognosis of her fetus. The status of the patient was discussed in a multidisciplinary approach and with the full involvement of her family. Somatic support continued until the patient was 32 of weeks gestation. Obstetric complications of the patient were frequently assessed and managed. Lower segment cesarean section (LSCS) was then performed. A preterm male in breech presentation was delivered with an average weight of 750 gm, and an Apgar score of 6, 7, and 9 at 1, 5, and 10 minutes, respectively. Prolonging somatic support in a pregnant woman with brain death to allow fetal survival resulted in a successful outcome in terms of saving the life of the fetus. The results are consistent with previous published case reports in the literature on the appropriateness and safety of such a strategy that involved an intensive multidisciplinary approach. Despite being a tragedy, maternal death can represent an opportunity to save the life of the fetus and for organ donation. Consensus future recommendations that can guide the management of similar conditions may also be adapted, especially with the growing medical experience in this context. PMID- 24404464 TI - Undiagnosed diabetes presenting as hypertriglyceridemia-induced pancreatitis. PMID- 24404465 TI - The A1chieve study: Mapping the Ibn Battuta trail. PMID- 24404466 TI - Kleiber's law and the A1chieve study. PMID- 24404467 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Agadir cohort of the A1chieve study. AB - BACKGROUND: A1chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Agadir, Morocco. RESULTS: A total of 201 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 98), insulin detemir (n = 54), insulin aspart (n = 8), basal insulin plus insulin aspart (n = 8) and other insulin combinations (n = 33). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 10.7%) and insulin user (mean HbA1c: 9.1%) groups. After 24 weeks of treatment, both groups showed improvement in HbA1c (insulin naive: -2.7%, insulin users: 1.3%). No major hypoglycaemia was observed at 24 weeks. SADRs were reported in 1.5% of insulin users. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404468 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Marrakech cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Marrakech, Morocco. RESULTS: A total of 196 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 71), insulin detemir (n = 83), insulin aspart (n = 5), basal insulin plus insulin aspart (n = 14) and other insulin combinations (n = 23). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 9.3%) and insulin user (mean HbA1c: 9.3%) groups. After 24 weeks of treatment, both the study groups showed improvement in HbA1c (insulin naive: 2.3%, insulin users: -1.9%). SADR's including major hypoglycaemic events did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404469 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Casablanca cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Casablanca, Morocco. RESULTS: A total of 495 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 231), insulin detemir (n = 151), insulin aspart (n = 19), basal insulin plus insulin aspart (n = 53) and other insulin combinations (n = 41). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 10.2%) and insulin user (mean HbA1c: 9.4%) groups. After 24 weeks of treatment, both groups showed improvement in HbA1c (insulin naive: 2.3%, insulin users: -1.8%). Major hypoglycaemia was observed in the insulin naive group after 24 weeks. SADRs were reported in 1.2% of insulin naive and 2.1% of insulin user groups. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404470 TI - Clinical experience with insulin detemir type 2 diabetes mellitus, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Rabat-Sale-Zemmour-Zaer Region cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66 726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Rabat-Sale-Zemmour-Zaer region, Morocco. RESULTS: A total of 424 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 177), insulin detemir (n = 150), insulin aspart (n = 11), basal insulin plus insulin aspart (n = 45) and other insulin combinations (n = 41). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 10.1%) and insulin user (mean HbA1c: 9.4%) groups. After 24 weeks of treatment, all the study groups showed improvement in HbA1c (insulin naive: -2.5%, insulin users: -1.8%). Major hypoglycaemia was observed in the insulin user group after 24 weeks (0.1 events/patient-year). SADRs were reported in 0.5% of insulin users. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404471 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from North and the oriental region of Morocco cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66 726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Oriental, Morocco. RESULTS: A total of 180 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 146), insulin detemir (n = 22), insulin aspart (n = 6), basal insulin plus insulin aspart (n = 2) and other insulin combinations (n = 4). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 9.0%) and insulin user (mean HbA1c: 8.8%) groups. After 24 weeks of treatment, both the study groups showed improvement in HbA1c (insulin naive: -1.7%, insulin users: -1.6%). SADRs including major hypoglycaemia did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404472 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Saiss cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66 726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Saiss, Morocco. RESULTS: A total of 145 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 47), insulin detemir (n = 56), insulin aspart (n = 1), basal insulin plus insulin aspart (n = 35) and other insulin combinations (n = 6). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 10.4%) and insulin user (mean HbA1c: 9.8%) groups. After 24 weeks of treatment, both the study groups showed improvement in HbA1c (insulin naive: 2.7%, insulin users: -2.5%). SADRs including major hypoglycaemia did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404473 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Northern Tunisia cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Northern Tunisia. RESULTS: A total of 443 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 137), insulin detemir (n = 243), insulin aspart (n = 11), basal insulin plus insulin aspart (n = 39) and other insulin combinations (n = 13). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 10.2%) and insulin user (mean HbA1c: 9.8%) groups. After 24 weeks of treatment, both the study groups showed improvement in HbA1c (insulin naive: -2.1%, insulin users: -0.9%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404474 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Central and Southern Tunisia cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Central and Southern Tunisia. RESULTS: A total of 142 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 32), insulin detemir (n = 66), insulin aspart (n = 2), basal insulin plus insulin aspart (n = 39) and other insulin combinations (n = 3). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 10.5%) and insulin user (mean HbA1c: 9.9%) groups. After 24 weeks of treatment, both groups showed improvement in HbA1c (insulin naive: -2.4%, insulin users: -1.7%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404475 TI - Clinical experience with biphasic insulin aspart in people with type 2 diabetes: Results from the Libya cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled in biphasic insulin aspart sub group from Libya. RESULTS: A total of 179 patients were enrolled in the biphasic insulin aspart subgroup. All the patients were prior insulin users. At baseline glycaemic control was poor (mean HbA1c: 9.3%). After 24 weeks of treatment there was an improvement in HbA1c (-0.9%). Hypoglycaemic events reduced from 7.2 events/patient-year to 3.7 events/patient-year in 24 weeks. SADRs did not occur in any of the study patients. CONCLUSION: Starting or switching to biphasic insulin aspart was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404476 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Taif, Saudi Arabia cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for participants enrolled from Taif, Saudi Arabia. RESULTS: A total of 791 subjects were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients were started on or were switched to biphasic insulin aspart (n = 238), insulin detemir (n = 325), insulin aspart (n = 9), basal insulin plus insulin aspart (n = 85) and other insulin combinations (n = 127). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 9.7%) and insulin user (mean HbA1c: 9.8%) groups. After 24 weeks of treatment, both the study groups showed improvement in HbA1c (insulin naive: -2.3%, insulin users: -2.6%). SADRs including major hypoglycaemic events did not occur in the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404477 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Yanbu cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Yanbu, Saudi Arabia. RESULTS: A total of 499 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 256), insulin detemir (n = 146), insulin aspart (n = 3), basal insulin plus insulin aspart (n = 55) and other insulin combinations (n = 37). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 9.4%) and insulin user (mean HbA1c: 9.5%) groups. After 24 weeks of treatment, both the study groups showed improvement in HbA1c (insulin naive: -2.1%, insulin users: -1.8%). SADRs including major hypoglycaemic events did not occur in the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404478 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Central Saudi Arabia cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Central Saudi Arabia. RESULTS: A total of 2819 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 1100), insulin detemir (n = 1156), insulin aspart (n = 34), basal insulin plus insulin aspart (n = 314) and other insulin combinations (n = 170). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 9.9%) and insulin user (mean HbA1c: 9.8%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naive: -2.6%, insulin users: -2.5%). SADRs including major hypoglycaemic events did not occur in the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404479 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Southwest Saudi Arabia cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from southwest Saudi Arabia. RESULTS: A total of 2561 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 987), insulin detemir (n = 1121), insulin aspart (n = 21), basal insulin plus insulin aspart (n = 280) and missing or other insulin combinations (n = 152). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 9.9%) and insulin user (mean HbA1c: 9.5%) groups. After 24 weeks of treatment, both the study groups showed improvement in HbA1c (insulin naive: -2.5%, insulin users: -2.2%). Major hypoglycaemic events did not occur in any of the study patients. SADRs were reported in 0.1% of insulin naive and 0.1% of insulin user groups. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404480 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Eastern Saudi Arabia cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Eastern Saudi Arabia. RESULTS: A total of 1040 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 489), insulin detemir (n = 360), insulin aspart (n = 37), basal insulin plus insulin aspart (n = 96) and other insulin combinations (n = 57). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 10.0%) and insulin user (mean HbA1c: 9.2%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naive: 2.7%, insulin users: -1.7%). No major hypoglycaemic episodes were observed at 24 weeks. SADR was reported in 0.6% of insulin users. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404481 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Yemen cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Yemen. RESULTS: A total of 104 patients were enrolled in the study. Three different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 94), insulin aspart (n = 4), basal insulin plus insulin aspart (n = 1) and other insulin combinations (n = 2). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 10.6%) and insulin user (mean HbA1c: 9.8%) groups. After 24 weeks of treatment, both the study groups showed improvement in HbA1c (insulin naive: -2.7%, insulin users: -1.8%). SADR's including major hypoglycaemia events did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404482 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Bahraini cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, is a multicentric (28 countries), 24-weeks, non interventional study to evaluate the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Manama, kingdom of Bahrain. RESULTS: A total of 115 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 67), insulin detemir (n = 16), insulin aspart (n = 4), basal insulin plus insulin aspart (n = 21) and other insulin combinations (n = 7). At baseline, glycaemic control was poor for both insulin naive (mean HbA1c: 10.2%) and insulin users (mean HbA1c: 9.8%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naive: -1.1%, insulin users: -1.3%). SADRs including major hypoglycaemic events did not occur in the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404483 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Kuwait cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Kuwait. RESULTS: A total of 1185 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 472), insulin detemir (n = 472), insulin aspart (n = 4), basal insulin plus insulin aspart (n = 188) and other insulin combinations (n = 48). At baseline, glycaemic control was poor for both insulin naive (mean HbA1c: 9.8%) and insulin user (mean HbA1c: 9.4%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naive: -2.4%, insulin users: -1.7%). No major hypoglycaemic episodes were observed at 24 weeks. SADR was reported in 0.1% of insulin users. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404484 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Qatar cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Qatar. RESULTS: A total of 91 patients were enrolled in the study. Two insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 88), insulin detemir (n = 2), and other insulin combinations (n = 1). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 10.9%) and insulin users (mean HbA1c: 9.1%) groups. After 24 weeks of treatment, all the study groups showed improvement in HbA1c (insulin naive: -1.8%, insulin users: 1.3%). Major hypoglycaemia did not occur in the study patients. SADRs were reported in 1.4% of insulin users. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404485 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Dubai cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Dubai. RESULTS: A total of 767 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 231), insulin detemir (n = 369), insulin aspart (n = 29), basal insulin plus insulin aspart (n = 111) and other insulin combinations (n = 26). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 9.2%) and insulin user (mean HbA1c: 9.1%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naive: -1.9%, insulin users: -1.8%). SADRs did not occur in any of the study patients. Major hypoglycaemia was nil similar to that of baseline in insulin naive group whereas major hypoglycaemic events reduced from 0.3 events/patient-year to 0.1 events/patient-year in insulin users. CONCLUSION: Starting or switching to insulin analogues was associated with improvements in glycaemic control with a low rate of hypoglycaemia. PMID- 24404486 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Abu Dhabi cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Abu Dhabi. RESULTS: A total of 383 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 134), insulin detemir (n = 152), insulin aspart (n = 13), basal insulin plus insulin aspart (n = 42) and other insulin combinations (n = 41). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 9.4%) and insulin user (mean HbA1c: 9.1%) groups. After 24 weeks of treatment, both groups showed improvement in HbA1c (insulin naive: -2.1%, insulin users: 1.8%). SADRs did not occur in any of the study patients. Major hypoglycaemic events remained same as that of baseline (0.1 events/patient-year) for insulin naive group whereas major hypoglycaemia reduced from 0.1 events/patient-year to 0.0 events/patient-year in insulin users. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404487 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Oman cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Oman. RESULTS: A total of 349 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 121), insulin detemir (n = 171), insulin aspart (n = 2), basal insulin plus insulin aspart (n = 38) and other insulin combinations (n = 17). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 9.2%) and insulin user (mean HbA1c: 8.8%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naive: -2.1%, insulin users: -1.6%). SADRs including major hypoglycaemic events did not occur in the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia and no weight gain. PMID- 24404488 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the West India cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from West India. RESULTS: A total of 4192 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 2846), insulin detemir (n = 596), insulin aspart (n = 517), basal insulin plus insulin aspart (n = 140) and other insulin combinations (n = 83). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 8.8%) and insulin user (mean HbA1c: 9.1%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naive: 1.6%, insulin users: -1.7%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404489 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the North India cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from North India. RESULTS: A total of 4912 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 3619), insulin detemir (n = 880), insulin aspart (n = 331), basal insulin plus insulin aspart (n = 37) and other insulin combinations (n = 44). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 9.8%) and insulin user (mean HbA1c: 9.8%) groups. After 24 weeks of treatment, both the study groups showed improvement in HbA1c (insulin naive: 2.7%, insulin users: -2.6%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404490 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the South India cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from South India. RESULTS: A total of 9273 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 7217), insulin detemir (n = 1001), insulin aspart (n = 734), basal insulin plus insulin aspart (n = 117) and other insulin combinations (n = 189). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 9.2%) and insulin user (mean HbA1c: 9.1%) groups. After 24 weeks of treatment both the groups showed improvement in HbA1c (insulin naive: 1.6%, insulin users: -1.3%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404491 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the East India cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from East India. RESULTS: A total of 2177 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n=1605), insulin detemir (n=230), insulin aspart (n=233), basal insulin plus insulin aspart (n=49) and other insulin combinations (n=54). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 8.9%) and insulin user (mean HbA1c: 9.1%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naive: -1.6%, insulin users: -1.6%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404492 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the North East India cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from North East, India. RESULTS: A total of 730 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 518), insulin detemir (n = 88), insulin aspart (n = 74), basal insulin plus insulin aspart (n = 19) and other insulin combinations (n = 30). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 9.5%) and insulin users (mean HbA1c: 9.2%) groups. After 24 weeks of treatment, both groups showed improvement in HbA1c (insulin naive: -1.6%, insulin users: 1.5%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404493 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Maharashtra cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Maharashtra, India. RESULTS: A total of 3069 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 2115), insulin detemir (n = 461), insulin aspart (n = 333), basal insulin plus insulin aspart (n = 92) and other insulin combinations (n = 61). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 8.8) and insulin user (mean HbA1c: 9.1%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naive: -1.4%, insulin users: -1.4%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404494 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Mumbai cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Mumbai, India. RESULTS: A total of 2112 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 1561), insulin detemir (n = 313), insulin aspart (n = 144), basal insulin plus insulin aspart (n = 53) and other insulin combinations (n = 41). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 8.7%) and insulin user (mean HbA1c: 9.2%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naive: -1.4%, insulin users: -1.8%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404495 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Gujarat cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Gujarat, India. RESULTS: A total of 812 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 502), insulin detemir (n = 89), insulin aspart (n = 155), basal insulin plus insulin aspart (n = 45) and other insulin combinations (n = 21). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 8.9%) and insulin user (mean HbA1c: 9.1%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naive: -2.2%, insulin users: -2.5%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404496 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Rajasthan cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Rajasthan, India. RESULTS: A total of 477 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 340), insulin detemir (n = 90), insulin aspart (n = 37), basal insulin plus insulin aspart (n = 7) and other insulin combinations (n = 2). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 8.3%) and insulin user (mean HbA1c: 8.4%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naive: -0.9%, insulin users: -1.2%). Major hypoglycaemic events decreased from 0.5 events/patient-year to 0.0 events/patient-year in insulin naive group while no change from baseline (1.3 events/patients-year) was observed for insulin users. SADRs were not reported in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404497 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Delhi cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Delhi, India. RESULTS: A total of 2242 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 1515), insulin detemir (n = 521), insulin aspart (n = 176), basal insulin plus insulin aspart (n = 11) and other insulin combinations (n = 19). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 10.0%) and insulin user (mean HbA1c: 11.0%) groups. After 24 weeks of treatment both the groups showed improvement in HbA1c (insulin naive: -3.1%, insulin users: -3.6%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404498 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Punjab cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Punjab, India. RESULTS: A total of 655 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 587), insulin detemir (n = 28), insulin aspart (n = 24), basal insulin plus insulin aspart (n = 13) and other insulin combinations (n = 3). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 9.1%) and insulin user (mean HbA1c: 9.1%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naive: -0.8%, insulin users: -1.0%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404499 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Haryana cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Haryana, India. RESULTS: A total of 345 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 236), insulin detemir (n = 66), insulin aspart (n = 28), basal insulin plus insulin aspart (n = 1) and other insulin combinations (n = 14). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 10.7%) and insulin user (mean HbA1c: 10.5%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naive: -3.9%, insulin users: -3.3%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404500 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Andhra Pradesh cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Andhra Pradesh, India. RESULTS: A total of 3077 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 2452), insulin detemir (n = 308), insulin aspart (n = 226), basal insulin plus insulin aspart (n = 21) and other insulin combinations (n = 68). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 8.9%) and insulin user (mean HbA1c: 9.2%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naive: -1.2%, insulin users: -1.1%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404501 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Hyderabad cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Hyderabad, India. RESULTS: A total of 1249 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 893), insulin detemir (n = 158), insulin aspart (n = 124), basal insulin plus insulin aspart (n = 19) and other insulin combinations (n = 54). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 9.0%) and insulin user (mean HbA1c: 9.5%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naive: 0.9%, insulin users: -1.1%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404502 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Karnataka cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Karnataka, India. RESULTS: A total of 2243 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 1855), insulin detemir (n = 211), insulin aspart (n = 111), basal insulin plus insulin aspart (n = 16) and other insulin combinations (n = 40). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 9.2%) and insulin user (mean HbA1c: 9.0%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naive: -1.4%, insulin users: -1.7%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404503 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Bangalore cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Bangalore, India. RESULTS: A total of 1533 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 1262), insulin detemir (n = 165), insulin aspart (n = 86), basal insulin plus insulin aspart (n = 11) and other insulin combinations (n = 2). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 9.2%) and insulin users (mean HbA1c: 8.8%) groups. After 24 weeks of treatment, both groups showed improvement in HbA1c (insulin naive: -1.3%, insulin users: -1.5%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404504 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Kerala cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Kerala, India. RESULTS: A total of 1732 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 1203), insulin detemir (n = 212), insulin aspart (n = 312), basal insulin plus insulin aspart (n = 1) and other insulin combinations (n = 1). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 10.0%) and insulin user (mean HbA1c: 8.3%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naive: -2.4%, insulin users: -0.5%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404505 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Trivandrum cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Trivandrum, India. RESULTS: A total of 528 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 392), insulin detemir (n = 65), insulin aspart (n = 70) and other insulin combinations (n = 1). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 9.9%) and insulin user (mean HbA1c: 8.1%) groups. After 24 weeks of treatment, both the study groups showed improvement in HbA1c (insulin naive: -2.4%, insulin users: -1.0%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404506 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Tamil Nadu cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Tamil Nadu, India. RESULTS: A total of 2221 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 1707), insulin detemir (n = 270), insulin aspart (n = 85), basal insulin plus insulin aspart (n = 79) and other insulin combinations (n = 80). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 9.2%) and insulin user (mean HbA1c: 9.2%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naive: -1.7%, insulin users: -1.7%). SADRs including major hypoglycaemic events did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404507 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Chennai cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Chennai, India. RESULTS: A total of 1334 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 983), insulin detemir (n = 205), insulin aspart (n = 42), basal insulin plus insulin aspart (n = 41) and other insulin combinations (n = 63). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 9.4%) and insulin users (mean HbA1c: 9.3%) groups. After 24 weeks of treatment, both groups showed improvement in HbA1c (insulin naive: -2.1%, insulin users: 1.9%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404508 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the West Bengal cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from West Bengal, India. RESULTS: A total of 1133 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 897), insulin detemir (n = 94), insulin aspart (n = 90), basal insulin plus insulin aspart (n = 28) and other insulin combinations (n = 19). At baseline glycaemic control was poor for both insulin naive (mean HbA1c: 8.5%) and insulin user (mean HbA1c: 8.9%) groups. After 24 weeks of treatment, both the study groups showed improvement in HbA1c (insulin naive: -1.3%, insulin users: -1.6%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404509 TI - Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Kolkata cohort of the A1chieve study. AB - BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Kolkata, India. RESULTS: A total of 576 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 417), insulin detemir (n = 70), insulin aspart (n = 55), basal insulin plus insulin aspart (n = 19) and other insulin combinations (n = 15). At baseline, glycaemic control was poor for both insulin naive (mean HbA1c: 8.3%) and insulin user (mean HbA1c: 8.6%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naive: -1.3%, insulin users: -1.4%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID- 24404510 TI - Targeting the Peroxisome Proliferator-Activated Receptor-gamma to Counter the Inflammatory Milieu in Obesity. AB - Adipose tissue, which was once viewed as a simple organ for storage of triglycerides, is now considered an important endocrine organ. Abnormal adipose tissue mass is associated with defects in endocrine and metabolic functions which are the underlying causes of the metabolic syndrome. Many adipokines, hormones secreted by adipose tissue, regulate cells from the immune system. Interestingly, most of these adipokines are proinflammatory mediators, which increase dramatically in the obese state and are believed to be involved in the pathogenesis of insulin resistance. Drugs that target peroxisome proliferator activated receptor-gamma have been shown to possess anti-inflammatory effects in animal models of diabetes. These findings, and the link between inflammation and the metabolic syndrome, will be reviewed here. PMID- 24404512 TI - Diabetogenic effect of statins: a double-edged sword? AB - Statins are widely prescribed cholesterol-lowering agents, which have been demonstrated to significantly reduce cardiovascular morbidity and mortality. However, recent trials have reported that statins cause worsening of hyperglycemia and increase the risk of new-onset diabetes. The association between the diabetogenic effect of statins with intensive dose and accompanying major risk factors for diabetes has been demonstrated. However, statins do not appear to have a class effect on insulin sensitivity in non-diabetic patients. Numerous mechanisms have been suggested to explain how statins cause beta-cell insulin secretory dysfunction and peripheral insulin resistance leading to incident diabetes. According to findings from an aggregate of large clinical trials, the benefits of statin treatment appear to outweigh the risk of new-onset diabetes. Therefore, it would be inappropriate to discontinue the use of statins for prevention of cardiovascular events because of its potential risk for development of incident diabetes. This review addresses the currently available evidence related to statin use and new-onset diabetes from a clinical perspective. PMID- 24404511 TI - Resistin in rodents and humans. AB - Obesity is characterized by excess accumulation of lipids in adipose tissue and other organs, and chronic inflammation associated with insulin resistance and an increased risk of type 2 diabetes. Obesity, type 2 diabetes, and cardiovascular diseases are major health concerns. Resistin was first discovered as an adipose secreted hormone (adipokine) linked to obesity and insulin resistance in rodents. Adipocyte-derived resistin is increased in obese rodents and strongly related to insulin resistance. However, in contrast to rodents, resistin is expressed and secreted from macrophages in humans and is increased in inflammatory conditions. Some studies have also suggested an association between increased resistin levels and insulin resistance, diabetes and cardiovascular disease. Genetic studies have provided additional evidence for a role of resistin in insulin resistance and inflammation. Resistin appears to mediate the pathogenesis of atherosclerosis by promoting endothelial dysfunction, vascular smooth muscle cell proliferation, arterial inflammation, and formation of foam cells. Indeed, resistin is predictive of atherosclerosis and poor clinical outcomes in patients with coronary artery disease and ischemic stroke. There is also growing evidence that elevated resistin is associated with the development of heart failure. This review will focus on the biology of resistin in rodents and humans, and evidence linking resistin with type 2 diabetes, atherosclerosis, and cardiovascular disease. PMID- 24404513 TI - Clinical marker of platelet hyperreactivity in diabetes mellitus. AB - Atherothrombotic complications are important causes of morbidity and mortality in diabetic patients. Diabetes has been considered to be a prothrombotic status. Several factors contribute to the prothrombotic condition, such as increasing coagulation, impaired fibrinolysis, endothelial dysfunction, and platelet hyperreactivity. Among the factors that contribute to the prothrombotic status in diabetes, altered platelet function plays a crucial role. Although understanding platelet function abnormalities in diabetes still remains as a challenge, more attention should be focused on platelet function for effective management and the prediction of atherothrombotic events in diabetic patients. This review will provide an overview on the current status of knowledge of platelet function abnormalities and clinical marker of platelet hyperreactivity in patients with diabetes. PMID- 24404514 TI - Metformin based dual-combination therapies in drug naive type 2 diabetic patients. PMID- 24404515 TI - Prevalence and Management of Dyslipidemia in Korea: Korea National Health and Nutrition Examination Survey during 1998 to 2010. AB - BACKGROUND: Dyslipidemia is a major risk factor of cardiovascular disease. The aim of this study was to investigate the changing trends in the prevalence and management status of dyslipidemia among Korean adults. METHODS: The prevalence of dyslipidemia and the rates of awareness, treatment, and control of dyslipidemia were investigated in adults aged >=20 years from the Korea National Health and Nutrition Surveys (KNHANES) 1998 to 2010. The updated National Cholesterol Education Program criteria was used, which define dyslipidemia as having one or more of the following lipid abnormalities: hypercholesterolemia (total cholesterol >=240 mg/dL or diagnosis of dyslipidemia or use of lipid-lowering drugs), hypertriglyceridemia (>=150 mg/dL), hyper-low density lipoprotein (LDL) cholesterolemia (>=160 mg/dL or diagnosis of dyslipidemia or use of lipid lowering drugs), and hypo-high density lipoprotein (HDL)-cholesterolemia (<40 mg/dL in men and <50 mg/dL in women). RESULTS: The number of participants was 6,921, 4,894, 5,312, 2,733, 6,295, 6,900, and 5,738 in KNHANES 1998, 2001, 2005, 2007, 2008, 2009, and 2010, respectively. Age-standardized prevalence rates of dyslipidemia were 54.0%, 65.8%, 66.5%, 60.6%, 58.7%, 58.9%, and 59.0% in 1998, 2001, 2005, 2007, 2008, 2009, and 2010, respectively. Hypertriglyceridemia and hypo-HDL-cholesterolemia were the two most frequent lipid abnormalities. The overall prevalence of hypercholesterolemia and hyper-LDL-cholesterolemia increased by 1.36- and 1.35-fold in 2010 compared with 2007, respectively. Awareness, treatment, and control rates of dyslipidemia improved over the period of surveys in both sexes. In 2010, about 30% of dyslipidemic patients who received lipid-lowering treatment reached target levels. CONCLUSION: Although the management status of dyslipidemia has improved during recent years, effective strategy is required for achieving better prevention, treatment, and control of dyslipidemia. PMID- 24404516 TI - Subclinical hypothyroidism is independently associated with microalbuminuria in a cohort of prediabetic egyptian adults. AB - BACKGROUND: Recent evidence has suggested an association between subclinical hypothyroidism (SCH) and microalbuminuria in patients with type 2 diabetes. However, whether SCH is related to microalbuminuria among subjects with prediabetes has not been studied. Thus, we evaluated the association between SCH and microalbuminuria in a cohort of prediabetic Egyptian adults. METHODS: A total of 147 prediabetic subjects and 150 healthy controls matched for age and sex were enrolled in this study. Anthropometric measurements, plasma glucose, lipid profile, homeostasis model assessment of insulin resistance (HOMA-IR), thyroid stimulating hormone (TSH), free thyroxine, triiodothyronine levels, and urinary albumin-creatinine ratio (UACR) were assessed. RESULTS: The prevalence of SCH and microalbuminuria in the prediabetic subjects was higher than that in the healthy controls (16.3% vs. 4%, P<0.001; and 12.9% vs. 5.3%, P=0.02, respectively). Prediabetic subjects with SCH were characterized by significantly higher HOMA-IR, TSH levels, UACR, and prevalence of microalbuminuria than those with euthyroidism. TSH level was associated with total cholesterol (P=0.05), fasting insulin (P=0.01), HOMA-IR (P=0.01), and UACR (P=0.005). UACR was associated with waist circumference (P=0.01), fasting insulin (P=0.05), and HOMA-IR (P=0.02). With multiple logistic regression analysis, SCH was associated with microalbuminuria independent of confounding variables (beta=2.59; P=0.01). CONCLUSION: Our findings suggest that prediabetic subjects with SCH demonstrate higher prevalence of microalbuminuria than their non-SCH counterparts. SCH is also independently associated with microalbuminuria in prediabetic subjects. Screening and treatment for SCH may be warranted in those patients. PMID- 24404517 TI - Relative skeletal muscle mass is associated with development of metabolic syndrome. AB - BACKGROUND: Visceral adiposity is related to insulin resistance. Skeletal muscle plays a central role in insulin-mediated glucose disposal; however, little is known about the association between muscle mass and metabolic syndrome (MS). This study is to clarify the clinical role of skeletal muscle mass in development of MS. METHODS: A total of 1,042 subjects were enrolled. Subjects with prior MS and chronic diseases were excluded. After 24 months, development of MS was assessed using NCEP-ATP III criteria. Skeletal muscle mass (SMM; kg), body fat mass (BFM; kg), and visceral fat area (VFA; cm(2)) were obtained from bioelectrical analysis. Then, the following values were calculated as follows: percent of SMM (SMM%; %): SMM (kg)/weight (kg), skeletal muscle index (SMI; kg/m(2)): SMM (kg)/height (m(2)), skeletal muscle to body fat ratio (MFR): SMM (kg)/BFM (kg), and skeletal muscle to visceral fat ratio (SVR; kg/cm(2)): SMM (kg)/VFA (cm(2)). RESULTS: Among 838 subjects, 88 (10.5%) were newly diagnosed with MS. Development of MS increased according to increasing quintiles of BMI, SMM, VFA, and SMI, but was negatively associated with SMM%, MFR, and SVR. VFA was positively associated with high waist circumference (WC), high blood pressure (BP), dysglycemia, and high triglyceride (TG). In contrast, MFR was negatively associated with high WC, high BP, dysglycemia, and high TG. SVR was negatively associated with all components of MS. CONCLUSION: Relative SMM ratio to body composition, rather than absolute mass, may play a critical role in development of MS and could be used as a strong predictor. PMID- 24404518 TI - Glycemic Effectiveness of Metformin-Based Dual-Combination Therapies with Sulphonylurea, Pioglitazone, or DPP4-Inhibitor in Drug-Naive Korean Type 2 Diabetic Patients. AB - BACKGROUND: This study compared the glycemic effectiveness of three metformin based dual therapies according to baseline hemoglobin A1c (HbA1c) to evaluate the appropriateness of the guideline enforced by the National Health Insurance Corporation of Korea for initial medication of type 2 diabetes (T2D). METHODS: This prospective observational study was conducted across 24 weeks for drug-naive Korean T2D patients with HbA1c greater than 7.5%. Subjects were first divided into three groups based on the agent combined with metformin (group 1, gliclazide modified release or glimepiride; group 2, pioglitazone; group 3, sitagliptin). Subjects were also classified into three categories according to baseline HbA1c (category I, 7.5%<=HbA1c<9.0%; category II, 9.0%<=HbA1c<11.0%; category III, 11.0%<=HbA1c). RESULTS: Among 116 subjects, 99 subjects completed the study, with 88 subjects maintaining the initial medication. While each of the metformin-based dual therapies showed a significant decrease in HbA1c (group 1, 8.9% to 6.4%; group 2, 9.0% to 6.6%; group 3, 9.3% to 6.3%; P<0.001 for each), there was no significant difference in the magnitude of HbA1c change among the groups. While the three HbA1c categories showed significantly different baseline HbA1c levels (8.2% vs. 9.9% vs. 11.9%; P<0.001), endpoint HbA1c was not different (6.4% vs. 6.6% vs. 6.0%; P=0.051). CONCLUSION: The three dual therapies using a combination of metformin and either sulfonylurea, pioglitazone, or sitagliptin showed similar glycemic effectiveness among drug-naive Korean T2D patients. In addition, these regimens were similarly effective across a wide range of baseline HbA1c levels. PMID- 24404520 TI - Letter: predicting mortality of critically ill patients by blood glucose levels (diabetes metab j 2013;37:385-90). PMID- 24404519 TI - Pattern of Stress-Induced Hyperglycemia according to Type of Diabetes: A Predator Stress Model. AB - BACKGROUND: We aimed to quantify stress-induced hyperglycemia and differentiate the glucose response between normal animals and those with diabetes. We also examined the pattern in glucose fluctuation induced by stress according to type of diabetes. METHODS: To load psychological stress on animal models, we used a predator stress model by exposing rats to a cat for 60 minutes and measured glucose level from the beginning to the end of the test to monitor glucose fluctuation. We induced type 1 diabetes model (T1D) for ten Sprague-Dawley rats using streptozotocin and used five Otsuka Long-Evans Tokushima Fatty rats as obese type 2 diabetes model (OT2D) and 10 Goto-Kakizaki rats as nonobese type 2 diabetes model (NOT2D). We performed the stress loading test in both the normal and diabetic states and compared patterns of glucose fluctuation among the three models. We classified the pattern of glucose fluctuation into A, B, and C types according to speed of change in glucose level. RESULTS: Increase in glucose, total amount of hyperglycemic exposure, time of stress-induced hyperglycemia, and speed of glucose increase were significantly increased in all models compared to the normal state. While the early increase in glucose after exposure to stress was higher in T1D and NOT2D, it was slower in OT2D. The rate of speed of the decrease in glucose level was highest in NOT2D and lowest in OT2D. CONCLUSION: The diabetic state was more vulnerable to stress compared to the normal state in all models, and the pattern of glucose fluctuation differed among the three types of diabetes. The study provides basic evidence for stress-induced hyperglycemia patterns and characteristics used for the management of diabetes patients. PMID- 24404523 TI - Non-invasive Ventilation in Premature Infants: Based on Evidence or Habit. AB - Despite surfactant and mechanical ventilation being the standard of care for preterm infants with respiratory failure, non-invasive respiratory support is increasingly being employed in neonatal units. The latter can be accomplished in a variety of ways but none of them have been proven so far to be superior to intubation and mechanical ventilation. Nonetheless, they appear to be safe and effective in experienced hands. This article relates to the use of non-invasive forms of respiratory support and evidence is reviewed from the clinical trials which have evaluated the use of these techniques. PMID- 24404524 TI - Could heart rate variability expect extubation readiness in preterm infants? PMID- 24404525 TI - Nasal Ventilation is Not Superior to Nasal CPAP in Extreme Preterm Infants. PMID- 24404526 TI - Intravenous Immunoglobulin Doesn't Decrease Mortality for Suspected or Proven Sepsis in the Neonate. PMID- 24404527 TI - Importance of Normal Values of CSF Parameters in Term Versus Preterm Neonates. AB - BACKGROUND: Evaluation of the cerebrospinal fluid (CSF) white blood cell (WBC) count and glucose and protein concentrations is used to assess the probability of the presence of central nervous system (CNS) infection. Although normal values are well established for CSF cell counts and protein and glucose contents in children and adults, this is not the case for neonates. AIMS: The purpose of this study was to evaluate the composition of noninfected CSF obtained by nontraumatic lumbar puncture in neonates (age<28 days), specifically distinguishing CSF profiles of those term babies compared with those premature infants. MATERIALS AND METHODS: The CSF samples obtained by lumbar puncture from 120 neonates were examined by routine procedures. RESULTS: By comparing CSF parameters between term gestation neonate group with premature neonate one, nontraumatic puncture, there was no statistically significant difference (P<0.05) in the mean WBC (P=0.6). The mean protein concentration was significantly greater in those premature neonates (P<0.04). The mean glucose concentration was also analogous in both groups (P=0.5). CONCLUSION: The CSF profile, like any other laboratory determination, should be evaluated within the clinical context of the individual case. PMID- 24404528 TI - Study of Umbilical Cord Blood Culture in Diagnosis of Early-onset Sepsis Among Newborns with High-risk Factors. AB - CONTEXT: Blood culture is gold standard for diagnosis of neonatal sepsis. Low sensitivity of blood culture is usually due to small volume of blood sample, intrapartum antibiotics, and antibiotics given to newborn before sampling. AIM: We evaluated use of Umbilical cord blood culture (UCBC) in diagnosis of neonatal sepsis as compared to peripheral venous blood culture. SETTINGS AND DESIGN: This study was done in tertiary care teaching hospital during May-June 2012. A total of 45 newborns with presence of two or more risk factors of sepsis were included. SUBJECTS AND METHODS: Blood sample from placental end of umbilical cord was collected and cultured. Primary outcome was diagnosis of neonatal sepsis by use of umbilical cord blood sample as compared with venous blood sample. Secondary outcome was to compare organisms identified by UCBC and venous blood culture. STATISTICAL ANALYSIS: Sensitivity, specificity, positive and negative predictive values of UCBC were calculated. RESULTS: A total of 24.44% (11 out of 45) high risk newborns had positive UCBC. A total of 17.8% (8 out of 45) newborns had positive blood culture report. Organisms grown in UCBC were Pseudomonas (45%, 5 out of 11), Acinetobacter (27.27%, 3 out of 11), Escherichia coli (18.18%, 2 out of 11), and Klebsiella (9%, 1 out of 11). CONCLUSION: UCBC is a good method for diagnosis of neonatal sepsis among high-risk newborns as compared to venous blood culture with a sensitivity of 80% and specificity of 91.43%. Organisms grown are comparable to blood culture samples. PMID- 24404529 TI - Examination of the percentage of immature platelet fraction in term and preterm infants at birth. AB - BACKGROUND: Reticulated platelets (RPs) are newly synthesized platelets. Recently, an automatic method was established to detect RPs as a percentage of the immature platelet fraction (IPF%). Although, neonates often develop thrombocytopenia at some time during their hospitalization, the details of IPF% in neonates remain unclear. We, therefore, studied the relations between IPF% and other factors to gain a more detailed understanding of IPF% in neonates. METHODS: The following clinical data were obtained from the medical records of 105 neonates who met our inclusion criteria: Gestational age, birth weight, IPF% and platelet count of neonatal peripheral blood at birth, and perinatal data. The subjects were divided into three groups: Group A, birth weight standard deviation score (SDS) >= -2 standard deviation (SD) and <= +2 SD; Group S, < -2 SD; and Group L, > +2 SD. RESULTS: IPF% correlated negatively with platelet count at birth in the whole study population. IPF% was 2.8 +/- 1.3% in term neonates, and IPF correlated negatively with gestational age and birth weight. Platelet count correlated positively with birth weight SDS in the whole study population and in Group S. IPF% correlated negatively with birth weight SDS in the whole study population and in Group S. In neonates with a platelet count below 25 * 10(4)/MUl, IPF% correlated negatively with platelet count. Among other neonates, however, IPF% remained almost constant. CONCLUSION: Monitoring of IPF% is useful for estimating the function of thrombocytopoiesis in neonates and preterm infants. PMID- 24404530 TI - Nucleated red blood cell in cord blood as a marker of perinatal asphyxia. AB - BACKGROUND: Perinatal asphyxia is a major cause of neurological morbidity and mortality in India. The purpose of this study was to investigate variations in nucleated red blood cell (NRBC) in blood associated with perinatal asphyxia and its relationship to both the severity and short term prognosis of asphyxia. METHODS: A prospective (case-control) study was undertaken at Gandhi Medical College and Associated Hospitals. A total of 100 neonates were included in the study. Levels of NRBC/100 white blood cells (WBC) and absolute NRBC counts in cord blood were compared for 50 asphyxiated (case group) and 50 normal neonates (control group). These parameters were also related to the severity of asphyxia and clinical outcome. RESULTS: The number of NRBC/100 WBC in the blood of 50 newborns each in the asphyxiated and in the control group were mean 29.5 +/- 26.0, range 7-144 NRBCs/100 WBC and mean +/- standard deviation 5.9 +/- 2.6, range 3-14 NRBCs/100 WBC respectively (P < 0.01). Using quartile deviation, staging of hypoxic ischemic encephalopathy (HIE) was done on basis of NRBC count and there was 80% agreement between clinical and NRBC staging of HIE. There was a significant (P < 0.01) correlation of the number of NRBC?100 WBC with Apgar scoring, HIE staging and mortality. CONCLUSIONS: The NRBCs/100 WBCs can be used as a simple marker for the assessment of severity and early outcome of perinatal asphyxia. PMID- 24404531 TI - An Outbreak of Neonatal Candidemia Due to Non-albicans Candida Species in a Resource Constrained Setting of Uttarakhand State, India. AB - This case report describes the outbreak of candidemia caused by non-albicans Candida (NAC) species, which within a short period of 11 days, affected six neonates housed in the same room of neonatal intensive care unit of a rural tertiary care center in Uttarakhand state, India. The NAC species isolated showed complete resistance to azole compounds tested. All the neonates were having central venous catheters at the time of diagnosis, received total parenteral nutrition and were on broad spectrum antibiotics. Though two neonates survived the infection, but four of them had an unfortunate outcome and they died despite of aggressive therapy with amphotericin B. It was concluded that candidemia was associated with previously described risk factors and that poor infection control practices were likely responsible for outbreak. PMID- 24404532 TI - Symptomatic infantile hepatic hemangioendothelioma successfully treated with steroid. AB - A case of hepatic hemangioendothelioma presenting as congestive cardiac failure in a neonate is being reported which was managed successfully with oral prednisolone, resulting in improvement of symptoms and regression of tumor within 3 months. PMID- 24404533 TI - Stress induced hyperglycemia in a term baby mimicking diabetic ketoacidosis with stroke. AB - Stress/sepsis induced transient hyperglycemia in the newborn may present with extremely high blood sugar values and may mimic neonatal diabetes mellitus. We present a case of neonatal septicemia with stress induced hyperglycemia mimicking neonatal diabetes mellitus. Extremely high blood sugar values upto 1529 mg/dl with metabolic acidosis were noted in a term good weight baby causing a diagnostic dilemma. It can be seen even in term babies, contrary to the belief that it occurs in preterm and small for gestation babies. Considering the prognostic implications it may cause it is important that hyperglycemia is promptly treated by insulin infusion. PMID- 24404534 TI - Congenital Longitudinal Radial Deficiency in Infants: Spectrum of Isolated Cases to VACTERL Syndrome. AB - Congenital longitudinal radial deficiency is a rare congenital anomaly and encompasses a spectrum ranging from mild hypoplasia to complete absence of radius. Furthermore known as radial club hand or radial dysplasia, there is variable degree of deficiency along the radial side of the limb. The authors report a case series of four cases; two cases of isolated radial club hand and two associated with other anomalies, including VACTERL syndrome. The rarity of the disease and the need to exclude other associated anomalies are emphasized. PMID- 24404535 TI - Congenital bilateral perislyvian syndrome: case report and review of literature. AB - Congenital bilateral Perislyvian syndrome (CBPS) is a rare structural malformation of the brain in which the underlying anomaly is polymicrogyria. Polymicrogyria is a malformation of cortical development that is characterized by abnormal arrangement and excessive folding of cerebral cortical cell layers, often with fusion of the gyral surfaces, which can be focal or regional or involve the whole cortical mantle. Clinical manifestations depend upon the anatomical region of the brain involved. We report a case of 7-year-old male child with magnetic resonance imaging findings of CBPS. PMID- 24404536 TI - Cutis marmorata telangiectatica congenita. AB - Cutis Marmarata Telangiectatica is a benign vascular anomaly that manifests as dilatation of superficial capilllaries and veins usually present at birth. PMID- 24404537 TI - A classical case of neonatal varicella. AB - The presentation of varicella in the newborn depends upon the time of onset of infection in the mother. Varicella in neonates presents as congenital or neonatal varicella. Our case, admitted to us on day 5 of life had a severe infection as the mother had developed rashes only 2 days prior to delivery. PMID- 24404538 TI - A saudi patient with an interstitial deletion of short arm of chromosome. PMID- 24404539 TI - Cardiovascular risk assessment in prediabetes and undiagnosed diabetes mellitus study: international collaboration research overview. AB - The study aims to develop a screening protocol for the risk of future cardiovascular disease and diabetes mellitus in people with prediabetes and undiagnosed diabetes; and to establish a framework for early identification and intervention of prediabetes including strategies for holistic management and monitoring of progression. The first phase is to identify prediabetes and undiagnosed diabetes in volunteers who are >=18-years-old for 5 years. Point-of care testing and questionnaire will be used to screen for prediabetes and cardiovascular disease. We anticipate screening more than 2000 individuals of both genders by the end of first phase. The second and third phases which shall run for 5-10 years will be longitudinal study involving participants identified in the first phase as having prediabetes without dyslipidaemia, or clinically established cardiovascular disease. The second phase shall focus on preventive management of risk of progress to diabetes with explicit diagnosis of cardiovascular disease. Oxidative stress measurements will be performed cum evaluation of the use of antioxidants, exercise, and nutrition. The third phase will include probing the development of diabetes and cardiovascular disease. Binomial logistic regression would be performed to generate and propose a model chart for the assessment of cardiovascular disease risk in prediabetes. PMID- 24404540 TI - Anaphylactic Shock: Kounis Hypersensitivity-Associated Syndrome Seems to be the Primary Cause. AB - Experiments have shown that anaphylaxis decreases cardiac output; increases left ventricular end diastolic pressure; induces severe early acute increase in respiratory resistance with pulmonary interstitial edema; and decreases splanchnic, cerebral, and myocardial blood flow more than what would be expected from severe arterial dilation and hypotension. This is attributed to the constrictive action of inflammatory mediators released during anaphylactic shock. Inflammatory mediators such as histamine, neutral proteases, arachidonic acid products, platelet-activating factor (PAF), and a variety of cytokines and chemokines constitute the pathophysiologic basis of Kounis hypersensitivity associated acute coronary syndrome. Although the mechanisms of anaphylactic shock still remain to be elucidated, myocardial involvement due to vasospasm-induced coronary blood flow reduction manifesting as Kounis syndrome should be always considered. Searching current experimental and clinical literature on anaphylactic shock pathophysiology, causality, clinical appearance, and treatment via PubMed showed that differentiating global hypoperfusion from primary tissue suppression due to mast cell mediator constrictive action on systemic arterial vasculature is a challenging procedure. Combined tissue suppression from arterial involvement and peripheral vasodilatation, perhaps, occur simultaneously. In cases of anaphylactic shock treatment targeting the primary cause of anaphylaxis together with protection of coronary vasculature and subsequently the cardiac tissue seems to be of paramount importance. PMID- 24404541 TI - Comparison of different phenotypic and genotypic methods for the detection of methicillin-resistant Staphylococcus aureus. AB - BACKGROUND: Staphylococcus aureus is known as a powerful pathogen that causes various infections. Emergence of methicillin-resistant S. aureus (MSRA) is responsible for nosocomial and community-acquired infections worldwide. AIMS: The present study aimed to evaluate the performance and ability of eight different phenotypic and genotypic methods for the detection of MSRA. MATERIALS AND METHODS: A total of 186 S. aureus isolates were defined as methicillin susceptible S. aureus (MSSA; 95) and MSRA (91) using polymerase chain reaction (PCR) as the gold standard. Susceptibility to methicillin was investigated using oxacillin, methicillin, cefotetan, cefoxitin, and cefmetazole disks, by oxacillin Adata Tab and strips. For all S. aureus isolates minimal inhibitory concentrations of oxacillin were determined using the broth microdilution method according to Clinical and Laboratory Standards Institute guidelines. RESULTS: Among the diagnostic methods studied, broth microdilution and the cefoxitin disk had the highest specificity (98.9 and 94.7%), sensitivity (100 and 98.9%), and concordance with PCR results (98.9 and 93.6%). The cefotetan and cefmetazole disks had the lowest concordance with PCR results. CONCLUSION: Our results suggest that microdilution and cefoxitin disk methods have high sensitivities compared with other methods for detection of MSRA. The cefoxitin disk method may be preferred in clinical laboratories because it is easy to perform and does not require special equipment. PMID- 24404542 TI - Prevalence and correlates of insomnia and obstructive sleep apnea in chronic kidney disease. AB - BACKGROUND: Poor sleep quality, insomnia, and restless legs syndrome (RLS) and sleep apnea are common in patients with chronic kidney disease (CKD). Clinical correlates of these problems are poorly understood. AIMS: This study was to find out the prevalence and correlates of insomnia and subjects with 'high risk for obstructive sleep apnea (OSA)' in adults with chronic kidney disease. MATERIALS AND METHODS: One hundred and four adults with CKD were included. Their demographic data, details regarding kidney disease and hemodialysis (HD) were recorded. Presence of insomnia and its severity was assessed. They were screened for sleep apnea using a validated questionnaire. RESULTS: Average age was 54.17 (+/- 12.96) years. 89.4% had stage 5 nephropathy and 78.8% subjects were on regular HD. Males outnumbered females. Insomnia was reported by 35.5%. Among these, 50% had chronic insomnia. Insomnia subjects had higher prevalence of diabetes (P = 0.01) and depression (P < 0.001). Fifty-one percent subjects were at "high risk for sleep apnea". They had higher prevalence of diabetes (P < 0.001), coronary disease (P = 0.02), insomnia (P = 0.008), and experienced daytime symptoms of insomnia (P < 0.001). However, in the logistic regression, only male gender (odds ratio, OR = 13.59) and daytime symptoms of insomnia (OR = 7.34) were found to be associated with "higher risk for sleep apnea". CONCLUSION: Insomnia was prevalent in CKD. Nearly half of these patients are at high risk for sleep apnea and a third of them suffer from insomnia. Hence, these patients should be screened for sleep disorders. PMID- 24404543 TI - Clinical spectrum of rheumatic Fever and rheumatic heart disease: a 10 year experience in an urban area of South India. AB - BACKGROUND: Rheumatic fever (RF) is an important problem concerning developing countries like India. Rheumatic heart disease (RHD) is one of the most readily preventable chronic diseases. AIM: This study was done to find out the clinical profile, risk factors, compliance with treatment and outcome among RF/RHD cases so as to suggest better case management strategies. MATERIALS AND METHODS: Clinical records of 51 RF and 71 RHD cases admitted in tertiary care hospitals in Mangalore between 2001 and 2010 were reviewed retrospectively. RESULTS: Mean age of RF cases were 17.4 +/- 12.1 years and RHD cases were 33.2 +/- 18.6 years. More than half of RF and RHD cases were males. Commonest risk factors among RF cases were poor socioeconomic status (60.4%), history of upper respiratory tract infection before disease onset (58.8%) and undernutrition (35.3%). Commonest clinical manifestation among RF cases was fever 39 (76.5%) followed by polyarthritis 34 (66.7%). Commonest valvular lesions among RHD cases was mitral stenosis with mitral regurgitation found in 42.9% cases. Compliance of patients with prophylactic antibiotics was found to be 37 (30.3%). Mortality rate was significantly more among RHD cases (P = 0.0399). CONCLUSIONS: Improvement of socioeconomic and nutritional factors is an important task required for primary prophylaxis and of compliance for secondary prophylaxis of RF. PMID- 24404544 TI - Prevalence of overweight and obesity in portuguese adolescents: comparison of different anthropometric methods. AB - BACKGROUND: The recommended anthropometric methods to assess the weight status include body mass index (BMI), skinfold thickness, and waist circumference. However, these methods have advantages and disadvantages regarding the classification of overweight and obesity in adolescents. AIMS: The study was to analyze the correlation between the measurements of BMI, skinfold thickness and waist circumference to assess overweight and obesity in Portuguese adolescents. MATERIALS AND METHODS: A sample of 966 students of Portugal was used. Of them, 437 (45.2%) were males and 529 (54.8%) were females aged between 10 and 16 years. The evaluations included BMI calculation, skinfold thickness, and waist circumference measurements. RESULTS: This study revealed a high prevalence of overweight and obesity with values ranging from 31.6%, 61.4%, and 41.1% according to the measurement of BMI, skinfold thickness, and waist circumference, respectively. The results found a high level of correlation between BMI and skinfold thickness (P < 0.001, r = 0.712), between BMI and waist circumference (P < 0.001, r = 0.884), and waist circumference and skinfold thickness (P < 0.001, r = 0.701). CONCLUSIONS: This study revealed a high prevalence of overweight and obesity in Portuguese adolescents using three different anthropometric methods, where the BMI showed the lowest values of prevalence of overweight and obesity and the skinfold thickness showed the highest values. The three anthropometric methods were highly correlated. PMID- 24404545 TI - Hyponatremia associated with unilateral hand weakness and numbness: a case report. AB - CONTEXT: The key clinical features in this case are to make the diagnosis apical lung cancer (Pancoast tumor) in a patient with brachial plexopathy and to recognize the association between syndrome of inappropriate secretion of antidiuretic hormone (SIADH) as a paraneoplastic syndrome and non-small cell lung cancer (NSCLC). CASE REPORT: We herein describe a rare case of NSCLC presented as pancoast tumor complicated by brachial plexopathy and associated with SIADH as a paraneoplastic phenomena. There were no renal insufficiency, congestive cardiac failure, liver insufficiency, volume depletion, diuretic use, hypoadrenalism, and hypothyroidism in our patient. Furthermore, the findings of serum hyponatraemia and hypo-osmolality associated with an inappropriate high urinary osmolality indicate that the SIADH was present in our patient due to the NSCLC. CONCLUSION: Our case also emphasizes that early recognition and appropriate applied management may significantly improve symptoms and prevent complications of hyponatremia which may enhance quality of life in patients with paraneoplastic SIADH. PMID- 24404546 TI - Posttraumatic nonunion of the clavicle in a 13-year-old boy causing an arteriovenous fistula. AB - CONTEXT: Fractures of the clavicle are one of the most common injuries to the bone in childhood, but posttraumatic nonunion of pediatric clavicle fractures are extremely rare, with only isolated reports in literature. CASE REPORT: We report a case of a posttraumatic painful nonunion of a clavicle fracture in a 13-year old boy that caused symptomatic compression of the external jugular vein (EJV) and the formation of an arteriovenous fistula. The fracture was treated successfully with open reduction and internal fixation with a contoured recon plate 6 months following the injury. The fistula was treated by ligation and closure. CONCLUSION: The patient made a full recovery 6 months following surgery and was asymptomatic with full range of shoulder movement. Fracture union was confirmed by computed tomography (CT) scanning and no residual fistula was found. PMID- 24404547 TI - Gastrointestinal Kaposi's Sarcoma Presenting as Ileocolic Intussusception. AB - CONTEXT: Kaposi's sarcoma (KS) is the most common neoplasm in patients with acquired immune deficiency syndrome (AIDS). Gastrointestinal (GI) involvement with KS commonly occurs in association with cutaneous lesions or lymph node involvement, with GI tract involvement alone occurring in only 3.5% of cases. There are several case reports described in the literature about asymptomatic intestinal KS with skin manifestations. Although GI KS is usually asymptomatic, hemorrhages from the oral cavity, esophagus, stomach, and large bowel have been reported in this disease. CASE REPORT: Our case is unique, in a way that the patient does not have skin manifestation, and also is that the first manifestation presented as acute intestinal intussusception and obstruction with nodular mass lesions of the stomach and GI tract due to GI KS. CONCLUSION: As a differential diagnosis of KS, nonHodgkin lymphomas frequently involve the gut in AIDS patients. Furthermore, tumors of the gut with spindle-shaped cells such as leiomyomas, rhabdomyosarcomas, high-grade pleomorphic sarcomas, or GI stromal tumors have to be considered in the differential diagnosis. Overall, the visceral involvement of the KS is usually associated with poor prognosis. Our case illustrates the importance of physicians to recognize GI KS as a differential diagnosis for HIV positive patients with recurrent abdominal pain. It is commonly occurs in association with cutaneous lesions or lymph node involvement and rarely presents with GI involvement alone, which is makes it a challenge to the physician. PMID- 24404548 TI - Brown bowel syndrome: a rare and often overlooked complication of intestinal atresia. PMID- 24404549 TI - Clinicopathological prognostic implicators of oral squamous cell carcinoma: need to understand and revise. AB - In spite of the vast amount of research and the advances, oral squamous cell carcinoma implies quite significant mortality and morbidity rates. This has motivated the search of factors with prognostic relevance. A web based search was initiated for all published articles by using Medline/PubMed, Google Scholar with key words such as prognosis, survival rate, risk factors associated with oral squamous cell carcinoma, prognosis of oral squamous cell carcinoma. The search was restricted to articles published in English language with no restriction to date of publication. This review was focused on clinical, pathological and molecular factors associated with survival and prognosis of oral squamous cell carcinoma patients. Most articles had described one or two parameters related to prognosis. Considering the biological behavior and nature of cancer, all the parameters were interrelated and so could not predict the prognosis independently. Consideration of all the parameters was required to assess the prognosis. We hypothesize the use of combination of clinical and pathological indicators together to assess the prognosis. The care givers can assess the prognosis in a more better and definitive way by using prognosis assessment sheet. PMID- 24404550 TI - Prevalence of traditional cardiovascular risk factors and evaluation of cardiovascular risk using three risk equations in nigerians living with human immunodeficiency virus. AB - BACKGROUND: Reports from middle- and high-income countries suggest that the improved health outcome from highly active antiretroviral therapy (HAART) in people living with human immunodeficiency virus (PLWHIV) is being mitigated by increase in deaths from cardiovascular disease (CVD). AIMS: This study was to determine the prevalence of traditional cardiovascular risk factors (CVRFs) and the 10-year cardiovascular risk using three risk equations in PLWHIV with no overt vascular disease. MATERIALS AND METHODS: This cross-sectional study involved 265 PLWHIV. We classified the subjects as having low, moderate or high cardiovascular risk using the Framingham, World Health Organization/International Society of Hypertension (WHO/ISH) and Systematic Coronary Risk Evaluation (SCORE) equations. RESULTS: The mean age of the cohort was 38.7 +/- 8.7 years; 179 (67.5%) were females and 214 (80.8%) were on HAART. The prevalent traditional CVRFs in our cohort were low physical activity (66%), low HDL-C (49.1%), hypercholesterolaemia (33.6%), BMI >= 25 kg/m(2) (32.8%) and elevated LDL-C (28.3%). The prevalence of smoking was very low (1.9%). The prevalence of moderate to high 10-year coronary risk was 11.7, 12.8, and 12.8% according to the Framingham, WHO/ISH and SCORE risk equations, respectively. CONCLUSION: Most of our patients had low overall cardiovascular risk according to the three risk equations. PMID- 24404551 TI - Intestinal amebiasis: a concerning cause of acute gastroenteritis among hospitalized lebanese children. AB - BACKGROUND: Intestinal amebiasis is an important public health problem worldwide. More severe disease is associated with young age, malnutrition and immunosuppression. AIM: The aim of this study is to evaluate the prevalence and characteristic nature of intestinal amebiasis among pediatric population, and compare it with other causes of gastroenteritis. MATERIALS AND METHODS: This is a retrospective comparative study conducted at Makassed General Hospital between January 2008 and December 2012, including all pediatric patients between birth and 15 years of age, who presented with symptoms of acute gastroenteritis. RESULTS: One thousand three hundred ninety-five patients were included in the study, and were divided into four groups: Group I (Entameba histolytica group = 311 cases, 22.3%), group II (Rotavirus group = 427 cases, 30.6%), group III (bacterial group = 107 cases, 7.7%), group IV (unidentified group = 550 cases, 39.4%). Significant leukocytosis, neutrophilia and positive C-reactive protein were found among more than 50% of admitted Entemaba histolytica cases with a picture of severe invasive disease in young infants. CONCLUSION: Entameba histolytica can be an emerging serious infection, especially when it finds suitable environmental conditions and host factors, so we should be ready to face it with effective preventive measures. PMID- 24404552 TI - Acquired unilateral vocal fold paralysis: retrospective analysis of a single institutional experience. AB - BACKGROUND: Vocal cord paralysis continues to be an important issue in laryngology and is considered as a sign of underlying disease; the etiologies of this problem are varied and changing. AIMS: The study was to carry out a retrospective analysis of patients with unilateral vocal fold paralysis diagnosed. MATERIALS AND METHODS: The medical records of 53 patients diagnosed and treated for unilateral vocal fold paralysis were studied retrospectively. Data regarding age, sex, duration of symptoms, etiology, and side of paralysis were recorded. RESULTS: Out of the 53 cases, 36 were females and 17 males with a ratio of 2.1:1. The age of the patients ranged from 17-75 years. In 18.9% the cause was idiopathic. Surgical trauma (iatrogenic) problems was the most encountered etiology (66%), others included malignancy (non laryngeal) (7.5%), central (3.8%), external neck trauma (1.9%) and radiation therapy 1.9%. Thyroid surgery was the most commonly reported neck surgery in 50.9%. CONCLUSIONS: Thyroidectomy continues to be the single most common surgical procedure responsible for unilateral vocal cord paralysis. For this reason, routine pre and postoperative laryngoscopy should be considered in all patients undergoing surgeries with a potential risk for recurrent nerve paralysis to reduce the postoperative morbidity. PMID- 24404553 TI - Oxidative Low Density Lipoprotien Prohibited Plasmodium Falciparum Clearance in type 2 Diabetes Mellitus Via Cluster Differentiation 36. AB - BACKGROUND: Cluster of differentiation 36 (CD36) is reported to function as a receptor of erythrocytes infected with Plasmodium falciparum (PF) and as an oxidized low-density lipoprotein (oxLDL). AIM: The aim of this study was to investigate the impact of CD36 in PF parasitized red blood cells in high concentration of oxLDL of T2 diabetes mellitus patients. MATERIAL AND METHODS: This cross-sectional study was conducted among diabetic patients. A total of 45 samples were collected from diabetic patients with more than 8% of HbA1c and more than 170 mg/dL of oxLDL. RESULTS: The mean difference between CD36 negative and positive controls was found to be statistically significant (P <= 0.001). The mean difference between CD36 positive control and CD36 in diabetic patients with oxLDL >= 170 mg/dL also was statistically significant. CONCLUSION: High concentration of oxidative low density of lipoprotein more than 170 mg/dL leads to block CD36 receptor on infected red blood. This process believed to contribute in parasite survival by avoiding phagocytic clearance in the spleen. PMID- 24404554 TI - Intestinal protozoans in adults with diarrhea. AB - BACKGROUND: Diarrhea is one of the most common presenting complaints in human immunodeficiency virus-infected individuals. AIMS: The study was designed to determine the magnitude of opportunistic and nonopportunistic intestinal parasitic infections among diarrheal patients and association between CD4(+) T cell counts and human immunodeficiency virus (HIV)-infected intestinal parasites. MATERIALS AND METHODS: A cross-sectional study was conducted among 207 enrolled diarrheal patients attending HIV integrated counseling and testing center from January 2012 to December 2012. Stool samples were subjected to special modified Ziehl-Neelsen and chromotrope staining method for detection of opportunistic protozoans. Blood samples were also collected from all study subjects for HIV testing and CD4(+) T-cell counts were estimated by only in HIV-infected patients. RESULTS: Intestinal parasitic pathogens were detected in 46.1% HIV-infected patients and the major pathogens were opportunistic protozoans 32.2% (37/115), most common being Isospora belli 16.5% (19/115) followed by Cryptosporidium parvum 12.2% (14/115). In HIV noninfected diarrheal patients, major pathogens detected were Entamoeba histolytica/Entamoeba dispar 8.7% (8/92) and Ascaris lumbricoides 3.3% (3/92). CONCLUSIONS: The opportunistic intestinal protozoans especially I. belli and C. parvum were most commonly isolated in HIV-infected patients with diarrhea. Majority of the infections occurred in patients when a CD4(+) T-cell counts were less than 200 cells/MUl. PMID- 24404555 TI - Registration of Clinical Trials: Is it Really Needed? AB - BACKGROUND AND AIMS: Withholding findings of clinical trials for publication or presentation to the regulatory authorities is a major concern. We aimed to address the importance of clinical trial registration and whether it is needed or not. DISCUSSION: For ethical conduct of clinical trial, registration is an important but debatable issue due to proprietary interest of the pharmaceutical industry. Over the years, investigating agencies uncovered several instances of misconduct during the clinical trial. The International committee of medical journal editors requires registration of trial methodology, but does not require registration of trial results; however, the U.S. Food and Drug Administration Amendments does require researchers to register results. CONCLUSION: Prospective registration of clinical trial is mandatory for more transparent research and sustaining the validity of evidence based practice and availability of reliable data. Clinical trials registration has the potential to contribute substantially to improve clinical trial transparency and reducing publication bias and selective reporting. PMID- 24404556 TI - Accuracy of Endoscopic Ultrasound-guided Fine Needle Aspiration in Diagnosing Solid Pseudopapillary Tumor. AB - BACKGROUND: Solid pseudopapillary tumors are rare pancreatic tumors. Accurate preoperative diagnosis helps in planning of the surgery. AIM: This study was to evaluate accuracy of endoscopic ultrasound-guided fine needle aspiration and immunohistochemistry in diagnosing solid pseudopapillary tumors. MATERIALS AND METHODS: A retrospective review was performed by reviewing medical records to identify patients treated for solid pseudopapillary tumors over a 5-year period. Patients who were noted to have pancreatic lesions by computer tomography abdomen underwent endoscopic ultrasound. Fine needle aspiration was obtained from each of these lesions and subjected to immunohistochemistry. RESULTS: Five patients were identified. Endoscopic ultrasound was able to identify the pancreatic lesions in all five patients noted in computer tomography abdomen. Solid pseudopapillary tumors were diagnosed by immunohistochemistry. All five patients underwent surgery and the resected lesions confirmed solid pseudopapillary tumors in 80% patients. CONCLUSION: Endoscopic ultrasound-guided fine needle aspiration has a higher degree of accuracy in diagnosing solid pseudopapillary tumors. PMID- 24404557 TI - Primary adrenal lymphoma with paraneoplastic syndrome. AB - CONTEXT: The adrenal gland is a common site for neoplastic diseases and primary adrenal lymphoma (PAL) is a rare tumor with around 120 cases reported so far. CASE REPORT: We present a rare case of 76-year-old male who presented with headache, confusion, inappropriate body movements and abdominal pain. Adrenal biopsy revealed PAL and he has had an excellent neurologic outcome to date with chemotherapy and involved field radiation. CONCLUSION: The majority of cases of PAL are B cell lymphomas with diffuse large cell in 70% of cases. Clinical symptoms are variable and patients may present with abdominal pain, fever, anorexia, weight loss, fatigue or symptoms of adrenal insufficiency. Therapeutic modalities for PAL include surgery, chemotherapy and radiotherapy and corticosteroid replacement. With this case report, we hope to raise awareness about this rare disease and to include lymphoma in the differential of adrenal masses. PMID- 24404558 TI - The Impact of Myocardial Infarction vs. Pneumonia on Outcome in Acute Ischemic Stroke. AB - The aim of this study was to examine the association between MI and PNA in the setting of acute ischemic stroke and patient outcome. Eligible patients were identified from a prospectively collected stroke registry and included if transthoracic echocardiography (TTE) was performed during their inpatient stay. 426 patients met inclusion criteria (mean age 64, 73% Black, 48% female). Twenty one patients (4.9%) experienced an MI. Patients who later suffered a MI initially presented with more severe strokes (median NIHSS 7 vs. 5, p=0.014). More patients in the MI group experienced pneumonia (26% vs. 9%, p=0.004). After adjusting for age, baseline glucose and NIHSS, the odds of in-hospital mortality for patients with MI was 3 times that of those without MI (OR 3.2 95% CI 1.1-9.7, p=0.036). When adjustment was made for pneumonia, age, baseline glucose and NIHSS, MI was no longer significantly related to in-hospital mortality (OR 2.5 95% CI 0.8-8.2, p=0.131). In our sample, while MI was significantly associated with in-hospital mortality, this association was attenuated after adjusting for presence of pneumonia. Our findings raise the question as to whether the prevention of pneumonia could improve in-hospital mortality among patients who experience MI in the setting of ischemic stroke. PMID- 24404559 TI - Relationship between bone mineral density and the frequent administration of epidural steroid injections in postmenopausal women with low back pain. AB - BACKGROUND: Epidural steroid injection (ESI) is one of the most common nonsurgical treatments for low back pain. In general, corticosteroid therapy often results in bone loss and osteoporosis. In previous studies, bone mineral density (BMD) was evaluated after epidural injections of relatively small numbers and relatively low total doses of corticosteroids. However, the relationship between BMD and multiple ESIs remains to be elucidated. OBJECTIVE: To explore the relationship between BMD and multiple ESIs in postmenopausal women with low back pain. METHODS: Medical records of postmenopausal women with low back pain treated with or without ESIs were reviewed. BMD was measured in the lumbar spine, femoral neck and total femur after the treatments. A total of 71 patients were divided into two groups: group 1 included patients who had received non-ESI medications; and group 2 included those who had received ESIs >10 times, with a cumulative administered triamcinolone dose >200 mg. RESULTS: Patients in group 2 showed lower BMD in the femoral neck and total femur. However, no significant intergroup differences in the BMD of the lumbar spine were observed. The prevalences of osteoporosis and osteopenia in the lumbar spine and femoral neck were significantly higher in group 2; these patients also had lower femoral neck BMD Z scores. CONCLUSIONS: Multiple ESIs (approximately 14 injections with a cumulative triamcinolone dose of approximately 400 mg) can reduce BMD in postmenopausal women with low back pain. PMID- 24404560 TI - Self-reporting hybridisation assay for miRNA analysis. AB - Hybridisation assays, which are commonly used to analyse oligonucleotides such as siRNAs and miRNAs, often employ detection probes with fluorescent tags. The signal emitted by a fluorescent tag covers a broad range of wavelengths and this limits the multiplexing potential due to overlapping signals. A novel method of indirect oligonucleotide analysis has been developed which combines a hybridisation assay with cleavable small molecule mass tags using HPLC-ESI MS detection. A self-reporting detection probe has been designed which incorporates a DNA/RNA chimeric oligonucleotide sequence in the reporter region, which generates small nucleotide products upon RNase cleavage of the ribose-phosphate backbone. These small nucleotides can then serve as mass tags for the indirect detection of oligonucleotide analytes. The narrow mass range covered by a small molecule mass tag combined with the wide range of possible mass tags provides a high degree of multiplexing potential. This approach has been demonstrated for the analysis of a synthetic miRNA. PMID- 24404561 TI - Ultrasensitive detection of 3'-5' exonuclease enzymatic activity using molecular beacons. AB - An ultrasensitive and rapid turn-on fluorescence assay has been developed for the detection of 3'-5' exonuclease activity of exonuclease III (Exo III) using molecular beacons (MBs). This method has a linear detection range from 0.04 to 8.00 U mL(-1) with a limit of detection of 0.01 U mL(-1). In order to improve the selectivity of the method, a dual-MB system has been developed to distinguish between different exonucleases. With the introduction of two differently designed MBs which respond to different exonucleases, the T5 exonuclease, Exo III and RecJf exonucleases can be easily distinguished from each other. Furthermore, fetal bovine serum and fresh mouse serum were used as complex samples to investigate the feasibility of the dual-MB system for the detection of the enzymatic activity of Exo III. As a result, the dual-MB system showed a similar calibration curve for the detection of Exo III as in the ideal buffer solution. The designed MB probe could be a potential sensor for the detection of Exo III in biological samples. PMID- 24404562 TI - A model system for targeted drug release triggered by biomolecular signals logically processed through enzyme logic networks. AB - A new Sense-and-Act system was realized by the integration of a biocomputing system, performing analytical processes, with a signal-responsive electrode. A drug-mimicking release process was triggered by biomolecular signals processed by different logic networks, including three concatenated AND logic gates or a 3 input OR logic gate. Biocatalytically produced NADH, controlled by various combinations of input signals, was used to activate the electrochemical system. A biocatalytic electrode associated with signal-processing "biocomputing" systems was electrically connected to another electrode coated with a polymer film, which was dissolved upon the formation of negative potential releasing entrapped drug mimicking species, an enzyme-antibody conjugate, operating as a model for targeted immune-delivery and consequent "prodrug" activation. The system offers great versatility for future applications in controlled drug release and personalized medicine. PMID- 24404563 TI - An octanuclear {Cu(II)4Dy(III)4} coordination cluster showing single molecule magnet behaviour from field accessible states. AB - The structure and magnetic properties of an octanuclear coordination cluster with a {Cu(II)4Dy(III)4} core are described and a model for the unusual SMM behaviour is proposed. PMID- 24404564 TI - Synthesis of renewable high-density fuels using cyclopentanone derived from lignocellulose. AB - By the combination of solvent-free aldol condensation and one-step hydrodeoxygenation under mild reaction conditions, a high-density (0.866 g mL( 1)) bicyclic C10 hydrocarbon was synthesized in high overall yield (up to 80%) using cyclopentanone derived from lignocellulose. PMID- 24404565 TI - Toward a clearer understanding of causal concepts in epidemiology. AB - PURPOSE: In this manuscript, I share insights into causal concepts that emerged from creating and refining a simple example originally designed for teaching causal epidemiologic concepts. METHODS: The insights that emerged are primarily related to the difference between how a causal effect occurs in an individual and what our methods assume about how a causal effect occurs when we estimate its effect in a population. In an individual, the causal effect of exposure on disease occurrence results from the interaction of several causal factors in that individual, not from a single factor in isolation. The result of this interaction within an individual determines an individual's causal type (e.g., doomed, exposure causative, exposure preventive, immune) with respect to a particular exposure contrast and target (etiologic) time period. In a population, the causal effect of exposure on disease frequency depends on the distribution of causal types of individuals in that population, not necessarily on the population distribution of covariates. Yet in epidemiology, when we attempt to estimate the effect of a potential cause of interest, we (through the methods we use) usually do not account for this within individual causal interaction. RESULTS: This failure to account for within-individual causal interactions has interesting implications for causal inference, as I illustrate here: (1) an effect estimate can be simultaneously confounded and unconfounded, (2) there can be confounding even if no variables satisfy the traditional criteria for being considered a confounder, (3) there can be no confounding even if there are variables that do satisfy the traditional confounder criteria, (4) the magnitude of confounding caused by a variable need not depend on the strength of the exposure-variable association, (5) a directed acyclic graph does not always correctly identify the presence of confounding, (6) the common-cause confounder criterion is imperfect, and (7) a time-varying confounder does not necessarily lead to time-varying confounding. CONCLUSIONS: Our example illustrates that confounding is a "team sport": single variables do not confound by themselves; confounding depends on how variables interact in individuals, not just on how variables are distributed within and across populations. Because confounding depends on how variables interact in individuals, methods that ignore causal interactions in individuals are not guaranteed to be confounding identification methods. PMID- 24404566 TI - The risk of cancer among patients with sleep disturbance: a nationwide retrospective study in Taiwan. AB - PURPOSE: To investigate the risk of cancer among patients with nonapnea sleep disorders (SDs). METHODS: We included newly diagnosed SD patients aged 20 years and older without antecedent cancer between 2000 and 2010 from the National Health Insurance Research Database. Standardized incidence ratios (SIRs) of cancers were calculated to compare the cancer incidence of patients with SD with that of the general population. RESULTS: During the 10-year study period, 2062 cancers developed among 63,381 SD patients, who were observed for 382,826 person years (median follow-up of 6.23 years). The SIR for all cancers was 1.19 (95% confidence interval [CI], 1.14e1.24). For specific cancer types, SD patients exhibited an increased SIR for liver and lung cancers (1.44; 95% CI, 1.28e1.61 and 1.34; 95% CI, 1.18e1.51, respectively). CONCLUSIONS: We observed that overall cancer risk is increased among Asian SD patients. In terms of individual cancers, the risks of liver and lung cancers were elevated. Clinicians should be aware of the possibility of increased liver and lung cancers among SD patients in Taiwan. A prospective study is necessary to confirm these findings. PMID- 24404567 TI - The relationships between ambient air pollutants and childhood asthma and eczema are modified by emotion and conduct problems. AB - PURPOSE: This study examined the hypothesis that emotion and conduct problems (ECPs) may modify the relationships between ambient air pollutants and childhood asthma and eczema. METHODS: In the cross-sectional study, 4209 French schoolchildren (aged 10e12 years) were investigated between March 1999 and October 2000. Ambient air pollutants exposures were estimated with dispersion modeling. Health outcomes and ECPs were evaluated by validated questionnaires, completed by the parents. Marginal models were used to analyze the relationships of exposures to ambient air pollutants and/or ECPs to asthma phenotypes and current eczema, adjusting for potential confounders. RESULTS: In our population, interactions were found between ECPs and exposures to ambient air pollutants (benzene, carbon monoxide, nitrogen dioxide, nitrogen oxides, particulate matter with an aerodynamic diameter below 10 mm, volatile organic compounds) (P < .20). In addition, ECPs were related to current wheezing (adjusted prevalence odds ratio [aOR], 2.35; 95% confidence interval [CI], 1.59e3.47), current doctor diagnosed asthma (aOR, 1.82; 95% CI, 1.25e2.66), and current eczema (aOR, 2.21; 95% CI, 1.61e3.02). Children with ECPs had 1.17e1.51 times higher aORs for the associations between ambient air pollutants and asthma phenotypes and current eczema than those without ECPs. CONCLUSIONS: ECPs may modify the relationships between ambient air pollutants and childhood asthma and eczema. PMID- 24404568 TI - Childhood social hardships and fertility: a prospective cohort study. AB - PURPOSE: To examine the effect of lifetime social hardships on fertility. METHODS: Using the British National Child Development Study, a longitudinal cohort study, the impact of exposure to childhood hardships on becoming pregnant, reported infertility, and time-to-pregnancy was investigated. In total, 6477 women reported on whether they had become pregnant by 41 years, and 5198 women had data on at least one pregnancy. Factor analysis was used to identify six types of childhood hardships (as reported by parent, child, social worker, or teacher); retrospective report of child abuse was also examined. Logistic regression and discrete failure-time analysis was used to adjust for potential confounders. RESULTS: Never-married women were more likely to have become pregnant at some point if they had experienced more childhood hardships. Retrospectively, reported child abuse was associated with an increased likelihood of having been told that one was unable to have children. Among ever-married women, childhood hardships were associated with reduced fecundability, but the association was weakened by adjustment for adult social class. CONCLUSIONS: The relationship between childhood adversity and adult fertility is complex. Future research should investigate pathways between characteristics of adversities and fertility. PMID- 24404569 TI - Does liver damage explain the inverse association between vitamin D status and mortality? AB - PURPOSE: Several observational studies have linked vitamin D deficiency with an increased risk of all cause mortality. Vitamin D deficiency is common among patients with liver diseases. In a random sample of the general population, we investigated whether the inverse association between vitamin D status and all cause mortality could be explained by liver damage as reflected by increased levels of liver enzymes. METHODS: We included a total of 2649 persons examined in 1993e1994. Vitamin D status was assessed as serum 25-hydroxyvitamin D and liver enzyme levels were measured. Information on all-cause mortality was obtained from the Danish Central Personal Register until July 2011. Median follow-up time was 17.0 years, and there were 736 deaths. RESULTS: Multivariable Cox regression analyses with age as underlying time axis and delayed entry showed lower mortality risk with higher vitamin D levels and this was essentially unaffected by adjustment for liver enzyme levels with hazard ratio, 0.96 (95% confidence interval, 0.93e0.99) for a 10 nmol/L higher vitamin D level. CONCLUSIONS: The present study did not support our hypothesis that the well-known association between low vitamin D status and mortality is explained by liver damage as reflected by levels of liver enzymes. PMID- 24404570 TI - Comparative metabolic profiling revealed limitations in xylose-fermenting yeast during co-fermentation of glucose and xylose in the presence of inhibitors. AB - During lignocellulosic ethanol fermentation, yeasts are exposed to various lignocellulose-derived inhibitors, which disrupt the efficiency of hexose and pentose co-fermentation. To understand the metabolic response of fermentation microbes to these inhibitors, a comparative metabolomic investigation was performed on a xylose-fermenting Saccharomyces cerevisiae 424A (LNH-ST) and its parental strain 4124 with and without three typical inhibitors (furfural, acetic acid, and phenol). Three traits were uncovered according to fermentation results. First, the growth of strain 424A (LNH-ST) was more sensitive to inhibitors than strain 4124. Through metabolomic analysis, the variance of trehalose, cadaverine, glutamate and g-aminobutyric acid (GABA) suggested that strain 424A (LNH-ST) had a lower capability to buffer redox changes caused by inhibitors. Second, lower ethanol yield in glucose and xylose co-fermentation than glucose fermentation was observed in strain 424A (LNH-ST), which was considered to be correlated with the generation of xylitol, as well as the reduced levels of lysine, glutamate, glycine and isoleucine in strain 424A (LNH-ST). Accumulation of glycerol, galactinol and mannitol was also observed in strain 424A (LNH-ST) during xylose fermentation. Third, xylose utilization of strain 424A (LNH-ST) was more significantly disturbed by inhibitors than glucose utilization. Through the analysis of fermentation and metabolomic results, it was suggested that xylose catabolism and energy supply, rather than xylose uptake, were the limiting steps in xylose utilization in the presence of inhibitors. PMID- 24404571 TI - Italian perspective on psoriasis, spondyloarthritis, rheumatoid arthritis and juvenile idiopathic arthritis: immunopathology and role of etanercept. Abstracts of a Seminars in Research. October 14-15, 2011. Italy. PMID- 24404572 TI - Author's reply: To PMID 23261803. PMID- 24404573 TI - Author's reply: To PMID 23443856. PMID- 24404574 TI - Author's reply: To PMID 23665986. PMID- 24404575 TI - Author's reply: To PMID 23835301. PMID- 24404577 TI - Effect of the antineoplastic agent busulfan on rat molar root development. AB - OBJECTIVE: The antineoplastic bifunctional-alkylating agent busulfan (Bu) induces developmental anomalies. We examined histopathological changes in the molar roots of rats that received Bu at different stages of root formation. DESIGN: At different developmental stages, i.e., on postnatal days (P) 13, 15, and 19, rats were administered 7.5 mg/kg of Bu dissolved in dimethyl sulfoxide (DMSO) and then killed on P 30. After micro-computed tomography analysis, the maxillary first molars underwent immunohistochemical analysis for cytokeratin 14 (CK14), nestin, and dentin sialoprotein (Dsp). This was followed by histomorphometric analysis. RESULTS: The rats receiving Bu at an early stage (i.e., P 13 and P 15) showed osteodentin formation and complete destruction of the Hertwig's epithelial root sheath (HERS). Cells around osteodentin showed nestin and Dsp immunoreactivity. The root lengths in rats treated with Bu at P 13 (1228.44 +/- 62.17 MUm) and P 15 (1536.08 +/- 109.71 MUm) were lower than that in the control rats (1674.10 +/- 40 MUm). A narrowed apical foramen and an increased amount of osteodentin were also present, depending on the rat's age at the time of treatment (P < 0.05). CONCLUSION: Busulfan treatment in juvenile rats resulted in abnormal root development, depending on the stage at which Bu was administered. This abnormal development may result from the destruction of the HERS. The administration of Bu caused a shortage of HERS cells, which are required for normal root development. This disturbs root formation, resulting in osteodentin formation and a narrowed apex foramen. PMID- 24404578 TI - Anti-ageing effects of dentifrices containing anti-oxidative, anti-inflammatory, and anti-bacterial agents (Tomarina(r)) on gingival collagen degradation in rats. AB - OBJECTIVE: Previous studies have demonstrated the relationship between ageing and oxidative stress. In this study, we examined the effects of topical application of a dentifrice containing anti-oxidative, anti-inflammatory, and anti-bacterial agents (Tomarina(r)) to the gingival surface on gingival collagen degradation in rats. DESIGN: Fischer 344 male rats (4 or 8 months old) were divided into two groups: experimental group and control group. Tomarina(r) (the experimental group) or control dentifrice (the control group) was applied 5 days per week for 2 months. RESULTS: In the control group, gingival collagen density decreased with ageing. In the experimental group, the collagen density did not change with ageing, and was greater than that in the control group at 10 months of age (p < 0.0083). In addition, the control group showed an increase in serum oxidative stress with ageing. The experimental group also showed increased serum oxidative stress, but the value was lower than the control group at 10 months of age (p < 0.0083). Furthermore, low expressions of protein oxidative damage in the periodontal tissue were observed in the experimental group, compared to the control group at 6 months and 10 months. CONCLUSION: These findings indicate that Tomarina(r) might suppress the effects of ageing on gingival collagen degradation, by decreasing oxidative stress in the rat model. PMID- 24404579 TI - Sensory properties and drivers of liking for Greek yogurts. AB - Greek yogurt is currently the largest growing sector in the dairy industry. Because no standard of identity exists for Greek yogurts in the United States, and they can be made by a variety of methods, variability in sensory properties is expected. Knowledge of consumer perception and specific drivers of liking will be useful information for product developers. The objective of this study was to document the sensory properties of commercial Greek yogurts and to determine drivers of liking through descriptive profiling and consumer testing. Flavor and texture attributes of commercial Greek yogurts (n = 24) were evaluated in triplicate by a trained descriptive sensory panel. An online survey (n = 520) was used to collect consumer usage and attitude information for Greek yogurts before consumer acceptance testing. Consumer acceptance testing (n = 155) was then conducted on commercial Greek yogurts (n = 10). Univariate and multivariate statistical analyses were used for data analysis. Sensory properties of yogurt differed with fat content and manufacture (Greek vs. fortified Greek). Full-fat yogurts were characterized by firmness and denseness, whereas low- and non-fat yogurts lacked firmness, denseness, cohesiveness, and, after stirring, viscosity. Fortified Greek yogurts generally had more surface shine and jiggle and lower denseness compared with traditional Greek yogurts. Fewer flavor differences were observed among yogurts compared with texture differences. Fortified Greek yogurts displayed a burnt/beefy flavor not documented in traditional Greek yogurts, but this flavor was not evident in all fortified Greek yogurts. Consumer preferred Greek yogurts with firm, dense texture, moderate sweet aromatic, milkfat and dairy sour flavors, and moderate sour taste. Consumers were aware of the increased protein content of Greek yogurts but generally unaware of differences between strained and fortified Greek yogurts; both strained Greek and fortified Greek yogurts received the highest overall liking scores in blinded acceptance testing. Successful Greek yogurts can be manufactured using addition of dried dairy ingredients or by traditional straining and centrifugation. PMID- 24404576 TI - Wernicke's area revisited: parallel streams and word processing. AB - Auditory word-form recognition was originally proposed by Wernicke to occur within left superior temporal gyrus (STG), later further specified to be in posterior STG. To account for clinical observations (specifically paraphasia), Wernicke proposed his sensory speech center was also essential for correcting output from frontal speech-motor regions. Recent work, in contrast, has established a role for anterior STG, part of the auditory ventral stream, in the recognition of species-specific vocalizations in nonhuman primates and word-form recognition in humans. Recent work also suggests monitoring self-produced speech and motor control are associated with posterior STG, part of the auditory dorsal stream. Working without quantitative methods or evidence of sensory cortex' hierarchical organization, Wernicke co-localized functions that today appear dissociable. "Wernicke's area" thus may be better construed as two cortical modules, an auditory word-form area (AWFA) in the auditory ventral stream and an "inner speech area" in the auditory dorsal stream. PMID- 24404582 TI - Short communication: Little change takes place in Camembert-type cheese water activities throughout ripening in terms of relative humidity and salt. AB - Water activity (a(w)) affects the growth and activity of ripening microorganisms. Moreover, it is generally accepted that a(w) depends on relative humidity (RH) and salt content; these 3 variables were usually measured on a given day in a cheese without the microorganism layer and without accounting for a distinction between the rind, the underrind, and the core. However, a(w) dynamics have never been thoroughly studied throughout cheese ripening. Experimental Camembert cheeses were ripened under controlled and aseptic conditions (temperature, gaseous atmosphere, and RH) for 14 d. In this study, only RH was varied. Samples were taken from the cheese (microorganism layer)-air interface, the rind, and the core. The aw of the cheese-air interface did not change over ripening when RH varied between 91 and 92% or between 97 and 98%. However, on d 5, we observed a small but significant increase in a(w), which coincided with the beginning of growth of Penicillium camemberti mycelia. After d 3, no significant differences were found between the a(w) of the cheese-air interface, the rind, and the core. From d 0 to 3, cheese rind a(w) increased from 0.94 to 0.97, which was probably due to the diffusion of salt from the rind to the core: NaCl content in the rind decreased from 3.7 to 1.6% and NaCl content in the core increased from 0.0 to 1.6%. Nevertheless, aw did not significantly vary in the core, raising questions about the real effect of salt on a(w). PMID- 24404581 TI - Surface biotechnology for refining cochlear implants. AB - The advent of the cochlear implant is phenomenal because it is the first surgical prosthesis that is capable of restoring one of the senses. The subsequent rapid evolution of cochlear implants through increasing complexity and functionality has been synchronized with the recent advancements in biotechnology. Surface biotechnology has refined cochlear implants by directly influencing the implant tissue interface. Emerging surface biotechnology strategies are exemplified by nanofibrous polymeric materials, topographical surface modification, conducting polymer coatings, and neurotrophin-eluting implants. Although these novel developments have received individual attention in the recent literature, the time has come to investigate their collective applications to cochlear implants to restore lost hearing. PMID- 24404580 TI - The potent oncogene NPM-ALK mediates malignant transformation of normal human CD4(+) T lymphocytes. AB - With this study we have demonstrated that in vitro transduction of normal human CD4(+) T lymphocytes with NPM-ALK results in their malignant transformation. The transformed cells become immortalized and display morphology and immunophenotype characteristic of patient-derived anaplastic large-cell lymphomas. These unique features, which are strictly dependent on NPM-ALK activity and expression, include perpetual cell growth, proliferation, and survival; activation of the key signal transduction pathways STAT3 and mTORC1; and expression of CD30 (the hallmark of anaplastic large-cell lymphoma) and of immunosuppressive cytokine IL 10 and cell-surface protein PD-L1/CD274. Implantation of NPM-ALK-transformed CD4(+) T lymphocytes into immunodeficient mice resulted in formation of tumors indistinguishable from patients' anaplastic large-cell lymphomas. Our findings demonstrate that the key aspects of human carcinogenesis closely recapitulating the features of the native tumors can be faithfully reproduced in vitro when an appropriate oncogene is used to transform its natural target cells; this in turn points to the fundamental role in malignant cell transformation of potent oncogenes expressed in the relevant target cells. Such transformed cells should permit study of the early stages of carcinogenesis, and in particular the initial oncogene-host cell interactions. This experimental design could also be useful for studies of the effects of early therapeutic intervention and likely also the mechanisms of malignant progression. PMID- 24404583 TI - GPRC5B a putative glutamate-receptor candidate is negative modulator of insulin secretion. AB - GPRC5B is an orphan receptor belonging to the group C family of G protein-coupled receptors (GPCRs). GPRC5B is abundantly expressed in both human and mouse pancreatic islets, and both GPRC5B mRNA and protein are up-regulated 2.5-fold in islets from organ donors with type 2 diabetes. Expression of Gprc5b is 50% lower in islets isolated from newborn (<3 weeks) than in adult (>36 weeks) mice. Lentiviral shRNA-mediated down-regulation of Gprc5b in intact islets from 12 to 16 week-old mice strongly (2.5-fold) increased basal (1 mmol/l) and moderately (40%) potentiated glucose (20 mmol/l) stimulated insulin secretion and also enhanced the potentiating effect of glutamate on insulin secretion. Downregulation of Gprc5b protected murine insulin-secreting clonal MIN6 cells against cytokine-induced apoptosis. We propose that increased expression of GPRC5B contributes to the reduced insulin secretion and b-cell viability observed in type-2 diabetes. Thus, pharmacological targeting of GPRC5B might provide a novel means therapy for the treatment and prevention of type-2 diabetes. PMID- 24404584 TI - Type V collagen fibrils in mouse metanephroi. AB - Type V collagen (Col V) molecule, a minor component of kidney connective tissues, was found in adult cornea, and has been considered as a regulatory fibril-forming collagen that emerges into type I collagen to trigger the initiation of Col I fiber assembly. Col V was also found in injured, wound healing tissues or placenta, and was considered as a dysfunctional extracellular matrix (ECM). Reconstituted Col V fibril was characterized as an ECM to detach cells in vitro, and our previous study showed that the reconstituted Col V fibril facilitated the migration of glomerular endothelial cells and induced ECM remodeling, whereas Col V molecules stabilized cells. These facts suggest that not only the structure but also the function of Col V fibril are different from Col V molecule. Recently, Col V molecule has been reported existing in various developing tissues such as bone and lung, but Col V fibril has not been reported yet. In this study, we firstly explored the existence of Col V fibril in metanephroi, and found it distributed in the immature kidney tissues whereas disappeared when the tissues reached mature. It is likely that Col V fibril may form a prototype of pericellular microenvironment and the transient existence of Col V fibril may play a role as the pioneering ECM during metanephric tissue morphogenesis. PMID- 24404585 TI - The protein kinases TPL2 and EGFR contribute to ERK1/ERK2 hyperactivation in CFTRDeltaF508-expressing airway epithelial cells exposed to Pseudomonas aeruginosa. AB - Excessive inflammation and Pseudomonas aeruginosa infection are two major characteristics of cysticfibrosis (CF) lung disease. In this manuscript, we describe a novel mechanism of ERK1/ERK2 activationand CXCL8 expression in airway epithelial cells (AECs) lacking functional CFTR. In both non-CF and CFAECs, the protein kinase TPL2 is required for ERK1/ERK2 MAPK activation. However, we have found that EGFR is strongly phosphorylated in the airway epithelium of CF lung and contributes to ERK1/ERK2 MAPK activation in CF AECs exposed to P. aeruginosa diffusible material (PsaDM). Moreover, PsaDM stimulates the expression of the EGFR pro-ligand HB-EGF more strongly, and in a sustained manner, in CF AECs compared to non-CF cells. Finally, although both non-CF and CF AECs expresses CXCL8 in response to PsaDM, the levels of CXCL8 are higher and EGFR plays a more important role in regulating CXCL8 synthesis in CF AECs. Together, our finding shows that in addition to the TLR-mediated TPL2 activation of ERK1/ERK2, an additional pathway contributing to ERK1/ERK2 activation is triggered by infection of CF AECs: the EGFR signaling pathway. This second pathway may contribute to excessive inflammation observed in CF. PMID- 24404586 TI - The role of autophagy in doxorubicin-induced cardiotoxicity. AB - Doxorubicin (Dox) is an effective chemotherapeutic agent, however, its use is limited by cardiotoxicity. The mechanisms causing cardiotoxicity have not been clearly elucidated, but known to involve, at least in part, oxidative stress, mitochondrial dysfunction and apoptosis. More recently, it has been suggested that dysregulation of autophagy may also play an important role in Dox-induced cardiotoxicity. Autophagy has dual functions. Under physiological conditions, autophagy is essential for optimal cellular function and survival by ridding the cell of damaged or unwanted proteins and organelles. Under pathological conditions, autophagy may be stimulated in order to protect the cell from stress stimuli or, alternatively, to contribute to cell death. Thus, appropriate regulation of autophagy can be a matter of life or death. The role of autophagy in Dox-induced cardiotoxicity has recently been explored, however, conflicting reports on the effects of Dox on autophagy and its role in cardiotoxicity exist. Most, but not all, of the studies conclude that Dox upregulates cardiac autophagy and contributes to the pathogenesis of Dox-induced toxicity. Dox may induce autophagy by suppressing the expression of GATA4 and/or S6K1, which may directly or indirectly regulate expression of essential autophagy genes such as Atg12, Atg5, Beclin1 and Bcl-2. Interestingly, the Dox-induced autophagic response may be species specific as Dox treatment has been shown to stimulate autophagy in rat models, but suppress autophagy in mouse models. Additional studies will elucidate this possibility. PMID- 24404587 TI - Anti-inflammatory effects of anethole in lipopolysaccharide-induced acute lung injury in mice. AB - AIMS: Anethole, the major component of the essential oil of star anise, has been reported to have antioxidant, antibacterial, antifungal, anti-inflammatory, and anesthetic properties. In this study, we investigated the anti-inflammatory effects of anethole in a mouse model of acute lung injury induced by lipopolysaccharide (LPS). MAIN METHODS: BALB/C mice were intraperitoneally administered anethole (62.5, 125, 250, or 500 mg/kg) 1 h before intratracheal treatment with LPS (1.5 mg/kg) and sacrificed after 4 h. The anti-inflammatory effects of anethole were assessed by measuring total protein and cell levels and inflammatory mediator production and by histological evaluation and Western blot analysis. KEY FINDINGS: LPS significantly increased total protein levels; numbers of total cells, including macrophages and neutrophils; and the production of inflammatory mediators such as matrix metalloproteinase 9 (MMP-9), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and nitric oxide (NO) in bronchoalveolar lavage fluid. Anethole (250 mg/kg) decreased total protein concentrations; numbers of inflammatory cells, including neutrophils and macrophages; and the inflammatory mediators MMP-9, TNF-alpha and NO. In addition, pretreatment with anethole decreased LPS-induced histopathological changes. The anti-inflammatory mechanism of anethole in LPS-induced acute lung injury was assessed by investigating the effects of anethole on NF-kappaB activation. Anethole suppressed the activation of NF-kappaB by blocking IkappaB-alpha degradation. SIGNIFICANCE: These results, showing that anethole prevents LPS induced acute lung inflammation in mice, suggest that anethole may be therapeutically effective in inflammatory conditions in humans. PMID- 24404588 TI - Oxidatively modified LDL particles in the human placenta in early and late onset intrauterine growth restriction. AB - INTRODUCTION: Reduced serum LDL concentrations have been observed in pregnancies complicated by intrauterine growth restriction (IUGR) as compared to healthy pregnant women. Since increased oxidative stress has been suggested to play a major role in IUGR we now hypothesized that the lower LDL concentrations are accompanied by an accumulation of oxidized LDLs in the placenta. METHODS: Fifteen placentas of near term and preterm born IUGR, and a gestational age matched control group (CTRL n = 15) were analyzed. Placental minimal modified LDL and fully oxidized LDL particles were measured by ELISA, and by immunohistochemistry, and were related to maternal and fetal serum lipid profiles. RESULTS: We found fully oxidized LDL but not minimal modified LDL being increased in the preterm subgroup of IUGR (n = 10) as compared to preterm CTRL (n = 10; p < 0.05). An increased staining intensity of trophoblasts in preterm IUGR subjects as compared to preterm CTRL has been confirmed by immunohistochemistry (p < 0.05). No difference could be found between the term groups (n = 5 each). Correlation analysis revealed an inverse relationship of maternal LDL (rho = -0.49, p = 0.03) and fetal HDL cholesterol (rho = -0.46, p = 0.04) with placental fully oxidized LDL particle concentration within preterms. DISCUSSION: IUGR is a heterogeneous entity. Different pathomechanisms seem to underlie the disease in preterm and term subjects with oxidation of LDL within the placenta possibly taking place in preterm IUGRs. CONCLUSIONS: We conclude that the reduced maternal LDL cholesterol concentration in IUGR pregnancies is attributed to increased accumulation of oxidized LDL particles within the placenta at least in early onset IUGR PMID- 24404589 TI - E-cadherin gene promoter hypermethylation may contribute to the risk of bladder cancer among Asian populations. AB - There are increasing scientific evidences suggesting that E-cadherin gene promoter hypermethylation may contribute to the development and progression of bladder cancer, but existing studies have yielded inconclusive results. This meta analysis aims to assess the role of E-cadherin promoter hypermethylation in bladder carcinogenesis. We conducted an extensive literature search for relevant studies on PubMed, Embase, Web of Science, Cochrane Library, and CBM databases from their inception through May 1st, 2013. This meta-analysis was performed using the STATA 12.0 software. Crude risk ratio (RR) with 95% confidence interval (CI) was calculated. Ten clinical studies were included in this meta-analysis with a total of 620 bladder cancer samples,199 normal adjacent samples and 131 normal urothelium tissue. Our meta-analysis revealed that the methylation frequencies in bladder cancer tissues were obviously higher than those in normal control tissues (RR = 2.02, 95%CI: 1.00-4.12, P = 0.050). Subgroup analysis by ethnicity indicated that higher methylation frequencies were observed in bladder cancer tissues among Asian populations (RR = 2.35, 95%CI: 1.11-4.95, P = 0.025), but not among Caucasian populations (RR = 1.62, 95%CI: 0.48-5.53, P = 0.439). Univariate and multivariate meta-regression analyses showed that ethnicity may be the major source of heterogeneity (Pb0.05).No publication bias was detected in this meta-analysis (P=0.358). The present meta-analysis indicates that E-cadherin gene promoter hypermethylation may contribute to increased risk of bladder cancer among Asian populations. PMID- 24404590 TI - Decreased circulating miR-375: a potential biomarker for patients with non-small cell lung cancer. AB - MicroRNAs (miRNAs) are directly involved in cancer initiation, progression and metastasis. Alterations of miRNAs expression in cancer tissue may be reflected in circulation.We attempted to investigate the expression and clinical significance of plasma miR-20a, miR-31 and miR-375 in patients with non-small cell lung cancer (NSCLC). The plasma levels of miR-20a, miR-31 and miR-375 in 164 NSCLC patients and 164 healthy controls (discovery cohort)were evaluated and compared among various clinicopathological characteristics. The relationship between miRNA expression and clinical outcome of NSCLC patients was examined in an independent cohort (53 cases and 53 controls). The expression level of miR-375 in tissue was also examined. Plasma miR-375 levels in NSCLC patients were significantly decreased in both patient cohorts (P b 0.05). In addition, patients with metastatic NSCLC had lower plasma miR-375 expression than those with non metastatic NSCLC (P b 0.05). Survival analysis showed that patients with low miR 375 expression had worse overall survival rates than those with high miR-375 expression (hazard ratios (HR)=1.537 (1.046-2.258), P=0.029). This association was independently validated in a separate cohort of 53 NSCLC patients (HR=2.406, 95% CI 1.170-4.945, P=0.017). The expression level of miR-375 was also found to be significantly down-regulated in NSCLC tissues compared with paracancerous tissues (P b 0.001). These findings indicate that miR-375 has an important role in NSCLC initiation and progression, and may be an independent poor prognostic factor in NSCLC patients. PMID- 24404591 TI - Transient activation of protein kinase C contributes to fluoride-induced apoptosis of rat erythrocytes. AB - Role of PKC in fluoride-induced apoptosis of rat erythrocytes was studied in vitro and in vivo. Treatment of erythrocytes with 5 mM NaF for 1-24 h caused progressive accumulation of cytosolic Ca2+ and PS exposure at outer membrane surface. After 1 h, these processes were suppressed by PKC inhibitors staurosporine, GF 109203X and chelerythrine, but increased by PKC activator PMA. Following 24 h, NaF-induced Ca2+ uptake and PS externalization were partly prevented by PMA or staurosporine, but not by GF 109293X and chelerythrine. Application of PP inhibitor OA augmented NaF-induced cell responses within 1 h, but not after 24 h. Incubation of erythrocytes with 0.1-10 mM NaF for 1 h produced a dose-dependent PKCa translocation from cytosol to membranes with appearance of active PKM fragment. 24 h NaF exposure led to complete loss of cytosolic PKCa and proteolysis of membrane PKCa. Besides, NaF weakly stimulated membrane PKCf, although its subcellular distribution was not altered. Thus, transient PKCa activation/translocation positively contributes to NaF-induced apoptosis in vitro. Consumption of 2-20 ppm fluoride by the rats for 12 months also induced dose-dependent PKCa translocation to membranes and activation of membrane PKCf, what indicates that PKC stimulation is an important physiological mechanism of fluoride toxicity. PMID- 24404592 TI - The Adiponectin variants contribute to the genetic background of type 2 diabetes in Turkish population. AB - Adiponectin, an adipose tissue specific protein encoded by the Adiponectin gene, modulates insulin sensitivity and plays an important role in regulating energy homeostasis. Many studies have shown that single nucleotide polymorphisms (SNPs) in the Adiponectin gene are associated with low plasma Adiponectin levels, insulin resistance and an increased risk of type 2 diabetes mellitus. The aim of the present study was to evaluate the contribution of the Adiponectin gene polymorphisms in genetic background of type 2 diabetes in a Turkish population. In total, 169 unrelated and non-obese diabetic patients and 119 age- and BMI matched nondiabetic individuals with no family history of diabetes were enrolled in this study. We detected a significant association between type 2 diabetes and two SNPs: SNP -11391G N A, which is located in the promoter region of the Adiponectin gene, and SNP +276G N T, which is found in intron 2 of the gene (P b 0.05). The silence SNP G15G (+45TN G) in exon 1 and SNP+349ANG in intron 2 also showed a weak association with type 2 diabetes (P=0.06 and P=0.07, respectively),while SNPs-3971ANG in intron 1 and Y111H, R112C and H241P in exon 3 showed no association (P N 0.05). In conclusion, these findings suggest that Adiponectin gene polymorphisms might be effective on susceptibility for type 2 diabetes development which emerged from the interactions between multiple genes, variants and environmental factors. PMID- 24404593 TI - Compost bedded pack dairy barn management, performance, and producer satisfaction. AB - The objective of the research was to characterize herd performance, producer satisfaction and recommendations, and management practices used by compost bedded pack (CBP) managers in Kentucky (42 farms and 47 CBP facilities). Farms were visited between October 2010 and March 2011. A random selection of cows housed solely in the CBP were scored for locomotion and hygiene. Changes in monthly Dairy Herd Improvement Association performance records, including milk production, SCC, reproductive performance, and daily bulk-tank somatic cell count after moving into the CBP were analyzed using the MIXED procedure of SAS (SAS 9.3; SAS Institute Inc., Cary, NC). The GLM procedure of SAS (SAS 9.3) was used to develop models to describe CBP moisture, CBP temperature at 20.3 cm, and mean herd hygiene. Producers provided 9.0 +/- 2.2 m2 of pack space per cow (n = 44). Barns constructed with an attached feed alley cost $1,051 +/- 407 per cow (n = 40). Barns constructed without an attached feed alley cost $493 +/- 196 per cow (n = 13). Kiln-dried shavings required 0.05 +/- 0.04 m3 of bedding per cow per day (n = 15). Green shavings required 0.07 +/- 0.06 m3 of bedding per cow per day (n = 12). The most-frequently cited benefits of the CBP included cow comfort (n = 28), cow cleanliness (n = 14), and the low-maintenance nature of the system (n = 10). Increased stirring frequency, stirring depth, and ambient temperature increased pack temperature, measured at 20.3 cm below the CBP surface. Increased stirring depth, pasture-adjusted space per cow, and drying rate decreased CBP moisture. Mean herd locomotion and hygiene scores were 1.5 +/- 0.3 (n = 34) and 2.2 +/- 0.4 (n = 34), respectively. Increased 20.3-cm depth CBP temperature and ambient temperatures improved mean herd hygiene. Bulk-tank somatic cell count decreased from the year before to the year after moving into the CBP barn (323,692 +/- 7,301 vs. 252,859 +/- 7,112 cells/mL, respectively) for farms using the CBP barn as the primary housing facility (n = 9). Daily milk production, collected from monthly Dairy Herd Improvement Association tests, increased from before moving into the CBP barn to the second year after (29.3 +/- 0.3 vs. 30.7 +/- 0.3 kg, respectively) for farms using the CBP barn as the primary housing facility (n = 8). Calving interval decreased from the year before to the second year after (14.3 +/- 0.1 vs. 13.7 +/- 0.1 mo) moving into the CBP barn for farms using the CBP as primary housing (n = 8). PMID- 24404594 TI - [Treatment of scabies: from recommendations to pediatric practice]. PMID- 24404595 TI - Construction and operation of microbial fuel cell with Chlorella vulgaris biocathode for electricity generation. AB - In this study, a modified microbial fuel cell (MFC) with a tubular photobioreactor (PHB) configuration as a cathode compartment was constructed by introducing Chlorella vulgaris to the cathode chamber used to generate oxygen in situ. Two types of cathode materials and light/dark cycles were used to test the effect on MFC with algae biocathode. Results showed that the use of algae is an effective approach because these organisms can act as efficient in situ oxygenators, thereby facilitating the cathodic reaction. Dissolved oxygen and voltage output displayed a clear light positive response and were drastically enhanced compared with the abiotic cathode. In particular, carbon paper-coated Pt used as a cathode electrode increased voltage output at a higher extent than carbon felt used as an electrode. The maximum power density of 24.4 mW/m2 was obtained from the MFC with algae biocathode which utilized the carbon paper coated Pt as the cathode electrode under intermittent illumination. This density was 2.8 times higher than that of the abiotic cathode. Continuous illumination shortened the algal lifetime. These results demonstrated that intermittent illumination and cathode material-coated catalyst are beneficial to a more efficient and prolonged operation of MFC with C. vulgaris biocathode. PMID- 24404596 TI - [Impact on the indoor environment of allergic children of the medical counselor on indoor environment, after two successive visits at 6 months interval]. AB - BACKGROUND: The aim of this retrospective study was to assess the impact of a medical indoor environment counselor (MIEC) on the allergic child's indoor home environment, as well as the real-life experience of patients' families. METHODS: We enrolled 50 children (age, 4-18 years) with allergic respiratory illness (96 % asthmatics) from March 2011 to January 2012. During the first visit, the CMEI gave advice according to the results of the assessment. Home environmental exposures were assessed 6 months later. A satisfaction questionnaire was completed by the parents. RESULTS: We found a significant decrease in the presence of house dust mites (P = 0.0047), humidity, and molds (P = 0.0047) as well as volatile organic compounds (P = 0.0047). Smoking habits were not significantly changed (P = 0.083), nor was the presence of domestic pets (P = 0.3173). Over 74 % of the families were very satisfied with the CMEI's intervention. DISCUSSION: According to de Blay's study, a home visit by the MEIC increased compliance with mite reduction. The intervention to advise parents of asthmatic children on the risks of passive smoking was ineffective in reducing their children's exposure to environmental tobacco smoke. The advice given by the MEIC was better understood by the patients than that expressed by the medical teams. CONCLUSION: A targeted home-based environmental intervention increased the compliance to mite, humidity, and mold reduction. The role of the CMEI will undoubtedly develop: follow-up studies are necessary to justify their activity (cost-efficacy ratio of their intervention). PMID- 24404597 TI - [Anaphylaxis: recognize and treat early]. AB - Allergic emergencies in children are now more frequent and unpredictable and can cause death by anaphylactic shock, bronchospasm, and airway angioedema. Despite the publication of recent guidelines, many studies show that caregivers are still not at ease with the management of anaphylaxis and intramuscular administration of adrenaline. The prognosis depends on the early diagnosis of anaphylaxis and adrenaline administration before cardiorespiratory failure. The biphasic course of anaphylaxis requires systematic hospitalization of at least 6-24 hours depending on severity. To prevent recurrence, each child with anaphylaxis should permanently be in possession of two unexpired self-injectable adrenaline devices with a demonstration and written instructions on its use. Close collaboration between emergency departments, allergist, and family is essential to adapt therapeutic education and allergen avoidance to the allergen identified. This article focuses on opportunities to improve the skills of caregivers and standardize the management of anaphylaxis by proposing a practical definition and a therapeutic strategy based on Ring grading of severity. PMID- 24404598 TI - [Prolonged fever in a big child]. AB - Causes of prolonged fever in children vary according to age. Infections are more frequent in young children than in older patients. Careful history and physical examinations are mandatory and are helpful for the diagnosis procedure in most of the cases. PMID- 24404599 TI - [News in pharmaceutics]. PMID- 24404600 TI - Comparison of psychophysical properties of two intraoral digital sensors on low contrast perceptibility. AB - OBJECTIVES: The psychophysical properties of a new complementary metal oxide semi conductor-based detector, ProSensor(r) (Planmeca Oy, Helsinki, Finland), in terms of dose response function and perceptibility curve test were performed and compared with those of a charged couple device-based sensor, Dixi(r) (Planmeca Oy). METHODS: Dose response functions at 66 kVp for a Dixi and a ProSensor were determined by means of multiple exposures to a homogeneous X-ray field covering the whole exposure range. The entry dose of each exposure was measured and registered. The mean grey level in each image was plotted as function of the corresponding exposures for both digital systems. Radiographs of a test object containing ten holes of increasing depth were obtained throughout the exposure range of the two digital sensors at 66 kVp. 12 observers were asked to register the number of perceptible holes in each radiograph. Based on the mean value of the observers' evaluation, the perceptibility curves were constructed, and the integral value under the perceptibility curves were compared between two intraoral sensors. RESULTS: The results based on dose response function showed that the ProSensor was more sensitive than the Dixi sensor. Paired t-test showed that the minimal perceptible low-contrast details were significantly higher for the ProSensor than for the Dixi sensor (p < 0.001). The integrals below the two perceptibility curves were 33.4 and 69.2 for the Dixi and ProSensor, respectively. CONCLUSION: Applying the new ProSensor may be beneficial to patients owing to its reduced radiation dose and increased perception for low contrast details in dentistry. PMID- 24404601 TI - Influence of lead apron shielding on absorbed doses from panoramic radiography. AB - OBJECTIVES: This study investigated the absorbed doses in a full anthropomorphic body phantom from two different panoramic radiography devices, performing protocols with and without applying a lead apron. METHODS: A RANDO(r) full body phantom (Alderson Research Laboratories Inc., Stamford, CT) was equipped with 110 thermoluminescent dosemeters at 55 different sites and set up in two different panoramic radiography devices [SCANORA(r) three-dimensional (3D) (SOREDEX, Tuusula, Finland) and ProMax(r) 3D (Planmeca, Helsinki, Finland)] and exposed. Two different protocols were performed in the two devices. The first protocol was performed without any lead shielding, whereas the phantom was equipped with a standard adult lead apron for the second protocol. RESULTS: A two-tailed paired samples t-test for the SCANORA 3D revealed that there is no difference between the protocol using lead apron shielding (m = 87.99, s = 102.98) and the protocol without shielding (m = 87.34, s = 107.49), t(54) = -0.313, p > 0.05. The same test for the ProMax 3D showed that there is also no difference between the protocol using shielding (m = 106.48, s = 117.38) and the protocol without shielding (m = 107.75, s = 114,36), t(54) = 0.938, p > 0.05. CONCLUSIONS: In conclusion, the results of this study showed no statistically significant differences between a panoramic radiography with or without the use of lead apron shielding. PMID- 24404602 TI - A retrospective study of digital subtraction technique to detect sclerotic changes in alveolar bone on intraoral radiographs of bisphosphonate-treated patients. AB - OBJECTIVES: Several reports have suggested that sclerotic changes in cancellous bone of the jaw and thickening of the lamina dura are characteristic radiographic changes of an early silent stage of bisphosphonate (BP)-related osteonecrosis of the jaw. No quantitative evaluation has been reported to support this hypothesis. Emago(r) software (Oral Diagnostic Systems, Amsterdam, Netherlands) can perform digital subtraction on intraoral radiographs even if they were obtained by non standardized radiography, provided the dimensional error is within a certain limit. The purpose of this study was to evaluate whether sclerotic changes of alveolar bone or thickening of lamina dura in patients using BP can be detected using the subtraction function of Emago. METHODS: The authors selected 46 pairs of intraoral radiographs of the mandibular molar area in dental patients. All radiographs were obtained at intervals of 6 months or more. Among the 46 pairs, 7 pairs were from patients who were being treated with BP (study subjects), and 39 pairs were from patients who had not been using BP (controls). All pairs of radiographs underwent digital subtraction by Emago. The number of pixels of the sclerotic areas was counted and compared between subjects and controls. RESULTS: The sclerotic changes were significantly distinguishable in two of the seven subjects (28.6%) using BP. CONCLUSIONS: Digital subtraction function of Emago was able to detect sclerotic changes in alveolar bone. Therefore, it is suggested that the subtraction function of Emago is a useful tool for quantitatively detecting sclerotic changes that are observed at an early, silent stage of BP related osteonecrosis of the jaw. PMID- 24404603 TI - The effect of scan parameters on cone beam CT trabecular bone microstructural measurements of human mandible. AB - The objective of this study was to investigate the effect of different cone beam CT scan parameters on trabecular bone microstructure measurements. A human mandibular cadaver was scanned using a cone beam CT (3D Accuitomo 170; J.Morita, Kyota, Japan). 20 cone beam CT images were obtained using 5 different fields of view (4*4 cm, 6*6 cm, 8*8 cm, 10*10 cm and 10*5 cm), 2 types of rotation steps (180 degrees and 360 degrees ) and 2 scanning resolutions (standard and high). Image analysis software was used to assess the trabecular bone microstructural parameters (number, thickness and spacing). All parameters were measured twice by one trained observer. Intraclass correlation coefficients showed high intraobserver repeatability (intraclass correlation coefficient, 0.95-0.97) in all parameters across all tested scan parameters. Trabecular bone microstructural measurements varied significantly, especially in smaller fields of view (p = 0.001). There was no significant difference in the trabecular parameters when using different resolutions (number, p = 0.988; thickness, p = 0.960; spacing, p = 0.831) and rotation steps (number, p = 1.000; thickness, p = 0.954; spacing, p = 0.759). The scan field of view significantly influences the trabecular bone microstructure measurements. Rotation steps (180 degrees or 360 degrees ) and resolution (standard or high) selections are not relevant. PMID- 24404604 TI - Reply: To PMID 23820231. PMID- 24404605 TI - Prospective multicenter study of toric IOL outcomes when dual zone automated keratometry is used for astigmatism planning. AB - PURPOSE: To evaluate clinical outcomes when toric intraocular lens (IOL) calculations are based on the keratometric output from the Lenstar LS-900 dual zone automated keratometer (Haag-Streit AG, Koeniz, Switzerland). METHODS: Eligible subjects presenting for toric IOL implantation at five sites were measured with a dual-zone automated keratometer. The data were used to plan the power and angle of the toric IOL to be implanted. Refractive and visual acuity status were checked at 1 and 3 months postoperatively. RESULTS: A total of 102 eyes had relevant data for analysis. More than 76% of eyes had 0.50 diopter or less of refractive astigmatism at 1 and 3 months, with no difference by level of astigmatism corrected. More than half of the eyes had uncorrected distance visual acuity of 20/20 or better and 78% were 20/25 or better. A new measure of effectiveness of toric correction power is described that suggested lens selection was appropriate. Results appeared better than those obtained in previous studies when the IOL cylinder power and alignment were calculated using manual keratometry. CONCLUSIONS: In this series of eyes from multiple centers, the calculation of toric IOL power using dual-zone automated keratometry measurements produced clinical results that were better than results in the literature where manual keratometry was used. PMID- 24404606 TI - Impact of fluorescein on the antimicrobial efficacy of photoactivated riboflavin in corneal collagen cross-linking. AB - PURPOSE: To investigate the effect of fluorescein on the antimicrobial efficacy of photoactivated riboflavin in corneal collagen cross-linking (CXL) in vitro. METHODS: The ultraviolet light-A (UVA) absorption by fluorescein and riboflavin in different concentrations was analyzed with a spectrophotometer. The killing rate of Staphylococcus aureus strains after CXL with UV-A irradiation using different solutions containing riboflavin and/or fluorescein, was evaluated in vitro. RESULTS: Fluorescein absorbed UV-A to a significant extent, which augmented with increasing concentration. Moreover, addition of fluorescein to the riboflavin solution contributed to a significant reduction of the killing rate of S. aureus strains after 30 minutes of UV-A irradiation in vitro with a killing rate of 85%, whereas it was 47% in the presence of 2% fluorescein (P = .0247). CONCLUSIONS: The results indicate that fluorescein competes with riboflavin for the absorption of UV-A during CXL and reduces the antimicrobial effect of the procedure. The authors recommend that physicians treating infectious ulcerative keratitis by CXL should not stain the cornea with fluorescein for visualization of the corneal ulceration prior to CXL PMID- 24404607 TI - Corneal hysteresis with intraocular pressure of a wide range: a test on porcine eyes. AB - PURPOSE: To investigate the relationship between corneal hysteresis (CH) and intraocular pressure (IOP) using porcine eyes in the low to high IOP ranges. METHODS: In vitro porcine eyes were used to investigate the relationship of CH and IOP. IOP was altered by changing the height of a drip stand within the dynamic range of 60 mm Hg. CH and IOP were measured with the Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments, Depew, NY) at different heights. Second-order polynomial regression method was employed to assess the nonlinear correlation of CH and IOP. RESULTS: CH demonstrated an initial plateau stage with low IOP, which then decreased as IOP increased to higher values up to 60 mm Hg. The maximum CH value of approximately 6 to 8 mm Hg was achieved when IOP ranged from 11 to 25 mm Hg. The nonlinear regression lines of Goldmann correlated IOP (IOPg) and CH can be described as CH = - 0.0029 * IOPg2 + 0.1005 * IOPg + 5.2824, R2 = 0.3676, P < .05. CONCLUSIONS: CH was relatively constant for lower values of IOP and showed a decreasing relationship at higher values of IOP. This nonlinear relationship provides insight into understanding the viscoelastic nature of CH over a wider range of IOP values. The experimental data on porcine eyes may indicate that IOP should be taken into account when analyzing the deformation response of the cornea to an applied air puff. PMID- 24404608 TI - New technique of intracorneal ring segments suturing after migration. AB - PURPOSE: To describe a new technique for suturing of the intracorneal ring segments to stabilize it in the proper location and to prevent recurrent displacement of the ring. METHODS: Two patients with recurrent ring segment migration toward the incision were treated with this new surgical technique between 2010 and 2013. The first case had Intacs ring (Addition Technology, Fremont, CA) and migration occurred 2 months after implantation. The second case had Keraring segment (Mediphacos, Belo Horizonte, Brazil) and migration occurred 1 week postoperatively. The ring segments were fixated to the cornea with a 10-0 nylon suture through the channel. The suture was removed at 1 month postoperatively. RESULTS: Ring segments remained in the desired location with a follow-up period of at least 6 months after implantation. CONCLUSIONS: This newly described ring suturing technique is an effective procedure that can be used to treat ring segment migration in the channel. PMID- 24404609 TI - Laser-assisted cataract surgery in small pupils using mechanical dilation devices. AB - PURPOSE: To describe methods for performing laser-assisted cataract surgery in small pupils. METHODS: Iris retractors or a Malyugin Ring (Microsurgical Technology, Redmond, WA) were used for mechanical pupil dilation before laser capsulotomy and lens fragmentation. The laser treatment can be performed with or without use of ophthalmic viscosurgical devices (OVD). RESULTS: In 73 eyes with small pupils, laser treatment was possible after mechanical dilation device installation. With and without an OVD, no flattening of the anterior chamber or other complications occurred during re-docking, laser treatment, or the manual part of the operation. Small adhesions of the anterior capsulotomy were more frequent when the anterior chamber was still filled with the OVD and did not occur when the OVD was removed. CONCLUSION: A small, poorly dilating pupil constitutes a major challenge in cataract surgery, particularly when performing capsulorhexis. Femtosecond laser treatment can be employed with considerable benefit for the patient, even in these difficult cases. PMID- 24404610 TI - Corneal ectasia after intrastromal presbyopic surgery. AB - PURPOSE: To report histopathologic findings in a case of bilateral corneal ectasia following intrastromal femtosecond laser presbyopia surgery. METHODS: Case report. RESULTS: A 56-year-old patient was referred for bilateral corneal ectasia. He was treated for hyperopia using LASIK twice in both eyes. A bilateral femtosecond laser intrastromal presbyopia correction was secondarily performed. The patient complained of progressive loss of distance visual acuity shortly after. Corneal topography showed a bilateral central corneal protrusion. Rigid contact lenses were successfully fitted on the right eye and, because the patient still complained, a deep anterior lamellar keratoplasty was performed in the left eye. Light and electronic microscopy of the corneal button revealed that the inner intrastromal incision crossed the LASIK interface and led to stromal bed dehiscence. CONCLUSION: This case illustrates that intrastromal refractive surgery should not be recommended in eyes previously treated by lamellar refractive surgery. PMID- 24404611 TI - Neighbourhood income and cardiac rehabilitation access as determinants of nonattendance and noncompletion. AB - BACKGROUND: Despite known benefits of exercise-based cardiac rehabilitation (CR), attendance and completion rates remain low. Our objective was to review attendance and completion of CR overall and by level of neighbourhood income in Saskatoon, Canada and then determine the effect of opening a new CR facility in close proximity to low-income neighbourhoods. METHODS: From January 2007 to December 2011, our retrospective cohort included hospital discharge data, CR attendance, and completion rates, stratified according to neighbourhood income, and adjusted for sex and age. RESULTS: Residents from low-income neighbourhoods were more likely (odds ratio [OR], 1.76; 95% confidence interval [CI], 1.60-1.94) to be hospitalized for ischemic heart disease (IHD), percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass graft (CABG) than residents from high-income neighbourhoods. Among those hospitalized for IHD, PTCA, or CABG, 12.7% attended CR. Patients of low-income neighbourhoods were less likely (OR, 1.58; 95% CI, 1.39-1.71) to attend CR than patients of high-income neighbourhoods. Among those who attended, 66.7% quit before program completion. Participants from low-income neighbourhoods were more likely (OR, 1.38; 95% CI, 0.57-3.50) to not complete CR. In total, only 4.2% of patients hospitalized for IHD, PTCA, or CABG started and completed CR. Expanding access to those living in low-income neighbourhoods did not increase attendance (OR, 1.31; 95% CI, 0.79 2.19) or completion rates (OR, 1.25; 95% CI, 0.23-2.41) to a significant level. CONCLUSIONS: High rates of nonattendance and noncompletion of CR were observed. Living in a low-income neighbourhood was associated with lower rates of attendance and completion. Expanding access to CR did not increase attendance or completion among patients of low-income neighbourhoods to a significant level. PMID- 24404612 TI - Successful ablation of atrioventricular nodal re-entrant tachycardia in a patient with interruption of inferior vena cava and azygos continuation. AB - Congenital anomalies of the venous system are a challenge for cardiac catheterization and radiofrequency ablation. This article describes ablation of atrioventricular nodal re-entrant tachycardia performed solely through the azygos continuation in a patient with inferior vena cava interruption. PMID- 24404613 TI - Unusual cause of an ejection murmur: myxoma in the left ventricular outflow tract. AB - We present the case of a healthy, asymptomatic 50-year-old woman with a systolic ejection murmur who was found to have an obstructive left ventricular outflow tract mass. Transthoracic echocardiography revealed a large mobile mass attached to the basal anterior septum of the left ventricle. Surgical resection was performed and a benign left ventricular outflow tract myxoma was diagnosed. The patient's postoperative course was unremarkable. We describe the clinical presentation and role of 2- and 3-dimensional transthoracic and transesophageal echocardiography in surgical management. PMID- 24404614 TI - Rapidly progressing mycotic aortic aneurysm masquerading as acute coronary syndrome. AB - Mycotic aortic aneurysms are rare. The most common cause of a mycotic aortic aneurysm is bacterial seeding in a diseased or injured aortic intima with subsequent arteritis. Because the clinical presentation of mycotic aortic aneurysms can be quite variable, the diagnosis hence can often be quite challenging. We herewith report an interesting case study in which the patient with a mycotic aortic aneurysm presented with the clinical picture masquerading as an acute coronary syndrome. The scenario reiterates the fact that despite the availability of accurate noninvasive imaging techniques, strong clinical suspicion might be imperative for the diagnosis of mycotic aneurysms. PMID- 24404615 TI - Coronary artery aneurysm and fistula with left ventricular drainage. PMID- 24404616 TI - Platelet reactivity measurements reveal patient noncompliance during ticagrelor maintenance therapy. PMID- 24404617 TI - [Vision screening of children: rational and cost effective]. PMID- 24404621 TI - [Final word]. PMID- 24404618 TI - [Problematic diagnoses in orthopedic trauma surgery expert assessment]. PMID- 24404622 TI - Single-use technology: how to overcome existing limits. PMID- 24404623 TI - Interview with Prof. Dr. Ing. Regine Eibl Head of Section for Cell Cultivation Technique, ZHAW Wadenswil. Interview by Elsbeth Heinzelmann. PMID- 24404624 TI - Targeted attack on cancer. PMID- 24404647 TI - [The usefulness of fecal calprotectin in differentiating between functional and organic bowel diseases: application in pediatric constipation patients]. PMID- 24404648 TI - Spontaneous isolated superior mesenteric artery dissection mimicking superior mesenteric artery syndrome. PMID- 24404649 TI - [Is infantile inflammatory bowel disease curable with hematopoietic stem cell transplantation?]. PMID- 24404650 TI - Opioid pain control: safe or effective? PMID- 24404651 TI - Health care costs must come down. PMID- 24404652 TI - [Modeling of lateral amyotrophic sclerosis: a transgenic method]. PMID- 24404653 TI - [Methods of adjustment of antipsychotic treatment of the needs of the individual patients with schizophrenia]. PMID- 24404654 TI - [Antioxidant energocorrection in acute and chronic cerebrovascular disorders]. PMID- 24404655 TI - [MRI-diagnosis of progressive multifocal leukoencephalopathy]. PMID- 24404656 TI - [Contemporary conception of neuroplasticity (theoretical aspects and practical significance)]. PMID- 24404657 TI - Reply from author. PMID- 24404658 TI - Reply from the author. PMID- 24404659 TI - Neuromuscular disorders. PMID- 24404660 TI - Comparison of anterior segment optical coherence tomography and ultrasound biomicroscopy for iris parameter measurements in patients with primary angle closure glaucoma. AB - PURPOSE: To compare the repeatability and consistency of anterior segment optical coherence tomography (AS-OCT) and ultrasound biomicroscopy (UBM) in measuring iris parameters in patients with primary angle closure glaucoma. METHODS: Twenty two patients (38 eyes) with primary angle closure glaucoma, including 5 eyes with acute angle closure glaucoma, 10 fellow eyes of acute angle closure glaucoma, and 23 eyes with chronic angle closure glaucoma, were recruited consecutively in our hospital. All subjects underwent anterior scanning by AS-OCT and UBM. Peripheral iris thickness (PIT) and iris curvature (IC) in the anterior segment image obtained by AS-OCT and UBM were measured twice. The reproducibility of these two scans was evaluated by the intraclass correlation coefficient (ICC). A paired t test was used to compare the difference between the two scans and the 95% limits of agreement (LoA) were calculated. RESULTS: The ICCs of PIT and IC measured by UBM were 0.892 and 0.936 respectively, while for AS-OCT these values were 0.629 and 0.859, respectively. UBM had a higher reproducibility in both PIT and IC measurements as compared with AS-OCT. Differences in PIT measurement between AS OCT and UBM (P = 0.331) were not statistically significant, the 95% LoA (-0.178 0.156) mm was 36.1-41.2% of the mean. The IC was 0.053 mm smaller when measured by UBM than by AS-OCT (P = 0.017), with the 95% LoA (-0.100-0.206) mm, or 36.2 74.6% of the mean. CONCLUSION: UBM had a higher reproducibility in measuring iris parameters than AS-OCT. The consistency between AS-OCT and UBM in measuring iris parameters was low in primary angle closure glaucoma patients. PMID- 24404661 TI - Surgical treatment for the proliferative retinal detachment associated with macular hole in the morning glory syndrome. AB - PURPOSE: To evaluate the efficacy of vitrectomy with peripapillary photocoagulation and silicone oil tamponade for the proliferative retinal detachment associated with macular hole in children with morning glory syndrome. METHODS: Eight children with morning glory syndrome (mean age 8.0 +/- 2.8 years; range 5-13 years) were included; all patients had unilateral eye disease and were initially misdiagnosed as having bilateral squint or amblyopia, with best corrected visual acuity < 6/60. Five patients could not cooperate with the fundus examination and one patient had lens opacities. B-ultrasound confirmed that all eight patients had retinal detachment and optic disc dysplasia. All patients underwent standard 3-port pars plana vitrectomy surgery (20G for three cases and 23G for five cases). At surgery, all patients were confirmed to have morning glory syndrome, macular hole, and proliferative retinal detachment; two cases had a funnel-shaped bulge. All the retinal detachments involved the macular area, and macular hole was detected in the abnormal expansion excavation of the optic disk. The epiretinal membrane and subretinal membrane were completely removed during surgery. Combined photocoagulation in the abnormal expansion excavation of the optic disk, and silicone oil tamponade were also performed. RESULTS: All eyes achieved anatomical resolution of retinal detachment. After follow-ups ranging from eight months to four years, the visual function for all patients was improved by postoperative refractive correction associated with vision training. Best corrected visual acuity was 6/600 to 6/30 at the final follow-up, no retinal detachment recurred, and no silicone oil fluid entered the subretinal space. The silicone oil was successfully removed postoperatively after a mean of 1.5 years. CONCLUSION: Vitrectomy with peripapillary photocoagulation and silicone oil tamponade is effective in treating the proliferative retinal detachment associated with macular hole in children with morning glory syndrome. PMID- 24404662 TI - Clinical application of X-ray, B-scan, and CT in the diagnosis of ocular foreign bodies. AB - PURPOSE: To analyze the sensitivity and specificity of X-ray, B-ultrasound, and CT scan in diagnosing ocular foreign bodies, and to compare the accuracy of these three imaging tools in locating these foreign bodies. METHODS: A retrospective review was conducted of radiographic and clinical eye examination data from 62 patients (66 eyes), suspected of having ocular foreign bodies at time of first presentation to the Zhongshan Ophthalmic Center (Guangzhou, China) between August 2007 and October 2011. The sensitivity and specificity of X-ray, B-ultrasound and CT scan in the diagnosis of ocular foreign bodies were investigated and their accuracy in locating these foreign bodies was compared. RESULTS: A total of 75.8% (n = 47) subjects had ocular foreign bodies; 66% of these were metallic. Patients with intraocular, eye wall, and extraocular foreign bodies accounted for 46, 28, and 26% of the total, respectively. The sensitivities of X-ray, CT scan, and B ultrasound in the diagnosis of ocular foreign bodies were 58.3%, 61.7%, and 75%, the specificityies were 63.3%, 100%, and 87.5%, and the accuracy in locating foreign bodies was 73.4%, 94.7%, and 86.5%, respectively. The properties of foreign bodies affected the diagnosistic accuracy of X-ray, but exerted little impact upon B-ultrasound and CT scan. CONCLUSION: A fairly high incidence of ocular foreign bodies was noted in patients suspected with ocular foreign bodies at their first presentations. X-ray combined with CT scan or X-ray in combination with B-ultrasound showed a relatively high sensitivity and specificity in diagnosing ocular foreign bodies. CT scan had the highest accuracy in locating ocular foreign bodies. PMID- 24404663 TI - Comparison of central corneal thickness using ultrasound pachymetry during corneal collagen cross-linking. AB - PURPOSE: To study variation in central corneal thickness (CCT) during corneal collagen cross-linking(CXL) using ultrasound pachymetry. METHODS: Twenty patients (26 eyes) with progressing keratoconus undergoing riboflavin-UVA-induced CXL were involved in this study. Intraoperative CCT measurement using ultrasonic pachymetry was performed during the procedure. Measurements were obtained before operation, after epithelial removal, after riboflavin drop instillation, and after UVA irradiation. RESULTS: Mean CCT was 495 +/- 56 and 450 +/- 52 microm before and after epithelial removal, respectively. Mean CCT was 443 +/- 42 and 411 +/- 39 microm after riboflavin drop instillation and after UVA irradiation, respectively. Statistically significant decreases in CCT occurred between the preoperative period and after epithelial removal, after riboflavin drop instillation and after UVA irradiation. Twenty-six eyes from 20 patients undergoing CXL were divided into 2 groups (I with CCT > or = 400 microm after UVA irradiation and II with CCT < 400 microm after UVA irradiation). No statistically significant difference was noted between I and II in preoperative endothelial cell count, but a statistically greater postoperative endothelial cell count was noted in I compared to II. A statistically significant difference was evident between preoperative and postoperative endothelial cell counts in Group II (P < 0.05). CONCLUSION: Performing CXL with the use of riboflavin and UVA irradiation resulted in a statistically significant decrease in CCT, to a level where the corneal endothelium may be damaged. PMID- 24404664 TI - Comparative study of the disinfection effects of three types of conjunctiva sac irrigations. AB - PURPOSE: The antiseptic effectiveness of 5% anerdian III, 0.016% gentamicin, and 0.5% tobramycin solutions in pre-surgical irrigation of conjunctival sac were compared. METHODS: A total of 295 cataract patients (302 eyes) who had undergone phacoemulsification aspiration combined with intraocular lens insertion (IOL) were recruited in this prospective study. Operative eyes were given 0.3% levofloxacin eye drops for 3 days and then were randomized into three treatment groups: anerdian (A), gentamicin (B) and tobramycin (C). The patients received conjunctival sac irrigation using the respective solutions at 10 minutes preoperatively. Conjunctival sac sampling was performed before and after irrigation and the samples were used for subsequent bacterial culture and swab tests. The positive culture rate was used as the main outcome. RESULTS: The positive rates of bacterial culture before conjunctival sac irrigation were 17.31% (18 eyes) in group A, 13.86% (14 eyes) in group B and 17.3% (14 eyes) in group C. Post irrigation, the positive rates in the three groups decreased to 5.76% (6 eyes), 5.94% (6 eyes) and 7.22% (7 eyes), respectively. The positive rates among the three groups did not differ significantly. However, the positive rate in group A only significantly differed before and after the irrigation (P < 0.05). No toxic or allergic reactions were observed on the ocular surface of any patient after irrigation. CONCLUSION: The antiseptic effects of the three types of con junctival sac irrigations did not differ. PMID- 24404665 TI - Tissue-engineered epithelium transplantation for severe ocular surface burns. AB - PURPOSE: To evaluate the clinical outcomes of tissue-engineered epithelium transplantation for severe ocular surface burns. METHODS: This was a retrospective observational case series. From October 2005 to May 2011, 19 eyes of 19 patients with grade IV to VI ocular surface burns (Dua Classification) were treated by autologous transplantation of corneal stem cells cultivated on a fibrin gel membrane, with a mean follow-up of 16.2 months (range 12-36 months). Postoperative corneal surface stability, visual acuity (VA), corneal opacity, and neovascularization were evaluated. RESULTS: No corneal perforations occurred and the entire corneal surface was free from epithelial defects in all eyes. At the final follow-up visit, VA in 17 eyes was improved after surgery, with 6 eyes achieving a VA of 20/100 or better. Corneal vascularization was significantly reduced in 17 (89.5%) eyes. Corneal opacity was also improved in 12 (63.2%) eyes. All donor eyes remained healthy. CONCLUSION: Tissue-engineered epithelium transplantation can promote rapid reepithelialization of the ocular surface, inhibit corneal neovascularization, and improve vision for patients with severe ocular surface burns. PMID- 24404666 TI - Clinical efficacy of surgical removal of deep corneal plant foreign bodies. AB - PURPOSE: To describe a technique for removing deep corneal plant foreign bodies. METHODS: Twelve patients (7 males and 5 females, aged 5 to 56 years) with plant foreign bodies embedded in the deep cornea were treated between July 2011 and December 2012. The course of disease ranged from 1 to 11 d. Four of the patients had wooden foreign bodies, 3 had bamboo foreign bodies, and 5 had flower thorns; all underwent surgical removal. During the surgery, a novel suture needle was used to remove the foreign bodies. For injuries with a deep tunnel caused by the foreign bodies, the tunnel was cut open with a keratome. The foreign bodies were then removed and necrotic tissue was thoroughly debrided. Incisions were closed with interrupted sutures. The corneal foreign bodies were collected postoperatively for fungus and bacterial culture and appropriatemedical treatment was provided. RESULTS: Bacteria were identified in 3 cases, fungus in 3 cases, and no bacteria or fungus in 6 cases. All corneal foreign bodies were embedded deep in the corneal stroma without incidence of full-thickness corneal penetration or intraocular infection. CONCLUSION: Plant foreign bodies embedded in the deep cornea should be removed immediately. During the surgery, the foreign bodies and surrounding necrotic corneal stroma should be completely removed. The injured cornea should be cut open to eliminate necrotic tissues when necessary. PMID- 24404667 TI - Corneal biomechanical properties and associated factors in school-age children. AB - PURPOSE: To study and analyze the correlation among corneal biomechanical properties and associated factors including central corneal thickness (CCT), corneal curvature (CT), and intraocular pressure (IOP) in school-age children. METHODS: A cross sectional investigation was conducted. An ocular response analyzer was utilized to assess the corneal biomechanical properties, such as corneal hysteresis and corneal resistance factors, in children of school age. Multivariate regression analysis was used to investigate the relationship between corneal biomechanical properties and other ocular parameters including CCT, corneal curvature (k1 and k2), and IOP. The right eyes of all subjects were selected for statistical analysis. RESULTS: A total of 571 children were enrolled: 303 male and 268 female, with an average age of 10.47 +/- 1.0 years. The mean value of corneal hysteresis was 10.98 +/- 1.78 mmHg, corneal resistance factor was 11.46 +/-1.69 mmHg, and CCT was 556.01 +/- 28.97, microm. CONCLUSION: The feasibility of corneal biomechanical detection in school age children was validated. This study provides fundamental data on corneal biomechanical properties in school-age children and associated factors. PMID- 24404668 TI - Idiopathic orbital inflammation associated with panuveitis in an adult and a review of the literature. AB - PURPOSE: To report an unusual case of idiopathic orbital inflammation associated with panuveitis. CASE REPORT: We report a case of a 47-year-old female with a history of uveitis who presented with abrupt and painful prop tosis with complete vision loss unresponsive to antibiotic therapy. B-scan ultrasonography and magnetic resonance imaging both showed retinal detachment and an orbital space occupying mass. The patient underwent orbitotomy and the diagnosis of idiopathic orbital inflammation was confirmed by histopathology. Anterior uveitis is rarely seen in idiopathic orbital inflammation in adults. We report for the first time an unusual case of idiopathic orbital inflammation associated with panuveitis. CONCLUSION: Inflammation involving both the eye and the orbit is rarely seen in adults. Idiopathic orbital inflammation and panuveitis may share a similar mechanism in this case. PMID- 24404669 TI - Orbital trauma with a large plant foreign body: a case report. AB - We report a case of a large plant foreign body in the orbit. A 30-year-old male presented to our hospital 6 h after a penetrating orbital injury in his left superior eyelid when he skidded from his motorcycle while riding. When the patient reported to us, he already had an inability to open his left eye and a continuous pain in the left orbit. On examination, there was a large plant foreign body penetrating the nasal orbit through the left upper eyelid. Orbital CT revealed a low density linear foreign body measuring 3.6 x 0.5 cm in the left orbit. An emergency operation was performed to remove the foreign body. The patient's visual acuity did not recover satisfactorily due to optic nerve injury. This case highlights the fact that careful surgical removal of foreign bodies is the treatment of choice and that all patients should receive post-operative antibiotic therapy because of the high incidence of secondary orbital infections. The final outcome and prognosis depend greatly upon the composition and location of the foreign body and whether there are serious complications. PMID- 24404670 TI - Leber hereditary optic neuropathy in a boy with fibrous boney dysplasia. AB - PURPOSE: To report a case of Leber hereditary optic neuropathy combined with fibrous boney dysplasia. METHODS: Case report. RESULTS: A 16-year-old boy presented with painless vision loss in both eyes. He had a history of a right humerus fracture and right femoral fracture surgery after an uncomplicated fall. On examination in our clinic, his visual acuity was counting fingers at 20 cm OD and counting fingers at 40 cm OS. Both pupils reacted sluggishly to light. The findings on slit-lamp examination and funduscopy after pupillary dilation were all unremarkable. Computed tomography scans demonstrated fibrous dysplasia involving the right frontal, temporal, parietal, and occipital bones but no stenosis of either optic canal. His serum alkaline phosphatase was 522 U/L (reference range: 40-150 U/L). His vision showed no improvement after intravenous methylprednisolone pulse therapy. Finally, a 11778 mitochondrial DNA mutation was detected. He still had no visual recovery after treatment with oral coenzyme Q10, vitamin B1, and citicoline. CONCLUSION: Fibrous dysplasia of bone may be associated with Leber hereditary optic neuropathy, possibly due to the fact that it increases local oxygen consumption. PMID- 24404671 TI - Presumed acquired retinal astrocytoma in association with anterior uveitis. AB - PURPOSE: To report a case of presumed acquired retinal astrocytoma in association with anterior uveitis. METHODS: A 29-year-old man presented with mutton fat keratic precipitates in the inferiorlower cornea, with complicated cataract and a circumscribed, solitary, yellowish-white retinal lesion in the right eye. Phacoemulsification with intraocular lens implantation was performed, with election to observeand the lesion was observed periodically. The lesion was followed for over two years without any change in size, shape or, and appearance. The anterior uveitis has not recurred at the time of writing. RESULTS: Systemic medical and laboratory evaluations, including chest computed tomography, cranial magnetic resonance imaging, and serum angiotensin converting enzyme level, were normal. The characteristic fundus, FA, OCT scan, ultrasound scan, and lack of other contributory laboratory findings strongly supported the diagnosis of acquired retinal astrocytoma in this patient. CONCLUSION: We hypothesized that anterior uveitis may contribute to the growth and maintenance of retinal lesions. PMID- 24404672 TI - Hacking medicine... PMID- 24404673 TI - Change. PMID- 24404675 TI - Breast cancer facts. PMID- 24404674 TI - Opioid prescribing guidelines for Oklahoma emergency departments (ED) and urgent care clinics (UCC). PMID- 24404676 TI - Some thoughts and solutions on the private practice of medicine in 2013 in Oklahoma. PMID- 24404677 TI - Joint Commission announces 2013 list of Top Performer hospitals. PMID- 24404678 TI - Joint Commission releases new Speak Up brochure on memory challenges. PMID- 24404679 TI - Clarification: Requirements for collecting a patient's preferred language. PMID- 24404680 TI - New Alert provides guidance on preventing URFOs. PMID- 24404681 TI - Maintaining fire equipment and building features. A deep dive into EC.02.03.05. PMID- 24404682 TI - R.I.P. KKK. How states can help us respond to our battles on the street. PMID- 24404683 TI - Tag it. PMID- 24404685 TI - Communicate compassion. Being a respected leader doesn't mean ruling with an iron fist. PMID- 24404684 TI - Not so buzzworthy. PMID- 24404686 TI - So long, superstar. Not everyone wants a party. PMID- 24404687 TI - Thin blood. Risk of internal bleeding heightened with anticoagulant therapy. AB - The case detailed here is not uncommon. A day rarely passes at UMC where we don't evaluate and subsequently admit a patient from the Las Vegas valley and surrounding regions that has sustained an intracranial hemorrhage secondary to oral anticoagulants. Because of this, EMS and emergency department personnel should have an increased incidence of suspicion for the possibility of a bleeding complication in patients taking oral anticoagulants. You should always question patients who have atrial fibrillation in regard to oral anticoagulant usage. In the case discussed here, probing questions by paramedics were able to elucidate a history of atrial fibrillation and the use of an oral anticoagulant. This allowed the paramedics to stratify the patient's risk for hemorrhage and need for further medical care. Ultimately, the patient was assessed and transported to a hospital that could care for any possible complications related to the injury. PMID- 24404688 TI - Trouble in Texas? Is the Austin-Travis County EMS system broken? PMID- 24404689 TI - Bus rollovers. Knowing & overcoming the challenges of MCIs involving passenger coaches. PMID- 24404690 TI - Crosshairs on EMS. Responding to MCIs caused by low-tech terrorism. PMID- 24404691 TI - World's largest gathering. Muslim mass pilgrimage poses EMS logistical & planning challenges. AB - The Hajj is a "mega-gathering" event attended yearly by millions of Muslims from across the world. Planning, communications and logistical support are the foundations of its success. EMS systems and major event planners throughout the world can learn from studying the special challenges involved with managing such a large multilingual, multicultural crowd. Current studies predict that by 2020 there will be more than 10 million pilgrims in attendance for the event. New construction and supportive infrastructures are already underway to meet the ever growing needs of the pilgrims. With the improvement of systems and design, there is already a steady decrease in the number of accidents and requests for help. Continuous monitoring of emerging health situations ensures that a simple case of the flu does not become a worldwide epidemic. There will always be a need for emergent care during the Hajj and the Saudi Red Crescent Authority and supportive agencies will be ready to serve those who come to participate. PMID- 24404692 TI - Being there. EMS chaplains provide spiritual support for providers & staff. PMID- 24404693 TI - Failure to flow. How to identify, assess & treat renal failure. PMID- 24404694 TI - Phutball. A guide to EMS gridiron infractions. PMID- 24404695 TI - An IT blunder or a lack of communication? PMID- 24404696 TI - Making clinical data analytics count. Does size, volume really matter? PMID- 24404697 TI - Untangling heathcare's Gordian knot. The integrity of clinical documentation is vital to protecting an organization's bottom line. PMID- 24404698 TI - Three keys to successful RCM in 2014. ICD-10, new payment models, HIEs will all impact revenue cycle. PMID- 24404699 TI - Healthcare records--keeping tabs. Addressing security, integration and operating system choices. PMID- 24404700 TI - An elegant solution to improve workflow. This EHR enables clinicians to capture structured data at the POC. PMID- 24404703 TI - Perioperative preceptorship. PMID- 24404702 TI - Looking back--moving forward. PMID- 24404701 TI - Closing the EMR donut hole. How to address the disclosure management gap in critical capabilities. PMID- 24404704 TI - Quality of operation notes in orthopaedic hip arthroplasty surgery: are we complying with British Orthopaedic Association's guide to good practice? AB - This retrospective audit evaluates the compliance of our operation notes with the British Orthopaedic Society Primary Hip Arthroplasty 'A guide to good practice' using a 24-data point question (BOA 2006). Ninety-nine notes reviewed, of which 94% had patient identifiers, the surgical team was documented in 92.5%, post operative instruction in 97%, and prosthesis stability in 97% of cases. Despite high standards, we did not achieve the 100% gold standard. We suggest that increased awareness of the 24-point BOA guideline via education and proformas would help to ensure better practice PMID- 24404705 TI - Evaluative survey-questionnaire exploring the perceptions and experiences of endoscopy and sterile service staff. AB - There is considerable research surrounding professionalization and the barriers that emerging allied health professions may face. In order to develop any emerging profession, the move to voluntary registration and academic qualification will substantially pave the way towards raising the profile and professional recognition with a regulatory governing body. The aim of this evaluative survey-questionnaire was to explore the attitudes and experiences of endoscopy and sterile service staff in their current job roles and to identify any perceived barriers during the proposed transition to professionalization. This article concludes by highlighting the positive and negative aspects of current job roles in relation to job satisfaction, staff retention and career progression opportunities. PMID- 24404706 TI - Preceptorship: professional development and support for newly registered practitioners. AB - Preceptorship is one aspect of continuous professional development which is vital to support healthcare professionals in the delivery of safe, effective, person centred care. This article outlines the various aspects of preceptorship for nurses, midwives and specialist community public health nurses in Northern Ireland. It is hoped that the elements within it have transferability across other healthcare professions. The article will help the reader understand where preceptorship fits within a professional development and support continuum. PMID- 24404707 TI - Increasing compliance with the World Health Organisation's Surgical Safety Checklist. AB - The World Health Organisation Surgical Safety Checklist (WHO SSC) is a validated tool for reducing in-patient surgical morbidity and mortality. It is not performed universally with full compliance. Two audit cycles were completed at two different trauma and orthopaedic units and compliance was measured. Site 1 was found to have a significantly lower compliance with the team-brief (p<0.001). Following a change in practice the compliance significantly increased (p>0.00001) at Site 1. The team de-brief was found to be consistently poorly complied with. We recommend regular audit of compliance and change in practice for all surgical units, and suggest national monitoring to ensure the benefits of the WHO checklist are applied to all in-patient surgery. PMID- 24404708 TI - Do current methods for endotracheal tube cuff inflation create pressures above the recommended range? A review of the evidence. AB - Inflation and measurement of endotracheal (ET) tube cuff pressure is often not seen as a critical aspect of care in surgical patients. The morbidity associated by an overinflated cuff has been regularly highlighted in literature, for example mucosal ulceration (Combes et al 2001) and vocal cord paralysis (Holley & Gildea 1971). This article will outline techniques for the methods of inflation based on the latest scientific evidence. The author will seek to examine if intraoperative cuff assessment and monitoring should become routine for the anaesthetic practitioner and if current practice for inflating cuffs creates pressures outside the safe range. PMID- 24404709 TI - John Langdon Down: Down's syndrome. AB - When I was a medical student in the 1940's we youngsters were well familiar with the condition called 'Mongolism'. We saw these patients--labelled 'Mongols'--as children in the paediatric clinics, and as older patients on our visits to the local enormous mental hospital during our attachment in psychiatry, where many of them spent the whole of their lives. PMID- 24404710 TI - [We nurses keep being, for the judges, physicians' assistants]. PMID- 24404711 TI - [The nurse and her past]. AB - We are in Japan shortly before launch its offensive against the United States in 1941 and enters fully into World War 2. The nurse Nobu lives in Fukuoka, the largest city in Kyushu. This island, the third largest and southernmost of which make up the Japanese archipelag, is held by the origin of Japanese civilization. Fukuoka is located approximately halfway between the two cities on which atomic bombs dropped: Hiroshima, to the north, and on the island of Honshu, and Nagasaki, in southern island of Kyushu itself Although he received no atomic bomb, was severely punished by the constant bombardment of the air forces of the United States towards the end of World War 2. PMID- 24404712 TI - [Design and preliminary validation of a tool for nursing assessment and classification for pediatric patients in primary health care emergency. "VEUPAP"]. AB - OBJECTIVE: Design a tool for nursing assessment and classification for pediatric patients in primary care emergency. DESIGN: Comprehensive literature review of systems of evaluation and classification of urgent patients, work in groups of experts, creation of the instrument and test its validity, reliability and ease of use in normal operation conditions of service. LOCATION: Pediatric Emergency Department Dr. Jaime Chaves. Tenerife. Canary Islands. PARTICIPANTS: Nine nurses and nine pediatricians with training and experience in emergency pediatric care. The validity and reliability tests are performed on a sample of 200 pediatric patients who came calling attention to the emergency service alter request informed consent. INTERVENTIONS: Training sessions, motivational and expert group consensus. Nurses apply the classification tool to test at patient entry and level of classification given by the pediatrician at discharge. RESULTS: Final version of the instrument with the fields of assessment and related documents. Validity tests show a sensitivity of 100% and a specificity of 94% and a concordance between nurse and pediatric of 83% and reliability agreement among nurses of 76% (p < 0.001 in all cases). CONCLUSIONS: The instrument, called VEUPAP (Nurse Pediatric Emergency Valuation in Primary Care), is valid, reliable, simple and useful for application in primary care. PMID- 24404713 TI - [The issuance of nursing publications and professional development]. PMID- 24404714 TI - [Treatment of infected diabetic foot ulcers clinical effectiveness of a dressing of alginate and hydrocolloid, with silver fiber. Analysis of results of a series of cases]. AB - INTRODUCTION: High levels of bacterial load have shown a deleterious influence on wound healing. Using antimicrobial dressings can control ulcers' bioburden. The aim of our study was to evaluate the improving of infected diabetic foot ulcers due an alginate's fiber and hydrocolloid silver dressing. MATERIAL AND METHODS: We analysed a case series of 6 patients with diabetic foot ulcers without peripheral vascular disease and diagnosed from critical colonization and/or local infection according the presence of inflammation clinical signs. Patients were treated for a minimum period of two weeks. We analysed the percentage reduction in ulcer area from the day of enrolment to antimicrobial dressing removal. RESULTS: The duration of treatment had a median of 5 weeks with a minimum of 2 weeks and up to 6. The median percentage of area reduction of the wounds was 47.7% (range: 0.5%-90%). The mean percentage reduction on the lesion was 58% from 2 weeks and 67.14% at 3 weeks. All patients had reduced significantly their size at 3 weeks from beginning of treatment (p < 0.05). CONCLUSION: The use of an alginate's fiber and hydrocolloid silver dressing promotes healing on diabetic foot ulcers with local infection, reducing the inflammatory clinical signs significantly over a period of three weeks. PMID- 24404715 TI - [Prevalence of anxiety in the presurgical area]. AB - INTRODUCTION: Anxiety is a complex personal reaction against situations and stimuli that is potentially dangerous or at least perceived as such by the sufferer. Surgery is an important stressing agent, which may cause problems not only for the patient and their family but also for the healthcare system and therefore addressing the anxiety prior to surgery must be a priority. OBJECTIVES: This research is centered on the prevalence of anxiety in the pre-surgical area of the Royo Villanova Hospital located in Zaragoza, Spain, and the risk factors. MATERIALS AND METHODS: The present study is a transverse descriptive observational study of 100 patients aged between 50 and 95 years. Data collection was carried out in the pre-surgical area by means of a personal interview and a STAI-STADO test. RESULTS: Out of 100 patients, 45% showed light anxiety, while 34% of the sample showed high or acute anxiety. Statistically significant differences were determined in the levels of anxiety reported between married and non-married patients as well as in the levels of those patients that had not undertaken a previous surgical procedure versus those that had. Both of these groups experienced lower levels of anxiety. CONCLUSION: The lack of a partner (widowed or single patients) has been identified as a risk factor for experiencing higher pre-surgical anxiety. Not having experienced any prior surgical procedure has been identified as a protective factor with these patients reporting lower pre-surgical anxiety than those with prior surgical procedures. PMID- 24404716 TI - [Managing complications in severe traumatic injury with VAC therapy with instillation]. AB - The complex fractures caused by high energy trauma, poses a major surgical challenge. Vessels, skin and subcutaneous tissues. The Vacuum Assisted Therapy (VAC) has become a very useful tool since the last century's 90 decade. Based in the application of negative pressure to the wound bed, promotes healing by granulation tissue formation, keeping the wound clean and avoiding bacterial colonization. Used as a primary method or in combination with others, VAC therapy allows more conservative options in the treatment of these wounds. We describe the application of the VAC therapy in a clinical case with complex injury, showing its efficacy, added the benefit of the instillation therapy. PMID- 24404717 TI - [Efficiency in the prescription of drugs. Impact of a health policy: automatic change to prescription by active ingredient]. AB - In the Basque Country in June 2010 were changed in the electronic prescription system the treatments prescribed by a brand by active ingredients, all the patients who had prescribed these molecules: atorvastatin, clopidogrel, weekly risedronate and losartan-hydrochlorothiazide. The aim of this study was to evaluate the economic impact of this change automated done in June 2010. Retrospective study of the prescriptions made in the Basque Country of the selected active ingredients. The use of generics of these molecules from May to December 2010 increased from 64 points to 87. Particularly clopidogrel increased from 6.25% in generic prescriptions to 93.76%, losartan + hydrochlorothiazide from 17.94% to 93.83%, 18.92% for atorvastatin acid and 96.03% risedronic 1.76% to 65.97%. If we make the estimation of the amount of active ingredient in generic containers that have been dispensed from June to December 2010. If they had dispensed brand drugs you get this quantity of total savings: 8 104 762.22 euros. This work suggests that a program to promote use of generics increased efficiency in the use of drugs. To promote the use of generic drugs is an efficiency measure implemented in the NHS and in the neighboring countries, in recent figures are reached 40% in securities of U.S.A packaging and around 65% in the Basque Country the consume in early 2010 was much lower than these figures stand at 20% and at the end of the year stood at 27% thanks to the measures taken. PMID- 24404718 TI - [Perceptions of dependent elderly cared for by immigrant workers concerning the help they need and receive]. AB - INTRODUCTION: Social-demographic changes such as the increasing number of dependent elderly people, the incorporation of women into the workforce, and declining family size have led to the emergence of a new occupation, that of home care for elderly dependents. This work is usually carried out by women immigrants. Little is known about how this care is perceived by the elderly. OBJECTIVE: To evaluate the daily lives of elderly people cared for by hired immigrants to identify aspects of their health and the care they receive. METHODOLOGY: A qualitative study conducted through twelve theoretical sampling interviews that were recorded, transcribed and analyzed with computer support of Atlas Ti V5. RESULTS: The elderly do not anticipate or prepare for the problems of old age. Their main concerns regarding health are illness, pain and death. All wish to remain as autonomous as possible. The need to arrange home care services is often first perceived by the family. Home-help workers assist in basic and instrumental daily activities and provide care and company. Cultural conflicts in the practice of care are rare. Despite general satisfaction with help received, the elderly consider that the workers lack specific training in caring for the elderly. CONCLUSIONS: The elderly are aware of the current difficulties of families to care for them and they are adapting to the new reality of home care. They value the worker who helps them because besides helping with housework, they provide company, entertainment and affection. Primary care nurses can play a key role in training immigrant workers in caring for the elderly. PMID- 24404719 TI - [Quality of life of the elderly population]. PMID- 24404720 TI - [A national health strategy is not limited to the optimization of individual care]. PMID- 24404722 TI - [Time and use of discussion forums in type 1 diabetes: contribution to patient education]. AB - INTRODUCTION: The purpose of this study was to elucidate the concept of temporality in discussions on forums used by individuals concerned by type 1 diabetes: adults and parents of children. The contents of messages were first converted into skills, and their temporality was then analysed, particularly in terms of the duration of active threads. METHODS: Two types of temporality are involved in the use of forums: prescribed time governed by the therapeutic requirements related to a chronic disease and the decisions to be taken, and open ended social time available on the Internet and the resulting reflexive processes. RESULTS: Our results show that topics relating to self-care and adaptation skills are often discussed and new threads on the topic are frequently introduced. Considerable diversity in the activity level associated with the various threads was observed, as most threads were only active for short periods. DISCUSSION: Following this study, our research perspectives concern: (i) the ways in which patients and their families reconcile the temporality dictated by a chronic disease (prescribed time) with the open-ended social time available on the Internet; and (ii) the ways in which this temporality is characteristic of patient learning processes via discussion forums. Future research will focus on the concept of rythmo-apprenance (rhythmic learning) in therapeutic patient education. PMID- 24404721 TI - [Improvement of hospital working conditions: ORSOSA, from research to preventive actions]. AB - The health of hospital workers, nurses and nurse-aids constitutes a public health challenge for three reasons: maintenance of personnel at work in a context in which many express their desire to quit their jobs, protection of their health, and maintenance of quality of care. ORSOSA (ORganisation des SOins et SAnte des soignants) is a multidisciplinary interventional population health research programme designed to improve quality of life in the workplace of healthcare workers. This programme is designed to develop a tool to diagnose psychosocial and organisational work factors (POWFs) and mechanical constraints (MC), and then to implement this method in primary prevention interventions. ORSOSA consists of two steps: research (ORSOSA 1) and intervention (ORSOSA 2). In ORSOSA 1, a prospective cohort of healthcare workers was developed to construct and validate the diagnostic tool of work-related constraints at the work unit level. ORSOSA 2 consists of using the tool to implement both a collective and consensual dynamic based on collective restitution of the strengths and weaknesses of the work unit in order to propose recommendations for better quality of life at work. ORSOSA is now deployed in 4 teaching hospitals (Lille, Bordeaux, Grenoble and Strasbourg), each with 5 peripheral hospitals. Evaluation and follow-up of the programme is ongoing. PMID- 24404723 TI - [Regional health agencies: only sham autonomy two years later]. AB - From the outset, reform of regional health agencies in France, has been torn between two conflicting approaches: traditional state planning and the more recent New Public Management. In fact, the "Hopital Patients Santa Territoires" (Hospital Patients Health Territories) bill juxtaposes rather than supplants these conflicting approaches. Based on a sociological and qualitative survey conducted nationwide and in three regional health agencies, this article highlights the contradictions in which regional health agency management is entangled and how it tries to accommodate them in its everyday professional activity. Officially, and paradoxically, regional agencies are required to be "autonomous" and "innovative" to ensure more "territorialized" health policies, but in fact, they are caught in a meshwork of somewhat arbitrary national regulatory and budgetary controls that are very similar to the traditional French model of administration. In the light of the example of three different schemes of regional/territorial delegation regulations, this article shows how the various stakeholders are nevertheless trying to innovate even if, ultimately, they are faced with a more traditional, centralised healthcare system with decreased participation at the more local levels. PMID- 24404724 TI - [A health education program based on training and support of stakeholders in the field]. AB - Education Sante Territoire (EST) is a health education programme for children and adolescents. It was developed on the basis of the international literature and the results of interventional studies conducted in France. It is based on local resources and develops a territorial approach centered on the school as the reference site of the "perceived territory" of children and adolescents. It therefore comprises a local environment approach (school and college) and a territorial approach, as it is centered on participation and is designed to mobilize local stakeholders involved in the education of young people. It concerns educational activities (in the schoolroom, in the institution, in the context of extracurricular activities, in leisure centres, in sports clubs); the school-community relationship; the quality of life of children and adolescents. The available results show major changes in practices and a wide range of modalities of participation. Factors that determine participation are essentially related to individual determinants (adhesion to the underlying values of the programme, compatibility of representations, perception of the relevance of the content) and contextual factors (numbers, school environment, social environment). Training and the history of involvement in the programme appear to be key elements determining participation. PMID- 24404725 TI - [Improving the management of emergencies: the contribution of modeling and flow simulation]. AB - INTRODUCTION: The increasing demands on hospital emergency services have resulted in longer waiting times and have had an impact on resource use for the treatment of life-threatening conditions. METHODS: The purpose of this study was to test and validate different strategies aimed at reducing or minimizing the average length of stay in the emergency department of Ibn Rushd Hospital in Casablanca, Morocco. The paper focuses on patient flow analysis using modeling and simulation. RESULTS: An analysis of the current configuration of the emergency department shows that there are bottlenecks in the hospital's general medical services and in radiology. The average length of stay was 6 hours. To address this issue, a model for an extensive reorganization of the hospital's emergency department was proposed and tested by simulation. The results revealed a 30% reduction in the average length of stay. DISCUSSION: The study shows that the organizational structure of the emergency department has a significant impact on the average length of stay. PMID- 24404726 TI - [Impact of the referral letter on triage decisions in adult patients admitted to the emergency department]. AB - INTRODUCTION: We conducted a two-month prospective study (8,171 admissions) in the Angers university hospital emergency room to analyse the impact of the referral letter on the initial triage of patients admitted to the emergency room performed by the reception and triage nurse. METHODS: We analysed the level of priority of the CIMU triage scale (nurse's classification of emergency room patients), the presenting complaint, and the need for an urgent procedure before and after reading the referral letter and examined the nurse's comments for explanations concerning any triage changes. RESULTS: 1,516 patients arriving with a referral letter (18.5% of admissions) were included and interpretable data were available for 756 of these cases. After reading the referral letter, nurses modified the CIMU triage level for 34 (4.5%) patients, the presenting complaint for 50 (6.6%) patients and eliminated the need for an urgent procedure for 70 (9.3%) patients. No significant difference was observed concerning the choice of the CIMU triage level (p = 0.908). However, changes in triage level were significantly more frequently towards a more urgent category (p = 0.005). Analysis of the nurse's comments showed that these results can be explained by the signs of severity indicated in the referral letter. Certain histories and/or diagnostic hypotheses appeared to lead nurses to eliminate the need for an urgent procedure. CONCLUSION: In this study, the referring physician's letter had a limited impact on the choice of triage level defined by the nurse on admission to the emergency room except for patients in whom the referral letter mentioned signs of severity, not observed at reception, led the nurse to apply a more urgent triage level. It would be interesting to study the information contained in the referral letter, useful for triage of patients admitted to the emergency room, in order to improve the impact of the referral letter on the quality of triage. PMID- 24404727 TI - [Community trajectories of mentally ill and intellectually disabled young people]. AB - AIMS: In the context of reforms in the field of disability, this study documents the trajectories and mechanisms of support for young people with mental illness or intellectual disability or pervasive developmental disorders, during the teen adult life transition period; andfactorsfostering or impeding this transition for their maintenance in an everyday environment, particularly in SESSAD (special education and home care service) and the SAMSAH/ SPAC (medico-social support for adults with disabilities/support services in social life). METHODS: This study was conducted in the French department of Seine-et-Marne. It was supported by a mixed call for tenders, in which 77 respondents (professionals, families and users), and 26 organizations were consulted. RESULTS: The study shows that few young adults in SAMSAH/SPAC programmes are derived from SESSAD, and they encounter major difficulties living in an everyday environment, particularly during the transition period. Clinical or socio-economic factors related to the profiles of users or healthcare service organization facilitate or hinder the inclusion of young people in an everyday environment. Support for users was also often limited to followup over a suboptimal period, and was hampered by insufficient networking within the regional healthcare system. On the other hand, empowerment of users and their optimal inclusion in an everyday environment, as founding principles of the reform, constitute major action priorities for healthcare structures. CONCLUSION: Strengthening services for young people (16-25 years), including integration strategies, is recommended in order to establish an integrated network of services in the field of disability. PMID- 24404728 TI - [Geographical distribution of family physicians: which solutions for a complex problem?]. AB - AIM: This article examines the geographical distribution of family physicians, focusing on attraction issues. METHODS: This analysis is based on a configurational approach. In simple terms, this approach stipulates that the impacts of an intervention are related, on the one hand, to the internal consistency between the characteristics of an intervention and, on the other hand, the consistency between this intervention and its context. A longitudinal case study was performed, corresponding to the Quebec experience over a 35-year period. RESULTS: The measures implemented essentially consisted of training, incentives (positive and negative), support, and, since 2004, a certain degree of coercion. Note that selection of applicants for medicine training programmes according to certain individual variables likely to have an impact on the subsequent site of practice, were only rarely used. An improvement of the efficacy of the combination of measures was observed over time: this improvement can be interpreted in terms of the consistency between the characteristics of the intervention and the consistency between the intervention and its context. CONCLUSION: Interventions designed to promote a more balanced distribution of healthcare professionals cannot be limited to activation of a single lever, but must be considered in the context of complex interventions. PMID- 24404729 TI - [Building resilience in healthcare to improve patient safety? The case of anesthesia]. AB - Patient safety is a major issue and a challenge to be addressed by public policy. New alternative approaches are currently being developed within the international community. In particular, these new approaches include the concept of "resilience" In this context, this literature review presents this new trend called "resilience engineering". It is based on scientific articles in French and English identified in two large databases (Cairn and Science Direct). The overall objective was to determine how this concept can help us to understand the functioning of the healthcare system and propose new ways to improve patient safety. Three main characteristics of the resilience approach were identified, supporting the value of resilience engineering in healthcare systems. To illustrate these results, the review presents an illustrative example in the field of anaesthesia. In conclusion, it is now clear that traditional approaches to safety have many limitations for risk prevention in healthcare: work organization must promote adaptive strategies built by healthcare teams. The new concept of "resilience" appears to be a relevant tool to achieve this goal. PMID- 24404730 TI - [HIV seroprevalence among tuberculous patients in Kisangani in the Democratic Republic of Congo]. AB - INTRODUCTION: HIV testing among TB patients is still low in DRC This study aimed to determine HIV infection prevalence among TB patients with positive microscopy (TPM+) in Kisangani city. METHODS: In the period of 15 h August to 31th December 2010, a cross-sectional study was conducted including pulmonary tuberculosis patients with positive microscopy (TPM+) from 15 to 49-years-old received in seven tuberculosis screening and treatment centers (STC). The Chi-square and Fisher's exact test were used to compare proportions and the Wilcoxon test to examine the relationships between quantitative variables with skewed distributions. RESULTS: HIV test has been proposed to 136 TPM+ patients. Among them, 118 (86.76%) agreed to be tested. 24 (20.3%) of them were HIV positive. HIV positive patients were significantly older (P = 0.02), predominantly female (P < 0.001) unemployed (p = 0.01). There were more cases of TB treatment relapse (p < 0.01) and less knowledge of TB signs (p = 0.01) among HIV-positive patients. DISCUSSION: The Ministry of Health and its partners should extend to all STC provider-initiated HIV counceling and testing, ensure access to antiretroviral treatment for all HIV-positive TB patients and intensify TB screening in all patients living with HIV PMID- 24404731 TI - [HIV seroprevalence among drug users in Togo]. AB - CONTEXT: In the context of implementing a serological and behavioural surveillance system among drugs users, this study estimated the prevalence of HIV infection and related risk behaviours among drug users (DUs) in Togo. METHOD: A cross-sectional study was conducted among DUs in Togo from November 2011 to January 2012. This study involved all DUs regardless of the type of drug and the mode of consumption, over the age of 18 years, who had lived in Togo for at least 3 months. Behavioural data were collected by face-to-face interviews and serum was obtained for HIV antibody testing. HIV prevalence was estimated together with its 95% confidence interval (CI). Univariate and then multivariate analyses were performed to study the factors associated with HIV prevalence. RESULTS: A total of 387 DUs participated in the survey and 235 (60.7%) of them were enrolled in Lome, the country's capital. The median age of DUs was 32 years with an interquartile range of [25-39 years] and 10 (2.6%) were women. The mode of drug consumption was: smoking or inhaling drugs in 92.8% of cases and 2.8% of DUs used drugs by injection. HIV testing was accepted in 98.4% of cases. The estimated HIV prevalence among drugs users was 5.5%, (95% CI, 3.2-7.8%). CONCLUSION: This study, the first to be conducted among DUs in Togo, found an HIV prevalence of 5.5%, which is higher than the HIV prevalence in the general population (3.2% in 2010). Specific care of DUs is essential in order to reduce HIV prevalence in Togo. PMID- 24404732 TI - [Improvement of the quality of prevention of mother-to-child transmission in Cote d'Ivoire]. AB - OBJECTIVE: This study analysed the impact of improvement collaborative activities on the quality of prevention of mother-to-child transmission of AIDS in 28 health services in Cote d'Ivoire. METHODS: This descriptive, longitudinal, analytical study was based on the main information concerning HIV-infected pregnant women, and the integration and maintenance of HIV-infected subjects in the healthcare system. The study was conducted in 28 heathcare structures of 26 health districts in 12 health areas of Cote d'Ivoire,from January to September 2009. Monitoring of HIV-infected pregnant women and their children was analysed by quality indicators developed in the context of the demonstration phase of the collaborative. RESULTS: This study shows that only 16 (57.1%) out of 28 structures had the 6 PMTCT documents defined in this study. The various quality indicators gradually improved on all sites, from 34.7% to 90.3% of items collected in the PMTCT register; the testing rate of infants born to HIV-positive women increased from 30% to 62.5%. More than 95% of children screened were referred to paediatric care. CONCLUSION: Improvement collaborative approach is important for the improvement of the quality of PMTCT. However, the sustainability of the results of this approach remains the key challenge and will only be possible on the basis of a quality culture of health workers, and greater commitment of authorities. PMID- 24404733 TI - [Evaluation of free cesarean sections in Benin]. AB - INTRODUCTION: The Benin Government introduced free caesarean section in public hospitals in 2009 and a national agency was created to manage free caesarean section. METHODS: Three years after introduction of free caesarean section, we evaluated this measure in the Ouidah hospital area (HZO) by analysing the hospital structure, the implementation process and the results. RESULTS: This study showed the efficacy of free caesarean section, which has helped to increase the caesarean rate from 2.38% in 2009 to 3.48% in 2012, a caesarean section mortality rate of 0.99%, insufficient information for beneficiaries, some drugs are not covered by this measure, and additional costs must be paid by beneficiaries. DISCUSSION: These results indicate the need for a detailed cost analysis to adjust the unit cost for caesarean section. This type of evaluation should be performed in all public hospitals in the country to more clearly identify malfunctions. PMID- 24404734 TI - [Analysis of the Burkinabe National Health Program for the Elderly (BNPEH) 2008 2012]. AB - INTRODUCTION: As a result of ageing of the population, most countries of sub Saharan Africa, either spontaneously and/or in response to international incentives, are starting to develop sectorial or multisectorial action plans in favour of the elderly. Are these plans relevant and consistent and do they improve the health of the elderly? This study was performed to assess the relevance, consistency and implementation of the National Health Programme for the Elderly (PNSPA) 2008-2012 in Burkina Faso. METHODS: This qualitative analysis was conducted in Ouagadougou in November-December 2011 in 47 subjects including 27 elderly subjects and 20 stakeholders responsible for the design and/or implementation of the PNSPA. These respondents were selected rattionally and were individually interviewed. Content analysis was therefore performed. RESULTS: The PNSPA is relevant in the Burkinabe context. It takes into account the health needs of elderly people in Burkina Faso as well as the availability of resources in health centres. It presents several consistency problems. It has rarely been implemented due to lack of political support and inadequate financial resources. DISCUSSION: The Burkina Faso PNSPA has encountered more difficulties than similar plans in Senegal and Mali, which have also encountered low implementation rates. This situation confirms that the elderly in sub-Saharan Africa constitute a top priority vulnerable population but which is neglected by all actors to varying degrees. PMID- 24404735 TI - [Pre-financing community healthcare: the willingness of households to pay for primary health care in Benin]. AB - OBJECTIVES: This study aims to determine factors associated with Benin rural households' willingness to pre-finance their primary health care. METHODS: This study was conducted in Seme-Podji, Department Oueme Benin. The contingent valuation method, namely "bidding game" or "dichotomous choice" was used to determine the willingness to pay for health care. We conducted a probit regression analysis on a sample of 150 rural households. RESULTS: The value of household willingness to pre-finance their primary health care is between 6,000 and 12,000 FCFA per person per year with a median value of 8,000 FCFA/person/year. This value is determined by several factors. Income level, age, usage patterns of health services and promptness in receiving patients have a positive impact on the households' willingness to pay for their health care. The physical characteristics of health centers seem to constitute a barrier to the willingness to pay for health care. CONCLUSION: The pre-financing of health care by households is determined by socio-economic characteristics as well as physical characteristics of health centers. PMID- 24404736 TI - If the face is familiar, the patient may be overusing healthcare. AB - Patients who use the healthcare system excessively, and often for avoidable issues, create a burden for hospitals and consume a significant portion of healthcare expenditures. Many frequent users have complex medical and psychosocial needs, are uninsured, or have behavioral health issues. Case managers should identify patients who are potential frequent utilizers and make sure they are connected with a primary care provider. Take the time to find out barriers to care and call in a social worker to help line up community resources. PMID- 24404737 TI - Super-utilizers get red carpet treatment. AB - MetroHealth Medical Center in Cleveland has partnered with two health plans to provide intensive care coordination for high-cost patients with multiple medical problems and, often, behavioral health issues. Nurse practitioners at two primary care sites provide one-on-one care coordination for super-utilizers. They assess the patients' needs, help coordinate community resources, and prepare a treatment plan that is flagged when patients visit the emergency department. The nurse practitioners meet with health plan representatives monthly and brainstorm on ways to meet patients' needs. PMID- 24404738 TI - CMs coordinate care for frequent utilizers. AB - At the University of Michigan Health System, complex case managers coordinate inpatient and outpatient treatment and psychosocial services for patients who frequently visit the emergency department or are hospitalized. Patients in the program have complex medical needs, behavioral health issues, and/or lack of physical resources or social support. Complex case managers complete a comprehensive assessment of patient needs and work with practitioners to develop a treatment plan that the emergency department can use when patients present for treatment. Case managers follow the patients until they are stable, sometimes for a year or longer. PMID- 24404739 TI - Community collaborates on services for mentally ill. AB - Faced with the closing of the state psychiatric hospital in their community, hospitals, law enforcement, mental health providers, and community agencies in Raleigh, NC, began collaborating on improving care and transitions for the mentally ill. The coalition created a standardized assessment tool and standardized transfer guidelines for mentally ill patients, along with other process improvements. As a result, Duke Raleigh Hospital is transferring more patients to mental health facilities direct from the emergency department rather than keeping them in an inpatient bed waiting for an opening. Hospital case managers get behavioral health patients a follow-up appointment with a mental health provider before they leave the hospital. PMID- 24404740 TI - ED navigators help patients find a PCP. AB - Carondelet Health Network in Tucson, AZ, places community health outreach workers in the emergency department to help patients who use the ED for non-emergent conditions find a primary care provider. Navigators coordinate primary care appointments and get patients set up in a medical home. If patients have a primary care provider but can't get an appointment, the navigators try to get them in or direct them to a walk-in clinic. Navigators assess patients for psychosocial needs and can help them access community resources and sign up for benefits. PMID- 24404742 TI - The problem with our health care cost crisis? Hint: it has nothing to do with providers. PMID- 24404741 TI - Embedded CMs work with high-risk patients. AB - Care managers embedded in primary care clinics work with patients with high-risk diagnoses and multiple visits to the emergency department or hospital. Patients are identified though risk assessments, suggestions from inpatient case management, and requests from primary care clinicians. Care managers call patients before their clinic visits, look for gaps in care and find out patients' questions and concerns, sharing the information with the treating clinicians. Care managers follow patients for four weeks after their visit, helping them meet their health care goals and follow their treatment plan. PMID- 24404743 TI - Updated guidelines highlight lack of meds for heart failure. PMID- 24404745 TI - Metabolic syndrome program aims for competitive advantage. PMID- 24404744 TI - A conversation with Uwe E. Reinhardt, PhD. Health care deserves more respect. PMID- 24404746 TI - New DNA test quickly identifies multidrug-resistant tuberculosis. PMID- 24404747 TI - Prevalence and antimicrobial resistance of Salmonella isolated from poultry slaughterhouses in Korea. AB - We determined the antimicrobial resistance of Salmonella serovars from a total of 154 (44 chilling waters and 110 carcasses) samples collected from 22 poultry slaughterhouses. Standard culture techniques, Kauffmann-White slide agglutination and disc diffusion tests were used to isolate, and identify the serovars and to assess the antimicrobial activity, respectively. A total of 88 isolates belonging to 34 Salmonella serovars from 67 (43.5%) positive samples were identified. Among the samples examined, 68.2% (15/22), 22.7% (5/22), and 42.7% (47/110) from the first chilling waters, the last chilling waters, and carcasses were found contaminated with Salmonella, respectively. The prevalent serovars were S. Enteritidis (12.5%) followed by S. Montevideo and S. Senftenberg (8.0%). Rare Salmonella serovars such as S. Aba, S. Malmoe, S. Westhampton, S. Takoradi, and S. Baiboukoum in chicken slaughterhouses and S. Newbrunswick, S. Huddinge S. Glostrup, S. Dujugu, S. Goettingen and S. II in duck slaughterhouses were also detected. Among the serovars, 52.3% (46/88) and 21.6% (19/88) were resistant to one antibiotic and more than two antibiotics, respectively. High antimicrobial resistance rates against sulfamethoxazole (39.8%) followed by tetracycline (22.7%), nalidixic acid (21.6%), ampicillin and amoxicillin-clavulanic acid (8.0%), and chloramphenicol (4.5%) were observed. These results suggest more stringent hygienic measures should be taken to reduce the incidence of pathogen contamination in the food chain. PMID- 24404748 TI - Expression and characterization of cathepsin B from tsetse (Glossina morsitans morsitans). AB - Digestive enzymes in tsetse fly midgut are thought to modulate the development of African trypanosome which is a causative agent of trypanosomosis in human and animal. Cathepsin B is induced after the first blood meal ingestion and being higher in trypanosome infected flies. A DNA fragment encoding pro-cathepsin B (930 bp) (Accession No. AF329480_1) was cloned and expressed in E. coli and P. pastoris protein expression systems. An active recombinant cathepsin B (rGmcathB) produced by P. pastoris was migrating from 35 to 45 kDa under reducing condition, rGmcathB exhibited the highest proteolytic activity at pH 4.0 with wide range temperature 25-30 degrees C, also degraded bovine hemoglobin and serum albumin. rGmcathB exhibited hydrolysis preference for Z-Arg-Arg-MCA (K(cat)/K(M) 7.58 mM( 1)sec(-1)) and bovine hemoglobin (K(cat)/K(M) 3.77 x 10(3) mM(-1)sec(-1)). The proteolytic activity of rGmcathB was inhibited by specific cysteine protease inhibitor (E-64) confirmed belonging to papain-like cysteine protease family. These results indicated that rGmcathB shows the activity of cathepsin B and have high affinity with blood protein referring a role in blood meal digestion. In this study, the recombinant protein expressed by E. coli expression system was not enzymatically active as shown in the recombinant protein expressed by P. pastoris expression system. This finding implies that P. pastoris expression system is more suitable for expressing enzymatically active recombinant proteases than E. coli expression system. PMID- 24404749 TI - In vitro maturation system for individual culture of bovine oocytes using micro volume multi-well plate. AB - As a preliminary study for the development of individual in vitro maturation (IVM) culture of bovine oocytes, a multi-well (MW) plate was used. Maturation, fertilization and development to blastocysts were examined and compared with those of IVM oocytes cultured in 50-microl droplets in groups and in 10-microl droplets individually. The maturation rates were similar in all experimental groups. Normal fertilization rates in MW and 50-microl droplets were similar, but lower in 10-microl droplets (p < 0.01). The blastocyst rate in 10-microl droplets tended to be lower than those in MW (p = 0.15) and 50-microl droplets (p = 0.19). These results indicate that an IVM system using MW supports the acquisition of developmental competence by bovine oocytes the same as conventional group IVM culture. PMID- 24404750 TI - Bisphosphonates: therapeutics potential and recent advances in drug delivery. AB - CONTEXT: Bisphosphonates (BPs) are widely used for prevention and treatment of osteoporosis. BPs are known as gold standard for osteoporosis (OP) treatment due to their positive results in clinical studies. But some serious side effects are associated with BPs like gastrointestinal adverse effect i.e. esophagitis and ulcer of esophagus. Oral bioavailability (BA) of BPs ranges from 0.6 to 1% due to poor absorption through gastrointestinal tract (GIT). OBJECTIVE: The main objective of this review is to explore the role of novel drug delivery systems (DDSs) for the delivering of BPs and minimizing the drawbacks associated with them. METHODS: The current review is focusing on classification, mechanism of action, and limitations of BPs, and is also dwelling on the use of novel DDSs like nanoparticles, liposomes, topical, transdermal systems, implants, bisphosphonate osteotropic DDS (BP-ODDS), microspheres, and calcium phosphate cements (CPCs) for BPs. This review also gives a critically reviewed compilation of the various in vitro and in vivo studies conducted till date. CONCLUSION: On the basis of the exhaustive literature, it has been found that the novel DDS minimizes the side effects associated with BPs and enhances the BA. The advance drug delivery has a greater impact on reducing the undesirable effects and increasing the BA of BPs. PMID- 24404752 TI - Comparison of testosterone fractions between Framingham Heart Study participants and Japanese participants. AB - OBJECTIVES: To determine testosterone fractions in Japanese men and to compare these values with those of Framingham Heart Study participants. METHODS: We enrolled 498 healthy Japanese men. Total testosterone was assayed by liquid chromatography tandem mass spectrometry, sex hormone-binding globulin was assayed by immunoassay and free testosterone was calculated by a laboratory at the Boston Medical Center. Analog-based free testosterone and immunoassay-based total testosterone were determined by immunoassay. We compared mass spectrometry assay based total testosterone and calculated free testosterone values in the Japanese participants with values in the American Framingham Heart Study third generation cohort. RESULTS: The mean serum mass spectrometry assay-based total testosterone, sex hormone-binding globulin, and calculated free testosterone values were 439.4 +/- 167 ng/dL, 65.34 +/- 30.61 nmol/L, and 58.75 +/- 20.0 pg/mL, respectively. The correlation coefficients with age for mass spectrometry assay-based total testosterone, sex hormone-binding globulin, and calculated free testosterone were 0.0010, 0.5041, and -0.496, respectively. There were no age-related changes in mass spectrometry assay-based total testosterone values in healthy men (P = 0.981), whereas sex hormone-binding globulin and calculated free testosterone levels showed similar age-related changes (P < 0.0001). Serum analog-based free testosterone levels (8.24 +/- 2.9 pg/mL) showed age-related changes (P < 0.0001) regardless of immunoassay-based total testosterone levels (P = 0.828). Serum immunoassay-based total testosterone values (486.1 +/- 162.5 ng/dL) correlated with serum mass spectrometry assay-based total testosterone values (r = 0.740, 95% confidence interval 0.6965-0.7781, P < 0.0001). Similarly, analog-based free testosterone and calculated free testosterone values showed a highly significant correlation (r = 0.706, 95% confidence interval 0.6587-0.7473, P < 0.0001). The analog-based free testosterone values were approximately 10% of the calculated free testosterone values. CONCLUSIONS: In contrast to the Framingham Heart Study cohort, total testosterone values in Japanese men are not associated with advancing age; thus, they cannot be used to diagnose late-onset hypogonadism in Japan. The analog-based free testosterone value can be considered instead as a suitable biochemical determinant for diagnosing late-onset hypogonadism syndrome. PMID- 24404758 TI - Relative age effects in Australian Football League National Draftees. AB - This study examined the birth distribution for adolescent (i.e. <20 years) and mature age players (i.e. >=20 years) selected in the Australian Football League (AFL) National Draft between 2001 and 2012. Birth-date information was accessed for all first time AFL national draftees and players were then classified as either adolescent (N = 736) or mature age (N = 70) draftees. Chi-squared analysis showed a clear bias in the birth distribution of adolescent draftees towards players born in the first part of the classification period for both quartile (P < 0.001) and half-year (P < 0.001) compared to the Australian national population. There was a reverse relative age effect (RAE) for mature age draftees, with a significant bias towards players born in the latter part of the selection period for both quartile (P = 0.047) and half-year (P = 0.028) compared to the Australian national population. The selection bias towards relatively older players in adolescent AFL draftees may be related to advanced physical and psychological maturity, and exposure to higher-level coaching compared to their younger counterparts. The reverse RAE in mature age draftees is a novel finding and supports the need for strategies to encourage continued participation pathways for talented Australian football players born later in the selection year. PMID- 24404757 TI - Bioactive compounds from Vitex leptobotrys. AB - A new lignan, vitexkarinol (1), as well as a known lignan, neopaulownin (2), a known chalcone, 3-(4-hydroxyphenyl)-1-(2,4,6-trimethoxyphenyl)-2-propen-1-one (3), two known dehydroflavones, tsugafolin (4) and alpinetin (5), two known dipeptides, aurantiamide and aurantiamide acetate, a known sesquiterpene, vemopolyanthofuran, and five known carotenoid metabolites, vomifoliol, dihydrovomifoliol, dehydrovomifoliol, loliolide, and isololiolide, were isolated from the leaves and twigs of Vitex leptobotrys through bioassay-guided fractionation. The chalcone (3) was found to inhibit HIV-1 replication by 77% at 15.9 MUM, and the two dehydroflavones (4 and 5) showed weak anti-HIV activity with IC50 values of 118 and 130 MUM, respectively, while being devoid of cytotoxicity at 150 MUM. A chlorophyll-enriched fraction of V. leptobotrys, containing pheophorbide a, was found to inhibit the replication of HIV-1 by 80% at a concentration of 10 MUg/mL. Compounds 1 and 3 were further selected to be evaluated against 21 viral targets available at NIAID (National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA). PMID- 24404766 TI - Fabrication of low-cost, cementless femoral stem 316L stainless steel using investment casting technique. AB - Total hip arthroplasty is a flourishing orthopedic surgery, generating billions of dollars of revenue. The cost associated with the fabrication of implants has been increasing year by year, and this phenomenon has burdened the patient with extra charges. Consequently, this study will focus on designing an accurate implant via implementing the reverse engineering of three-dimensional morphological study based on a particular population. By using finite element analysis, this study will assist to predict the outcome and could become a useful tool for preclinical testing of newly designed implants. A prototype is then fabricated using 316L stainless steel by applying investment casting techniques that reduce manufacturing cost without jeopardizing implant quality. The finite element analysis showed that the maximum von Mises stress was 66.88 MPa proximally with a safety factor of 2.39 against endosteal fracture, and micromotion was 4.73 MUm, which promotes osseointegration. This method offers a fabrication process of cementless femoral stems with lower cost, subsequently helping patients, particularly those from nondeveloped countries. PMID- 24404768 TI - Low-frequency Raman scattering study of six nucleosides. AB - Raman spectroscopy was used to study the low-frequency (?200 cm(-1)) vibrations in crystalline samples of six naturally occurring nucleosides: deoxythymidine (dT), deoxycytidine (dC), deoxyadenosine (dA), uridine (rU), cytidine (rC), and adenosine (rA). Such low-frequency vibrations are important for biological processes in which the conformation of a nucleic acid molecule changes. These experiments also provide a test for the low-frequency vibrational modes of dT, dC, and dA predicted by Shishkin et al. PMID- 24404767 TI - Genome-based approaches to develop epitope-driven subunit vaccines against pathogens of infective endocarditis. AB - Infective endocarditis (IE) has emerged as a public health problem due to changes in the etiologic spectrum and due to involvement of resistant bacterial strains with increased virulence. Developing potent vaccine is an important strategy to tackle IE. Complete genome sequences of eight selected pathogens of IE paved the way to design common T-cell driven subunit vaccines. Comparative genomics and subtractive genomic analysis were applied to identify adinosine tri phosphate (ATP)-binding cassette (ABC) transporter ATP-binding protein from Streptococcus mitis (reference organism) as common vaccine target. Reverse vaccinology technique was implemented using computational tools such as ProPred, SYFPEITHI, and Immune epitope database. Twenty-one T-cell epitopes were predicted from ABC transporter ATP-binding protein. Multiple sequence alignment of ABC transporter ATP-binding protein from eight selected IE pathogens was performed to identify six conserved T-cell epitopes. The six selected T-cell epitopes were further evaluated at structure level for HLA-DRB binding through homology modeling and molecular docking analysis using Maestro v9.2. The proposed six T-cell epitopes showed better binding affinity with the selected HLA-DRB alleles. Subsequently, the docking complexes of T-cell epitope and HLA-DRBs were ranked based on XP Gscore. The T-cell epitope (208-LNYITPDVV-216)-HLA-DRB1(*)0101 (1T5 W) complex having the best XP Gscore (-13.25 kcal/mol) was assessed for conformational stability and interaction stability through molecular dynamic simulation for 10 ns using Desmond v3.2. The simulation results revealed that the HLA-DRB-epitope complex was stable throughout the simulation time. Thus, the epitope would be ideal candidate for T-cell driven subunit vaccine design against infective endocarditis. PMID- 24404769 TI - Binding of polarity-sensitive hydrophobic ligands to erythroid and nonerythroid spectrin: fluorescence and molecular modeling studies. AB - We have used three polarity-sensitive fluorescence probes, 6-propionyl 2-(N,N dimethyl-amino) naphthalene (Prodan), pyrene and 8-anilino 1-naphthalene sulphonic acid, to study their binding with erythroid and nonerythroid spectrin, using fluorescence spectroscopy. We have found that both bind to prodan and pyrene with high affinities with apparent dissociation constants (Kd) of .50 and .17 MUM, for prodan, and .04 and .02 MUM, for pyrene, respectively. The most striking aspect of these bindings have been that the binding stoichiometry have been equal to 1 in erythroid spectrin, both in dimeric and tetrameric form, and in tetrameric nonerythroid spectrin. From an estimate of apparent dielectric constants, the polarity of the binding site in both erythroid and nonerythroid forms have been found to be extremely hydrophobic. Thermodynamic parameters associated with such binding revealed that the binding is favored by positive change in entropy. Molecular docking studies alone indicate that both prodan and pyrene bind to the four major structural domains, following the order in the strength of binding to the Ankyrin binding domain > SH3 domain > Self-association domain > N-terminal domain of alpha-spectrin of both forms of spectrin. The binding experiments, particularly with the tetrameric nonerythroid spectrin, however, indicate more toward the self association domain in offering the unique binding site, since the binding stoichiometry have been 1 in all forms of dimeric and tetrameric spectrin, so far studied by us. Further studies are needed to characterize the hydrophobic binding sites in both forms of spectrin. PMID- 24404770 TI - beta-structure of the coat protein subunits in spherical particles generated by tobacco mosaic virus thermal denaturation. AB - Conversion of the rod-like tobacco mosaic virus (TMV) virions into "ball-like particles" by thermal denaturation at 90-98 degrees C had been described by R.G. Hart in 1956. We have reported recently that spherical particles (SPs) generated by thermal denaturation of TMV at 94-98 degrees C were highly stable, RNA-free, and water-insoluble. The SPs were uniform in shape but varied widely in size (53 800 nm), which depended on the virus concentration. Here, we describe some structural characteristics of SPs using circular dichroism, fluorescence spectroscopy, and Raman spectroscopy. It was found that the structure of SPs protein differs strongly from that of the native TMV and is characterized by coat protein subunits transition from mainly (about 50%) alpha-helical structure to a structure with low content of alpha-helices and a significant fraction of beta sheets. The SPs demonstrate strong reaction with thioflavin T suggesting the formation of amyloid-like structures. PMID- 24404771 TI - Insights into the structural stability of nuclear matrix ribonucleoprotein, LMG160: thermodynamic and spectroscopic analysis. AB - Low-mobility group nonhistone chromatin protein, LMG160, is a nuclear matrix ribonucleoprotein particle (RNP) which has a RNA molecule with approximately 300 bases. In this study, structural stability of the intact LMG160 (I-LMG160) was investigated at different ionic strength and in the absence of its RNA moiety (T LMG160) employing spectroscopic and thermodynamic techniques. The UV absorption spectra showed hypochromicity and red shift under increasing ionic strength for both forms of LMG160 but in different extents. The fluorescence emission intensity was decreased as ionic strength was increased and the Stern-Volmer quenching constant (Ksv) for T-LMG160 was 3.7 times less than for I-LMG160. In the absence of sodium chloride, I-LMG160 exhibited a very stable structure against the temperature change compared to T-LMG160. The thermodynamic parameters showed that the positive values of DeltaHm and DeltaSm increased by increasing ionic strength in both forms of LMG160. Removal of the RNA moiety altered secondary structure: as T-LMG160 showed more helical content than I-LMG160. From the results, it is concluded that I-LMG160 is more sensitive to alteration of environment and the RNA has an important role in this RNP conformation. Also, interaction of both I- and T-LMG160 with sodium chloride is entropy driven and is usually accompanied by surface hydrophobicity. PMID- 24404772 TI - Structural insight into the binding complex: beta-arrestin/CCR5 complex. AB - The chemokine receptor 5 (CCR5) belongs to the superfamily of serpentine G protein-coupled receptors (GPCRs). The DRY motif (Asp, Arg, Tyr) of the intracellular loop 2 (ICL2), which is highly conserved in the GPCRs has been shown to be essential for the stability of folding of CCR5 and the interaction with beta-arrestin. But the molecular mechanism by which it recognizes and interacts with beta-arrestin has not been elucidated. In the present study, we described the active state of the beta-arrestin structure using normal mode analysis and characterized the binding cleft of CCR5-ICL2 with beta-arrestin using SABRE(c) docking tool and molecular dynamics simulation. Based on our computational results, we proposed a mode of binding between the ICL2 loop of CCR5 and beta-arrestin structure, and modeled the energetically stable beta arrestin/CCR5 complex. In view of CCR5's importance as a therapeutic target for the treatment of HIV, this observation provides novel insight into the beta arrestin/CCR5 pathway. As a result, the current computational study of the detailed beta-arrestin/CCR5 binding complex could provide the rationale for the development of next generation of HIV peptide inhibitors as therapeutic agents. PMID- 24404773 TI - Structural insights into the interactions of xpt riboswitch with novel guanine analogues: a molecular dynamics simulation study. AB - Ligand recognition in purine riboswitches is a complex process requiring different levels of conformational changes. Recent efforts in the area of purine riboswitch research have focused on ligand analogue binding studies. In the case of the guanine xanthine phosphoribosyl transferase (xpt) riboswitch, synthetic analogues that resemble guanine have the potential to tightly bind and subsequently influence the genetic expression of xpt mRNA in prokaryotes. We have carried out 25 ns Molecular Dynamics (MD) simulation studies of the aptamer domain of the xpt G-riboswitch in four different states: guanine riboswitch in free form, riboswitch bound with its cognate ligand guanine, and with two guanine analogues SJ1 and SJ2. Our work reveals novel interactions of SJ1 and SJ2 ligands with the binding core residues of the riboswitch. The ligands proposed in this work bind to the riboswitch with greater overall stability and lower root mean square deviations and fluctuations compared to guanine ligand. Reporter gene assay data demonstrate that the ligand analogues, upon binding to the RNA, lower the genetic expression of the guanine riboswitch. Our work has important implications for future ligand design and binding studies in the exciting field of riboswitches. PMID- 24404774 TI - Probing tertiary structure of proteins using single Trp mutations with circular dichroism at low temperature. AB - Trp is the most spectroscopically informative aromatic amino acid of proteins. However, the near-UV circular dichroism (CD) spectrum of Trp is complicated because the intensity and sign of (1)La and (1)Lb bands vary independently. To resolve vibronic structure and gain site-specific information from complex spectra, deconvolution was combined with cooling and site-directed tryptophan substitution. Low temperature near-UV CD was used to probe the local tertiary structure of a loop and alpha-helix in tear lipocalin. Upon cooling, the enhancement of the intensities of the near-UV CD was not uniform, but depends on the position of Trp in the protein structure. The most enhanced (1)Lb band was observed for Trp at position 124 in the alpha-helix segment matching the known increased conformational mobility during ligand binding. Some aspects of the CD spectra of W28 and W130 were successfully linked to specific rotamers of Trp previously obtained from fluorescence lifetime measurements. The discussion was based on a framework that the magnitude of the energy differences in local conformations governs the changes in the CD intensities at low temperature. The Trp CD spectral classification of Strickland was modified to facilitate the recognition of pseudo peaks. Near-UV CD spectra harbor abundant information about the conformation of proteins that site directed Trp CD can report. PMID- 24404777 TI - Different clinical presentation of Klinefelter's syndrome in monozygotic twins. AB - There is a wide variability in the clinical presentation of Klinefelter's syndrome. We report the case of a 45-year-old man who was incidentally diagnosed a 47,XXY/46,XY karyotype in a bone marrow aspiration (case 1). He presented hypogonadic features with undetectable testosterone levels and a height in accordance with mid-parental height. He had a monozygous sibling (case 2) who did not show clinical signs of hypogonadism and whose height exceeded mid-parental height. Both patients had presented language disorders since childhood. The karyotype of lymphocytes in peripheral blood of both subjects was compatible with mosaic Klinefelter's syndrome (46,XY/47,XXY). Testosterone replacement was initiated in case 1. Lack of testicular involvement due to mosaicism and the overexpression of the SHOX gene in case 2 could explain the marked differences in phenotype in these homozygous twins. PMID- 24404778 TI - Double-locus sequence typing using porA and peb1A for epidemiological studies of Campylobacter jejuni. AB - Campylobacter jejuni is the leading cause of foodborne bacterial gastroenteritis worldwide. Bacterial typing schemes play an important role in epidemiological investigations to trace the source and route of transmission of the infectious agent by identifying outbreak and differentiating among sporadic infections. In this study, a double-locus sequence typing (DLST) scheme for C. jejuni based on concatenated partial sequences of porA and peb1A genes is proposed. The DLST scheme was validated using 50 clinical and environmental C. jejuni strains isolated from human (C5, H, H15-H19), chicken (CH1-CH15), water (W2-W17), and ovine samples (OV1-OV6). The scheme was found to be highly discriminatory (discrimination index [DI]=0.964) and epidemiologically concordant based on C. jejuni strains studied. The DLST showed discriminatory power above 0.95 and excellent congruence to multilocus sequence typing and can be recommended as a rapid and low-cost typing scheme for epidemiological investigation of C. jejuni. It is suggested that the DLST scheme is suitable for identification of outbreak strains and differentiation of the sporadic infection strains. PMID- 24404779 TI - Effect of temperatures on the growth, toxin production, and heat resistance of Bacillus cereus in cooked rice. AB - Bacillus cereus is capable of producing enterotoxin and emetic toxin, and Bacillus foodborne illnesses occur due to the consumption of food contaminated with endospores. The objectives of this study were to investigate the growth and toxin production of B. cereus in cooked rice and to determine the effect of temperature on toxin destruction. Cooked rice inoculated with B. cereus was stored at 15, 25, 35, and 45 degrees C or treated at 80, 90, and 100 degrees C. The results indicated that emetic toxin was produced faster than enterotoxin (which was not detected below 15 degrees C) at all the storage temperatures (15 45 degrees C) during the first 72 h. Emetic toxin persisted at 100 degrees C for 2 h, although enterotoxin was easily to be destroyed by this treatment within 15 min. In addition, B. cereus in cooked rice stored at a warm temperature for a period was not inactivated due to survival of the thermostable endospores. These data indicate that the contaminated cooked rice with B. cereus might present a potential risk to consumers. Results from this study may help enhance the safety of such food, and provide valuable and reliable information for risk assessment and management, associated with the problem of B. cereus in cooked rice. PMID- 24404780 TI - Chronic sequelae of E. coli O157: systematic review and meta-analysis of the proportion of E. coli O157 cases that develop chronic sequelae. AB - OBJECTIVE: This was a systematic review and meta-analysis to determine the proportion of Escherichia coli O157 cases that develop chronic sequelae. DATA SOURCES: We conducted a systematic review of articles published prior to July 2011 in Pubmed, Agricola, CabDirect, or Food Safety and Technology Abstracts. STUDY SELECTION: Studies were selected that reported the number of E. coli O157 cases that developed reactive arthritis (ReA), hemolytic uremic syndrome (HUS), irritable bowel syndrome, inflammatory bowel disease, or Guillain Barre syndrome. METHODS: Three levels of screening and data extraction of articles were conducted using predefined data fields. Meta-analysis was performed on unique outcome measures using a random-effects model, and heterogeneity was assessed using the I2 value. Meta-regression was used to explore the influence of nine study-level variables on heterogeneity. RESULTS: A total of 82 studies were identified reporting 141 different outcome measures; 81 reported on HUS and one reported on ReA. Depending on the number of cases of E. coli O157, the estimate for the proportion of E. coli O157 cases that develop HUS ranged from 17.2% in extra small studies (<50 cases) to 4.2% in extra-large studies (>1000 cases). Heterogeneity was significantly associated with group size (p<0.0001); however, the majority of the heterogeneity was unexplained. CONCLUSIONS: High unexplained heterogeneity indicated that the study-level factors examined had a minimal influence on the variation of estimates reported. PMID- 24404781 TI - Antimicrobial susceptibility and molecular typing of methicillin-resistant staphylococcus aureus in retail foods in Shaanxi, China. AB - The aims of this study were to evaluate the occurrence of methicillin-resistant Staphylococcus aureus (MRSA) in retail foods in Shaanxi, China and to investigate antimicrobial resistance and molecular characteristics of these strains. A total of 1979 retail food samples were randomly collected during 2008-2012 from supermarkets and farmers markets and screened for S. aureus, and then S. aureus isolates were further examined to determine whether they were MRSA. MRSA isolates were further characterized by antimicrobial susceptibility test, pulsed-field gel electrophoresis, spa typing, multilocus sequence typing, and SCCmec typing, and were examined for genes encoding enterotoxins, exfoliative toxins, Panton Valentine leukocidin (pvl), and toxic shock syndrome toxin 1. Among all the samples examined, four (1.4%) raw milk samples, six (2.3%) chicken samples, one (0.6%) pork sample, three (0.6%) ready-to-eat food samples, and three (2.5%) dumpling samples were positive for MRSA. No MRSA isolates were recovered from infant foods. A total of 23 MRSA isolates were recovered from the 17 MRSA positive samples. Antimicrobial susceptibility tests showed that, among these MRSA isolates, resistance was most frequently observed to penicillin, ampicillin, oxacillin, cefoxitin, and clindamycin (each 100%), followed by erythromycin (95.7%) and clarithromycin (87.0%). The commonly detected toxin genes were pvl, seg, seb, sed, followed by see, sec, and sei. Seven spa types (t189, t377, t437, t899, t10793, t5762, and a new spa type) and three SCCmec types (II, IVb, and V) were identified. More than half (52.2%) of the MRSA isolates belonged to ST9, followed by ST88, ST59, ST188, ST72, and ST630. Our findings indicate that MRSA in food could be from both animal and human origin. Although the prevalence is low, the presence of multidrug resistant and enterotoxigenic MRSA strains in foods poses a potential threat to consumers and emphasizes the need for better control of sources of contamination. PMID- 24404784 TI - Does humidity trigger tree phenology? Proposal for an air humidity based framework for bud development in spring. PMID- 24404785 TI - Effects of community-based meditative Tai Chi programme on improving quality of life, physical and mental health in chronic heart-failure participants. AB - BACKGROUND: There is increasing evidence that coronary heart disease is linked with a number of psychosocial risk factors and biophysiological risk factors such as metabolic syndrome. This study aimed to compare Tai Chi programme heart failure participants between the pre-intervention phase and six month after intervention time in health-related quality of life (HRQoL), including physical health, role-physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health. In addition, the difference between pre intervention and post-intervention time in psychological distress and resilience, body mass index (BMI), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were compared. METHODS: A prospective intervention study was conducted in 2012 to evaluate the effectiveness of a community-based meditation Tai Chi intervention programme to improve heart-failure patients' health. Measures included the Short-Form 12 Health Survey (SF-12), General Health Questionnaire (GHQ30), resilience scale, BMI, blood pressure and waist circumference. Univariate analysis of variance was used to compare the difference between pre- and post-intervention in Tai Chi participants. RESULTS: Outcomes differed in significance and magnitude across four HRQoL measures, psychological distress and resilience between the pre- and post-intervention time in heart-failure patients who participated in the Tai Chi exercise. The participants in the post intervention time also reduced BMI, SBP, and waist circumference. CONCLUSIONS: Regular and more than six months Tai Chi exercises had a beneficial effect to HRQoL, reducing psychological distress, promoting resilience, and reducing the BMI and blood pressure level in heart-failure patients. PMID- 24404786 TI - Observing micopapillary thyroid cancers. PMID- 24404789 TI - Comparison of in-hospital and out-of-hospital cardiac arrest outcomes in a Scandinavian community. AB - BACKGROUND: Reported incidence and survival from in-hospital and out-of-hospital cardiac arrest show great variability, making it difficult to compare the groups. In order to eliminate effects of time and culture, we investigated out-of hospital cardiac arrest compared with in-hospital cardiac arrest in our community over a 1-year period. METHODS: We conducted a cohort study including patients with in-hospital and out-of-hospital cardiac arrest. Multiple data sources were screened in order to identify all cardiac arrest patients. Utstein style data were collected prospectively from 1 December 2008 to 30 November 2009 with subsequent analysis. RESULTS: A total of 380 resuscitations because of cardiac arrest were included, 154 (40.6%) in-hospital and 226 (59.4%) out-of-hospital. The in-hospital cardiac arrest group was older, had higher proportions of witnessed cardiac arrest, bystander cardiopulmonary resuscitation, bystander direct current (DC) shock and professional first rescuer. Survival to hospital discharge was 16.2% for in-hospital cardiac arrest vs. 16.8% for out-of-hospital cardiac arrest. CONCLUSION: Survival from in-hospital and out-of-hospital cardiac arrest in this cohort is similar. PMID- 24404796 TI - Predictors of neutrophilic airway inflammation in young smokers with asthma. AB - INTRODUCTION: Asthma is one of the most widespread chronic diseases worldwide. In spite of numerous detrimental effects on asthma, smoking is common among asthma patients. These smoking-induced aggravations of asthma may be attributed to changes in airway inflammation, which is characterized by a higher degree of neutrophilic inflammation than in non-smokers. A state of neutrophilic inflammation may lead to increased steroid resistance and an accelerated loss of lung function owing to tissue destruction. The aim of this study was to elucidate predictors of neutrophilic inflammation in young asthmatic smokers not on steroid treatment, including analysis of tobacco history and bacterial colonization. METHODS: In a cross-sectional study, 52 steroid-free, current smokers with asthma were examined with induced sputum, fractional exhaled nitric oxide (FeNO), lung function, ACQ6 score, mannitol and methacholine challenge. A sample from the sputum induction was taken for bacterial analysis using 16S gene PCR technique and sequencing. RESULTS: Using one-way analysis of variance and binary and linear regression models, only age and ACQ6 score were found to be significant predictors for airway neutrophilia. The investigation also included analysis for effect of pack years, current tobacco consumption, body mass index, lung function, FeNO; methacholine and mannitol responsiveness, atopy, gender, asthma history and presence of bacteria. The most common potentially pathogenic bacteria found were Streptococcus spp., Haemophilus spp. and Mycoplasma spp. CONCLUSION: In this study, no tobacco-related predictors of airway neutrophilia were found, indicating that in the younger years of asthma patients who smoke, the amount of tobacco smoked in life does not influence the degree of neutrophilia. Conversely, for asthmatic smokers, neutrophilia may be induced when a certain threshold of tobacco consumption is reached. PMID- 24404797 TI - Bronchodilator response as a hallmark of uncontrolled asthma: a randomised clinical trial. AB - INTRODUCTION: The goal of this study is to determine whether bronchodilator (BD) response can be used as a reliable measure of asthma control by analyzing the effects of a short course of oral corticosteroids (OC) or placebo (P) on spirometry, sputum cytology and BD response in controlled asthma patients scoring less than 1.5 on the ACQ5. METHODS: Seventy patients with moderate to severe asthma who were undergoing combination therapy and were considered to be controlled based on ACQ5 scores, but who exhibited persistent positive BD response, were randomly assigned to two groups, one receiving OC and the other P. Patients were evaluated before and after 2 weeks of treatment. Intervention response (comparison of FEV(1) before and after OC or P treatment) was used as a measure of intervention efficacy, with values equal to or greater than 200 mL considered positive. RESULTS: Patients who received OC showed significant improvement in FEV(1), and no longer exhibited a positive BD response. Those in the P group showed no change. In addition, sputum eosinophil counts significantly decreased in the OC group. CONCLUSIONS: BD response can be used as a reliable measure of asthma control. This study suggests that ACQ5 scores alone are not sufficient to fully assess asthma control, and that BD response should be included as an essential measurement in any algorithm of asthma control evaluation. PMID- 24404798 TI - Associations of maternal asthma severity and control with pregnancy complications. AB - OBJECTIVES: To assess the associations of maternal asthma severity and control with pregnancy-induced hypertension (PIH), gestational diabetes and cesarean delivery. METHODS: A cohort of 41 660 pregnancies from women with and without asthma who delivered between 1990 and 2002 was constructed by linking Quebec's administrative databases. Maternal asthma was defined by at least one asthma diagnosis and one dispensed prescription for an asthma medication in the 2 years before or during pregnancy. Asthma severity and control were assessed using validated indexes during the entire pregnancy to study cesarean delivery and 1 year prior to week 20 of gestation to study PIH and gestational diabetes. Generalized Estimation Equation models were used to obtain odds ratios (OR) for PIH, gestational diabetes and cesarean in association with maternal asthma severity and control. RESULTS: Almost one-third of the women had uncontrolled asthma and up to 5% had severe asthma. Severe asthma increased the risk of cesarean delivery (OR = 1.35; 95% CI: 1.11-1.63) compared with mild asthma, but no association was found between asthma severity and the other outcomes. The level of asthma control was not associated with any of the outcomes, except for a near-significant increased risk of PIH among uncontrolled women (OR = 1.18; 95% CI: 0.97-1.42). CONCLUSIONS: The risk of gestational diabetes was not associated with asthma severity or control, and the risk of PIH was not associated with asthma severity. However, further studies are needed to clarify the association between asthma control and PIH. The increased risk of cesarean among women with severe asthma may be explained by the physician's and patient's concerns over the safety of normal delivery. PMID- 24404799 TI - Discrepancies between medical record data and parent reported use of preventive asthma medications. AB - OBJECTIVE: To assess whether medical record documentation reflects actual home practices regarding the administration of preventive medications to urban children with persistent asthma. METHODS: Baseline data from a prompting asthma intervention were used for this cross-sectional analysis. As part of the larger study, we enrolled children (2-12 years) with persistent asthma in the waiting room at 12 primary care offices (2009-2012). Prior to their visit with a healthcare provider, caregivers reported information regarding their child's asthma symptom severity and current preventive medications (i.e. name and frequency of use). We compared caregiver-reported medication information with medical record data to determine the rate of complete concordance, defined as total consistency between the prescribed medication data documented in the medical record and parent report describing how the child is actually using the medication at home. RESULTS: According to 310 completed medical record reviews, 194 (62%) children had a current prescription for a daily preventive asthma medication. Of these children, 110 (57%) had caregivers who reported complete concordance. Those reporting complete concordance were more likely to have children with greater symptom severity, including fewer symptom-free days in the prior two weeks (6.9 vs. 8.7, p = 0. 018), and >=1 asthma-related hospitalization in the prior year (16% vs. 6%, p = 0. 042). CONCLUSIONS: Medical records may poorly reflect actual home practices and providers should specifically inquire about medication use and barriers to adherence at the time of an office visit to promote guideline-based, consistent treatment for children with persistent asthma. PMID- 24404800 TI - Minimum prick test panel for adult patients with asthma and rhinitis in Ankara, Turkey. AB - OBJECTIVE: Determination of the number and type of allergens needed to be tested in epidemiological studies is important in order to identify most of the sensitized subjects with a cost-effective approach. This study aimed to investigate the minimum skin prick test panel for the identification of at least 95% of the sensitized subjects with symptoms of asthma and/or allergic rhinitis (AR) in Ankara, Turkey. METHODS: Skin prick test results of 7492 patients who were referred to our outpatient clinic with clinical symptoms of asthma and/or AR between 1991 and 2005 were evaluated retrospectively. Seven allergens were tested in all and 13 allergens in 4202 patients. The allergen group needed for detection of 95% of the sensitized subjects was determined for both the 7 and 13 allergen panels. The study protocol was approved by the local ethics committee of Hacettepe University. RESULTS: The atopy prevalences in the whole study population and in 4202 patients tested with the 13 allergen panel were calculated as 32.2% and 42.6%, respectively. Three allergens (Phleum pratense, Dermatophagoides pteronyssinus and Artemisia vulgaris) within the 7 allergen panel were adequate for the identification of at least 95% of the sensitized subjects. Olea europae was added to the previous three allergens when the 13 allergen panel was applied. CONCLUSION: Three to four allergens are sufficient for identification at least 95% of sensitized subjects with asthma and/or AR in Ankara, Turkey. PMID- 24404807 TI - Perceived distributed effort in team ball sports. AB - In this study, we explored the multifaceted concept of perceived mental and physical effort in team sport contexts where athletes must invest individual and shared efforts to reach a common goal. Semi-structured interviews were conducted with a convenience sample of 15 Catalan professional coaches (3 women and 12 men, 3 each from the following sports: volleyball, basketball, handball, soccer, and water polo) to gain their views of three perceived effort-related dimensions: physical, psychological, and tactical. From a theoretical thematic analysis, it was found that the perception of effort is closely related to how effort is distributed within the team. Moreover, coaches viewed physical effort in relation to the frequency and intensity of the players' involvement in the game. They identified psychological effort in situations where players pay attention to proper cues, and manage emotions under difficult circumstances. Tactical effort addressed the decision-making process of players and how they fulfilled their roles while taking into account the actions of their teammates and opponents. Based on these findings, a model of perceived distributed effort was developed, which delineates the elements that compose each of the aforementioned dimensions. Implications of perceived distributed effort in team coordination and shared mental models are discussed. PMID- 24404812 TI - Alteration of the microRNA expression profile during the activation of pancreatic stellate cells. AB - OBJECTIVE. Pancreatic stellate cells (PSCs) play a pivotal role in the pancreatic fibrosis associated with chronic pancreatitis and pancreatic cancer. In response to pancreatic injury or inflammation, PSCs are activated to myofibroblast-like cells. MicroRNA (miRNA) is a small RNA, consisting of 17-25 nucleotides, which targets 3'-untranslated region sequences of mRNA. miRNAs regulate a variety of cell functions such as cell proliferation, differentiation, and carcinogenesis. We examined here whether the miRNA expression profiles are altered during the activation of PSCs. MATERIALS AND METHODS. Rat PSCs were isolated from the pancreas tissue of male Wistar rats. PSCs were activated in vitro by culture in serum-containing medium. miRNAs were prepared from quiescent (day 1) PSCs and culture-activated (day 14) PSCs. Agilent's miRNA microarray containing probes for 680 miRNAs was used to identify differentially expressed miRNAs. Ingenuity Pathway Analysis (IPA) was used for the integrated analysis of altered miRNAs. RESULTS. Upon activation, 42 miRNAs were upregulated (>2.0-fold) and 42 miRNAs were downregulated (<0.5-fold). Upregulated miRNAs included miR-31, miR-143, and miR-221. Downregulated miRNAs included miR-126, miR-146a, and miR-150. IPA revealed the most impacted biological processes including cellular development, cellular growth, and cell movement. Interestingly, IPA identified 22 miRNAs affected both in pancreatic cancer and PSC activation. The top network generated by IPA revealed the interactions of altered miRNAs with signaling pathways such as p38 mitogen-activated protein kinase, extracellular-signal-regulated kinase, and Smad2/3. CONCLUSIONS. Our results suggest a novel role of miRNAs in the activation of PSCs. PMID- 24404813 TI - The role of reading on the health and well-being of people with neurological conditions: a systematic review. AB - OBJECTIVES: Little research has been conducted that investigates the benefits of reading for people with neurological conditions despite its age old use to improve well-being. The aim of this study was to identify and review the evidence of the effect of 'lone' reading, reading aloud and shared reading groups on the health and well-being of people with neurological conditions in clinical and long term care settings. METHODS: A literature search was conducted incorporating a systematic search of electronic databases, internet searching, 'snowballing' technique from references of relevant studies and consultation with clinicians and academics in the field. RESULTS: Twelve studies (five quantitative, three qualitative and four mixed methods) met the criteria for inclusion in the review. No randomised controlled trials were identified. Significant heterogeneity in the results of the quantitative studies precluded statistical data synthesis. Thematic analysis and synthesis was applied to the three qualitative studies and the qualitative data of the mixed-method studies. All but one of the quantitative studies reported that the reading interventions had a positive effect. The evidence from the qualitative studies demonstrated multiple positive effects of shared reading groups. CONCLUSIONS: The effect of 'lone' reading, reading aloud and shared reading groups on the health and well-being of people with neurological conditions is currently an under-researched area. Although this review reports encouraging results of positive effects, the results should be viewed with caution due to the lack of randomisation, the small numbers of participants involved, and the limited and heterogeneous evidence base. PMID- 24404814 TI - Delivering healthcare information via the internet: cardiac patients' access, usage, perceptions of usefulness, and web site content preferences. AB - OBJECTIVES: To assess patients' usage of the Internet as a source of personal healthcare information and patients' perceptions of usefulness and content preferences of more locally focused online health-related material. MATERIALS AND METHODS: A paper-based survey was undertaken by a convenience sample of cardiac outpatients. Age, gender, Internet access, Internet usage, perception of usefulness of online information, predicted intention to use a local cardiology Web site if available, and preferred components to be included were recorded. Univariate and bivariate statistics were used. RESULTS: Two hundred thirty-seven patients responded (62.1% males). One hundred seventy-six (74.3%) used the Internet, with 126 (63%) using it daily. For patients who did not have direct access to the Internet, 26 (50%) had a family member to do this on their behalf. Thus, the majority of patients (202 [85%]) had access to the Internet at home or someone who could access it on their behalf. Internet usage declined with age (Kendall's tau_b=0.321, p<0.001). There was no difference in use with gender (p=0.235). There was considerable interest expressed in a locally delivered Web based information service. CONCLUSIONS: Online healthcare information services have the potential to reach the vast majority of cardiac patients either directly or through family support. The most elderly patients are less likely to use these services. Despite apparent satisfaction with existing online resources, there appears to be an unmet need for more information and considerable support for a locally based cardiac patient Web resource to deliver this. These findings may help guide future patient information Web site redesign. PMID- 24404815 TI - Evaluating a speech-language pathology technology. AB - BACKGROUND: The creation of new educational strategies based on technology is the essence of telehealth. This innovative learning is an alternative to promote integration and improve the professional practices in speech-language pathology (SLP). The objective of this study was to evaluate an SLP technology designed for distance learning. MATERIALS AND METHODS: The survey selected fourth-year SLP students (n=60) from three public universities in the state of Sao Paulo, Brazil. The experimental group (EG) contained 10 students from each university (n=30), and the remaining students formed the control group (CG). Initially, both groups answered a preprotocol questionnaire, and the EG students received the technology, the recommendations, and the deadline to explore the material. In the second stage all students answered the postprotocol questionnaire in order to evaluate the validity and the learning of the technology contents. RESULTS: The comparison between the CG students showed that their performance worsened in the majority in comparison with the EG students, who showed an improved performance. CONCLUSIONS: Therefore, this study concluded that the technology instrument actually responded to the population studied and is recommended to complement traditional teaching. PMID- 24404817 TI - Hot spot: impact of July 2011 heat wave in southern Italy (Apulia) on cardiovascular disease assessed by emergency medical service and telemedicine support. AB - BACKGROUND: Heat waves have been reported as being associated with increased rates of hospitalizations and deaths. MATERIALS AND METHODS: In July 2011, a heat wave hit southern Italy. We enrolled 9,282 consecutive patients who called the Apulia (southeastern Italy) regional free public emergency medical service (EMS) "118" number (out of 4 million inhabitants) during July 2011. All patients were evaluated with a prehospital electrocardiogram (ECG) thanks to telecardiology support provided by a single telemedicine hub. Local temperatures and relative humidity were recorded and combined in order to calculate the heat index (HI), a more accurate parameter to assess perceived discomfort caused by hot temperatures. RESULTS: The mean number of calls to the telecardiology hub for prehospital ECG screening in the case of suspected heart disease was increased 48 h after days with an HI >= 44 (402 +/- 68 versus 275 +/- 52, p<0.001, +46%), when the number of calls was directly related to HI values (p < 0.01). ECG diagnoses of new-onset atrial fibrillation were significantly increased 24 h after days with an HI >= 44 (12 +/- 7 versus 8 +/- 3, p<0.01, +50%). ECG diagnoses of ST elevation acute myocardial infarction, in contrast, remained substantially unchanged. No significant gender or age (>70 versus <70 years) differences were observed (chi-squared p not significant); increased rates of EMS callings were found 48 h after days with an HI >= 44 in hypertensive patients (131 +/- 42 versus 78 +/- 26, p<0.001, +68%) and subjects with prior cardiovascular disease (137 +/- 43 versus 89 +/- 22, p<0.001, +54%). CONCLUSIONS: Increased work burden for EMS assessed with prehospital telecardiology screening accompanies heat waves because of subjects calling for suspected acute heart disease. Prehospital screening with telecardiology support may be of help in identifying subjects who do not require hospitalization in the event of heat waves with increased calls to EMS. PMID- 24404816 TI - A novel telemonitoring device for improving diabetes control: protocol and results from a randomized clinical trial. AB - BACKGROUND: Telemedicine is one approach to managing patients with chronic illness. Several telephone-based monitoring studies of diabetes patients have shown improved glycosylated hemoglobin (HbA1c), blood pressure (BP), and low density lipoprotein (LDL) levels. The purpose of this study was to evaluate an investigational in-home telemetry device for improving glucose and BP control over 6 months for patients with type 2 diabetes. The device was used to transmit weekly blood glucose, weight, and BP readings to a diabetes care manager. SUBJECTS AND METHODS: We conducted a two-arm, parallel-comparison, single-blind, randomized controlled trial among Kaiser Permanente Northern California members 18-75 years old with type 2 diabetes mellitus and entry HbA1c levels between 7.5% and 10.0%. Participants were randomly assigned to either the telemonitoring arm or the usual care arm. RESULTS: We observed very small, nonsignificant changes in fructosamine (telemonitoring, -54.9 MUmol; usual care, -59.4 MUmol) and systolic BP (telemonitoring, -6.3 mm Hg; usual care, -3.2 mm Hg) from baseline to 6 weeks in both groups. At 6 months, we observed no significant intergroup differences in change from baseline for HbA1c, fructosamine, or self-efficacy. However, LDL cholesterol in the telemonitoring arm decreased more than in the usual care arm ( 17.1 mg/dL versus -5.4 mg/dL; P=0.045). CONCLUSIONS: Although HbA1c improved significantly over 6 months in both groups, the difference in improvement between the groups was not significant. This lack of significance may be due to the relatively healthy status of the volunteers in our study and to the high level of care provided by the care managers in the Santa Rosa, CA clinic. Further study in subgroups of less healthy diabetes patients is recommended. PMID- 24404818 TI - Smart devices and a future of hybrid tobacco cessation programs. AB - The Internet and mobile "apps" on smart devices are increasingly being seen as primary tools to combat tobacco abuse with the development of several online tobacco cessation programs. This article reviews the small and recent body of research into the functionality and effectiveness of these Web-based programs, most of which are now being designed for mobile devices rather than for fixed computers. Based on current research findings, it is apparent that successful future tobacco cessation programs will utilize a wide variety of features available through smart devices and mobile applications, but will also incorporate the capacity to easily access live healthcare professionals as necessary, either online or in-person. These hybrid models of behavioral intervention for tobacco cessation appear likely to be more successful than previous approaches, but require more evaluation than has occurred in the past. PMID- 24404819 TI - Effect of home telemonitoring on glycemic and blood pressure control in primary care clinic patients with diabetes. AB - OBJECTIVE: Patient self-management support may be augmented by using home-based technologies that generate data points that providers can potentially use to make more timely changes in the patients' care. The purpose of this study was to evaluate the effectiveness of short-term targeted use of remote data transmission on treatment outcomes in patients with diabetes who had either out-of-range hemoglobin A1c (A1c) and/or blood pressure (BP) measurements. MATERIALS AND METHODS: A single-center randomized controlled clinical trial design compared in home monitoring (n=55) and usual care (n=53) in patients with type 2 diabetes and hypertension being treated in primary care clinics. Primary outcomes were A1c and systolic BP after a 12-week intervention. RESULTS: There were no significant differences between the intervention and control groups on either A1c or systolic BP following the intervention. CONCLUSIONS: The addition of technology alone is unlikely to lead to improvements in outcomes. Practices need to be selective in their use of telemonitoring with patients, limiting it to patients who have motivation or a significant change in care, such as starting insulin. Attention to the need for effective and responsive clinic processes to optimize the use of the additional data is also important when implementing these types of technology. PMID- 24404821 TI - Design and analysis of an implantable CPW-fed X-monopole antenna for 2.45-GHz ISM band applications. AB - A novel antenna design that effectively covers the industrial, scientific, and medical (ISM) band at 2.45 GHz using an X-shaped structure with a coplanar waveguide (CPW) feed is described. The antenna has a compact size of 67.6 mm(3). The proposed design is effective for ISM band biotelemetry with a wakeup controller (2.45 GHz). An experimental prototype of the compact implantable CPW fed X-shaped monopole antenna was fabricated on a biocompatible alumina Al2O3 ceramic substrate. The optimal antenna was fabricated and tested in minced tissue from the front leg of a pig and on a human body phantom liquid. The simulated and measured bandwidths are 180 MHz and 210 MHz in the ISM band, respectively. PMID- 24404820 TI - Self-assessment tool of disease activity of rheumatoid arthritis by using a smartphone application. AB - OBJECTIVES: The disease activities of rheumatoid arthritis (RA) tend to fluctuate between visits to doctors, and a self-assessment tool can help patients accommodate to their current status at home. The aim of the present study was to develop a novel modality to assess the disease activity of RA by a smartphone without the need to visit a doctor. SUBJECTS AND METHODS: This study included 65 patients with RA, 63.1 +/- 11.9 years of age. The 28-joint disease activity score (DAS28) was measured for all participants at each clinic visit. The patients assessed their status with the modified Health Assessment Questionnaire (mHAQ), a self-assessed tender joint count (sTJC), and a self-assessed swollen joint count (sSJC) in a smartphone application. The patients' trunk acceleration while walking was also measured with a smartphone application. The peak frequency, autocorrelation (AC) peak, and coefficient of variance of the acceleration peak intervals were calculated as the gait parameters. RESULTS: Univariate analyses showed that the DAS28 was associated with mHAQ, sTJC, sSJC, and AC (p<0.05). In a stepwise linear regression analysis, mHAQ (beta = 0.264, p<0.05), sTJC (beta = 0.581, p<0.001), and AC (beta = -0.157, p<0.05) were significantly associated with DAS28 in the final model, and the predictive model explained 67% of the DAS28 variance. CONCLUSIONS: The results suggest that noninvasive self-assessment of a combination of joint symptoms, limitations of daily activities, and walking ability can adequately predict disease activity of RA with a smartphone application. PMID- 24404822 TI - Psychometric properties of the Montreal Cognitive Assessment (MoCA): an analysis using the Rasch model. AB - In the present study we analyzed the psychometric characteristics of the MoCA (Portuguese version) using the Rasch model for dichotomous items. The total sample comprised of 897 participants distributed between two main subgroups: (I) healthy group that was comprised of 650 cognitively healthy community dwellers and (II) clinical group that was comprised of 90 patients with Mild Cognitive Impairment, 90 patients with Alzheimer's disease, 33 patients with frontotemporal dementia, and 34 patients with vascular dementia recruited at a reference dementia clinic. All patients were investigated through a comprehensive neuropsychological assessment, laboratory tests essential to exclude a reversible form of dementia, imaging studies (CT or MRI and SPECT or FDG-PET), Apolipoprotein E allele genotyping and CSF biomarker (Abeta42,Tau, and P-tau) analyses. The clinical diagnosis was established through the consensus of a multidisciplinary team, based on international criteria. The results demonstrated an overall good fit of both items and the person's values, a high variability on cognitive performance level, and a good quality of the measurements. The MoCA scores also demonstrated adequate discriminant validity, with high diagnostic value. DIF analyses indicated the generalized validity of the MoCA scores. In conclusion, the results of this study show the overall psychometric adequacy of the MoCA and verify the discriminant and generalized validity of the obtained results. PMID- 24404835 TI - Effects of endurance and high-intensity swimming exercise on the redox status of adolescent male and female swimmers. AB - Throughout adolescence, swimmers begin to carry out demanding endurance and high intensity training sets, the effect of which on redox status is largely unknown. The aim of the present study was to investigate the effects of 2000-m continuous swimming and 6 * 50-m maximal swimming on the redox status of adolescent swimmers. Fifteen male and 15 female swimmers, aged 14-18 years, provided blood samples before, immediately after, 1 h after, and 24 h after each exercise for the determination of redox status parameters. Oxidative damage was short-lived and manifest as increases in 8-hydroxy-2?-deoxyguanosine (8-OHdG) 1 h after high intensity exercise (39%, P < 0.001) and in malondialdehyde immediately after both exercises (65%, P < 0.001). Alterations in antioxidant parameters were sustained during recovery: reduced glutathione decreased 24 h post-exercise (11%, P = 0.001), uric acid increased gradually after high-intensity exercise (29%, P < 0.001) and bilirubin peaked 24 h post-exercise (29%, P < 0.001). Males had higher 8-OHdG (49%, P = 0.001) and uric acid (29%, P < 0.001) concentrations than females. However, females showed higher values of malondialdehyde than males immediately post-exercise (30%, P = 0.039), despite lower pre-exercise values. In conclusion, both endurance and high-intensity exercise perturbed the redox balance without inducing prolonged oxidative damage in trained adolescent male and female swimmers. These swimming training trials were not found to be detrimental to the redox homeostasis of adolescents. PMID- 24404836 TI - Editorial comment to RENAL nephrometry score is a predictive factor for the annual growth rate of renal mass. PMID- 24404837 TI - Saliva: a fluid of study for OMICS. AB - Saliva is a fluid that can be collected easily and noninvasively. Its functions in the oral cavity are well known. Advances in molecular biology and technology, as well as research conducted by the various disciplines of omics (genomics, transcriptomics, proteomics, metabolomics, and metagenomics) have contributed to the identification and characterization of salivary components, including DNA, RNA, proteins, metabolites, and microorganisms. These biomolecules enter the saliva through extracellular and intracellular routes, providing information from several organs and systems and raising the possibility of their use as disease biomarkers. In recent years, these factors have expanded the potential use of saliva as a diagnostic fluid for oral and systemic diseases. This review integrates information regarding salivary biomolecules studied through omics and explores their utility as biomarkers for the diagnosis of several infectious and noninfectious diseases, and the opportunity they represent for the development of point of care devices for clinical application. We also discuss the advantages, disadvantages, and challenges to be overcome in order to establish saliva as a useful fluid for the accurate diagnosis and monitoring of a wide range of diseases. PMID- 24404838 TI - An integrated approach (CLuster Analysis Integration Method) to combine expression data and protein-protein interaction networks in agrigenomics: application on Arabidopsis thaliana. AB - Experimental co-expression data and protein-protein interaction networks are frequently used to analyze the interactions among genes or proteins. Recent studies have investigated methods to integrate these two sources of information. We propose a new method to integrate co-expression data obtained through DNA microarray analysis (MA) and protein-protein interaction (PPI) network data, and apply it to Arabidopsis thaliana. The proposed method identifies small subsets of highly interacting proteins. Based on the analysis of the basis of co localization and mRNA developmental expression, we show that these groups provide important biological insights; additionally, these subsets are significantly enriched with respect to KEGG Pathways and can be used to predict successfully whether proteins belong to known pathways. Thus, the method is able to provide relevant biological information and support the functional identification of complex genetic traits of economic value in plant agrigenomics research. The method has been implemented in a prototype software tool named CLAIM (CLuster Analysis Integration Method) and can be downloaded from http://bio.cs.put.poznan.pl/research_fields . CLAIM is based on the separate clustering of MA and PPI data; the clusters are merged in a special graph; cliques of this graph are subsets of strongly connected proteins. The proposed method was successfully compared with existing methods. CLAIM appears to be a useful semi-automated tool for protein functional analysis and warrants further evaluation in agrigenomics research. PMID- 24404842 TI - Inoculation of the nonlegume Capsicum annuum (L.) with Rhizobium strains. 1. Effect on bioactive compounds, antioxidant activity, and fruit ripeness. AB - Pepper (Capsicum annuum L.) is an economically important agricultural crop and an excellent dietary source of natural colors and antioxidant compounds. The levels of these compounds can vary according to agricultural practices, like inoculation with plant growth-promoting rhizobacteria. In this work we evaluated for the first time the effect of the inoculation of two Rhizobium strains on C. annuum metabolites and bioactivity. The results revealed a decrease of organic acids and no effect on phenolics and capsaicinoids of leaves from inoculated plants. In the fruits from inoculated plants organic acids and phenolic compounds decreased, showing that fruits from inoculated plants present a higher ripeness stage than those from uninoculated ones. In general, the inoculation with Rhizobium did not improve the antioxidant activity of pepper fruits and leaves. Considering the positive effect on fruit ripening, the inoculation of C. annuum with Rhizobium is a beneficious agricultural practice for this nonlegume. PMID- 24404843 TI - The recovery process after day surgery within the symptom management theory. AB - PURPOSE: The aim was to illustrate two cases in a postoperative situation following day surgery within the framework of the symptom management theory. METHOD: Template analysis using the symptom management theory. RESULT: Neither the woman nor the man was able to return to their normal activities, health status or functional status, within a week. CONCLUSION: The results illustrate how a postoperative situation may involve personal suffering up to 3 months. PRACTICAL IMPLICATION: To obtain an outcome following day surgery, as optimal as possible, improving clinical practices and routines, such as discharge criteria, guidelines, and care pathways, is necessary. PMID- 24404844 TI - Citizen social science: a methodology to facilitate and evaluate workplace learning in continuing interprofessional education. AB - Workplace learning in continuing interprofessional education (CIPE) can be difficult to facilitate and evaluate, which can create a number of challenges for this type of learning. This article presents an innovative method to foster and investigate workplace learning in CIPE - citizen social science. Citizen social science involves clinicians as co-researchers in the systematic examination of social phenomena. When facilitated by an open-source online social networking platform, clinicians can participate via computer, smartphone, or tablet in ways that suit their needs and preferences. Furthermore, as co-researchers they can help to reveal the dynamic interplay that facilitates workplace learning in CIPE. Although yet to be tested, citizen social science offers four potential benefits: it recognises and accommodates the complexity of workplace learning in CIPE; it has the capacity to both foster and evaluate the phenomena; it can be used in situ, capturing and having direct relevance to the complexity of the workplace; and by advancing both theoretical and methodological debates on CIPE, it may reveal opportunities to improve and sustain workplace learning. By describing an example situated in the youth health sector, this article demonstrates how these benefits might be realised. PMID- 24404845 TI - Exploring new healthcare professionals' roles through interprofessional education. AB - This article presents findings from a simulation-based interprofessional education (IPE) program involving trainee advanced practice nurses (APNs) and internal medicine residents (IMRs) based in Singapore. Trainee APNs and IMRs participated in a semester-long series of high-fidelity simulations of medical emergencies. Learners' attitudes toward the IPE intervention were assessed using validated Likert scaled surveys and written comments. Overall satisfaction was high among learners, with strongly positive attitudes toward teamwork, collaboration and patient centredness. Of most interest, written comments highlight the utility of IPE in defining the professional scope and boundaries of APNs. Comments from both professions observed that participation in the IPE scenarios greatly aided their understanding of the scope and role of APN's practice within the health care team. This aspect of IPE may find further application in other similarly novel roles in healthcare. PMID- 24404847 TI - Interprofessional learning at work: what spatial theory can tell us about workplace learning in an acute care ward. AB - It is widely recognized that every workplace potentially provides a rich source of learning. Studies focusing on health care contexts have shown that social interaction within and between professions is crucial in enabling professionals to learn through work, address problems and cope with challenges of clinical practice. While hospital environments are beginning to be understood in spatial terms, the links between space and interprofessional learning at work have not been explored. This paper draws on Lefebvre's tri-partite theoretical framework of perceived, conceived and lived space to enrich understandings of interprofessional learning on an acute care ward in an Australian teaching hospital. Qualitative analysis was undertaken using data from observations of Registered Nurses at work and semi-structured interviews linked to observed events. The paper focuses on a ward round, the medical workroom and the Registrar's room, comparing and contrasting the intended (conceived), practiced (perceived) and pedagogically experienced (lived) spatial dimensions. The paper concludes that spatial theory has much to offer understandings of interprofessional learning in work, and the features of work environments and daily practices that produce spaces that enable or constrain learning. PMID- 24404849 TI - How to determine the size of folding nuclei of protofibrils from the concentration dependence of the rate and lag-time of aggregation. I. Modeling the amyloid protofibril formation. AB - The question about the size of nuclei of formation of protofibrils (which constitute mature amyloid fibrils) formed by different proteins and peptides is yet open and debatable because of the absence of solid knowledge of underlying mechanisms of amyloid formation. In this work, a kinetic model of the process of formation of amyloid protofibrils is suggested, which allows calculation of the size of the nuclei using only kinetic data. In addition to the stage of primary nucleation, which is believed to be present in many protein aggregation processes, the given model includes both linear growth of protofibrils (proceeding only at the cost of attaching of monomers to the ends) and exponential growth of protofibrils at the cost of growth from the surface, branching, and fragmentation with the secondary nuclei. Theoretically, only the exponential growth is compatible with the existence of a pronounced lag-period (which can take much more time then the growth of aggregates themselves). The obtained analytical solution allows us to determine the size of the primary and secondary nuclei from the experimentally obtained concentration dependences of the time of growth and the new parameter-the ratio Lrel of the lag-time duration to the time of growth of amyloid protofibrils. PMID- 24404850 TI - Prolonged mechanical ventilation in 540 seriously ill older adults: effects of increasing age on clinical outcomes and survival. AB - OBJECTIVES: To investigate effects of older age, comorbidities, and physiological measures on outcomes of elderly adults requiring prolonged mechanical ventilation (PMV). DESIGN: Retrospective cohort study. SETTING: Public long-term acute care hospital (LTACH) with an active program for ventilator weaning from PMV. PARTICIPANTS: Chronically seriously ill individuals with PMV aged 65 and older divided into six cohorts (65-69, 70-74, 75-79, 80-84, 85-89, >= 90) for comparative purposes (n = 540). MEASUREMENTS: Main outcomes were weaning criteria met, weaning success, discharge dispositions, and long-term survival. Other outcomes included weaning duration, LTACH days, discharge physical function, tracheostomy decannulation, and relapses to ventilator support. Weaning success was defined as 4 weeks or longer entirely free from mechanical ventilator support. RESULTS: The main finding from age cohort comparisons was that the likelihood of meeting weaning criteria (P = .001) and subsequent successful weaning (P = .002) decreased with age. Best predictors for weaning success in multivariable analysis were lower comorbidity burden (P < .001) and less-severe illness (P = .001). Other clinically important predictors were more-normal values in the respiratory physiology measures of rapid shallow breathing (P = .001) and static compliance (P = .003). Successful weaning was also associated with a 62% lower risk of death (P < .001). CONCLUSION: Although meeting weaning criteria and being successfully weaned decreased with increasing age, age was not the dominant factor in predicting outcomes. More importantly, individuals with PMV with better respiratory physiology and lower comorbidity burdens were more likely to be weaned and have longer survival, no matter their age. PMID- 24404853 TI - Male immunity to the chlamydial 60 kDa heat shock protein (HSP 60) - associated with semen quality? AB - The role of Chlamydia trachomatis for male infertility is a matter of constant debate. It is assumed that in its persistent form this pathogen may produce high levels of 60 kD heat shock protein (Chlam HSP60). Cross-reactivity between epitopes of the bacterial and human HSPs, involved in many steps of the reproductive process, might induce an autoimmune response with potential impairment of semen quality and sperm fertilising capacity. This prospective study included asymptomatic males of a total of 128 unselected subfertile couples (median duration of infertility 3 years) to determine the clinical relevance of male immunity to Chlam HSP60 during infertility investigation. After medical history and clinical examination of both partners, serum antibodies (Ab) to Chlam HSP60 were determined. Same day semen quality evaluation included microscopical standard sperm analysis, determination of seminal white blood cells (WBC) and of antisperm Ab (ASA) of the Ig G- and Ig-A class (mixed antiglobulin reaction, MAR), microbial screening and examination of sperm functional capacity. Sperm/mucus interaction was tested in vitro and in vivo. Simultaneously, patients' female partners were tested for Chlam HSP60 Ab and results were compared with a standard serology evaluation for antichlamydial IgG Ab. The presence of ChlamHSP60 Ab (positive in 24% of males) was not significantly associated with semen quality, seminal WBC and antisperm AB of the IgG- or Ig A class, the outcome of the microbial screening nor with sperm functional capacity and results of sperm/mucus interaction testing in vitro and in vivo. Chlam HSP60 Ab were significantly more frequent in female partners of Chlam HSP60 Ab-positive men, and results correlated with the outcome of standard chlamydial serology evaluation. In conclusion, when serum Chlam HSP60 Ab are used as marker, male immunity to the chlamydial 60 kD heat shock protein is not associated with semen quality, sperm functional capacity and other clinically relevant parameters of male fertility. PMID- 24404859 TI - Apatite-coated collagen sponge for the delivery of bone morphogenetic protein-2 in rabbit posterolateral lumbar fusion. AB - Bone morphogenetic proteins (BMPs) need an effective delivery system for efficient bone regeneration. In this study, we evaluated the efficiency of an apatite-coated collagen sponge for the long-term delivery of BMP-2 in a rabbit model of lumbar posterolateral fusion. A total of 15 rabbits, divided into three groups, underwent posterolateral lumbar fusion. The first group (control group) received uncoated collagen sponges without BMP-2. The second group (uncoated group) received uncoated collagen sponges with BMP-2 (40 MUg each side). The third group (apatite-coated group) received apatite-coated collagen sponges with the same level of BMPs (40 MUg each side). All rabbits were euthanized 6 weeks after operation, and the fusion status was assessed by radiographic study, micro CT, manual palpation, biomechanical study, and histological examination. Fusion rates as determined by radiographic study, micro-CT, and manual palpation showed that the apatite-coated group had a significantly higher rate of fusion than the control group (P = 0.024), while the uncoated group did not (P = 0.083). Biomechanical study showed significantly higher tensile strength in the apatite coated group than the uncoated group (P = 0.032). Denser trabeculations were found in the apatite-coated group compared with the uncoated group. It is concluded that the use of apatite-coated collagen sponges for BMP-2 delivery enhanced bone regeneration. PMID- 24404860 TI - Hormone-mediated maternal stress affects embryonic development during incubation without adverse effect on chick weight and body composition. AB - 1. The objective of this study was to evaluate the effect of maternal stress (MS) induced by supplementing the hen's diet with 2 mg/hen/d dietary corticosterone (CORT) on embryonic development, biochemical blood parameters and hatching performance of broiler chicks. 2. A total of 200 Ross broiler breeder hens at 42 weeks of age were randomly divided into two groups: MS or control. Hens in the MS were fed 2 mg/hen/d CORT for 14 d. Eggs (648 and 635 eggs for MS and control, respectively) were collected from d 3 to 14 of dietary CORT supplementation and incubated. Weights of embryo, chicks and organs and body composition were determined during incubation and at hatch. Biochemical blood parameters were measured at internal pipping stage and day of hatch. Hatching performance and embryonic mortalities were recorded. 3. Hens fed a diet supplemented with CORT had lighter body weight and produced less eggs at the end of the 14-d treatment period. Although MS embryos were heavier than control from 12 to 18 d of incubation, chick weight was similar at the day of hatch. Lower relative weights for yolk sac and bursa were observed at 12 d of incubation for MS chicks compared to control. Chicks from both groups had similar body content in spite of higher fat content of MS embryos on d 18 of incubation. 4. MS had no effect on the duration of incubation or hatching performance but increased mortality at the pipping stage. 5. The results suggest that hormone-mediated MS might affect embryonic development during incubation without adverse effect on chick weight and body composition. PMID- 24404861 TI - The influence of 2 weeks of low-volume high-intensity interval training on health outcomes in adolescent boys. AB - The present study aimed to establish whether 2 weeks of high-intensity interval training would have a beneficial effect on aerobic fitness, fat oxidation, blood pressure and body mass index (BMI) in healthy adolescent boys. Ten adolescent boys (15.1 +/- 0.3 years, 1.3 +/- 0.2 years post-estimated peak height velocity) completed six sessions of Wingate-style high-intensity interval training over a 2 week period. The first session consisted of four sprints with training progressed to seven sprints in the final session. High-intensity interval training had a beneficial effect on maximal O2 uptake (mean change, +/-90% confidence intervals: 0.19 L . min(-1), +/-0.19, respectively), on the O2 uptake at the gas exchange threshold (0.09 L . min(-1), +/-0.13) and on the O2 cost of sub-maximal exercise (-0.04 L . min(-1), +/-0.04). A beneficial effect on the contribution of lipid (0.06 g . min(-1), +/-0.06) and carbohydrate (-0.23 g . min(-1), +/-0.14) oxidation was observed during sub-maximal exercise, but not for the maximal rate of fat oxidation (0.04 g . min(-1), +/-0.08). Systolic blood pressure (1 mmHg, +/ 4) and BMI (0.1 kg . m2, +/-0.1) were not altered following training. These data demonstrate that meaningful changes in health outcomes are possible in healthy adolescent boys after just six sessions of high-intensity interval training over a 2-week period. PMID- 24404862 TI - Naturally occurring level of mixed aflatoxins B and G stimulate toll-like receptor-4 in bovine mononuclear cells. AB - BACKGROUND: As common contaminants of agricultural commodities, aflatoxins (AFs) are highly hazardous carcinogenic mycotoxins originating from very common fungi present in the environment. Their effect on bovine key immune-surveillance molecules is unclear. OBJECTIVE: To determine the in vitro effects of naturally occurring level of AFs on toll-like receptor-4 (TLR4) and viability in bovine peripheral blood mononuclear cells (PBMCs) as a model system for immunotoxicity. METHODS: Ten healthy dairy cows were selected as a source of PBMCs. The mRNA expression of TLR4 was quantitatively evaluated in PBMCs treated with a mix of 1.0, 0.5, 0.25 and 0.25 ng/ml of AFB1, AFB2, AFG1 and AFG2, respectively, and 10 ng/ml of the well-known TLR4 agonist lipopolysaccharide (LPS) for 0.5, 2, 5 and 18 hours. We also analyzed the viability of PBMCs exposed to AFs by means of the trypan blue exclusion method and the tetrazolium bromide assay. RESULTS: Compared with control PBMCs, transcription of TLR4 in AFs-treated PBMCs was significantly up-regulated at post-exposure hours (PEH) 2 and 5, but was unchanged at PEH 0.5 and 18. Unsurprisingly, much higher up-regulation of TLR4 transcript was observed in LPS-treated PBMCs at PEH 0.5, 2, 5 and 18. Conversely, the viability of post AFs and/or LPS-exposed PBMCs revealed no significant changes. CONCLUSION: Naturally occurring levels of AFs result in increased expression of TLR4 mRNA in bovine PBMCs. CLINICAL IMPORTANCE: The increased expression of TLR4 mRNA in bovine PBMCs by AFs also emphasizes the need to reduce admissible levels of AFs in feed for preventive measures. PMID- 24404863 TI - Editorial comment from Dr Shiota to Prognostic impact of young age on stage IV prostate cancer treated with primary androgen deprivation therapy. PMID- 24404864 TI - Inhibitory effects of the leaves of loquat (Eriobotrya japonica) on bone mineral density loss in ovariectomized mice and osteoclast differentiation. AB - The loquat, Eriobotrya japonica Lindl. (Rosaceae), is a small tree native to Japan and China that is widely cultivated for its succulent fruit. Its leaves are used as an ingredient of a tasty tea called "Biwa cha" in Japanese. The anti osteoporosis effects of the leaves of loquat in vitro and in vivo have been investigated. After 15 days of feeding normal diet or diet supplemented with 5% loquat leaves, the body weight, viscera weights, and bone mineral density (BMD) of both groups of eight ovariectomized (OVX) mice were compared. The result showed that the loss of BMD in loquat-fed mice was significantly prevented in three parts of the body, especially in the trabecular bone of the head (P < 0.05), abdomen (P < 0.01), and lumbar (P < 0.05) compared to the control group. No hypertrophy in the uterus by the loquat leaves diet was observed. The effect of the extract (447.25 g) prepared from the dried leaves of loquat (2.36 kg) was further studied on RANKL-induced osteoclast differentiation and cell viability. The extract suppressed the differentiation of osteoclasts under 50, 125, 250, and 500 MUg/mL. Through bioactivity-guided fractionation, ursolic acid (1) was isolated and inhibited osteoclast differentiation under 4 and 10 MUg/mL. It was concluded that loquat leaves possess the potential to suppress ovariectomy induced bone mineral density deterioration. PMID- 24404865 TI - Revealing the adsorption mechanisms of nitroxides on ultrapure, metallicity sorted carbon nanotubes. AB - Carbon nanotubes are a natural choice as gas sensor components given their high surface to volume ratio, electronic properties, and capability to mediate chemical reactions. However, a realistic assessment of the interaction of the tube wall and the adsorption processes during gas phase reactions has always been elusive. Making use of ultraclean single-walled carbon nanotubes, we have followed the adsorption kinetics of NO2 and found a physisorption mechanism. Additionally, the adsorption reaction directly depends on the metallic character of the samples. Franck-Condon satellites, hitherto undetected in nanotube-NOx systems, were resolved in the N 1s X-ray absorption signal, revealing a weak chemisorption, which is intrinsically related to NO dimer molecules. This has allowed us to identify that an additional signal observed in the higher binding energy region of the core level C 1s photoemission signal is due to the C ? O species of ketene groups formed as reaction byproducts . This has been supported by density functional theory calculations. These results pave the way toward the optimization of nanotube-based sensors with tailored sensitivity and selectivity to different species at room temperature. PMID- 24404866 TI - Liposomes co-modified with cholesterol anchored cleavable PEG and octaarginines for tumor targeted drug delivery. AB - Tumor targeted drug delivery system with high efficiency of tumor accumulation, cell internalization and endosomal escape was considered ideal for cancer therapy. Herein, a cleavable polyethylene glycol (PEG) and octaarginines (R8) co modified liposome (CL-R8-LP) was developed, in which the cholesterol was used as an alternative anchor to the commonest phospholipids for the diversified development of surface modification. The in vitro hemolysis assay and bio distribution study demonstrated that CL-R8-LP improved biocompatibility and tumor accumulation compared with the single R8 modified liposomes (R8-LP), since the strong positive charges, toxicity and non-specificity of R8 were efficiently shielded by the outer cleavable PEG. And the cellular uptake, cytotoxicity and apoptosis of CL-R8-LP on C26 cells were much stronger than that of control liposomes in which R8 was not included or exposed. In addition, it was confirmed that CL-R8-LP entered cells via clathrin-mediated endocytosis and the macropinocytosis, and followed by a more efficient endosomal escape compared with R8-LP due to the topology change of R8. The enhanced in vivo delivery efficiency and anti-tumor efficacy were validated in C26 bearing mice. In conclusion, the results demonstrated that CL-R8-LP was a promising vehicle for enhancing the chemotherapy of solid cancers. PMID- 24404869 TI - Effects of 254 nm UV irradiation on the mobility and survival of larvae of the invasive fouling mussel Limnoperna fortunei. AB - In order to investigate the feasibility of using ultraviolet (UV) irradiation to prevent the invasive Asian mussel, Limnoperna fortunei, from colonizing components of the cooling systems of industrial and power plants, the mobility and mortality of its larvae were assessed after exposure to different doses of UVC (lambda = 254 nm) in laboratory conditions. Total (100%) mortality was achieved with a dose of 149 mJ cm(-2) at 23 degrees C and 103 mJ cm(-2) at 25.8 degrees C. Immediately after exposure, larvae were alive but had reduced mobility. The proportion of active larvae increased after 24 h, but fell again at 48 and 72 h to levels similar to those immediately after exposure. The highest mortality rates were always recorded at the last observation, 72 h after exposure. These results indicate that the larvae of L. fortunei are highly sensitive to UVC, suggesting that UV irradiation has the potential to control fouling by this mussel when the water is relatively clear. However, application of UV-based technologies in plants that use cooling water from water bodies with high loads of suspended solids (eg the Parana-Uruguay basin, with ca 160 mg l(-1) of suspended solids and absorbance values around 0.255) is unlikely to be effective without prior filtration of the water. PMID- 24404871 TI - Prolonged remission of Paget disease of the vulva after chemotherapy for breast carcinoma. PMID- 24404872 TI - pKa determination of D-ribose by Raman spectroscopy. AB - Determination of the pKa of OH groups present in D-ribose is crucial in order to elucidate the origin and mechanism of many catalytic processes that involve the ribose unit. However, there is hardly any reports about the experimental pKa of the OH group due to the lack of an appropriate method. In this study we investigated the protonation state of OH groups in D-ribose by introducing C-D labeling and measuring the changes in the isolated C-D frequency in several isotopologues of the compound with pH. The large shift in the nuC-D of D-ribose C1-D in ionized condition compared to other deuterium-substituted D-riboses (e.g., D-ribose-C2-D, D-ribose-C3-D, etc.) confirmed that the C1-OH group preferred ionization, and the ionization pKa was 11.8. Both the ionized and the unionized structures of D-ribose preferred the pyranose conformation, which was supported by (13)C NMR experiments. Electronic redistribution via resonance and intramolecular hydrogen-bond formation were proposed to account for the stabilization of the ionized structure. PMID- 24404875 TI - CBCT Morphologic Analysis of Edentulous Posterior Mandible for Mandibular Body Bone Graft. PMID- 24404874 TI - Levine's Conservation Model: A Framework for Advanced Gerontology Nursing Practice. AB - PURPOSE: Growing numbers of older adults place increased demands on already burdened healthcare systems. The cost of managing chronic illnesses mandates greater emphasis on management and prevention. This article explores the adaptation of Levine's Conservation Model as a structure for providing care to the older adult by the adult-gerontology primary care nurse practitioner (AGNP). CONCLUSION: The AGNP role, designed to provide quality care to adult and older adult populations, offers the opportunity to not only manage health care of the elderly, but to also advocate, lead in collaborative care efforts, conduct advanced planning, and manage and negotiate health delivery systems. The use of nursing models can foster the design of effective interventions that promote health of the older adult, particularly in the long-term care environment. PRACTICE IMPLICATION: Levine's Conservation Model provides a useful structure for older adult care in the long-term care setting. As an ideal care manager, the AGNP would be well served to consider use of the model to guide advanced nursing practice. Recommendations for clinical practice, research, and health policy. PMID- 24404878 TI - Effects of photoperiod on broodiness, egg-laying and endocrine responses in native laying hens. AB - 1. The effects of photoperiod on broodiness, egg-laying and endocrine responses in native laying hens were investigated. A total of 648, 18-week-old native laying hens (Beijing You Chicken, BYC) were randomly allocated to 6 groups with 3 replicates. The birds were exposed to 1 of 6 different photoperiods, including 16L:8D (06:00 to 22:00 h) for group 1; 12L:2D:4L:6D for group 2; 8L:4D:4L:8D for group 3; 16L:8D (03:00 to 19:00 h) for group 4; 14L:10D for group 5; and 18L:6D for group 6. 2. The broodiness rate and egg-laying rate for weeks 20-26, 27-33, 34-40, 41-47, 48-54 and 55-61 were calculated, and serum prolactin (PRL), luteinising hormone (LH), 17-beta-oestradiol (E2), melatonin (Mel) and progesterone (P4) concentrations were measured at the end of each stage. 3. Significant effects were observed on the rate of broodiness by the photoperiod and stage, but the interaction of photoperiod and stage was not significant. The rate of broodiness for group 3 (5.9%) was significantly higher than other groups, with group 2 being the lowest (2.8%). Broodiness rate was the highest for weeks 41-47 (9.9%). Significant effects were observed on average egg-laying rate by photoperiod and stage: the rate of egg-laying of groups 2 and 5 were significantly higher than groups 1, 4 and 6. 4. There were no significant effects of photoperiod on PRL, LH and Mel concentrations at 26, 33, 40 and 54 weeks of age (P > 0.05), but at 47 weeks of age, PRL and LH concentrations of group 1 were significantly lower than those in other groups. 5. The study suggests that the photoperiod of group 2 (12L:2D:4L:6D) is optimal for the birds' performance to give the lowest broodiness rate and the highest egg-laying rate during the whole laying period, and 41-47 weeks may be a key stage for the photomodulation of broodiness. PMID- 24404879 TI - Synchronized pulsatile speed control of turbodynamic left ventricular assist devices: review and prospects. AB - Turbodynamic blood pumps are used clinically as ventricular assist devices (VADs). They are mostly operated at a constant rotational speed, which results in a reduced pulsatility. Previous research has analyzed pulsing pump speeds (speed modulation) to alter the interaction between the cardiovascular system and the blood pump. In those studies, sine- or square-wave speed profiles that were synchronized to the natural cardiac cycle were analyzed in silico, in vitro and in vivo. The definitions of these profiles with respect to both timing and speed levels vary among different research groups. The current paper provides a definition of the timing of these speed profiles such that the resulting hemodynamic effects become comparable. The results published in the literature are summarized and compared using this definition. Further, applied to a turbodynamic VAD, a series of measurements is conducted on a hybrid mock circulation using a constant speed as well as different types of square-wave speed profiles and a sine-wave speed profile. When a consistent definition of the timing of the speed profiles is used, the hemodynamic effects observed in previous work are in agreement with the measurement data obtained for the current paper. These findings allow the conclusion that the speed modulation of turbodynamic VADs represents a consistent tool to systematically change the ventricular load and the pulsatility in the arterial tree. The timing that yields the minimal left ventricular load also yields the minimal arterial pulse pressure. PMID- 24404882 TI - How does knee pain affect trunk and knee motion during badminton forehand lunges? AB - Badminton requires extensive lower extremity movement and a precise coordination of the upper extremity and trunk movements. Accordingly, this study investigated motions of the trunk and the knee, control of dynamic stability and muscle activation patterns of individuals with and without knee pain. Seventeen participants with chronic knee pain and 17 healthy participants participated in the study and performed forehand forward and backward diagonal lunges. This study showed that those with knee pain exhibited smaller knee motions in frontal and horizontal planes during forward lunge but greater knee motions in sagittal plane during backward lunge. By contrast, in both tasks, the injured group showed a smaller value on the activation level of the paraspinal muscles in pre-impact phase, hip-shoulder separation angle, trunk forward inclination range and peak centre of mass (COM) velocity. Badminton players with knee pain adopt a more conservative movement pattern of the knee to minimise recurrence of knee pain. The healthy group exhibit better weight-shifting ability due to a greater control of the trunk and knee muscles. Training programmes for badminton players with knee pain should be designed to improve both the neuromuscular control and muscle strength of the core muscles and the knee extensor with focus on the backward lunge motion. PMID- 24404886 TI - The impact of amelogenesis imperfecta and support needs of adolescents with AI and their parents: an exploratory study. AB - BACKGROUND: Amelogenesis imperfecta (AI) is a rare inherited dental defect where enamel does not form properly on the teeth. Research has shown that adolescents with AI may experience adverse psychosocial effects; however the impact on parents has not been explored. AIMS: We aimed to explore: (1) experience and perceptions of AI from both the adolescent and their parent's perspective (2) their views on the usefulness of an online support group (OSG) for patients/parents and the potential salient functions of such a resource. DESIGN: We conducted two focus groups; one for adolescent AI patients and one for their parents. Transcripts were analysed using Thematic Analysis. RESULTS: Three themes emerged from the data: 'Living with AI: Do I look bothered?', 'Need for the 'right' online environment' and 'Support needs: Information and beyond'. CONCLUSIONS: The adolescents did not appear to experience adverse psychosocial effects of having AI, which was contrary to their parents' perceptions. Parents reported some adverse consequences of having a child with AI (e.g., practical challenges). If an OSG was to be developed, it would need to be primarily information based and moderated by an AI specialist. Parents may benefit from additional support beyond that of information, such as emotional and tangible support. PMID- 24404887 TI - Canine mesenchymal stem cells: state of the art, perspectives as therapy for dogs and as a model for man. AB - Interest in mesenchymal stem cells (MSCs) both for regenerative and reparative therapies in dogs is emerging, as the current treatment options for several conditions often do not result either in the desired clinical outcome or in the patients' return to normal function. In addition, canine MSCs have been evaluated in some experimental and preclinical studies on efficacy and safety testing of novel treatments for humans, since the dog is considered to be a superior model for humans than rodents. Although these MSCs can be derived from several sources, clinical use has favoured bone marrow and adipose tissue because of their relative ease of stem cell recovery and the minimal donor-site morbidity. Before any type of stem cell can be applied clinically, its unequivocal characterization by a set of specific functional or phenotypic markers is crucial. However, no uniform characterization criteria are available for canine MSCs so far. Moreover, although multi-lineage potential of canine MSCs has been demonstrated in a limited number of studies, research on the differentiation potential of MSCs towards tenocytes is still lacking in canine medicine. In contrast, this latter subject has been explored already in human as well as in equine medicine, demonstrating the need for a specific 'niche', i.e. factors with a positive influence on the MSC differentiation. Since most of these factors are still unknown regarding canine MSC, critical basic knowledge is urgently required to motivate and correctly translate the potential therapeutic applications of these stem cells in both dog and man. PMID- 24404888 TI - Quantification of high-efficiency trapping of nanoparticles in a double nanohole optical tweezer. AB - We measure the dynamics of 20 nm polystyrene particles in a double nanohole trap to determine the trap stiffness for various laser powers. Both the autocorrelation analysis of Brownian fluctuations and the trapping transient analysis provide a consistent value of ~ 0.2 fN/nm stiffness for 2 mW of laser power, which is similar to theoretical calculations for aperture trapping. As expected, the stiffness increases linearly with laser power. This is comparable to the stiffness obtained for conventional optical traps for trapping, but for ten times smaller dielectric particles and less power. This approach will allow us to quantitatively evaluate future aperture-based optical traps, with the goal of studying the folding dynamics of smaller proteins (~ 10 kDa) and small molecule interactions. PMID- 24404889 TI - Mussel-inspired direct immobilization of nanoparticles and application for oil water separation. AB - Immobilization of various nanoparticles onto complex 2D or 3D macroscopic surface is an important issue for nanotechnology, but the challenge remains to explore a facile, general and environmentally friendly method for achieving this goal. Taking inspiration from the adhesion of marine mussels, we reported here that oxide nanoparticles of different compositions and sizes were directly and robustly anchored on the surface of monolithic foams ranging from polymer to metals in an aqueous solution of dopamine. The effective immobilization of the nanoparticles was strongly dependent on the oxidation of dopamine, which could be tuned by either pH or by adding n-dodecanethiol. Interestingly, the thiol addition not only allowed the immobilization to take place in a wide pH range, but also led to superhydrophobicity of the resulting foams. Application of the superhydrophobic foams was illustrated by fast and selective collecting oils from water surface. Because catecholic derivatives exhibit high affinity to a variety of substances, the present strategy might be extendable to fabricate hybrid nanomaterials desirable for self-cleaning, environmental protection, sensors and catalysts, and so forth. PMID- 24404892 TI - Oral administration of Lactobacillus fermentum I5007 favors intestinal development and alters the intestinal microbiota in formula-fed piglets. AB - The present study was conducted to evaluate the effects of early administration of Lactobacillus fermentum I5007 on intestinal development and microbial composition in the gastrointestinal tract using a neonatal piglet model. Full term 4 day old piglets, fed with milk replacer, were divided into a control group (given placebo of 0.1% peptone water) and a L. fermentum I5007 group (dosed daily with 6 * 10(9) CFU/mL L. fermentum I5007). The experiment lasted 14 days. On day 14, a significant increase in the jejunum villous height (583 +/- 33 vs 526 +/- 18) and increases in the concentrations of butyrate (7.55 +/- 0.55 vs 5.33 +/- 0.39) and branched chain fatty acids in the colonic digesta were observed in piglets in the L. fermentum I5007 treatment (P < 0.05). mRNA expression of IL 1beta (1.29 +/- 0.29 vs. 0.62 +/- 0.07) in the ileum were lower after 14 days of treatment with L. fermentum I5007. Denaturing gradient gel electrophoresis (DGGE) revealed that L. fermentum I5007 affected the colonic microbial communities on day 14 and, in particular, reduced numbers of Clostridium sp. L. fermentum I5007 play a positive role in gut development in neonatal piglets by modulating microbial composition, intestinal development, and immune status. L. fermentum I5007 may be useful as a probiotic for application in neonatal piglets. PMID- 24404893 TI - Impact of the exopolysaccharides Pel and Psl on the initial adhesion of Pseudomonas aeruginosa to sand. AB - In this study, the impact of the exopolysaccharides Pel and Psl on the cell surface electron donor-electron acceptor (acid-base) properties and adhesion to quartz sand was investigated by using Pseudomonas aeruginosa PAO1 and its isogenic EPS-mutant strains Deltapel, Deltapsl and Deltapel/Deltapsl. The microbial adhesion to hydrocarbon (MATH) test and titration results showed that both Pel and Psl contribute to the surface hydrophobicity of the cell. The results of contact angle measurement, however, showed no correlation with the cell surface hydrophobicity measured by the MATH test and the titration method. Packed-bed column experiments indicated that the exopolysaccharides Pel and Psl are involved in the initial cell attachment to the sand surface and the extent of their impact is dependent on the ionic strength (IS) of the solution. Overall, the Deltapel/Deltapsl double mutant had the lowest adhesion coefficient to sand compared with the wild-type PAO1, the Deltapel mutant and the Deltapsl mutant. It is hypothesized that in addition to bacterial surface hydrophobicity and DLVO forces, other factors, eg steric repulsion caused by extracellular macromolecules, and cell surface appendages (flagella and pili) also contribute significantly to the interaction between the cell surface and a sand grain. PMID- 24404894 TI - Social problem-solving, perceived stress, negative life events, depression and life satisfaction in psoriasis. AB - BACKGROUND: Psoriasis is a chronic dermatosis which may cause significant impairment of the patient's quality of life. OBJECTIVE: The purpose of this study was to investigate the social problem-solving skills, perceived stress, negative life events, depression and life satisfaction in psoriasis patients. METHODS: Data were gathered by means of questionnaires and clinical evaluations from 51 psoriatic patients and 51 matched healthy controls. RESULTS: Average disease duration was 16.47 years and average Psoriasis Area and Severity Index score was 3.67. Compared with the controls, the patients displayed lower social problem solving skills. They displayed higher negative problem orientation and impulsive careless problem-solving style scores than the controls. Patients tended also to show more avoidant problem-solving style and lower life satisfaction than controls. There was no difference between psoriatic patients and controls in terms of depression, perceived stress and negative life events. Higher social problem-solving skills were associated with lower depression, perceived stress and fewer numbers of negative life events but higher level of life satisfaction. LIMITATIONS: The patient group largely included mild and moderate psoriatic cases. CONCLUSION: The findings of the study suggest that problem-solving training or therapy may be a suitable option for alleviating levels of psychological distress in patients suffering from psoriasis. PMID- 24404896 TI - Neonatal Fc receptor (FcRn): a novel target for therapeutic antibodies and antibody engineering. AB - The biomedical applications of antibodies as prophylactics, therapeutics and diagnostics are developing rapidly. Neonatal Fc receptor (FcRn) is a major IgG Fc receptor capable of facilitating the translocation of IgG. FcRn can protect IgG from intracellular catabolism, thereby increasing its half-life. In recent decade, the interaction between FcRn and the Fc region has been reported with the focuses on either prolonging the plasma half-life of therapeutic IgG or shortening the half-life of pathogenic IgG. The FcRn-IgG interaction can be altered by modifying the Fc region to change their affinity (increase or decrease), and/or by reducing the Fc fragments of IgG to enhance its penetration into tissues or cells. By over expression of FcRn, the exogenous catabolism can be reduced, meanwhile the circulating IgG level could be enhanced. It has been confirmed in different FcRn over-expressed transgenic mice models, substantial humoral responses against antigens with weak immunogenicity can be mounted. In addition, designing inhibitors for FcRn-IgG interaction is another application prospect for treating IgG-mediated autoimmune diseases. Recent research advancements strengthen the understanding that FcRn is a key and promising drugable target in IgG intervention in the field of antibody engineering. PMID- 24404897 TI - The dermatology outpatient discharge decision: understanding a critical but neglected process. AB - Discharge from dermatology outpatients is a critical endpoint of patient care. Despite this, there has been very little research concerning the discharge process and factors influencing the discharge decision. To identify the factors influencing discharge decisions, articles from 1970 to April 2013 were searched in MEDLINE via Ovid, CINAHL, PROQUEST and Google Scholar using the keywords 'patient discharge', 'discharge decision', 'factors influencing discharge', 'clinical decision making', 'discharge decision making', 'process of discharge decision', 'outpatient', 'follow up', 'skin disease' and 'dermatology'. Only articles describing outpatient discharge decisions were included. Seventeen outpatient discharge articles were identified, 12 from the U.K. (seven dermatology) and five from the U.S.A., Canada, Australia and Taiwan (all nondermatology). The main influences on outpatient discharge identified were diagnosis and disease severity, clinician's level of experience and perception, patient's preferences, patient's behaviour and quality of life. These influences affected the clinician's judgement on discharge decisions both in appropriate and in inappropriate ways. Little is known concerning discharge decision making in dermatology. Given the central importance of such decisions in the appropriate care of patients and the efficient running of any dermatology service, greater understanding of the influences on discharge decision making is needed. It is therefore critical for dermatologists to be aware of these influences and to ensure that decisions are taken only in the best interests of patients. Further research is required to inform the training of dermatologists on how to take the most appropriate discharge decisions. PMID- 24404898 TI - Nurse Practitioner Role Transition: A Concept Analysis. AB - AIM: A concept analysis of nurse practitioner (NP) role transition. BACKGROUND: The Affordable Care Act is expected to provide 32 million Americans with health insurance, and NPs are gaining attention in addressing this increasing demand for healthcare providers. However, there is limited analysis of the transition from registered nurse to NP. Oftentimes, during this transition, there is a shift from an experienced, expert status to an inexperienced, novice status, with a subsequent loss of confidence in one's ability and competence. This can hinder successful role development and affect employment continuity within the first year of practice. METHODS AND SOURCES: NP role transition was examined using Walker and Avant's method of concept analysis. Electronic databases were searched using the terms role transition and nurse practitioner. Thirty articles from nursing, psychology, and business were included. FINDINGS AND CONCLUSIONS: The four defining attributes of NP role transition are absorption of the role, the shift from provider of care to prescriber of care, straddling two identities, and mixed emotions. Personal and environmental antecedents and consequences of the concept are identified. The development of empirical knowledge on NP role transition through further research is important in order for new-to-practice NPs to become high-quality, full-functioning providers. PMID- 24404899 TI - Phosphorus binding sites in proteins: structural preorganization and coordination. AB - Phosphorus is a ubiquitous element of the cell, which is found throughout numerous key molecules related to cell structure, energy and information storage and transfer, and a diverse array of other cellular functions. In this work, we adopt an approach often used for characterizing metal binding and selectivity of metalloproteins in terms of interactions in a first shell (direct residue interactions with the metal) and a second shell (residue interactions with first shell residues) and use it to characterize binding of phosphorus compounds. Similar analyses of binding have previously been limited to individual structures that bind to phosphate groups; here, we investigate a total of 8307 structures obtained from the RCSB Protein Data Bank (PDB). An analysis of the binding site amino acid propensities reveals very characteristic first shell residue distributions, which are found to be influenced by the characteristics of the phosphorus compound and by the presence of cobound cations. The second shell, which supports the coordinating residues in the first shell, is found to consist mainly of protein backbone groups. Our results show how the second shell residue distribution is dictated mainly by the first shell of the binding site, especially by cobound cations and that the main function of the second shell is to stabilize the first shell residues. PMID- 24404900 TI - Clinical proteomics in obstetrics and neonatology. AB - Clinical proteomics has been applied to the identification of biomarkers of obstetric and neonatal disease. We will discuss a number of encouraging studies that have led to potentially valid biomarkers in the context of Down's syndrome, preterm birth, amniotic infections, preeclampsia, intrauterine growth restriction and obstructive uropathies. Obtaining noninvasive biomarkers (e.g., from the maternal circulation, urine or cervicovaginal fluid) may be more feasible for obstetric diseases than for diseases of the fetus, for which invasive methods are required (e.g., amniotic fluid, fetal urine). However, studies providing validated proteomics-identified biomarkers are limited. Efforts should be made to save well-characterized samples of these invasive body fluids so that many valid biomarkers of pregnancy-related diseases will be identified in the coming years using proteomics based analysis upon adoption of 'clinical proteomics guidelines'. PMID- 24404902 TI - p-type CuRhO2 as a self-healing photoelectrode for water reduction under visible light. AB - Polycrystalline CuRhO2 is investigated as a photocathode for the splitting of water under visible irradiation. The band edge positions of this material straddle the water oxidation and reduction redox potentials. Thus, photogenerated conduction band electrons are sufficiently energetic to reduce water, while the associated valence band holes are energetically able to oxidize water to O2. Under visible illumination, H2 production is observed with ~0.2 V underpotential in an air-saturated solution. In contrast, H2 production in an Ar-saturated solution was found to be unstable. This instability is associated with the reduction of the semiconductor forming Cu(s). However, in the presence of air or O2, bulk Cu(s) was not detected, implying that CuRhO2 is self-healing when air is present. This property allows for the stable formation of H2 with ca. 80% Faradaic efficiency. PMID- 24404901 TI - "Sliding Full-Thickness Pedicle Flap" for Primary Wound Closure of the Socket Preservation Site. PMID- 24404903 TI - Is uremic cardiomyopathy a direct consequence of chronic kidney disease? AB - Heart failure is a major cause of morbidity and mortality in chronic kidney disease (CKD). Rather than merely secondary to traditional vascular factors, CKD is also an independent risk factor for heart failure, termed uremic cardiomyopathy (UCM). Echocardiography commonly reveals structural left ventricular hypertrophy in CKD, without clarifying whether it is adaptive or maladaptive. Corresponding functional assessments have been mostly conducted at rest. To unravel the extents and mechanisms UCM, a next step involves the adoption of direct measurements of CKD-induced cardiac pumping incapacity at peak exercise. This could potentially lead to future novel interventions to ameliorate or reverse UCM. PMID- 24404904 TI - Experimental measurements of energy augmentation for mechanical circulatory assistance in a patient-specific Fontan model. AB - A mechanical blood pump specifically designed to increase pressure in the great veins would improve hemodynamic stability in adolescent and adult Fontan patients having dysfunctional cavopulmonary circulation. This study investigates the impact of axial-flow blood pumps on pressure, flow rate, and energy augmentation in the total cavopulmonary circulation (TCPC) using a patient-specific Fontan model. The experiments were conducted for three mechanical support configurations, which included an axial-flow impeller alone in the inferior vena cava (IVC) and an impeller with one of two different protective stent designs. All of the pump configurations led to an increase in pressure generation and flow in the Fontan circuit. The increase in IVC flow was found to augment pulmonary arterial flow, having only a small impact on the pressure and flow in the superior vena cava (SVC). Retrograde flow was neither observed nor measured from the TCPC junction into the SVC. All of the pump configurations enhanced the rate of power gain of the cavopulmonary circulation by adding energy and rotational force to the fluid flow. We measured an enhancement of forward flow into the TCPC junction, reduction in IVC pressure, and only minimally increased pulmonary arterial pressure under conditions of pump support. PMID- 24404905 TI - Stable U(IV) complexes form at high-affinity mineral surface sites. AB - Uranium (U) poses a significant contamination hazard to soils, sediments, and groundwater due to its extensive use for energy production. Despite advances in modeling the risks of this toxic and radioactive element, lack of information about the mechanisms controlling U transport hinders further improvements, particularly in reducing environments where U(IV) predominates. Here we establish that mineral surfaces can stabilize the majority of U as adsorbed U(IV) species following reduction of U(VI). Using X-ray absorption spectroscopy and electron imaging analysis, we find that at low surface loading, U(IV) forms inner-sphere complexes with two metal oxides, TiO2 (rutile) and Fe3O4 (magnetite) (at <1.3 U nm(-2) and <0.037 U nm(-2), respectively). The uraninite (UO2) form of U(IV) predominates only at higher surface loading. U(IV)-TiO2 complexes remain stable for at least 12 months, and U(IV)-Fe3O4 complexes remain stable for at least 4 months, under anoxic conditions. Adsorbed U(IV) results from U(VI) reduction by Fe(II) or by the reduced electron shuttle AH2QDS, suggesting that both abiotic and biotic reduction pathways can produce stable U(IV)-mineral complexes in the subsurface. The observed control of high-affinity mineral surface sites on U(IV) speciation helps explain the presence of nonuraninite U(IV) in sediments and has important implications for U transport modeling. PMID- 24404906 TI - Ipriflavone reverses the adverse effects of a low-calcium diet on the histology of the tibia in caged layers. AB - 1. Ipriflavone (IP) has been widely studied in humans and is effective for inhibiting osteoclastic bone resorption and enhancing osteoblastic bone formation. The aim of this study was to investigate the effects of IP on the structural histology and histomorphometric parameters of tibia in laying hens fed on a low-calcium diet. 2. A total of 200 Hy-Line Brown laying hens, 24 weeks of age, were divided randomly into 4 groups which were fed on one of 4 diets (CaN, standard diet; CaL, low-calcium diet; IP1, low-calcium diet + 8 mg/kg of IP; IP2, low-calcium diet + 20 mg/kg of IP) for 60 d after which 10 hens of each group, chosen at random, were killed and the tibiae were processed and assessed under a fluorescent microscope 3. The cortical bone showing resorption cavities had become porous, and medullary bone did not completely fill the marrow cavity in the CaL group compared with the CaN group. However, in the IP2 group, the cortical bone showed a structure comparable to the CaN group with an absence of resorption cavities, and more medullary bone filled the marrow cavity compared with the CaL group. 4. The CaL hens had significantly lower trabecular bone area, trabecular perimeter, per cent trabecular area, trabecular number and trabecular thickness and significantly wider trabecular separation compared with CaN. These results indicated that the low-calcium diet led to increased loss of tibial bone, eventually causing osteoporosis. However, compared with the CaL group, the IP2 group caused a significant increase in trabecular bone area and bone quality. 5. It is concluded that even in hens fed on a low-calcium diet, the addition of 20 mg/kg IP exerted beneficial effects on histological structure and structural histomorphometric parameters of tibia, indicating an alleviation of caged layer osteoporosis (CLO). PMID- 24404907 TI - Transfer of momentum from different arm segments to a light movable target during a straight punch thrown by expert boxers. AB - The aim of this study was to determine the relationship between the reductions in momentum of punching arm segments and the impulse of the impact force when boxers throw a punch at a movable target with a mass almost equal to that of the human head. Nine male expert collegiate boxers threw a rear-hand straight punch at the target with their full effort. The reductions in momentum of the upper arm, forearm and fist plus glove of the punching arm during impact and the impulse were determined using a motion capture system and an accelerometer attached to the target. The reduction in momentum of the punching arm explained approximately 95% of the impulse: 40%, 35% and 20% for the upper arm, forearm and fist plus glove, respectively. The Pearson correlation coefficient between the peak and impulse of the impact force was 0.902. These results suggest that for boxers increasing the momentum of the punching arm rather than that of the other body segments immediately before the impact is effective at increasing the impulse of the punch into the face of an opponent. PMID- 24404910 TI - Responsiveness of the Child Perceptions Questionnaire11-14 for Cambodian children undergoing basic dental care. AB - BACKGROUND: Oral-Health-Related Quality of Life (OHRQoL) instruments are useful outcome measures in dental health services research; however, there are no reports of the use OHRQoL measures in evaluating the outcome of basic dental care in children anywhere. AIM: The aims of this study are to evaluate the responsiveness of the Khmer version of the Child Perceptions Questionnaire11-14 (CPQ11-14) and to describe changes in OHRQoL associated with the provision of basic dental care. DESIGN: A pre-test/post-test design, with a clinical convenience sample of children aged from 8 to 14 years of age who received basic dental care from a local nongovernmental organisation (NGO). RESULTS: Of the 140 children in the baseline sample, 116 (82.9%) were followed up. The mean change in CPQ11-14 overall score for those with caries was 1.7, representing a small improvement in OHRQoL. There was a moderate (one in three) statistically significant reduction in the prevalence of impacts across the whole sample (P < 0.001; McNemar test), and one in five improved by the minimally important difference (MID) of five-scale points. CONCLUSIONS: The Khmer version of the CPQ11-14 appears to be a valid and responsive measure for assessing treatment associated changes in OHRQoL in children with dental caries in Cambodia. PMID- 24404911 TI - Concerted or stepwise: how much do free-energy landscapes tell us about the mechanisms of elimination reactions? AB - The base-catalyzed dehydration of benzene cis-1,2-dihydrodiols is driven by formation of an aromatic product as well as intermediates potentially stabilized by hyperaromaticity. Experiments exhibit surprising shifts in isotope effects, indicating an unusual mechanistic balance on the E2-E1cB continuum. In this study, both 1- and 2-dimensional free energy surfaces are generated for these compounds with various substituents, using density functional theory and a mixed implicit/explicit solvation model. The computational data help unravel hidden intermediates along the reaction coordinate and provide a novel conceptual framework for distinguishing between competing pathways in this and any other system with borderline reaction mechanisms. PMID- 24404914 TI - Detection of D-penicillamine in skin lesions in a case of dermal elastosis after a previous long-term treatment for Wilson's disease. AB - BACKGROUND: Skin adverse events associated with D-Penicillamine (DPA) are common and multi-faceted, although the presence of DPA or its metabolites has never been documented in the skin, because of inherent difficulties in determining its tissue levels. Thus, the association between DPA and DPA-related dermatoses has been only hypothesized on the basis of careful history, clinical observation and typical histopathological findings. OBJECTIVE: To detect DPA in biopsy specimens in a unique case of 25-year-late-onset elastosis perforans serpiginosa and pseudo pseudoxanthoma elasticum associated with a history of long-term high dose DPA, by applying a recently described analytical method to assess the presence of DPA in skin. METHODS: We used a reliable analytical method based on high-performance liquid chromatography coupled with amperometric detection to look for the presence of DPA in skin biopsy specimens. RESULTS: A chromatographic peak corresponding to DPA was evidenced in some affected skin samples collected from the patient. CONCLUSION: We documented the effective presence and the persistence after 25 years of DPA in the skin of a woman affected by elastotic cutaneous change due to a long-term therapy with DPA. This report provides further evidence of the relationship between DPA deposit in affected skin and clinical manifestation. PMID- 24404915 TI - Antihypertensive effect of angiotensin-converting enzyme inhibitory peptide RVPSL on spontaneously hypertensive rats by regulating gene expression of the renin angiotensin system. AB - Hen eggs are well-known for their biological functions beyond basic nutrition. In this study, the antihypertensive effect of peptide RVPSL from egg protein has been evaluated by an in vivo model. In addition, the mRNA levels of renin, AT1 receptor, angiotensin-converting enzyme (ACE), and AT2 receptor in the rat kidney were investigated through real-time polymerase chain reaction. The Ang I, Ang II, renin, and aldosterone concentrations of serum were also measured. Our results indicated that the blood pressure of the spontaneously hypertensive rats administered RVPSL for 4 weeks decreased significantly compared to that of the negative group. The mRNA levels of renin, ACE, and AT1 receptor in kidney also decreased significantly. The serum Ang II, renin, and aldosterone concentrations of the treatment group were reduced in comparison to those of the negative group. It is hoped this study will help our understanding and potential use of RVPSL in the treatment or prevention of hypertension. PMID- 24404918 TI - Self-organization of amine-based cathode interfacial materials in inverted polymer solar cells. AB - We present a strategy to fabricate polymer solar cells in inverted geometry by self-organization of alcohol soluble cathode interfacial materials in donor acceptor bulk heterojunction blends. An amine-based fullerene [6,6]-phenyl-C61 butyric acid 2-((2-(dimethylamino)-ethyl)(methyl)amino)ethyl ester (PCBDAN) is used as an additive in poly(3-hexylthiophene) (P3HT) and 6,6-phenyl C61-butyric acid methyl ester (PCBM) blend to give a power conversion efficiency of 3.7% based on devices ITO/P3HT:PCBM:PCBDAN/MoO3/Ag where the ITO alone is used as the cathode. A vertical phase separation in favor of the inverted device architecture is formed: PCBDAN is rich on buried ITO surface reducing its work function, while P3HT is rich on air interface with the hole-collecting electrode. The driving force of the vertical phase separation is ascribed to the surface energy and its components of the blend compositions and the substrates. Similar results are also found with another typical alcohol soluble cathode interfacial materials, poly[(9,9-bis(3'-(N, N-dimethylamino)propyl)-2,7-fluorene)-alt-2,7-(9,9 dioctylfluorene)] (PFN), implying that self-organization may be a general phenomenon in ternary blends. This self-organization procedure could eliminate the fabrication of printing thin film of interlayers or printing on such thin interlayers and would have potential application for roll-to-roll processing of polymer solar cells. PMID- 24404922 TI - Patient stories: an innovative direction for nurses providing support to hematology patients in rural areas. AB - AIMS: This study set out to explore the attitudes toward a "Patient Stories" DVD as a psychosocial support initiative for patients diagnosed with a hematological malignancy. DESIGN: A qualitative research design was employed through a series of open-ended interviews and one focus group. PARTICIPANTS: Participants were purposively sampled from a database of patients maintained by the Leukaemia Foundation of Queensland. In total, there were 50 participants (n=26 male, n=24 female), which represented the following major hematological diagnostic groups: multiple myeloma (n=15), lymphoma (n=14), leukemia (n=17), and other (n=4). Of the overall cohort, 11 participants had undergone a bone marrow transplant, and 15 had undergone a stem cell transplant (allogeneic and autologous transplants). RESULTS AND CONCLUSION: Most participants believed that a "Patient Stories" DVD would be a beneficial and effective way for nurses delivering psychosocial support to hematology patients. Such benefits included a sense of normalization from hearing similar stories and providing convenient support that did not require travel or potentially uncomfortable social situations. However, some participants did not show interest in the idea for reasons such as already having a local support system and not wanting to watch potentially frightening stories. PMID- 24404923 TI - Intranasal therapeutic strategies for management of Alzheimer's disease. AB - Alzheimer's disease (AD) is a chronic and progressive age-related irreversible neurodegenerative disorder that represents 70% of all dementia with 35 million cases worldwide. Successful treatment strategies for AD have so far been limited, and present therapy is based on cholinergic replacement therapy and inhibiting glutamate excitotoxicity. In this context, role of neuroprotective drugs has generated considerable interest in management of AD. Recently, direct intranasal (IN) delivery of drug moieties to the central nervous system (CNS) has emerged as a therapeutically viable alternative to oral and parenteral routes. IN delivery bypasses the blood-brain barrier by delivering and targeting drugs to the CNS along the olfactory and trigeminal neural pathways which are in direct contact with both the environment and the CNS. In an attempt to understand how neurotherapeutics/nanoparticulate delivery systems can be transported from the nose to the CNS, the present review sets out to discuss the mechanism of transport from nose to brain. The aim of this review is to discuss and summarize the latest findings of some of the major studies on IN drug delivery in AD models, with a focus on the potential efficacy of neuroprotective treatments. PMID- 24404926 TI - A behavioural dynamic model of the relative age effect. AB - The relationship between date of birth and success in a variety of sports, including hockey, is well established. This phenomenon is known as the relative age effect (RAE). We model the RAE in Canadian youth hockey as a positive feedback loop where an initial age advantage is reinforced through additional training and playing opportunities based on perceived skill superiority. The same causal mechanism leads to a higher quit rate for relatively younger players. Our model effectively replicates the birth month distribution of Canadian National Hockey League players (R2 = 86.79%) when driven by Canadian birth distributions. We use this model to evaluate three policies that aim to lessen the RAE. All of the policies reduce the RAE with a significant delay. The most effective policy is a combination of providing additional support to age disadvantaged children and rotating the cut-off date for youth leagues between January 1st and July 1st annually. In equilibrium, this approach leads to a 96% reduction in the RAE compared to the base case. PMID- 24404930 TI - Phosphatase and tensin homologue status in sporadic and Cowden syndrome associated trichilemmomas: evaluation of immunohistochemistry and fluorescence in situ hybridization. PMID- 24404932 TI - Deprescribing: a brave new word? PMID- 24404933 TI - Reflective writing in pharmacy practice. PMID- 24404934 TI - Copper-catalyzed Chan-Lam coupling between sulfonyl azides and boronic acids at room temperature. AB - A mild and efficient method for the synthesis of N-arylsulfonamides in the presence of 10 mol % of CuCl is demonstrated. The reaction proceeds readily at room temperature in an open flask using a variety of sulfonyl azides and boronic acids without any base, ligand, or additive. PMID- 24404935 TI - Changes three. PMID- 24404938 TI - Tracing maternal transfer of methylmercury in the sheepshead minnow (Cyprinodon variegatus) with an enriched mercury stable isotope. AB - Maternal transfer of methylmercury (MeHg) to eggs is an important exposure pathway for developing offspring. However, our understanding of this process is limited, particularly in estuarine fish. We conducted a 91-day chronic laboratory exposure of Cyprinodon variegatus to four concentrations of dietary MeHg ranging from 0.04 to 9.90 MUg g(-1) dw. Juvenile fish were fed a preoogenesis MeHg diet for 28 days, after which the diet was switched to a diet enriched with Me(199)Hg, spanning the period of oogenesis, allowing us to differentiate between mercury stored in female tissues and mercury assimilated from the maternal diet during oogenesis. We found that both maternal body burden and clutch size were strong predictors of egg Hg content. A constant percentage of preoogenesis Hg was transferred to eggs in each treatment. Additionally, preoogenesis Hg and during oogenesis Hg were transferred proportionally to eggs, suggesting that both female tissues and the maternal diet during oogenesis are significant sources of Hg. PMID- 24404939 TI - Drug-induced pemphigoid: a review of the literature. AB - Bullous pemphigoid is an acquired autoimmune disease that is characterized by subepidermal blistering and affects mainly the elderly. The pathogenesis of the condition has not yet been fully elucidated, but it is widely accepted that a strong correlation with various medications may exist. In reality, more than 50 different drugs have been associated with the appearance of bullous pemphigoid and as new therapies emerge, this number is very likely to increase. A number of pathogenetic mechanisms have been proposed in the past. It is true that a delicate immunological balance is disturbed in all patients with the disease. The variable effects that may be exhibited by the use of biological drugs could shed some light in this complex immunological behaviour. At the same time, drug induced bullous pemphigoid is difficult to differentially diagnose from its idiopathic counterpart, as the clinical picture and histopathological findings in both conditions may only have subtle differences. Patients who present with bullous pemphigoid and receive multiple regimens should always be suspected of suffering from the drug-induced variant of the condition. This possibility must be considered, as after the withdrawal of the suspect medication most patients respond rapidly to treatment and do not experience relapses. PMID- 24404940 TI - Unfolding kinetics of human telomeric G-quadruplexes studied by NMR spectroscopy. AB - Characterization of the unfolding kinetics of G-quadruplexes (G4s) is the key to a better understanding of the biological function of G4s and is important for biomedical research and material design. Of interest is that slight variations of human telomeric sequences can form different types of G4 structures. In general, there is a correlation between unfolding kinetics and thermal stability. Here we examined this correlation by first systematic analysis of the unfolding kinetics of a variety of telomeric G4 structures using the real-time imino proton NMR spectra of DNA hybridization and hydrogen-deuterium exchange (HDX). We then measured the melting temperature (Tm) and determined the Gibbs free energy (DeltaG) of these G4 structures using differential scanning calorimetry (DSC). Our results showed that both Tm and DeltaG are slightly structure-dependent, except the Tm of the parallel G4 structure is ~10 degrees C higher than that of nonparallel G4 structures. The hybridization results showed that the decay times of different imino proton signals for each telomeric G4 structure are quite similar, which are also consistent with the time constant of the central G-tetrad obtained from HDX measurements. It is suggested that global unfolding is the rate determining step for HDX, and each real-time imino proton NMR measurement can provide the intrinsic unfolding rate constant. The key finding is that the unfolding times of these various G4 structures are quite different and show no correlation between thermal stability and unfolding kinetics. Our results raised an issue that the folding and unfolding kinetics is more relevant for better understanding of biological function of G4 structures. PMID- 24404941 TI - Weighing outcomes by time or against time? Evaluation rules in intertemporal choice. AB - Models of intertemporal choice draw on three evaluation rules, which we compare in the restricted domain of choices between smaller sooner and larger later monetary outcomes. The hyperbolic discounting model proposes an alternative-based rule, in which options are evaluated separately. The interval discounting model proposes a hybrid rule, in which the outcomes are evaluated separately, but the delays to those outcomes are evaluated in comparison with one another. The tradeoff model proposes an attribute-based rule, in which both outcomes and delays are evaluated in comparison with one another: People consider both the intervals between the outcomes and the compensations received or paid over those intervals. We compare highly general parametric functional forms of these models by means of a Bayesian analysis, a method of analysis not previously used in intertemporal choice. We find that the hyperbolic discounting model is outperformed by the interval discounting model, which, in turn, is outperformed by the tradeoff model. Our cognitive modeling is among the first to offer quantitative evidence against the conventional view that people make intertemporal choices by discounting the value of future outcomes, and in favor of the view that they directly compare options along the time and outcome attributes. PMID- 24404944 TI - Shared versus separate processes for letter and digit identification. AB - Letters and digits, although similar in many respects, also differ in potentially significant ways. Most importantly, letters are elements of an alphabetic writing system, whereas digits are logographs. In this article, we explore whether letters and digits are identified by a single character identification process that makes no fundamental distinction between the two types of characters, or whether instead letter and digit identification processes diverge at least in some respects. We present evidence from an acquired dyslexic patient, L.H.D., who is impaired in both letter and digit identification. Working within a theoretical framework specifying the levels of representation implicated in letter identification, we systematically compare L.H.D.'s letter and digit processing. The results provide evidence that letter and digit identification implicate the same levels of representation, and further that L.H.D.'s identification errors for both letters and digits arise at the same point in processing. On the basis of these results, we argue for a shared process that mediates identification of both letters and digits. Finally, we discuss relevant previous results in light of this conclusion. PMID- 24404945 TI - Environment of care: vertical evacuation concerns for acutely ill patients and others with restricted mobility. AB - This perspective paper was intended to raise awareness and the urgency of needing additional evacuation-related, hospital building design policies. We addressed the challenges to maintain the integrity of exits and inadequate hospital design considerations for individuals with restricted mobility. Hospitals are occupied by people who may have restricted mobility and visitors who are likely unfamiliar with their surroundings. A hospital fire threatens all people in the building, but especially patients in the intensive care unit who are frail and have limited mobility. Evacuating immobile patients is complex, involving horizontal and vertical evacuation approaches. Hospital design must consider the needs of individuals with restricted mobility, who are the most vulnerable in case of a hospital fire. Consequently, we urge that acutely ill patients and others with restricted mobility should occupy units located on the ground floor or Level 2. In addition, when configuring the physical environment of hospitals, providing step-free ground floor access (indoor or outdoor ramps) and evacuation aids for vertical evacuation is crucial. Step-free ground floor access between Level 2 and the ground floor should be wide enough to allow transporting patients on their beds. A standard revision to include these recommendations is desperately needed. PMID- 24404946 TI - Electron transfer from plant phenolates to carotenoid radical cations. Antioxidant interaction entering the Marcus theory inverted region. AB - beta-Carotene, lycopene, and zeaxanthin are maximally regenerated by plant phenolates from their radical cations formed during laser flash photolysis in 9:1 (v/v) chloroform/methanol for a driving force corresponding to the reorganization energy according to the Marcus theory. For beta-carotene, the reorganization energy has values of 0.41 +/- 0.04 and 0.40 +/- 0.04 eV for the plant phenols in the presence of 1 and 2 equiv of base, respectively, at 23 degrees C. For a driving force lower than the reorganization energy, regeneration of the carotenoids is less efficient as is seen for m-hydroxybenzoic acid, vanillic acid, and p-coumaric acid. For a driving force above the maximum rate as determined to have kET = 6.3 * 10(9) L.mol(-1).s(-1) for syringic acid and beta carotene, the reaction becomes gradually slower and regeneration less efficient as is seen for the more reducing caffeic acid, rutin, and quercetin corresponding to an inverted region for the rate of electron transfer. Lycopene and zeaxanthin show a similar behavior for the same series of plant phenols with slightly lower reorganization energy, in agreement with the lower reduction potential of their radical cations, while, for the ketocarotenoids astaxanthin and canthaxanthin, fast reactions with a solvent of radical cations inhibit regeneration from being detected. Intermediate reducing plant phenols accordingly yield maximal protection of carotenoids against photobleaching in foods and beverages. PMID- 24404949 TI - Prevalence and antimicrobial resistance of Arcobacter species isolated from poultry meat in Iran. AB - 1. The objective of this study was to determine the prevalence and antimicrobial resistance of Arcobacter spp. isolated from different species of retail poultry meat in Iran. 2. From August 2012 to April 2013, a total of 540 raw poultry meat samples from chicken (n = 100), turkey (n = 100), quail (n = 100), partridge (n = 80), duck (n = 50), ostrich (n = 60) and geese (n = 50) were purchased from randomly selected retail outlets in Shahrekord, Isfahan, Sari and Rasht, Iran. 3. Using culture techniques, 71 of 540 poultry meat samples (13.1%) were positive for Arcobacter spp. The highest prevalence of Arcobacter spp. was found in chicken meat (28.0%), followed by quail (12.0%), duck (11.4%), turkey (11.0%), geese (8.0%), partridge (7.5%) and ostrich (3.3%) meat. The number of A. butzleri isolated from poultry meat samples (90.1%) was significantly higher than A. cryaerophilus (7.1%) and A. skirrowii (2.8%). Significantly more poultry meat samples were found to contain Arcobacter spp. by the PCR assay than by the culture method. 4. Susceptibilities of Arcobacter isolates were determined for 14 antimicrobial drugs using the disk diffusion method. All of the 71 Arcobacter isolates tested were resistant to one or more antimicrobial agents. Resistance to cephalothin and vancomycin (95.8%) was the most common finding, followed by resistance to methicillin, azithromycin and ampicillin. All Arcobacter isolates were susceptible to gentamicin, streptomycin, tetracyclin and kanamycin. 5. The results of this study indicated the importance of poultry meat, especially chicken meat, as potential sources of Arcobacter spp. infection in people. Furthermore, the strains indicated resistance to a broad spectrum of antibiotics. PMID- 24404950 TI - Fabrication of 10 nm-scale complex 3D nanopatterns with multiple shapes and components by secondary sputtering phenomenon. AB - We introduce an advanced ultrahigh-resolution (~ 15 nm) patterning technique that enables the fabrication of various 3D high aspect ratio multicomponents/shaped nanostructures. This methodology utilizes the repetitive secondary sputtering phenomenon under etching plasma conditions and prepatterned fabrication control. The secondary sputtering phenomenon repetitively generates an angular distribution of target particles during ion-bombardment. This method, advanced repetitive secondary sputtering lithography, provides many strategies to fabricate complex continuous patterns and multilayer/material patterns with 10 nm scale resolution. To demonstrate the versatility of this method, we show induced vertical alignment of liquid crystals (LCs) on indium-tin-oxide (ITO) grid patterns without any alignment layers. The ITO grid pattern fabricated in this method is found to have not only an alignment capability but also electrode properties without electrical or optical damage. PMID- 24404951 TI - Near infrared spectroscopy monitoring in the pediatric cardiac catheterization laboratory. AB - Near-infrared spectroscopy (NIRS) is a noninvasive method used to evaluate tissue oxygenation. We evaluated the relationship between cerebral and renal NIRS parameters during transcatheter intervention and adverse events in the catheterization room. Between January 1 and May 31, 2012, 123 of 163 pediatric patients undergoing cardiac catheterization were followed by NIRS. All were monitored by electrocardiography, noninvasive blood pressure measurement, pulse oxymetry, initial and final blood lactate level measurement. The number of interventional procedures was 73 (59%). During the procedures, 39 patients experienced a total of 41 adverse events: 18 (19.5%) had desaturation, 10 (8.1%) arrhythmia, three (2.4%) had respiratory difficulty, six (4.8%) had a situation calling for cardiopulmonary resuscitation, three (2.4%) had anemia necessitating transfusion, and one (0.8%) had a cyanotic spell. Cranial NIRS values worsened in 12 (9.8%) and renal measurements worsened in 13 (12.5%) patients. The sensitivity and specificity of a 9% impairment of cranial values were 90 and 61%, respectively, while the corresponding calculations for a 21% fall in renal measurements were 54% sensitivity and 90% specificity. When arrhythmia developed, NIRS values fell simultaneously, while the development of a desaturation problem was heralded by NIRS falling 10-15 s earlier than changes in pulse oxymetry; on improving saturation, NIRS returned to earlier values 10-15 s before pulse oxymetry readings. NIRS monitoring may provide an early warning with regard to complications likely to develop during a procedure. A fall of 9% in cranial NIRS values, or of 21% in renal measurements, should raise clinician awareness. PMID- 24404953 TI - Three new olean-type triterpenoid saponins from aerial parts of Eclipta prostrata (L.). AB - Three new olean-type triterpenoid saponins, namely 3-O-(2-O-acetyl-beta-D glucopyranosyl) oleanolic acid-28-O-(beta-D-glucopyranosyl) ester (1), 3-O-(6-O acetyl-beta-D-glucopyranosyl) oleanolic acid-28-O-(beta-D-glucopyranosyl) ester (2) and 3-O-(beta-D-glucopyranosyl) oleanolic acid-28-O-(6-O-acetyl-beta-D glucopyranosyl) ester (3), were isolated from the aerial parts of Eclipta prostrata (L.). Their structures were elucidated based on 1D and 2D NMR and MS spectroscopic data. PMID- 24404954 TI - Two new dihydroamentoflavone glycosides from Cycas revoluta. AB - Phytochemical investigation of the ethyl acetate extract of Cycas revoluta Thunb. leaflets afforded five compounds including two new dihydroamentoflavone glucosides, (2S)-I-(2,3)-dihydro-I-7-O-beta-D-glucopyranosylamentoflavone (1) and (2S)-I-(2,3)-dihydro-I-7,II-7-di-O-beta-D-glucopyranosylamentoflavone (2), in addition to the known compounds prunin (3), vitexin-2"-rhamnoside (4) and protocatechuic acid (5). Compounds (3) and (4) being reported for the first time in this plant. The structures of these compounds were established by the detailed analysis of their spectroscopic data, mainly 1D NMR, 2D NMR, CD and HR-MSD-TOF. The ethyl acetate extract showed weak cytotoxicity against HepG2 (IC50 = 207.6 MUg/mL) and RAW 264.2 cells (IC50 = 160.8 MUg/mL). Compound 4 showed significant activity towards Leishmania donavani (IC50 = 13.8 MUM, IC90 = 34.6 MUM). The isolated compounds showed weak antimicrobial activity (IC50>10 MUg/mL). PMID- 24404955 TI - Optimisation of phenolics recovery from Vitex agnus-castus Linn. leaves by high pressure and temperature extraction. AB - To optimise recovery of phenolics from Vitex agnus-castus Linn., a non conventional high-pressure (2-24 bar) and temperature (100-180 degrees C) extraction method was used under nitrogen atmosphere with methanol as a solvent. Optimal temperature was between 100 and 140 degrees C, and optimal extraction time was about one half that of conventional solid/liquid extraction at room temperature. Final yields of total polyphenols, total flavonoids, o-diphenols and anthocyanins extraction were 2.0, 3.0, 2.5 and 11-fold those obtained by conventional extraction. PMID- 24404958 TI - Biochemical characterization and comparison of two closely related active mariner transposases. AB - Most DNA transposons move from one genomic location to another by a cut-and-paste mechanism and are useful tools for genomic manipulations. Short inverted repeat (IR) DNA sequences marking each end of the transposon are recognized by a DNA transposase (encoded by the transposon itself). This enzyme cleaves the transposon ends and integrates them at a new genomic location. We report here a comparison of the biophysical and biochemical properties of two closely related and active mariner/Tc1 family DNA transposases: Mboumar-9 and Mos1. We compared the in vitro cleavage activities of the enzymes on their own IR sequences, as well as cross-recognition of their inverted repeat sequences. We found that, like Mos1, untagged recombinant Mboumar-9 transposase is a dimer and forms a stable complex with inverted repeat DNA in the presence of Mg(2+) ions. Mboumar-9 transposase cleaves its inverted repeat DNA in the manner observed for Mos1 transposase. There was minimal cross-recognition of IR sequences between Mos1 and Mboumar-9 transposases, despite these enzymes having 68% identical amino acid sequences. Transposases sharing common biophysical and biochemical properties, but retaining recognition specificity toward their own IR, are a promising platform for the design of chimeric transposases with predicted and improved sequence recognition. PMID- 24404962 TI - Development of dual responsive nanocomposite for simultaneous delivery of anticancer drugs. AB - In this paper novel stimuli-responsive cationic mesoporous silica nanoparticles (MSNs) were fabricated through the facile polymerization method. The synthesis process was characterized and validated by Fourier transform infrared spectroscopy and hydrogen nuclear magnetic resonance spectroscopy. The prepared nanoparticles were characterized using scanning electron microscopy (SEM), Zeta potential and thermogravimetric analysis methods. SEM results revealed the uniformity in size and shape of nanoparticles with a mean diameter of approximately 60 nm. Two model anticancer drugs, Doxorubicin (DOX) and Methotroxate (MTX) were loaded effectively to functionalized MSNs through electrostatic interactions. Our developed HPLC-UV method was applied for simultaneous determination of DOX and MTX. Modified MSNs yielded a pH and temperature-triggered release of entrapped drugs at tumor tissue environment (lower pH and higher temperature than physiological condition). In-vitro cytotoxicity assay showed that the blank carrier showed no cytotoxicity on both A549 and MCF7 cells at different amounts after incubation for 72 h confirming its suitability as a drug carrier. Multi anticancer drug-loaded MSNs, in the other hand, caused an efficient anticancer performance verified by DAPI staining and MTT assay tests. It was concluded that our findings may open the possibilities for cooperative thermo and pH-responsive targeted delivery of DOX and MTX to the cancerous tissues. PMID- 24404961 TI - Differential gene expression in laboratory strains of human head and body lice when challenged with Bartonella quintana, a pathogenic bacterium. AB - Human head and body lice are obligatory hematophagous ectoparasites that belong to a single species, Pediculus humanus. Only body lice, however, are vectors of the infectious Gram-negative bacterium Bartonella quintana. Because of their near identical genomes, yet differential vector competence, head and body lice provide a unique model system to study the gain or loss of vector competence. Using our in vitro louse-rearing system, we infected head and body lice with blood containing B. quintana in order to detect both differences in the proliferation of B. quintana and transcriptional differences of immune-related genes in the lice. B. quintana proliferated rapidly in body lice at 6 days post-infection, but plateaued in head lice at 4 days post-infection. RNAseq and quantitative real time PCR validation analyses determined gene expression differences. Eight immunoresponse genes were observed to be significantly different with many associated with the Toll pathway: Fibrinogen-like protein, Spaetzle, Defensin 1, Serpin, Scavenger receptor A and Apolipoporhrin 2. Our findings support the hypothesis that body lice, unlike head lice, fight infection from B. quintana only at the later stages of its proliferation. PMID- 24404963 TI - Skin ulcers related to chronic graft-versus-host disease: clinical findings and associated morbidity. AB - BACKGROUND: According to the National Institutes of Health classification of chronic graft-versus-host disease (cGVHD), skin ulcers after allogeneic haematopoietic stem-cell transplantation (HSCT) are recorded as having the maximal severity score but published data are scarce. OBJECTIVES: To describe skin ulcers related to cGVHD with an emphasis on clinical findings, associated morbidity, management and evolution. PATIENTS AND METHODS: A multicentre retrospective analysis was carried out of patients with a diagnosis of cGVHD skin ulcers. RESULTS: All 25 patients included in the study had sclerotic skin cGVHD and 21 had lichenoid skin lesions associated with the sclerotic skin lesions. Thirteen patients had severe cGVHD without considering the skin, because of the involvement of an extracutaneous organ by cGVHD. The median time from HSCT to the onset of ulcers was 44 months. In addition to scleroderma, initial skin lesions at the site of ulcers were bullous erosive lichen in 21 patients and bullous erosive morphoea in four patients. Fifteen patients had an inaugural oedema. Ulcers were mostly bilateral with a predilection for the lower limbs. They were frequently colonized but few infections occurred. Four patients died during a median follow-up period of 55 months. CONCLUSIONS: Chronic graft-versus-host disease skin ulcers occur in patients with sclerodermatous skin cGVHD, are associated with severe cGVHD, often start with bullous lichenoid lesions or bullous morphoea and seem to cause more morbidity than mortality, given the low rate of mortality observed in our series of patients. PMID- 24404964 TI - Physiological, movement and technical demands of centre-wicket Battlezone, traditional net-based training and one-day cricket matches: a comparative study of sub-elite cricket players. AB - This study compared physiological, physical and technical demands of Battlezone, traditional cricket training and one-day matches. Data were initially collected from 11 amateur, male cricket players (age: 22.2 +/- 3.3 year, height: 1.82 +/- 0.06 m body mass: 80.4 +/- 9.8 kg) during four Battlezone and four traditional cricket training sessions encompassing different playing positions. Heart rate, blood lactate concentration, rating of perceived exertion and movement patterns of players were measured. Retrospective video analysis was performed to code for technical outcomes. Similar data were collected from 42 amateur, male cricket players (23.5 +/- 4.7 year, 1.81 +/- 0.07 m, 81.4 +/- 11.4 kg) during one-day matches. Significant differences were found between Battlezone, traditional cricket training and one-day matches within each playing position. Specifically, Battlezone invoked the greatest physiological and physical demands from batsmen in comparison to traditional cricket training and one-day matches. However, the greatest technical demand for batsmen was observed during traditional cricket training. In regards to the other playing positions, a greater physiological, physical and technical demand was observed during Battlezone and traditional training than during one-day matches. These results suggest that the use of Battlezone and traditional cricket training provides players with a suitable training stimulus for replicating the physiological, physical and technical demands of one-day cricket. PMID- 24404967 TI - Prenatal latex sensitization in patients with spina bifida: a pilot study. AB - OBJECT: Patients with spina bifida are particularly vulnerable to developing immunoglobulin E (IgE)-mediated latex sensitization. Even though many risk factors leading to latex allergy in these patients have been described, it is still unclear whether the increased prevalence of latex sensitization is disease associated or due to the procedures used to treat spina bifida. The aim of this study was to assess prenatal latex sensitization in patients with spina bifida by examining IgE levels in umbilical cord blood. METHODS: Patients with spina bifida and matched healthy infants were recruited from the University Medical Center Hamburg-Eppendorf and Children's Hospital Altona. Latex-specific and total IgE were assessed in umbilical cord blood using ImmunoCAP testing to evaluate the degree of prenatal latex sensitization. RESULTS: Twenty-two subjects, 10 with spina bifida and 12 healthy individuals, were included. Subjects were selected after matching for sex, gestational age, weight, parental allergy profile, number of prenatal examinations, and utilization of latex tools during pregnancy (propensity score estimates, p = 0.36). In patients with spina bifida, latex specific and total IgE levels were significantly higher than those in healthy individuals (p = 0.001). After normalization to total IgE, latex-specific IgE levels were higher, yet not significantly increased (p = 0.085). CONCLUSIONS: Perinatally, there is a significant augmentation of total and latex-specific IgE in patients with spina bifida. After correcting for total IgE, latex-specific IgE was increased, yet not significantly higher than in matched, healthy controls. This pilot study gives novel insights in the immunological reactions related to spina bifida. The increased latex-specific IgE levels could possibly be associated with the occurrence of a latex allergy in the future. PMID- 24404968 TI - Analysis of complications in 430 consecutive pediatric patients treated with intrathecal baclofen therapy: 14-year experience. AB - OBJECT: This single-center study investigated adverse events that occurred in children and adolescent patients treated with intrathecal baclofen (ITB) therapy for spasticity and/or dystonia. METHODS: In a 14-year period, 430 consecutive patients with a mean age of 13.3 +/- 5.9 years received ITB over a mean follow-up period of 8.6 +/- 3.8 years (range 12 months to 14 years). Eighty-nine percent of these patients had cerebral palsy. Major complications, defined as those that required a surgical intervention, were infections, CSF leaks, and device problems related to the catheter or pump. Assessing infections, the authors compared the 2 groups of patients implanted with an ITB system by either the subcutaneous or subfascial technique. The temporal distribution of events related to the catheter was also considered. RESULTS: At least 1 complication was present in 25% of the patients: 9.3% experienced an infection, 4.9% a CSF leak, 15.1% a problem with the catheter, and 1% a problem related to the pump. Five percent of the assessed patients suffered more than 1 complication. The rate of infections was significantly lower (p < 0.001) in patients with the pump placed subfascially compared with those with the pump placed subcutaneously. A higher rate of infection was found after pump replacement compared with the first pump implantation (10.6% vs 6%, respectively). Catheter problems were the most common complication and occurred more frequently during the 1st year after the implant. CONCLUSIONS: While ITB is an effective treatment to manage spasticity of different origins, adverse events may occur and need to be managed. The surgical procedure should be meticulous and different techniques may have a diverse impact on the infection rate, which is the most critical complication. Despite the adverse events that occurred in this study, the majority of patients were satisfied with the treatment received. PMID- 24404969 TI - Clinical significance of imaging and histological characteristics of filum terminale in tethered cord syndrome. AB - OBJECT: The pathophysiology of tethered cord syndrome (TCS) is uncertain; however, it has been suggested that fibrous and fatty elements within the filum terminale (FT) play a role. The objective of this study was to describe the radiological and histological features of the FT in TCS and determine if there are associations between those features and clinical outcomes, complications, and urodynamics. METHODS: In this retrospective study, histological, MRI, and clinical data obtained in 293 patients with TCS who underwent FT transection were reviewed and analyzed in a multivariate analysis. RESULTS: The median patient age was 4.9 years (range 0.3-64.3 years). On MRI, a fatty filum was present in 65% of patients and a thickened filum (> 2 mm) was seen in 45%. Histologically, the FT contained prominent fibrous tissue in 95%, nerve twigs in 79%, adipose tissue in 59%, and vascular tissue in 36%. Histological features associated with a thickened filum on MR images were adipose tissue (OR 3.5, p < 0.001), nerve twigs (OR 2.2, p = 0.028), and vascular tissue (OR 0.5, p = 0.025). Adipose tissue was associated with a conus level below the L2-3 disc space (OR 2.3, p = 0.031) and with a fatty filum on imaging (OR 9.8, p < 0.001). Nerve twigs were associated with abnormal urodynamics (OR 10.9, p = 0.049). The only variable predictive of clinical improvement was conus level; patients with conus levels caudal to L-2 were less likely to improve postoperatively (OR 0.3, p = 0.042). CONCLUSIONS: Fibrous tissue was ubiquitous and may be important in the pathophysiology of TCS. Nerve twigs and adipose tissue were associated with abnormal urodynamics and low lying coni, respectively. Although the majority of patients clinically improved, patients with normal conus levels had significantly better outcomes. PMID- 24404970 TI - The comparative effectiveness of ventricular shunt placement versus endoscopic third ventriculostomy for initial treatment of hydrocephalus in infants. AB - OBJECT: The purpose of this study was to compare the effectiveness of CSF diversion with endoscopic third ventriculostomy (ETV) versus shunt therapy in infants with hydrocephalus. METHODS: The authors conducted a retrospective analysis of 5416 infants 1 year of age or younger with hydrocephalus (congenital or acquired) in whom CSF diversion was performed using either ETV or shunt placement at 41 children's hospitals between 2004 and 2009. Data were obtained from the Pediatric Health Information Systems database. Surgical failure was defined as the need for a repeat diversion operation within 1 year of initial surgery. The authors compared failure rates of ETV and shunt, as well as patient demographics and clinical characteristics, using hierarchical regression according to treatment group. RESULTS: During the period examined, 872 infants (16.1%) initially underwent ETV and 4544 (83.9%) underwent ventricular shunt placement. The median infant age was 37 days (IQR 11-122 days) for both ETV and shunt placement. More infants who underwent ETV rather than shunt placement were born prematurely (41.6% vs 23.9%, respectively; p < 0.01) and had intraventricular hemorrhage (45.4% vs 17.5%, respectively; p < 0.01). Higher operative failure rates at 1 year were observed in infants who underwent ETV as opposed to shunt surgery (64.5% vs 39.6%, respectively; OR 2.9 [95% CI 2.3-3.5], p < 0.01). After controlling for prematurity, intraventricular hemorrhage, and spina bifida, ETV remained associated with a higher risk of failure (OR 2.6 [95% CI 2.1-3.2]). CONCLUSIONS: In infants with hydrocephalus, a greater 1-year CSF diversion failure rate may occur after ETV compared with shunt placement. This risk is most significant for procedures performed within the first 90 days of life. Further investigation of the need for multiple reoperations, cost, and impact of surgeon and hospital experience is necessary to distinguish which treatment is more effective in the long term. PMID- 24404971 TI - Magnesium-dependent RNA binding to the PA endonuclease domain of the avian influenza polymerase. AB - Influenza A viruses are highly pathogenic and pose an unpredictable public health danger to humans. An attractive target for developing new antiviral drugs is the PA N-terminal domain (PAN) of influenza polymerase, which is responsible for the endonuclease activity and essential for viral replication. Recently, the crystal structures of the holo form of PAN as well as PAN bound to different inhibitors have been reported, but the potency and selectivity of these inhibitors still need to be improved. New drug design can be guided by a better understanding of the endonuclease activity of PAN. However, this requires the structure of PAN in complex with the host mRNA, which has not been determined yet. In particular, divalent metal ions are known to be essential for RNA cleavage, but it is not clear whether there is either one or two Mg ions in the PAN active site. In the present work, we have modeled the complex of the PAN endonuclease domain with the host mRNA in the presence of either one or two Mg(2+) by using all-atom molecular dynamics. These simulations identify crucial interactions between the enzyme and the nucleic acid. Moreover, they validate a previous hypothesis that a second metal ion binds in the presence of the RNA substrate and therefore support a two metal ion mechanism, in which K134 decreases the pKa of the nucleophilic water. Nevertheless, at low Mg concentrations an alternative, one-metal ion mechanism is possible, with K137 as the catalytic lysine and H41 as the general base, rationalizing previous unexpected mutagenesis results. The RNA-enzyme interactions determined here could likely be used to design more specific endonuclease inhibitors to fight influenza viral infections. PMID- 24404972 TI - Pd-catalyzed oxidative coupling of enamides and alkynes for synthesis of substituted pyrroles. AB - A novel and efficient palladium(II)-catalyzed alkenyl C-H activation oxidative annulation of enamides with alkynes for the synthesis of substituted pyrroles has been developed. The reaction tolerates a wide range of functional groups and is a reliable method for the synthesis of triaryl-substituted pyrroles in high yields. PMID- 24404975 TI - Antibacterial and antigelatinolytic effects of Satureja hortensis L. essential oil on epithelial cells exposed to Fusobacterium nucleatum. AB - The present report examined the effects of essential oils (EOs) from Satureja hortensis L. and Salvia fruticosa M. on the viability and outer membrane permeability of the periodontopathogen Fusobacterium nucleatum, a key bacteria in oral biofilms, as well as the inhibition of matrix metalloproteinase (MMP-2 and MMP-9) activities in epithelial cells exposed to such bacteria. Membrane permeability was tested by measuring the N-phenyl-1-naphthylamine uptake and bacterial viability by using the commercially available Live/Dead BacLight kit. In addition, gelatin zymography was performed to analyze the inhibition of F. nucleatum-induced MMP-2 and MMP-9 activities in HaCaT cells. We showed that 5, 10, and 25 MUL/mL of Sat. hortensis L. EO decreased the ratio of live/dead bacteria and increased the outer membrane permeability in a range of time from 0 to 5 min. Treatments with 10 and 25 MUL/mL of Sal. fruticosa M. also increased the membrane permeability and 5, 10, and 25 MUL/mL of both EOs inhibited MMP-2 and MMP-9 activities in keratinocytes induced after exposure of 24 h to F. nucleatum. We conclude that antibacterial and antigelatinolytic activities of Sat. hortensis L. EO have potential for the treatment of periodontal inflammation. PMID- 24404976 TI - Antihyperglycemic effect of crude extracts of some Egyptian plants and algae. AB - Diabetes mellitus is a major global health problem. Various plant extracts have proven antidiabetic activity and are considered as promising substitution for antidiabetic drugs. The antihyperglycemic effect of 16 plants and 4 algae, commonly used in Egypt for the treatment of diabetes mellitus, was investigated. A diabetes model was induced by intraperitoneal injection of nicotinamide (120 mg/kg body weight [b.wt.]), then streptozotocin (200 mg/kg b.wt.) after 15 min. Hydroethanolic extracts (80%) of the plants and algae under investigation were prepared. The extracts were orally administered to nicotinamide-streptozotocin induced diabetic mice by a gastric tube at doses 10 or 50 mg/kg b.wt. for 1 week. The antidiabetic activity was assessed by detection of serum glucose concentrations at the fasting state and after 2 h of oral glucose loading (4.2 mg/kg b.wt.). Extracts prepared from Cassia acutifolia, Fraxinus ornus, Salix aegyptiaca, Cichorium intybus, and Eucalyptus globulus showed the highest antihyperglycemic activity among the tested plants. Extracts prepared from Sonchus oleraceus, Bougainvillea spectabilis (leaves), Plantago psyllium (seeds), Morus nigra (leaves), and Serena repens (fruits) were found to have antihyperglycemic potentials. Extracts prepared from Caulerpa lentillifera and Spirulina versicolor showed the most potent antihyperglycemic activity among the tested algae. However, some of the tested plants have insulinotropic effects, all assessed algae have not. Identification of lead compounds from these plants and algae for novel antidiabetic drug development is recommended. PMID- 24404977 TI - Evaluation of Chios mastic gum on lipid and glucose metabolism in diabetic mice. AB - Chios mastic gum (MG), a resin produced from Pistacia lentiscus var. Chia, is reported to possess beneficial cardiovascular and hepatoprotective properties. This study investigated the effect of crude Chios MG on metabolic parameters in diabetic mice. Streptozotocin-induced diabetic 12-week-old male C57bl/6 mice were assigned to three groups: NC (n=9) control; LdM (n=9) animals receiving low dose mastic for 8 weeks (20 mg/kg body weight [BW]); and HdM (n=9) animals receiving high dose mastic (500 mg/kg BW) for the same period. Serum lipid and glucose levels were determined at baseline, at 4 and 8 weeks. Serum total protein, adiponectin, and resistin levels were also measured at the end of the experiment. Histopathological examination for liver, kidney, aorta, and heart lesions was performed. After 4 weeks, MG administration resulted in decreased serum glucose and triglyceride levels in both LdM and HdM, whereas BW levels were reduced in LdM group compared with controls. At the end of the experiment, LdM presented significantly lower serum glucose, cholesterol, low-density lipoprotein cholesterol, and triglyceride levels and improved high-density lipoprotein cholesterol levels compared with control group. HdM group had ameliorated serum triglyceride levels. Hepatic steatosis observed in control group was partially reversed in LdM and HdM groups. MG administered in low dosages improves glucose and lipid disturbances in diabetic mice while alleviating hepatic damage. PMID- 24404979 TI - Inhibition of human low-density lipoprotein oxidation in vitro by ginger extracts. AB - Oxidative modification of low-density lipoprotein (LDL) is thought to play a key role in atherosclerotic plaque formation. Currently, there is a renewed interest in ginger because of its antioxidants and cardioprotective properties. The effects of ethanol, methanol, ethyl acetate, and hexane solvent extracts of ginger and pure major ginger constituents on Cu(2+)-induced oxidation of human LDL in vitro were examined. The LDL oxidation inhibition by ethanol, methanol, ethyl acetate, and hexane extracts of ginger was 71%, 76%, 67%, and 67%, respectively, at their optimum extraction conditions. Inhibition of LDL oxidation by water extracts of ginger, which was prepared by ultrasonic-assisted extraction conditions of 52 degrees C for 15 min, was about 43%. Phenolic bioactives of ginger-6-gingerols, 8-gingerols, 10-gingerols, and 6-shogaol-seem to be strong inhibitors of Cu(+2)-induced LDL oxidation. Overall, ginger extracts, including the water extract possess the antioxidant activities to inhibit human LDL oxidation in vitro. PMID- 24404978 TI - Raspberry ketone promotes the differentiation of C3H10T1/2 stem cells into osteoblasts. AB - The decrease in the bone mass associated with osteoporosis caused by ovariectomy, aging, and other conditions is accompanied by an increase in bone marrow adipose tissue. The balance between osteoblasts and adipocytes is influenced by a reciprocal relationship. The development of modalities to promote local/systemic bone formation by inhibiting bone marrow adipose tissue is important in the treatment of fractures or metabolic bone diseases such as osteoporosis. In this study, we examined whether raspberry ketone [4-(4-hydroxyphenyl)butan-2-one; RK], which is one of the major aromatic compounds of red raspberry and exhibits anti obesity action, could promote osteoblast differentiation in C3H10T1/2 stem cells. Confluent C3H10T1/2 stem cells were treated for 6 days with 10-100 MUg/mL of RK in culture medium containing 10 nM all-trans-retinoic acid (ATRA) or 300 ng/mL recombinant human bone morphogenetic protein (rhBMP)-2 protein as an osteoblast differentiating agent. RK in the presence of ATRA increased alkaline phosphatase (ALP) activity in a dose-dependent manner. RK in the presence of rhBMP-2 also increased ALP activity. RK in the presence of ATRA also increased the levels of mRNAs of osteocalcin, alpha1(I) collagen, and TGF-betas (TGF-beta1, TGF-beta2, and TGF-beta3) compared with ATRA only. RK promoted the differentiation of C3H10T1/2 stem cells into osteoblasts. However, RK did not affect the inhibition of early-stage adipocyte differentiation. Our results suggest that RK enhances the differentiation of C3H10T1/2 stem cells into osteoblasts, and it may promote bone formation by an action unrelated to adipocyte differentiation. PMID- 24404980 TI - Food and water intake and selective feeding in rabbits on four feeding regimes. AB - Diet plays an important role in maintaining rabbit health. Feeding an incorrect diet, particularly a low fibre diet, has been linked with digestive, dental and urinary tract disease. However, food intake and dietary requirements have been poorly studied in pet rabbits. This study assessed the effects of two commonly fed pet rabbit diets [extruded nuggets with hay (EH) and muesli with hay (MH)] alongside hay only (HO) and muesli only (MO) on food and water intake in 32 Dutch rabbits. Dry matter (DM) intake was greater in the HO group and lower in the MO group than in the EH and MH groups (p < 0.001). The portion of the diet made of hay was greater in the EH group than in the MH group (p < 0.001). Water intake was positively correlated with DM intake and was greatest in the HO group (p < 0.001). Selective feeding occurred in all rabbit groups fed muesli, whether or not hay was also available. Pellets were rejected, and grains and extrudates selected. The presence of selective feeding in all rabbits fed muesli leads to the consumption of an unbalanced diet. In addition, hay intake and water intake were lower when muesli was fed. Conclusions drawn from this study are based on general recommendations for pet rabbits, and clinical disease may have developed by feeding the study diets over a longer time period, as many diet-related conditions typically present in older rabbits. However, the study demonstrates that the feeding of muesli diets cannot be recommended. PMID- 24404981 TI - Insect gamma-aminobutyric acid receptors and isoxazoline insecticides: toxicological profiles relative to the binding sites of [3H]fluralaner, [3H]-4' ethynyl-4-n-propylbicycloorthobenzoate, and [3H]avermectin. AB - Isoxazoline insecticides, such as fluralaner (formerly A1443), are noncompetitive gamma-aminobutyric acid (GABA) receptor (GABA-R) antagonists with selective toxicity for insects versus mammals. The isoxazoline target in house fly ( Musca domestica ) brain has subnanomolar affinity for [3H]fluralaner and a unique pattern of sensitivity to isoxazolines and avermectin B(1a) (AVE) but not to fipronil and alpha-endosulfan. Inhibitor specificity profiles for 15 isoxazolines examined with Musca GABA-R and [3H]fluralaner, [3H]-4'-ethynyl-4-n propylbicycloorthobenzoate ([3H]EBOB), and [3H]AVE binding follow the same structure-activity trends although without high correlation. The 3 most potent of the 15 isoxazolines tested in Musca [3H]fluralaner, [3H]EBOB, and [3H]AVE binding assays and in honeybee (Apis mellifera) brain [3H]fluralaner assays are generally those most toxic to Musca and four agricultural pests. Fluralaner does not inhibit [3H]EBOB binding to the human GABA-R recombinant beta3 homopentamer, which is highly sensitive to all of the commercial GABAergic insecticides. The unique isoxazoline binding site may resurrect the GABA-R as a major insecticide target. PMID- 24404984 TI - Improving unit performance with a staff-driven peer review process. AB - PURPOSE: A staff-driven peer review process was developed and implemented to determine if it would improve the perception of the quality of nursing care delivered and unit performance. CONCLUSIONS: Perceived quality of care, as measured on the National Database of Nursing Quality Indicators Survey, improved by the second year after all nurses had completed the process. The unit performance improvement indicators showed improvement in the first year after implementation, with further improvements noted the second year. PRACTICE IMPLICATION: This project demonstrated that staff nurses could and would autonomously improve practice and unit performance based on unit data. PMID- 24404989 TI - Night-time ground hyperspectral imaging for urban-scale remote sensing of ambient PM--modal concentrations retrieval. AB - Retrieval of aerosol loading in vertical atmospheric columns is a common product of satellite and ground instruments that measure spectral extinction of solar radiation throughout the entire atmosphere. Here we study ground hyperspectral imaging of artificial light sources as a complementary method for retrieving fine aerosol concentrations along quazi-horizontal ambient open paths. Previously, we reported hyperspectral measurements of the aerosol optical thickness in the 500 900 nm range over urban-scale distances (180 m to 4 km), measuring the extinction of radiation emitted from a halogen source. Here we confirm in a laboratory-setup the basic premise that different accumulation-size aerosols generate distinct hyperspectral signatures in this spectral range. Measured hyperspectral attenuation signatures of fine aerosols were comparable to calculated Mie scattering signatures, suggesting that modal aerosol concentrations can be retrieved. A genetic algorithm was adapted to estimate the aerosol modal concentrations from its hyperspectral extinction signature. Retrievals of aerosol concentrations from measured and synthetic hyperspectral signatures indicated a robust algorithm, with an expected retrieval error of 0.2-22% for typical ambient concentrations along an urban-scale open path. The retrieval accuracy was found to depend on the relative aerosol modal concentrations, especially when there is a substantial overlap between the modal spectral signatures. PMID- 24404992 TI - Cognitive behavioural anger management intervention for people with intellectual disabilities: costs of intervention and impact on health and social care resource use. AB - BACKGROUND: Anger and aggression among adults with intellectual disability (ID) are associated with a range of adverse consequences for their well-being and that of their family or staff carers. The aims were to evaluate the effectiveness of an anger management intervention for adults with mild to moderate ID and to evaluate the costs of the intervention and its impact on health and social care resource use. This paper is concerned with the latter aim. METHODS: A cluster randomised controlled trial was conducted involving day services for adults with ID in Scotland, England and Wales. Incremental costs of delivering the intervention and its impact on subsequent total health and social care package costs were calculated. Full data comparing costs between baseline and follow-up 10 months later were collected for 67 participants in the intervention arm and 62 participants in the control arm. Cost differences between the groups at follow up, adjusted for baseline levels, were calculated using non-parametric bootstrapping controlling for clustering. RESULTS: The mean hourly excess cost of intervention over treatment as usual was L12.34. A mean adjusted cost difference of L22.46 per person per week in favour of the intervention group was found but this was not statistically significant. CONCLUSIONS: The baseline-adjusted cost difference at follow-up would result in a fairly immediate compensation for the excess costs of intervention, provided the difference is not a statistical artefact. Further research is needed to clarify the extent to which it might represent a real saving in service support costs. PMID- 24404993 TI - Causes of false-positive HIV rapid diagnostic test results. AB - HIV rapid diagnostic tests have enabled widespread implementation of HIV programs in resource-limited settings. If the tests used in the diagnostic algorithm are susceptible to the same cause for false positivity, a false-positive diagnosis may result in devastating consequences. In resource-limited settings, the lack of routine confirmatory testing, compounded by incorrect interpretation of weak positive test lines and use of tie-breaker algorithms, can leave a false-positive diagnosis undetected. We propose that heightened CD5+ and early B-lymphocyte response polyclonal cross-reactivity are a major cause of HIV false positivity in certain settings; thus, test performance may vary significantly in different geographical areas and populations. There is an urgent need for policy makers to recognize that HIV rapid diagnostic tests are screening tests and mandate confirmatory testing before reporting an HIV-positive result. In addition, weak positive results should not be recognized as valid except in the screening of blood donors. PMID- 24404994 TI - Treatment of cytomegalovirus infections beyond acute disease to improve human health. AB - Human cytomegalovirus is a common virus that establishes latency and persistence after a primary infection in 50-90% of populations worldwide. In otherwise healthy persons, the infection is generally mild or asymptomatic, although it may cause mononucleosis, prolonged episodes of fever, and hepatitis. However, in AIDS patients and transplant recipients who are immunosuppressed, severe, life threatening infections may develop. CMV is also the most common congenital infection and may cause birth defects and deafness. Emerging evidence shows a high prevalence of this virus in patients with chronic inflammatory diseases or tumours of different origin, such as breast, colon, and prostate cancer, neuroblastoma, medulloblastoma, and glioblastoma. Several drugs are available to treat CMV infections. This review will highlight the possibility of using anti CMV therapy to improve outcome not only in patients with acute CMV infections but also in patients with inflammatory diseases and cancer. PMID- 24404995 TI - Effects of climate changes on skin diseases. AB - Global climate is changing at an extraordinary rate. Climate change (CC) can be caused by several factors including variations in solar radiation, oceanic processes, and also human activities. The degree of this change and its impact on ecological, social, and economical systems have become important matters of debate worldwide, representing CC as one of the greatest challenges of the modern age. Moreover, studies based on observations and predictive models show how CC could affect human health. On the other hand, only a few studies focus on how this change may affect human skin. However, the skin is the most exposed organ to environment; therefore, it is not surprising that cutaneous diseases are inclined to have a high sensitivity to climate. The current review focuses on the effects of CC on skin diseases showing the numerous factors that are contributing to modify the incidence, clinical pattern and natural course of some dermatoses. PMID- 24404996 TI - Predictors of hepatitis C treatment response: what's new? AB - Hepatitis C virus infection is a growing, global health problem, with mortality expected to reach a peak in the next ten years in many western countries. A number of host and viral factors have been established as useful predictors of treatment response in the context of interferon and ribavirin. Several new markers have recently been identified that improve our understanding of treatment response. The addition of protease inhibitors to treatment regimens has highlighted the importance of viral kinetics on-treatment in predicting response to treatment. Many new classes of direct acting anti-virals are currently being developed and expected to be clinically available in the near future. Current predictors of treatment response will be redefined in the context of interferon free regimens. PMID- 24404997 TI - Effects of dietary oregano and garlic essential oils on carcass characteristics, meat composition, colour, pH and sensory quality of broiler meat. AB - 1. An experiment was conducted to determine the individual and combined effects of two essential oils, oregano and garlic, on carcass characteristics, meat composition, colour, pH and sensory quality of broiler meat. 2. The diets were supplemented with no essential oil (control), oregano essential oil or garlic essential oil at 300 mg/kg and oregano essential oil at 150 mg/kg + garlic essential oil at 150 mg/kg. 3. Dietary oregano and garlic oil supplementation did not affect carcass yields, the relative weight of carcass parts, breast and thigh meat composition, pH or b* value of breast meat. Oregano + garlic oil supplementation significantly decreased the L* value. The a* value of breast meat in birds given a diet supplemented with oregano oil was lower than that in birds given a diet supplemented with garlic oil and oregano oil + garlic oil. The essential oil addition had no positive effect on the oxidative stability. There was no difference between the treatments in breast appearance. 4. The juiciness, flavour, oxidised flavour and acceptability of breast meat samples were affected by treatments. PMID- 24404998 TI - Hemiarthroplasty of the shoulder joint using a custom-designed high-density nano hydroxyapatite/polyamide prosthesis with a polyvinyl alcohol hydrogel humeral head surface in rabbits. AB - In this study, a novel custom-designed high-density nano-hydroxyapatite/polyamide (n-HA/PA) prosthesis with a polyvinyl alcohol (PVA) hydrogel humeral head surface was employed to repair the shoulder joint head for hemiarthroplasty in rabbits. The prosthesis was fabricated using three-dimensional computed tomography and computer-aided design and computer-aided manufacturing systems for perfect fitting. Sixteen New Zealand white rabbits underwent humeral head excision, and received the composite prostheses for hemiarthroplasty. The implant sites were free from suppuration and necrosis at all periods. The X-ray results showed that there was a clear space between the prosthesis head and the glenoid surface, and the joint capsules and surfaces of the glenoid and PVA were well preserved without any damage during the whole inspection period. A high density of bone was observed around the firmware part of the prosthesis. Histological results revealed that significant osteogenesis was surrounding the firmware part, and the joint space was clear and the cartilage of the upper joint surface was basically intact. There was no visible absorption of the joint surfaces even after 3 months of continuous functional motions. The maximum tensile strength between the prosthesis and host bone reached 2.63 MPa at the 12th week postimplantation. In conclusion, the customized prosthesis by combination of PVA and high-density n HA/PA has excellent biocompatibility and biological fixation, and offers a promising substitute for both the cartilage and the bone of the humeral head in a rabbit model as level V evidence. PMID- 24404999 TI - Prevalence and correlates of sexual morbidity in long-term breast cancer survivors. AB - OBJECTIVE: Breast cancer survivors report adverse sexual effects (sexual morbidity) such as disrupted sexual function, sexual distress and body dissatisfaction. However, most studies have failed to evaluate the persistence of these effects in long-term survivors. The present study comprehensively assessed the prevalence and predictors of sexual/body image problems among survivors three or more years post diagnosis. DESIGN/OUTCOME MEASURES: Eighty-three breast cancer survivors completed surveys a median of seven years post diagnosis. Survey items probed demographic, diagnostic and clinical information, in addition to sexual activity, sexual function (Female Sexual Function Index [FSFI]), body image, and distress regarding body changes and sexual problems (Female Sexual Distress Scale revised; FSDS-R). RESULTS: Seventy-seven percent of all participants and 60% of sexually active participants qualified for sexual dysfunction based on the FSFI. Between 37 and 51% met criteria for female sexual dysfunction, based on two FSDS R clinical cut-offs. Body satisfaction was worse than normative values, while body change stress was mid-range. Notable sexual morbidity predictors included mastectomy, which was associated with worse sexual/body change distress, and post treatment weight gain, which predicted greater body dissatisfaction/body change stress. CONCLUSIONS: Breast cancer survivors report substantial sexual morbidity years after treatment, especially after mastectomy or post-treatment weight gain. Breast cancer patients and their providers should be aware of these potential sexual effects. PMID- 24405000 TI - Attacks on linking: stressors and identity challenges for mothers of daughters with long lasting anorexia nervosa. AB - The purpose of the current study was to focus on the subjective experience of mothers of daughters with ongoing anorexia nervosa. Specifically, we explored the stressors faced by these mothers while coping with their daughters' illnesses; we also looked at how they experienced their maternal selves and roles, and their perceived competence in coping with their daughters' illnesses. Two related aspects were found to be central in the participants' experiences. One aspect was their network of relationships and how these relationships were challenged or compromised as a result of their daughters' illnesses. This aspect included the mothers' relationships with their daughters, the mothers' relationships with other family members and with their spouses/partners, the mothers' relationships with the professionals treating their daughters, and the mothers' relationships with themselves. The second related aspect was the challenge presented to the participants' self-perception as 'good mothers' by their daughters' illnesses. The findings showed that coping with a daughter's eating disorder (ED) posed a significant obstacle to the mother's ability to maintain a satisfying relationship with her daughter and her environment, as well as to maintain a positive maternal self-perception. The implications of these findings for professionals working with caregivers are discussed, and a more nuanced, gender specific attitude is suggested in working with mothers caring for daughters with EDs. PMID- 24405004 TI - Nuclear quadrupole resonance investigation of hydrogen bonding in some cocrystals of 2,3,5,6-tetramethylpyrazine and carboxylic acids. AB - Cocrystals of 2,3,5,6-tetramethylpyrazine and several carboxylic acids have been prepared, and the complete (14)N nuclear quadrupole resonance spectra have been measured. The (14)N nuclear quadrupole resonance spectra have been used to check whether the cocrystals are indeed formed and to investigate the hydrogen bonding scheme of 2,3,5,6-tetramethylpyrazine molecules. Since a 2,3,5,6 tetramethylpyrazine molecule has two hydrogen bond acceptors, it may form either 1:1 or 1:2 cocrystals with carbocylic acids. (14)N nuclear quadrupole resonance is used to distinguish between these two possibilities. Rather large (14)N quadrupole coupling constants in the investigated cocrystals show that in these systems proton transfer O-H...N -> O(-)...H-N(+) does not occur. The quadrupole coupling tensor in 2,3,5,6-tetramethylpyrazine cocrystals has been analyzed in terms of the deformation of the electron lone pair orbital and population of the pi-electron orbital. The analysis shows that the two effects are correlated. PMID- 24405007 TI - Evaluation of a behavioral treatment intervention for premature ejaculation using a handheld stimulating device. AB - Premature ejaculation is usually considered to be the most common male sexual complaint. Psychosocial treatment interventions have been recommended by clinicians since the 1950s, but concerns have been raised regarding their efficacy, especially so since the introduction of pharmaceutical treatment interventions. However, as noted in reviews and meta-analyses, one reason for these concerns is the lack of methodologically robust studies that have attempted to evaluate the efficacy of psychosocial treatment interventions. The present study aimed to replicate a recent study showing promising results for a behavioral treatment intervention using a handheld, vibrating stimulation device in a variation of the classical stop-start technique first introduced by Semans in 1956. The present study enrolled 11 men and used a randomized wait list controlled design. Results provide further support for the efficacy of this novel treatment intervention and suggest that effects are stable or improved further 6 months after completing treatment. The present study contributes to the growing number of studies that suggest that psychosocial treatment interventions are promising alternatives to pharmacological treatment. PMID- 24405010 TI - Nurse intention to implement creative group activities among psychiatric patients. AB - PURPOSE: This study examined the factors that affect nurse intention to implement creative group activities among psychiatric patients. DESIGN AND METHODS: The study used a cross-sectional design. One hundred psychiatric nurses completed a questionnaire based on the theory of reasoned action. FINDINGS: The findings indicate that the theory predicts nurse intention to implement these activities, and the most significant factors for this intention are their previous implementation and the effect of nursing managers. PRACTICE IMPLICATIONS: Nursing managers should support nurses to implement creative group activities among psychiatric patients, and provide appropriate training. PMID- 24405011 TI - The association of host and genetic melanoma risk factors with Breslow thickness in the Western Australian Melanoma Health Study. AB - BACKGROUND: Breslow thickness is the most important predictor of survival in localized malignant melanoma. A number of melanoma risk factors have been shown to be associated with Breslow thickness; however, the role of genetic loci has been little investigated to date. OBJECTIVES: To investigate the association of known melanoma susceptibility genetic loci with Breslow thickness. METHODS: Participants were 800 individuals from the Western Australian Melanoma Health Study who completed a questionnaire and provided a DNA sample. Genetic association analyses between single-nucleotide polymorphisms (SNPs) from 15 candidate melanoma susceptibility genes and Breslow thickness were performed, controlling for relevant covariates. RESULTS: Older age at diagnosis and absence of naevi were associated with increased Breslow thickness. Following adjustment for multiple testing, no SNPs were significantly associated with Breslow thickness. CONCLUSIONS: Associations observed between Breslow thickness and age and naevi reinforce current knowledge. Some evidence of shared genetic determinants between melanoma risk and Breslow thickness was found. Further studies are required to confirm this finding. PMID- 24405012 TI - ZnO nanowire arrays on 3D hierachical graphene foam: biomarker detection of Parkinson's disease. AB - We report that vertically aligned ZnO nanowire arrays (ZnO NWAs) were fabricated on 3D graphene foam (GF) and used to selectively detect uric acid (UA), dopamine (DA), and ascorbic acid (AA) by a differential pulse voltammetry method. The optimized ZnO NWA/GF electrode provided a high surface area and high selectivity with a detection limit of 1 nM for UA and DA. The high selectivity in the oxidation potential was explained by the gap difference between the lowest unoccupied and highest occupied molecular orbitals of a biomolecule for a set of given electrodes. This method was further used to detect UA levels in the serum of patients with Parkinson's disease (PD). The UA level was 25% lower in PD patients than in healthy individuals. This finding strongly implies that UA can be used as a biomarker for PD. PMID- 24405014 TI - A prospective analysis of corneal endothelial polymegethism and cell density in young adult Asians. AB - PURPOSE: The aim was to assess the morphology of the Asian corneal endothelium, particularly the index of polymegethism and its relationship to endothelial cell density assessments. METHODS: The central regions of the corneal endothelium of 72 healthy, normal weight, non-contact lens wearers were assessed by non-contact specular microscopy. There were six groups of persons, aged between 18 and 27 years, whose ethnic origins were self-reported as Asian (Mainland China, Hong Kong, India, Malaysia, Pakistan or other Asian groups). Single images including at least 100 contiguous cells were obtained from each subject and were processed by planimetry after manual border marking to minimise errors. Calculations were made of the coefficient of variation of cell area (COV; polymegethism) as well as the endothelial cell density and percentage of six-sided cells. RESULTS: The COV values ranged from 18 to 30.4 per cent (group mean 24.5 +/- 2.8 per cent). The corneas had essentially normal thickness (0.530 +/- 0.026 mm), with the endothelia showing a high percentage of six-sided cells (66.3 +/- 7.1 per cent) and none showing even mild signs of polymegethism. Endothelial cell density estimates based on average cell areas ranged from 2,020 to 3,623 cells per mm(2) and from 2,157 to 3,835 with calculations based on individual cell areas. The difference between the two estimates of endothelial cell density was strongly related to the coefficient of variation (r = 0.765). CONCLUSIONS: This result is consistent with several older reports indicating that it is uncommon to find polymegethism in healthy young adult Asian individuals. Nonetheless, even low coefficient of variation values can substantially affect the estimations of the cell density. PMID- 24405013 TI - Fate and uptake of pharmaceuticals in soil-plant systems. AB - Pharmaceuticals have been detected in the soil environment where there is the potential for uptake into crops. This study explored the fate and uptake of pharmaceuticals (carbamazepine, diclofenac, fluoxetine, propranolol, sulfamethazine) and a personal care product (triclosan) in soil-plant systems using radish (Raphanus sativus) and ryegrass (Lolium perenne). Five of the six chemicals were detected in plant tissue. Carbamazepine was taken up to the greatest extent in both the radish (52 MUg/g) and ryegrass (33 MUg/g), whereas sulfamethazine uptake was below the limit of quantitation (LOQ) (<0.01 MUg/g). In the soil, concentrations of diclofenac and sulfamethazine dropped below the LOQ after 7 days. However, all pharmaceuticals were still detectable in the pore water at the end of the experiment. The results demonstrate the ability of plant species to accumulate pharmaceuticals from soils with uptake apparently specific to both plant species and chemical. Results can be partly explained by the hydrophobicity and extent of ionization of each chemical in the soil. PMID- 24405017 TI - Drinking preferences in chinchillas (Chinchilla laniger), degus (Octodon degu) and guinea pigs (Cavia porcellus). AB - Chinchilla (Chinchilla laniger), degus (Octodon degus) and guinea pigs (Cavia porcellus) are South American rodents living in a semi-arid habitat with varying, species-specific adaptations to water deprivation. Nonetheless, several diseases have been linked to insufficient water intake when these species are kept as pets, such as urolithiasis or obstipation. This study evaluated preferences for drinking systems. Six animals of each species were given a choice between an open dish and a nipple drinker. Food intake and water intake were measured daily for 13 days. Chinchillas in this study had significantly lower water intakes than the other two species, indicating particular species-specific adaptations to aridity. All chinchillas favoured open dishes, whereas the degus and guinea pigs had variable individual preferences. Water intake of chinchillas was similar or higher in this study than in previous studies where nipple drinkers were used. The results indicate that degus and guinea pigs can meet their drinking water needs with nipple drinkers; for chinchillas, other drinking systems may be more adequate. PMID- 24405018 TI - Monoterpenoids from the whole herb of Veronicastrum axillare. AB - CONTEXT: Veronicastrum axillare (Sieb. et Zucc.) Yamazaki (Scrophulariaceae) embraces varieties of bioactivities such as anti-inflammatory, anti-pyresis and detoxification activity, while little is known of the phytochemical components of this medicinal plant. OBJECTIVE: To isolate and identify bioactive constituents from the whole herb of V. axillare. MATERIALS AND METHODS: Ethanol extract of the whole herb of V. axillare was subjected to successive column chromatography. Chemical structures of the compounds were elucidated by detailed spectroscopic analyses on the basis of NMR, IR and HR-MS data. RESULTS: A new monoterpenoid, axillacetal A (1) and a known analogue, tarumal (2), were isolated from the whole herb of V. axillare. The structure of tarumal (2) was also revised according to our NMR data. DISCUSSION AND CONCLUSION: This is the first report on the isolation and authentication of novel chemical constituents from V. axillare. PMID- 24405019 TI - Galactosylated poly(ethylene glycol) methacrylate-st-3-guanidinopropyl methacrylamide copolymers as siRNA carriers for inhibiting Survivin expression in vitro and in vivo. AB - In this report, galactosylated poly(ethylene glycol) methacrylate-st-3 guanidinopropyl methacrylamide copolymers (galactosylated PEGMA-st-GPMA, GGP) are developed as siRNA carriers to inhibit Survivin mRNA expression. GGPs are combined with Survivin siRNAs to form siRNA/GGP polyplexes. The polyplexes particles were examined by a dynamic light scattering. It showed that GGP copolymers could condense siRNA to form particles with diameter from 128 to 423 nm and zeta potential value in the range from +2.4 to +14.9 mV at various charge ratios (N/P). The MTT assay data of siRNA/GGP polyplexes on human hepatocellular liver carcinoma cells (HepG2) and human cervix epithelial carcinoma cells (HeLa) indicated that GGP copolymer had better cell viabilities than polyethyleimine (PEI). The transfection of siRNA/GGP polyplexes was detected by real-time quantitative PCR (RT-qPCR) in HepG2 cell line. We found that the siRNA/GGP polyplexes could effectively silence Survivin mRNA expression in the serum-free media (p < 0.01). In the presence of 10% serum medium, the Survivin mRNA expressed has significant difference between siRNA/GGP polyplexes and blank (p < 0.05). The galactose competition assay showed that galactosylated PEGMA-st-GPMA (GGP) may provide the targeting to HepG2 cells mediating by asialoglycoproteins receptors (ASGP-R). Furthermore, Survivin siRNA/GGP polyplexes could significantly (p < 0.01) inhibit both HepG2 tumor growth and Survivin protein expression in vivo studies in a xenograft mouse model. PMID- 24405020 TI - Preliminary evaluation of novel skin closure of Pfannenstiel incisions using cold helium plasma and chitosan films. AB - OBJECTIVE: To assess the safety and performance of a new energy-based skin closure system (BioWeld1(TM)) for the surgical Pfannenstiel incision in patients scheduled for elective cesarean section. METHODS: This prospective, single center, non-randomized study included 20 patients who were scheduled for elective cesarean section. The BioWeld1 system was performed after suturing the internal layers of the cesarean section incision. A clinical evaluation of safety and efficacy was performed for 1, 2, 4-7, 21, and 45 d after the procedure. The Vancouver Scar Scale (VSS) was used to evaluate scarring. RESULTS: Up to 21 d after the procedure, no safety device-related adverse events were reported. All patients had full closure of the epidermis, a very low total VSS score, and no evidence of discharge, redness, edema, or thermal damage. None of the patients exhibited more than a mild degree of encrustation. CONCLUSION: The BioWeld1 System has been shown to be safe and effective for skin closure in cesarean section. PMID- 24405022 TI - LiPbSb3S6: a semiconducting sulfosalt with very low thermal conductivity. AB - The new semiconductor LiPbSb3S6 crystallizes in the space group P21/c. The structure is a member of the lillianite homologous series and is composed of layers of PbS archetype Sb/Li-S separated by trigonal-prismatic-coordinated Pb/Li. Electronic band structure calculations indicate an indirect band gap, with direct gaps lying very close in energy. LiPbSb3S6 has one of the lowest thermal conductivities seen in a crystalline material, ~0.24 W m(-1) K(-1) at room temperature, and a high resistivity, ~4 * 10(9) Omega.cm, and exhibits strong light absorption with a nearly direct band gap of 1.6 eV. PMID- 24405024 TI - Asymmetric conjugate hydrocyanation of alpha,beta-unsaturated N-acylpyrroles with the Ru(phgly)2(binap)-CH3OLi catalyst system. AB - Asymmetric conjugate hydrocyanation of alpha,beta-unsaturated carboxylic acid derivatives catalyzed by a Ru[(S)-phgly]2[(S)-binap]-CH3OLi system was examined. The N-acylpyrrole gave the best result in terms of reactivity and enantioselectivity. A series of substrates with alkyl or heterosubstituted alkyl groups at the beta-position reacted with a substrate-to-catalyst molar ratio of 200-2000 to afford the beta-cyano products in the range of 88%->99% ee. The mode of enantioselection in the hydrocyanation was proposed. PMID- 24405026 TI - Air-stable, solution-processed oxide p-n heterojunction ultraviolet photodetector. AB - Air-stable solution processed all-inorganic p-n heterojunction ultraviolet photodetector is fabricated with a high gain (EQE, 25 300%). Solution-processed NiO and ZnO films are used as p-type and n-type ultraviolet sensitizing materials, respectively. The high gain in the detector is due to the interfacial trap-induced charge injection that occurs at the ITO/NiO interface by photogenerated holes trapped in the NiO film. The gain of the detector is controlled by the post-annealing temperature of the solution-processed NiO films, which are studied by X-ray photoelectron spectroscopy (XPS). PMID- 24405025 TI - Culturing muscle fibres in hanging drop: a novel approach to solve an old problem. AB - BACKGROUND INFORMATION: The satellite cells (SCs) associated with muscle fibres play a key role in postnatal growth and regeneration of skeletal muscle. Commonly used methods of isolation and in vitro culture of SCs lead to the mixture of their subpopulations that exist within muscle. To solve this problem, we used the well established technique, the hanging drop system, to culture SCs in a three dimensional environment and thus, to monitor them in their original niche. RESULTS: Using hanging drop technique, we were able to culture SCs associated with the fibre at least for 9 days with one transfer of fibres to the fresh drops. In comparison, in the classical method of myofibres culture, that is, on the dishes coated with Matrigel, SCs leave the fibres within 3 days after the isolation. Cells cultured in both systems differed in expression of Pax7 and MyoD. While almost all cells cultured in adhesion system expressed MyoD before the fifth day of the culture, the majority of SCs cultured in hanging drop still maintained expression of Pax7 and were not characterised by the presence of MyoD. Among the cells cultured with single myofibre for up to 9 days, we identified two different subclones of SCs: low proliferative clone and high proliferative clone, which differed in proliferation rate and membrane potential. CONCLUSIONS: The hanging drop enables the myofibres to be kept in suspension for at least 9 days, and thus, allows SCs and their niche to interact each other for prolonged time. In a consequence, SCs cultured in hanging drop maintain expression of Pax7 while those cultured in a traditional adhesion culture, that is, devoid of signals from the original niche, activate and preferentially undergo differentiation as manifested by expression of MyoD. Thus, the innovative method of SCs culturing in the hanging drop system may serve as a useful tool to study the fate of different subpopulations of these cells in their anatomical location and to determine reciprocal interactions between them and their niche. PMID- 24405028 TI - Acute effects of static and dynamic stretching on hamstrings' response times. AB - The main purposes of this study were to (a) investigate acute effects of static and dynamic lower limb stretching routines on total response time, pre-motor time and motor time of the medial and lateral hamstrings during maximal eccentric isokinetic knee flexion; and (b) determine whether static and dynamic routines elicit similar responses. A total of 38 active adults completed the following intervention protocols in a randomised order on separate days: (a) non-stretching (control condition), (b) static stretching and (c) dynamic stretching. After the stretching or control intervention, total response time, pre-motor time and motor time of the medial and lateral hamstrings were assessed during eccentric knee flexion movements with participants prone. Measures were compared via a mixed design factorial ANOVA. There were no main effects for total response time, pre motor time and motor time. The results suggest that dynamic and static stretching has no influence on hamstrings response times (total response time, pre-motor time and motor time) and hence neither form of stretching reduces this primary risk factor for anterior cruciate ligament injury. PMID- 24405029 TI - Molecular typing of Iranian field isolates Mycoplasma synoviae and their differentiation from the live commercial vaccine strain MS-H using vlhA gene. AB - 1. The single-copy domain of the N-terminal region of the vlhA gene of Mycoplasma synoviae was sequenced, analysed and verified and used to type Iranian field isolates of M. synoviae and the MS-H live vaccine strain. In addition, a restriction fragment length polymorphism (RFLP) method was developed to differentiate between field isolates of Iranian and MS-H vaccine strains. 2. All sequences were analysed and aligned; the percentage similarity of the DNA was calculated and dendrograms were constructed. Based on single nucleotide polymorphism (SNP) that existed in all field isolates in Iran, the PCR-RFLP method allowed the differentiation of all M. synoviae field isolates from the vaccine strain. 3. Using phylogenetic analysis, the isolates were assigned to 8 unique genotypes and, within each group, DNA had a high level of similarity. 4. DNA sequence analysis and PCR-RFLP of the amplicon based on percent similarity and evolutionary relationship appeared to be useful tools for strain differentiation whether M. synoviae clinical isolates from infected chickens were derived from the vaccine strain or wild-type strains. 5. This study confirms the potential value of strain typing for epidemiological purposes and suggests that phylogenetic studies are essential to understand the true relationships between strains. PMID- 24405030 TI - A historical case of amelogenesis imperfecta: Giovanna of Austria, Grand Duchess of Tuscany (1547-1578). AB - The skeletal remains of Giovanna of Austria (1547-1578), daughter of the Emperor Ferdinand I of Habsburg (1503-1564) and first wife of the Grand Duke of Tuscany, Francesco I (1541-1587), exhumed from the Basilica of San Lorenzo in Florence, were submitted to paleopathological study. Examination of the dentition, which was in a good state of preservation, showed maxillary retrognathism, together with a caries lesion, moderate periodontal disease, malposition of the upper second premolars and tooth wear. Furthermore, several horizontal grooves were observed in both the buccal and the lingual crown surfaces of almost all teeth, especially the anterior ones. The orthopantomogram showed hypomineralized enamel and alveolar bone loss. Two third-molar teeth were investigated using micro computed tomography (micro-CT) analysis, revealing highly irregular enamel caps with reduced average thickness. The observed features suggest a diagnosis of hypoplastic amelogenesis imperfecta, a developmental condition affecting enamel formation. PMID- 24405031 TI - Disruption of vector transmission by a plant-expressed viral glycoprotein. AB - Vector-borne viruses are a threat to human, animal, and plant health worldwide, requiring the development of novel strategies for their control. Tomato spotted wilt virus (TSWV) is one of the 10 most economically significant plant viruses and, together with other tospoviruses, is a threat to global food security. TSWV is transmitted by thrips, including the western flower thrips, Frankliniella occidentalis. Previously, we demonstrated that the TSWV glycoprotein GN binds to thrips vector midguts. We report here the development of transgenic plants that interfere with TSWV acquisition and transmission by the insect vector. Tomato plants expressing GN-S protein supported virus accumulation and symptom expression comparable with nontransgenic plants. However, virus titers in larval insects exposed to the infected transgenic plants were three-log lower than insects exposed to infected nontransgenic control plants. The negative effect of the GN-S transgenics on insect virus titers persisted to adulthood, as shown by four-log lower virus titers in adults and an average reduction of 87% in transmission efficiencies. These results demonstrate that an initial reduction in virus infection of the insect can result in a significant decrease in virus titer and transmission over the lifespan of the vector, supportive of a dose-dependent relationship in the virus-vector interaction. These findings demonstrate that plant expression of a viral protein can be an effective way to block virus transmission by insect vectors. PMID- 24405032 TI - Effectors as tools in disease resistance breeding against biotrophic, hemibiotrophic, and necrotrophic plant pathogens. AB - One of most important challenges in plant breeding is improving resistance to the plethora of pathogens that threaten our crops. The ever-growing world population, changing pathogen populations, and fungicide resistance issues have increased the urgency of this task. In addition to a vital inflow of novel resistance sources into breeding programs, the functional characterization and deployment of resistance also needs improvement. Therefore, plant breeders need to adopt new strategies and techniques. In modern resistance breeding, effectors are emerging as tools to accelerate and improve the identification, functional characterization, and deployment of resistance genes. Since genome-wide catalogues of effectors have become available for various pathogens, including biotrophs as well as necrotrophs, effector-assisted breeding has been shown to be successful for various crops. "Effectoromics" has contributed to classical resistance breeding as well as for genetically modified approaches. Here, we present an overview of how effector-assisted breeding and deployment is being exploited for various pathosystems. PMID- 24405033 TI - Pleiotropic function of the putative zinc-finger protein MoMsn2 in Magnaporthe oryzae. AB - The mitogen-activated protein kinase MoOsm1-mediated osmoregulation pathway plays crucial roles in stress responses, asexual and sexual development, and pathogenicity in Magnaporthe oryzae. Utilizing an affinity purification approach, we identified the putative transcriptional activator MoMsn2 as a protein that interacts with MoOsm1 in vivo. Disruption of the MoMSN2 gene resulted in defects in aerial hyphal growth, conidial production, and infection of host plants. Quantitative reverse transcription-polymerase chain reaction analysis showed that the expression of several genes involved in conidiophore formation was reduced in DeltaMomsn2, suggesting that MoMsn2 might function as a transcriptional regulator of these genes. Subsequently, MoCos1 was identified as one of the MoMsn2 targets through yeast one-hybrid analysis in which MoMsn2 binds to the AGGGG and CCCCT motif of the MoCOS1 promoter region. Phenotypic characterization showed that MoMsn2 was required for appressorium formation and penetration and pathogenicity. Although the DeltaMomsn2 mutant was tolerant to the cell-wall stressor Calcofluor white, it was sensitive to common osmotic stressors. Further analysis suggests that MoMsn2 is involved in the regulation of the cell-wall biosynthesis pathway. Finally, transcriptome data revealed that MoMsn2 modulates numerous genes participating in conidiation, infection, cell-wall integrity, and stress response. Collectively, our results led to a model in which MoMsn2 mediates a series of downstream genes that control aerial hyphal growth, conidiogenesis, appressorium formation, cell-wall biosynthesis, and infection and that also offer potential targets for the development of new disease management strategies. PMID- 24405034 TI - The Potyviridae cylindrical inclusion helicase: a key multipartner and multifunctional protein. AB - A unique feature shared by all plant viruses of the Potyviridae family is the induction of characteristic pinwheel-shaped inclusion bodies in the cytoplasm of infected cells. These cylindrical inclusions are composed of the viral-encoded cylindrical inclusion helicase (CI protein). Its helicase activity was characterized and its involvement in replication demonstrated through different reverse genetics approaches. In addition to replication, the CI protein is also involved in cell-to-cell and long-distance movements, possibly through interactions with the recently discovered viral P3N-PIPO protein. Studies over the past two decades demonstrate that the CI protein is present in several cellular compartments interacting with viral and plant protein partners likely involved in its various roles in different steps of viral infection. Furthermore, the CI protein acts as an avirulence factor in gene-for-gene interactions with dominant-resistance host genes and as a recessive-resistance overcoming factor. Although a significant amount of data concerning the potential functions and subcellular localization of this protein has been published, no synthetic review is available on this important multifunctional protein. In this review, we compile and integrate all information relevant to the current understanding of this viral protein structure and function and present a mode of action for CI, combining replication and movement. PMID- 24405035 TI - Sinorhizobium meliloti flavin secretion and bacteria-host interaction: role of the bifunctional RibBA protein. AB - Sinorhizobium meliloti, the nitrogen-fixing bacterial symbiont of Medicago spp. and other legumes, secretes a considerable amount of riboflavin. This precursor of the cofactors flavin mononucleotide and flavin adenine dinucleotide is a bioactive molecule that has a beneficial effect on plant growth. The ribBA gene of S. meliloti codes for a putative bifunctional enzyme with dihydroxybutanone phosphate synthase and guanosine triphosphate (GTP) cyclohydrolase II activities, catalyzing the initial steps of the riboflavin biosynthesis pathway. We show here that an in-frame deletion of ribBA does not cause riboflavin auxotrophy or affect the ability of S. meliloti to establish an effective symbiosis with the host plant but does affect the ability of the bacteria to secrete flavins, colonize host-plant roots, and compete for nodulation. A strain missing the RibBA protein retains considerable GTP cyclohydrolase II activity. Based on these results, we hypothesize that S. meliloti has two partly interchangeable modules for biosynthesis of riboflavin, one fulfilling the internal need for flavins in bacterial metabolism and the other producing riboflavin for secretion. Our data also indicate that bacteria-derived flavins play a role in communication between rhizobia and the legume host and that the RibBA protein is important in this communication process even though it is not essential for riboflavin biosynthesis and symbiosis. PMID- 24405039 TI - Hierarchical folding free energy landscape of HP35 revealed by most probable path clustering. AB - Adopting extensive molecular dynamics simulations of villin headpiece protein (HP35) by Shaw and co-workers, a detailed theoretical analysis of the folding of HP35 is presented. The approach is based on the recently proposed most probable path algorithm which identifies the metastable states of the system, combined with dynamical coring of these states in order to obtain a consistent Markov state model. The method facilitates the construction of a dendrogram associated with the folding free-energy landscape of HP35, which reveals a hierarchical funnel structure and shows that the native state is rather a kinetic trap than a network hub. The energy landscape of HP35 consists of the entropic unfolded basin U, where the prestructuring of the protein takes place, the intermediate basin I, which is connected to U via the rate-limiting U -> I transition state reflecting the formation of helix-1, and the native basin N, containing a state close to the NMR structure and a native-like state that exhibits enhanced fluctuations of helix-3. The model is in line with recent experimental observations that the intermediate and native states differ mostly in their dynamics (locked vs unlocked states). Employing dihedral angle principal component analysis, subdiffusive motion on a multidimensional free-energy surface is found. PMID- 24405036 TI - Tobacco and alcohol use in the context of adolescent pregnancy and postpartum: a scoping review of the literature. AB - Adolescent girls are more likely than women of other ages to smoke tobacco or drink alcohol during pregnancy. The health impacts of smoking and drinking for girls and the interconnections between alcohol and tobacco use with adolescent pregnancy underscore the urgent need for integrated approaches to prevent and reduce alcohol and tobacco use among pregnant girls/young women. This article reports on the results of a scoping review of the literature focused on adolescents' use of tobacco and alcohol during pregnancy and postpartum. A search of CINAHL, Medline, Social Science Index and Web of Science identified 40 articles published in the two decades between 1990 and 2012 that met our inclusion criteria related to this age group, pregnancy/motherhood status, and use of both alcohol and tobacco. The review points to compelling gaps in our knowledge and our responsiveness to adolescents aged 19 and under who use alcohol and tobacco during pregnancy and the postpartum period. Research has been primarily descriptive, with separate, parallel streams of investigation to identify trends and predictors of alcohol and tobacco use, prior to, during and following pregnancy. There is a marked lack of effective interventions described in the literature that are designed to prevent or reduce alcohol and tobacco use during pregnancy among adolescent girls; and there are few examples of gender informed prevention or treatment programmes for this population. Research is needed on interventions that attend to the context of adolescent girls' substance use as well as their preferences and developmental needs for support that encourage sustained behaviour change throughout pregnancy and the postpartum period and that effectively address the influence of partners and friends on use. PMID- 24405042 TI - The Western Australian family connections genealogical project: detection of familial occurrences of single gene and chromosomal disorders. AB - AIM: To investigate using a Western Australian (WA) genealogical database for the identification of single gene and chromosome disorders among families. METHOD: Hospital admissions for single gene and chromosome disorders recorded during 2000 2006 were identified from the WA Hospital Morbidity Data System. The proportion of these conditions occurring in family groups was then identified using genealogical links created through the WA Family Connections Genealogical Project. RESULTS: There were 216 family clusters among 11,303 people who were recorded as having a genetic or chromosomal disorder on their hospital admission record. The most common single gene conditions found to occur in multiple family members included blood clotting disorders such as Factor VIII deficiency and Von Willebrand's disease, followed by cystic fibrosis, myotonic dystrophies, neurofibromatosis, tuberous sclerosis, and osteogenesis imperfecta. DISCUSSION: Single gene disorders most commonly occurring in multiple family members have been identified using the WA Family Connections Genealogical Project. These disorders reflect the most common single gene disorders requiring hospital admission, but which are not fatal before reproductive age and do not result in a loss of fertility. They are also restricted to disorders with earlier onset, as the WA Family Connections Genealogical Project currently covers 2-3 of the most recent generations. This study demonstrates the utility of record linkage genealogies to identify kindred with genetic disorders, offering a rich resource of information for focused genetic epidemiological research. PMID- 24405043 TI - Uniaxially aligned electrospun all-cellulose nanocomposite nanofibers reinforced with cellulose nanocrystals: scaffold for tissue engineering. AB - Uniaxially aligned cellulose nanofibers with well oriented cellulose nanocrystals (CNCs) embedded were fabricated via electrospinning using a rotating drum as the collector. Scanning electron microscope (SEM) images indicated that most cellulose nanofibers were uniaxially aligned. The incorporation of CNCs into the spinning dope resulted in more uniform morphology of the electrospun cellulose/CNCs nanocomposite nanofibers (ECCNN). Polarized light microscope (PLM) and transmission electron microscope (TEM) showed that CNCs dispersed well in ECCNN nonwovens and achieved considerable orientation along the long axis direction. This unique hierarchical microstructure of ECCNN nonwovens gave rise to remarkable enhancement of their physical properties. By incorporating 20% loading (in weight) of CNCs, the tensile strength and elastic modulus of ECCNN along the fiber alignment direction were increased by 101.7 and 171.6%, respectively. Their thermal stability was significantly improved as well. In addition, the ECCNN nonwovens were assessed as potential scaffold materials for tissue engineering. It was elucidated from MTT tests that the ECCNN were essentially nontoxic to human cells. Cell culture experiments demonstrated that cells could proliferate rapidly not only on the surface but also deep inside the ECCNN. More importantly, the aligned nanofibers of ECCNN exhibited a strong effect on directing cellular organization. This feature made the scaffold particularly useful for various artificial tissues or organs, such as blood vessel, tendon, nerve, and so on, in which cell orientation was crucial for their performance. PMID- 24405044 TI - Vitamin B12 supplement alleviates N'-nitrosodimethylamine-induced hepatic fibrosis in rats. AB - Abstract Context: Altered vitamin B12 levels have been correlated with hepatotoxicity; however, further evidence is required to establish its protective role. Objective: To evaluate the effects of vitamin B12 supplement in protecting N'-nitrosodimethylamine (NDMA)-induced hepatic fibrosis in Wistar rats. Materials and methods: Hepatic fibrosis was induced by administering NDMA in doses of 10 mg/kg body weight thrice a week for 21 days. Another group received equal doses (10 mg/kg body weight) of vitamin B12 subsequent to NDMA treatment. Animals from either group were sacrificed weekly from the start of the treatment along with their respective controls. Progression of hepatic fibrosis, in addition to the effect of vitamin B12, was assessed biochemically for liver function biomarkers, liver glycogen, hydroxyproline (HP) and B12 reserves along with histopathologically by hematoxylin and eosin (H & E) as well immunohistochemical staining for alpha-SMA expression. Results and discussion: Elevation in the levels of aminotransferases, SALP, total bilirubin and HP was observed in NDMA treated rats, which was concomitant with remarkable depletion in liver glycogen and B12 reserves (p < 0.05). Liver biopsies also demonstrated disrupted lobular architecture, collagen amassing and intense fibrosis by NDMA treatment. Immunohistochemical staining showed the presence of activated stellate cells that was dramatically increased up to day 21 in fibrotic rats. Following vitamin B12 treatment, liver function biomarkers, glycogen contents and hepatic vitamin B12 reserves were restored in fibrotic rats, significantly. Vitamin B12 administration also facilitated restoration of normal liver architecture. Conclusion: These findings provide interesting new evidence in favor of protective role for vitamin B12 against NDMA-induced hepatic fibrosis in rats. PMID- 24405047 TI - Optimization of antimicrobial and physical properties of alginate coatings containing carvacrol and methyl cinnamate for strawberry application. AB - Increasing strawberry consumption has led to a growing safety concern because they are not washed after harvest. An antimicrobial edible coating could be an effective postharvest technique to ensure microbial safety and, at the same time, retain overall quality of the fruits. Response surface methodology was used to optimize the antimicrobial activity against Escherichia coli O157:H7 and Botrytis cinerea and several physical properties (turbidity, viscosity, and whitish index) of an alginate coating. A full factorial design was used to select the concentrations of carvacrol and methyl cinnamate on the basis of their effect against E. coli and B. cinerea. A central composite design was then performed to evaluate the effects/interactions of the two antimicrobials on the coating characteristics. The results from analysis of variance showed the significant fitting of all responses to the quadratic model. To attain the desirable responses, the optimal concentrations were 0.98% (w/w) carvacrol and 1.45% (w/w) methyl cinnamate. PMID- 24405048 TI - Epstein-Barr virus-driven bone marrow aplasia and plasmacytosis mimicking a plasma cell neoplasm. PMID- 24405051 TI - Assessment of the performance of automated focimeters in the measurement of single vision spectacle lenses. AB - BACKGROUND: The accuracy and precision of any instrument should not be taken for granted. While there is an international standard for checking focimeters, there is no report of any study on their performance. METHOD: A sample set of 51 focimeters (11 brands), were used to measure the spherical power of a set of lenses and the prismatic power of two lenses complying with ISO 9342-1:2005 and other calibrated prismatic lenses and the spherical power of some grey filters. RESULTS: The mean measured spherical power corresponded very closely with the calibrated values; however, the spread of results was substantial and 10 focimeters did not comply with ISO 8598:1996. The measurement of prism was much more accurate and precise and all the focimeters complied easily. With the grey filters, about one-third of the focimeters either showed erratic reading or an error with the equivalent of category 4 sunglasses. On the other hand, nine focimeters had stable and accurate reading on a filter with a luminous transmittance of 0.5 per cent. CONCLUSIONS: These results confirm that, in common with all other measurement instruments, there is a need to ensure that a focimeter is reading accurately and precisely over the range of refractive powers and luminous transmittances. The accurate and precise performance of an automated focimeter over its working life cannot be assumed. Checking before purchase with a set of calibrated lenses and some dark sunglass tints will indicate the suitability of a focimeter. Routine checking with the calibrated lenses will inform the users if a focimeter continues to indicate accurately. PMID- 24405052 TI - Realizing ferromagnetic coupling in diluted magnetic semiconductor quantum dots. AB - Manipulating the ferromagnetic interactions in diluted magnetic semiconductor quantum dots (DMSQDs) is a central theme to the development of next-generation spin-based information technologies, but this remains a great challenge because of the intrinsic antiferromagnetic coupling between impurity ions therein. Here, we propose an effective approach capable of activating ferromagnetic exchange in ZnO-based DMSQDs, by virtue of a core/shell structure that engineers the energy level of the magnetic impurity 3d levels relative to the band edge. This idea has been successfully applied to Zn(0.96)Co(0.04)O DMSQDs covered by a shell of ZnS or Ag2S. First-principles calculations further indicate that covering a ZnS shell around the Co-doped ZnO core drives a transition of antiferromagnetic-to ferromagnetic interaction, which occurs within an effective depth of 1.2 nm underneath the surface in the core. This design opens up new possibility for effective manipulation of exchange interactions in doped oxide nanostructures for future spintronics applications. PMID- 24405053 TI - A pilot study of potential pre-operative barriers to couples' sexual recovery after radical prostatectomy for prostate cancer. AB - Prostate cancer affects couples' sexual intimacy, but men rarely use recommended proerectile aids. This mixed-methods study aimed to identify couples' preprostatectomy barriers to sexual recovery. Interviews about anticipated sexual recovery were paired with surveys: the Dyadic Assessment Scale, the Protective Buffering Scale, the Expanded Prostate Cancer Index Composite, the Sexual Experience Questionnaire (men), and the Female Sexual Function Index. Potential barriers were derived using Grounded Theory. Quantitative data triangulated qualitative findings. Heterosexual couples (N = 28) participated. Men's average age was 62 years and their partners' average age was 58 years. Preexisting and diagnosis-related barriers included aging-related sexual dysfunction, inadequate sexual problem-solving skills, stressors, worry, avoidance of planning for sexual recovery, and dislike of artificially assisted sex. Participants endorsed moderate/high marital satisfaction (DAS: for men, M = 110.0, SD = 11.4; for partners, M = 114.1, SD = 12.1) and communication (PBS: for men, M = 24.5.2, SD = 6.1; for partners, M = 25.1, SD +/- 6.2). Men reported mild erectile dysfunction and incontinence (EPIC sexual function M = 76.6, SD = 21.5, urinary incontinence M = 88.4, SD = 18.2). Men's couple sexual satisfaction was lowest (Sexual Experience Questionnaire: M = 60.1, SD = 26.9). Mean total Female Sexual Function Index was low (M = 21.6, SD = 7.8). Heterosexual couples face prostatectomy related sexual side-effects having experienced developmental sexual losses. Couples use avoidant strategies to defend against worry about cancer and anticipated prostatectomy-related sexual changes. These potential barriers are modifiable if couples can learn to cope with sexual losses and accept sexual rehabilitation strategies. PMID- 24405056 TI - Experiments and synthesis of bone-targeting epirubicin with the water-soluble macromolecular drug delivery systems of oxidized-dextran. AB - Epirubicin (EPI) is a broad spectrum antineoplastic drug, commonly used as a chemotherapy method to treat osteosarcoma. However, its application has been limited by many side-effects. Therefore, targeted drug delivery to bone has been the aim of current anti-bone-tumor drug studies. Due to the exceptional affinity of Bisphosphonates (BP) to bone, 1-amino-ethylene-1, 1-dephosphate acid (AEDP) was chosen as the bone targeting moiety for water-soluble macromolecular drug delivery systems of oxidized-dextran (OXD) to transport EPI to bone in this article. The bone targeting drug of AEDP-OXD-EPI was designed for the treatment of malignant bone tumors. The successful conjugation of AEDP-OXD-EPI was confirmed by analysis of FTIR and (1)H-NMR spectra. To study the bone-seeking potential of AEDP-OXD-EPI, an in vitro hydroxyapatite (HAp) binding assay and an in vivo experiment of bone-targeting capacity were established. The effectiveness of AEDP-OXD-EPI was demonstrated by inducing apoptosis and necrosis of MG-63 tumor cell line. The obtained experimental data indicated that AEDP-OXD-EPI is an ideal bone-targeting anti-tumor drug. PMID- 24405057 TI - Toward a safer working environment on psychiatric wards: service users' delayed perspectives of aggression and violence-related situations and development ideas. AB - PURPOSE: To explore service users' (n = 9) delayed perceptions of and suggestions for improvement of management of aggression/violence in psychiatry. DESIGN AND METHOD: Focus group interviews, inductive content analysis. FINDINGS: Participants reported aggression/violence-related negative perceptions (including loneliness, boredom, excessive control, and fear) but also memories of humane and caring personnel. The suggestions included meaningful activities and humane, interactive nursing. PRACTICE IMPLICATIONS: Delayed perceptions and proposals resembled the proximate ones. Perceptions may persist for years. Such perceptions and proposals, if taken into account from the beginning of treatment, may prevent negative long-term consequences of witnessed or experienced aggression/violence. Humane, interactive nursing models should be studied and disseminated. PMID- 24405058 TI - Membrane-based assay for iodide ions based on anti-leaching of gold nanoparticles. AB - We report a label-free colorimetric strategy for the highly selective and sensitive detection of iodide (I(-)) ions in human urine sample, seawater and edible salt. A poly(N-vinyl-2-pyrrolidone)-stabilized Au nanoparticle (34.2-nm) was prepared to detect I(-) ions using silver (Ag(+)) and cyanide (CN(-)) ions as leaching agents in a glycine-NaOH (pH 9.0) solution. For the visual detection of the I(-) ions by naked eye, and for long time stability of the probe, Au nanoparticles (NPs) decorated mixed cellulose ester membrane (MCEM) was prepared (Au NPs/MCEM). The Au NPs-based probe (CN(-)/Ag(+)-Au NPs/MCEM) operates on the principle that Ag(+) ions form a monolyar silver atoms/ions by aurophilic/argentophilic interactions on the Au NPs and it accelerates the leaching rate of Au atoms in presence of CN(-) ions. However, when I(-) is introduced into this system, it inhibits the leaching of Au atoms because of the strong interactions between Ag/Au ions and I(-) ions. Inductively coupled plasma mass spectrometry, surface-assisted laser desorption/ionization time-of-flight mass spectrometry were used to characterize the surface properties of the Au NPs in the presence of Ag(+) and I(-). Under optimal solution conditions, the CN( )/Ag(+)-Au NPs/MCEM probe enabled the detection of I(-) by the naked eye at nanomolar concentrations with high selectivity (at least 1000-fold over other anions). In addition, this cost-effective probe allowed the determination of I(-) ions in complex samples, such as urine, seawater, and edible salt samples. PMID- 24405059 TI - POP-pincer ruthenium complexes: d(6) counterparts of osmium d(4) species. AB - A wide range of ruthenium complexes stabilized by the POP-pincer ligand xant(P(i)Pr2)2 (9,9-dimethyl-4,5-bis(diisopropylphosphino)xanthene) were prepared starting from cis-RuCl2{kappa-S-(DMSO)4} (1; DMSO = dimethyl sulfoxide). Treatment of toluene solutions of this adduct with the diphosphine under reflux leads to RuCl2{xant(P(i)Pr2)2}(kappa-S-DMSO) (2), which reacts with H2 in the presence of a Bronsted base. The reaction in the presence of Et3N affords RuHCl{xant(P(i)Pr2)2}(kappa-S-DMSO) (3), whereas NaH removes both chloride ligands to give RuH2{xant(P(i)Pr2)2}(kappa-S-DMSO) (4). The stirring of 3 in 2 propanol under 3 atm of H2 for a long time produces the elimination of DMSO and the coordination of H2 to yield the dihydrogen derivative, RuHCl(eta(2) H2){xant(P(i)Pr2)2} (5). In contrast to H2, PPh3 easily displaces DMSO from the metal center of 3 to afford RuHCl{xant(P(i)Pr2)2}(PPh3) (6), which can be also obtained starting from RuHCl(PPh3)3 (7) and xant(P(i)Pr2)2. In contrast to 3, complex 4 does not undergo DMSO elimination to give RuH2(eta(2) H2){xant(P(i)Pr2)2} (8) under a H2 atmosphere. However, the latter can be prepared by hydrogenation of Ru(COD)(COT) (9; COD = 1,5-cyclooctadiene and COT = 1,3,5-cyclooctatriene) in the presence of xant(P(i)Pr2)2. A more efficient procedure to obtain 8 involves the sequential hydrogenation with ammonia borane of the allenylidene derivative RuCl2(?C?C?CPh2){xant(P(i)Pr2)2} (10), which is formed from the reaction of 2 with 1,1-diphenyl-2-propyn-1-ol. The hydrogenation initially gives RuCl2(?C?CHCHPh2){xant(P(i)Pr2)2} (11), which undergoes the subsequent reduction of the Ru-C double bond to yield the hydride tetrahydroborate complex, RuH(eta(2)-H2BH2){xant(P(i)Pr2)2} (12). The osmium complex, OsCl2{xant(P(i)Pr2)2}(kappa-S-DMSO) (13), reacts with 1,1-diphenyl-2 propyn-1-ol in a similar manner to its ruthenium counterpart 2 to yield the allenylidene derivative, OsCl2(?C?C?CPh2){xant(P(i)Pr2)2} (14). Ammonia borane also reduces the Cbeta-Cgamma double bond of the allenylidene of 14. However, the resulting vinylidene species, OsCl2(?C?CHCHPh2){xant(P(i)Pr2)2} (15), is inert. Complex 12 is an efficient catalyst precursor for the hydrogen transfer from 2 propanol to ketones, the alpha-alkylations of phenylacetonitrile and acetophenone with alcohols, and the regio- and stereoselective head-to-head (Z) dimerization of terminal alkynes. PMID- 24405062 TI - Maintenance of multipotency in human dermal fibroblasts treated with Xenopus laevis egg extract requires exogenous fibroblast growth factor-2. AB - Direct reprogramming of a differentiated somatic cell into a developmentally more plastic cell would offer an alternative to applications in regenerative medicine that currently depend on either embryonic stem cells (ESCs), adult stem cells, or induced pluripotent stem cells (iPSCs). Here we report the potential of select Xenopus laevis egg extract fractions, in combination with exogenous fibroblast growth factor-2 (FGF2), to affect life span, morphology, gene expression, protein translation, and cellular localization of OCT4 and NANOG transcription factors, and the developmental potential of human dermal fibroblasts in vitro. A gradual change in morphology is accompanied by translation of embryonic transcription factors and their nuclear localization and a life span exceeding 60 population doublings. Cells acquire the ability to follow adipogenic, neuronal, and osteogenic differentiation under appropriate induction conditions in vitro. Analysis of active extract fractions reveals that Xenopus egg protein and RNAs as well as exogenously supplemented FGF2 are required and sufficient for induction and maintenance of this phenotypic change. Factors so far identified in the active fractions include FGF2 itself, transforming growth factor-beta, maskin, and nucleoplasmin. Identification of critical factors needed for reprogramming may allow for nonviral, chemically defined derivation of human-induced multipotent cells that can be maintained by exogenous FGF2. PMID- 24405063 TI - Nanomaterial building blocks based on spider silk-oligonucleotide conjugates. AB - Self-assembling protein nanofibrils are promising structures for the "bottom-up" fabrication of bionanomaterials. Here, the recombinant protein eADF4(C16), a variant of Araneus diadematus dragline silk ADF4, which self-assembles into nanofibrils, and short oligonucleotides were modified for site-specific azide alkyne coupling. Corresponding oligonuleotide-eADF4(C16) "click" conjugates were hybridized in linear or branched fashion according to the designed complementarities of the DNA moieties. Self-assembly properties of higher ordered structures of the spider silk-DNA conjugates were dominated by the silk component. Assembled beta-sheet rich conjugate fibrils were similar in appearance to fibrils of unmodified eADF4(C16) but enabled the specific attachment of neutravidin-modified gold nanoparticles on their surface directed by complementary biotin-oligonucleotides, providing the basis for functionalization of such conjugates. PMID- 24405064 TI - Vestibular schwannoma growth and hearing loss. PMID- 24405065 TI - Anterior temporal lobectomy. PMID- 24405066 TI - Treatment of Moyamoya disease in the adult population with pial synangiosis. AB - OBJECT: Surgical treatment of moyamoya disease in the adult population commonly uses direct revascularization, the superficial temporal artery (STA) to middle cerebral artery (MCA) bypass (STA-MCA). Pial synangiosis, a method of indirect revascularization, has been used in adult patients with moyamoya when STA-MCA bypass was not technically feasible. Although the effectiveness of pial synangiosis has been well described in children, only limited reports have examined its role in adult patients with moyamoya disease. In this study the authors report on their experience with pial synangiosis revascularization for this population. METHODS: The authors reviewed the clinical and radiographic records of all adult patients (>= 18 years of age) with moyamoya disease who underwent cerebral revascularization surgery using pial synangiosis at a single institution. RESULTS: From 1985 to 2010, 66 procedures (6 unilateral, 30 bilateral) were performed on 36 adult patients with moyamoya disease. The mean age at surgery was 28.3 years, and 30 patients were female. Twenty-eight patients (77.8%) presented with transient ischemic attacks (TIAs), 24 (66.7%) with stroke, and 3 (8.3%) with hemorrhage. Preoperative Suzuki stage was III or higher in 50 hemispheres (75.8%) and 3 patients had undergone prior treatments to the affected hemisphere before pial synangiosis surgery. Clinical follow-up was available for an average of 5.8 years (range 0.6-14.1 years), with 26 patients (72.2%) followed for longer than 2 years. Postoperative angiography was available for 24 patients and 46 revascularized hemispheres, and 39 (84.8%) of the 46 hemispheres demonstrated good collateral formation (Matsushima Grade A or B). Postoperative complications included 3 strokes, 5 TIAs, and 2 seizures, and there was no hemorrhage during the follow-up period. One patient required additional revascularization surgery 8 months after pial synangiosis. CONCLUSIONS: Pial synangiosis is a safe and durable method of cerebral revascularization in adult patients with moyamoya and can be considered as a potential treatment option for moyamoya disease in adults. PMID- 24405067 TI - Association of Kallikrein gene polymorphisms with sporadic intracranial aneurysms in the Chinese population. AB - OBJECT: Variants of Kallikreins have been shown to be risk factors for intracranial aneurysm (IA) in a Finnish population. In the present study, the authors investigated the correlation between polymorphisms in the Kallikrein gene cluster and IAs in the Chinese population. METHODS: The association of Kallikrein variants (rs1722561 and rs1701946) with sporadic IAs was tested in 308 cases and 443 controls. The differences in allelic frequencies between patients and the control group were evaluated with the chi-square test. RESULTS: The C allele of rs1722561 showed a significant reduction in the risk of sporadic IA (OR 0.71, 95% CI 0.53-0.95; p = 0.023). However, no association of the variant rs1701946 with sporadic IA was found (OR 0.78, 95% CI 0.57-1.06; p = 0.115). CONCLUSIONS: The variant rs1722561 of Kallikreins might reduce the risk of sporadic IAs among individuals of Chinese Han ethnicity. This study confirms the association between Kallikreins and IAs. PMID- 24405068 TI - Initial Gamma Knife radiosurgery for nonfunctioning pituitary adenomas. AB - OBJECT: Nonfunctioning pituitary adenomas (NFAs) are the most common type of pituitary adenoma and, when symptomatic, typically require surgical removal as an initial means of management. Gamma Knife radiosurgery (GKRS) is an alternative therapeutic strategy for patients whose comorbidities substantially increase the risks of resection. In this report, the authors evaluated the efficacy and safety of initial GKRS for NFAs. METHODS: An international group of three academic Gamma Knife centers retrospectively reviewed outcome data in 569 patients with NFAs. RESULTS: Forty-one patients (7.2%) underwent GKRS as primary management for their NFAs because of an advanced age, multiple comorbidities, or patient preference. The median age at the time of radiosurgery was 69 years. Thirty-seven percent of the patients had hypopituitarism before GKRS. Patients received a median tumor margin dose of 12 Gy (range 6.2-25.0 Gy) at a median isodose of 50%. The overall tumor control rate was 92.7%, and the actuarial tumor control rate was 94% and 85% at 5 and 10 years postradiosurgery, respectively. Three patients with tumor growth or symptom progression underwent resection at 3, 3, and 96 months after GKRS, respectively. New or worsened hypopituitarism developed in 10 patients (24%) at a median interval of 37 months after GKRS. One patient suffered new onset cranial nerve palsy. No other radiosurgical complications were noted. Delayed hypopituitarism was observed more often in patients who had received a tumor margin dose > 18 Gy (p = 0.038) and a maximum dose > 36 Gy (p = 0.025). CONCLUSIONS: In this study, GKRS resulted in long-term control of NFAs in 85% of patients at 10 years. This experience suggests that GKRS provides long-term tumor control with an acceptable risk profile. This approach may be especially valuable in older patients, those with multiple comorbidities, and those who have endocrine-inactive tumors without visual compromise due to mass effect of the adenoma. PMID- 24405069 TI - Uncertainty and agreement in the management of unruptured intracranial aneurysms. AB - OBJECT: The management of unruptured intracranial aneurysms remains controversial. The goal of this study was to evaluate the clinical community agreement in decision making regarding unruptured intracranial aneurysms. METHODS: A portfolio of 41 cases of unruptured intracranial aneurysms with angiographic images, along with a short description of the patient presentation, was sent to 28 clinicians (16 radiologists and 12 surgeons) with varying years of experience in the management of unruptured intracranial aneurysms. Five senior clinicians responded twice at least 3 months apart. Nineteen cases (46%) were selected from patients recruited in the Canadian UnRuptured Endovascular versus Surgery trial, an ongoing randomized comparison of coil embolization and clip placement. For each case, the responder was to first choose between 3 treatment options (observation, surgical clip placement, or endovascular coil embolization) and then indicate their level of certainty on a quantitative 0-10 scale. Agreement in decision making was studied using kappa statistics. RESULTS: Decisions to coil were more frequent (n = 612, 53%) than decisions to clip (n = 289, 25%) or to observe (n = 259, 22%). Interjudge agreement was only fair (kappa = 0.31 +/- 0.02) for all cases and all judges, despite substantial intrajudge agreement (range 0.44-0.83 +/- 0.10), with high mean individual certainty levels for each case (range 6.5-9.4 +/- 2.0 on a scale of 0-10). Agreement was no better within specialties (surgeons or radiologists), within capability groups (those able to perform endovascular coiling alone, surgical clipping alone, or both), or with more experience. There was no correlation between certainty levels and years of experience. Agreement was lower when the cases were taken from the randomized trial (kappa = 0.19 +/- 0.2) compared with nontrial cases (kappa = 0.35 +/- 0.2). CONCLUSIONS: Individuals do not agree regarding the management of unruptured intracranial aneurysms, even when they share a background in the same specialty, similar capabilities in aneurysm management, or years of practice. If community equipoise is a necessary precondition for trial participation, this study has found sufficient uncertainty and disagreement among clinicians to justify randomized trials. PMID- 24405070 TI - Inducing transient language disruptions by mapping of Broca's area with modified patterned repetitive transcranial magnetic stimulation protocol. AB - OBJECT: Until now there has been no reliable stimulation protocol for inducing transient language disruptions while mapping Broca's area. Despite the promising data of only a few studies in which speech arrest and language disturbances have been induced, certain concerns have been raised. The purpose of this study was to map Broca's area by using event-related navigated transcranial magnetic stimulation (nTMS) to generate a modified patterned nTMS protocol. METHODS: Eleven right-handed subjects underwent nTMS to Broca's area while engaged in a visual object-naming task. Navigated TMS was triggered 300 msec after picture presentation. The modified patterned nTMS protocol consists of 4 stimuli with an interstimulus interval of 6 msec; 8 or 16 of those bursts were repeated with a burst repetition rate of 12 Hz. Prior to mapping of Broca's area, the primary motor cortices (M1) for hand and laryngeal muscles were mapped. The Euclidian distance on MRI was measured between cortical points eliciting transient language disruptions and M1 for the laryngeal muscle. RESULTS: On stimulating Broca's area, transient language disruptions were induced in all subjects. The mean Euclidian distance between cortical spots inducing transient language disruptions and M1 for the laryngeal muscle was 17.23 +/- 4.73 mm. CONCLUSIONS: The stimulation paradigm with the modified patterned nTMS protocol was shown to be promising and might gain more widespread use in speech localization in clinical and research applications. PMID- 24405072 TI - Editorial: Gamma Knife radiosurgery and nonfunctioning pituitary adenomas. PMID- 24405071 TI - Hydrocephalus shunt technology: 20 years of experience from the Cambridge Shunt Evaluation Laboratory. AB - OBJECT: The Cambridge Shunt Evaluation Laboratory was established 20 years ago. This paper summarizes the findings of that laboratory for the clinician. METHODS: Twenty-six models of valves have been tested long-term in the shunt laboratory according to the expanded International Organization for Standardization 7197 standard protocol. RESULTS: The majority of the valves had a nonphysiologically low hydrodynamic resistance (from 1.5 to 3 mm Hg/[ml/min]), which may result in overdrainage related to posture and during nocturnal cerebral vasogenic waves. A long distal catheter increases the resistance of these valves by 100%-200%. Drainage through valves without a siphon-preventing mechanism is very sensitive to body posture, which may result in grossly negative intracranial pressure. Siphon-preventing accessories offer a reasonable resistance to negative outlet pressure; however, accessories with membrane devices may be blocked by raised subcutaneous pressure. In adjustable valves, the settings may be changed by external magnetic fields of intensity above 40 mT (exceptions: ProGAV, Polaris, and Certas). Most of the magnetically adjustable valves produce large distortions on MRI studies. CONCLUSIONS: The behavior of a valve revealed during testing is of relevance to the surgeon and may not be adequately described in the manufacturer's product information. The results of shunt testing are helpful in many circumstances, such as the initial choice of shunt and the evaluation of the shunt when its dysfunction is suspected. PMID- 24405073 TI - Peripheral nerve injuries due to osteochondromas: analysis of 20 cases and review of the literature. AB - OBJECT: Nerve compressions due to osteochondromas are extremely rare. The aim of this retrospective study was to investigate the mechanisms, diagnostic evaluations, and treatment of nerve lesions due to osteochondromas, and to review the literature. METHODS: The authors retrospectively reviewed their clinic data archive from 1998 through 2008, and 20 patients who were operated on due to peripheral nerve injuries caused by osseous growth were enrolled in the study. Patients' age, duration of symptoms, localizations, intraoperative findings, and modified British Medical Research Council (MRC) and electromyography data obtained from hospital records were evaluated. The literature on this topic available in PubMed was also reviewed. All 20 patients underwent surgery, which consisted of tumor excision performed by orthopedic surgeons and nerve decompression performed by neurosurgeons. RESULTS: There were 17 men and 3 women included in the study, with a mean age of 21 years (range 18-25 years). Three patients had multiple hereditary exostoses, and 17 had a solitary exostosis. All of the patients underwent en bloc resection. The most common lesion site was the distal femur (45%). The peroneal and posterior tibial nerves were the structures that were affected the most frequently. The mean follow-up was 3.9 years (range 2 7 years). After the surgery, all patients (100%) experienced good sensory recovery (modified MRC Grade S4 or S5). CONCLUSIONS: To the authors' knowledge, no large series have reported peripheral nerve compression due to exostoses. The authors have several recommendations as a result of their findings. First, all patients with peripheral nerve compression due to an osteochondroma should undergo surgery. Second, preoperative electromyographic examinations and radiographic evaluation, consisting of MRI and CT to provide optimal information about the lesion, are crucially important. Third, immediate treatment is mandatory to regain the best possible recovery. And fourth, performing nerve decompression first and en bloc resection of osteochondroma consecutively in a multidisciplinary fashion is strongly recommended to avoid peripheral nerve injury. PMID- 24405074 TI - Stereotactic placement of depth electrodes in medically intractable epilepsy. AB - OBJECT: Despite its long-reported successful record, with almost 60 years of clinical use, the technical complexity regarding the placement of stereoelectroencephalography (SEEG) depth electrodes may have contributed to the limited widespread application of the technique in centers outside Europe. The authors report on a simplified and novel SEEG surgical technique in the extraoperative mapping of refractory focal epilepsy. METHODS: The proposed technique was applied in patients with medically refractory focal epilepsy. Data regarding general demographic information, method of electrode implantation, time of implantation, number of implanted electrodes, seizure outcome after SEEG guided resections, and complications were prospectively collected. RESULTS: From March 2009 to April 2012, 122 patients underwent SEEG depth electrode implantation at the Cleveland Clinic Epilepsy Center in which the authors' technique was used. There were 65 male and 57 female patients whose mean age was 33 years (range 5-68 years). The group included 21 pediatric patients (younger than 18 years). Planning and implantations were performed in a single stage. The time for planning was, on average, 33 minutes (range 20-47 minutes), and the time for implantation was, on average, 107 minutes (range 47-150 minutes). Complications related to the SEEG technique were observed in 3 patients. The calculated risk of complications per electrode was 0.18%. The seizure-free rate after SEEG-guided resections was 62% in a mean follow-up period of 12 months. CONCLUSIONS: The authors report on a safe, simplified, and less time-consuming method of SEEG depth electrode implantation, using standard and widely available surgical tools, making the technique a reasonable option for extraoperative monitoring of patients with medically intractable epilepsy in centers lacking the Talairach stereotactic armamentarium. PMID- 24405075 TI - Male sex as a risk factor for the clinical course of skull base chordomas. AB - OBJECT: Chordomas of the skull base are rare and locally invasive and have a poor prognosis. The aim of this retrospective multicenter study was to evaluate the current pattern of care and clinical course and to identify prognostic factors. METHODS: A total of 47 patients (26 men; mean age 48.5 years) treated in 5 centers were included. Histology was centrally reviewed; additionally, semiquantitative N- and E-cadherin expression analysis was performed. Prognostic factors were obtained from multivariate regression models. For survival analysis the Kaplan-Meier method was used. RESULTS: The median follow-up period was 5.2 years. Complete resection, incomplete resection, and extended biopsy were performed in 14.9%, 80.9%, and 4.3% of patients, respectively. Surgical morbidity was not associated with extent of resection. Adjuvant radiation therapy was performed in 30 (63.8%) of 47 patients. The median progression-free survival (PFS) was 7.3 years. Complete resection prolonged median overall survival (OS) (p = 0.04). Male patients presented with worse PFS (4.8 years vs 9.8 years; p = 0.04) and OS (8.3 years vs not reached; p = 0.03) even though complete resection was exclusively achieved in the male subpopulation. Multivariate analysis confirmed male sex as the most important risk factor for tumor progression (p = 0.04) and death (p = 0.02). Age, duration of symptoms, initial Karnofsky Performance Scale score, brainstem compression, involvement of the petrous bone, infiltration of the dura mater, modality and dose of radiation therapy, and the E and N-cadherin expression patterns did not gain prognostic relevance. CONCLUSIONS: In skull base chordomas, male patients bear a higher risk of progressive disease and death. Male patients might benefit from more aggressive adjuvant therapy and/or from a closer follow-up schedule. PMID- 24405076 TI - Women's strategies to achieve access to healthcare in Ontario, Canada: a meta synthesis. AB - As part of a mixed methods study on women's access to the healthcare system in Ontario, Canada, we undertook a qualitative meta-synthesis to better understand the contextual conditions under which women access healthcare. An earlier phase of the synthesis demonstrated a series of factors that complicate women's access to healthcare in Ontario. Here, we consider women's agency in responding to these factors. We used meta-study methods to synthesise findings from qualitative studies published between January 2002 and December 2010. Studies were identified by searches of numerous databases, including CINAHL, MEDLINE, Scopus, Gender Studies Database and LGBT Life. Inclusion criteria included use of a qualitative research design; published in a peer-reviewed journal during the specified time period; included a sample at least partially recruited in Ontario; included distinct findings for women participants; and in English language. Studies were included in the final sample after appraisals using a qualitative research appraisal tool. We found that women utilised a spectrum of responses to forces limiting access to healthcare: mobilising financial, social and interpersonal resources; living out shortfalls by making do, doing without, and emotional self management; and avoiding illness and maintaining health. Across the studies, women described their efforts to overcome challenges to accessing healthcare. However, there were evident limits to women's agency and many of their strategies represented temporary measures rather than viable long-term solutions. While women can be resourceful and resilient in overcoming access disparities, systemic problems still need to be addressed. Women need to be involved in designing and implementing interventions to improve access to healthcare, and to address the root problems of these issues. PMID- 24405077 TI - Efficient synthesis of 9-aryldihydrophenanthrenes by a cascade reaction involving arynes and styrenes. AB - A mild, general, and transition-metal-free protocol for the synthesis of 9,10 dihydrophenanthrenes is reported. The aryne generated by the fluoride-induced 1,2 elimination of 2-(trimethylsilyl)aryl triflates undergoes an efficient cascade reaction initiated by the Diels-Alder reaction with the differently substituted styrenes leading to the formation of 9-aryl-9,10-dihydrophenanthrene derivatives in moderate to good yields. PMID- 24405078 TI - Retrospective study of technical aspects and complications of endoscopic submucosal dissection for large superficial colorectal tumors. AB - BACKGROUND AND AIM: Colorectal endoscopic submucosal dissection (ESD) is widely carried out, but is still considered difficult. In 2010, a tumor size of >= 50 mm and less experience in colorectal ESD were reported as independent risk factors for complications such as perforation, delayed perforation and postoperative bleeding. In order to overcome such difficulties, we developed a scissors-type grasping device and reported the treatment results of a multicenter study. The aim of the present study was to investigate therapeutic outcomes of colorectal ESD of different tumor sizes. METHODS: Group A (134 tumors): tumor size < 50 mm, and Group B (16 tumors): tumors >= 50 mm. All tumors were removed by ESD. We retrospectively evaluated the clinicopathological features of the tumors and the treatment results. RESULTS: Age, sex, tumor location and histopathological diagnosis were not different between the two groups. Laterally spreading tumor non-granular type was more often observed in Group A (64/134, 47.8%) than in Group B (0/16, 0%). Procedure time was significantly longer in Group B (Group A: 38 min; Group B: 86 min, P < 0.01). However, procedure speed was significantly faster in Group B (Group A: 0.21 cm(2) /min; Group B: 0.37 cm(2) /min, P < 0.01). No complications were observed in either group. The en bloc resection rate, en bloc R0 resection rate, and en bloc curative resection rate were similar between the groups with no significant differences. CONCLUSIONS: Procedure speed for Group B was faster than that for Group A. Group B was treated as safely as Group A. PMID- 24405080 TI - Changes in transverse relaxation time of quadriceps femoris muscles after active recovery exercises with different intensities. AB - The purpose of this study was to examine the changes in the metabolic state of quadriceps femoris muscles using transverse relaxation time (T2), measured by muscle functional magnetic resonance (MR) imaging, after inactive or active recovery exercises with different intensities following high-intensity knee extension exercise. Eight healthy men performed recovery sessions with four different conditions for 20 min after high-intensity knee-extension exercise on separate days. During the recovery session, the participants conducted a light cycle exercise for 20 min using a cycle (50%, 70% and 100% of the lactate threshold (LT), respectively: active recovery), and inactive recovery. The MR images of quadriceps femoris muscles were taken before the trial and after the recovery session every 30 min for 120 min. The percentage changes in T2 for the rectus femoris and vastus medialis muscles after the recovery session in 50% LT and 70% LT were significantly lower than those in either inactive recovery or 100% LT. There were no significant differences in those for vastus lateralis and vastus intermedius muscles among the four trials. The percentage changes in T2 of rectus femoris and vastus medialis muscles after the recovery session in 50% LT and 70% LT decreased to the values before the trial faster than those in either inactive recovery or 100% LT. Those of vastus lateralis and vastus intermedius muscles after the recovery session in 50% LT and 70% LT decreased to the values before the trial faster than those in 100% LT. Although the changes in T2 after active recovery exercises were not uniform in exercised muscles, the results of this study suggest that active recovery exercise with the intensities below LT are more effective to recover the metabolic state of quadriceps femoris muscles after intense exercise than with either intensity at LT or inactive recovery. PMID- 24405079 TI - Bioactivity screening of five Centaurea species and in vivo anti-inflammatory activity of C. athoa. AB - CONTEXT: Centaurea L. (Asteraceae) species used as herbal remedies in Turkish traditional medicine have shown several biological properties. OBJECTIVE: Extracts obtained from the aerial parts of Centaurea aphrodisea Boiss., Centaurea athoa DC., Centaurea hyalolepis Boiss., Centaurea iberica Trev. and Centaurea polyclada DC. were evaluated for their antioxidant, cytotoxic and anti inflammatory activities. MATERIALS AND METHODS: Extracts of Centaurea species were tested for their antioxidant activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS) screening assays and for in vitro anti-inflammatory activity by Nf-kappaB and iNOS inhibition assays. The extracts were tested for their in vitro cytotoxicities against a panel of human solid tumor cell lines (SK-MEL: malignant melanoma, KB: oral epidermal carcinoma, BT-549: breast ductal carcinoma and SK-OV 3: ovary carcinoma) as well as non-cancerous kidney fibroblast (Vero) and kidney epithelial cells (LLC-PK1) by Neutral Red assay. In vivo anti-inflammatory activity of C. athoa was evaluated by the carrageenan-induced paw edema test in rats. RESULTS: Antioxidant activities were observed for methanol extracts of plants. C. polyclada had the strongest effect on BT-549, KB and SK-OV-3 cell lines (30, 33 and 47 ug/ml, respectively). Nf-kappaB inhibition of chloroform extract of C. athoa was determined equivalent to positive control parthenolide (IC50: 6 ug/ml). This extract also showed anti-inflammatory activity by the carrageenan-induced paw edema test in rats, in all hours at a dose of 50 mg/kg compared to the control group. DISCUSSION AND CONCLUSION: C. athoa is suggested to be a potential source of lead compounds for inflammatory diseases due to the significant in vitro and in vivo anti-inflammatory results. PMID- 24405081 TI - Metformin, oral contraceptives or both to manage oligo-amenorrhea in adolescents with polycystic ovary syndrome? A clinical review. AB - The management of oligo-amenorrhea in adolescent patients with polycystic ovary syndrome (PCOS) represents an important and difficult challenge. Metformin and/or oral contraceptives (OCs) are different strategies widely proposed in these patients. The objective of the current review was to provide an overview on the use of metformin and/or OCs for the management of oligo-amenorrhea in adolescents with PCOS underlining their potential risks and benefits in order to help the clinician to choose the best patients' tailored treatment. PMID- 24405086 TI - Minor polar compounds in extra virgin olive oil: correlation between HPLC-DAD-MS and the Folin-Ciocalteu spectrophotometric method. AB - Minor polar compounds of 88 extra virgin olive oils were analyzed by HPLC-DAD-MS (high-performance liquid chromatography-diode array detector-mass spectrometry) and by the Folin-Ciocalteu (FC) spectrophotometric method, to validate and evaluate, for olive oils, the linear association between FC and HPLC data. The Pearson correlation coefficients were calculated between HPLC and FC results. The highest, positive R were related with deacetoxyoleuropein aglycone (R = 0.93) and oleuropein aglycone (R = 0.93) as single compounds and with the sum of orthodiphenols (R = 0.94) and the sum of all compounds (R = 0.95), showing that both estimations of total phenols content are reliably correlated, regardless for the absolute contents and are independent of the relative composition of the phenolic fraction. On the other hand the HPLC quantifications of apigenin and lignans showed no significant correlation with FC. These results, supported also by principal component analysis, may suggest caution about the interpretation of FC results to compare olive oils with very different phenolic profiles. PMID- 24405087 TI - Advances in understanding the leukaemia microenvironment. AB - Dynamic interactions between leukaemic cells and cells of the bone marrow are a feature of haematological malignancies. Two distinct microenvironmental niches in the bone marrow, the 'osteoblastic (endosteal)' and 'vascular' niches, provide a sanctuary for subpopulations of leukaemic cells to evade chemotherapy-induced death and allow acquisition of drug resistance. Key components of the bone marrow microenvironment as a home for normal haematopoietic stem cells and the leukaemia stem cell niches, and the molecular pathways critical for microenvironment/leukaemia interactions via cytokines, chemokines and adhesion molecules as well as hypoxic conditions, are described in this review. Finally, the genetic abnormalities of leukaemia-associated stroma are discussed. Further understanding of the contribution of the bone marrow niche to the process of leukaemogenesis may provide new targets that allow destruction of leukaemia stem cells without adversely affecting normal stem cell self-renewal. PMID- 24405090 TI - Diffusion of 1-ethyl-3-methyl-imidazolium acetate in glucose, cellobiose, and cellulose solutions. AB - Solutions of glucose, cellobiose and microcrystalline cellulose in the ionic liquid 1-ethyl-3-methyl-imidazolium ([C2mim][OAc]) have been examined using pulsed-field gradient (1)H NMR. Diffusion coefficients of the cation and anion across the temperature range 20-70 degrees C have been determined for a range of concentrations (0-15% w/w) of each carbohydrate in [C2mim][OAc]. These systems behave as an "ideal mixture" of free ions and ions that are associated with the carbohydrate molecules. The molar ratio of carbohydrate OH groups to ionic liquid molecules, alpha, is the key parameter in determining the diffusion coefficients of the ions. Master curves for the diffusion coefficients of cation, anion and their activation energies are generated upon which all our data collapses when plotted against alpha. Diffusion coefficients are found to follow an Arrhenius type behavior and the difference in translational activation energy between free and associated ions is determined to be 9.3 +/- 0.9 kJ/mol. PMID- 24405091 TI - PirB is a novel potential therapeutic target for enhancing axonal regeneration and synaptic plasticity following CNS injury in mammals. AB - A major barrier to axonal regeneration in mammals is the unfavorable extracellular environment that develops following injury to the central nervous system (CNS). In particular, three myelin-associated inhibitory proteins (MAIs) - Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp) - are known to inhibit axonal regeneration and functional recovery. These MAIs share a common receptor, glycosylphosphatidylinositol anchored Nogo receptor (NgR). However, paired immunoglobulin-like receptor B (PirB) - which was originally identified as a receptor for class I major histocompatibility complex (MHCI) in the immune system - is also expressed in neurones and plays a similarly inhibitory role in axonal regeneration and synaptic plasticity following CNS injury through its association with MAIs. Importantly, suppression of PirB activity through antibody antagonism or genetic means can partially relieve the inhibition of neurite outgrowth in vitro and in vivo. In this review, we present the molecular features, expression patterns and known signaling pathways of PirB, and we specifically focus on putative roles for PirB in the CNS and its potential as a target of molecular therapies for enhancing axonal regeneration and synaptic plasticity following CNS injury. PMID- 24405092 TI - Fabrication of bifunctional gold/gelatin hybrid nanocomposites and their application. AB - Herein, a facile method is presented to integrate large gold nanoflowers (~80 nm) and small gold nanoparticles (2-4 nm) into a single entity, exhibiting both surface-enhanced Raman scattering (SERS) and catalytic activity. The as-prepared gold nanoflowers were coated by a gelatin layer, in which the gold precursor was adsorbed and in situ reduced into small gold nanoparticles. The thickness of the gelatin shell is controlled to less than 10 nm, ensuring that the small gold nanoparticles are still in a SERS-active range of the inner Au core. Therefore, the reaction catalyzed by these nanocomposites can be monitored in situ using label-free SERS spectroscopy. In addition, these bifunctional nanocomposites are also attractive candidates for application in SERS monitoring of bioreactions because of their excellent biocompatibility. PMID- 24405093 TI - An unusual metallic oxygen cluster consisting of a {AlMo12O40(MoO2)}. AB - A novel aluminum-containing, bimolybdenum-capped Keggin-type polyoxomolybate cluster of the {AlMo12O40(MoO2)2} anion has been synthesized and characterized. This is the first experimentally determined Keggin-type {AlMo12O40} polyoxoanion. The polyoxometalate crystal exhibits high selectivity toward the heterogeneous catalytic oxidation of cyclohexanol to cyclohexanone. PMID- 24405094 TI - Efficient phosphodiester cleaving nanozymes resulting from multivalency and local medium polarity control. AB - The self-organization of Zn(II) complexes on the surface of 1.6-nm diameter gold nanoparticles (nanozymes) allows the spontaneous formation of multiple bimetallic catalytic sites capable to promote the cleavage of a RNA model substrate. We show that by tuning the structure of the nanoparticle-coating monolayer, it is possible to decrease the polarity of the reaction site, and this in turn generates remarkable increments of the cleavage efficiency. PMID- 24405101 TI - CCR5 plays important roles in hepatitis B infection. AB - In humans, hepatitis B virus (HBV) is the most prevalent and the main infectious agent that leads to liver disease. Previous investigations identified that long term HBV-infected patients are unable to eradicate HBV completely from hepatocytes. The main mechanisms responsible for long-term forms of the infections are yet to be clarified. However, researchers believe that the differences in genetic and immunological parameters in the patients in comparison to subjects who successfully clear HBV infections may be the causes for long-term infection. Previous studies demonstrated that chemokines play important roles in the regulation of immune cell migration and activation, which is crucial for a comprehensive immune response against HBV. RANTES, MIP-1alpha, and MIP-1beta are important CC chemokines which act through CC chemokines receptor 5 (CCR5). This receptor is expressed on several effector immune cells including NK cells, T lymphocytes, and macrophages, and plays a crucial role in the regulation of activation and migration of the immune cells during immune responses against viruses, including HBV. Therefore, alterations in its expression or functions could be associated with attenuated immune responses against HBV. In addition, previous studies identified that a 32 base pair deletion (Delta32) in exon 1, as well as three polymorphisms in the promoter region of the CCR5 gene results in downregulation of the molecule. Previous studies revealed that CCR5 expression was altered in hepatitis B but the role of the CCR5 Delta32 mutation and CCR5 promoter polymorphisms in this disease is controversial. This review addresses the recent information regarding the status of CCR5 expression on immune cells and the association of CCR5 promoter polymorphisms with HBV-infected patients. PMID- 24405104 TI - Review of alternative carrier materials for ocular surface reconstruction. AB - Severe ocular surface disorders can result in deficiency of limbal stem cells that is potentially associated with chronic inflammation, impaired vision and even blindness. Advanced stem cells deficiency requires reconstruction of the OS with autologous or allogeneic limbal stem cells. To address such deficiency, a limbal tissue biopsy is taken and limbal cells are expanded on a carrier, which then can be used for OS reconstruction. Human amniotic membrane - currently the most common carrier for transplantation of limbal epithelial stem cells - has the downsides of carrying the risk of disease transmission, limited transparency, variable and unstable quality and low mechanical strength. This article reviews the advantages and disadvantages of the established carrier materials for limbal stem cell transplantation, as well as discussing emerging alternatives, including carriers based on collagen, fibrin, siloxane hydrogel contact lenses, poly(epsilon-caprolactone), gelatin-chitosan, silk fibroin, human anterior lens capsule, keratin, poly(lactide-co-glycolide), polymethacrylate, hydroxyethylmethacrylate and poly(ethylene glycol) for their potential use in the treatment of limbal stem cell deficiency. PMID- 24405102 TI - DNA-epitope vaccine provided efficient protection to mice against lethal dose of influenza A virus H1N1. AB - Swine influenza virus (SIV) is a fast-evolving viral pathogen in pig populations. However, commercial vaccines, based on inactivated viruses, cannot provide complete protection with induced humoral immunity only and require frequent updates to fight against current isolates. A DNA vaccine delivering conservative epitopes was designed in this study in the hope of meeting the need. In this study, a B-cell epitope (HA2.30-130), a quadruplicated Th-cell epitope (NP55-69), and a quadruplicated CTL epitope (NP147-158) were fused separately to the C terminal of VP22c gene in the modified pcDNA3.1 plasmid. The expression of epitopes was confirmed by in vitro transfection of 293FT cells. The DNA vaccine administered intramuscularly stimulated epitope-specific immunity against the two T-cell epitopes in all ten mice before the virus challenge. Only two out of ten mice were ELISA positive against the B-cell epitope. All vaccinated mice survived a lethal dose of virus challenge, while all mice in the challenge control group died. The DNA vaccine delivering epitopes in this study showed promising protection against influenza virus in an animal model; however, more work needs to be done to evaluate the best conserved protective epitopes which can be applied in developing a universal DNA vaccine. PMID- 24405105 TI - Effects of invasive cordgrass on presence of Marsh Grassbird in an area where it is not native. AB - The threatened Marsh Grassbird (Locustella pryeri) first appeared in the salt marsh in east China after the salt marsh was invaded by cordgrass (Spartina alterniflora), a non-native invasive species. To understand the dependence of non native Marsh Grassbird on the non-native cordgrass, we quantified habitat use, food source, and reproductive success of the Marsh Grassbird at the Chongming Dongtan (CMDT) salt marsh. In the breeding season, we used point counts and radio tracking to determine habitat use by Marsh Grassbirds. We analyzed basal food sources of the Marsh Grassbirds by comparing the delta(13) C isotope signatures of feather and fecal samples of birds with those of local plants. We monitored the nests through the breeding season and determined the breeding success of the Marsh Grassbirds at CMDT. Density of Marsh Grassbirds was higher where cordgrass occurred than in areas of native reed (Phragmites australis) monoculture. The breeding territory of the Marsh Grassbird was composed mainly of cordgrass stands, and nests were built exclusively against cordgrass stems. Cordgrass was the major primary producer at the base of the Marsh Grassbird food chain. Breeding success of the Marsh Grassbird at CMDT was similar to breeding success within its native range. Our results suggest non-native cordgrass provides essential habitat and food for breeding Marsh Grassbirds at CMDT and that the increase in Marsh Grassbird abundance may reflect the rapid spread of cordgrass in the coastal regions of east China. Our study provides an example of how a primary invader (i.e., cordgrass) can alter an ecosystem and thus facilitate colonization by a second non-native species. PMID- 24405107 TI - Modulating brain mechanisms resolving lexico-semantic Interference during word production: A transcranial direct current stimulation study. AB - The aim of the current study was to shed further light on control processes that shape semantic access and selection during speech production. These processes have been linked to differential cortical activation in the left inferior frontal gyrus (IFG) and the left middle temporal gyrus (MTG); however, the particular function of these regions is not yet completely elucidated. We applied transcranial direct current stimulation to the left IFG and the left MTG (or sham stimulation) while participants named pictures in the presence of associatively related, categorically related, or unrelated distractor words. This direct modulation of target regions can help to better delineate the functional role of these regions in lexico-semantic selection. Independent of stimulation, the data show interference (i.e., longer naming latencies) with categorically related distractors and facilitation (i.e., shorter naming latencies) with associatively related distractors. Importantly, stimulation location interacted with the associative effect. Whereas the semantic interference effect did not differ between IFG, MTG, and sham stimulations, the associative facilitation effect was diminished under MTG stimulation. Analyses of latency distributions suggest this pattern to result from a response reversal. Associative facilitation occurred for faster responses, whereas associative interference resulted in slower responses under MTG stimulation. This reduction of the associative facilitation effect under transcranial direct current stimulation may be caused by an unspecific overactivation in the lexicon or by promoting competition among associatively related representations. Taken together, the results suggest that the MTG is especially involved in the processes underlying associative facilitation and that semantic interference and associative facilitation are linked to differential activation in the brain. PMID- 24405106 TI - Medial-lateral organization of the orbitofrontal cortex. AB - Emerging evidence suggests that specific cognitive functions localize to different subregions of OFC, but the nature of these functional distinctions remains unclear. One prominent theory, derived from human neuroimaging, proposes that different stimulus valences are processed in separate orbital regions, with medial and lateral OFC processing positive and negative stimuli, respectively. Thus far, neurophysiology data have not supported this theory. We attempted to reconcile these accounts by recording neural activity from the full medial lateral extent of the orbital surface in monkeys receiving rewards and punishments via gain or loss of secondary reinforcement. We found no convincing evidence for valence selectivity in any orbital region. Instead, we report differences between neurons in central OFC and those on the inferior-lateral orbital convexity, in that they encoded different sources of value information provided by the behavioral task. Neurons in inferior convexity encoded the value of external stimuli, whereas those in OFC encoded value information derived from the structure of the behavioral task. We interpret these results in light of recent theories of OFC function and propose that these distinctions, not valence selectivity, may shed light on a fundamental organizing principle for value processing in orbital cortex. PMID- 24405108 TI - Palladium-catalyzed acetylation of arenes. AB - A simple method for the preparation of aryl methyl ketones is reported. The transformation involves the Pd-catalyzed coupling of an acyl anion equivalent, acetyltrimethylsilane, with aryl bromides to afford the corresponding acetylated arenes in synthetically useful yields. The methodology is tolerant of heterocycles and provides a new method for arene functionalization. PMID- 24405109 TI - Reclosure of ruptured incision after peroral endoscopic myotomy using endoloops and metallic clips. PMID- 24405115 TI - Efficient protocol for rapid Aloe vera micropropagation. AB - CONTEXT: Aloe vera Linn. (Liliaceae) is a medicinal plant and has a number of curative properties. Vegetative propagation has not enough potential for supplying market demand. However, via in vitro propagation makes possible the mass production of Aloe plants. OBJECTIVE: The current study was conducted to investigate growth regulators' effects on proliferation of A. vera. MATERIALS AND METHODS: In this study, for comparison of plant growth regulators' effects on proliferation, the shoot tips and auxiliary buds of A. vera were cultured in the Murashige and Skoog (MS) medium. Rooted plantlets were transferred to garden soil, compost, and sand in the proportion of 1:1:1, respectively, after hardening. RESULTS: The maximum number of shoots was obtained on the medium supplemented with 1 mg/L IAA+4 mg/L BAP and 0.2 mg/L IAA+0.8 BAP mg/L. Rooting was also achieved in the same media composition proliferation of shoot. The acclimatized plants showed 100% of survival. The regenerated plants looked healthy, and they were morphologically similar to that of stock plants. CONCLUSION: These results suggest that in vitro culture may be used as a technique for rapid propagation of A. vera. PMID- 24405118 TI - Increasing the coverage of medicinal chemistry-relevant space in commercial fragments screening. AB - Analyzing the chemical space coverage in commercial fragment screening collections revealed the overlap between bioactive medicinal chemistry substructures and rule-of-three compliant fragments is only ~25%. We recommend including these fragments in fragment screening libraries to maximize confidence in discovering hit matter within known bioactive chemical space, while incorporation of nonoverlapping substructures could offer novel hits in screening libraries. Using principal component analysis, polar and three-dimensional substructures display a higher-than-average enrichment of bioactive compounds, indicating increasing representation of these substructures may be beneficial in fragment screening. PMID- 24405119 TI - Graphene quantum dots/L-cysteine coreactant electrochemiluminescence system and its application in sensing lead(II) ions. AB - A new coreactant electrochemiluminescence (ECL) system including single-layer graphene quantum dots (GQDs) and L-cysteine (L-Cys) was found to be able to produce strong cathodic ECL signal. The ECL signal of GQD/L-Cys coreactant system was revealed to be mainly dependent on some key factors, including the oxidation of L-Cys, the presence of dissolved oxygen and the reduction of GQDs. Then, a possible ECL mechanism was proposed for the coreactant ECL system. Furthermore, the ECL signal of the GQD/L-Cys system was observed to be quenched by lead(II) ions (Pb(2+)). After optimization of some important experimental conditions, including concentrations of GQDs and L-Cys, potential scan rate, response time, and pH value, an ECL sensor was developed for the detection of Pb(2+). The new methodology can offer a rapid, reliable, and selective detection of Pb(2+) with a detection limit of 70 nM and a dynamic range from 100 nM to 10 MUM. PMID- 24405120 TI - Moral disengagement and associated processes in performance-enhancing drug use: a national qualitative investigation. AB - This study investigated psychosocial processes associated with avoidance of health- and morality-based deterrents to performance-enhancing drug (PED) use. In depth semi-structured interviews were conducted with 64 English male bodybuilders with experience of doping. Resultant data were content analysed deductively using definitions for the eight mechanisms of moral disengagement (MD; Bandura, A. (1991). Social cognitive theory of moral thought and action. In W. M. Kurtines & J. L. Gewirtz (Eds.), Handbook of moral behavior and development: Theory research and applications (pp. 71-129). Hillsdale, NJ: Lawrence Erlbaum Associates.), and three further themes from Boardley and Grix (2013. Doping in bodybuilders: A qualitative investigation of facilitative psychosocial processes. Qualitative Research in Sport, Exercise, and Health. Advance online publication, doi 10.1080/2159676X.2013.766809). These analyses evidenced six MD mechanisms, and all three of the themes from Boardley and Grix (2013. Doping in bodybuilders: A qualitative investigation of facilitative psychosocial processes. Qualitative Research in Sport, Exercise, and Health. Advance online publication). Subsequent frequency analyses revealed six of the eight MD mechanisms, and two of the three additional themes, were common across the sample. Overall, the findings suggest MD may help athletes circumvent health- and morality-based deterrents to doping, describe a process linking supplement and PED use and detail how some athletes may actively avoid social censure for doping by only discussing PED use with other PED users from within their training environment. PMID- 24405122 TI - Chemical and physical pathways for the preparation of superoleophobic surfaces and related wetting theories. PMID- 24405121 TI - PI3KCA plays a major role in multiple myeloma and its inhibition with BYL719 decreases proliferation, synergizes with other therapies and overcomes stroma induced resistance. AB - The phosphatidylinositide 3-kinase (PI3K) pathway is activated and correlated with drug resistance in multiple myeloma (MM). In the present study we investigated the role of PI3KCA (PI3K-alpha) in the progression and drug resistance in MM. We showed that the gene expression of PI3KCA isoform was higher in MM compared to normal subjects. BYL719, a novel and specific PI3KCA inhibitor inhibited the survival of primary MM cells and cell lines but not normal peripheral blood mononuclear cells. BYL719 induced the apoptosis of MM cells and inhibited their cell cycle by causing G1 arrest. BYL719 inhibited PI3K signalling, decreased proliferation and cells cycle signalling, and induced apoptosis signalling in MM cells. Finally, BYL719 synergized with bortezomib and carfilzomib, and overcame drug resistance induced by bone marrow stroma. These results were confirmed using in silico simulation of MM cell lines, BYL719 and bortezomib, and showed similar trends in survival, proliferation, apoptosis, cell signalling and synergy with drugs. In conclusion, PI3KCA plays a major role in proliferation and drug resistance of MM cells, the effects of which were inhibited with BYL719. These results provide a preclinical basis for a future clinical trial of BYL719 in MM as a single agent or in combination with other drugs. PMID- 24405123 TI - Evaluation of (131)I-pentamidine for scintigraphy of experimentally Leishmania tropica-infected hamsters. AB - We aimed to assess the ability of (131)I-Pentamidine scintigraphy to detect the lesions of Leishmania tropica infection. An experimental model of cutaneous leishmaniasis was developed. The presence of cutaneous leishmaniasis was confirmed. Pentamidine was radioiodinated with (131)I. The radiolabeled pentamidine was validated by the requisite quality control tests to check its radiolabeling efficiency, in vitro stability. (131)I-Pentamidine (activity: 18.5 MBq/100 ul) was injected intracardiacally into infected hamsters. Static whole body images of the hamsters were acquired under the gamma camera at 5 and 30 min, 2, 6 and 24 h following the administration. On the scintigrams, anatomically adjusted regions of interest (ROIs) were drawn over the right feet (target) and left feet (not-target) and various organs. Accumulation of (131)I-Pentamidine at sites of infection is expressed as the target to non-target (T/NT) ratio. The results T/NT ratio decreased with time. In concluding the (131)I-Pentamidine has poor sensitivity in detection of L. tropica infection. PMID- 24405124 TI - Encountering women veterans with military sexual trauma. AB - PURPOSE: As women veterans (WVs) are returning from Operation Iraqi Freedom and Operation Enduring Freedom with military sexual trauma (MST), the purpose of this article is twofold. First, important exploratory questions that can assist with a thorough assessment and history are presented as well as the applicable treatment for any new, recurrent, or unresolved symptoms that involve MST. DESIGN AND METHODS: Review of multiple literary materials, as well as a clinical situation. FINDINGS: WVs will be encountered in a variety of military or civilian primary and community care healthcare settings. Every woman (and man) in the civilian sector should be asked, "Have you ever served in the military?" PRACTICE IMPLICATIONS: Recognition, acknowledgment, and applicable interventions for MST and associated comorbidities, especially post-traumatic stress disorder, are presented as currently 80-90% of MST experiences have gone unreported. Immediate treatment and follow-up are critical for the well-being of the WVs. PMID- 24405127 TI - Introduction to the special issue on implementation research. PMID- 24405128 TI - Creating an EBP framework on a journey to becoming an EBP agency: pioneers in the field of children's mental health. AB - Agencies servicing children, youth, and families have been particularly pressured to demonstrate service effectiveness and accountability by government funders. The human service fields have not fully embraced research evidence into the organizational culture creating a challenge of introducing research evidence into agencies. Gaps in knowledge have been identified when agencies attempt to travel down the path of introducing evidence-based practice into organizational culture. The paradigm shift of introducing research into practice was the journey taken by one mid-sized agency in southwestern Ontario, Canada. A framework for assessing evidence-based practice programs in services was created as part of their journey. PMID- 24405129 TI - Changing organization culture: data driven participatory evaluation and revision of wraparound implementation. AB - Family members and professionals in a Substance Abuse and Mental Health Services Administration Children's Mental Health Systems of Care Initiative in Houston, Texas conducted a participatory evaluation to examine wraparound implementation. Results guided systematic, theory-based program revisions. By focusing through empirically derived frameworks for implementation, the evaluation team identified and generated useful data sources to support and improve wraparound provision. Despite working with a more diverse population in which youth displayed more severe behaviors than in similar grants, after 18 months more families received service and outcomes improved as fidelity scores advanced above the national mean. PMID- 24405130 TI - Adapting an empirically supported intervention for a new population and setting: findings and lessons learned from Proyecto Puentes. AB - With an increasing emphasis on evidence-based practice, the need for social work researchers and practitioners to adapt empirically supported interventions for new populations and cultures is essential. However, social work suffers from a lack of guidance and detailed examples of intervention adaptations that may not proceed "by the book" and actually falter but recover. Many of these situations result from lack of attention to setting and context even when researchers believe they have full stakeholder buy-in. This article presents process evaluation findings from an intervention adaptation called Proyecto Puentes that allowed for self-correction and successful intervention development. PMID- 24405131 TI - The trials and tribulations of a practitioner-researcher: challenges and lessons learned through testing a feminist-cognitive-relational social work model of practice. AB - In practice with adult women who survived childhood sexual abuse, the field of social work currently lacks an evidence-based intervention. The current interventions, from the 1990s, come primarily from psychologists. The hypothesis that the Feminist-Cognitive-Relational Social Work Model and Intervention will be more effective in decreasing cognitive distortions, and increasing intimacy and relational health when compared to the standard agency intervention was tested in a quasi-experimental study. The challenges in carrying out the study in small, non-profit organizations are explored to highlight the difficulties in developing evidence-based interventions. Changes to implementation that resulted from the research findings are discussed. PMID- 24405132 TI - An exploration of the knowledge base used by Irish and U.S. child protection social workers in the assessment of intimate partner violence. AB - Child welfare practitioners in many countries now have increased responsibility for assessing intimate partner violence (IPV) as part of their child risk assessment process. Much research-based knowledge has accumulated about IPV and its impact on children that can inform this process. This exploratory study examined the extent to which research-based knowledge in IPV is influencing what child welfare practitioners explore in relation to IPV during their assessment process. Using a focus group format, two cohorts of child welfare practitioners, one located in Dublin County, Ireland, and one from the New York City metropolitan area, were asked what information they deem critical to explore about IPV, why they explore this content, and how they explore it. Results indicated that a wide range of information about IPV was reported as gathered by both groups, however, explicit research knowledge was not identified as a major influence for exploring these areas. Standardized IPV risk assessment instruments were also not reported as used by any of the participants. Other influences, such as practice experience, social work education, and legal or regulatory directives, had a much greater influence on the social worker's information gathering process in relation to IPV than research. PMID- 24405133 TI - Improving impulse control: using an evidence-based practice approach. AB - School social workers in a suburban school district implemented a two-year collaboration to identify empirically effective interventions and apply them to their own practice. During the first year of the project, the workers and the consultant discussed the use of evidence-based practice and developed strategies and tools for monitoring and evaluating practice. In the second year, each worker monitored the progress of one student using a standardized intervention. Five social workers completed the project; collected data on outcomes showed improved self-control for all participants. Limits on measurement and adaptations to individualize interventions make it impossible to be certain that the intervention was the primary cause of these outcomes. After the project the workers were not yet completely comfortable with the use of evidence-based practice to monitor and evaluate their practice. Recommendations for improving implementation of new evidence-based practice programs include providing ongoing discussion and feedback to workers, encouraging flexibility in implementation of curricula, simplifying record keeping so data reporting is consistent, and increasing baseline and follow-up measurements to strengthen the research. PMID- 24405135 TI - Resident responses to Section 8 relocation outcomes: "If you're gonna move, you want to move up". AB - Economic hardship and the lack of social supports of households moving with Section 8 vouchers during mixed-income redevelopment is a concern to relocation counselors. Since residents are able to select their housing location they need to know the risks and benefits of various housing choices. Twenty-five residents facing the choice of remaining in a phased redevelopment, moving with a Section 8 voucher, or moving to another public housing development were interviewed in order to determine how to engage residents in evidence-informed decision making. Many residents want to move with Section 8 vouchers, but require supports to make the choice sustainable. PMID- 24405136 TI - An organizational cybernetics framework for achieving balance in evidence-based practice and practice-based evidence. AB - This article applies the systems science of organizational cybernetics to the implementation of evidence-based practice (EBP) in the provision of social work services in a residential treatment center setting. It does so by systemically balancing EBP with practice-based evidence (PBE) with a focus on the organizational and information system infrastructures necessary to ensure successful implementation. This application is illustrated by discussing a residential treatment program that implemented evidence-based programming and evaluated the results; however, the systemic principles articulated can be applied to any human services organizational setting. PMID- 24405134 TI - Statewide implementation of the 4 Rs and 2 Ss for strengthening families. AB - Embedding evidence-informed practices for children with mental health needs into "real-world" community settings has proven challenging. In this article, we discuss how the Practical, Robust, Implementation, and Sustainability Model (PRISM) guided statewide (New York) implementation of an evidence-informed intervention targeting families and youth with oppositional defiant and conduct disorders, collectively referred to as disruptive behavior disorders. Additionally, we present qualitative findings based on provider reports of integrating a novel, evidence-informed intervention within their respective community mental health settings. Finally, we discuss a process of modifying the intervention to address agency-level factors, as well as inform more widespread implementation efforts. PMID- 24405137 TI - Using growth curve analysis to examine challenges in instrumentation in longitudinal measurement in home visiting. AB - Home visitation programs aim to decrease child maltreatment, yet limited longitudinal data exists concerning their screening and assessment instruments. "At risk" families (N = 2,054) were screened using the Family Stress Checklist and referred to Healthy Families Indiana. The Home Observation Measurement of the Environment Scale (HOME) and Community Life Skills Scale (CLS) were administered at multiple intervals. Growth curve analyses indicate families with lower HOME and CLS scores received more home visits and visits between assessments. However, these instruments may have "ceiling effects" and may be unsuitable for longitudinal assessment and program evaluation. Programmatic changes were made based on evaluation results. PMID- 24405138 TI - The role of relationships in connecting social work research and evidence-based practice. AB - Critics of evidence-based practice (EBP) often challenge the efficacy of applying social work research in practice. Such skepticism underscores the historic chasm that still exists between social work researchers and practitioners. If taught and implemented consistently, the EBP model can mend the connection between researchers and practitioners by merging their roles. Merging their roles, however, requires a renewed emphasis on relationships in the research process. This article explores the role of relationships in social work research. Using a researcher/practitioner continuum, we assess the types of interactions faculty have with stakeholders. We then offer strategies for cultivating relationships with stakeholders that lead to community-derived and implemented research that is critical to advancing the widespread use of EBP in social work. PMID- 24405139 TI - Translating social work research for social justice: focusing translational research on equity rather than the market. AB - Management of the dissemination of effective interventions in social work is often uncertain, and even when attention is paid to diffusing effective, innovative interventions, the focus is often disproportionately on a marketplace orientation of increasing the market share of branded, manualized interventions and social service treatment products. Public health frameworks of dissemination can improve knowledge translation in social interventions by focusing dissemination efforts on achieving equity and increasing the availability of effective interventions to all those who can benefit from them rather than simply focusing on commercial processes. This article identifies three equity-focused translation frameworks that can aid the dissemination of effective social interventions at the macro-, meso-, and micro-levels. Implications for policy and practice are discussed. PMID- 24405140 TI - Insuring the integrity and validity of social work interventions: the case of the subsidized guardianship waiver experiments. AB - The near loss of the ability to conduct randomized controlled trials in the Title IV-E waiver demonstrations makes the negotiation of a ceasefire urgent in the "causal wars." Results-oriented accountability is a conceptual framework for managing the micro-macro tensions that arise in social work practice and research. This article uses subsidized guardianship experiments to illustrate the results-oriented accountability process by which innovation is aggregated from the micro level through formative implementation and evaluation into a usable, stable intervention that can be rigorously tested through summative implementation and evaluation at the macro level, and if validated, generalized to the micro level through translative implementation and evaluation. PMID- 24405141 TI - From ethnography to randomized controlled trial: an innovative approach to developing complex social interventions. AB - The evidence base for mental health social work is vastly under-developed in contrast to medicine and psychology. Without randomized controlled trial evidence of effectiveness, social work interventions are largely absent from UK clinical guidelines and are increasingly difficult to defend in multidisciplinary teams. This article will discuss an innovative and thorough approach to developing a social intervention which will be amenable to evaluation in a randomized controlled trial. Using ethnography to capture practice wisdom, underpinned by social capital theory with its own rich evidence base, the intervention will help people recovering from an episode of psychosis to connect, or reconnect, with other people. It is envisaged that by ensuring the intervention is grounded in the lived experience of workers and service users it will be more amenable to implementation in routine practice, and produce better outcomes. PMID- 24405142 TI - Collaborative adaptations in social work intervention research in real-world settings: lessons learned from the field. AB - Social work research has identified the crucial role that service practitioners play in the implementation of evidence-based practices. This has led some researchers to suggest that intervention research needs to incorporate collaborative adaptation strategies in the design and implementation of studies focused on adapting evidence-based practices to real-world practice settings. This article describes a collaborative approach to service adaptations that was used in an intervention study that integrated evidence-based mental health and correctional services in a jail reentry program for people with serious mental illness. This description includes a discussion of the nature of the collaboration engaged in this study, the implementation strategies that were used to support this collaboration, and the lessons that the research team has learned about engaging a collaborative approach to implementing interventions in research projects being conducted in real-world social service delivery settings. PMID- 24405143 TI - Implementation frameworks and MSW curricula: encouraging pursuit and use of model pertinent data. AB - Graduate preparation of social workers and the infrastructure of service delivery too often limit the pursuit and use of data to inform practice. We review literature addressing student and practitioner motivation and interests, as well as masters-level social work curriculum content. This establishes a context for presentation of Masters in Social Work (MSW) student evaluations of program implementation at 34 field placement sites throughout the greater Kansas City region. Their evaluations focus through frameworks identified by the National Implementation Research Network to examine patterns of implementation and program data usage. Based on student lessons learned, we suggest MSW curricula revision to foster student and program appreciation and use of data. PMID- 24405144 TI - Selecting an EBP to reduce long-term foster care: lessons from a university-child welfare agency partnership. AB - A growing implementation literature outlines broad evidence-based practice implementation principles and pitfalls. Less robust is knowledge about the real world process by which a state or agency chooses an evidence-based practice to implement and evaluate. Using a major U.S. initiative to reduce long-term foster care as the case, this article describes three major aspects of the evidence based practice selection process: defining a target population, selecting an evidence-based practice model and purveyor, and tailoring the model to the practice context. Use of implementation science guidelines and lessons learned from a unique private-public-university partnership are discussed. PMID- 24405145 TI - Using principles of practice-based research to teach evidence-based practice in social work. AB - Social work educators are in a good position to encourage the uptake of evidence based practice more widely throughout the profession. Despite increasing attention being paid to it within professional literature, it seems to be making inroads to practice only very slowly. This article interprets that slow uptake as a function of confusion about the definition and scope of evidence-based practice, and also as an expression of the distance between the practice and research communities within the profession. Practice-based research is introduced as a framework that responds to both of these concerns. Finally the importance of social work education as a catalyst of evidence-based practice is articulated and the five-step evidence-based practice process is explicated with considerations from practice-based research incorporated along with pedagogical implications. PMID- 24405146 TI - Cardiac resynchronization therapy: extending current responses to phrenic nerve stimulation. PMID- 24405147 TI - Effect of acid on the ultraviolet-visible absorption and emission properties of curcumin. AB - Steady-state and time-resolved emission techniques were employed to study the acid-base effects on the UV-vis spectrum of curcumin in several organic solvents. The fluorescence-decay rate of curcumin increases with increasing acid concentration in all of the solvents studied. In methanol and ethanol solutions containing about 1 M HCl, the short-wavelength fluorescence (lambda < 560 nm) decreases by more than an order of magnitude. (The peak fluorescence intensity of curcumin in these solvents is at 540 nm.) At longer wavelengths (lambda >= 560 nm) the fluorescence quenching is smaller by a factor of ~3. A new fluorescence band with a peak at about 620 nm appears at an acid concentration of about 0.2 M in both methanol and ethanol. The 620 nm/530 nm band intensity ratio increases with an increase in the acid concentration. In trifluoroethanol and also in acetic acid in the presence of formic acid, the steady-state emission of curcumin shows an emission band at 620 nm. We attribute this new emission band in hydrogen bond-donating solvents to a protonated curcumin ROH2(+) form. At high acid concentrations in acetic acid and in trifluoroethanol, the ground state of curcumin is also transformed to ROH2(+) which absorbs at longer wavelengths with a band peak at ~530 nm compared to 420 nm in neutral-pH samples or 480 nm in basic solutions. In hydrogen-bond-accepting solvents such as dimethyl sulfoxide and also in methanol and ethanol, curcumin does not accept a proton to form the ground-state ROH2(+) PMID- 24405149 TI - Systematic review with meta-analysis: inflammatory bowel disease in the elderly. AB - BACKGROUND: Elderly patients represent an increasing proportion of the inflammatory bowel disease (IBD) population. AIM: To critically review available data regarding the care of elderly IBD patients. METHODS: Bibliographic searches (MEDLINE) up to June 2013. RESULTS: Approximately 10-15% of cases of IBD are diagnosed in patients aged >60 years, and 10-30% of the IBD population are aged >60 years. In the elderly, IBD is easily confused with other more common diseases, mainly diverticular disease and ischaemic colitis. The clinical features of IBD in older patients are generally similar to those in younger patients. Crohn's disease (CD) in elderly patients is characterised by its predominantly colonic localisation and uncomplicated course. Proctitis and left sided ulcerative colitis are more common in patients aged >60 years. Infections are associated with age and account for significant mortality in IBD patients. The treatment of IBD in the elderly is generally similar. However, the therapeutic approach in the elderly should be 'start low-go slow'. The benefit of thiopurines in older CD patients remains debatable. Although the indications for anti-tumour necrosis factors in the elderly are generally similar to those for younger patients, lower response and higher adverse events have been reported in the elderly. Surgery in elderly patients does not generally differ. Ileal pouch anal anastomosis can be successful, provided the patient retains good anal sphincter function. CONCLUSIONS: Management of the older IBD patient differs from that of younger patients; therefore, conventional practice algorithms may have to be modified to account for advanced age. PMID- 24405155 TI - Molecular promoting of aluminum metal-organic framework topology MIL-101 by N,N dimethylformamide. AB - In situ NMR and DFT modeling demonstrate that N,N-dimethylformamide (DMF) promotes the formation of metal-organic framework NH2-MIL-101(Al). In situ NMR studies show that upon dissociation of an aluminum-coordinated aqua ligand in NH2 MOF-235(Al), DMF forms a H-Cl-DMF complex during synthesis. This reaction induces a transformation from the MOF-235 topology into the MIL-101 topology. Electronic structure density functional theory (DFT) calculations show that the use of DMF instead of water as the synthesis solvent decreases the energy gap between the kinetically favored MIL-101 and thermodynamically favored MIL-53 products. DMF therefore promotes MIL-101 topology both kinetically and thermodynamically. PMID- 24405156 TI - Regulation of interleukin-6 in head and neck squamous cell carcinoma is related to papillomavirus infection. AB - The prevalence of head and neck squamous cell carcinoma (HNSCC) related to human papillomavirus (HPV) is increasing, unlike tobacco- and alcohol-associated cancers. To gain a clearer understanding of the molecular mechanisms implicated in HNSCC, depending on the presence or not of a viral sequence, we investigated the expression of proteins detected in the tumor regions of HNSCC patients. Twenty-two untreated HNSCC patients were selected according to the presence of HPV-16. For six patients, tumor and controlateral healthy tissues were tested for viral detection before quantitative proteomic analysis. After confirmation by Western blot, proteins were connected into a network, leading to investigate interleukin-6 (IL-6) by immunocytochemistry and ELISA. 41 +/- 5% of proteins quantified by proteomics were differentially expressed in tumor compared with healthy regions. Among them, 36 proteins were retained as modulated in HPV-16 positive or negative tumors, including cytokeratins, tubulins, annexin A1, and serpin B1. Network analysis suggested a central role of IL-6, confirmed by overexpression of IL-6 in tumor tissues as in sera of HPV-negative HNSCC compared with HPV-16-positive tumors. This modulation may contribute to the survival and proliferation of cancer cells, although it was not related to tumor stage or to the level of HPV-16 DNA. PMID- 24405157 TI - De novo design of Ln(III) coiled coils for imaging applications. AB - A new peptide sequence (MB1) has been designed which, in the presence of a trivalent lanthanide ion, has been programmed to self-assemble to form a three stranded metallo-coiled coil, Ln(III)(MB1)3. The binding site has been incorporated into the hydrophobic core using natural amino acids, restricting water access to the lanthanide. The resulting terbium coiled coil displays luminescent properties consistent with a lack of first coordination sphere water molecules. Despite this the gadolinium coiled coil, the first to be reported, displays promising magnetic resonance contrast capabilities. PMID- 24405158 TI - Probing the mechanisms of translation with force. PMID- 24405160 TI - Twelve-month employment intervention outcomes for drug-involved offenders. AB - BACKGROUND: Employment has been identified as an important part of substance abuse treatment and is a predictor of treatment retention, treatment completion, and decreased relapse. Although employment interventions have been designed for substance abusers, few interventions have focused specifically on drug-involved offenders. OBJECTIVES: The purpose of this study was to examine employment outcomes for drug-involved offenders who received a tailored employment intervention. METHODS: In a randomized controlled trial, baseline and follow-up data were collected from 500 drug-involved offenders who were enrolled in a drug court program. Participants were randomly assigned to drug court as usual (control group) or to the employment intervention in addition to drug court. RESULTS: Intent-to-treat analyses found that the tailored intervention was associated only with more days of paid employment at follow-up (210.1 vs. 199.9 days). When focusing on those with greater employment assistance needs, a work trajectory analyses, which took into account participants' pre-baseline employment pattern (negative or positive), revealed that intervention group participants had higher rates of employment (82.1% vs. 64.1%), more days paid for employment (188.9 vs. 157.0 days), and more employment income ($8623 vs. $6888) at follow-up than control group participants. CONCLUSION: The present study adds to the growing substance abuse and employment literature. It demonstrates the efficacy of an innovative employment intervention tailored for drug-involved offenders by showing positive changes in 12-month employment outcomes, most strongly for those who have not had recent employment success. PMID- 24405159 TI - Reversal of SIN-1-induced eNOS dysfunction by the spin trap, DMPO, in bovine aortic endothelial cells via eNOS phosphorylation. AB - BACKGROUND AND PURPOSE: Nitric oxide (NO) derived from eNOS is mostly responsible for the maintenance of vascular homeostasis and its decreased bioavailability is characteristic of reactive oxygen species (ROS)-induced endothelial dysfunction (ED). Because 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), a commonly used spin trap, can control intracellular nitroso-redox balance by scavenging ROS and donating NO, it was employed as a cardioprotective agent against ED but the mechanism of its protection is still not clear. This study elucidated the mechanism of protection by DMPO against SIN-1-induced oxidative injury to bovine aortic endothelial cells (BAEC). EXPERIMENTAL APPROACH: BAEC were treated with SIN-1, as a source of peroxynitrite anion (ONOO-), and then incubated with DMPO. Cytotoxicity following SIN-1 alone and cytoprotection by adding DMPO was assessed by MTT assay. Levels of ROS and NO generation from HEK293 cells transfected with wild-type and mutant eNOS cDNAs, tetrahydrobiopterin bioavailability, eNOS activity, eNOS and Akt kinase phosphorylation were measured. KEY RESULTS: Post treatment of cells with DMPO attenuated SIN-1-mediated cytotoxicity and ROS generation, restoration of NO levels via increased in eNOS activity and phospho eNOS levels. Treatment with DMPO alone significantly increased NO levels and induced phosphorylation of eNOS Ser1179 via Akt kinase. Transfection studies with wild-type and mutant human eNOS confirmed the dual role of eNOS as a producer of superoxide anion (O2-) with SIN-1 treatment, and a producer of NO in the presence of DMPO. CONCLUSION AND IMPLICATIONS: Post-treatment with DMPO of oxidatively challenged cells reversed eNOS dysfunction and could have pharmacological implications in the treatment of cardiovascular diseases. PMID- 24405164 TI - A systematic review of the safety of probiotics. AB - INTRODUCTION: There is growing evidence on the use of probiotics in various diseases, especially in gastrointestinal (GI) diseases. Although probiotics have been found helpful in many illnesses, they do not always seem to be safe. Through interference with commensal microflora, they can result in opportunistic performances in the host due to bacterimia and fungemia. Since considerable numbers of consumers use probiotic products worldwide, assurance of safety of these products is necessary. AREAS COVERED: This review evaluates all the existing information about the safety of probiotics in humans and animal models up to May 2013. In all eligible published studies in which adverse effects and tolerability of probiotics were investigated and reported, no language limitations were applied. The main key search terms were 'probiotics,' 'safety,' 'side effects,' 'clinical trial' and 'adverse effects.' The vast majority of trials investigated Bifidobacterium (B) and Lactobacillus (L) species. EXPERT OPINION: The main observed adverse effects of probiotics were sepsis, fungemia and GI ischemia. Generally, critically ill patients in intensive care units, critically sick infants, postoperative and hospitalized patients and patients with immune-compromised complexity were the most at-risk populations. While the overwhelming existing evidence suggests that probiotics are safe, complete consideration of risk-benefit ratio before prescribing is recommended. PMID- 24405165 TI - Economic valuation of subsistence harvest of wildlife in Madagascar. AB - Wildlife consumption can be viewed as an ecosystem provisioning service (the production of a material good through ecological functioning) because of wildlife's ability to persist under sustainable levels of harvest. We used the case of wildlife harvest and consumption in northeastern Madagascar to identify the distribution of these services to local households and communities to further our understanding of local reliance on natural resources. We inferred these benefits from demand curves built with data on wildlife sales transactions. On average, the value of wildlife provisioning represented 57% of annual household cash income in local communities from the Makira Natural Park and Masoala National Park, and harvested areas produced an economic return of U.S.$0.42 ha( 1) . year(-1). Variability in value of harvested wildlife was high among communities and households with an approximate 2 orders of magnitude difference in the proportional value of wildlife to household income. The imputed price of harvested wildlife and its consumption were strongly associated (p< 0.001), and increases in price led to reduced harvest for consumption. Heightened monitoring and enforcement of hunting could increase the costs of harvesting and thus elevate the price and reduce consumption of wildlife. Increased enforcement would therefore be beneficial to biodiversity conservation but could limit local people's food supply. Specifically, our results provide an estimate of the cost of offsetting economic losses to local populations from the enforcement of conservation policies. By explicitly estimating the welfare effects of consumed wildlife, our results may inform targeted interventions by public health and development specialists as they allocate sparse funds to support regions, households, or individuals most vulnerable to changes in access to wildlife. PMID- 24405166 TI - Intraductal radiofrequency ablation for refractory benign biliary stricture: pilot feasibility study. AB - BACKGROUND AND AIM: Endoscopic management of benign biliary stricture (BBS) remains challenging. There is no reported method for the amelioration of biliary fibroplasia endoscopically. We report our initial experience of radiofrequency ablation (RFA) for the management of BBS. METHODS: Nine patients with BBS (postoperation stricture four, liver transplant three, and chronic inflammation two), seven of whom had previously unsuccessful endoscopic or percutaneous interventions, were enrolled. Intraductal bipolar RFA was delivered at power of 10 W for 90 s per stricture segment, followed by balloon dilatation with/without stent placement. RESULTS: All patients had immediate stricture improvements after RFA. No severe adverse event occurred except for one patient with mild post endoscopic retrograde cholangiopancreatography pancreatitis. During median (SD) follow-up duration of 12.6 (3.9) months, BBS resolution without the need for further stenting was achieved in four patients whereas two patients had stent(s) in situ waiting scheduled removal. However, one patient had stricture relapse after initial resolution, one underwent surgery, and another patient died of other cause. CONCLUSIONS: Endobiliary RFA appears to be safe and effective for the treatment of BBS, especially for refractory cases. Further studies are warranted. PMID- 24405167 TI - Enhanced ergonomics approaches for product design: a user experience ecosystem perspective and case studies. AB - This paper first discusses the major inefficiencies faced in current human factors and ergonomics (HFE) approaches: (1) delivering an optimal end-to-end user experience (UX) to users of a solution across its solution lifecycle stages; (2) strategically influencing the product business and technology capability roadmaps from a UX perspective and (3) proactively identifying new market opportunities and influencing the platform architecture capabilities on which the UX of end products relies. In response to these challenges, three case studies are presented to demonstrate how enhanced ergonomics design approaches have effectively addressed the challenges faced in current HFE approaches. Then, the enhanced ergonomics design approaches are conceptualised by a user-experience ecosystem (UXE) framework, from a UX ecosystem perspective. Finally, evidence supporting the UXE, the advantage and the formalised process for executing UXE and methodological considerations are discussed. Practitioner Summary: This paper presents enhanced ergonomics approaches to product design via three case studies to effectively address current HFE challenges by leveraging a systematic end-to end UX approach, UX roadmaps and emerging UX associated with prioritised user needs and usages. Thus, HFE professionals can be more strategic, creative and influential. PMID- 24405168 TI - Psychiatric nursing care for adult survivors of child maltreatment: a systematic review of the literature. AB - PURPOSE: To determine what is known from the literature about nursing care of psychiatric patients with a history of child maltreatment. CONCLUSIONS: Psychiatric nurses underline the importance of a routine inquiry of child abuse on admission of patients to psychiatric care, but are reluctant to ask about child abuse. They often feel insufficiently competent to respond effectively to patients with a history of child maltreatment. PRACTICE IMPLICATIONS: Psychiatric nurses need training in how to assess a history of child abuse and the late-life consequences of abuse in adult psychiatric patients. They also need to be trained to respond effectively to these patients. PMID- 24405171 TI - Validation challenge of density-functional theory for peptides-example of Ac-Phe Ala5-LysH(+). AB - We assess the performance of a group of exchange-correlation functionals for predicting the secondary structure of peptide chains, up to a new many-body dispersion corrected hybrid density functional, dubbed PBE0+MBD* by its original authors. For the purpose of validation, we first compare to published, high-level benchmark conformational energy hierarchies (coupled cluster at the singles, doubles, and perturbative triples level, CCSD(T)) for 73 conformers of small three-residue peptides, establishing that the van der Waals corrected PBE0 functional yields an average error of only ~20 meV (~0.5 kcal/mol). This compares to ~40-50 meV for nondispersion corrected PBE0 and 40-100 meV for different empirical force fields (estimated for the alanine tetrapeptide). For longer peptide chains that form a secondary structure, CCSD(T) level benchmark data are currently unaffordable. We thus turn to the experimentally well studied Ac-Phe Ala5-LysH(+) peptide, for which four closely competing conformers were established by infrared spectroscopy. For comparison, an exhaustive theoretical conformational space exploration yields at least 11 competing low energy minima. We show that (i) the many-body dispersion correction, (ii) the hybrid functional nature of PBE0+MBD*, and (iii) zero-point corrections are needed to reveal the four experimentally observed structures as the minima that would be populated at low temperature. PMID- 24405172 TI - Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 1. Discovery of a novel tool compound for in vivo proof-of-concept. AB - Small molecule activators of glucokinase have shown robust efficacy in both preclinical models and humans. However, overactivation of glucokinase (GK) can cause excessive glucose turnover, leading to hypoglycemia. To circumvent this adverse side effect, we chose to modulate GK activity by targeting the endogenous inhibitor of GK, glucokinase regulatory protein (GKRP). Disrupting the GK-GKRP complex results in an increase in the amount of unbound cytosolic GK without altering the inherent kinetics of the enzyme. Herein we report the identification of compounds that efficiently disrupt the GK-GKRP interaction via a previously unknown binding pocket. Using a structure-based approach, the potency of the initial hit was improved to provide 25 (AMG-1694). When dosed in ZDF rats, 25 showed both a robust pharmacodynamic effect as well as a statistically significant reduction in glucose. Additionally, hypoglycemia was not observed in either the hyperglycemic or normal rats. PMID- 24405173 TI - Brugada syndrome: a heterogeneous disease with a common ECG phenotype? AB - Our understanding of Brugada syndrome (BrS) has evolved since the syndrome was first described in 1992. BrS is considered to be a primary inherited channelopathy often involving the inward sodium current and the diagnosis has traditionally required the exclusion of overt structural heart disease. In view of recently published observations about BrS, we propose that the term BrS may actually encompass a heterogeneous group of disorders with a variety of genetic and clinical phenotypes. This disease has classically been described as a primary electrical disorder involving the sodium channel leading to the characteristic electrocardiogram (ECG) changes of BrS. We challenge the current understanding and propose that patients with structurally normal hearts, family history of sudden cardiac death, with associated genetic abnormalities only account for a subset of patients with the "Brugada pattern" ECG. There may also be some patients with a diagnosis of BrS who may also have features which overlap with arrhythmogenic right ventricular cardiomyopathy. In these patients there may be an underlying structural abnormality. In this context, it is possible that catheter ablation may abolish the "Brugada pattern" ECG changes as well as abolishing the risk of life threatening arrhythmias in these patients. Given the recent developments in the field, we propose a novel comprehensive multimodality model for risk stratification and assessment of patients with BrS. Identification of variations of diseases may facilitate more specific risk stratification models and management paradigms in patients with Brugada ECG pattern. PMID- 24405176 TI - Motivational priming as a strategy for maximising exercise outcomes: effects on exercise goals and engagement. AB - Using a scrambled sentence priming protocol, the first aim of this study was to investigate whether differences in novel exercise-related goals existed between participants primed with motivational or non-motivational material (i.e. autonomous, controlled or neutral primes). The second aim was to explore whether an indirect effect was present between priming condition and the goal-related exercise sessions that individuals performed over the week following administration of the prime. No effects were observed across priming conditions with respect to subjective vitality, goal concordance and the frequency with which participants planned to exercise. However, autonomy-primed individuals set goals for their exercise sessions that were significantly longer in intended duration (M = 57.72 min, SD = 37.42) than those set by their counterparts in both the controlled-prime condition (M = 44.12 min, SD = 27.78) and the neutral-prime condition (M = 37.10 min, SD = 20.47). Bootstrapped analyses also revealed a significant indirect relationship between prime and exercise behaviour, with the autonomy prime predicting longer goal-based exercise sessions, via the effect on the duration of participants' intended exercise sessions. These findings highlight the potential influence that priming autonomous motivation may have on individuals' exercise aspirations, as well as the way in which primes may indirectly shape exercise engagement. PMID- 24405177 TI - Pharmacological evaluation for anti-asthmatic and anti-inflammatory potential of Woodfordia fruticosa flower extracts. AB - CONTEXT: Woodfordia fruticosa Kurz. (Lythraceae) flowers are ethnopharmacologically acclaimed in the Indian medicinal system to treat asthma. OBJECTIVE: To evaluate W. fruticosa flower extracts for anti-asthmatic effect. MATERIALS AND METHODS: Ethyl acetate, acetone, methanol, and hydro-alcohol extracts of W. fruticosa flowers were obtained successively and standardized. Ability of extracts to stabilize free radicals and compound-48/80-induced mast cell degranulation was evaluated. In vitro anti-inflammatory potential of extracts at 100 and 200 ug/ml by membrane stabilization and in vivo inhibition of rat paw edema up to 5 h (100 and 200 mg/ml; p.o.) was evaluated. In vitro bronchorelaxant effect was examined against histamine- and acetylcholine (1 ug/ml; independently)-induced guinea pig tracheal contraction. Extracts were evaluated for bronchoprotection (in vivo) ability against 0.1% histamine- and 2% acetylcholine-induced bronchospasm in guinea pigs at 100 and 200 mg/ml; p.o. RESULTS: Standardization studies revealed that the methanol extract exhibited highest polyphenolic (62.66 GAE), and flavonoid (6.32 RE) content and HPLC fingerprinting confirmed the presence of gallic acid (Rt 1.383). IC50 values for DPPH scavenging and metal chelation by the methanol extract were 40.42 and 31.50 ug/ml. Methanol and ethyl acetate extracts at 100 ug/ml exhibited 06.52 and 07.12% of histamine release. Methanol, ethyl acetate, and hydro alcohol extracts at 200 mg/kg demonstrated 32.73, 29.83, 26.75% and 32.46, 9.38, 26.75% inhibition of egg albumin and carrageenan-induced inflammation, respectively. Methanol extract exhibited 100% bronchorelaxation and 48.83% bronchoprotection. CONCLUSION: Woodfordia fruticosa flower (WFF) extracts exhibited anti-asthmatic effect by demonstrating bronchoprotection, bronchorelaxation, anti-inflammatory, antioxidant, and mast cell stabilization ability. PMID- 24405178 TI - Serum YKL-40 concentrations are elevated and correlated with disease severity in patients with obstructive sleep apnea syndrome. AB - Abstract Inflammation plays a critical role in the pathogenesis of obstructive sleep apnea syndrome (OSAS). YKL-40 is a novel biomarker of systemic inflammation. We aim to detect serum YKL-40 concentrations in OSAS patients and to clarify their relationship with clinical severity of the disease. We enrolled 159 OSAS patients and 104 healthy controls. The presence and severity of OSAS was assessed by Apnea-hypopnea index (AHI). Serum YKL-40 concentrations were detected by enzyme-linked immunosorbent assay (ELISA). We demonstrated that serum YKL-40 concentrations were significantly elevated in OSAS patients than those in controls. Multivariate logistic regression including all variables revealed that YKL-40 was the significant and independent predictor for the present of OSAS. In OSAS patients, there is a significant positive correlation between increments in serum YKL-40 concentrations and severity of OSAS. Serum YKL-40 concentrations were independently and significantly correlated with AHI scores. These results suggest that YKL-40 could be used as a potential biomarker for predicting the development and progression of OSAS. PMID- 24405180 TI - Toddler fearfulness is linked to individual differences in error-related negativity during preschool. AB - We investigated associations between early fearfulness and error-related negativity (ERN) in preschoolers. Children were classified as low, moderate, or high in fearfulness based on observations at age 2 years. ERN was measured at age 4.5 years. ERN was visible in preschoolers who were moderate or high in fear during toddlerhood, but was characterized differently in children based on associations with fearfulness during toddlerhood. A non-localized ERN was visible across midline electrodes in high-fear children and an adult like ERN distribution was visible in moderately fearful children. In contrast, low-fear children showed no evidence of ERN at 4.5 years of age. PMID- 24405181 TI - A critical review of psychosocial outcomes following childhood stroke (1995 2012). AB - Childhood stroke (CS) is a neurological condition occurring in 7:100000 children ( Hartel, Schilling, Sperner, & Theyen, 2004 ). Consequences include physical, cognitive, and language deficits and psychosocial disturbance, with the latter least researched. We critically reviewed the literature over the last 18 years. We identified 16 papers addressing psychosocial outcomes, which highlighted that CS confers increased risk of psychosocial impairment. Little is known regarding the contribution of stroke-specific and environmental influences. Small samples, variable age at onset and time since onset, lack of controls, and a focus on parent ratings limit generalizability of findings. Further investigation is needed to provide information regarding rehabilitation within the psychosocial domain. PMID- 24405182 TI - Masculinity/femininity predicts brain volumes in normal healthy children. AB - Previous research has shown sex differences in brain morphology ( De Bellis et al., 2001 ). However, these studies have not taken gender into account. Gender is a phenotype that describes behavior. In this study, we examined the relationship between gender, sex, and brain volumes in children. One hundred and eight children ages 7 to 17 were administered the Children's Sex Role Inventory ( Boldizar, 1991 ) and obtained volumetric brain data via magnetic resonance imaging (MRI). We found that, in the frontal lobe, higher masculinity predicted greater volumes of white matter. Also, in the temporal lobe, higher femininity predicted greater volumes of gray matter. PMID- 24405183 TI - Neurocognitive dysfunction and regional cerebral blood flow in medically naive patients with obsessive-compulsive disorder. AB - Previous research characterizes obsessive compulsive disorder (OCD) as a complex neurobehavioral disorder that may have multiple etiologies ( den Braber et al., 2008 ). This study analyzed neurocognitive function and change in regional cerebral blood flow (rCBF) to characterize OCD. Neurocognitive function and rCBF were examined in medically naive patients with OCD and contrasted with controls. Results of this study indicated that the neurocognitive functions impaired in OCD are memory, attention, and executive function, which are primarily associated with the frontal and occipital lobes. Dysfunction in the basal ganglia and occipital lobes were associated with OCD and may be an etiological factor in the disorder. PMID- 24405184 TI - Executive systems constrain the flexibility of online control in children during goal-directed reaching. AB - We examined the influence of inhibitory load on online motor control in children. A sample of 129 school children was tested: younger, mid-age, and older children. Online control was assessed using a double-step perturbation paradigm across three trail types: non-jump, jump, and anti-jump. Results show that mid-aged children were able to implement online adjustments to jump trials as quickly as older children, but their performance on anti-jump trials regressed toward younger children. This suggests that rapid unfolding of executive systems during middle childhood may constrain the flexibility with which online control can be implemented, particularly when inhibitory demands are imposed. PMID- 24405185 TI - Decomposing decision components in the stop-signal task: a model-based approach to individual differences in inhibitory control. AB - The stop-signal task, in which participants must inhibit prepotent responses, has been used to identify neural systems that vary with individual differences in inhibitory control. To explore how these differences relate to other aspects of decision making, a drift-diffusion model of simple decisions was fitted to stop signal task data from go trials to extract measures of caution, motor execution time, and stimulus processing speed for each of 123 participants. These values were used to probe fMRI data to explore individual differences in neural activation. Faster processing of the go stimulus correlated with greater activation in the right frontal pole for both go and stop trials. On stop trials, stimulus processing speed also correlated with regions implicated in inhibitory control, including the right inferior frontal gyrus, medial frontal gyrus, and BG. Individual differences in motor execution time correlated with activation of the right parietal cortex. These findings suggest a robust relationship between the speed of stimulus processing and inhibitory processing at the neural level. This model-based approach provides novel insight into the interrelationships among decision components involved in inhibitory control and raises interesting questions about strategic adjustments in performance and inhibitory deficits associated with psychopathology. PMID- 24405186 TI - Brain signature of working memory for sentence structure: enriched encoding and facilitated maintenance. AB - Sentences are easier to memorize than ungrammatical word strings, a phenomenon known as the sentence superiority effect. Yet, it is unclear how higher-order linguistic information facilitates verbal working memory and how this is implemented in the neural system. The goal of the current fMRI study was to specify the brain mechanisms underlying the sentence superiority effect during encoding and during maintenance in working memory by manipulating syntactic structure and working memory load. The encoding of sentence material, as compared with the encoding of ungrammatical word strings, recruited not only inferior frontal (BA 47) and anterior temporal language-related areas but also the medial temporal lobe, which is not classically reported for language tasks. During maintenance, it was sentence structure as contrasted with ungrammatical word strings that led to activation decrease in Broca's area, SMA, and parietal regions. Furthermore, in Broca's area, an interaction effect revealed a load effect for ungrammatical word strings but not for sentences. The sentence superiority effect, thus, is neurally reflected in a twofold pattern, consisting of increased activation in classical language as well as memory areas during the encoding phase and decreased maintenance-related activation. This pattern reflects how chunking, based on sentential syntactic and semantic information, alleviates rehearsal demands and thus leads to improved working memory performance. PMID- 24405187 TI - Prestimulus oscillations in the alpha band of the EEG are modulated by the difficulty of feature discrimination and predict activation of a sensory discrimination process. AB - Recent work has demonstrated that the occipital-temporal N1 component of the ERP is sensitive to the difficulty of visual discrimination, in a manner that cannot be explained by simple differences in low-level visual features, arousal, or time on task. These observations provide evidence that the occipital-temporal N1 component is modulated by the application of top-down control. However, the timing of this control process remains unclear. Previous work has demonstrated proactive, top-down modulation of cortical excitability for cued spatial attention or feature selection tasks. Here, the possibility that a similar top down process facilitates performance of a difficult stimulus discrimination task is explored. Participants performed an oddball task at two levels of discrimination difficulty, with difficulty manipulated by modulating the similarity between target and nontarget stimuli. Discrimination processes and cortical excitability were assessed via the amplitude of the occipital-temporal N1 component and prestimulus alpha oscillation of the EEG, respectively. For correct discriminations, prestimulus alpha power was reduced, and the occipital temporal N1 was enhanced in the hard relative to the easy condition. Furthermore, within the hard condition, prestimulus alpha power was reduced, and the occipital temporal N1 was enhanced for correct relative to incorrect discriminations. The generation of ERPs contingent on relative prestimulus alpha power additionally suggests that diminished alpha power preceding stimulus onset is related to enhancement of the occipital-temporal N1. As in spatial attention, proactive control appears to enhance cortical excitability and facilitate discrimination performance in tasks requiring nonspatial, feature-based attention, even in the absence of competing stimulus features. PMID- 24405188 TI - PFC neurons reflect categorical decisions about ambiguous stimuli. AB - We examined whether PFC neuron activity reflects categorical decisions in monkeys categorizing ambiguous stimuli. A morphing system was used to systematically vary stimulus shape and precisely define category boundaries. Ambiguous stimuli were centered on a category boundary, that is, they were a mix of 50% of two prototypes and therefore had no category information, so monkeys guessed at their category membership. We found that the monkeys' trial-by-trial decision about the category membership of an ambiguous image was reflected in PFC activity. Activity to the same ambiguous image differed significantly, depending on which category the monkey had assigned it to. This effect only occurred when that scheme was behaviorally relevant. These indicate that PFC activity reflects categorical decisions. PMID- 24405189 TI - Planar active organic waveguide and wavelength filter: self-assembled meso tetratolylporphyrin hexagonal nanosheet. AB - We have fabricated nearly monodispersed nanocrystalline sheet waveguides from a well-known red emitting meso-tetratolylporphyrin molecule (1) by following a bottom-up solvent assisted self-assembly technique. The nano-sheets thickness is in the range of 110-180 nm. Localized laser illumination showed excitation position dependent exciton polariton (653 and 719 nm) propagation behavior of the sheets. The spatially resolved fluorescence spectra of the sheets showed optical modes at the input and output points, indicating cavity effect. Additionally, because of the reabsorption of the 653 nm emission, the nanosheets also act as wave length filter by cutting off the 653 nm photons from reaching the output end. PMID- 24405192 TI - Founder mutation for Huntington disease in Caucasus Jews. AB - Huntington disease (HD), an autosomal dominant disorder involving HTT, is characterized by chorea, psychiatric illness and cognitive decline. Diagnosis and age of onset depend on the degree of expansion of the trinucleotide CAG repeat within the gene. The prevalence of HD is known for Europeans but has not been studied in the Israeli population. Between 2006 and 2011 we diagnosed in our adult genetics clinic ten HD probands, nine of whom were Caucasus Jews (CJ) (Azerbaijani), and one Ashkenazi Jewish. We performed haplotype analysis to look for evidence of a founder mutation, and found that of the nine CJ, eight shared the same haplotype that was compatible with the A1 haplogroup. We calculated the coalescence age of the mutation to be between 80 and 150 years. Ninety percent of our HD patients are CJ, as are 27% of the HD patients in Israel, although the CJ comprise only 1.4% of the Israeli population. Our findings suggest a higher prevalence of HD among CJ compared to the general Israeli population and are consistent with a recent founder mutation. We recommend a higher degree of suspicion for HD in CJ with subtle clinical findings. PMID- 24405193 TI - Longitudinal monitoring of CYP3A activity in patients receiving 3 cycles of itraconazole pulse therapy for onychomycosis. AB - WHAT IS KNOWN AND OBJECTIVE: Itraconazole, a CYP3A inhibitor, is used for the treatment for onychomycosis with a three-cycle pulse therapy over 3 months, but its effects on in vivo CYP3A activity during the entire course remain unknown. METHODS: Urinary 6beta-hydroxycortisol/cortisol ratios were determined in 19 patients with onychomycosis, before therapy, during three cycles of itraconazole pulse therapy (200 mg twice daily for a week in each monthly cycle) and at 3 month after completion of therapy. RESULTS AND DISCUSSION: The mean 6beta hydroxycortisol/cortisol ratio was reduced by 68% from baseline (P < 0.05) after the 1st pulse dosing, but the inhibitory effect appeared to be resolved before the next pulse dosing and at 3 months post-treatment. The magnitude of inhibition appeared in proportion to the baseline CYP3A activity. WHAT IS NEW AND CONCLUSION: The inhibitory effect of itraconazole pulse therapy on the in vivo CYP3A activity appears clinically relevant at the end of each cycle, but the inhibition resolves, on average, within 3 weeks. PMID- 24405194 TI - Neighborhood effects on the self-rated health of older adults from four racial/ethnic groups. AB - Building upon the sizable literature on individual-level predictors of self-rated health, this study examined the impact of neighborhood characteristics, using older adult samples of four racial/ethnic groups. The considered neighborhood characteristics include (a) the proportion of individuals age 65 and older, (b) the proportion of individuals below poverty, and (c) the proportion of individuals from the same racial/ethnic background in the Census-block group. The samples were drawn from the 2004-2005 Survey of Older Floridians, which includes Whites (n = 488), Blacks (n = 345), Cubans (n = 319), and non-Cuban Latinos (n = 230). Using the reported residential address, each participant was linked to the 2000 Census at block-group level to retrieve the above-mentioned neighborhood characteristics. Multilevel analysis of self-rated health was estimated for each racial/ethnic group, considering individual-level variables (e.g., age, gender, marital status, education, financial strain, and chronic conditions) and each of the neighborhood characteristics. Regardless of racial/ethnic groups, those living in the neighborhood with a higher proportion of residents below poverty were likely to report poorer health. The proportion of older adults in the neighborhood was significant only in Cubans, and the proportion of residents with the same ethnic background was only in Whites. The findings show the overall importance of neighborhood context in the health of older adults and indicate different implications of neighborhood characteristics for diverse racial/ethnic groups. PMID- 24405195 TI - Beaten and poor? A study of the long-term economic situation of women victims of severe violence. AB - This 10-year follow-up study based on Swedish national registers compares the economic situation of women victims of violence leading to hospitalization (n = 6,085) to nonexposed women (n = 55,016) in 1992 to 2005. Women exposed to severe violence had a poorer financial situation prior to the assault. Violence seems to heavily reinforce this pattern, indicating a continued need of support from the social work profession. Assaulted women had a worse income development, lower odds for being in employment, and higher odds for having low incomes and means tested social assistance during the 10-year follow-up, independent of having children or not. PMID- 24405196 TI - Living in danger: previous violence, socioeconomic position, and mortality risk among women over a 10-year period. AB - Violence against women has many negative consequences. In this short report the authors investigate patterns of mortality among women experiencing violence leading to inpatient care from 1992 to 2006. Do women who are victims of severe violence have an increased mortality risk (a) in general? (b) by violence? (c) by suicide? Does socioeconomic position have any bearing on the mortality risk? The study was based on Swedish national registers, where 6,085 women exposed to violence resulting in inpatient care were compared with a nonexposed population sample of 55,016 women. Women of all social strata previously exposed to severe violence and treated in hospital had a highly increased risk of premature death from all-cause mortality, violence, or suicide. Women previously exposed to severe violence continue to live a life in danger. There is need for a societal response to support and protect these women against further violence after discharge from hospital. PMID- 24405197 TI - Political and medical views on medical marijuana and its future. AB - The policies, laws, politics, public opinions, and scientific inferences of medical marijuana are rapidly changing as the debate on medical use of marijuana has always been political, rather than scientific. Federal law has barred the use of medical marijuana though 18 state governments and Washington, DC, support the medical use of marijuana. Unfortunately, not many studies exist on medical marijuana to back these laws and policies. The judiciary, on the other hand, has elicited a diverse response to medical marijuana through its rulings over several decades. Some rulings favored the federal government's opinion, and others supported the larger public view and many state governments with legalized medical marijuana. Public opinion on legalizing medical marijuana has always favored the use of medical marijuana. The movement of scientific knowledge of medical marijuana follows an erratic, discontinuous pathway. The future place of medical marijuana in U.S. society remains unknown. The three forces-scientific knowledge, social-political acceptance, and laws-play a role in the direction that medical marijuana takes in society. Overcoming political-social forces requires a concerted effort from the scientific community and political leaders. The results of scientific research must guide the decisions for laws and medical use of marijuana. This article aims to trace the political dilemma and contradictory views shared by federal and state governments and predict the future of medical marijuana by tracing the past history of medical marijuana with its bumpy pathway in the social-political arena. PMID- 24405198 TI - Reproductive health policy affecting low-income women: historical precedents and current need for social work action. AB - This article provides an overview of the historical arguments surrounding reproductive health policy and current policy initiatives. Because reproductive policy itself is a vast subject matter with sometimes blurry boundaries, the struggle concerning the advent of birth control is used to illustrate the historic complexities of policy affecting such a wide array of individuals. The battle over introduction of the birth control pill is pertinent because the very same arguments are used today in debates over reproductive health policy. PMID- 24405199 TI - Access to obstetric care in the United States from the National Health Interview Survey. AB - This cross-sectional observational study uses data from the National Health Interview Survey from 1999 to 2006 to identify demographic factors associated with whether pregnant women have seen an OB/GYN within the last year. This analysis includes 2,748 women who were pregnant at the time of the interview. In total, 86.3% of women had seen an OB/GYN in the previous year. Women who are uninsured, have not completed high school, are Asian, or who live in the Midwest or Western regions may be at lower odds for receiving prenatal care. This study identifies vulnerable populations that may not be receiving adequate obstetric care. PMID- 24405200 TI - The Beveridge Report and Japan. AB - After World War II, Japanese health insurance systems rejected the idea of a flat rate premium contribution, a central concept in the Beveridge Report. Allegedly, outside of Great Britain, no other country was more influenced by this Report than Japan. However, the postwar Japanese health insurance systems adopted flat rate benefits and earnings-related contributions, a clear rejection of the flat rate premium contributions for flat-rate benefits advocated in the Report. This is not just a simple difference from the premium contributions method, it throws up fundamental questions concerning the essence of social insurance, and ultimately, the power of the State and the relationship between the State and the individual. This article aims to analyze the reasons for this rejection. PMID- 24405201 TI - An exploration of terminology related to sexuality and gender: arguments for standardizing the language. AB - There is currently no consensus on the best ways to define and operationalize research concepts related to sexuality and gender. This article explores some of the ways that sex/gender and sexuality terms have been used in health-related research and in keyword searches in the health sciences. Reasons for the diversity of terms and measurement approaches are explored and arguments for and against standardizing the language are presented. The article ends with recommendations for beginning a productive dialogue among health researchers to create some consistency in the terminology used to assess sexuality and gender. PMID- 24405202 TI - The small area predictors of ambulatory care sensitive hospitalizations: a comparison of changes over time. AB - The hospital admission for ambulatory care sensitive conditions (ACSCs) is a validated indicator of impeded access to good primary and preventive care services. The authors examine the predictors of ACSC admissions in small geographic areas in two cross-sections spanning an 11-year time interval (1995 2005). Using hospital discharge data from the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality for Arizona, California, Massachusetts, Maryland, New Jersey, and New York for the years 1995 and 2005, the study includes a multivariate cross-sectional design, using compositional factors describing the hospitalized populations and the contextual factors, all aggregated at the primary care service area level. The study uses ordinary least squares regressions with and without state fixed effects, adjusting for heteroscedasticity. Data is pooled over 2 years to assess the statistically significant changes in associations over time. ACSC admission rates were inversely related to the availability of local primary care physicians, and managed care was associated with declines in ACSC admissions for the elderly. Minorities, aged elderly, and percent under federal poverty level were found to be associated with higher ACSC rates. The comparative analysis for 2 years highlights significant declines in the association with ACSC rates of several factors including percent minorities and rurality. The two policy-driven factors, primary care physician capacity and Medicare-managed care penetration, were not found significantly more effective over time. Using small area analysis, the study indicates that improvements in socioeconomic conditions and geographic access may have helped improve the quality of primary care received by the elderly over the last decade, particularly among some minority groups. PMID- 24405207 TI - Biomolecular structure at solid-liquid interfaces as revealed by nonlinear optical spectroscopy. PMID- 24405208 TI - Role of the acceptor in tuning the properties of metal [M(II) = Ni, Pd, Pt] dithiolato/dithione (donor/acceptor) second-order nonlinear chromophores: combined experimental and theoretical studies. AB - The mixed-ligand complexes [M(II)(Et2dazdt)(mnt)] (M = Ni, 1; Pd, 2; Pt, 3) [Et2dazdt = N,N'-diethyl-perhydrodiazepine-2,3-dithione; mnt = maleonitrile-2,3 dithiolate] have been prepared and fully characterized. X-ray diffractometric studies on 1-3 (the structure of 1 was already known) show that the crystals are isostructural (triclinic, P-1), and two independent molecular entities are present in the unit cell. These entities differ in the orientation of the ethyl substituents with respect to the epta-atomic ring. In the C2S2MS2C2 dithiolene core the four sulfur atoms define a square-planar coordination environment of the metal where the M-S bond distances involving the two ligands are similar, while the C-S bond distances in the C2S2 units exhibit a significant difference in Et2dazdt (dithione) and mnt (dithiolato) ligands. 1-3 show in the visible region one or two moderately strong absorption peaks, having ligand-to-ligand charge transfer (CT) character with some contribution of the metal, and show negative solvatochromism and molecular quadratic optical nonlinearity, which was determined by the EFISH (electric-field-induced second-harmonic generation) technique. These complexes are redox active and show two reversible reduction waves and one irreversible oxidation wave. Theoretical calculations based on DFT and TD-DFT calculations on complexes 1-3 as well as on [Pt(Bz2pipdt)(mnt)] (4) and [Pt(Bz2pipdt)(dmit)] (5) highlight the factors which affect the optical properties of these second-order redox-active NLO chromophores. Actually, the torsion angle of the dithione system (delta2) inversely correlates either with the oscillator strengths of the main transition of the complexes or with their beta values. The high beta value of 5 can be attributed both to its lowest torsion angles and to the extent of the pi system of its dithiolate ligand, dmit. PMID- 24405209 TI - Copper-catalyzed intermolecular amidation and imidation of unactivated alkanes. AB - We report a set of rare copper-catalyzed reactions of alkanes with simple amides, sulfonamides, and imides (i.e., benzamides, tosylamides, carbamates, and phthalimide) to form the corresponding N-alkyl products. The reactions lead to functionalization at secondary C-H bonds over tertiary C-H bonds and even occur at primary C-H bonds. [(phen)Cu(phth)] (1-phth) and [(phen)Cu(phth)2] (1-phth2), which are potential intermediates in the reaction, have been isolated and fully characterized. The stoichiometric reactions of 1-phth and 1-phth2 with alkanes, alkyl radicals, and radical probes were investigated to elucidate the mechanism of the amidation. The catalytic and stoichiometric reactions require both copper and tBuOOtBu for the generation of N-alkyl product. Neither 1-phth nor 1-phth2 reacted with excess cyclohexane at 100 degrees C without tBuOOtBu. However, the reactions of 1-phth and 1-phth2 with tBuOOtBu afforded N-cyclohexylphthalimide (Cy-phth), N-methylphthalimide, and tert-butoxycyclohexane (Cy-OtBu) in approximate ratios of 70:20:30, respectively. Reactions with radical traps support the intermediacy of a tert-butoxy radical, which forms an alkyl radical intermediate. The intermediacy of an alkyl radical was evidenced by the catalytic reaction of cyclohexane with benzamide in the presence of CBr4, which formed exclusively bromocyclohexane. Furthermore, stoichiometric reactions of [(phen)Cu(phth)2] with tBuOOtBu and (Ph(Me)2CO)2 at 100 degrees C without cyclohexane afforded N-methylphthalimide (Me-phth) from beta-Me scission of the alkoxy radicals to form a methyl radical. Separate reactions of cyclohexane and d12-cyclohexane with benzamide showed that the turnover-limiting step in the catalytic reaction is the C-H cleavage of cyclohexane by a tert-butoxy radical. These mechanistic data imply that the tert-butoxy radical reacts with the C-H bonds of alkanes, and the subsequent alkyl radical combines with 1-phth2 to form the corresponding N-alkyl imide product. PMID- 24405210 TI - Identification of novel metabolites from Aspergillus flavus by high resolution and multiple stage mass spectrometry. AB - The filamentous fungus Aspergillus flavus is one of the most important species in the Aspergillus genus and is distributed worldwide as a prevalent aflatoxin producing food and feed contaminant. A. flavus contains more than 55 gene clusters that are predicted to encode proteins involved in secondary metabolite production. One of these, cluster 27, contains a polyketide synthase (pks27) gene that encodes a protein that is highly homologous to the aflatoxin cluster PKS. Comparative metabolomics, using ultra-high performance liquid chromatography (UHPLC) coupled to high resolution Orbitrap mass spectrometry (MS) was used to detect metabolites differentially expressed in the A. flavus wild-type and ?pks27 mutant strains. Metabolite profiling was aided by a statistical differential analysis of MS data using SIEVE software. This differential analysis combined with accurate mass data from the Orbitrap and ion trap multiple stage MS allowed four metabolites to be identified that were produced only by the wild-type culture. These included asparasone A (358 Da), an anthraquinone pigment, and related anthraquinones with masses of 316, 340 and 374 Da. These latter three compounds had similar fragmentation patterns to that of asparasone A. The 316 Da anthraquinone is particularly interesting because it is most likely formed by incorporation of seven malonyl-CoA units rather than the eight units required for the formation of asparasone A. The 340 and 374 Da metabolites are the dehydration and an oxy-derivative of asparasone A, respectively. Asparasone A was also identified in extracts from several other Aspergillus species. PMID- 24405213 TI - Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 2. Leveraging structure-based drug design to identify analogues with improved pharmacokinetic profiles. AB - In the previous report , we described the discovery and optimization of novel small molecule disruptors of the GK-GKRP interaction culminating in the identification of 1 (AMG-1694). Although this analogue possessed excellent in vitro potency and was a useful tool compound in initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by a combination of metabolite identification and structure-based design, we have successfully discovered a potent and metabolically stable GK-GKRP disruptor (27, AMG-3969). When administered to db/db mice, this compound demonstrated a robust pharmacodynamic response (GK translocation) as well as statistically significant dose-dependent reductions in fed blood glucose levels. PMID- 24405214 TI - From population viability analysis to coviability of farmland biodiversity and agriculture. AB - Substantial declines in farmland biodiversity have been reported in Europe for several decades. Agricultural changes have been identified as a main driver of these declines. Although different agrienvironmental schemes have been implemented, their positive effect on biodiversity is relatively unknown. This raises the question as to how to reconcile farming production and biodiversity conservation to operationalize a sustainable and multifunctional agriculture. We devised a bioeconomic model and conducted an analysis based on coviability of farmland biodiversity and agriculture. The coviability approach extended population viability analyses by including bioeconomic risk. Our model coupled stochastic dynamics of both biodiversity and farming land-uses selected at the microlevel with public policies at the macrolevel on the basis of financial incentives (taxes or subsidies) for land uses. The coviability approach made it possible for us to evaluate bioeconomic risks of these public incentives through the probability of satisfying a mix of biodiversity and economic constraints over time. We calibrated the model and applied it to a community of 34 common birds in metropolitan France at the small agricultural regions scale. We identified different public policies and scenarios with tolerable (0-0%) agroecological risk and modeled their outcomes up to 2050. Budgetary, economic, and ecological (based on Farmland Bird Index) constraints were essential to understanding the set of viable public policies. Our results suggest that some combinations of taxes on cereals and subsidies on grasslands could be relevant to develop a multifunctional agriculture. Moreover, the flexibility and multicriteria viewpoint underlying the coviability approach may help in the implementation of adaptive management. PMID- 24405216 TI - Mapping and ablation of a narrow QRS tachycardia in a patient with ischemic cardiomyopathy. PMID- 24405218 TI - Ab initio potential energy curves for the ground and low-lying excited states of OH and OH(-) and a study of rotational fine structure in photodetachment. AB - Complete basis set extrapolated ab initio potential energy curves obtained from multireference configuration interaction (MRCI) level calculations for the ground state (X(1)Sigma(+)) of OH(-), and the ground state (X(2)Pi) and the first excited state (A(2)Sigma(+)) of OH are reported. The potential energy curves for the excited states A(1)Pi, a(3)Pi, and b(3)Pi of OH(-) have been computed using the V6Z basis set at the MRCI level. Lambda-doubling parameters p and q were calculated for the ground and the first excited vibrational states of the ground electronic state of OH using second-order perturbation theory. Using the computed potential energy curves and the rovibrational spectra for photodetachment including the fine splitting, the threshold for electron detachment has been computed. The result is in agreement with the experimental results of Goldfarb et al. [J. Chem. Phys. 1985, 83, 4364]. PMID- 24405217 TI - Effects of radiant heat exposure on pacing pattern during a 15-km cycling time trial. AB - The goal of this study was to investigate the effects of different durations of skin temperature manipulation on pacing patterns and performance during a 15-km cycling time trial. Nineteen well-trained men completed three 15-km cycling time trials in 18 degrees C and 50% relative humidity with 4.5-km (short-heat), 9.0 km (long-heat) or without (control) radiant heat exposure applied by infrared heaters after 1.5 km in the time trial. During the time trials, power output, mean skin temperature, rectal temperature, heart rate and rating of perceived exertion were assessed. The radiant heat exposure resulted in higher mean skin temperature during the time trial for short-heat (35.0 +/- 0.6 degrees C) and long-heat (35.3 +/- 0.5 degrees C) than for control (32.5 +/- 1.0 degrees C; P < 0.001), whereas rectal temperature was similar (P = 0.55). The mean power output was less for short-heat (273 +/- 8 W; P = 0.001) and long-heat (271 +/- 9 W; P = 0.02) than for control (287 +/- 7 W), but pacing patterns did not differ (P = 0.55). Heart rate was greatest in control (177 +/- 9 beats . min(-1); P < 0.001), whereas the rating of perceived exertion remained similar. We concluded that a radiant heat exposure and associated higher skin temperature reduced overall performance, but did not modify pacing pattern during a 15-km cycling time trial, regardless of the duration of the exposure. PMID- 24405219 TI - Biliary tumor fragment of hepatocellular carcinoma containing lipiodol mimicking a bile duct stone. PMID- 24405224 TI - Children's perception of their synthetically corrected speech production. AB - We explore children's perception of their own speech - in its online form, in its recorded form, and in synthetically modified forms. Children with phonological disorder (PD) and children with typical speech and language development (TD) performed tasks of evaluating accuracy of the different types of speech stimuli, either immediately after having produced the utterance or after a delay. In addition, they performed a task designed to assess their ability to detect synthetic modification. Both groups showed high performance in tasks involving evaluation of other children's speech, whereas in tasks of evaluating one's own speech, the children with PD were less accurate than their TD peers. The children with PD were less sensitive to misproductions in immediate conjunction with their production of an utterance, and more accurate after a delay. Within-category modification often passed undetected, indicating a satisfactory quality of the generated speech. Potential clinical benefits of using corrective re-synthesis are discussed. PMID- 24405225 TI - Idiom understanding in adulthood: examining age-related differences. AB - Idioms are figurative expressions such as hold your horses, kick the bucket, and lend me a hand, which commonly occur in everyday spoken and written language. Hence, the understanding of these expressions is essential for daily communication. In this study, we examined idiom understanding in healthy adults in their 20s, 40s, 60s and 80s (n=30 per group) to determine if performance would show an age-related decline. Participants judged their own familiarity with a set of 20 idioms, explained the meaning of each, described a situation in which the idiom could be used, and selected the appropriate interpretation from a set of choices. There was no evidence of an age-related decline on any tasks. Rather, the 60s group reported greater familiarity and offered better explanations than did the 20s group. Moreover, greater familiarity with idioms was associated with better understanding in adults. PMID- 24405229 TI - Cerebral palsy risk factors and their impact on psychopathology. AB - OBJECTIVE: We examined whether the type of brain injury impacts the psychopathological profile and quality of life in children with cerebral palsy (CP). METHODS: We assessed 18 children with CP [9 premature, 9 asphyxia at term] and 16 siblings using parent forms of the child behavior checklist (CBCL), disruptive behavior disorder rating scale (DBDRS), and pediatric quality of life inventory (PEDSQL). RESULTS: Children with CP demonstrated more emotional and behavioral symptoms (depression, anxiety, and social, thought, and attention problems) and lower quality of life than their siblings. The pathopsychological profile of children with CP due to prematurity and asphyxia was similar. CONCLUSION: Etiology does not impact the psychopathology in children with CP. PMID- 24405226 TI - Gender influences on initiation of injecting drug use. AB - BACKGROUND AND OBJECTIVES: Gender differences in illicit drug use patterns and related harms (e.g. HIV infection) are becoming increasingly recognized. However, little research has examined gender differences in risk factors for initiation into injecting drug use. We undertook this study to examine the relationship between gender and risk of injection initiation among street-involved youth and to determine whether risk factors for initiation differed between genders. METHODS: From September 2005 to November 2011, youth were enrolled into the At Risk Youth Study, a cohort of street-involved youth aged 14-26 in Vancouver, Canada. Cox regression analyses were used to assess variables associated with injection initiation and stratified analyses considered risk factors for injection initiation among male and female participants separately. RESULTS: Among 422 street-involved youth, 133 (32.5%) were female, and 77 individuals initiated injection over study follow-up. Although rates of injection initiation were similar between male and female youth (p = 0.531), stratified analyses demonstrated that, among male youth, risk factors for injection initiation included sex work (Adjusted Hazard Ratio [AHR] = 4.74, 95% Confidence Intervals [CI]: 1.45-15.5) and residence within the city's drug use epicenter (AHR = 1.95, 95% CI: 1.12-3.41), whereas among female youth, non-injection crystal methamphetamine use (AHR = 4.63, 95% CI: 1.89-11.35) was positively associated with subsequent injection initiation. CONCLUSION: Although rates of initiation into injecting drug use were similar for male and female street youth, the risk factors for initiation were distinct. These findings suggest a possible benefit of uniquely tailoring prevention efforts to high-risk males and females. PMID- 24405232 TI - Estimation of the change in hydraulic conductivity above mined longwall panels. AB - The change in hydraulic conductivity (K) above subsided longwall panels at underground coal mines is determined using a data base of pre-mining and post mining K measurements made at multiple locations down the depth profile at each of a number of sites worldwide. Results show that, following caving of roof strata, there is a clear difference in the magnitude of changes in K above and below the top of the collapsed zone. Within the collapsed zone, relative increases in K are larger, even when taking account of measurements made in potentially unsaturated strata. A generalized conceptual model is presented for K change above subsided longwall panels. These results form a third independent database supporting the height of desaturation reported in an earlier study. PMID- 24405233 TI - Sensitive chemiluminescence immunoassay for E. coli O157:H7 detection with signal dual-amplification using glucose oxidase and laccase. AB - A novel, sensitive chemiluminescence (CL) immunoassay for Escherichia coli O157:H7 detection with signal dual-amplification using glucose oxidase (GOx) and laccase was investigated. The method was based on the characterization of a luminol-H2O2-laccase reaction. Compared with the horseradish peroxidase-based biosensor, laccase exhibited high catalytic activity in strong alkaline medium, which was compatible with the luminol system. The capture antibody was immobilized onto the magnetic bead (MB) surfaces. The detection antibody was linked with GOx through biotin-avidin recognition. Accordingly, the bioconjugation of MB-caputure antibody- E. coli O157:H7-detection antibody-GOx catalyzed the substrate glucose, thereby generating H2O2. E. coli O157:H7 was then detected by measuring the CL intensity after H2O2 formation. Under optimal conditions, the calibration plot obtained for E. coli O157:H7 was approximately linear from 4.3 * 10(3) colony-forming unit (CFU) mL(-1) to 4.3 * 10(5) CFU mL( 1), and the total assay time was <2.0 h without any enrichment. The limit of detection for the assay was 1.2 * 10(3) CFU mL(-1) (3sigma), which was considerably lower than that of enzyme-linked immunosorbent assay method (1.0 * 10(5) CFU mL(-1)) (3sigma). A series of repeatability measurements of using 1.7 * 10(4) CFU mL(-1) E. coli O157:H7 exhibited reproducible results with a relative standard deviation (RSD) of 3.5% (n = 11). Moreover, the proposed method was successfully used to detect E. coli O157:H7 in synthetic samples (spring water, apple juice, and skim milk), which indicated its potential practical application. This protocol can be applied in various fields of study. PMID- 24405234 TI - Introduction to the special issue: Coping with chronic cancer: clinical approaches for oncology social work practice. PMID- 24405235 TI - Metastasis, the new "C word". AB - Patients dealing with stage IV disease have historically been isolated and marginalized much as the cancer community was many years ago before the "coming out" of Betty Ford and Happy Rockefeller. Only recently has there been an attempt to rectify this stigmatization and to give voice to these patients. With this recognition comes the obligation to find venues to serve this population. This piece reviews this history and sets the stage for advocacy and program development. PMID- 24405236 TI - Chronic cancer: counseling the individual. AB - Advances in medicine significantly improved outcomes for many cancer patients, effectively moving it from an acute disease to a more chronic one. Living with a chronic cancer often prompts an existential search for meaning, as multiple losses impact the individual on a personal and familial level. At the same time, these patients must learn to adapt to the functional and relational changes necessitated by their disease. Two theoretical perspectives, meaning-making and family systems, are useful in understanding the experience of patients with chronic cancer and offering psychosocial interventions aimed at improving overall adjustment. PMID- 24405237 TI - Group work with individuals with chronic cancer. AB - This article discusses the value and importance of support groups for people living with chronic cancer. It is a primer for the professional mental health practitioner interested in leading a support group. Group formation, screening, open versus closed groups, size, co-facilitation, duration and phases-beginning, middle and end will be discussed. Leadership, structure, and group dynamics are explained using case examples to highlight the issues. The effect of the deterioration and death of group members on both the facilitators and the group's members will be explored. The paper ends with a discussion of counter transference, stress, self-care and resiliency. PMID- 24405238 TI - Parenting with chronic cancer: a relational perspective. AB - Living with chronic cancer poses unique challenges for parents caring for minor children. The demands of the illness such as pain, fatigue, and loss of mobility, as well as caregiver responsibilities, can conflict with the patient's and partner's idea of what it means to parent. This article examines the ways in which chronic cancer impacts the parental role using Attachment as a theoretical framework. Case examples and implications for clinical practice in both health care and mental health settings are provided. PMID- 24405239 TI - Spiritual assessment: a patient-centered approach to oncology social work practice. AB - Spirituality is central to many people's lives, yet social workers often defer discussing the topic with patients. Their avoidance can be linked to the lack of training on how to speak with patients about spiritual matters (Lemmer, 2010) With further education, clinical social workers are empowered to assess this significant aspect of the patient's cancer experience as they progress along the illness continuum. The social worker's comfort and familiarity with spiritual assessment, spiritual language, and various forms of religious and/or spiritual practices will improve their clinical work with patients who have chronic cancer by providing insight to guide appropriate social work interventions designed to enhance spiritual well-being. PMID- 24405240 TI - Chronic cancer: bringing palliative care into the conversation. AB - Palliative care is a treatment model that aims to relieve patient suffering and improve quality of life, and is essential for those living with chronic cancer. However, most palliative care referrals are made as a last resort when all other treatment options have failed. This article argues that social workers have an important role in early palliative care discussions because of their unique skill set. Techniques for early introduction of palliative care are addressed, as are ways for empowering patient advocacy. A case narrative of a young woman with chronic cancer is included as an example of the need for ongoing palliative care conversations. PMID- 24405245 TI - Tip induced crystallization lithography. AB - We demonstrate a new technique for efficiently fabricating large-area organic crystal arrays on substrates using tip induced crystallization lithography (TICL). This technique depends on coating an amorphous organic thin film on a substrate and then inducing crystallization of the thin film using an atomic force microscope tip. After the noncrystalline materials are removed from the substrate by heating or washing, the organic crystal arrays are stable on the substrate. In this communication, the size of the smallest feature made using TICL technique is less than 1 MUm. PMID- 24405246 TI - Maltodextrin-modified magnetic microspheres for selective enrichment of maltose binding proteins. AB - In this work, maltodextrin-modified magnetic microspheres Fe3O4@SiO2-Maltodextrin (Fe3O4@SiO2-MD) with uniform size and fine morphology were synthesized through a facile and low-cost method. As the maltodextrins on the surface of microspheres were combined with maltose binding proteins (MBP), the magnetic microspheres could be applied to enriching standard MBP fused proteins. Then, the application of Fe3O4@SiO2-MD in one-step purification and immobilization of MBP fused proteins was demonstrated. For the model protein we examined, Fe3O4@SiO2-MD showed excellent binding selectivity and capacity against other Escherichia coli proteins in the crude cell lysate. Additionally, the maltodextrin-modified magnetic microspheres can be recycled for several times without significant loss of binding capacity. PMID- 24405247 TI - Physicochemical determinants of multiwalled carbon nanotubes on cellular toxicity: influence of a synthetic method and post-treatment. AB - Since the discovery of carbon nanotubes (CNTs), scientists have performed extensive studies on nanotubes in the fields of materials science, physics, and electronic engineering. Because multiwalled CNTs (MWCNTs) are not homogeneous materials, and because it is not feasible to test every newly synthesized MWCNT, this study was aimed at investigating the physicochemical properties that primarily determine the cellular toxicity of MWCNTs. This study analyzed the relationship between cell viability and physicochemical characteristics following exposure to eight different MWCNTs. We generated eight different MWCNTs using various synthetic methods and post-treatments. From this analysis, we sought to identify the major physicochemical determinants that could predict the cellular toxicity of MWCNTs, regardless of the synthetic method and post-treatment conditions. Creation of binding sites on the tube walls by breaking C-C bonds played a pivotal role in increasing toxicity and was most clearly demonstrated by a Raman G peak shift and the ID/IG ratio. In addition, several factors were found to be strongly related to cellular toxicity: surface charge in the case of MWCNTs created by the chemical vapor deposition method and surface area and EPR intensity in the case of MWCNTs created by the arc discharge based method. The methods developed in this study could be applied to the prediction of the toxicity of newly synthesized MWCNTs. PMID- 24405248 TI - Income inequality and population health: an analysis of panel data for 21 developed countries, 1975-2006. AB - The relative income-health hypothesis postulates that income distribution is an important determinant of population health, but the age and sex patterns of this association are not well known. We tested the relative income-health hypothesis using panel data collected for 21 developed countries over 30 years. Net of trends in gross domestic product per head and unobserved period and country factors, income inequality measured by the Gini index is positively associated with the mortality of males and females at ages 1-14 and 15-49, and with the mortality of females at ages 65-89 albeit less strongly than for the younger age groups. These findings suggest that policies to decrease income inequality may improve health, especially that of children and young-to-middle-aged men and women. The mechanisms behind the income inequality-mortality association remain unknown and should be the focus of future research. PMID- 24405249 TI - Assessing risk to birds from industrial wind energy development via paired resource selection models. AB - When wildlife habitat overlaps with industrial development animals may be harmed. Because wildlife and people select resources to maximize biological fitness and economic return, respectively, we estimated risk, the probability of eagles encountering and being affected by turbines, by overlaying models of resource selection for each entity. This conceptual framework can be applied across multiple spatial scales to understand and mitigate impacts of industry on wildlife. We estimated risk to Golden Eagles (Aquila chrysaetos) from wind energy development in 3 topographically distinct regions of the central Appalachian Mountains of Pennsylvania (United States) based on models of resource selection of wind facilities (n = 43) and of northbound migrating eagles (n = 30). Risk to eagles from wind energy was greatest in the Ridge and Valley region; all 24 eagles that passed through that region used the highest risk landscapes at least once during low altitude flight. In contrast, only half of the birds that entered the Allegheny Plateau region used highest risk landscapes and none did in the Allegheny Mountains. Likewise, in the Allegheny Mountains, the majority of wind turbines (56%) were situated in poor eagle habitat; thus, risk to eagles is lower there than in the Ridge and Valley, where only 1% of turbines are in poor eagle habitat. Risk within individual facilities was extremely variable; on average, facilities had 11% (SD 23; range = 0-100%) of turbines in highest risk landscapes and 26% (SD 30; range = 0-85%) of turbines in the lowest risk landscapes. Our results provide a mechanism for relocating high-risk turbines, and they show the feasibility of this novel and highly adaptable framework for managing risk of harm to wildlife from industrial development. PMID- 24405250 TI - Analytic density functional theory calculations of pure vibrational hyperpolarizabilities: the first dipole hyperpolarizability of retinal and related molecules. AB - We present a general approach for the analytic calculation of pure vibrational contributions to the molecular (hyper)polarizabilities at the density functional level of theory. The analytic approach allows us to study large molecules, and we apply the new code to the study of the first dipole hyperpolarizabilities of retinal and related molecules. We investigate the importance of electron correlation as described by the B3LYP exchange-correlation functional on the pure vibrational and electronic hyperpolarizabilities and compare the computed hyperpolarizabilities with available experimental data. The effects of electron correlation on the pure vibrational corrections vary signficantly even between these structurally very similar molecules, making it difficult to estimate these effects without explicit calculations at the density functional theory level. As expected, the frequency-dependent first hyperpolarizability, which determines the experimentally observed second-harmonic generation, is dominated by the electronic term, whereas for the static hyperpolarizability, the vibrational contribution is equally important. As a consequence, frequency extrapolation of the measured optical hyperpolarizabilities can only provide an estimate for the electronic contribution to the static hyperpolarizability, not its total value. The relative values of the hyperpolarizabilities for different molecules, obtained from the calculations, are in reasonable agreement with experimental data. PMID- 24405254 TI - Approval gap of pharmacogenomic biomarkers and in vitro companion diagnostics between the United States and Japan. AB - WHAT IS KNOWN AND OBJECTIVES: In vitro companion diagnostic devices (CDx) provide information on pharmacogenomic biomarkers (PGBMs) to enable the safe and effective use of targeted agents for personalized therapy. These devices require specific regulations that strike a balance between scientific evidence and financial burden. The aims were to compare approval of PGBMs and CDx in the USA and Japan and to help inform current discussions on personalized medicine. METHODS: We analysed published documentation from the USA and Japan for CDx and PGBMs, listed by the US Food and Drug Administration (FDA). Aspects evaluated were aim, approval state and therapeutic area. Coverage by the National Health Insurance in Japan was also investigated. RESULTS AND DISCUSSION: Thirty-eight PGBMs were listed in the FDA table as of March 2013. In the USA, the aim was efficacy in 55% (21/38). The largest therapeutic area was oncology (39%, 15/38). Fifty-three per cent (20/38) of the PGBMs had a corresponding CDx approved. Of the 38 PGBMs in the FDA table, six had no approved drug in Japan; in 16 of the remaining 32 PGBMs, the aim was efficacy. The largest therapeutic area was oncology (34%, 11/32). Of the 32 PGBMs, 15 were associated with an approved and/or covered CDx, with only 11 having an approved CDx. Four PGBMs had a covered CDx without prior approval in Japan. WHAT IS NEW AND CONCLUSION: Our study confirms that there is still a substantial gap in the approval of PGBMs and CDx between Japan and the USA. Complementary coverage of unapproved CDx by the National Health Insurance, however, is raising access to a similar level in both countries. Because the number of expensive personalized medicines and CDx is increasing, patient access will continue to be an important challenge to healthcare systems in all countries. PMID- 24405256 TI - Social networks and alcohol use disorders: findings from a nationally representative sample. AB - BACKGROUND: While some argue that social network ties of individuals with alcohol use disorders (AUD) are robust, there is evidence to suggest that individuals with AUDs have few social network ties, which are a known risk factor for health and wellness. OBJECTIVES: Social network ties to friends, family, co-workers and communities of individuals are compared among individuals with a past-year diagnosis of alcohol dependence or alcohol abuse to individuals with no lifetime diagnosis of AUD. METHOD: Respondents from Wave 2 of the National Epidemiologic Survey on Alcohol Related Conditions (NESARC) were assessed for the presence of past-year alcohol dependence or past-year alcohol abuse, social network ties, sociodemographics and clinical characteristics. RESULTS: Bivariate analyses showed that both social network size and social network diversity was significantly smaller among individuals with alcohol dependence, compared to individuals with alcohol abuse or no AUD. When social and clinical factors related to AUD status were controlled, multinomial logistic models showed that social network diversity remained a significant predictor of AUD status, while social network size did not differ among AUD groups. CONCLUSION: Social networks of individuals with AUD may be different than individuals with no AUD, but this claim is dependent on specific AUD diagnosis and how social networks are measured. PMID- 24405257 TI - Exercise only, exercise with mechanical traction, or exercise with over-door traction for patients with cervical radiculopathy, with or without consideration of status on a previously described subgrouping rule: a randomized clinical trial. AB - STUDY DESIGN: Randomized clinical trial. OBJECTIVES: To examine the effectiveness of cervical traction in addition to exercise for specific subgroups of patients with neck pain. BACKGROUND: Cervical traction is frequently used, but its effectiveness has not been adequately examined. Existing studies have failed to target patients most likely to respond. Traction is typically recommended for patients with cervical radiculopathy. A prediction rule has been described to identify a narrower subgroup of patients likely to respond to cervical traction. METHODS: Patients with neck pain and signs of radiculopathy were randomized to 4 weeks of treatment with exercise, exercise with mechanical traction, or exercise with over-door traction. Baseline assessment included subgrouping-rule status. The primary outcome measure (Neck Disability Index, scored 0-100) and secondary outcome measure (neck and arm pain intensity) were assessed at 4 weeks, 6 months, and 12 months after enrollment. The primary analyses examined 2-way treatment-by time interactions. Secondary analyses examined validity of the subgrouping rule by adding 3-way interactions. RESULTS: Eighty-six patients (53.5% female; mean age, 46.9 years) were enrolled in the study. Intention-to-treat analysis found lower Neck Disability Index scores at 6 months in the mechanical traction group compared to the exercise group (mean difference between groups, 13.3; 95% confidence interval: 5.6, 21.0) and over-door traction group (mean difference between groups, 8.1; 95% confidence interval: 0.8, 15.3), and at 12 months in the mechanical traction group compared to the exercise group (mean difference between groups, 9.8; 95% confidence interval: 0.2, 19.4). Secondary outcomes favored mechanical traction at several time points. The validity of the subgrouping rule was supported on the Neck Disability Index at the 6-month time point only. CONCLUSION: Adding mechanical traction to exercise for patients with cervical radiculopathy resulted in lower disability and pain, particularly at long-term follow-ups. The study protocol was registered at http://clinicaltrials.gov (NCT00979108). PMID- 24405258 TI - Immediate effects of 2 types of braces on pain and grip strength in people with lateral epicondylalgia: a randomized controlled trial. AB - STUDY DESIGN: Repeated-measures, crossover, double-blinded randomized controlled trial. OBJECTIVES: To compare the immediate effectiveness of 2 types of counterforce braces in improving pain-free grip strength, pressure pain threshold, and wrist angle during a gripping task in individuals with lateral epicondylalgia. BACKGROUND: Sports medicine management of lateral epicondylalgia often includes application of a counterforce brace, but the comparative effectiveness of different braces is unclear. The most common brace design consists of a single strap wrapped around the proximal forearm. A variation of this brace is the use of an additional strap that wraps above the elbow, which aims to provide further unloading to the injured tissue. METHODS: Pain-free grip strength, pressure pain threshold, and wrist angle during a gripping task were measured on 34 participants with a clinical diagnosis of lateral epicondylalgia (mean +/- SD age, 47.8 +/- 8.5 years). Measurements were made without a brace, as well as immediately before and after the application of 2 types of counterforce braces. Each condition was tested during a separate session, with a minimum of 48 hours between sessions. Analysis-of-variance models were used to test the differences within and between conditions. RESULTS: Pain-free grip strength (17.2 N; 95% confidence interval: 7.5, 26.8) and pressure pain threshold (42.2 kPa; 95% confidence interval: 16.5, 68.0) significantly improved on the affected side immediately following the intervention conditions as well as the control condition. There was no significant difference between braces or the control condition for any outcome. CONCLUSION: Both types of counterforce braces had an immediate positive effect in participants with lateral epicondylalgia, without differences between interventions and similar to a no-brace control condition. Therefore, while the use of a brace may be helpful in managing immediate symptoms related to lateral epicondylalgia, the choice of which brace to use may be more a function of patient preference, comfort, and cost. Further research is required to investigate the comparative longer-term and clinical effects of the 2 braces. TRIAL REGISTRATION: ACTRN12609000354280 ( www.anzctr.org.au). PMID- 24405259 TI - Effect of nutritional status on survival outcome of diffuse large B-cell lymphoma patients treated with rituximab-CHOP. AB - The impact of pretreatment nutritional status on the treatment outcome of non Hodgkin lymphoma has never been explored. Among the 953 patients who were registered in a prospective cohort at Samsung Medical Center., we analyzed 262 patients who had been treated with Ruximab-cyclophosphamide, doxorubicin, vincristine, and prednisone for newly diagnosed diffuse large B-cell lymphoma (DLBCL) and for whom data were available regarding pretreatment nutritional status. Nutritional status at diagnosis was assessed by triceps skin fold (TSF), mid-arm muscle circumference (MAMC), body mass index (BMI), serum albumin, prealbumin, and transferrin. For patients aged 60 yr and older, poor performance and higher tumor burden were associated with malnourishment represented by albumin <3.5 g/dL, prealbumin < 17 g/dL, and transferrin <170 mg/L. Lower BMI (<20), serum albumin, prealbumin, and transferrin were identified as risk factors for febrile neutropenia in univariate analysis, but not in multivariate analysis. In the univariate analysis for OS, all nutritional parameters except MAMC showed a significant association with survival. However, BMI was the only parameter that was independently prognostic for OS in the multivariate analysis (P = 0.031; hazards ratio = 3.32). Nutritional insufficiency encountered in DLBCL patients might influence the occurrence of treatment-related toxicity and poor survival outcome of patients. PMID- 24405262 TI - Effects of ebselen on ischemia/reperfusion injury in rat brain. AB - AIM: Interruption of blood flow may result in considerable tissue damage via ischemia/reperfusion (I/R) injury-induced oxidative stress in brain tissues. The aim of the present study was to investigate the effects of Ebselen treatment in short-term global brain I/R injury in rats. MATERIAL AND METHODS: The study was carried out on 27 Wistar-albino rats, divided into three groups including Sham group (n = 11), I/R group (n = 8) and I/R+Ebselen group (n = 8). RESULTS: Malondialdehyde (MDA) levels were significantly increased in I/R group in comparison with the Sham group and I/R+Ebselen group (p < 0.001 and p < 0.01). Superoxide dismutase (SOD) activity was significantly lower in I/R group in comparison to both Sham (p < 0.001) and I/R+Ebselen (p < 0.01) groups. Similarly, SOD activity was decreased in I/R+Ebselen group when compared with Sham group (p < 0.001). Sham and I/R groups were similar in terms of nitric oxide (NO) levels. In contrast, the NO level was lower in I/R+Ebselen group when compared with Sham (p < 0.001) and I/R (p < 0.01) groups. There was no significant difference among the groups in terms of glutathione peroxidase and catalase activities. In histopathological examination, the brain tissues of rats that received Ebselen showed morphological improvement. CONCLUSION: Ebselen has neuron-protective effects due to its antioxidant properties as shown by the decrease in MDA overproduction, increase in SOD activity and the histological improvement after administration of Ebselen to I/R in brain tissue. PMID- 24405263 TI - An enigmatic brainstem posterior fossa ganglioglioma in an adult. AB - Ganglioglioma is a rare central nervous system neoplasm representing 0.4% to 1.7% of all brain tumors and most frequently occurs in the pediatric population with an incidence of 7.6%. These tumors are usually slow-growing and well circumscribed solid or cystic lesions. Gangliogliomatosis infrequently occurs in the frontal lobe, pineal gland, basal ganglia, hypothalamus, and optic chiasm, with very few reports of brainstem ganglioglioma. We report a case of a 35-year old female who initially presented with headache, vertigo, ataxia, saccadic dysfunction, dysarthria, and dysmetria for several years due to an unknown etiology. Her brain imaging showed multiple lesions in the pons and the cerebellum with cystic changes and size reduction and enlargement over the next few years while her neurological symptoms continued to worsen. The patient received courses of steroid treatment that improved her neurological symptoms, suggesting an inflammatory component of her disease. Extensive workup for an inflammatory or infectious etiology was unfruitful and two brain biopsies were inconclusive. A third biopsy showed atypical glial nuclei, binucleated cells, and Rosenthal fibers and the presence of BRAF V600E mutation was detected. The diagnosis of gangliogliomatosis was consequently established. This case illustrates that gangliogliomatosis may present with the waxing-and-waning neurological signs and symptoms. It can masquerade inflammatory processes in the central nervous system on brain imaging and deserves careful consideration in the diagnosis of patients with an indolent course of neurological deterioration. PMID- 24405264 TI - Whose goals and outcomes are they? PMID- 24405265 TI - Vasoactive intestinal peptide induces an immunosuppressant microenvironment in the maternal-fetal interface of non-obese diabetic mice and improves early pregnancy outcome. AB - PROBLEM: Impaired pregnancy in non-obese diabetic (NOD) mice was related to limited vascular remodeling and autoimmune background. Vasoactive intestinal peptide (VIP) has anti-inflammatory and immunosuppressant effects, so we explored its ability to modulate the immune microenvironment at the early maternal placental interface and improve pregnancy in NOD mice. METHOD OF STUDY: Implantation sites were isolated from pregnant NOD mice at gestational day 9.5 and were incubated with VIP for evaluation of cytokine or transcription factor expression by RT-PCR, immunoblotting, and immunohistochemistry. Alternatively, pregnant mice were injected with VIP at day 6.5 and studied at day 9.5. RESULTS: VIP and VPAC receptors were detected in viable implantation sites. VIP immunostaining was found predominantly on trophoblast giant cells. The in vitro treatment of viable implantation sites with VIP increased IL-10, TGF-beta, and Foxp3 expression. Sites with resorption processes presented lower VIP expression, reduced suppressant markers, and increased IL-17 and RORgammaT expression compared with viable sites and VIP reduced RORgammaT expression. Pregnant mice treated with VIP at day 6.5 presented an even distribution of viable implantation sites with an increased expression of IL-10, TGF- beta, and Foxp3. CONCLUSION: VIP induces an immunosuppressant profile at the early maternal-placental interface of NOD mice and improves pregnancy outcome. PMID- 24405266 TI - MicroRNA let-7f: a novel regulator of innate immune response in human endocervical cells. AB - PROBLEM: Endocervical epithelial cells express pattern recognition receptors (PRRs) that aid in innate immune responses. Mechanisms regulating signaling of PRRs are poorly understood. METHODS OF STUDY: Endocervical cells (End1/E6E7) were treated with ligands of TLR9 and RIG-I once or after pre-stimulation with same ligand. Cytokine responses were determined by ELISA. Differential gene expression was analyzed by microarray. Differentially expressed genes were validated by qPCR /Western blot. Role of let-7f was studied by inhibition and over-expression studies using commercial inhibitors and let-7f encoding plasmids, respectively. RESULTS: Single stimulation of cells with TLR9 ligand, but not RIG-I ligand, induced tolerance to subsequent challenge to the same ligand. Stimulation with TLR9 decreased let-7f and increased its target Blimp-1. Conversely, RIG-I stimulation increased let-7f and decreased Blimp-1 expression. Inhibition and over-expression revealed let-7f is involved in induction of immune tolerance. CONCLUSION: We identify let-7f as a novel regulator of PRR signaling in endocervical cells. PMID- 24405267 TI - Influence of PD-L1 cross-linking on cell death in PD-L1-expressing cell lines and bovine lymphocytes. AB - Programmed death-ligand 1 (PD-L1) blockade is accepted as a novel strategy for the reactivation of exhausted T cells that express programmed death-1 (PD-1). However, the mechanism of PD-L1-mediated inhibitory signalling after PD-L1 cross linking by anti-PD-L1 monoclonal antibody (mAb) or PD-1-immunogloblin fusion protein (PD-1-Ig) is still unknown, although it may induce cell death of PD-L1(+) cells required for regular immune reactions. In this study, PD-1-Ig or anti-PD-L1 mAb treatment was tested in cell lines that expressed PD-L1 and bovine lymphocytes to investigate whether the treatment induces immune reactivation or PD-L1-mediated cell death. PD-L1 cross-linking by PD-1-Ig or anti-PD-L1 mAb primarily increased the number of dead cells in PD-L1(high) cells, but not in PD L1(low) cells; these cells were prepared from Cos-7 cells in which bovine PD-L1 expression was induced by transfection. The PD-L1-mediated cell death also occurred in Cos-7 and HeLa cells transfected with vectors only encoding the extracellular region of PD-L1. In bovine lymphocytes, the anti-PD-L1 mAb treatment up-regulated interferon-gamma (IFN-gamma) production, whereas PD-1-Ig treatment decreased this cytokine production and cell proliferation. The IFN gamma production in B-cell-depleted peripheral blood mononuclear cells was not reduced by PD-1-Ig treatment and the percentages of dead cells in PD-L1(+) B cells were increased by PD-1-Ig treatment, indicating that PD-1-Ig-induced immunosuppression in bovine lymphocytes could be caused by PD-L1-mediated B-cell death. This study provides novel information for the understanding of signalling through PD-L1. PMID- 24405268 TI - Aragonite crystals grown on bones by reaction of CO2 with nanostructured Ca(OH)2 in the presence of collagen. Implications in archaeology and paleontology. AB - The loss of mechanical properties affecting archeological or paleontological bones is often caused by demineralization processes that are similar to those driving the mechanisms leading to osteoporosis. One simple way to harden and to strengthen demineralized bone remains could be the in situ growth of CaCO3 crystals in the aragonite polymorph - metastable at atmospheric pressure -which is known to have very strong mechanical strength in comparison with the stable calcite. In the present study the controlled growth of aragonite crystals was achieved by reaction between atmospheric CO2 and calcium hydroxide nanoparticles in the presence of collagen within the deteriorated bones. In a few days the carbonation of Ca(OH)2 particles led to a mixture of calcite and aragonite, increasing the strength of the mineral network of the bone. Scanning electron microscopy coupled with energy dispersive X-ray spectroscopy (SEM-EDS) and Fourier transform infrared (FT-IR) spectrometry showed that aragonite crystallization was achieved. The effect of the aragonite crystal formation on the mechanical properties of the deteriorated bones was investigated by means of X-rays microtomography, helium porosimetry, atomic force microscopy (AFM), and Vickers microhardness techniques. All these data enabled to conclude that the strength of the bones increased of a factor of 50-70% with respect to the untreated bone. These results could have immediate impact for preserving archeological and paleontological bone remains. PMID- 24405272 TI - Response to editorial comments to tubeless simultaneous bilateral percutaneous nephrolithotomy: safety, feasibility and efficacy in an Indian setting. PMID- 24405273 TI - In vitro inhibition of human liver cytochrome P450 (CYP) and UDP glucuronosyltransferase (UGT) enzymes by rose bengal: system-dependent effects on inhibitory potential. AB - 1. Rose bengal (4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein) is being developed for the treatment of cutaneous melanoma and hepatocellular carcinoma. Interestingly, rose bengal can generate singlet oxygen species upon exposure to light. 2. We evaluated rose bengal as an in vitro inhibitor of cytochrome P450 (CYP) or UDP-glucuronosyltransferase (UGT) enzymes in both human liver microsomes (HLM) and cryopreserved human hepatocytes (CHHs) under both yellow light and dark conditions. 3. Rose bengal directly inhibited CYP3A4/5 and UGT1A6 in HLM under yellow light with inhibitor concentration that causes 50% inhibition (IC50) values of 0.072 and 0.035 MUM, respectively; whereas much less inhibition was observed in the dark with the IC50 values increasing 43- and 120-fold, respectively. To determine if a more physiologically-relevant test system could be protected from such an effect, rose bengal was evaluated as an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4/5 and UGT enzymes in CHH. All IC50 values were similar (64 +/- 8 MUM) and little to no effect of light on inhibitory potential was observed. 4. Given the IC50 values in CHH increased an order of magnitude compared to HLM and the atypical pharmacokinetics of the drug, the risk of rose bengal to cause clinically relevant drug-drug interactions is likely low, particularly when administered to cancer patients on an intermittent schedule. PMID- 24405274 TI - Long-term oncologic outcomes of minimally invasive partial nephrectomy for renal cell carcinoma. AB - PURPOSE: To report the long-term oncologic outcomes and survival estimates associated with minimally invasive partial nephrectomy (MIPN) and to determine factors associated with those outcomes and survival estimates. PATIENTS AND METHODS: A single-institution, retrospective review was performed on all patients undergoing MIPN for renal-cell carcinoma between 1998 and 2011 with minimum 1 year follow-up. Bivariate and multivariate analyses were performed to assess associations between demographic, perioperative, and tumor factors with recurrence and survival. Survival was estimated using the Kaplan-Meier method. RESULTS: Of 417 patients undergoing MIPN, median overall and oncologic follow-up were 3.3 and 2.9 years, respectively. The mean patient age was 63 years (standard deviation [SD]+/- 13.4). The mean tumor size was 2.9 cm (SD +/- 1.48). Only 6.7% of patients had a pathologic stage T2 or greater. There was only one cancer related death. Estimates for overall survival at 2, 5, and 10 years were 95.6%, 89.1%, and 70.7%, respectively. Estimates for recurrence-free survival (any recurrence) at 2, 5, and 10 years were 98.2%, 93.5%, and 88.3%, respectively. On multivariate analysis, only tumor stage was associated with recurrence, and only patient age and American Society of Anesthesiologists score were associated with overall survival. Technical aspects of the procedure, such as positive margins or use of enucleation, did not influence recurrence or survival. CONCLUSIONS: Cancer recurrence after MIPN, in a cohort of patients with mostly pT1 tumors, is rare. Recurrence and overall survival are associated with nonmodifiable factors rather than technical ones. PMID- 24405275 TI - A single molecule level study of the temperature-dependent kinetics for the formation of metal porphyrin monolayers on Au(111) from solution. AB - Scanning tunneling microscopy was used to make the first molecular scale measurements of the temperature dependence of composition of an adlayer at the solution-solid interface. We conclusively demonstrate that metal porphyrins adsorb very strongly on Au(111) at the solution solid interface such that the monolayer composition is entirely kinetically controlled below about 100 degrees C. The barrier for desorption is so great in fact that a temperature of 135 degrees C is required to induce desorption over a period of hours. Moreover, cobalt(II) octaethylporphyrin (CoOEP) and NiOEP desorb at different rates from different sites on the surface. We have measured the rate constant for desorption of CoOEP into phenyloctane to be 6.7 * 10(-5)/s at 135 degrees C. On the basis of these measurements, an upper bound can be set for the desorption rate of NiOEP into phenyloctane as 6.7 * 10(-4)/s at 135 degrees C. For solutions of the order of 100 MUM in NiOEP or CoOEP, a dense monolayer is formed within seconds, and the adsorption rate constants fall within 40% of each other. The structures of NiOEP and CoOEP monolayers are essentially identical, and the molecular spacing for both can be described by A = 1.42 +/- 0.02 nm, B = 1.32 +/- 0.02 nm, and alpha = 57 degrees +/- 2 degrees . The solubility of CoOEP and NiOEP in phenyloctane at room temperature was measured to be 0.228 and 0.319 g/L, respectively. PMID- 24405276 TI - Polyamine transport inhibitors: design, synthesis, and combination therapies with difluoromethylornithine. AB - The development of polyamine transport inhibitors (PTIs), in combination with the polyamine biosynthesis inhibitor difluoromethylornithine (DFMO), provides a method to target cancers with high polyamine requirements. The DFMO+PTI combination therapy results in sustained intracellular polyamine depletion and cell death. A series of substituted benzene derivatives were evaluated for their ability to inhibit the import of spermidine in DFMO-treated Chinese hamster ovary (CHO) and L3.6pl human pancreatic cancer cells. Several design features were discovered which strongly influenced PTI potency, sensitivity to amine oxidases, and cytotoxicity. These included changes in (a) the number of polyamine chains appended to the ring system, (b) the polyamine sequence, (c) the attachment linkage of the polyamine to the aryl core, and (d) the presence of a terminal N methyl group. Of the series tested, the optimal design was N(1),N(1'),N(1") (benzene-1,3,5-triyltris(methylene))tris(N(4)-(4-(methylamino)butyl)butane-1,4 diamine, 6b, which contained three N-methylhomospermidine motifs. This PTI exhibited decreased sensitivity to amine oxidases and low toxicity as well as high potency (EC50 = 1.4 MUM) in inhibiting the uptake of spermidine (1 MUM) in DFMO-treated L3.6pl human pancreatic cancer cells. PMID- 24405277 TI - Fast contact of solid-liquid interface created high strength multi-layered cellulose hydrogels with controllable size. AB - Novel onion-like and multi-layered tubular cellulose hydrogels were constructed, for the first time, from the cellulose solution in a 7% NaOH/12% urea aqueous solvent by changing the shape of the gel cores. In our findings, the contacting of the cellulose solution with the surface of the agarose gel rod or sphere loaded with acetic acid led to the close chain packing to form immediately a gel layer, as a result of the destruction of the cellulose inclusion complex by acid through inducing the cellulose self-aggregation. Subsequently, multi-layered cellulose hydrogels were fabricated via a multi-step interrupted gelation process. The size, layer thickness and inter-layer space of the multi-layered hydrogels could be controlled by adjusting the cellulose concentrations, the gel core diameter and the contacting time of the solid-liquid interface. The multi layered cellulose hydrogels displayed good architectural stability and solvent resistance. Moreover, the hydrogels exhibited high compressive strength and excellent biocompatibility. L929 cells could adhere and proliferate on the surface of the layers and in interior space, showing great potential as tissue engineering scaffolds and cell culture carrier. This work opens up a new avenue for the construction of the high strength multi-layered cellulose hydrogels formed from inner to outside via a fast contact of solid-liquid interface. PMID- 24405278 TI - Multiple myeloma: genome sequencing, drug development and the future outlook. AB - Keith Stewart is the Dean for Research at Mayo Clinic (AZ, USA). He holds the Vasek and Anna Maria Polak Endowed Professorship in Cancer Research. He received his medical degree at Aberdeen University Medical School and trained in internal medicine and hematology in Glasgow, Kingston, Toronto and Boston. He was a consultant at the Toronto General and Princess Margaret Hospitals from 1992 to 2005 and a Professor in the Faculty of Medicine at the University of Toronto. He joined Mayo Clinic in Arizona in 2005. His lab-based research has focused on the genomics and developmental therapeutics of multiple myeloma. He has led numerous clinical trials from 'first in man', through to large international Phase III studies. Funding for his research includes the National Cancer Institute, the Leukemia and Lymphoma Society (LLS) and the Multiple Myeloma Research Foundation (MMRF). In addition, he is an associate editor of Blood, the journal of the American Society of Hematology (ASH). PMID- 24405280 TI - Early pregnancy changes in bacterial vaginosis-associated bacteria and preterm delivery. AB - BACKGROUND: We evaluated the importance of measuring early vaginal levels of eight bacterial vaginosis (BV)-associated bacteria, at two points in pregnancy, and the risk of spontaneous preterm delivery (SPTD) among pregnant women and the subgroup of pregnant women with a history of preterm delivery (PTD). METHODS: This prospective cohort study enrolled women at five urban obstetric practices at Temple University Hospital in Philadelphia PA. Women with singleton pregnancies less than 16 weeks gestation self-collected vaginal swabs at two points in pregnancy, prior to 16 weeks gestation and between 20-24 weeks gestation, to measure the presence and level of eight BV-associated bacteria. Women were followed-up for gestational age at delivery via medical records. RESULTS: Among women reporting a prior PTD, women with higher levels of Leptotrichia/Sneathia species, BVAB1 and Mobiluncus spp., prior to 16 weeks gestation, were significantly more likely to experience a SPTD. In addition, pregnant women with a prior PTD and increasing levels of Leptotrichia/Sneathia species (aOR: 9.1, 95% CI 1.9, 42.9), BVAB1 (aOR: 16.4, 95% CI 4.3, 62.7) or Megasphaera phylotype 1 (aOR: 6.2, 95% CI 1.9, 20.6), through 24 weeks gestation, were significantly more likely to experience an SPTD. Among the overall group of pregnant women, the levels of BV-associated bacteria were not related to SPTD. CONCLUSION: Among the group of women reporting a prior PTD, increasing levels of BVAB1, Leptotrichia/Sneathia species, and Megasphaera phylotype 1, through mid-pregnancy were related to an increased risk of SPTD. PMID- 24405282 TI - A review of the response to HIV/AIDS in Trinidad and Tobago: 1983-2010. AB - This paper examines the character of the response to HIV/AIDS in Trinidad and Tobago and assesses the impact of the response on reducing the spread of the epidemic. The launch of the National HIV/AIDS Strategic Plan in 2004 signalled the intent of the government to take the response to HIV/AIDS to a different level. This is seen by the sheer increase in the volume of resources allocated to the response from the levels of the 1980s and 1990s. The expectation was that there would be increased cohesiveness, which would allow for targeted interventions to be more effective. Though in 2009, there was a slight increase in the HIV prevalence rate to 1.5%, this was due mainly to improvements in access to antiretrovirals and same-day testing as well as improvements in data collection and analysis. The annual number of new infections fell from a high of 1709 in 2003 to 1154 in 2010. Additionally, great strides have been made in the prevention of mother-to-child transmission programme with some regions reporting 100% coverage of antenatal attendees. The study indicates that the country has responded relatively well in the areas of Strategic Planning, Care and Support, and Prevention and there has been involvement by both the public and private sector (NGOs in particular), in the response. However, there are gaps in the provision of social services and the implementing legislation to protect the rights of persons living with HIV/AIDS. Of note is the fact that a successful response to the HIV/AIDS epidemic is one that embraces all social groups, all spheres of activity and all areas of the country. PMID- 24405283 TI - Awareness and practices of contraceptive use among university students in Botswana. AB - In Botswana, unplanned pregnancies, especially among the youth constitutes a growing health and social problem. Research in the field of contraceptive practices, and the causes of sexual practices in Botswana, remains scarce and relatively limited. The objectives of this study was to investigate the awareness and utilization of various contraceptive methods, among university students in Botswana. A descriptive, cross-sectional, research study was conducted among 346 randomly selected students, who completed confidential, self-administered questionnaires. The average age of the respondents was 21 years (SD = 2.8 years). The level of awareness among students regarding contraception was good (score >=9). Both the male and the female students had almost similar awareness level of contraceptive use, as their mean scores were 8.79 and 8.72, respectively (p = .733). All the female students (100%) were 'aware' that the effectiveness of the contraceptives used, as compared to male students, being 93.7%. A greater proportion of the female students (90.6%) knew that using contraceptives irregularly would result in pregnancy, in contrast to 76.4% males. More than half (59.0%) of the students indicated that they had engaged in sexual acts. Significantly, more male students (68.5%) had sexual experiences prior to the study, compared to 54.5% of their female counterparts (p = .038).The majority of the students (76%) reported that they had always used contraceptive methods. The most commonly used contraceptive method was the condom (95.6%), followed by oral contraceptive pill (86.7%). There was no significant association found between the level of awareness and the use of contraceptives. Results suggested that many students still engaged in risky, contraceptive practices by engaging in unprotected sexual acts. Therefore, there is a need to educate the students about sexually transmitted infections, the different contraceptive methods and the regular use of the available contraceptives. PMID- 24405281 TI - Prevention of ventilator-induced lung edema by inhalation of nanoparticles releasing ruthenium red. AB - The acute respiratory distress syndrome (ARDS), a devastating lung disease that has no cure, is exacerbated by life-supportive mechanical ventilation that worsens lung edema and inflammation through the syndrome of ventilator-induced lung injury. Recently, the membrane ion channel transient receptor potential vanilloid 4 (TRPV4) on alveolar macrophages was shown to mediate murine lung vascular permeability induced by high-pressure mechanical ventilation. The objective of this study was to determine whether inhalation of nanoparticles (NPs) containing the TRPV4 inhibitor ruthenium red (RR) prevents ventilator induced lung edema in mice. Poly-lactic-co-glycolic acid NPs containing RR were evaluated in vitro for their ability to block TRPV4-mediated calcium signaling in alveolar macrophages and capillary endothelial cells. Lungs from adult C57BL6 mice treated with nebulized NPs were then used in ex vivo ventilation perfusion experiments to assess the ability of the NPs to prevent high-pressure mechanical ventilation-induced lung edema. Poly-lactic-co-glycolic acid NPs (300 nm) released RR for 150 hours in vitro, and blocked TRPV4-mediated calcium signaling in cells up to 7 days after phagocytosis. Inhaled NPs deposited in alveoli of spontaneously breathing mice were rapidly phagocytosed by alveolar macrophages, and blocked increased vascular permeability from high-pressure mechanical ventilation for 72 hours in ex vivo ventilation perfusion experiments. These data offer proof of principle that inhalation of NPs containing a TRPV4 inhibitor prevents ventilator damage for several days, and imply that this novel drug delivery strategy could be used to target alveolar macrophages in patients at risk of ventilator-induced lung injury before initiating mechanical ventilation. PMID- 24405284 TI - A comparison of quality of life between HIV positive and negative diamond miners in South Africa. AB - OBJECTIVE: To analyse the health-related quality of life (HR-QOL) in two groups of diamond miners (HIV negative and positive) in South Africa using three instruments. Two hypotheses were to be tested. One, was that the HR-QOL of HIV positive miners would be lower than that of HIV negative miners; and two, the selected instruments would behave consistently and thus all would confirm hypothesis one. METHODS: In our study, workers were recruited during a voluntary counselling and testing programme for HIV. HR-QOL were estimated using the Assessment of Quality of Life (AQOL) Mark 2, EQ-5D (EuroQOL), and Health Utilities Index 3 (HUI3) instruments. The data were analysed for utility values and for correlations between variables of interest (in particular HIV status). Goodness of fit, Pearson's r coefficient and t-tests were the statistical tests applied to the data. RESULTS: Just over 1100 respondents were included in the analysis. HIV positive workers scored significantly lower on quality of life on the HUI3 as compared to HIV negative workers but this relationship did not (surprisingly) hold for the AQOL or EQ-5D. There was a significant positive correlation between all three instruments. CONCLUSION: There was inconsistency among the instruments in measuring quality of life differences according to HIV status. The HUI3 confirmed the a priori expectation that the HR-QOL of HIV positive miners would be lower than HIV negative miners. There was no statistical difference for the AQOL and a confounding result was found for the EQ5D. PMID- 24405285 TI - HIV-related symptoms and management in HIV and antiretroviral therapy patients in KwaZulu-Natal, South Africa: a longitudinal study. AB - AIM: The study aimed to determine the prevalence, predictors, and self-reported management of HIV- or ARV-related symptoms among HIV patients prior to antiretroviral therapy (ART) and over three time points while receiving ART in KwaZulu-Natal, South Africa. METHOD: A total of 735 consecutive patients (29.8% male and 70.2% female) who attended three HIV clinics completed assessments prior to ARV initiation, 519 after 6 months, 557 after 12 months, and 499 after 20 months on ART. RESULTS: The HIV patients reported an average of 7.5 symptoms (prior to ART), 1.2 symptoms after 6 months on ART, 0.3 symptoms after 12 months on ART, and 0.2 symptoms after 20 months on ART on the day of the interview, with a higher symptom frequency amongst patients who were not employed, had lower CD4 cell counts, experienced internalised stigma, and used alcohol. The most common symptoms or conditions identified by the self-report included tuberculosis, diarrhoea, headaches, rash, nausea and vomiting, pain, neuropathy, lack of appetite, cough, and chills. Overall, the participants reported medications as the most frequently occurring management strategy, with the second being spiritual, and the third being complementary or traditional treatments. The use of all other management strategies decreased over the four different assessment periods from prior to ART to 20 months on ART. CONCLUSION: This study found a high symptom burden among HIV patients, which significantly decreased with progression on antiretroviral treatment. Several symptoms that persisted over time and several sociodemographic factors were identified that can guide symptom management. The utilisation of different symptom management strategies (medical, spiritual, complementary, and traditional) should be taken into consideration in HIV treatment. PMID- 24405286 TI - HIV knowledge, disclosure and sexual risk among pregnant women and their partners in rural South Africa. AB - Partner involvement has been deemed fundamental for the prevention of mother-to child transmission (PMTCT) of HIV, although it remains difficult to achieve. This study aimed to explore the attitudes and behaviours of pregnant women and their partners who participated in a behavioural risk reduction intervention in six community health centres in the Mpumalanga province of South Africa. Qualitative methods only were used in this study. Women and their partners took part in four gender-concordant groups that addressed HIV, PMTCT, disclosure of HIV status and safer sex practices. The results indicate that men value and understand the importance of being involved in women's reproductive health, although some components of the PMTCT programme such as condom use were still met with some resistance. Participants demonstrated high levels of HIV- and sexually transmitted infection-related knowledge. Men lacked knowledge about PMTCT but were interested in acquiring information so that they could support their partners. All groups highlighted the emotional and physical benefits of disclosing one's HIV status. The involvement of men in antenatal care has the potential to prevent women from becoming infected with HIV both during pregnancy and post-partum when they are more vulnerable to infection and have a high risk of transmission to the infant. There is a need for interventions that focus on both increasing male involvement and promoting condom use during pregnancy. PMID- 24405288 TI - Unintentional wildlife poisoning and proposals for sustainable management of rodents. AB - In Europe, bromadiolone, an anticoagulant rodenticide authorized for plant protection, may be applied intensively in fields to control rodents. The high level of poisoning of wildlife that follows such treatments over large areas has been frequently reported. In France, bromadiolone has been used to control water voles (Arvicola terrestris) since the 1980s. Both regulation and practices of rodent control have evolved during the last 15 years to restrict the quantity of poisoned bait used by farmers. This has led to a drastic reduction of the number of cases of poisoned wildlife reported by the French surveillance network SAGIR. During the autumn and winter 2011, favorable weather conditions and high vole densities led to the staging of several hundreds of Red Kites (Milvus milvus) in the Puy-de-Dome department (central France). At the same time, intensive treatments with bromadiolone were performed in this area. Although no misuse has been mentioned by the authorities following controls, 28 Red Kites and 16 Common Buzzards (Buteo buteo) were found dead during surveys in November and December 2011. For all these birds, poisoning by bromadiolone as the main cause of death was either confirmed or highly suspected. Other observations suggest a possible impact of bromadiolone on the breeding population of Red Kites in this area during the spring 2011. French regulation of vole control for plant protection is currently under revision, and we believe this event calls for more sustainable management of rodent outbreaks. Based on large-scale experiments undertaken in eastern France, we propose that direct control of voles at low density (with trapping or limited chemical treatments) and mechanical destruction of vole tunnels, mole control, landscape management, and predator fostering be included in future regulation because such practices could help resolve conservation and agricultural issues. PMID- 24405291 TI - Plant-based vaccines for Alzheimer's disease: an overview. AB - Plants are considered advantageous platforms for biomanufacturing recombinant vaccines. This constitutes a field of intensive research and some plant-derived vaccines are expected to be marketed in the near future. In particular, plant based production of immunogens targeting molecules with implications on the pathology of Alzheimer's has been explored over the last decade. These efforts involve targeting amyloid beta and beta-secretase with several immunogen configurations that have been evaluated in test animals. The results of these developments are analyzed in this review. Perspectives on the topic are identified, such as exploring additional antigen configurations and adjuvants in order to improve immunization schemes, characterizing in detail the elicited immune responses, and immunological considerations in the achievement of therapeutic humoral responses via mucosal immunization. Safety concerns related to these therapies will also be discussed. PMID- 24405292 TI - Electrospray ionization deposition of ultrathin ionic liquid films: [C8C1Im]Cl and [C8C1Im][Tf2N] on Au(111). AB - We introduce a new method for preparing ultrathin ionic liquid (IL) films on surfaces by means of electrospray ionization deposition (ESID) under ultraclean and well-defined ultra-high-vacuum (UHV) conditions. In contrast to physical vapor deposition (PVD) of ILs under UHV, ESID even allows deposition of ILs, which are prone to thermal decomposition. As proof of concept, we first investigated ultrathin [C8C1Im][Tf2N] (=1-methyl-3-octyl imidazolium bis(trifluoromethyl)imide) films on Au(111) by angle-resolved X-ray photoelectron spectroscopy (ARXPS). Films obtained by ESID are found to be virtually identical to films grown by standard PVD. Thereafter, ESID of [C8C1Im]Cl on Au(111) was studied as a first example of an IL that cannot be prepared as ultrathin film otherwise. [C8C1Im]Cl forms a wetting layer with a checkerboard arrangement with the cationic imidazolium ring and the chloride anion adsorbed next to each other on the substrate and the alkyl chain pointing toward vacuum. This arrangement within the wetting layer is similar to that observed for [C8C1Im][Tf2N], albeit with a higher degree of order of the alkyl chains. Further deposition of [C8C1Im]Cl leads to a pronounced island growth on top of the wetting layer, which is independently confirmed by ARXPS and atomic force microscopy. This behavior contrasts the growth behavior found for [C8C1Im][Tf2N], where layer-by-layer growth on top of the wetting layer is observed. The dramatic difference between both ILs is attributed to differences in the cation-anion interactions and in the degree of order in the wetting layer of the two ILs. PMID- 24405294 TI - The role of executive function and the dorsolateral prefrontal cortex in the expression of neuroticism and conscientiousness. AB - The current study examined how specific neurological systems contribute to the expression of multiple personality dimensions. We used individuals with traumatic brain injuries to examine the contribution of the dorsolateral prefrontal cortex (DLPFC)--a region important for executive function and attention-to the expression of neuroticism and conscientiousness factors and facets. Results from Voxel-Based Lesion-Symptom Mapping analyses revealed that focal damage to the left DLPFC (Brodmann's area 9) was associated with high neuroticism and low conscientious factor and facet scores (anxiety and self-discipline, respectively). Compared with lesioned and normal controls, veterans with damage in left DLPFC also reported higher neuroticism and lower conscientiousness facet scores, slower reaction times on the California Computerized Assessment Package assessment, and lower scores on the Delis-Kaplan executive function battery. Findings suggest that while neuroticism and conscientiousness remain psychometrically independent personality dimensions, their component facets may rely on a common neurocognitive infrastructure and executive function resources in general. PMID- 24405295 TI - Angiosarcoma of the corpora cavernosa. PMID- 24405293 TI - A population biological approach to understanding the maintenance and loss of the T-cell repertoire during aging. AB - The adaptive immune system requires a diverse T-cell repertoire to be able to respond to a wide variety of pathogens. Worryingly, the repertoire diversity declines dramatically in old age. As thymic output generates novel T cells, the conventional view holds that a decrease in this output with age is responsible for the loss in the repertoire. However, many additional factors affect the repertoire such as homeostatic turnover and antigen-dependent expansion in response to infection. Mathematical models taking a population biology perspective are important tools for understanding how the interplay between these factors affects the immune repertoire. These models suggest that thymic decline is not a major factor but rather that some combination of virus-induced proliferation and T-cell-intrinsic genetic or epigenetic changes gives rise to the oligoclonal expansions that cause the decline in T-cell diversity. We also discuss consequences for strategies to rejuvenate the immune repertoire in old age. PMID- 24405297 TI - Sulforaphane induces DNA damage and mitotic abnormalities in human osteosarcoma MG-63 cells: correlation with cell cycle arrest and apoptosis. AB - Osteosarcoma is a recalcitrant bone malignancy with poor responsiveness to treatments; therefore, new chemotherapeutic compounds are needed. Sulforaphane (SFN) has been considered a promising chemotherapeutic compound for several types of tumors by inducing apoptosis and cytostasis, but its effects (e.g., genotoxicity) in osteosarcoma cells remains exploratory. In this work, the MG-63 osteosarcoma cell line was exposed to SFN up to 20 MUM for 24 and 48 h. SFN induced G2/M phase arrest and decreased nuclear division index, associated with disruption of cytoskeletal organization. Noteworthy, SFN induced a transcriptome response supportive of G2/M phase arrest, namely a decrease in Chk1- and Cdc25C encoding transcripts, and an increase in Cdk1-encoding transcripts. After 48-h exposure, SFN at a dietary concentration (5 MUM) contributed to genomic instability in the MG-63 cells as confirmed by increased number of DNA breaks, clastogenicity, and nuclear and mitotic abnormalities. The increased formation of nucleoplasmic bridges, micronuclei, and apoptotic cells positively correlated with loss of viability. These results suggest that genotoxic damage is an important step for SFN-induced cytotoxicity in MG-63 cells. In conclusion, SFN shows potential to induce genotoxic damage at low concentrations and such potential deserves further investigation in other tumor cell types. PMID- 24405298 TI - Mode-specific tunneling in the unimolecular dissociation of cis-HOCO to H + CO2. AB - We report mode-specific tunneling in the unimolecular dissociation of cis-HOCO to H + CO2 using a recent projection theory that makes use of a tunneling path along the imaginary-frequency normal mode, Qim, of a relevant saddle point. The tunneling probabilities and lifetimes are calculated for the ground vibrational state of cis-HOCO and highly excited overtones and combination bands of the modes that have large projections onto the Qim path. To go beyond the harmonic approximation, which is important for the OH stretch, energies and classical turning points are calculated using the anharmonic one-dimensional (1D) potential in that normal mode and used in the projection theory. The tunneling lifetimes calculated for a number of combination states of the OCO bend and CO stretch are in good accord with those estimated in a previous five degrees-of-freedom quantum wavepacket simulation of the dissociative photodetachment of HOCO(-). The present results are also consistent with the interpretation of the tunneling of cis-HOCO to H + CO2 seen in recent experiments. PMID- 24405299 TI - Insulin-stimulated leptin secretion requires calcium and PI3K/Akt activation. AB - Numerous studies have focused on the regulation of leptin signalling and the functions of leptin in energy homoeostasis; however, little is known about how leptin secretion is regulated. In the present study we studied leptin storage and secretion regulation in 3T3-L1 and primary adipocytes. Leptin is stored in membrane-bound vesicles that are localized predominantly in the ER (endoplasmic reticulum) and close to the plasma membrane of both 3T3-L1 and primary adipocytes. Insulin increases leptin secretion as early as 15 min without affecting the leptin mRNA level. Interestingly, treatment with the protein synthesis inhibitor cycloheximide and the ER-Golgi trafficking blocker Brefeldin A inhibit both basal and ISLS (insulin-stimulated leptin secretion), suggesting that insulin stimulates leptin secretion by up-regulating leptin synthesis and that leptin-containing vesicles go through the ER-Golgi route. The PI3K (phosphoinositide 3-kinase)/Akt, but not MAPK (mitogen-activated protein kinase), pathway is involved in ISLS in vitro and in vivo. Although Ca2+ triggers synaptic vesicle and secretory granule exocytosis, Ca2+ influx alone is not sufficient to induce leptin secretion. Remarkably, Ca2+ is required for ISLS possibly due to its involvement in insulin-stimulated Akt phosphorylation. We conclude that insulin stimulates leptin release through the PI3K/Akt pathway and that Ca2+ is required for robust Akt phosphorylation and leptin secretion. PMID- 24405300 TI - Quinagolide effects in normoprolactinemic galactorrhea. PMID- 24405302 TI - Tranexamic acid: more evidence for its use in joint replacement surgery. PMID- 24405303 TI - Hyperkalemic cardiac arrest in pediatric patients undergoing massive transfusion: unplanned emergencies. PMID- 24405304 TI - Transmission of hepatitis E virus by transfusion: what is the risk? PMID- 24405305 TI - Transfusion Medicine Illustrated: an unusual cause of red plasma. PMID- 24405307 TI - Stored red blood cells impair vascular function in vivo. PMID- 24405308 TI - Anti-A and anti-B titers in group O platelet units are reduced in PAS C versus conventional plasma units. PMID- 24405309 TI - Acquired peanut hypersensitivity after transfusion. PMID- 24405310 TI - Peripheral blood film examination a necessity for plateletpheresis in eastern India. PMID- 24405311 TI - Induction of myogenic differentiation of human mesenchymal stem cells cultured on Notch agonist (Jagged-1) modified biodegradable scaffold surface. AB - Engineered scaffold surface provides stem cells with vital cues that could determine the eventual fate of stem cells. In this work, biodegradable poly(L lactide-co-epsilon-caprolactone) (PLCL) scaffold conjugated with Notch agonist Jagged-1(JAG) peptide (2.1 kDa) was prepared to initiate myogenic differentiation of human mesenchymal stem cells (hMSCs). The scaffold surface was activated with oxygen plasma and acrylic acid was engrafted via UV polymerization to form a surface bearing carboxylic groups. JAG peptide was subsequently immobilized onto the carboxylated scaffold surface. Surface chemistry and topography were examined using attenuated total reflection Fourier transform infrared, X-ray photoelectron spectroscopy, and atomic force microscopy. Quantitative real time polymerase chain reaction analysis revealed activation of the Notch pathway; furthermore, several specific markers associated with myogenic but not osteogenic differentiation were shown to be up-regulated in hMSCs cultured on the engineered surface. The pro-myocardial effect of surface bound JAG peptide was further affirmed via immunodetection of the distinct myocardial marker, cardiac troponin T. Collectively, our results suggest that PLCL conjugated JAG peptide is a viable strategy to enhance the functional potential of scaffolds to be used as a bioengineered cardiac patch in myocardial infarction repair. PMID- 24405312 TI - What midlife women want from gynecologists: a survey of patients in specialty and private practices. AB - BACKGROUND: This study characterized the self-reported reason for a gynecology visit among midlife women in three different practice settings. We hypothesized that women seeking specialty care were more likely to report nonvasomotor symptoms potentially related to the menopausal transition. METHODS: Participants were 625 women aged 40-60 seen by gynecologists at three sites: an urban, academic, gynecologic menopause practice (Midlife Practice, or MLP) and urban (site A) and suburban (site B) locations of a general, nonacademic obstetrics and gynecology practice. Participants completed a self-report questionnaire asking them to choose and weigh the reason for their visit as "very much," "somewhat," or "not at all" for 15 common gynecologic and menopausal concerns. Demographic questions included age, self-rated health status, race/ethnicity, difficulty of paying for basics, and education. Comparisons between the three groups were made using parametric and nonparametric tests as appropriate. The main outcome measure was the response to the reason for participants' visit compared across the three sites. RESULTS: Women presenting to the MLP were significantly older and more likely to report vasomotor symptoms (VMS), moodiness, sexual problems, sleep problems, and weight and to learn more about menopause. When "very much" and "somewhat" reasons were combined, nearly 80% of the MLP responses listed sleep problems, 60% listed vaginal dryness or low desire, 34% listed weight gain, and 30.7% listed mood. CONCLUSIONS: Midlife women seeking care in a menopause gynecology practice had significantly more visits for vasomotor and nonvasomotor concerns than did women seeing general gynecologists. Women sought care for a broad range of concerns that are not typically in gynecologists' scope of practice, including sleep disturbances, moodiness, and weight management. PMID- 24405314 TI - Enrollment and monitoring of women in post-approval studies for medical devices mandated by the Food and Drug Administration. AB - BACKGROUND: Disease presentation, prevalence, and treatment effects vary by sex, thus it is important to ensure adequate participation of both sexes in medical device post-approval studies (PAS). METHODS: The goals of this study were to determine the participation rate of women in PAS mandated by the Food and Drug Administration (FDA) and if participation varied by clinical area. The study also evaluated the frequency in which enrollment by sex is reported by applicant reports and FDA reviews, as well as the frequency in which final study reports analyze whether outcomes differ by sex. RESULTS: Of 89 studies with enrollment completed, data on sex of participants were available in 93% of submitted reports, while data on enrollment by sex was evaluated and noted in 43% of FDA review memos. Study participation varied by clinical area, with female participation ranging from 32% in cardiovascular PAS to 90% in PAS for reconstructive devices. Of 53 completed studies, data on enrollment by sex was provided in 49 of the final reports. Of these 14% included a multivariate analysis that included sex as a covariate and 4% included a subgroup analysis for female participants. CONCLUSIONS: Data on sex was not routinely assessed in FDA reviews. Based on these findings, FDA implemented new procedures to ensure participation by sex is evaluated in PAS reviews. FDA will continue working with applicants to develop PAS that enroll and retain proportions of women consistent with the sex-specific prevalence for the disease or condition the device is used to treat. PMID- 24405313 TI - Onsite provision of specialized contraceptive services: does Title X funding enhance access? AB - BACKGROUND: This article presents the extent to which providers enrolled in California's Family Planning, Access, Care, and Treatment (Family PACT) program offer contraceptive methods onsite, thus eliminating one important access barrier. Family PACT has a diverse provider network, including public-sector providers receiving Title X funding, public-sector providers not receiving Title X funding, and private-sector providers. We explored whether Title X funding enhances providers' ability to offer contraceptive methods that require specialized skills onsite. METHODS: Data were derived from 1,072 survey responses to a 2010 provider-capacity survey matched by unique identifier to administrative claims data. RESULTS: A significantly greater proportion of Title X-funded providers compared to non-Title X public and private providers offered onsite services for the following studied methods: intrauterine contraceptives (90% Title X, 51% public non-Title X, 38% private); contraceptive implants (58% Title X, 19% public non-Title X, 7% private); vasectomy (8% Title X, 4% public non Title X, 1% private); and fertility-awareness methods (69% Title X, 55% public non-Title X, 49% private) (all p<0.0001). The association between onsite provision and Title X funding remained after stratifying individually by clinic specialty, facility capacity to provide reproductive health services (based on staffing), and rural/urban location. CONCLUSIONS: Extra funding for publicly funded family-planning programs, through mechanisms such as Title X, appears to be associated with increased onsite access to a wide range of contraceptive services, including those that require special skills and training. PMID- 24405315 TI - Regorafenib for treatment of advanced gastrointestinal stromal tumors. AB - INTRODUCTION: Gastrointestinal stromal tumors (GISTs) are abdominal sarcomas which are extremely refractory to chemotherapy treatment. The treatment of GISTs has been revolutionized by use of KIT/platelet-derived growth factor receptor alpha (PDGFRA) kinase inhibitors. Unfortunately, most tumors develop resistance to front-line (imatinib) or second-line (sunitinib) therapy. Regorafenib, a KIT/PDGFRA/vascular endothelial growth factor receptor (VEGFR) oral kinase inhibitor, has been shown to improve progression-free survival in the third- or fourth-line setting. AREAS COVERED: This review covers the preclinical and clinical studies of regorafenib for treatment of GIST. A literature search on regorafenib was carried out using the PubMed database up to October 2013. EXPERT OPINION: Currently, imatinib and sunitinib represent the only proven first- and second-line therapies, respectively, for advanced GISTs. Based on the results of a Phase III study, regorafenib is now established as the only proven third-line therapy. Regorafenib activity in this setting is believed to be due to its activity against oncogenic forms of KIT/PDGFRA. Although side effects are common with this agent, they can be effectively managed with a combination of supportive care, dose interruptions/reductions. The toxicity profile is similar to other oral kinase inhibitors with anti-VEGFR activity. Regorafenib is mainly metabolized by CYP3A4, and concomitant use of strong inducers/inhibitors of this enzyme should be avoided. PMID- 24405318 TI - Atomistic study of energy funneling in the light-harvesting complex of green sulfur bacteria. AB - Phototrophic organisms such as plants, photosynthetic bacteria, and algae use microscopic complexes of pigment molecules to absorb sunlight. Within the light harvesting complexes, which frequently have several functional and structural subunits, the energy is transferred in the form of molecular excitations with very high efficiency. Green sulfur bacteria are considered to be among the most efficient light-harvesting organisms. Despite multiple experimental and theoretical studies of these bacteria, the physical origin of the efficient and robust energy transfer in their light-harvesting complexes is not well understood. To study excitation dynamics at the systems level, we introduce an atomistic model that mimics a complete light-harvesting apparatus of green sulfur bacteria. The model contains approximately 4000 pigment molecules and comprises a double wall roll for the chlorosome, a baseplate, and six Fenna-Matthews-Olson trimer complexes. We show that the fast relaxation within functional subunits combined with the transfer between collective excited states of pigments can result in robust energy funneling to the initial excitation conditions and temperature changes. Moreover, the same mechanism describes the coexistence of multiple time scales of excitation dynamics frequently observed in ultrafast optical experiments. While our findings support the hypothesis of supertransfer, the model reveals energy transport through multiple channels on different length scales. PMID- 24405320 TI - Estimates of dietary exposure to bisphenol A (BPA) from light metal packaging using food consumption and packaging usage data: a refined deterministic approach and a fully probabilistic (FACET) approach. AB - The FACET tool is a probabilistic model to estimate exposure to chemicals in foodstuffs, originating from flavours, additives and food contact materials. This paper demonstrates the use of the FACET tool to estimate exposure to BPA (bisphenol A) from light metal packaging. For exposure to migrants from food packaging, FACET uses industry-supplied data on the occurrence of substances in the packaging, their concentrations and construction of the packaging, which were combined with data from a market research organisation and food consumption data supplied by national database managers. To illustrate the principles, UK packaging data were used together with consumption data from the UK National Diet and Nutrition Survey (NDNS) dietary survey for 19-64 year olds for a refined deterministic verification. The UK data were chosen mainly because the consumption surveys are detailed, data for UK packaging at a detailed level were available and, arguably, the UK population is composed of high consumers of packaged foodstuffs. Exposures were run for each food category that could give rise to BPA from light metal packaging. Consumer loyalty to a particular type of packaging, commonly referred to as packaging loyalty, was set. The BPA extraction levels used for the 15 types of coating chemistries that could release BPA were in the range of 0.00005-0.012 mg dm(-2). The estimates of exposure to BPA using FACET for the total diet were 0.0098 (mean) and 0.0466 (97.5th percentile) mg/person/day, corresponding to 0.00013 (mean) and 0.00059 (97.5th percentile) mg kg(-1) body weight day(-1) for consumers of foods packed in light metal packaging. This is well below the current EFSA (and other recognised bodies) TDI of 0.05 mg kg(-1) body weight day(-1). These probabilistic estimates were compared with estimates using a refined deterministic approach drawing on the same input data. The results from FACET for the mean, 95th and 97.5th percentile exposures to BPA lay between the lowest and the highest estimates from the refined deterministic calculations. Since this should be the case, for a fully probabilistic compared with a deterministic approach, it is concluded that the FACET tool has been verified in this example. A recent EFSA draft opinion on exposure to BPA from different sources showed that canned foods were a major contributor and compared results from various models, including those from FACET. The results from FACET were overall conservative. PMID- 24405319 TI - Development of an active wheat gluten film with Lactobacillus curvatus CRL705 bacteriocins and a study of its antimicrobial performance during ageing. AB - Antimicrobial wheat gluten film was obtained at pilot scale by Lactobacillus curvatus CRL705 bacteriocins inclusion in the film-forming solution. Bacteriocins' minimum inhibitory concentration for the film activation was 2133 AU cm(-3) (lactocin AL705) and 267 AU cm(-3) (lactocin 705). Mechanical and barrier properties as well as film ageing kinetics were not significantly affected by the addition of bacteriocins. The antimicrobial film performance during ageing was assessed. Film activity against Listeria innocua 7 and Lactobacillus plantarum CRL691 was observed over 50 days of ageing. Even when the release of bacteriocins from the film upon water contact was observed for both bacteriocins at the beginning of the ageing period, and anti-Listeria activity was delivered to the simulant up to the 15th day of ageing, film residual activity for both bacteriocins was observed over 50 days. The results confirm the potential of a gluten film doped with L. curvatus CRL705 bacteriocins as a carrier of bacteriocins to avoid Listeria and lactic acid bacterial growth, thus enhancing quality and safety in foods. PMID- 24405321 TI - Dioxin and dl-PCB exposure from food: the German LExUKon project. AB - Polychlorinated dibenzo-p-dioxin and -furan (PCDD/F) and dioxin-like polychlorinated biphenyl (dl-PCB) exposure from food were estimated using new food consumption data from the recent German food consumption survey (Nationale Verzehrsstudie II - NVS II). Based on these comprehensive data, information on the consumption of 545 individual food items by the German population was derived. Concentrations of dioxin-like compounds in food were compiled from the German Food Monitoring Programme (GFMP), the German Dioxin Database, other German authority programmes, European countries' authority programmes and the published literature covering the years 2000-2010. By multiplication with consumption data, estimates of intake from food were determined. The main food groups contributing most to the intake of the general public are dairy products (including milk), meat and fish (including seafood), followed - due to high consumption - by the main group vegetables. The combined intake of PCDD/F and dl-PCB (as toxic equivalents - TEQ) from food was estimated to be 2.11/1.53 pg kg(-1) bw and day and 3.56/2.85 pg kg(-1) bw and day (upper/lower bound) for average and high-end consumers, respectively. The estimated intake of average consumers is close to a reference value derived by the Scientific Committee on Food in 2001. Uncertainties in these estimates pertain to the influence of values below the limit of quantification (upper/lower bound ratio) and some foods not considered due to the lack of contamination data. PMID- 24405322 TI - Sex steroid levels in urine of cattle of different ages: evaluation of abuse control procedures. AB - Levels of several natural urinary steroids have been determined in the urine of a large number of animals of different cattle categories in the context of steroid abuse in beef production. Bovine animals of different breeds, sex and age included in the Slovene national residue detection plan for steroid abuse were studied. Urine from 120 males and 174 females was analysed. Urinary boldenone, boldione, androstenedione, equiline, medroxyprogesterone, medroxyprogesterone acetate, melengestrol acetate, progesterone, stanozolol, trenbolone, trenbolone acetate, 17alpha-ethinylestradiol, 17alpha-methyltestosterone, epitestosterone, 17beta-estradiol, testosterone, and nandrolone were determined by LC-MS/MS. Epitestosterone was found in all bulls; while the proportion of animals containing testosterone and androstenedione increased with age. Testosterone was not detected in bulls less than 5 months of age. Epitestosterone levels, however, were not age dependent. The ratio of testosterone to epitestosterone thus increased with age, from 0.13 +/- 0.09 at 1-7 months to 0.42 +/- 0.10 at 25-38 months. It was significantly (p < 0.01) higher in bulls above 13 months than in younger animals. In contrast to males, no urinary testosterone was found in females, whereas epitestosterone, androstenedione, progesterone and estradiol were present. The proportion of animals of various age groups in which epitestosterone was detected ranged from 68% to 100%, but the differences were not significant. The presence of both estradiol and progesterone in the same sample was not observed in any animal. The results of this study could be helpful in determining physiological urinary steroid levels in order to provide a baseline for the control of steroid abuse in beef production. PMID- 24405323 TI - Improvement of a sample preparation procedure for multi-elemental determination in Brazil nuts by ICP-OES. AB - Various sample preparation procedures, such as common wet digestions and alternatives based on solubilisation in aqua regia or tetramethyl ammonium hydroxide, were compared for the determination of the total Ba, Ca, Cr, Cd, Cu, Fe, Mg, Mn, Ni, P, Pb, Se, Sr and Zn contents in Brazil nuts using inductively coupled plasma optical emission spectrometry (ICP-OES). For measurement of Se, a hydride generation technique was used. The performance of these procedures was measured in terms of precision, accuracy and limits of detection of the elements. It was found that solubilisation in aqua regia gave the best results, i.e. limits of detection from 0.60 to 41.9 ng ml(-1), precision of 1.0-3.9% and accuracy better than 5%. External calibration with simple standard solutions could be applied for the analysis. The proposed procedure is simple, reduces sample handling, and minimises the time and reagent consumption. Thus, this can be a vital alternative to traditional sample treatment approaches based on the total digestion with concentrated reagents. A phenomenon resulting from levels of Ba, Se and Sr in Brazil nuts was also discussed. PMID- 24405324 TI - Trends in the use of natural antioxidants in active food packaging: a review. AB - The demand for natural antioxidant active packaging is increasing due to its unquestionable advantages compared with the addition of antioxidants directly to the food. Therefore, the search for antioxidants perceived as natural, namely those that naturally occur in herbs and spices, is a field attracting great interest. In line with this, in the last few years, natural antioxidants such as alpha-tocopherol, caffeic acid, catechin, quercetin, carvacrol and plant extracts (e.g. rosemary extract) have been incorporated into food packaging. On the other hand, consumers and the food industry are also interested in active biodegradable/compostable packaging and edible films to reduce environmental impact, minimise food loss and minimise contaminants from industrial production and reutilisation by-products. The present review focuses on the natural antioxidants already applied in active food packaging, and it reviews the methods used to determine the oxidation protection effect of antioxidant active films and the methods used to quantify natural antioxidants in food matrices or food simulants. Lastly consumers' demands and industry trends are also addressed. PMID- 24405325 TI - Partial spin ordering and complex magnetic structure in BaYFeO4: a neutron diffraction and high temperature susceptibility study. AB - The novel iron-based compound, BaYFeO4, crystallizes in the Pnma space group with two distinct Fe(3+) sites, that are alternately corner-shared [FeO5](7-) square pyramids and [FeO6](9-) octahedra, forming into [Fe4O18](24-) rings, which propagate as columns along the b-axis. A recent report shows two discernible antiferromagnetic (AFM) transitions at 36 and 48 K in the susceptibility, yet heat capacity measurements reveal no magnetic phase transitions at these temperatures. An upturn in the magnetic susceptibility measurements up to 400 K suggests the presence of short-range magnetic behavior at higher temperatures. In this Article, variable-temperature neutron powder diffraction and high temperature magnetic susceptibility measurements were performed to clarify the magnetic behavior. Neutron powder diffraction confirmed that the two magnetic transitions observed at 36 and 48 K are due to long-range magnetic order. Below 48 K, the magnetic structure was determined as a spin-density wave (SDW) with a propagation vector, k = (0, 0, (1)/3), and the moments along the b-axis, whereas the structure becomes an incommensurate cycloid [k = (0, 0, ~0.35)] below 36 K with the moments within the bc-plane. However, for both cases the ordered moments on Fe(3+) are only of the order ~3.0 MUB, smaller than the expected values near 4.5 MUB, indicating that significant components of the Fe moments remain paramagnetic to the lowest temperature studied, 6 K. Moreover, new high temperature magnetic susceptibility measurements revealed a peak maximum at ~550 K indicative of short-range spin correlations. It is postulated that most of the magnetic entropy is thus removed at high temperatures which could explain the absence of heat capacity anomalies at the long-range ordering temperatures. Published spin dimer calculations, which appear to suggest a k = (0, 0, 0) magnetic structure, and allow for neither low dimensionality nor geometric frustration, are inadequate to explain the observed complex magnetic structure. PMID- 24405327 TI - Macromolecular structure and interaction studies of SigF and Usfx in Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (Mtb) is an intracellular human parasite that causes tuberculosis (TB). The parasite is capable of surviving under stress conditions. The gene expression in Mtb is regulated by sigma factor family of proteins. The SigF protein belongs to the sigma factor family, expressed during stationary and growth phase, 14 genes are directly regulated by SigF and has a role in the expression of the principal sigma factor SigB as well. The interacting partner Usfx, the anti SigF protein, controls the regulation of SigF. The structures of SigF and Usfx were evaluated using comparative modelling techniques and validated. The active sites of the two proteins were identified. The protein protein interaction studies between SigF and Usfx reveal His53, Phe226 and Asp227 residues of SigF protein to be involved in binding with Arg108, Arg130 and Glu140 amino acids of Usfx. The present study focuses on identification of important residues involved in binding of SigF protein with Usfx, which are essential in the inhibition of transcription initiation and survival of Mtb. PMID- 24405328 TI - Waldenstrom macroglobulinemia: from biology to treatment. AB - Waldenstrom macroglobulinemia (WM) is distinct B-cell lymphoproliferative disorder primarily characterized by bone marrow infiltration of lymphoplasmacytic cells along with production of a serum monoclonal (IgM). In this review, we describe the biology of WM, the diagnostic evaluation for WM with a discussion of other conditions that are in the differential diagnosis and clinical manifestations of the disease as well as current treatment options. Within the novel agents discussed are everolimus, perifosine, enzastaurin, panobinostat, bortezomib and carfilzomib, pomalidomide and ibrutinib. Many of the novel agents have shown good responses and have a better toxicity profile compared to traditional chemotherapeutic agents, which makes them good candidates to be used as primary therapies for WM in the future. PMID- 24405329 TI - Circadian abnormalities in a mouse model of high trait anxiety and depression. AB - INTRODUCTION: Dysregulation of circadian rhythms is a key symptom of mood disorders, including anxiety disorders and depression. Whether the circadian abnormalities observed in depressed patients are cause or consequence of the disease remains elusive. Here we aimed to explore potential disturbances of circadian rhythms in a validated genetic animal model of high trait anxiety and co-morbid depression and examine its molecular correlates. MATERIALS AND METHODS: Mice selectively bred for high (HAB) and normal (NAB) anxiety- and co-segregating depression-like behavior were subjected to analysis of circadian wheel-running activity to determine light-entrained (LD) and free-running circadian (DD) rhythms and a light-induced phase shift. Clock gene expression in HAB/NAB hippocampal tissue was analyzed by qRT-PCR and verified by Western blotting. RESULTS: Compared to NABs, HAB mice were found to present with altered DD length of daily cycle, fragmented ultradiem rhythms, and a blunted phase shift response. Clock gene expression analysis revealed a selective reduction of Cry2 expression in hippocampal tissue of HAB mice. DISCUSSION: We provide first evidence for a dysregulation of circadian rhythms in a mouse model of anxiety and co-morbid depression which suggests an association between depression and altered circadian rhythms at the genetic level and points towards a role for Cry2. PMID- 24405332 TI - Risk of local extinction of Odonata freshwater habitat generalists and specialists. AB - Understanding the risk of a local extinction in a single population relative to the habitat requirements of a species is important in both theoretical and applied ecology. Local extinction risk depends on several factors, such as habitat requirements, range size of species, and habitat quality. We studied the local extinctions among 31 dragonfly and damselfly species from 1930 to 1975 and from 1995 to 2003 in Central Finland. We tested whether habitat specialists had a higher local extinction rate than generalist species. Approximately 30% of the local dragonfly and damselfly populations were extirpated during the 2 study periods. The size of the geographical range of the species was negatively related to extinction rate of the local populations. In contrast to our prediction, the specialist species had lower local extinction rates than the generalist species, probably because generalist species occurred in both low- and high-quality habitat. Our results are consistent with source-sink theory. PMID- 24405331 TI - Barrier-enforcing measures as treatment principle in allergic rhinitis: a systematic review. AB - BACKGROUND AND OBJECTIVES: Barrier-enforcing measures have been suggested as treatment options for allergic rhinitis. This review identifies and describes the literature on the subject. METHODS: Relevant publications were searched for in the PubMed database (search entries: 'allergic rhinitis' and 'treatment'). The evaluation comprised condition (seasonal or perennial allergic rhinitis), type of intervention, duration of treatment, study design, peer review status or not, number of test subjects, type of allergen exposure, and outcome in terms of effects or not on nasal symptoms of allergic rhinitis. RESULTS: Fifteen studies were either identified in the PubMed database search or from the reference lists of identified publications. Seven were placebo-controlled, randomized, and peer reviewed, and symptom-reducing effects were reported by all of these reports. Limitations of this review reflect that the remainder of the studies had inferior designs, particularly lack of placebo control. CONCLUSIONS: Barrier-enforcing measures as achieved by nasal administrations of cellulose powder and microemulsions, respectively, have symptom-reducing effects in allergic rhinitis. PMID- 24405333 TI - Tetrahydroquinoline derivatives as potent and selective factor XIa inhibitors. AB - Antithrombotic agents that are inhibitors of factor XIa (FXIa) have the potential to demonstrate robust efficacy with a low bleeding risk profile. Herein, we describe a series of tetrahydroquinoline (THQ) derivatives as FXIa inhibitors. Compound 1 was identified as a potent and selective tool compound for proof of concept studies. It exhibited excellent antithrombotic efficacy in rabbit thrombosis models and did not prolong bleeding times. This demonstrates proof of concept for the FXIa mechanism in animal models with a reversible, small molecule inhibitor. PMID- 24405338 TI - Case-crossover designs for more patient-centred epidemiology. PMID- 24405334 TI - Epidermoid cyst on the nipple: a rare location. PMID- 24405340 TI - Further dissemination of medical education projects after presentation at a pediatric national meeting (1998-2008). AB - BACKGROUND: Further dissemination of medical education work presented at national meetings is limited. PURPOSES: The purpose of this study was to explore dissemination outcomes of scholarly work in pediatric medical education. METHODS: Council on Medical Student Education in Pediatrics (COMSEP) members who presented at COMSEP national meetings from 1998 to 2008 received a questionnaire about scholarly dissemination outcomes. Descriptive statistics and chi-square analysis explored variables related to dissemination. Qualitative analysis of free text comments explored barriers to dissemination. RESULTS: Outcomes were determined for 81% of presentations (138/171). The dissemination rate was 67% (92/138 presentations), with 47 publications (34%). Dissemination rates did not vary by presentation type (poster vs. oral) or project type. There was no relationship between presentation type, project type, and dissemination method. Barriers included perceived inadequate time, mentorship, and methodological skills for scholarly work. CONCLUSIONS: Most projects were further disseminated. Additional resources including mentoring and protected time for scholarly work are needed by educators to optimize dissemination. PMID- 24405342 TI - Systematic training in internal medicine-pediatrics end of residency handoffs: residency director attitudes and perceived barriers. AB - BACKGROUND: It is unclear why systematic training in end-of-residency clinic handoffs is not universal. PURPOSES: We assessed Internal Medicine-Pediatrics (Med-Peds) residency program directors' attitudes regarding end-of-residency clinic handoff systems and perceived barriers to their implementation. METHODS: We surveyed all Med-Peds program directors in the United States about end-of residency outpatient handoff systems. RESULTS: Program directors rated systems as important (81.5%), but only 31 programs (46.3%) utilized them. Nearly all programs with (29/31 [93.5%]), and most programs without systems (24/33 [72.7%]) rated them as important. Programs were more likely to have a system if the program director rated it important (p = .049), and less likely if they cited a lack of faculty interest (p = .023) or difficulty identifying residents as primary providers (p = .04). CONCLUSIONS: Most program directors believe it important to formally hand off outpatients. Barriers to establishing handoff systems can be overcome with modest curricular and cultural changes. PMID- 24405341 TI - Impact of acute stress on resident performance during simulated resuscitation episodes: a prospective randomized cross-over study. AB - BACKGROUND: Medical trainees have identified stress as an important contributor to their medical errors in acute care environments. PURPOSES: The objective of this study was to determine if the addition of acute stressors to simulated resuscitation scenarios would impact on residents' simulated clinical performance. METHODS: Fifty-four residents completed a control and a high-stress simulated scenario on separate visits. Stress measures were collected before and after scenarios. Two assessors independently evaluated residents' videotaped performance. RESULTS: Both control and high-stress scenarios triggered significant stress responses among participants; however, stress responses were not significantly different between control and high-stress conditions. No difference in performance was found between control and high-stress conditions (F value = 2.84, p = .098). CONCLUSIONS: Residents exposed to simulated resuscitation scenarios experienced significant stress responses irrespective of the presence of acute stressors during these scenarios. This anticipatory stressful response could impact on resident learning and performance and should be further explored. PMID- 24405343 TI - Using an expanded outcomes framework and continuing education evidence to improve facilitation of patient-centered medical home recognition and transformation. AB - BACKGROUND: The patient-centered medical home is a model for delivering primary care in the United States. Primary care clinicians and their staffs require assistance in understanding the innovation and in applying it to practice. PURPOSES: The purpose of this article is to describe and to critique a continuing education program that is relevant to, and will become more common in, primary care. METHODS: A multifaceted educational strategy prepared 20 primary care private practices to achieve National Committee for Quality Assurance Level 3 recognition as Patient-Centered Medical Homes. RESULTS: Eighteen (90%) practices submitted an application to the National Committee for Quality Assurance. On the first submission attempt, 13 of 18 (72%) achieved Level 3 recognition and 5 (28%) achieved Level 1 recognition. CONCLUSION: An interactive multifaceted educational strategy can be successful in preparing primary care practices for Patient Centered Medical Homes recognition, but the strategy may not ensure transformation. Future educational activities should consider an expanded outcomes framework and the evidence of effective continuing education to be more successful with recognition and transformation. PMID- 24405344 TI - A patient-led educational program on Tourette Syndrome: impact and implications for patient-centered medical education. AB - BACKGROUND: Graduate medical education about Tourette Syndrome does not typically focus on understanding the perspectives and perceptions of individuals with the condition. PURPOSES: Explore the impact of patient-centered, patient-led education programs on participant knowledge and empathy for patients. METHODS: Seventy-nine medical residents and students at five training sites in New Jersey attended patient-led presentations. Results were obtained using a pretest posttest design assessing physician empathy, using the 10 perspective-taking items from the Jefferson Scale of Empathy. Additional understanding of residents' experience was obtained by analyzing participant generated reaction statements. RESULTS: A factorial ANOVA (pretest, Posttest * Gender * Specialty) revealed a significant increase (p < .05) from total pre-presentation scores to total post presentation scores indicating that participants endorsed a more empathic view following the patient-led presentation. Participant statements revealed themes concordant with the practice of patient-centered medicine. CONCLUSIONS: Providing patient-led educational presentations to medical residents can increase physician empathy, increase knowledge of Tourette Syndrome, and support the advancement of patient-centered medical education. PMID- 24405345 TI - A randomized controlled trial assessing the feasibility of examination room versus conference room teaching in a psychiatric setting. AB - BACKGROUND: Teaching in the presence of the patient is an acceptable model in medical settings. Questions have been raised about the appropriateness of this type of teaching (exam room teaching) with patients with mental health issues. PURPOSES: This prospective randomized controlled study examined outpatient exam room teaching in a psychiatric setting. METHODS: In 2011-2012, patients in the adult outpatient psychiatry clinic at the University of Iowa were randomized to have faculty-learner presentations either in the presence of the patient or in the conference room. Teaching encounters were timed and faculty, learners, and patients completed post encounter surveys. RESULTS: Participation included 126 patients, nine faculty, and 16 residents. Comparison of patient encounters randomized to exam room (n = 58) or conference room (n = 64) demonstrated that exam room teaching was roughly twice as time efficient as conference room teaching (p <= .0001). Patients expressed a preference for exam room teaching during future visits (p <= .003) for those patients who experienced exam room teaching during the study. Faculty were generally comfortable with exam room teaching and felt it had some advantages for patient decision making. Learners felt they had to choose their words more carefully in exam room teaching and expressed some concerns about depth of teaching. CONCLUSIONS: Once exposed to exam room teaching, this model is acceptable and feasible to faculty, learners, and patients in a psychiatry clinic setting. PMID- 24405346 TI - Medical students' observations, practices, and attitudes regarding electronic health record documentation. AB - BACKGROUND: Medical students are increasingly documenting their patient notes in electronic health records (EHRs). Documentation short-cuts, such as copy-paste and templates, have raised concern among clinician-educators because they may perpetuate redundant, inaccurate, or even plagiarized notes. Little is known about medical students' experiences with copy-paste, templates and other "efficiency tools" in EHRs. PURPOSES: We sought to understand medical students' observations, practices, and attitudes regarding electronic documentation efficiency tools. METHODS: We surveyed 3rd-year medical students at one medical school. We asked about efficiency tools including copy-paste, templates, auto inserted data, and "scribing" (documentation under a supervisor's name). RESULTS: Overall, 123 of 163 students (75%) responded; almost all frequently use an EHR for documentation. Eighty-six percent (102/119) reported at least sometimes observing residents copying data from other providers' notes and 60% (70/116) reported observing attending physicians doing so. Most students (95%, 113/119) reported copying from their own previous notes, and 22% (26/119) reported copying from residents. Only 10% (12/119) indicated that copying from other providers is acceptable, whereas 83% (98/118) believe copying from their own notes is acceptable. Most students use templates and auto-inserted data; 43% (51/120) reported documenting while signed in under an attending's name. Greater use of documentation efficiency tools is associated with plans to enter a procedural specialty and with lack of awareness of the medical school copy-paste policy. CONCLUSIONS: Students frequently use a range of efficiency tools to document in the electronic health record, most commonly copying their own notes. Although the vast majority of students believe it is unacceptable to copy-paste from other providers, most have observed clinical supervisors doing so. PMID- 24405347 TI - Looking beyond personal stressors: an examination of how academic stressors contribute to depression in Australian graduate medical students. AB - BACKGROUND: Medical school is a challenging environment that requires students to deal effectively with stress borne out of the medical education environment, as well as their personal lives. Previous research has not systemically distinguished between academic and personal sources of stress, and in particular has not explored the independent contribution that academic stressors make to medical student depression. PURPOSES: This study aimed to investigate whether academic stressors make a unique contribution to the level of depressive symptoms in medical students, over and above the contribution made by personal stressors alone. METHODS: Sixty-seven medical students completed an online questionnaire designed to measure the total number of recent life events (personal and academic), and their perceived impact, using a modified version of the Psychiatric Epidemiology Research Interview Life Events Scale. Depressive symptoms were measured using the Centre for Epidemiological Studies Depression Scale. RESULTS: Both the total number of personal stressors, r(67) = .363, p = .003, and their perceived impact, r(67) = .412, p = .001, were found to be positively related to depressive symptoms. A positive relationship was also observed between depressive symptoms and the total number of academic stressors, r(67) = .321, p = .008, and their perceived impact, r(67) = .489, p < .001. In addition, it was found that the perceived impact of academic stressors was able to explain higher levels of depressive symptoms in medical students over and above the effect afforded by personal stressors alone. CONCLUSION: The findings of this study suggest that stress borne out of the medical school environment contributes to depressive symptoms in medical students over and above the contribution made by personal stressors alone. This indicates that although it is important to help students cope with stress borne out of their personal lives, interventions by medical schools aimed at reducing the impact of academic stressors on medical student depression may also be of great importance. PMID- 24405348 TI - Implicit bias and its relation to health disparities: a teaching program and survey of medical students. AB - BACKGROUND: The varying treatment of different patients by the same physician are referred to as within provider disparities. These differences can contribute to health disparities and are thought to be the result of implicit bias due to unintentional, unconscious assumptions. PURPOSES: The purpose is to describe an educational intervention addressing both health disparities and physician implicit bias and the results of a subsequent survey exploring medical students' attitudes and beliefs toward subconscious bias and health disparities. METHODS: A single session within a larger required course was devoted to health disparities and the physician's potential to contribute to health disparities through implicit bias. Following the session the students were anonymously surveyed on their Implicit Association Test (IAT) results, their attitudes and experiences regarding the fairness of the health care system, and the potential impact of their own implicit bias. The students were categorized based on whether they disagreed ("deniers") or agreed ("accepters") with the statement "Unconscious bias might affect some of my clinical decisions or behaviors." Data analysis focused specifically on factors associated with this perspective. RESULTS: The survey response rate was at least 69%. Of the responders, 22% were "deniers" and 77% were "accepters." Demographics between the two groups were not significantly different. Deniers were significantly more likely than accepters to report IAT results with implicit preferences toward self, to believe the IAT is invalid, and to believe that doctors and the health system provide equal care to all and were less likely to report having directly observed inequitable care. CONCLUSIONS: The recognition of bias cannot be taught in a single session. Our experience supports the value of teaching medical students to recognize their own implicit biases and develop skills to overcome them in each patient encounter, and in making this instruction part of the compulsory, longitudinal undergraduate medical curriculum. PMID- 24405349 TI - Cross-cultural construct validity study of professionalism of Vietnamese medical students. AB - BACKGROUND: Although many studies have made efforts to define and assess medical professionalism, few have addressed issues of construct validity. PURPOSES: The purpose of this article is to explore further construct validity of medical professionalism employing exploratory and confirmatory factor analysis. METHODS: The 32-item instrument by the American Board of Internal Medicine (ABIM) was adapted to assess the perceptions on medical professionalism of Vietnamese medical students. A sample of 1,196 (487 first-year, 341 third-year, 368 sixth year) medical students participated voluntarily in the completion of the instrument. The data were randomly divided into three samples to assess the construct validity of medical professionalism by empirically deriving and confirming a model of professionalism. RESULTS: Exploratory and confirmatory factor analytic techniques resulted in a six-factor well-fitting model with a comparative fit index of .963 and root mean square error approximation of .029, 90% confidence interval [016, .039]: integrity, social responsibility, professional practice habits, ensuring quality care, altruism, and self awareness. Social responsibility was perceived least important, and self awareness was perceived most important by Vietnamese medical students. These constructs of medical professionalism were relatively similar with those found in Taiwanese medical students and the ABIM definitions but with some Vietnamese cultural differences. CONCLUSIONS: Although the results confirm that medical professionalism is a somewhat culturally sensitive construct, it nonetheless has many elements of medical professionalism that are universal. Future research should be conducted to test the generalizability of our six-factor model of professionalism with various samples (e.g., residents, physicians), cultures, and language groups. PMID- 24405350 TI - Effect of bedside physical diagnosis training on third-year medical students' physical exam skills. AB - BACKGROUND: Graduating medical students, when surveyed, noted a deficit in training in physical examination skills. PURPOSES: In an attempt to remedy this deficit we implemented a pilot program for 3rd-year medical students consisting of twice-weekly bedside diagnosis rounds as part of their 8-week medicine clerkship. METHODS: To assess the success of this program we reviewed students' objective structured clinical exam (OSCE) scores at the completion of the clerkship compared with prior years' students who did not have the bedside physical diagnosis training. RESULTS: Students who were trained (n = 109) had an overall higher OSCE physical exam score (p < .01) than students without the training (n = 85). CONCLUSIONS: Bedside physical diagnosis rounds appear to have elevated the overall OSCE score for 3rd-year medical students. PMID- 24405351 TI - Development, implementation, and evaluation of a movie-based curriculum to teach psychopathology. AB - BACKGROUND: Because medical students' attitudes toward psychiatry are often fostered by media, we provided an elective movie-based seminar to teach psychopathology. DESCRIPTION: We assessed attitudes toward psychiatry by using the Attitudes towards Psychiatry (ATP 35) scale in a pre-post design. Furthermore we evaluated the knowledge of diagnostic criteria in a pre-post design within one sample. EVALUATION: Of the 75 students who attended the seminar during 3 consecutive semesters, 54 (60.8% female) participated in the pre-post assessment. We observed a significant positive change in attitudes toward psychiatry and a significant gain of knowledge. CONCLUSIONS: Using movies is a feasible and effective method to teach psychiatry. PMID- 24405352 TI - Novel integration of systems-based practice into internal medicine residency programs: the Interactive Cost-Awareness Resident Exercise (I-CARE). AB - BACKGROUND: The Accreditation Council for Graduate Medical Education and American Board of Internal Medicine have identified cost-awareness as an important component to residency training. Cost-awareness is generally not emphasized in current, traditional residency curricula despite the recognized importance of this topic. DESCRIPTION: Using a traditional Morning Report structure and actual charge data from our institution, the charges associated with trainee-directed workup of clinical cases are compared in a friendly competition among medical students, interns, residents, and faculty. EVALUATION: Anonymous, voluntary survey of all participants and comparison of expenditures by training level were used to assess this pilot program. The educational quality of the I-CARE was rated higher than the prior format of Morning Report by participants (10-point Likert scale; 8.57, 6.81 respectively; p < .001). Open-ended comments were overwhelmingly supportive from faculty and trainees. Cost was lower for attending physicians than for trainees ($1,027.45 vs. $4,264.00, p = .02) and diagnostic accuracy was also highest for attending physicians. CONCLUSIONS: The I-CARE is easy and quick to implement, and the preliminary results show a popular cost awareness educational experience for internal medicine trainees. Further study is needed to determine change in practice habits. PMID- 24405353 TI - Critical thinking in health professions education: summary and consensus statements of the Millennium Conference 2011. AB - PURPOSE: Critical thinking is central to the function of health care professionals. However, this topic is not explicitly taught or assessed within current programs, yet the need is greater than ever, in an era of information explosion, spiraling health care costs, and increased understanding about metacognition. To address the importance of teaching critical thinking in health professions education, the Shapiro Institute for Education and Research and the Josiah Macy Jr. Foundation jointly sponsored the Millennium Conference 2011 on Critical Thinking. SUMMARY: Teams of physician and nurse educators were selected through an application process. Attendees proposed strategies for integrating principles of critical thinking more explicitly into health professions curricula. Working in interprofessional, multi-institutional groups, participants tackled questions about teaching, assessment, and faculty development. Deliberations were summarized into consensus statements. CONCLUSIONS: Educational leaders participated in a structured dialogue about the enhancement of critical thinking in health professions education and recommend strategies to teach critical thinking. PMID- 24405356 TI - Shock tube measurements of the rate constant for the reaction ethanol + OH. AB - The overall rate constant for the reaction ethanol + OH -> products was determined experimentally from 900 to 1270 K behind reflected shock waves. Ethan(18)ol was utilized for these measurements in order to avoid the recycling of OH radicals following H-atom abstraction at the beta-site of ethanol. Similar experiments were also performed with unlabeled ethan(16)ol in order to infer the rate constant that excludes reactivity at the beta-site. The two data sets were used to directly infer the branching ratio for the reaction at the beta-site. Experimental data in the current study and in previous low-temperature studies for the overall rate constant are best fit by the expression koverall = 5.07 * 10(5) T[K](2.31) exp(608/T[K]) cm(3) mol(-1) s(-1), valid from 300 to 1300 K. Measurements indicate that the branching ratio of the beta-site is between 20 and 25% at the conditions studied. Pseudo-first-order reaction conditions were generated using tert-butylhydroperoxide (TBHP) as a fast source of (16)OH with ethanol in excess. (16)OH mole fraction time-histories were measured using narrow line width laser absorption near 307 nm. Measurements were performed at the linecenter of the R22(5.5) transition in the A-X(0,0) band of (16)OH that does not overlap with any absorption features of (18)OH, thus producing a measurement of the (16)OH mole fraction that is insensitive to the presence of (18)OH. PMID- 24405357 TI - Immunological characteristics and T-cell receptor clonal diversity in children with systemic juvenile idiopathic arthritis undergoing T-cell-depleted autologous stem cell transplantation. AB - Children with systemic Juvenile Idiopathic Arthritis (sJIA), the most severe subtype of JIA, are at risk from destructive polyarthritis and growth failure, and corticosteroids as part of conventional treatment can result in osteoporosis and growth delay. In children where there is failure or toxicity from drug therapies, disease has been successfully controlled by T-cell-depleted autologous stem cell transplantation (ASCT). At present, the immunological basis underlying remission after ASCT is unknown. Immune reconstitution of T cells, B cells, natural killer cells, natural killer T cells and monocytes, in parallel with T cell receptor (TCR) diversity by analysis of the beta variable region (TCRVb) complementarity determining region-3 (CDR3) using spectratyping and sequencing, were studied in five children with sJIA before and after ASCT. At time of follow up (mean 11.5 years), four patients remain in complete remission, while one child relapsed within 1 month of transplant. The CD8(+) TCRVb repertoire was highly oligoclonal early in immune reconstitution and re-emergence of pre-transplant TCRVb CDR3 dominant peaks was observed after transplant in certain TCRVb families. Further, re-emergence of pre-ASCT clonal sequences in addition to new sequences was identified after transplant. These results suggest that a chimeric TCR repertoire, comprising T-cell clones developed before and after transplant, can be associated with clinical remission from severe arthritis. PMID- 24405358 TI - Gene-environment interaction. AB - With the advent of increasingly accessible technologies for typing genetic variation, studies of gene-environment (G*E) interactions have proliferated in psychological research. Among the aims of such studies are testing developmental hypotheses and models of the etiology of behavioral disorders, defining boundaries of genetic and environmental influences, and identifying individuals most susceptible to risk exposures or most amenable to preventive and therapeutic interventions. This research also coincides with the emergence of unanticipated difficulties in detecting genetic variants of direct association with behavioral traits and disorders, which may be obscured if genetic effects are expressed only in predisposing environments. In this essay we consider these and other rationales for positing G*E interactions, review conceptual models meant to inform G*E interpretations from a psychological perspective, discuss points of common critique to which G*E research is vulnerable, and address the role of the environment in G*E interactions. PMID- 24405359 TI - The cognitive neuroscience of insight. AB - Insight occurs when a person suddenly reinterprets a stimulus, situation, or event to produce a nonobvious, nondominant interpretation. This can take the form of a solution to a problem (an "aha moment"), comprehension of a joke or metaphor, or recognition of an ambiguous percept. Insight research began a century ago, but neuroimaging and electrophysiological techniques have been applied to its study only during the past decade. Recent work has revealed insight-related coarse semantic coding in the right hemisphere and internally focused attention preceding and during problem solving. Individual differences in the tendency to solve problems insightfully rather than in a deliberate, analytic fashion are associated with different patterns of resting-state brain activity. Recent studies have begun to apply direct brain stimulation to facilitate insight. In sum, the cognitive neuroscience of insight is an exciting new area of research with connections to fundamental neurocognitive processes. PMID- 24405361 TI - Combination psychotherapy and antidepressant medication treatment for depression: for whom, when, and how. AB - Major depressive disorder (MDD) is among the most frequent and debilitating psychiatric disorders. Efficacious psychotherapy and antidepressant medications have been developed, and two-thirds of depressed patients respond to single modality treatment; however, only about one-third of patients remit to single modality treatments with no meaningful differences in outcomes between treatment types. This article describes the major clinical considerations in choosing between single-modality or combination treatments for MDD. A review of the relevant literature and meta-analyses provides suggestions for which treatment to use for which patient and when each treatment or combination should be provided. The review summarizes the moderators of single-modality and combination-treatment outcomes. We describe models of mechanisms of treatment efficacy and discuss recent treatment-specific neurobiological mechanisms of change. PMID- 24405362 TI - The psychology of change: self-affirmation and social psychological intervention. AB - People have a basic need to maintain the integrity of the self, a global sense of personal adequacy. Events that threaten self-integrity arouse stress and self protective defenses that can hamper performance and growth. However, an intervention known as self-affirmation can curb these negative outcomes. Self affirmation interventions typically have people write about core personal values. The interventions bring about a more expansive view of the self and its resources, weakening the implications of a threat for personal integrity. Timely affirmations have been shown to improve education, health, and relationship outcomes, with benefits that sometimes persist for months and years. Like other interventions and experiences, self-affirmations can have lasting benefits when they touch off a cycle of adaptive potential, a positive feedback loop between the self-system and the social system that propagates adaptive outcomes over time. The present review highlights both connections with other disciplines and lessons for a social psychological understanding of intervention and change. PMID- 24405363 TI - The sociocultural appraisals, values, and emotions (SAVE) framework of prosociality: core processes from gene to meme. AB - The study of prosocial behavior--altruism, cooperation, trust, and the related moral emotions--has matured enough to produce general scholarly consensus that prosociality is widespread, intuitive, and rooted deeply within our biological makeup. Several evolutionary frameworks model the conditions under which prosocial behavior is evolutionarily viable, yet no unifying treatment exists of the psychological decision-making processes that result in prosociality. Here, we provide such a perspective in the form of the sociocultural appraisals, values, and emotions (SAVE) framework of prosociality. We review evidence for the components of our framework at four levels of analysis: intrapsychic, dyadic, group, and cultural. Within these levels, we consider how phenomena such as altruistic punishment, prosocial contagion, self-other similarity, and numerous others give rise to prosocial behavior. We then extend our reasoning to chart the biological underpinnings of prosociality and apply our framework to understand the role of social class in prosociality. PMID- 24405360 TI - Human infancy...and the rest of the lifespan. AB - Human infancy has been studied as a platform for hypothesis and theory testing, as a major physiological and psychological adjustment, as an object of adults' effects as well as a source of effects on adults, for its comparative value, as a stage of life, and as a setting point for the life course. Following an orientation to infancy studies, including previous reviews and a discussion of the special challenges infants pose to research, this article focuses on infancy as a foundation and catalyst of human development in the balance of the life course. Studies of stability and prediction from infancy illustrate the depth and complexity of modern research on infants and provide a long-awaited reply to key philosophical and practical questions about the meaningfulness and significance of infancy. PMID- 24405364 TI - Personality, well-being, and health. AB - A lifespan perspective on personality and health uncovers new causal pathways and provides a deeper, more nuanced approach to interventions. It is unproven that happiness is a direct cause of good health or that negative emotion, worry, and depression are significant direct causes of disease. Instead, depression-related characteristics are likely often reflective of an already-deteriorating trajectory. It is also unproven that challenging work in a demanding environment usually brings long-term health risks; on the contrary, individual strivings for accomplishment and persistent dedication to one's career or community often are associated with sizeable health benefits. Overall, a substantial body of recent research reveals that conscientiousness plays a very significant role in health, with implications across the lifespan. Much more caution is warranted before policy makers offer narrow health recommendations based on short-term or correlational findings. Attention should be shifted to individual trajectories and pathways to health and well-being. PMID- 24405366 TI - Current concepts and progress in RSV vaccine development. AB - Respiratory syncytial virus (RSV) disease is an important cause of morbidity and mortality in children and debilitated adults and remains one of the major global unmet challenges for vaccine development. Several immunological issues have delayed the development of vaccines, especially the poorly protective response to natural infection and the enhancement of disease following administration of formalin inactivated vaccines during trials conducted in the 1960s. Advances in knowledge of the immune system, of the virus and its antigenic properties combined with new vaccine technologies are now injecting new hope into the field and have given rise to many promising vaccine approaches. Some of these may be optimal for use in children, while others may be more appropriate for pregnant women or vulnerable older adults. With a multi-pronged approach to prevention, we propose that it may be possible to destabilise community circulation of RSV and thus to significantly lessen the impact of RSV disease. PMID- 24405365 TI - Different walls for rods and balls: the diversity of peptidoglycan. AB - Peptidoglycan performs the essential role of resisting turgor in the cell walls of most bacteria. It determines cell shape, and its biosynthesis is the target for many important antibiotics. The fundamental chemical building blocks of peptidoglycan are conserved: repeating disaccharides cross-linked by peptides. However, these blocks come in many varieties and can be assembled in different ways. So beyond the fundamental similarity, prodigious chemical, organizational and architectural diversity is revealed. Here, we track the evolution of our current understanding of peptidoglycan and underpinning technical and methodological developments. The origin and function of chemical diversity is discussed with respect to some well-studied example species. We then explore how this chemistry is manifested in elegant and complex peptidoglycan organization and how this is interpreted in different and sometimes controversial architectural models. We contend that emerging technology brings about the possibility of achieving a complete understanding of peptidoglycan chemistry, through architecture, to the way in which diverse species and populations of cells meet the challenges of maintaining viability and growth within their environmental niches, by exploiting the bioengineering versatility of peptidoglycan. PMID- 24405370 TI - NMR structure of the S-linked glycopeptide sublancin 168. AB - Sublancin 168 is a member of a small group of glycosylated antimicrobial peptides known as glycocins. The solution structure of sublancin 168, a 37-amino-acid peptide produced by Bacillus subtilis 168, has been solved by nuclear magnetic resonance (NMR) spectroscopy. Sublancin comprises two alpha-helices and a well defined interhelical loop. The two helices span residues 6-16 and 26-35, and the loop region encompasses residues 17-25. The 9-amino-acid loop region contains a beta-S-linked glucose moiety attached to Cys22. Hydrophobic interactions as well as hydrogen bonding are responsible for the well-structured loop region. The three-dimensional structure provides an explanation for the previously reported extraordinary high stability of sublancin 168. PMID- 24405371 TI - Economic perspectives on integrating early child stimulation with nutritional interventions. AB - There is a strongly held view that a narrow window exists for effective nutritional interventions and a widely known stylized depiction of age-dependent economic rates of returns to investments in cognitive and socioemotional development. Both indicate critical periods in early life. Moreover, the fact that both the physical and cognitive development of a child in these early years are highly dependent on childcare practices and on the characteristics of the caregivers motivates an interest in finding effective means to enhance stimulation in the context of nutritional programs, or vice versa. Nevertheless, there is relatively little evidence to date on how to align integrated interventions to these age-specific patterns and how to undertake benefit-cost analyses for integrated interventions. Thus, many core questions need further consideration in order to design integrated nutritional and stimulation programs. This paper looks at some of these questions and provides some guidelines as to how the economic returns from joint nutrition and stimulation programs might be estimated. PMID- 24405372 TI - Dysbetalipoproteinaemia: a mixed hyperlipidaemia of remnant lipoproteins due to mutations in apolipoprotein E. AB - Atherosclerosis is strongly associated with dyslipoproteinaemia, and especially with increasing concentrations of low-density lipoprotein and decreasing concentrations of high-density lipoproteins. Its association with increasing concentrations of plasma triglyceride is less clear but, within the mixed hyperlipidaemias, dysbetalipoproteinaemia (Fredrickson type III hyperlipidaemia) has been identified as a very atherogenic entity associated with both premature ischaemic heart disease and peripheral arterial disease. Dysbetalipoproteinaemia is characterized by the accumulation of remnants of chylomicrons and of very low density lipoproteins. The onset occurs after childhood and usually requires an additional metabolic stressor. In women, onset is typically delayed until menopause. Clinical manifestations may vary from no physical signs to severe cutaneous and tendinous xanthomata, atherosclerosis of coronary and peripheral arteries, and pancreatitis when severe hypertriglyceridaemia is present. Rarely, mutations in apolipoprotein E are associated with lipoprotein glomerulopathy, a condition characterized by progressive proteinuria and renal failure with varying degrees of plasma remnant accumulation. Interestingly, predisposing genetic causes paradoxically result in lower than average cholesterol concentration for most affected persons, but severe dyslipidaemia develops in a minority of patients. The disorder stems from dysfunctional apolipoprotein E in which mutations result in impaired binding to low-density lipoprotein (LDL) receptors and/or heparin sulphate proteoglycans. Apolipoprotein E deficiency may cause a similar phenotype. Making a diagnosis of dysbetalipoproteinaemia aids in assessing cardiovascular risk correctly and allows for genetic counseling. However, the diagnostic work-up may present some challenges. Diagnosis of dysbetalipoproteinaemia should be considered in mixed hyperlipidaemias for which the apolipoprotein B concentration is relatively low in relation to the total cholesterol concentration or when there is significant disparity between the calculated LDL and directly measured LDL cholesterol concentrations. Genetic tests are informative in predicting the risk of developing the disease phenotype and are diagnostic only in the context of hyperlipidaemia. Specialised lipoprotein studies in reference laboratory centres can also assist in diagnosis. Fibrates and statins, or even combination treatment, may be required to control the dyslipidaemia. PMID- 24405376 TI - Transfer of difenoconazole and azoxystrobin residues from chrysanthemum flower tea to its infusion. AB - Investigations of the transfer of pesticide residues from tea to its infusion can be important in the assessment of the possible health benefits of tea consumption. In this work the transfer of difenoconazole and azoxystrobin residues from chrysanthemum tea to its infusion was investigated at different water temperatures, infusion intervals and times. The transfer percentages were in the range of 18.7-51.6% for difenoconazole and of 38.1-71.2% for azoxystrobin, and increased considerably with longer infusion intervals. The results indicated that azoxystrobin with a lower octanol-water partition coefficient of 2.5, showed a higher transfer than that of difenoconazole with a relatively high octanol water partition coefficient of 4.4. Water temperature had no significant effect on the transfer of the two residues, and no obvious loss of difenoconazole and azoxystrobin occurred during the infusion process. The concentrations in the infusions decreased gradually from 0.67 to 0.30 MUg kg(-1) for difenoconazole and from 2.3 to 0.46 MUg kg(-1) for azoxystrobin after five infusions. To assess the potential health risk, the values of estimate expose risk were calculated to be 0.016 for difenoconazole and 0.0022 for azoxystrobin, meaning the daily residue intake of the two analytes from chrysanthemum tea was safe. This research may help assure food safety and identify the potential exposure risks from pesticides in chrysanthemum that may be health concerns. PMID- 24405373 TI - Novel constant-pressure irrigation technique for the treatment of renal pelvic tumors after ipsilateral ureterectomy. AB - We herein report a case of a renal pelvic tumor that developed in the residual left renal pelvis after right nephroureterectomy, left ureterectomy and total cystectomy in a patient with multiple urothelial tumors. The tumor was endoscopically ablated through a nephrostomy tract, and mitomycin C irrigation was carried out. We designed a novel constant-pressure irrigation system for effective and safe irrigation into the closed space of the renal pelvis. We created a hole in the urine bag tube, inserted a 5-Fr open-end ureteral catheter through the hole and kept the tip of the catheter at the end of the nephrostomy tube. The urine bag tube was placed 20 cm above the kidney level, and mitomycin C was continuously irrigated into the renal pelvis for 1 h. Six-weekly treatments were carried out, and tumor recurrence was not identified for 1 year. PMID- 24405377 TI - Structural basis of conformational transitions in the active site and 80's loop in the FK506-binding protein FKBP12. AB - The extensive set of NMR doublings exhibited by the immunophilin FKBP12 (FK506 binding protein 12) arose from a slow transition to the cis-peptide configuration at Gly89 near the tip of the 80's loop, the site for numerous protein-recognition interactions for both FKBP12 and other FKBP domain proteins. The 80's loop also exhibited linebroadening, indicative of microsecond to millisecond conformational dynamics, but only in the trans-peptide state. The G89A variant shifted the trans cis peptide equilibrium from 88:12 to 33:67, whereas a proline residue substitution induced fully the cis-peptide configuration. The 80's loop conformation in the G89P crystal structure at 1.50 A resolution differed from wild-type FKBP12 primarily at residues 88, 89 and 90, and it closely resembled that reported for FKBP52. Structure-based chemical-shift predictions indicated that the microsecond to millisecond dynamics in the 80's loop probably arose from a concerted main chain (psi88 and phi89) torsion angle transition. The indole side chain of Trp59 at the base of the active-site cleft was reoriented ~90o and the adjacent backbone was shifted in the G89P crystal structure. NOE analysis of wild-type FKBP12 demonstrated that this indole populates the perpendicular orientation at 20%. The 15N relaxation analysis was consistent with the indole reorientation occurring in the nanosecond timeframe. Recollection of the G89P crystal data at 1.20 A resolution revealed a weaker wild-type-like orientation for the indole ring. Differences in the residues that underlie the Trp59 indole ring and altered interactions linking the 50's loop to the active site suggested that reorientation of this ring may be disfavoured in the other six members of the FKBP domain family that bear this active-site tryptophan residue. PMID- 24405382 TI - Role of adiponectin in mediating the association of osteocalcin with insulin resistance and type 2 diabetes: a cross sectional study in pre- and post menopausal women. AB - OBJECTIVE: To analyse the association of osteocalcin with insulin resistance and type 2 diabetes and assess the role of adiponectin in these relationships. METHODS: This study comprised 98 newly diagnosed type 2 diabetic women (51 pre menopausal and 47 post-menopausal) and 102 age and BMI matched controls (53 pre menopausal and 49 post-menopausal). Insulin resistance was calculated by homeostasis model assessment-insulin resistance (HOMA-IR). RESULTS: Osteocalcin was significantly positively correlated with adiponectin in both pre-menopausal (p = 0.0026) and post-menopausal diabetic women (p = 0.0357). Significant negative association between osteocalcin and HOMA-IR was observed only in pre menopausal diabetic women (p = 0.0019), but the association was partially reduced (p = 0.0219) after additional adjustment for adiponectin. Adiponectin slightly attenuated the inverse association between osteocalcin and presence of type 2 diabetes in both pre- and post-menopausal women. CONCLUSION: The protective action of osteocalcin against the development of insulin resistance and type 2 diabetes in women may be partially mediated through up-regulation of adiponectin secretion. PMID- 24405378 TI - Gait analysis at multiple speeds reveals differential functional and structural outcomes in response to graded spinal cord injury. AB - Open-field behavioral scoring is widely used to assess spinal cord injury (SCI) outcomes, but has limited usefulness in describing subtle changes important for posture and locomotion. Additional quantitative methods are needed to increase the resolution of locomotor outcome assessment. This study used gait analysis at multiple speeds (GAMS) across a range of mild-to-severe intensities of thoracic SCI in the rat. Overall, Basso, Beattie, and Bresnahan (BBB) scores and subscores were assessed, and detailed automated gait analysis was performed at three fixed walking speeds (3.5, 6.0, and 8.5 cm/sec). Variability in hindpaw brake, propel, and stance times were analyzed further by integrating across the stance phase of stepping cycles. Myelin staining of spinal cord sections was used to quantify white matter loss at the injury site. Varied SCI intensity produced graded deficits in BBB score, BBB subscores, and spinal cord white matter and total volume loss. GAMS measures of posture revealed decreased paw area, increased limb extension, altered stance width, and decreased values for integrated brake, propel, and stance. Measures of coordination revealed increased stride frequency concomitant with decreased stride length, resulting in deviation from consistent forelimb/hindlimb coordination. Alterations in posture and coordination were correlated to impact severity. GAMS results correlated highly with functional and histological measures and revealed differential relationships between sets of GAMS dynamics and cord total volume loss versus epicenter myelin loss. Automated gait analysis at multiple speeds is therefore a useful tool for quantifying nuanced changes in gait as an extension of histological and observational methods in assessing SCI outcomes. PMID- 24405383 TI - Empirical trials of plant field guides. AB - We designed 3 image-based field guides to tropical forest plant species in Ghana, Grenada, and Cameroon and tested them with 1095 local residents and 20 botanists in the United Kingdom. We compared users' identification accuracy with different image formats, including drawings, specimen photos, living plant photos, and paintings. We compared users' accuracy with the guides to their accuracy with only their prior knowledge of the flora. We asked respondents to score each format for usability, beauty, and how much they would pay for it. Prior knowledge of plant names was generally low (<22%). With a few exceptions, identification accuracy did not differ significantly among image formats. In Cameroon, users identifying sterile Cola species achieved 46-56% accuracy across formats; identification was most accurate with living plant photos. Botanists in the United Kingdom accurately identified 82-93% of the same Cameroonian species; identification was most accurate with specimens. In Grenada, users accurately identified 74-82% of plants; drawings yielded significantly less accurate identifications than paintings and photos of living plants. In Ghana, users accurately identified 85% of plants. Digital color photos of living plants ranked high for beauty, usability, and what users would pay. Black and white drawings ranked low. Our results show the potential and limitations of the use of field guides and nonspecialists to identify plants, for example, in conservation applications. We recommend authors of plant field guides use the cheapest or easiest illustration format because image type had limited bearing on accuracy; match the type of illustration to the most likely use of the guide for slight improvements in accuracy; avoid black and white formats unless the audience is experienced at interpreting illustrations or keeping costs low is imperative; discourage false-positive identifications, which were common; and encourage users to ask an expert or use a herbarium for groups that are difficult to identify. PMID- 24405385 TI - A dimethylgallium boryl complex and its methyllithium addition compound. AB - The three-coordinate complex Me2Ga[B(NArCH)2] (Ar = C6H3iPr2-2,6) is accessible via a tandem Lewis acid-base metathesis protocol employing (THF)2Li[B(NArCH)2] and GaMe3. It features a very short Ga-B bond of 2.067(3) A, which was further investigated by DFT calculations and the analysis of the electron density. Reaction of MeLi with Me2Ga[B(NArCH)2] forms tetrameric [LiMe3Ga{B(NArCH)2}]4 with a "nanowheel" structure. PMID- 24405384 TI - Specific ion effects in amphiphile hydration and interface stabilization. AB - Specific ion effects can influence many processes in aqueous solutions: protein folding, enzyme activity, self-assembly, and interface stabilization. Ionic amphiphiles are known to stabilize the oil/water interface, presumably by dipping their hydrophobic tails into the oil phase while sticking their hydrophilic head groups in water. However, we find that anionic and cationic amphiphiles adopt strikingly different structures at liquid hydrophobic/water interfaces, linked to the different specific interactions between water and the amphiphile head groups, both at the interface and in the bulk. Vibrational sum frequency scattering measurements show that dodecylsulfate (DS(-)) ions do not detectably perturb the oil phase while dodecyltrimethylammonium (DTA(+)) ions do. Raman solvation shell spectroscopy and second harmonic scattering (SHS) show that the respective hydration-shells and the interfacial water structure are also very different. Our work suggests that specific interactions with water play a key role in driving the anionic head group toward the water phase and the cationic head group toward the oil phase, thus also implying a quite different surface stabilization mechanism. PMID- 24405389 TI - Treatment of primary hyperhidrosis with tap water iontophoresis in paediatric patients: a retrospective analysis. AB - OBJECTIVES: Primary hyperhidrosis is an under-recognized condition in children and adolescents. Iontophoresis is the second line of treatment for palmoplantar hyperhidrosis following topical treatment. The studies evaluating the efficacy of iontophoresis in children are limited. We aimed to investigate the efficacy and reliability of tap water iontophoresis in children with primary hyperhidrosis. METHODS: Twenty-one patients aged under 18 years, who received iontophoresis for primary palmoplantar hyperhidrosis, were included in the study. In our clinic, tap water iontophoresis was administered at regular intervals, starting with five times per week and decreased to once a week on fifth week. Then maintenance sessions once a week for 6 weeks are recommended. The presence of excessive sweating was scored by visual analogue scale (VAS): "0" as continuation of excessive sweating and "10" as the absence of excessive sweating. The demographic and clinical data were collected from files. Also, patients fulfilled a questionnaire for efficacy on follow-up visit. RESULTS: Nineteen patients completed the whole 21 sessions. The mean VAS score was 5.89 +/- 1.49 at the end of the 15th session and 6.36 +/- 2.06 at the end of the treatment. Side effects were well tolerated. Only seven patients were still free of excessive sweating on third months after treatment. The mean satisfaction score was 4.95 +/- 2.38, as measured by VAS where 0 indicated dissatisfaction and 10 indicated high satisfaction. CONCLUSION: Tap water iontophoresis is an effective method of treatment for primary palmoplantar and axillary hyperhidrosis in paediatric patients. But there are still unanswered questions about the mechanism of action, ideal session intervals and protocols for maximum efficacy. PMID- 24405390 TI - Clinical implications of body composition assessment by computed tomography in metastatic renal cell carcinoma. AB - According to computed tomography image analysis, skeletal muscle (SM) and adipose tissue areas vary widely in patients with the same body mass index or the same body surface area. Body composition variables such as SM mass, SM density and subcutaneous and visceral adipose tissue have shown value as potential independent predictive factors for survival in cancer patients, although data for patients with renal cell carcinoma (RCC) undergoing targeted therapy remain relatively scarce. Confirmation of their prognostic value is required before they can be considered useful adjuncts to conventional predictive models of survival in RCC patients. In addition, variability in SM mass might affect drug toxicity, with patients with a low rather than high SM mass being at a higher risk of toxicity. A dose tailored to the individual patient's SM mass might lower toxicity in RCC patients, enable completion of the treatment plan and thus impact favorably on treatment effectiveness. PMID- 24405386 TI - Human adipose-derived stromal/stem cells induce functional CD4+CD25+FoxP3+CD127- regulatory T cells under low oxygen culture conditions. AB - Human adipose tissue stromal/stem cells (ASCs) are known to induce proliferation of resting T cells under ambient (21%) O2 conditions; however, ASCs exist physiologically under lower oxygen (5% O2) conditions in adipose tissue. The effects of low oxygen levels on ASC immunomodulation of T cells are unknown. In this study, we show that ASCs stimulated proliferation of naive CD4(+) T cells and the percentage of CD25(+) T cells was significantly increased under both low and ambient O2. Forkhead box P3 (FoxP3) and transforming growth factor beta (TGF beta) mRNA expression were significantly increased when ASCs were cocultured with CD4(+) T cells under low compared with ambient O2 conditions. The low O2-induced regulatory T cells (iTregs) exhibited functionality when added to mixed lymphocyte reactions as demonstrated by inhibition of peripheral blood mononuclear cell proliferation, and by >300-fold increase in FoxP3 mRNA, and >2 fold increase in TGF-beta mRNA expression. These results demonstrate that under physiologically relevant low O2 conditions, direct contact of human ASCs with naive CD4(+) T cells induced functional iTregs. PMID- 24405392 TI - Comparison of a Schmidt and Haensch refractometer and an Atago PAL-USG Cat refractometer for determination of urine specific gravity in dogs and cats. AB - BACKGROUND: The performance of a digital Atago PAL-USG Cat refractometer (Atago) was compared with a Schmidt and Haensch, Goldberg type refractometer (S+H). MATERIALS AND METHODS: Specific gravity of 47 canine and feline urine samples was determined with both refractometers and the results were compared with Passing Bablok and Bland-Altman plots. In addition, the specific gravity of dilutions of 10% glucose, 10% NaCl, and 3% albumin solutions was determined and compared with expected values. RESULTS: Both refractometers consistently reported 1.000 with distilled water. The correlation between both refractometers based on Passing Bablok plots of 47 urine samples was excellent (r = .99), but, in the Bland Altman plots, there was a significant, proportional, negative error for the Atago readouts. This was also illustrated by the fact that 10 urine samples with an S+H result of > 1.030 were read out between 1.023 and 1.028 by Atago. Schmidt and Haensch results of various glucose solutions matched exactly expected values, but Atago results were lower. Likewise, S+H results with diluted NaCl solutions were closer to expected results than Atago results. In contrast, Atago results with dilutions of 3% albumin were closer to expected results than S+H results. DISCUSSION: The Atago refractometer reported lower specific gravity results in urine and standard solutions of glucose and NaCl, which could adversely affect clinical decisions concerning normal renal function based on solute concentrations determined in canine and feline urine samples. PMID- 24405395 TI - Evaluation of Tris[2-(acryloyloxy)ethyl]isocyanurate cross-linked polyethylenimine as antisense morpholino oligomer delivery vehicle in cell culture and dystrophic mdx mice. AB - Hyperbranched poly(ester amine)s (PEAs) based on tris[2 (acryloyloxy)ethyl]isocyanurate (TAEI) cross-linked low-molecular-weight polyethylenimine (Mw: 0.8k/1.2k/2.0k) have been evaluated for delivering antisense phosphorodiamidate morpholino oligomer (PMO) in vitro and in vivo in the dystrophic mdx mouse. The results show that the PEAs constructed with polyethylenimine (PEI) 2.0k (C series) improved PMO delivery more efficiently than those constructed with PEI 0.8k (A series) or 1.2k (B series) in a GFP reporter-based C2C12 mouse myoblast culture system. The highest efficiency of exon-skipping in vitro with the PMO oligonucleotide targeting human dystrophin exon 50 was obtained when the PEA C12 [TAEI-PEI 2.0k (1:2)] was used. Nearly all of the PEAs improved dystrophin expression in mdx mice by local injection with a 2-4-fold increase when compared with PMO alone. Improved transfection efficiency and lower toxicity indicate the potential of the biodegradable PEA polymers as safe and efficient PMO delivery vectors for in vivo applications. PMID- 24405391 TI - Mutagenesis studies of the 14 A internal cavity of histone deacetylase 1: insights toward the acetate-escape hypothesis and selective inhibitor design. AB - Histone deacetylase (HDAC) proteins are promising targets for cancer treatment, as shown by the approval of two HDAC inhibitors for the treatment of cutaneous T cell lymphoma. HDAC1 in particular has been linked to cell growth and cell cycle regulation and is therefore an attractive target for anticancer drugs. The HDAC1 active site contains a hydrophobic 11 A active-site channel, with a 14 A internal cavity at the bottom of the active site. Several computational and biochemical studies have proposed an acetate-escape hypothesis where the acetate byproduct of the deacetylation reaction escapes via the 14 A internal cavity. Selective HDAC inhibitors that bind to the 14 A cavity have also been created. To understand the influence of amino acids lining the HDAC1 14 A cavity in acetate escape and inhibitor binding, we used mutagenesis coupled with acetate competition assays. The results indicate that amino acids lining the 14 A cavity are critical for catalytic activity and acetate competition, confirming the role of the cavity in acetate escape. In addition, these mutagenesis studies will aid in HDAC1 inhibitor design that exploits the 14 A cavity. PMID- 24405396 TI - Commentary: the multifaceted nature of maternal depression as a risk factor for child psychopathology--reflections on Sellers et al. (2014). AB - While much has been learned about depression in mothers as a risk for the development of psychopathology in offspring, many questions about how the risk is transmitted remain unanswered. Moreover, maternal depression is too often considered to be a unitary construct, ignoring the likely diversity among mothers with depression, which could play essential roles in understanding not only mechanisms of risk but also moderators of risk, i.e. for whom the association between maternal depression and adverse offspring outcomes may be stronger. Sellers et al. address both mechanisms and moderators, thereby contributing to the understanding of risk to offspring of depressed mothers in these two important ways. There is much to learn from this work, on many levels and for different audiences, including both researchers and practitioners. A key take home message of this study for all readers is that understanding the role of maternal depression in associations with child psychopathology requires a nuanced view of the nature of risk to children from depression in mothers. The often co occurring disorders and highly correlated additional aspects of the context in which depression occurs play important roles in the development of psychopathology in the offspring of depressed mothers. PMID- 24405397 TI - Fracking and pollution: can China rescue its environment in time? PMID- 24405398 TI - Correlation between posture, balance control, and peripheral muscle function in adults with cystic fibrosis. AB - BACKGROUND: In addition to pulmonary involvement, adults with cystic fibrosis (CF) are at higher risk of developing skeletal muscle dysfunction, nutritional depletion, and bone and joint disease. OBJECTIVE: This study aimed to assess the correlation between posture, balance, and peripheral muscle function in adults with CF. METHODS: A cross-sectional study of 14 clinically stable patients who were subjected to postural assessment (photogrammetry), stabilometry, and peripheral muscle function. RESULTS: Comparing the right and left sides of the body, there were significant differences for the following variables: horizontal and vertical head alignments; heel angle; and vertical alignment of the trunk (p < 0.001 for all). Variables that represent the head-trunk position and the position of the lower limbs showed correlations with stabilometric parameters. The strongest correlation was observed between the vertical alignment of the body and the medial-lateral range (rho = -0.73; p = 0.002). We also noted a significant correlation between the quadriceps muscle strength and the medial lateral range (rho = -0.69; p = 0.003). CONCLUSIONS: In adults with CF, it is possible that the imbalance occurs by both distortion of the head-trunk relationship and lower extremity abnormalities as noted by the reduced quadriceps muscle strength. PMID- 24405399 TI - Community group exercise versus physiotherapist-led home-based physical activity program: barriers, enablers and preferences in middle-aged adults. AB - BACKGROUND/PURPOSE: Barriers and enablers of physical activity have been investigated, but it remains unclear what middle-aged adults' physical activity preferences are. Two physical activity interventions were compared to determine barriers, enablers and preferences for physical activity format in sedentary, community-dwelling 50- to 65-year-olds. METHODS: Using mixed methods, 37 Physical Activity at Home (PAAH) participants took part in focus groups at the end of the intervention period and completed the Active Australia Survey (AAS). Participants were divided into three sub-groups: (1) group exercise attendees (GA, n = 14); (2) group exercise non-attendees (GNA, n = 9); and (3) physiotherapist-led home based physical activity program attendees (HB, n = 14). Focus groups were audio taped, transcribed, coded and analysed using an inductive thematic approach. Thirty-seven exit telephone calls with GNA were included in the analysis. RESULTS: Cost, self-efficacy, work and carer commitments were major themes identified for GA and GNA. HB participants reported fewer barriers and a number of enablers, including flexibility of the program and physiotherapist instruction. HB and GNA were younger than GA (p< 0.05), more likely to be in paid employment and GNA participants were insufficiently active (p <= 0.01). All participants preferred some home-based physical activity, although a variety of formats was indicated. CONCLUSION: The barriers, enablers and preferences indicate that the physiotherapist-led home-based physical activity program with initial face-to-face contact and telephone support may increase the adoption and maintenance of physical activity in middle-aged adults, particularly for those not interested in, or unable to attend, group exercise. PMID- 24405400 TI - LeuO, a dormant sentinel for SPI-1? AB - A new mechanism for the turning-off of gene expression in Salmonella Pathogenicity Island 1 (SPI-1) is proposed by Espinosa and Casadesus, which involves the action of the LeuO quiescent regulator, by two different pathways. A major one through the activation of the hilE gene, where the HilE protein would in turn inactivate HilD, a major positive transcriptional regulator of SPI-1; and a minor HilE-HilD-independent pathway. This could constitute a back-up or an aid for the turn-off of SPI-1 genes mediated by the nucleoid protein H-NS. PMID- 24405402 TI - The potential of Physcomitrella patens as a platform for the production of plant based vaccines. AB - The moss Physcomitrella patens has a number of advantages for the production of biopharmaceuticals, including: i) availability of standardized conditions for cultivation in bioreactors; ii) not being part of the food chain; iii) high biosafety; iv) availability of highly efficient transformation methods; v) a haploid, fully sequenced genome providing genetic stability and uniform expression; vi) efficient gene targeting at the nuclear level allows for the generation of mutants with specific post-translational modifications (e.g., glycosylation patterns); and vii) oral formulations are a viable approach as no toxic effects are attributed to ingestion of this moss. In the light of this panorama, this opinion paper analyzes the possibilities of using P. patens for the production of oral vaccines and presents some specific cases where its use may represent significant progress in the field of plant-based vaccine development. The advantages represented by putative adjuvant effects of endogenous secondary metabolites and producing specific glycosylation patterns are highlighted. PMID- 24405403 TI - Vaccination issues in patients with chronic kidney disease. AB - Infections are an important cause of morbidity and mortality among patients at all stages of chronic kidney disease. Prevention through vaccination remains the best strategy to minimize the adverse consequences associated with these infectious diseases in this, and all, populations. Unfortunately, patients with chronic kidney disease demonstrate inadequacies of specific immune-cell function that are required for generating a protective vaccine response. Nevertheless, early vaccination of this high-risk population has demonstrated good clinical outcomes during progression to late-stage disease. We review the available evidence linking immune impairment in adult patients with late-stage chronic kidney disease to diminished vaccine responses. We highlight the importance of early vaccination in disease with high risk for development of CKD and novel vaccine approaches in development that may help to address improvement in protective boosting of immunity during late-stage disease. PMID- 24405404 TI - Guidance on water intake effectively improves urinary frequency in patients with nocturia. AB - OBJECTIVES: To evaluate how guidance on water-intake impacts the degree of nocturia. METHODS: A total of 67 male patients were enrolled in the present study. Patients were asked to adjust their water and food intakes so that their 24-h urine production/bodyweight would be equal or lower than 30 mL/kg. One month after the treatment, the therapeutic gain from and adverse effects of fluid restriction were examined by comparing the pretreatment and post-treatment value of various parameters. RESULTS: Overall, 65 eligible patients were evaluated. In 44 patients (67%), the frequency of nocturia was improved to one or more times. The change in frequency of nocturia showed a positive correlation with the change in nocturnal urine volume. The change in nocturnal urine volume showed a positive correlation with the changes in 24-h urine production/bodyweight, 24-h drinking volume and daytime drinking volume. The changes in 24-h urine production/bodyweight and daytime drinking volume were independent factors influencing therapeutic effect. None of the participants reported any adverse event. CONCLUSIONS: In patients with a 24-h urine production/bodyweight equal or higher than 30 mL/kg, guidance on water intake might be considered effective and safe as a lifestyle therapy. Water restriction should be carried out not only in the evening, but also during daytime. PMID- 24405401 TI - Promising alternative settings for HPV vaccination of US adolescents. AB - Vaccination in alternative settings, defined here as being outside of traditional primary care, can help address the pressing public health problem of low human papillomavirus vaccine coverage among adolescents in the United States. Pharmacies are promising because they are highly accessible and have well established immunization practices. However, pharmacies currently face policy and reimbursement challenges. School-located mass vaccination programs are also promising because of their high reach and demonstrated success in providing other vaccines, but control by local policymakers and challenges in establishing community partnerships complicate widespread implementation. Health centers in schools are currently too few to greatly increase access to human papillomavirus vaccine. Specialty clinics have experience with vaccination, but the older age of their patient populations limits their reach. Future steps to making alternative settings a success include expanding their use of statewide vaccine registries and improving their coordination with primary care providers. PMID- 24405405 TI - Hemodynamic effects of thoracoscopic surgery in neonates with cardiac anomalies. AB - INTRODUCTION: Thoracoscopic repair of esophageal atresia (EA) and congenital diaphragmatic hernia (CDH) repair is increasing in popularity. However, minimally invasive surgery is avoided in infants with heart defects. The aim of this study was to clarify whether cardiac anomalies are a reasonable contraindication to thoracoscopic surgery in term and preterm neonates. PATIENTS AND METHODS: In this retrospective, single-institution study 15 neonates (8 boys and 7 girls) with cardiac anomalies underwent thoracoscopic repair of either EA or CDH. Between January 2004 until November 2012 4 preterm and 11 term neonates were identified. Type of cardiac anomaly, operative procedure performed, operative time, intrapleural pressure, and early postoperative complications were evaluated. RESULTS: Over this 9-year period, 10 neonates underwent thoracoscopic EA repair, and 5 neonates underwent thoracoscopic CDH repair. Median operative time was 177 minutes with a median intrapleural pressure of 9 mm Hg. Cardiac anomalies ranged from persistent foramen ovale to atrium septal defect to ventricular septal defect and tetralogy of Fallot. In the postoperative course hemodynamic impairment was noted in only 1 patient. This patient presented cardiorespiratory instability already preoperatively and required dobutamine until postoperative Day 6. CONCLUSIONS: From this experience it appears that thoracoscopic surgery can be performed safely in term and preterm neonates with cardiac anomalies. Even in babies with multiple cardiac anomalies and complex heart defects, thoracoscopic repair of EA or CDH could be performed without hemodynamic instability. Nevertheless, further studies are necessary to gain sufficient information about the effects of thoracoscopy in neonates with heart defects. PMID- 24405406 TI - Multi-analyte methods for the detection of photoinitiators and amine synergists in food contact materials and foodstuffs--part I: HPLC-DAD screening of materials. AB - The objective of this work was to develop a HPLC-DAD method suitable for the screening of food contact materials for a total of 63 monomeric and polymeric photoinitiators and amine synergists. Such multi-analyte methods are worthwhile for official control laboratories, where normally no information about the composition of the applied inks or varnishes on the printed or lacquered materials is available and thus target analyses are not feasible. The polymeric analytes were each separated in a multitude of substance peaks, which largely overlaid those of the other compounds. Thus, for 13 polymeric photoinitiators and amine synergists a hydrolysis method was developed that reduced the number of ultraviolet (UV) detectable peaks to only one. This allowed easier identification and--preliminary--semi-quantification of these polymeric substances with adequate limits of detection. The remaining 50 photoinitiators and amine synergists were combined in one HPLC-DAD method. But since many of these substances are structurally related, partly retention times and spectra did not differ significantly. Thus selectivity was enhanced by preparing a database containing all spectra and retention times of the investigated compounds. Furthermore, the retention times of those 50 substances were calculated relative to two internal standards to overcome variances of retention from run to run or due to matrix effects. The developed method was tested for the analysis of food contact materials. Extractions of these were performed with acetonitrile and partially the extracts were subsequently concentrated in a steam of nitrogen. Limits of detection of photoinitiators and amine synergists in concentrated packaging extracts were in the range between 0.02 and 5.5 ug dm(-2). PMID- 24405413 TI - Antimicrobial agents in veterinary medicine. PMID- 24405414 TI - Peptide nucleic acids: a review on recent patents and technology transfer. AB - INTRODUCTION: DNA/RNA-based drugs are considered of major interest in molecular diagnosis and nonviral gene therapy. In this field, peptide nucleic acids (PNAs, DNA analogs in which the sugar-phosphate backbone is replaced by N-(2 aminoethyl)glycine units or similar building blocks) have been demonstrated to be excellent candidates as diagnostic reagents and biodrugs. AREAS COVERED: Recent (2002 - 2013) patents based on studies on development of PNA analogs, delivery systems for PNAs, applications of PNAs in molecular diagnosis, and use of PNA for innovative therapeutic protocols. EXPERT OPINION: PNAs are unique reagents in molecular diagnosis and have been proven to be very active and specific for alteration of gene expression, despite the fact that solubility and uptake by target cells can be limiting factors. Accordingly, patents on PNAs have taken in great consideration delivery strategies. PNAs have been proven stable and effective in vivo, despite the fact that possible long-term toxicity should be considered. For possible clinical applications, the use of PNA molecules in combination with drugs already employed in therapy has been suggested. Considering the patents available and the results on in vivo testing on animal models, we expect in the near future relevant PNA-based clinical trials. PMID- 24405415 TI - Kisspeptin-10 induces endothelial cellular senescence and impaired endothelial cell growth. AB - The KPs (kisspeptins) are a family of multifunctional peptides with established roles in cancer metastasis, puberty and vasoconstriction. The effects of KPs on endothelial cells have yet to be determined. The aim of the present study was to investigate the effects of KP-10 on endothelial cell growth and the mechanisms underlying those effects. The administration of recombinant KP-10 into the hindlimbs of rats with ischaemia significantly impaired blood flow recovery, as shown by laser Doppler, and capillary growth, as shown using histology, compared with the controls. HUVECs (human umbilical vein endothelial cells) express the KP receptor and were treated with KP-10 in culture studies. KP-10 inhibited endothelial cell tube formation and proliferation in a significant and dose dependent manner. The HUVECs treated with KP exhibited the senescent phenotype, as determined using a senescence-associated beta-galactosidase assay, cell morphology analysis, and decreased Sirt1 (sirtuin 1) expression and increased p53 expression shown by Western blot analysis. Intriguingly, a pharmacological Rho kinase inhibitor, Y-27632, was found to increase the proliferation of HUVECs and to reduce the number of senescent phenotype cells affected by KP-10. In conclusion, KP-10 suppressed endothelial cells growth both in vivo and in vitro in the present study. The adverse effect of KP on endothelial cells was attributable, at least in part, to the induction of cellular senescence. PMID- 24405417 TI - Cost-effectiveness of alternative conservation strategies with application to the Pacific leatherback turtle. AB - Although holistic conservation addressing all sources of mortality for endangered species or stocks is the preferred conservation strategy, limited budgets require a criterion to prioritize conservation investments. We compared the cost effectiveness of nesting site and at-sea conservation strategies for Pacific leatherback turtles (Dermochelys coriacea). We sought to determine which conservation strategy or mix of strategies would produce the largest increase in population growth rate per dollar. Alternative strategies included protection of nesters and their eggs at nesting beaches in Indonesia, gear changes, effort restrictions, and caps on turtle takes in the Hawaiian (U.S.A.) longline swordfish fishery, and temporal and area closures in the California (U.S.A.) drift gill net fishery. We used a population model with a biological metric to measure the effects of conservation alternatives. We normalized all effects by cost to prioritize those strategies with the greatest biological effect relative to its economic cost. We used Monte Carlo simulation to address uncertainty in the main variables and to calculate probability distributions for cost effectiveness measures. Nesting beach protection was the most cost-effective means of achieving increases in leatherback populations. This result creates the possibility of noncompensatory bycatch mitigation, where high-bycatch fisheries invest in protecting nesting beaches. An example of this practice is U.S. processors of longline tuna and California drift gill net fishers that tax themselves to finance low-cost nesting site protection. Under certain conditions, fisheries interventions, such as technologies that reduce leatherback bycatch without substantially decreasing target species catch, can be cost-effective. Reducing bycatch in coastal areas where bycatch is high, particularly adjacent to nesting beaches, may be cost-effective, particularly, if fisheries in the area are small and of little commercial value. PMID- 24405416 TI - Discovery of highly potent p53-MDM2 antagonists and structural basis for anti acute myeloid leukemia activities. AB - The inhibition of p53-MDM2 interaction is a promising new approach to non genotoxic cancer treatment. A potential application for drugs blocking the p53 MDM2 interaction is acute myeloid leukemia (AML) due to the occurrence of wild type p53 (wt p53) in the majority of patients. Although there are very promising preclinical results of several p53-MDM2 antagonists in early development, none of the compounds have yet proven the utility as a next generation anticancer agent. Herein we report the design, synthesis and optimization of YH239-EE (ethyl ester of the free carboxylic acid compound YH239), a potent p53-MDM2 antagonizing and apoptosis-inducing agent characterized by a number of leukemia cell lines as well as patient-derived AML blast samples. The structural basis of the interaction between MDM2 (the p53 receptor) and YH239 is elucidated by a co-crystal structure. YH239-EE acts as a prodrug and is the most potent compound that induces apoptosis in AML cells and patient samples. The observed superior activity compared to reference compounds provides the preclinical basis for further investigation and progression of YH239-EE. PMID- 24405418 TI - A mouse bone marrow stromal cell line with skeletal stem cell characteristics to study osteogenesis in vitro and in vivo. AB - Bone marrow stromal cells (BMSCs) are composed of progenitor and multipotent skeletal stem cells, which are able to differentiate in vitro into osteocytes, adipocytes, and chondrocytes. Mouse BMSCs (mBMSCs) are a versatile model system to investigate factors involved in BMSC differentiation in vitro and in vivo as a variety of transgenic mouse models are available. In this study, mBMSCs were isolated and osteogenic differentiation was investigated in tissue culture and in vivo. Three out of seven independent cell isolates showed the ability to differentiate into osteocytes, adipocytes, and chondrocytes in vitro. In vitro multipotency of an established mBMSC line was maintained over 45 passages. The osteogenic differentiation of this cell line was confirmed by quantitative polymerase chain reaction (qPCR) analysis of specific markers such as osteocalcin and shown to be Runx2 dependent. Notably, the cell line, when transplanted subcutaneously into mice, possesses full skeletal stem cell characteristics in vivo in early and late passages, evident from bone tissue formation, induction of vascularization, and hematopoiesis. This cell line provides, thus, a versatile tool to unravel the molecular mechanisms governing osteogenesis in vivo thereby aiding to improve current strategies in bone regenerative therapy. PMID- 24405419 TI - Fragment-based identification of amides derived from trans-2-(pyridin-3 yl)cyclopropanecarboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT). AB - Potent, trans-2-(pyridin-3-yl)cyclopropanecarboxamide-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using fragment-based screening and structure-based design techniques. Multiple crystal structures were obtained of initial fragment leads, and this structural information was utilized to improve the biochemical and cell-based potency of the associated molecules. Many of the optimized compounds exhibited nanomolar antiproliferative activities against human tumor lines in in vitro cell culture experiments. In a key example, a fragment lead (13, KD = 51 MUM) was elaborated into a potent NAMPT inhibitor (39, NAMPT IC50 = 0.0051 MUM, A2780 cell culture IC50 = 0.000 49 MUM) which demonstrated encouraging in vivo efficacy in an HT 1080 mouse xenograft tumor model. PMID- 24405422 TI - A study of facial pattern in patients with fanconi anemia. AB - OBJECTIVE: This study is aimed to evaluate craniofacial features in patients with Fanconi anemia (FA) through cephalometric analysis and to classify the facial growth pattern to observe possible facial discrepancies. DESIGN: This is a cross sectional study which employed a quantitative approach to compare linear and angular measurements of cephalometric analysis in lateral teleradiographic images of a clinical type sample of patients with FA. A retrospective cephalometric study was performed using cephalometric analyses of Ricketts and Steiner; growth patterns according to Ricketts' vertical growth pattern (VERT index) were also analyzed. PATIENTS: Fifty patients diagnosed with FA who were undergoing anti aplasia treatment at the outpatient Hematology service at the Federal University of Parana, Curitiba, Brazil were included in the study. INTERVENTIONS: The patients were evaluated in the School of Dentistry of the Pontifical Catholic University of Parana (PUCPR), Curitiba, Brazil. Exclusion criteria included patients who had used or were using growth hormone medication, had undergone bone marrow transplant, or had been previously subjected to dental treatment. MAIN OUTCOME MEASURES: Cephalometric points were plotted in order to set up linear and angular cephalometric measurements. Angular and linear measurements from 17 factors proposed by Ricketts' cephalometric analysis were assessed. RESULTS: Dolicofacial appearance was observed in 52% of individuals; braquifacial in 28%, and mesofacial in 20%. Significant maxillary/mandibular discrepancy was observed. It was concluded that upon anteroposterior evaluation of facial bone structures, the FA sample presented smaller median measurements in most variables evaluated; it also presented mandibular micrognathism and mainly dolicofacial vertical growth pattern. These findings, together with other features such as skin pigmentation and microphthalmia, may lead to a possible recognition of a FA condition from a patient's facial features. PMID- 24405424 TI - Cumulative Retrospective Exposure Assessment (REA) as a predictor of amphibole asbestos lung burden: validation procedures and results for industrial hygiene and pathology estimates. AB - CONTEXT: A detailed evaluation of the correlation and linearity of industrial hygiene retrospective exposure assessment (REA) for cumulative asbestos exposure with asbestos lung burden analysis (LBA) has not been previously performed, but both methods are utilized for case-control and cohort studies and other applications such as setting occupational exposure limits. OBJECTIVE: (a) To correlate REA with asbestos LBA for a large number of cases from varied industries and exposure scenarios; (b) to evaluate the linearity, precision, and applicability of both industrial hygiene exposure reconstruction and LBA; and (c) to demonstrate validation methods for REA. METHODS: A panel of four experienced industrial hygiene raters independently estimated the cumulative asbestos exposure for 363 cases with limited exposure details in which asbestos LBA had been independently determined. LBA for asbestos bodies was performed by a pathologist by both light microscopy and scanning electron microscopy (SEM) and free asbestos fibers by SEM. Precision, reliability, correlation and linearity were evaluated via intraclass correlation, regression analysis and analysis of covariance. Plaintiff's answers to interrogatories, work history sheets, work summaries or plaintiff's discovery depositions that were obtained in court cases involving asbestos were utilized by the pathologist to provide a summarized brief asbestos exposure and work history for each of the 363 cases. RESULTS: Linear relationships between REA and LBA were found when adjustment was made for asbestos fiber-type exposure differences. Significant correlation between REA and LBA was found with amphibole asbestos lung burden and mixed fiber-types, but not with chrysotile. The intraclass correlation coefficients (ICC) for the precision of the industrial hygiene rater cumulative asbestos exposure estimates and the precision of repeated laboratory analysis were found to be in the excellent range. The ICC estimates were performed independent of specific asbestos fiber type. CONCLUSIONS: Both REA and pathology assessment are reliable and complementary predictive methods to characterize asbestos exposures. Correlation analysis between the two methods effectively validates both REA methodology and LBA procedures within the determined precision, particularly for cumulative amphibole asbestos exposures since chrysotile fibers, for the most part, are not retained in the lung for an extended period of time. PMID- 24405425 TI - El Nino physics and El Nino predictability. AB - Much of the year-to-year climate variability on the Earth is associated with El Nino and the Southern Oscillation (ENSO). This variability is generated primarily by a coupled ocean-atmosphere instability near the eastern edge of the western equatorial Pacific warm pool. Here, I discuss the physics of this variability, including its phase locking to the seasonal cycle. ENSO growth typically occurs from April/May to November, and by July the perturbation is usually strong enough that it persists to the beginning of the following year, when ENSO events usually end. Consequently, predicting ENSO is easy from July to February but is more challenging across the April/May transition to the next event. I discuss precursors of this transition and recent results from dynamical and statistical models used for ENSO forecasting. PMID- 24405426 TI - Carbon cycling and storage in mangrove forests. AB - Mangroves are ecologically and economically important forests of the tropics. They are highly productive ecosystems with rates of primary production equal to those of tropical humid evergreen forests and coral reefs. Although mangroves occupy only 0.5% of the global coastal area, they contribute 10-15% (24 Tg C y( 1)) to coastal sediment carbon storage and export 10-11% of the particulate terrestrial carbon to the ocean. Their disproportionate contribution to carbon sequestration is now perceived as a means for conservation and restoration and a way to help ameliorate greenhouse gas emissions. Of immediate concern are potential carbon losses to deforestation (90-970 Tg C y(-1)) that are greater than these ecosystems' rates of carbon storage. Large reservoirs of dissolved inorganic carbon in deep soils, pumped via subsurface pathways to adjacent waterways, are a large loss of carbon, at a potential rate up to 40% of annual primary production. Patterns of carbon allocation and rates of carbon flux in mangrove forests are nearly identical to those of other tropical forests. PMID- 24405427 TI - Microbially mediated transformations of phosphorus in the sea: new views of an old cycle. AB - Phosphorus (P) is a required element for life. Its various chemical forms are found throughout the lithosphere and hydrosphere, where they are acted on by numerous abiotic and biotic processes collectively referred to as the P cycle. In the sea, microorganisms are primarily responsible for P assimilation and remineralization, including recently discovered P reduction-oxidation bioenergetic processes that add new complexity to the marine microbial P cycle. Human-induced enhancement of the global P cycle via mining of phosphate-bearing rock will likely influence the pace of P-cycle dynamics, especially in coastal marine habitats. The inextricable link between the P cycle and cycles of other bioelements predicts future impacts on, for example, nitrogen fixation and carbon dioxide sequestration. Additional laboratory and field research is required to build a comprehensive understanding of the marine microbial P cycle. PMID- 24405428 TI - Clinicopathologic and electrocardiographic features of Akita dogs with high and low erythrocyte potassium phenotypes. AB - BACKGROUND: Canine RBCs are expected to have high sodium and low potassium (LK) concentrations. However, some dogs have a low sodium and high potassium (HK) phenotype due to a Na-K pump in the mature RBC membrane. Awareness of this particularity avoids misinterpretation of hyperkalemia in affected dogs. OBJECTIVE: The purpose of this study was to compare the CBCs, serum biochemistry profiles, urinalysis data, and electrocardiography data in HK and LK Akita dogs. METHODS: In this study, the intra-RBC potassium (KRBC) was measured in 48 healthy adult Akita dogs. The HK group included dogs with KRBC concentration at least 5 fold that of plasma, while the LK dogs served as controls. RESULTS: The HK phenotype was determined in 10 dogs (21%). With the exception of higher plasma potassium concentrations in the HK group compared with LK controls (6.6 mmol/L vs 4.4 mmol/L, P < .001), there were no other differences in serum biochemistry variables. In hematology, mean HGB concentration (13.5 vs 15.9, P < .001), PCV (42.9 vs 46.7, P = .009), RBC (6.1 vs 7.4, P < .001), and MCHC (31.3 vs 34.0, P < .001) were significantly lower in the HK group, while MCV (70.0 vs 63.4, P < .001) was higher compared with the LK controls. There were no significant differences in urinalysis or electrocardiography data between groups. CONCLUSIONS: HK Akita dogs showed significant differences in several hematologic variables, as well as higher plasma potassium concentration. Therefore, the HK phenotype should be considered in the interpretation of these variables in this breed. PMID- 24405431 TI - Long-term trends and patterns of fatal traumatic brain injuries in the pediatric and adolescent population of austria in 1980-2012: analysis of 33 years. AB - Traumatic brain injuries (TBIs) are of special concern in the pediatric and adolescent population because of high incidence, mortality, and potential years of life lost (PYLL). Knowledge on causes and mortality trends is essential for effective prevention. The aim of this study was to analyze the long-term trends and causes of TBI-related mortality between 1980 and 2012 in the pediatric and adolescent populations of Austria. Death certificate data on TBI-related deaths of children and adolescents 0-19 years of age and exact population numbers were obtained from the Austrian Statistical Office. Five age groups were created. Mortality trends and causes of TBI were analyzed. PYLL were used to indicate the public health impact. Of 5319 identified TBI-related deaths, 75% were male victims. The annual mortality rates per 100,000 between 1980 and 2012 decreased from 25 to 2.6 in males, from 8.5 to 1.0 in females, and from 16.9 to 1.8 in the total population. Those 15-19 years of age had the highest mortalities, followed by 0-2 years of age. Over 80% of deaths were caused by accidents, inflicted TBIs were most common in those 0-2 years of age, and traffic accidents in those 15-19 years of age. In the studied period, 295,793 PYLL could be attributed to TBIs. Measures to prevent traffic accidents contributed significantly to the decrease of mortality and PYLL, especially in 15- to 19-year-old men. Causes and trends of TBI-related mortality exhibit age-group-specific patterns, and this knowledge could contribute to planning further preventive action to reduce TBI fatalities in the studied population. PMID- 24405437 TI - RENAL nephrometry score is a predictive factor for the annual growth rate of renal mass. AB - OBJECTIVE: To evaluate the association between the RENAL nephrometry score and annual growth rates of renal masses presumed to be renal cell carcinoma. METHODS: The current study included 47 renal tumors followed up for at least 12 months, of which 26 tumors were found to be pathologically proven renal cell carcinomas. Annual tumor growth rates were calculated from changes in the maximal diameter on computed tomography, and RENAL nephrometry scores were recorded on initial imaging by two senior urologists. The associations between clinical characteristics including the RENAL nephrometry score and annual growth rates were analyzed using a linear regression model. RESULTS: The median tumor size at diagnosis was 1.7 cm (range 0.6-5.8). The median nephrometry score at diagnosis was 7 (range 4-10). Overall, the median tumor growth rate was 0.34 cm per year (range -0.19-2.0). Linear regression analysis showed that the annual tumor growth rate was associated with the RENAL nephrometry score (P < 0.0001), but it was independent of the age at diagnosis, sex and initial tumor size. In addition, the correlation between the RENAL nephrometry score and annual growth rate remained significant in the 26 pathologically proven renal cell carcinomas. CONCLUSIONS: The RENAL nephrometry score is associated with the annual growth rate of renal masses. Our findings further support the association between the RENAL nephrometry score and tumor biology. PMID- 24405435 TI - Network analysis for motives in suicide cases: a cross-sectional study. AB - AIM: Suicide victims have various distresses or motives. There are few studies on how these motives toward suicide relate with each other. We used network analyses to extract the structures of correlations among the motives for suicide. METHODS: We obtained datasets of suicide victims from 2007-2009 in Japan in cooperation with Ibaraki Prefectural Police Headquarters. The data were analyzed by network centrality measures and a structural analysis by block modeling. RESULTS: Among the motives, depression and physical illness showed relatively high scores of 'degree centrality', whereas depression and unemployment showed relatively high scores of 'betweenness centrality'. Structural analysis by block modeling resulted in eight blocks. The most important block comprised eight motives, including conflict between parent and child, marital conflict, economic hardship, and overloaded with debt. CONCLUSION: Depression and physical illness were important and priority areas for completed suicides, although these two motives had different influences on suicide behaviors. Furthermore, structural analysis revealed the important role of a block, including some familial and financial motives, which induced hopelessness. Our results suggest that it might be useful to consider the common ways in which motivations for suicide are tied together when suicide intervention is launched from a social model point of view. PMID- 24405441 TI - Morphological variation in vanishing Mexican desert fishes of the genus Characodon (Goodeidae). AB - This study investigated a rapidly vanishing group of fishes in the genus Characodon (including Characodon lateralis and Characodon audax) from the upper Rio Mezquital drainage in Mexico. Using specimens from museum collections, morphological variation was assessed to quantify body shape differentiation among historic (i.e. extirpated and extant) collection sites. In both sexes, body shape (particularly head shape, the proportion of the caudal peduncle and the position and size of dorsal and anal fins) varied significantly among populations and species. Variation among collection sites could at least partially be attributed to geography, as the presence of distinct hydrographic units and a major waterfall coincided with major body shape differences. These results are discussed in the light of previously published molecular genetic analyses, as they have direct implications for taxonomic problems and the need for conservation measures for these endangered fishes. PMID- 24405442 TI - Allele and haplotype frequencies of HLA-DPA1 and -DPB1 in the population of Guadeloupe. AB - Genetic polymorphism of human leukocyte antigen (HLA)-DPA1 and -DPB1 loci was studied in 154 unrelated individuals from Guadeloupe, an archipelago of five islands located in the Carribean Sea. Thirty different DPB1 and eight different DPA1 alleles were observed with a heterozygosity index of 0.87 and 0.78, respectively. This high degree of heterozygosity corresponds with those found in African populations. The DPB1* 01:01:01 allele was most frequent (0.260), followed by 02:01:02 (0.143) and 04:01:01 (0.127). The DPA1 alleles 01:03 (0.380), 02:01 (0.302), 02:02 (0.175) and 03:01 (0.123) were identified in >35 individuals each, whereas 01:04, 01:05 and 04:01 were present only once. Haplotype estimations revealed the presence of 39 different haplotypes, with DPB1*01:01:01-DPA1*02:02 and DPB1*02:01:02-DPA1*01:03 as the most frequent (0.143 and 0.140, respectively). A striking difference was observed in DPB1/DPA1 associations between DPB1*04:02 and *105:01, that have identical exon 2 sequences. DPB1*04:02 was exclusively associated with DPA1*01:03, whereas DPB1*105:01 was present with DPA1*03:01, *03:02 or *04:01. This implies that the DP molecules are actually different, and this difference is relevant to consider in studies on the function of HLA-DP molecules in transplantation. Overall, HLA DPA1 and DPB1 allele frequencies and haplotypes of the population of Guadeloupe were most similar to African populations, with characteristic alleles and haplotypes that bespeaks the admixture with other ethnicities. PMID- 24405445 TI - The effect of nanoliposomal formulations on Staphylococcus epidermidis biofilm. AB - OBJECTIVE: The aim of the present study was to assess the in vitro antimicrobial activities of nanoliposomal formulations loaded with vancomycin or/and rifampin against the biofilm formed by Staphylococcus epidermidis at 37 degrees C under aerobic condition. MATERIALS AND METHODS: Liposomal formulations were prepared by dehydration-rehydration (DRV) method and characterized for size, zeta potential and encapsulation efficacy. The ability of different formulations on eradication of bacterial biofilm was assessed through optical density ratio (ODr) and the results implicate higher survival rates of S. epidermidis on biofilm. Positive control was defined as an ODr = 1.0. RESULTS: The zeta potential of anionic, cationic and PEGylated liposomes was -35 +/- 2, 35 +/- 1 and 27 +/- 2 mV whereas the mean sizes of these liposomal formulations were 145 +/- 4, 134 +/- 1 and 142 +/- 6 nm, respectively. Encapsulation efficacy of rifampin and vancomycin was more than 60% and about 25%, respectively. Cationic liposomal rifampin lowered the ODr to 0.61 and was the most effective formulations against S. epidermidis biofilm (p<0.001). The antibiofilm activity of liposomal formulations was concentration- and time-dependent manner. CONCLUSION: The results of this study showed that rifampin-loaded liposomes were effective against bacterial biofilm. PMID- 24405446 TI - An investigation of factors that influence help-seeking for hearing impairment in older adults. AB - OBJECTIVE: To examine the influence of audiological and non-audiological factors on help-seeking for hearing impairment (HI) in older adults. DESIGN: A retrospective research design was employed. Participants completed 14 measures, after which two multivariate, multinomial logistic regression models were fitted to the data to determine which factors were associated with consultation for HI and hearing aid uptake. STUDY SAMPLE: Three-hundred-and-seven individuals who were 60 years or older and who presented with a unilateral or bilateral HI participated in the study. Non-hearing aid owners were assigned to a non consulter group (n=55) or a consulter group (n=92); hearing aid owners were assigned to an unsuccessful hearing aid owner group (n=75) or a successful hearing aid owner group (n=85). RESULTS: A similar combination of factors was associated with the decisions to consult a health professional about HI and/or to adopt hearing aids. The most important factors related to attitudinal beliefs (e.g. perceived benefits of hearing aids) and external cues to action (e.g. support from significant others). Greater HI also influenced consultation and adoption of hearing aids. CONCLUSIONS: Findings highlight the importance of non audiological factors in hearing rehabilitation to improve consultation for HI and hearing aid adoption. PMID- 24405450 TI - Apoptosis-inducing agents: a patent review (2010 - 2013). AB - INTRODUCTION: Apoptosis is an important and extensively studied pathway of programmed cell death, which is central to different physiological processes. Varied pathological implications, not limited to cancer and neurodegenerative diseases, occur if a slight dysfunction happens in the intricate apoptotic pathway. Therefore, it has become one of the prime molecular target for drug discovery and development particularly for diseases like cancer. AREAS COVERED: As a promising drug target in the development of cancer chemotherapeutics, apoptosis has received extensive attention and hundreds of thousands of reports have been published. In the present review, the patents filed/published on apoptosis-inducing agents during the period of 2010 - 2013 have been compiled and discussed. EXPERT OPINION: Most of the chemotherapeutics employed in cancer treatment leads to suppression of tumor via cell death irrespective of the mechanism of action or molecular target. No effective drug has emerged from the direct activation/inhibition of apoptotic regulatory proteins and of late some potential drugs, such as oblimersen, navitoclax, etc., targeting Bcl-2 family of proteins are under clinical trials. However, most of these molecules lacks efficacy accompanied with significant toxicity and resistance. Concerted efforts are required such as combination therapies and identification of newer selective inhibitor to overcome these limitations. PMID- 24405447 TI - Differential subcellular localization of SK3-containing channels in the hippocampus. AB - Small-conductance, Ca(2+) -activated K(+) (SK) channels are expressed in the hippocampus where they regulate synaptic responses, plasticity, and learning and memory. To investigate the expression of SK3 (KCNN3) subunits, we determined the developmental profile and subcellular distribution of SK3 in the developing mouse hippocampus using western blots, immunohistochemistry and high-resolution immunoelectron microscopy. The results showed that SK3 expression increased during postnatal development, and that the localization of SK3 changed from being mainly associated with the endoplasmic reticulum and intracellular sites during the first postnatal week to being progressively concentrated in dendritic spines during later stages. In the adult, SK3 was localized mainly in postsynaptic compartments, both at extrasynaptic sites and along the postsynaptic density of excitatory synapses. Double labelling showed that SK3 co-localized with SK2 (KCNN2) and with N-methyl-D-aspartate receptors. Finally, quantitative analysis of SK3 density revealed two subcellular distribution patterns in different hippocampal layers, with SK3 being unevenly distributed in CA1 region of the hippocampus pyramidal cells and homogeneously distributed in dentate gyrus granule cells. Our results revealed a complex cell surface distribution of SK3 containing channels and a distinct developmental program that may influence different hippocampal functions. PMID- 24405451 TI - Ability of synbiotic encapsulated Saccharomyces cerevisiae boulardii to grow in berry juice and to survive under simulated gastrointestinal conditions. AB - The probiotic yeast, Saccharomyces cerevisiae boulardii, was microencapsulated in a mixture of alginate-inulin-xanthan gum, and its ability to grow in berry juice and survive 4 weeks of storage at 4 degrees C was determined. Exposure of the yeast in these forms to artificial gastrointestinal conditions was also assessed. Encapsulation significantly enhanced cell viability after fermentation and storage compared with the free yeast (7.59 log10 colony forming units/ml versus 6.98 log10 colony forming units/ml, respectively) and protected it from exposure to a simulated gastrointestinal transit after 4 weeks of storage. Conversely, a dramatic loss of viability was exhibited by free yeast after 4 weeks of storage, and viability values closer to zero (0.23 log10 cfu/ml) were found after the simulated gastrointestinal treatment. Microcapsules were capable of absorbing a certain amount of polyphenols and anthocyanins. This work, based on use of microencapsulated probiotic yeasts, might represent the starting point for the development of new functional foods or functional ingredients. Microcapsules were capable to absorb, from berry juice, a certain amount of anthocyanins which, maintaining their native form after the in vitro gastrointestinal transit, might in vivo therein be transformed into other, simpler molecules, with beneficial effect on microflora and human health too. PMID- 24405461 TI - Does early family risk and current quality of care predict indiscriminate social behavior in institutionalized Portuguese children? AB - The current study extends research on the effects of institutionalization, most notably by evaluating the influence of proximal relationship processes over and above prenatal and pre-institutional family experiences. By focusing on current quality of institutional care and the child's early family background, it examines the influence of variations in the institutionalization experience on displays of indiscriminate social behavior, after taking into account potentially confounding pre-admission experiences. Seventy-four Portuguese children (11-30 months) placed in 17 residential institutions and their primary caregivers participated in the study. Children's displays of indiscriminate social behavior were assessed based on an observational measure and a semi-structured interview administered to the child's caregiver. Data on children's physical and mental development were also collected. Three contextual-risk composites of early family behavior - prenatal, family relational, and emotional-neglect--were created. The quality of institutional care was examined in terms of structural, relational characteristics, and, additionally, of the quality of child-caregiver relationship. Current quality of care experienced in the institution, operationalized in terms of the absence (vs. presence) of a preferred caregiver, predicted indiscriminate social behavior over and above prenatal and family risk conditions that preceded the child's institutionalization. PMID- 24405452 TI - Effects of racing on reticulocyte concentrations in Greyhounds. AB - BACKGROUND: Greyhounds have several hematologic variables that are outside of the respective reference intervals of other dog breeds. In addition, increases in HCT, total protein and HGB concentration, and RBC and WBC counts occur immediately after exercise; these values return to resting values within a few hour after racing. OBJECTIVE: This study evaluated the effects of exercise on the concentration of reticulocytes in circulating blood in racing Greyhounds. We hypothesized that reticulocyte numbers are significantly increased immediately after a race, and return to baseline within one to 2 h postrace. METHODS: Fifty actively racing Greyhounds at the Wheeling Island Racetrack and Casino were included in the study. Samples were collected by jugular venipuncture one day prior to racing at the kennel (resting), immediately after racing, and one to 2 h after the race (recovery). Reticulocyte counts were determined with an IDEXX ProCyte Dx Hematology Analyzer (IDEXX Laboratories, Inc., Westbrook, ME, USA). Due to a nonparametric distribution, the results were statistically compared using the Friedman test. RESULTS: Reticulocyte concentrations were significantly different among the 3 sample collection times (P < .0001). There was a significant increase in reticulocyte concentration immediately after racing (P < .001); one to 2 h after racing, the reticulocyte numbers decreased significantly (P < .001) to counts comparable to resting samples. CONCLUSION: The increase in reticulocyte concentration is probably related to splenic contraction secondary to the release of catecholamines, although premature bone marrow release could also account for these changes. Thus, it is important to consider a Greyhound's activity and degree of excitement when interpreting selected hematologic data in a clinical setting. PMID- 24405462 TI - Conductive polymer nanotube patch for fast and controlled ex vivo transdermal drug delivery. AB - AIM: To uptake and release hydrophilic model drugs and insulin in a novel conductive polymer (CP) nanotube transdermal patch. MATERIALS & METHODS: The externally controlled transdermal delivery of model drugs and insulin were tested ex vivo and results were compared with CP films. The unique intrinsic properties of CPs provide electrostatic interaction between the model drugs and polymer backbone. RESULTS & DISCUSSION: When a pulsed potential was applied, the drug delivery release profile mimics that of injection delivery. With a constant potential applied, the release rate constants of the patch system were up to three-times faster than the control (0 V) and released approximately 80% more drug molecules over 24 h. CONCLUSION: The CP nanotube transdermal patch represents a new and promising drug method, specifically for hydrophilic molecules, which have been a large obstacle for conventional transdermal drug delivery systems. PMID- 24405463 TI - Letter to the editor: Bow hunter's syndrome. PMID- 24405464 TI - Biomechanics of lateral lumbar interbody fusion constructs with lateral and posterior plate fixation: laboratory investigation. AB - OBJECT: Lumbar interbody fusion is indicated in the treatment of degenerative conditions. Laterally inserted interbody cages significantly decrease range of motion (ROM) compared with other cages. Supplemental fixation options such as lateral plates or spinous process plates have been shown to provide stability and to reduce morbidity. The authors of the current study investigate the in vitro stability of the interbody cage with a combination of lateral and spinous process plate fixation and compare this method to the established bilateral pedicle screw fixation technique. METHODS: Ten L1-5 specimens were evaluated using multidirectional nondestructive moments (+/- 7.5 N . m), with a custom 6 degrees of-freedom spine simulator. Intervertebral motions (ROM) were measured optoelectronically. Each spine was evaluated under the following conditions at the L3-4 level: intact; interbody cage alone (stand-alone); cage supplemented with lateral plate; cage supplemented with ipsilateral pedicle screws; cage supplemented with bilateral pedicle screws; cage supplemented with spinous process plate; and cage supplemented with a combination of lateral plate and spinous process plate. Intervertebral rotations were calculated, and ROM data were normalized to the intact ROM data. RESULTS: The stand-alone laterally inserted interbody cage significantly reduced ROM with respect to the intact state in flexion-extension (31.6% intact ROM, p < 0.001), lateral bending (32.5%, p < 0.001), and axial rotation (69.4%, p = 0.002). Compared with the stand-alone condition, addition of a lateral plate to the interbody cage did not significantly alter the ROM in flexion-extension (p = 0.904); however, it was significantly decreased in lateral bending and axial rotation (p < 0.001). The cage supplemented with a lateral plate was not statistically different from bilateral pedicle screws in lateral bending (p = 0.579). Supplemental fixation using a spinous process plate was not significantly different from bilateral pedicle screws in flexion-extension (p = 0.476). The combination of lateral plate and spinous process plate was not statistically different from the cage supplemented with bilateral pedicle screws in all the loading modes (p >= 0.365). CONCLUSIONS: A combination of lateral and spinous process plate fixation to supplement a laterally inserted interbody cage helps achieve rigidity in all motion planes similar to that achieved with bilateral pedicle screws. PMID- 24405465 TI - Comparative effectiveness of surgical versus nonoperative management of unilateral, nondisplaced, subaxial cervical spine facet fractures without evidence of spinal cord injury: clinical article. AB - OBJECT: Facet joints are major stabilizers of cervical motion allowing for effortless and pain-free multidimensional cervical spine movements without significant linear or rotational translation, thus minimizing any chance for spinal cord or nerve root impingement. Unilateral, nondisplaced subaxial facet fractures do not meet the conventional criteria for spinal instability under physiological loads. Limited evidence indicates that even with no or minimal displacement, 20%-80% of these fractures fail nonoperative management. The risk factors for instability in isolated nondisplaced subaxial facet fractures remain uncertain. In this retrospective study of prospectively collected data, the authors attempted to identify the predictors of failure in the management of isolated, nondisplaced subaxial facet fractures admitted to their Level I trauma center over a 10-year period. METHODS: Demographic, clinical, imaging, and follow up data for 25 patients with unilateral nondisplaced subaxial facet fractures who were managed surgically (n = 10) or nonoperatively (n = 15) were statistically analyzed. RESULTS: The mean age of the patients was 38 years, 19 were male, and 21 of the fractures were the result of either motor vehicle accidents or falls. The mean motor score on the American Spinal Injury Association scale was 99.2, and the mean Subaxial Injury Classification (SLIC) severity score was 3 (operated 3.5, nonoperated 2.3). Allen mechanistic classification included 22 compressive extension Stage 1 and 2 distractive-extension Stage 1 fractures. Subaxial facet fractures involved C-7 in 17 patients (68%), C-6 in 7 (28%), and C-3 in 1 (4%). The anatomical plane of fracture through the lateral mass was sagittal in 12 patients, axial in 8, and coronal in 3 patients. Nondisplaced floating lateral mass injuries were noted in 2 patients. The mean instability score, considering 7 components of the discoligamentous complex on MRI, was 3.2 (operated 3.6, nonoperated 3.0). Ten (40%) of 25 patients in this investigation did not have successful management, 9 in the nonoperated and 1 in the operated group (p = 0.018). Unsuccessful management was significantly greater in younger patients (p = 0.0008), possibly indicating selection bias (p = 0.07, Wilcoxon ranksum test). Fracture plane, instability, and SLIC scores did not play a significant role in treatment failure in this study. CONCLUSIONS: In this study, surgery was superior to nonoperative management of isolated, nondisplaced, or minimally displaced subaxial cervical spine facet fractures. PMID- 24405466 TI - Impact of age on the likelihood of reaching a minimum clinically important difference in 374 three-column spinal osteotomies: clinical article. AB - OBJECT: Spinal osteotomies for adult spinal deformity correction may include resection of all 3 spinal columns (pedicle subtraction osteotomy [PSO] and vertebral column resection [VCR]). The relationship between patient age and health-related quality of life (HRQOL) outcomes for patients undergoing major spinal deformity correction via PSO or VCR has not been well characterized. The goal of this study was to characterize that relationship. METHODS: This study was a retrospective review of 374 patients who had undergone a 3-column osteotomy (299 PSOs and 75 VCRs) and were part of a prospectively collected, multicenter adult spinal deformity database. The consecutively enrolled patients were drawn from 11 sites across the United States. Health-related QOL outcomes, according to the visual analog scale (VAS), Oswestry Disability Index (ODI), 36-Item Short Form Health Survey (SF-36, physical component score [PCS] and mental component score), and Scoliosis Research Society-22 questionnaire (SRS), were evaluated preoperatively and 1 and 2 years postoperatively. Differences and correlations between patient age and HRQOL outcomes were investigated. Age groupings included young (age <= 45 years), middle aged (age 46-64 years), and elderly (age >= 65 years). RESULTS: In patients who had undergone PSO, age significantly correlated (Spearman's correlation coefficient) with the 2-year ODI (rho = 0.24, p = 0.0450), 2-year SRS function score (rho = 0.30, p = 0.0123), and 2-year SRS total score (rho = 0.30, p = 0.0133). Among all patients (PSO+VCR), the preoperative PCS and ODI in the young group were significantly higher and lower, respectively, than those in the elderly. Among the PSO patients, the elderly group had much greater improvement than the young group in the 1- and 2-year PCS, 2-year ODI, and 2-year SRS function and total scores. Among the VCR patients, the young age group had much greater improvement than the elderly in the 1-year SRS pain score, 1-year PCS, 2-year PCS, and 2-year ODI. There was no significant difference among all the age groups as regards the likelihood of reaching a minimum clinically important difference (MCID) within each of the HRQOL outcomes (p > 0.05 for all). Among the PSO patients, the elderly group was significantly more likely than the young to reach an MCID for the 1-year PCS (61% vs 21%, p = 0.0077) and the 2-year PCS (67% vs 17%, p = 0.0054), SRS pain score (57% vs 20%, p = 0.0457), and SRS function score (62% vs 20%, p = 0.0250). Among the VCR patients, the young group was significantly more likely than the elderly patients to reach an MCID for the 1-year (100% vs 20%, p = 0.0036) and 2-year (100% vs 0%, p = 0.0027) PCS scores and 1-year (60% vs 0%, p = 0.0173) and 2-year (70% vs 0%, p = 0.0433) SRS pain scores. CONCLUSIONS: The PSO and VCR are not equivalent surgeries in terms of HRQOL outcomes and patient age. Among patients who underwent PSO, the elderly group started with more preoperative disability than the younger patients but had greater improvements in HRQOL outcomes and was more likely to reach an MCID at 1 and 2 years after treatment. Among those who underwent VCR, all had similar preoperative disabilities, but the younger patients had greater improvements in HRQOL outcomes and were more likely to reach an MCID at 1 and 2 years after treatment. PMID- 24405467 TI - Creation of false pedicles and a neo-pelvis for lumbopelvic reconstruction following en bloc resection of an iliosacral chondrosarcoma with lumbar spine extension: technical note. AB - En bloc resection with negative tumor margins remains the principal treatment option for control or cure of primary pelvic chondrosarcomas, as current adjuvant therapies remain ineffective. Iliosacral chondrosarcomas with involvement of the sciatic notch are sufficiently challenging tumors. However, when there is concomitant lumbar extension requiring resection of the pedicles to maintain negative surgical margins, transpedicular screw fixation is not possible, making reconstruction of the lumbopelvic junction extremely challenging. A patient with an iliosacral chondrosarcoma with lumbar spine extension is presented in this report to illustrate a novel lumbopelvic spinal construct. Following combined external pelvectomy and hemisacrectomy with contralateral L3-5 hemilaminectomy and ipsilateral pediculotomy, bicortical transvertebral body screws were substituted for the missing pedicles, resulting in the creation of "false pedicles," which were further supplemented with an autologous vascularized fibular strut graft from the amputated lower limb and applied to the lateral aspect of the vertebral bodies. The creation of false pedicles allowed for a robust reconstruction of the lumbopelvic junction, including maintaining pelvic ring integrity with a "neo-pelvis", creating a functional load-bearing construct adequate for early mobilization and ambulation. The biomechanical dynamics of this unique construct are also discussed. PMID- 24405468 TI - Solvation of lithium salts in protic ionic liquids: a molecular dynamics study. AB - The structure of solutions of lithium nitrate in a protic ionic liquid with a common anion, ethylammonium nitrate, at room temperature is investigated by means of molecular dynamics simulations. Several structural properties, such as density, radial distribution functions, hydrogen bonds, spatial distribution functions, and coordination numbers, are analyzed in order to get a picture of the solvation of lithium cations in this hydrogen-bonded, amphiphilically nanostructured environment. The results reveal that the ionic liquid mainly retains its structure upon salt addition, the interaction between the ammonium group of the cation and the nitrate anion being only slightly perturbed by the addition of the salt. Lithium cations are solvated by embedding them in the polar nanodomains of the solution formed by the anions, where they coordinate with the latter in a solid-like fashion reminiscent of a pseudolattice structure. Furthermore, it is shown that the average coordination number of [Li](+) with the anions is 4, nitrate coordinating [Li](+) in both monodentate and bidentate ways, and that in the second coordination layer both ethylammonium cations and other lithiums are also found. Additionally, the rattling motion of lithium ions inside the cages formed by their neighboring anions, indicative of the so-called caging effect, is confirmed by the analysis of the [Li](+) velocity autocorrelation functions. The overall picture indicates that the solvation of [Li](+) cations in this amphiphilically nanostructured environment takes place by means of a sort of inhomogeneous nanostructural solvation, which we could refer to as nanostructured solvation, and which could be a universal solvation mechanism in ionic liquids. PMID- 24405469 TI - Predicting 10-year quality-of-life outcomes of patients with schizophrenia and schizoaffective disorders. AB - AIMS: This study aimed to determine predictors for 10-year good versus poor perceived general quality of life (QOL) outcomes from baseline variables in people with schizophrenia and schizoaffective disorder. METHODS: We compared patients with poor versus good 10-year QOL outcomes using baseline clinical, personality-related variables, demographic and background characteristics. Logistic regression analysis was used for predicting the 10-year QOL outcomes from baseline data. One-hundred-eight patients completed the Quality-of-Life Enjoyment and Life Satisfaction Questionnaire, the Positive and Negative Syndromes Scale (PANSS), the Talbieh Brief Distress Inventory, and psychosocial questionnaires at baseline and 10 years later. RESULTS: Logistic regression revealed six predictors of QOL outcomes: paranoid ideations (odds ratio [OR] 3.1), PANSS general psychopathology (OR 1.1), obsessiveness (OR 0.84), hostility (OR 0.4), PANSS positive scale scores (OR 0.4), and general QOL index (OR 0.4). This model classified 80.6% of the sample with good sensitivity (87% correctly identified 'poor outcome'), and specificity (71% correctly identified 'good outcome'). CONCLUSION: This study provides a pattern of baseline predictors for long-term QOL outcomes. Identified predictors are factors that can potentially be ameliorated, and thereby enhance the QOL of people with schizophrenia and schizoaffective disorder. PMID- 24405470 TI - Doxorubicin and lapatinib combination nanomedicine for treating resistant breast cancer. AB - Our objective was to design a polymeric micelle-based doxorubicin and lapatinib combination therapy for treating multidrug resistant (MDR) breast cancers. Poly(ethylene glycol)-block-poly(2-methyl-2-benzoxycarbonylpropylene carbonate) (PEG-PBC) polymers were synthesized for preparing doxorubicin and lapatinib loaded micelles using a film dispersion method. Micelles were characterized by determining critical micelle concentration (CMC), particle size distribution, and drug loading. The anticancer effects were determined in vitro with MTT assays as well as with lactate dehydrogenase (LDH) release studies. In addition, the cellular uptake of drug-loaded micelles was determined with fluorescence microscopy and flow cytometry. Finally, in vivo anticancer activity and tolerance of developed formulations were evaluated in resistant breast tumor bearing mice. PEG5K-PBC7K polymer synthesized in this study had a low CMC value (1.5 mg/L) indicating an excellent dynamic stability. PEG-PBC micelles could efficiently load both doxorubicin and lapatinib drugs with a loading density of 21% and 8.4%, respectively. The mean particle size of these micelles was 100 nm and was not affected by drug loading. The use of lapatinib as an adjuvant sensitized drug resistant MCF-7/ADR cells to doxorubicin treatment. Cellular uptake studies showed enhanced doxorubicin accumulation in MCF-7/ADR cells in the presence of lapatinib. The doxorubicin and lapatinib combination therapy showed a significant decrease in tumor growth compared to doxorubicin monotherapy. In conclusion, we have developed PEG-PBC micelle formulations for the delivery of doxorubicin and lapatinib. The combination therapy of doxorubicin plus lapatinib has a great potential for treating MDR breast cancer. PMID- 24405471 TI - In vitro effect of cortisol and urotensin I on arginine vasotocin and isotocin secretion from pituitary cells of gilthead sea bream Sparus aurata. AB - This study aimed at determining whether in vitro secretion of two neuropeptides, arginine vasotocin (AVT) and isotocin (IT), from pituitary cells of gilthead sea bream Sparus aurata was affected by cortisol and urotensin (UI). Pituitary cells were exposed to 1.4 * 10(-8) , 1.4 * 10(-7) and 0.4 * 10(-6) M cortisol and 10( 12) , 10(-10) and 10(-8) M UI for 6, 24 and 48 h, respectively. AVT and IT contents were determined in the culture media by high-performance liquid chromatography (HPLC). An increase in AVT secretion and a decrease in IT secretion were observed at all cortisol doses. UI increased AVT secretion after 6 h of incubation at all doses. After 24 h, however, only the highest dose of UI still displayed an effect. IT secretion was not influenced by UI. It was thus demonstrated that cortisol does influence AVT and IT secretion from S. aurata pituitary cells, while UI regulates AVT secretion, as a component of hypothalamic pituitary-interrenal (HPI) axis in this species. PMID- 24405474 TI - Prognostic impact of young age on stage IV prostate cancer treated with primary androgen deprivation therapy. AB - OBJECTIVES: To elucidate whether the disease characteristics and prognosis of stage IV prostate cancer treated with primary androgen deprivation therapy differ between young and elderly patients. METHODS: A total of 3006 patients identified from the database of the Japan Study Group of Prostate Cancer were included in the analysis according to the following entry criteria: age of 75 years or less and stage IV disease. These patients were stratified into three groups: young (aged <= 55 years); middle-aged (aged ? 56 and <= 65 years); and elderly (aged ? 66 and <= 75 years). Their prognoses were analyzed both within age groups and according to whether or not there was metastasis. RESULTS: The proportion of lymph node metastasis was significantly higher in the young group than in the elderly group (P = 0.007), and there were no significant differences in other factors among age groups. The overall survival rate at 5 years in the young group was significantly worse than that in the middle-aged and elderly groups (26.6%, 59.7% and 55.3%, respectively) in patients with stage IV disease with metastasis, although there was no difference among age groups in patients with stage IV disease without metastasis. Multivariate analysis showed that younger age was an independent strong prognostic factor in stage IV disease with metastasis. CONCLUSIONS: Young men with metastatic prostate cancer have a poor prognosis. Young age is an independent prognostic factor in stage IV metastatic prostate cancer patients treated with primary androgen deprivation therapy. PMID- 24405477 TI - Portable, universal, and visual ion sensing platform based on the light emitting diode-based self-referencing-ion selective field-effect transistor. AB - In this work, a novel and universal ion sensing platform was presented, which enables the visual detection of various ions with high sensitivity and selectivity. Coaxial potential signals (millivolt-scale) of the sample from the self-referencing (SR) ion selective chip can be transferred into the ad620-based amplifier with an output of volt-scale potentials. The amplified voltage is high enough to drive a light emitting diode (LED), which can be used as an amplifier and indicator to report the sample information. With this double amplification device (light emitting diode-based self-referencing-ion selective field-effect transistor, LED-SR-ISFET), a tiny change of the sample concentration can be observed with a distinguishable variation of LED brightness by visual inspection. This LED-based luminescent platform provided a facile, low-cost, and rapid sensing strategy without the need of additional expensive chemiluminescence reagent and instruments. Moreover, the SR mode also endows this device excellent stability and reliability. With this innovative design, sensitive determination of K(+), H(+), and Cl(-) by the naked eye was achieved. It should also be noticed that this sensing strategy can easily be extended to other ions (or molecules) by simply integrating the corresponding ion (or molecule) selective electrode. PMID- 24405478 TI - L-3,4-Dihydroxy-6-[F-18]fluorophenylalanine positron emission tomography demonstrating dopaminergic system abnormality in the brains of obsessive compulsive disorder patients. AB - AIM: Obsessive-compulsive disorder (OCD) is a chronic disabling neuropsychiatric disorder. Current treatment modalities, such as pharmacological and behavioral methods, are sometimes unsatisfactory. The mesolimbic dopaminergic pathway is supposed to have a role in the pathogenesis of OCD. In this study, L-3,4 Dihydroxy-6-[F-18]fluorophenylalanine (F-18 FDOPA) positron emission tomography (PET) is exploited to investigate the possible abnormality of dopaminergic neuronal circuits in the brains of OCD patients in vivo. METHODS: The study subjects were recruited after psychological assessment and gave written informed consent to participate. The F-18 FDOPA PET scans were performed on five OCD patients and six healthy volunteers at 120 min after 185 MBq of F-18 FDOPA intravenous injection. The PET results were analyzed with the Statistical Parametric Mapping tool. RESULTS: Compared to the healthy subjects, the OCD brains showed increased dopaminergic metabolism in the left frontal premotor cortex (P < 0.001), along with trends toward an increase in the left posterior cingulate gyrus, the left cuneus, the left lingual gyrus, the right cuneus and precuneus, the right lingual gyrus, the right middle temporal gyrus, the left cerebellum, and the right cerebellum (P < 0.01). CONCLUSION: Our observations suggest that the increased dopaminergic neuronal function in these brain areas may be implicated in the pathogenesis of OCD. PMID- 24405479 TI - A new allele, HLA-DQB1*05:50, identified by sequence-based typing in a Korean individual. AB - The new allele DQB1*05:50 showed one nucleotide difference with DQB1*05:03:01:01 at codon 39 (CGC/CAC). PMID- 24405482 TI - A highly sensitive fluorescent indicator dye for calcium imaging of neural activity in vitro and in vivo. AB - Calcium imaging of individual neurons is widely used for monitoring their activity in vitro and in vivo. Synthetic fluorescent calcium indicator dyes are commonly used, but the resulting calcium signals sometimes suffer from a low signal-to-noise ratio (SNR). Therefore, it is difficult to detect signals caused by single action potentials (APs) particularly from neurons in vivo. Here we showed that a recently developed calcium indicator dye, Cal-520, is sufficiently sensitive to reliably detect single APs both in vitro and in vivo. In neocortical neurons, calcium signals were linearly correlated with the number of APs, and the SNR was > 6 for in vitro slice preparations and > 1.6 for in vivo anesthetised mice. In cerebellar Purkinje cells, dendritic calcium transients evoked by climbing fiber inputs were clearly observed in anesthetised mice with a high SNR and fast decay time. These characteristics of Cal-520 are a great advantage over those of Oregon Green BAPTA-1, the most commonly used calcium indicator dye, for monitoring the activity of individual neurons both in vitro and in vivo. PMID- 24405484 TI - Corrigendum. PMID- 24405485 TI - Psychometric properties of the mother and father compulsive caregiving scales: a brief measure of current young adult caregiving behaviors toward parents. AB - This study assessed the psychometric properties of the Mother and Father Compulsive Caregiving Scales (MFCC). Exploratory (N = 1283, 71.5% Caucasian) and confirmatory (N = 2203, 76.6% Caucasian) factor analyses revealed two-factor structures for each parent: burden and autonomy. Correlational analyses with retrospective self-reports of parent-child relationship quality, family risk indicators, and psychological symptoms demonstrated similar convergent validity for both mother and father burden factors while, interestingly, the findings for mother and father autonomous factors showed different patterns. Results support that the MFCC is a short and convenient measure that would be clinically useful for the assessment of controlling/caregiving behaviors in young adulthood. PMID- 24405483 TI - Listeria monocytogenes antagonizes the human GTPase Cdc42 to promote bacterial spread. AB - The bacterial pathogen Listeria monocytogenes uses actin-based motility to spread from infected human cells to surrounding healthy cells. Cell-cell spread involves the formation of thin extensions of the host plasma membrane ('protrusions') containing motile bacteria. In cultured enterocytes, the Listeria protein InlC promotes protrusion formation by binding and antagonizing the human scaffolding protein Tuba. Tuba is a known activator of the GTPase Cdc42. In this work, we demonstrate an important role for Cdc42 in controlling Listeria spread. Infection of the enterocyte cell line Caco-2 BBE1 induced a decrease in the level of Cdc42 GTP, indicating that Listeria downregulates this GTPase. Genetic data involving RNA interference indicated that bacterial impairment of Cdc42 may involve inhibition of Tuba. Experiments with dominant negative and constitutively activated alleles of Cdc42 demonstrated that the ability to inactivate Cdc42 is required for efficient protrusion formation by Listeria. Taken together, these findings indicate a novel mechanism of bacterial spread involving pathogen induced downregulation of host Cdc42. PMID- 24405486 TI - Barriers and promoters of participation in facilitated peer support groups for carers of children with special needs. AB - BACKGROUND: Social support is essential for physical and mental health and well being. Evidence indicates that social and peer support is particularly important and beneficial for the well-being of those who care for children with chronic illness or disability in improving personal well-being and influencing parent child play opportunities and child behaviour and development positively. MyTime is a government-funded Australia-wide facilitated peer support group program for carers of children with special needs. AIM: The aim was to investigate the barriers and promoters of participation in this peer support group program. METHOD: A qualitative approach was adopted where semi-structured telephone interviews were conducted with 20 group members, four group facilitators and three play helpers. Interviews were recorded and transcribed. Inductive thematic analysis of the transcripts was conducted. RESULTS: Most group members described gaining significant social support from group participation. Good group facilitation, the availability of play helpers, access to disability-related information and expertise, and the mutual exchange of support between members emerged as the most important promoters of group participation. Barriers included insufficient funding to run the program throughout the year, too much diversity in group members' socio-economic position and severity of their children's disability. CONCLUSION: The facilitated peer support group program described in this paper appears to confer significant benefits to carers of children with disabilities and may be a model for other nations to consider in their strategies to improve services for carers of children with special needs. PMID- 24405487 TI - Proton transport in Clostridium pasteurianum [FeFe] hydrogenase I: a computational study. AB - To better understand the proton transport through the H2 production catalysts, the [FeFe] hydrogenases, we have undertaken a modeling and simulation study of the proton transfer processes mediated by amino acid side-chain residues in hydrogenase I from Clostridium pasteurianum. Free-energy calculation studies show that the side chains of two conserved glutamate residues, Glu-279 and Glu-282, each possess two stable conformations with energies that are sensitive to protonation state. Coordinated conformational changes of these residues can form a proton shuttle between the surface Glu-282 and Cys-299, which is the penultimate proton donor to the catalytic H-cluster. Calculated acid dissociation constants are consistent with a proton relay connecting the H-cluster to the bulk solution. The complete proton-transport process from the surface-disposed Glu-282 to Cys-299 is studied using coupled semiempirical quantum-mechanical/classical mechanical dynamics. Two-dimensional free-energy maps show the mechanisms of proton transport, which involve Glu-279, Ser-319, and a short internal water relay to connect functionally Glu-282 with the H-cluster. The findings of conformational bistability, PT event coupling with pKa mismatch, and water participation have implications in the design of artificial water reduction or general electrocatalytic H2-production catalysts. PMID- 24405490 TI - Comparative biophysical properties of tenofovir-loaded, thiolated and nonthiolated chitosan nanoparticles intended for HIV prevention. AB - AIM: This study is designed to test the hypothesis that tenofovir-loaded (an anti HIV microbicide) chitosan-thioglycolic acid-conjugated (CS-TGA) nanoparticles (NPs) exhibit superior biophysical properties for mucoadhesion compared with those of native CS NPs. MATERIALS & METHODS: The NPs are prepared by ionotropic gelation. The particle mean diameter, encapsulation efficiency and release profile are analyzed by dynamic light scattering and UV spectroscopy, respectively. The cytotoxicity, cellular uptake and uptake mechanism are assessed on VK2/E6E7 and End1/E6E7 cell lines by colorimetry/fluorimetry, and percentage mucoadhesion is assessed using porcine vaginal tissue. RESULTS: The mean diameter of the optimal NP formulations ranges from 240 to 252 nm, with a maximal encapsulation efficiency of 22.60%. Tenofovir release from CS and CS-TGA NPs follows first-order and Higuchi models, respectively. Both NPs are noncytotoxic in 48 h. The cellular uptake, which is time dependent, mainly occurs via the caveolin-mediated pathway. The percentage of mucoadhesion of CS-TGA NPs is fivefold higher than that of CS NPs, and reached up to 65% after 2 h. CONCLUSION: Collectively, CS-TGA NPs exhibit superior biophysical properties and can potentially maximize the retention time of a topical microbicide, such as tenofovir, intended for the prevention of HIV transmission. PMID- 24405491 TI - Glucokinase gene mutations (MODY 2) in Asian Indians. AB - BACKGROUND AND AIM: Heterozygous inactivating mutations in the glucokinase (GCK) gene cause a hyperglycemic condition termed maturity-onset diabetes of the young (MODY) 2 or GCK-MODY. This is characterized by mild, stable, usually asymptomatic, fasting hyperglycemia that rarely requires pharmacological intervention. The aim of the present study was to screen for GCK gene mutations in Asian Indian subjects with mild hyperglycemia. SUBJECTS AND METHODS: Of the 1,517 children and adolescents of the population-based ORANGE study in Chennai, India, 49 were found to have hyperglycemia. These children along with the six patients referred to our center with mild hyperglycemia were screened for MODY 2 mutations. The GCK gene was bidirectionally sequenced using BigDye((r)) Terminator v3.1 (Applied Biosystems, Foster City, CA) chemistry. In silico predictions of the pathogenicity were carried out using the online tools SIFT, Polyphen-2, and I-Mutant 2.0 software programs. RESULTS: Direct sequencing of the GCK gene in the patients referred to our Centre revealed one novel mutation, Thr206Ala (c.616A>G), in exon 6 and one previously described mutation, Met251Thr (c.752T>C), in exon 7. In silico analysis predicted the novel mutation to be pathogenic. The highly conserved nature and critical location of the residue Thr206 along with the clinical course suggests that the Thr206Ala is a MODY 2 mutation. However, we did not find any MODY 2 mutations in the 49 children selected from the population-based study. Hence prevalence of GCK mutations in Chennai is <1:1,517. CONCLUSIONS: This is the first study of MODY 2 mutations from India and confirms the importance of considering GCK gene mutation screening in patients with mild early-onset hyperglycemia who are negative for beta-cell antibodies. PMID- 24405492 TI - Hypoglycemia begets hypoglycemia: the order effect in the ASPIRE in-clinic study. AB - BACKGROUND: The ASPIRE in-clinic study established that automatic suspension of insulin with the threshold suspend (TS) feature reduces the duration of induced hypoglycemia. The study's crossover design allowed the effects of antecedent hypoglycemia to be studied. SUBJECTS AND METHODS: The study enrolled 50 subjects who exercised until plasma glucose (YSI glucose and lactate analyzer; YSI, Inc., Yellow Springs, OH) reached <=85 mg/dL. Hypoglycemia was evaluated after the YSI value reached <70 mg/dL. In TS experiments, insulin was stopped for 2 h once a sensor glucose (SG) value of <=70 mg/dL was detected; in control experiments, basal insulin delivery continued. Subjects were randomly assigned to Group A (TS in Period 1; control in Period 2) or Group B (control in Period 1; TS in Period 2). Experiments were separated by 3-10 days. RESULTS: Hypoglycemia was 63.7 min shorter in Period 1 TS experiments (no preceding control experiment) than in Period 2 TS experiments (one or more preceding control experiment(s)) (P<0.01). The number of experiments prior to a successful TS experiment was lower for Period 1 than for Period 2 (0.36 +/- 0.64 vs. 1.57 +/- 0.84; P<0.001), as was the cumulative duration of antecedent hypoglycemia (16.6 min vs. 204.6 min; P<0.001). The between-groups difference in hypoglycemia duration was not attributable to differences in SG rates of change, the duration of exercise, or area under the curve of <70 mg/dL * min in the 2 days before the successful experiment (all P>0.3). CONCLUSIONS: The TS feature's ability to mitigate hypoglycemia was decreased by an episode or episodes of prolonged antecedent hypoglycemia, suggesting hypoglycemia begets hypoglycemia. The effect of antecedent hypoglycemia should be taken into consideration in the design of future experiments assessing strategies to reduce hypoglycemia. PMID- 24405493 TI - Changes in PR and QTc intervals after switching from olanzapine to risperidone in patients with stable schizophrenia. AB - AIM: We examined the difference between the effects of olanzapine (OLZ) and risperidone (RIS) on PR and QT intervals among patients with stable schizophrenia using a cohort analysis. METHODS: Twenty-one subjects treated with OLZ were enrolled in the study. Following baseline assessments, which included PR and QT intervals, OLZ was switched to RIS for each subject. The same parameters were evaluated following the switch to RIS. RESULTS: All patients who had been treated with OLZ were successfully switched to RIS. In all patients, we observed a significant decrease in PR interval (t = 2.397, P = 0.029) and no change in either QTc or RR interval. In female patients, the QTc interval was significantly decreased (t = 3.495, P = 0.008) following the switch, while in male patients, the QTc interval did not change. No patients showed a PR interval of >200 ms or a QTc interval of >500 ms. CONCLUSION: OLZ treatment has a greater prolonging effect on PR and QT intervals compared with RIS. Careful attention may need to be paid to the cardiac conduction system in addition to QT prolongation during OLZ treatment. PMID- 24405494 TI - Editorial comment to Efficacy and safety of once-daily oxybutynin patch versus placebo and propiverine in Japanese patients with overactive bladder: a randomized double-blind trial. PMID- 24405495 TI - Identification of the KIR3DL1*0050105 allele by sequence-based techniques. AB - KIR3DL1*0050105 differs from KIR3DL1*0050101 with two nucleotide substitutions at 6709(C > T) and 13398 (G > A) in introns 5 and 7, respectively. PMID- 24405496 TI - Conversion disorder in children and adolescents: a disorder of cognitive control. AB - OBJECTIVE: To assess cognitive function in children and adolescents presenting with acute conversion symptoms. METHODS: Fifty-seven participants aged 8.5-18 years (41 girls and 16 boys) with conversion symptoms and 57 age- and gender matched healthy controls completed the IntegNeuro neurocognitive battery, an estimate of intelligence, and self-report measures of subjective emotional distress. RESULTS: Participants with conversion symptoms showed poorer performance within attention, executive function, and memory domains. Poorer performance was reflected in more errors on specific tests: Switching of Attention (t(79) = 2.17, p = .03); Verbal Interference (t(72) = 2.64, p = .01); Go/No-Go (t(73) = 2.20, p = .03); Memory Recall and Verbal Learning (interference errors for memory recall; t(61) = 3.13, p < .01); and short-delay recall (t(75) = 2.05, p < .01) and long-delay recall (t(62) = 2.24, p = .03). Poorer performance was also reflected in a reduced span of working memory on the Digit Span Test for both forward recall span (t(103) = -3.64, p < .001) and backward recall span (t(100) = -3.22, p < .01). There was no difference between participants and controls on IQ estimate (t(94) = -589, p = .56), and there was no correlation between cognitive function and perceived distress. CONCLUSIONS: Children and adolescents with acute conversion symptoms have a reduced capacity to manipulate and retain information, to block interfering information, and to inhibit responses, all of which are required for effective attention, executive function, and memory. PMID- 24405497 TI - Dabigatran versus warfarin in patients with mechanical heart valves: reply. PMID- 24405501 TI - Fibrosing mediastinitis mimicking sarcoidosis. AB - Fibrosing mediastinitis (FM), also called sclerosing mediastinitis or mediastinal fibrosis, is a rare disease characterized by excessive fibrotic reaction in the mediastinum and may compromise the airway, the great vessels and other mediastinal structures, with a morbidity directly related to the location and extent of fibrosis. The cause is not always known but is often the result of a granulomatous disease, most often the histoplasmosis. We report a 43-year-old woman with a history of tuberculosis infection 23 years ago. She attended the pulmonology clinic for cough and dyspnea. Physical examination revealed jugular venous distention at 90 degrees . In computed tomography scan of the chest with contrast (c/c), we observed a mediastinal nodal cast provoking cava compression and obliteration of main and intermediary right lobar bronchus. The pathological examination was FM. PMID- 24405504 TI - Prioritization of natural extracts by LC-MS-PCA for the identification of new photosensitizers for photodynamic therapy. AB - Photodynamic therapy (PDT) is an alternative treatment for cancer that involves administration of a photosensitive drug or photosensitizer that localizes at the tumor tissue followed by in situ excitation at an appropriate wavelength of light. Tumour tissues are then killed by cytotoxic reactive oxygen species generated by the photosensitizer. Targeted excitation and photokilling of affected tissues is achieved through focal light irradiation, thereby minimizing systemic side effects to the normal healthy tissues. Currently, there are only a small number of photosensitizers that are in the clinic and many of these share the same structural core based on cyclic tetrapyrroles. This paper describes how metabolic tools are utilized to prioritize natural extracts to search for structurally new photosensitizers from Malaysian biodiversity. As proof of concept, we analyzed 278 photocytotoxic extracts using a hyphenated technique of liquid chromatography-mass spectrometry coupled with principal component analysis (LC-MS-PCA) and prioritized 27 extracts that potentially contained new photosensitizers for chemical dereplication using an in-house UPLC-PDA-MS Photocytotoxic assay platform. This led to the identification of 2 new photosensitizers with cyclic tetrapyrrolic structures, thereby demonstrating the feasibility of the metabolic approach. PMID- 24405505 TI - Clinical features of patients with designer-drug-related disorder in Japan: a comparison with patients with methamphetamine- and hypnotic/anxiolytic-related disorders. AB - AIM: The aim of this study was to clarify the clinical features of designer-drug abusing patients through comparisons with methamphetamine-abusing patients and hypnotics/anxiolytics-abusing patients. METHODS: Information on 126 designer-drug abusing patients, 138 methamphetamine-abusing patients, and 87 hypnotics/anxiolytics-abusing patients was extracted from the 2012 database of 'The Nationwide Mental Hospital Survey on Drug-related Psychiatric Disorders' and the clinical variables of designer-drug-abusing patients compared with those of the other two groups. RESULTS: Multivariate analysis indicated the following significant differences between designer-drug-abusing patients and the other two types of patients: designer-drug-abusing patients were younger, included more men, had higher education and fewer relationships with antisocial groups, and included more patients meeting ICD-10 F1 sub-classification categories of 'Harmful use' and 'Psychotic disorders' than methamphetamine-abusing patients. Compared with hypnotics/anxiolytics-abusing patients, designer-drug-abusing patients were younger, included more men and more patients meeting criteria for 'Psychotic disorders', and more frequently cited 'peer pressure', 'unable to refuse', and 'seeking stimulation' as reasons for using the drug. CONCLUSION: The advent of designer drugs has created a new class of drug abuse, and abuse of designer drugs may carry a strong psychosis-inducing risk, exceeding that of methamphetamine. PMID- 24405506 TI - Trans-corneal reduction of anterior lens luxation in dogs with lens instability: a retrospective study of 19 dogs (2010-2013). AB - OBJECTIVE: To evaluate the success rate and outcome of trans-corneal reduction of anterior lens luxation (TR-ALL) in dogs with lens instability. ANIMALS STUDIED: Nineteen dogs with anterior lens luxation. PROCEDURES: Medical records of dogs with anterior lens luxation (ALL) were reviewed: dogs were included if TR-ALL was performed followed by medical therapy in the form of topical 0.005% latanoprost ophthalmic solution. The duration of ALL, vision status, ophthalmic examination abnormalities, reason for performing TR-ALL and details of TR-ALL were recorded. Success rate for TR-ALL as well as postprocedure complications were also assessed. RESULTS: Twenty eyes from 19 dogs met the inclusion criteria. Median age was 6.5 years (0.3-15 years) and 47% were terriers (9/19). Successful TR-ALL was achieved in 85% of eyes (17/20); failure was attributed to posterior synechia or vitreous expansion. Short-term complications included corneal ulceration (2/20) and anterior uveitis (3/20); recurrence of anterior luxation occurred in only one dog. Median follow-up for visual eyes (11) following successful TR-ALL was 353 days (range of 1 to 1182 days). Vision was retained in 54.5% (6/11) of eyes with a median time to vision loss of 12 months as a result of glaucoma or presumed retinal detachment. CONCLUSIONS: Trans-corneal reduction of ALL provides a non-surgical alternative to intracapsular lens extraction (visual eyes) or enucleation (nonvisual eyes) in dogs. Long-term visual outcome of TR-ALL is comparable to intracapsular lens extraction for ALL. PMID- 24405507 TI - Modeling trajectories of perceived leg exertion during maximal cycle ergometer exercise in children and adolescents. AB - BACKGROUND: Borg developed scales for rating pain and perceived exertion in adults that have also been used in pediatric populations. Models describing functional relationships between perceived exertion and work capacity have not been studied in children. We compared different models and their fits to individual trajectories and assessed the variability in these trajectories. METHODS: Ratings of perceived exertion (RPE) were collected from 79 children. Progressive cycle ergonometric testing was performed to maximal work capacity with test duration ranging from 6- 12 minutes. Ratings were obtained during each 1-minute increment. Work was normalized to individual maximal work capacity (Wmax). A delay was defined as the fraction of Wmax at which point an increase in ratings of leg fatigue occurred. Such a delay term allows the characterization of trajectories for children whose ratings were initially constant with increasing work. Two models were considered, a delay model and a power model that is commonly used to analyze Borg ratings. Individual model fit was assessed with root mean squared error (RMSE). Functional clustering algorithms were used to identify patterns. RESULTS: Leg tiredness developed quickly for some children while for others there was a delay before an in- creased ratings of leg exertion occurred with increasing work. Models for individual trajectories with the smallest RMSE included a delay and a quadratic term (quadratic-delay model), or a power function and a delay term (power-delay model) compared to a simple power function. The median delay was 40% Wmax (interquartile range (IQR): 26-49%) in a quadratic-delay model, while the median exponent was 1.03 (IQR: 0.83-1.78) in a power-delay model. Nine clusters were identified showing linear or quadratic patterns with or without a delay. Cluster membership did not depend on age, gender or diagnosis. CONCLUSION: Children and adolescents vary widely in their capacity to rate their perceptions and exhibit different functional relationships between ratings of perceived exertion and work capacity normalized across individuals. Models including a delay term, a linear component, or a power function can describe these individual trajectories of perceived leg exertion during incremental exercise to voluntary exhaustion. PMID- 24405508 TI - miR-20b regulates expression of proteinase-activated receptor-1 (PAR-1) thrombin receptor in melanoma cells. AB - The proteinase-activated receptor 1 (PAR-1) plays a central role in melanoma progression and its expression level is believed to correlate with the degree of cancer invasiveness. Here, we show that PAR-1 is post-transcriptionally regulated by miR-20b microRNA in human melanoma cells. PAR-1 was found to be expressed in metastatic melanoma cells but was barely detectable in primary melanoma. By transducing primary melanoma cells with a lentivirus containing a 3'-UTR construct of PAR-1 mRNA, we could show that endogenous melanoma microRNAs interacted with PAR-1 3'-UTR and silenced a fused luciferase reporter. Transfection of an inhibitor against miR-20b into primary melanoma cells reversed this process. Finally, transfection of miR-20b mimic into metastatic melanoma cells caused downregulation of the luciferase reporter. We conclude that miR-20b regulates expression of melanoma PAR-1 receptor, which may explain the differential expression of PAR-1 observed in human melanoma. PMID- 24405509 TI - Influence of health behaviours on the incidence of infection and allergy in adolescents: the AFINOS cross-sectional study. AB - BACKGROUND: Some health behaviours are liable to affect the incidence of allergies and/or common infections in young people; however, the extent and ways in which these might occur are mostly unknown. This study examines the association of health behaviours related to physical activity, sedentariness, diet and sleep with allergy and infection symptoms in adolescents, and also with biological markers that might mediate disease incidence. METHODS: The study comprised a total of 2054 adolescents (50.7% girls) from the Madrid region of Spain. The incidence of infection and allergy symptoms three months prior to the study was obtained from a self-administered questionnaire. Physical and sedentary activities, height and weight, food habits and sleep duration were also self reported and their influence on infection and allergy incidence was assessed by logistic regression analysis. Blood biomarkers (IgE, eosinophil percentage, leptin, interleukin (IL)-2, IL-4, IL-5 and IL-10) were evaluated in a subsample of 198 subjects. RESULTS: Adequate sleep duration (OR = 0.79, 95%CI: 0.64 to 0.97) and unhealthy weight status (overweight/obesity) (OR = 1.35, 95%CI: 1.04 1.74) were independently associated with decreased and increased allergy incidence, respectively. No significant association was observed with infection incidence. IgE and leptin differed between adolescents with and without allergy symptoms. In regression models IgE was significantly associated with inadequate sleep duration and leptin with weight status. CONCLUSION: Excess weight and inadequate sleep duration are independently associated with the incidence of allergy symptoms in adolescents. Adequate sleep duration and weight during adolescence might be relevant for a decreased risk of suffering allergy symptoms. PMID- 24405510 TI - Inoculation of the nonlegume Capsicum annuum L. with Rhizobium strains. 2. Changes in sterols, triterpenes, fatty acids, and volatile compounds. AB - Peppers (Capsicum spp.) are consumed worldwide, imparting flavor, aroma, and color to foods, additionally containing high concentrations of biofunctional compounds. This is the first report about the effect of the inoculation of two Rhizobium strains on sterols, triterpenes, fatty acids, and volatile compounds of leaves and fruits of pepper (Capsicum annuum L.) plants. Generally, inoculation with strain TVP08 led to the major changes, being observed a decrease of sterols and triterpenes and an increase of fatty acids, which are related to higher biomass, growth, and ripening of pepper fruits. The increase of volatile compounds may reflect the elicitation of plant defense after inoculation, since the content on methyl salicylate was significantly increased in inoculated material. The findings suggest that inoculation with Rhizobium strains may be employed to manipulate the content of interesting metabolites in pepper leaves and fruits, increasing potential health benefits and defense abilities of inoculated plants. PMID- 24405511 TI - The competition of sigma-hole...Cl(-) and pi-hole...Cl(-) bonds between C6F5X (X = F, Cl, Br, I) and the chloride anion and its potential application in separation science. AB - On the basis of the varying amplitude and patterns of the (19)F NMR chemical shift of C6F5X (X = F, Cl, Br, I) in the presence of chloride anions, bonding models of C6F5X.Cl(-) complexes were tentatively established, and the relevant binding constants were obtained. Interaction models were also simulated using computational chemistry. The theoretical computations were found to be highly consistent with the results of the experiments. The results show that C6F5Br/C6F5I and Cl(-) were prone to forming C-I/Br...Cl(-) sigma-hole bonding complexes with the (19)F NMR signal shifting to higher fields, and the interaction strength of the C6F5I...Cl(-) sigma-hole bond was larger than that of C6F5Br...Cl(-); C6F6/C6F5Cl and Cl(-) formed pi-hole...Cl(-) bonding complexes with the signal shifting to lower fields, and the interaction strength of C6F6 was larger than that of C6F5Cl. The binding constant of the C6F5I...Cl(-) sigma hole bonding complex is 38.0 M(-1), which is nearly 165- to 345-fold larger than that of the other C6F5X.Cl(-) complexes. On the basis of the above results, solid phase extraction experiments were designed, and the results demonstrated the potential applicability of the C-I...Cl(-) sigma-hole bond in separation science. PMID- 24405512 TI - Challenges facing providers of imported malaria-related healthcare services for Africans visiting friends and relatives (VFRs). AB - BACKGROUND: In many non-malarious countries, imported malaria disproportionately affects Africans visiting friends and relatives (VFRs). Most previous research has focused on understanding the knowledge, attitudes and practices of these travellers, but has not examined the quality of prevention, diagnosis and treatment services provided. The aim of this study was to understand the perspective of providers of malaria-related healthcare services to VFRs about factors impacting on the quality of these and to make recommendations about improvements. METHODS: Thirty semi-structured interviews were conducted with practice nurses providing pre-travel health advice (n = 10), general practitioners (GPs) (n = 10), hospital consultants (n = 3), and community pharmacists (n = 7) working in areas of London with large African communities and a relatively high burden of imported malaria. A thematic analysis of the results was undertaken. RESULTS: Time constraints in GPs' surgeries and competing priorities, lack of confidence in issuing advice on mosquito avoidance, the cost of chemoprophylaxis and travel at short notice prevented the provision of adequate malaria prevention advice. Long GP waiting times, misdiagnoses, lack of disclosure by VFRs about recent travel, and the issue of where malaria treatment should be provided were raised as potential barriers to diagnosis and treatment. CONCLUSIONS: Some issues raised by respondents are relevant to all travellers, irrespective of their reason for travel. The challenge for healthcare providers to reduce the burden of imported malaria in VFRs is to provide services of sufficient quality to persuade them to adopt these in preference to those with which they may be familiar in their country of birth. Although no single intervention will significantly lower the burden of imported malaria, addressing the issues raised in this research could make a significant impact. PMID- 24405513 TI - Quinapyramine sulfate-loaded sodium alginate nanoparticles show enhanced trypanocidal activity. AB - AIM: To reduce the dose, toxic effects and to ensure sustained release of quinapyramine sulfate (QS), a highly effective drug against Trypanosoma evansi. MATERIALS & METHODS: QS-loaded sodium alginate nanoparticles (QS-NPs) were formed by emulsion-crosslinking technology using dioctyl-sodium-sulfosuccinate and sodium alginate. The formulation was characterized for size, stability, morphology and functional groups by a zetasizer, scanning electron microscopy, atomic force microscopy, transmission electron microscopy and Fourier transform infrared spectroscopy. In vitro safety and toxicity studies were performed by metabolic assay in Vero cell lines, and in vivo efficacy was evaluated in mice. RESULTS: QS-NPs were <60 nm with 96.48% entrapment efficiency and 3.70% drug loading. The formulation showed an initial burst effect followed by slow drug release in accordance with quasi-Fickian Higuchi diffusion mechanism. QS-NPs were much less toxic and able to clear the parasite at a much lower concentration than QS. CONCLUSION: The QS-NPs synthesized are safe, less toxic and highly effective compared with QS. PMID- 24405514 TI - BMC Medicine: a decade of open access medical research. AB - On 24 November 2003, BMC Medicine published its first article. Ten years and over 900 articles later we look back at some of the most notable milestones for the journal and discuss advances and innovations in medicine over the last decade. Our editorial board members, Leslie Biesecker, Thomas Powles, Chris Del Mar, Robert Snow and David Moher, also comment on the changes they expect to see in their fields over the coming years. PMID- 24405515 TI - A criterion for the reliable use of MRI-only radiotherapy. AB - BACKGROUND: MRI-only radiotherapy will eliminate the systematic registration errors introduced when transferring MRI information to the CT. However, challenges concerning the missing information on electron density, necessary for dose calculation and patient setup on bony anatomy are introduced. This study presents a possible statistical approach to evaluate, if deviations based on MRI only radiotherapy as compared to the CT based radiotherapy are acceptable. METHODS: 18 head-and-neck, 21 prostate, 10 vesica and 8 pelvic patients were included in the study. Data from each patient contained a CT and a T2-weighted MRI scan, a structure set and a clinically approved CT based treatment plan, which was re-calculated with identical parameters on the density corrected MRI scans. A statistical analysis including a 95% confidence interval was performed in clinically relevant DVH points. RESULTS: The mean differences in the investigated DVH points were in the order of 1.5% for the PTV and up to 4.2% for organs at risk. In addition, a proposed criterion of 2% dose difference in the PTV coverage for 95% of the patients was fulfilled for all diagnostic groups for a bulk segmented MRI in the DVH points, D(median) and D2%, while only head-and neck and prostate further fulfilled the criterion in D98%. CONCLUSION: Here, we suggested a method for establishing a reliable use of MRI-only radiotherapy. A population-based study comparing CT based dose calculations with those obtained on a suggested segmentation of MRI should be initiated and acceptable deviations in clinically relevant DVH points should be established. Such a population-based approach could form a part of the clinical commissioning of MRI-only radiotherapy. PMID- 24405516 TI - Behavioral and brain measures (N400) of semantic priming in patients with schizophrenia: test-retest effect in a longitudinal study. AB - AIM: The purpose of this study was to investigate whether deficits in the behavioral and/or N400 semantic priming (SP) effect observed in patients with schizophrenia constitute a stable cognitive feature of the disorder or whether they may be influenced by the severity of each individual's symptomatology. METHODS: A 1-year test-retest study was conducted on 15 patients with schizophrenia and 10 healthy participants who performed an SP task. Both behavioral measures and event-related potentials measures of SP were recorded twice (test and retest sessions). RESULTS: At test, patients exhibited a deficit in SP as was revealed by both the behavioral and the event-related potentials measures of the amplitude of the N400 component. At retest, behavioral SP remained impaired, whereas N400 SP was significantly improved. CONCLUSION: These results provide evidence that SP impairments in schizophrenia as measured by N400 should not be considered as stable cognitive markers of the disorder. The behavioral and the N400 measures of SP indicated different levels of sensitivity to subtle cognitive and brain processes, which are subject to change over the clinical course of schizophrenic disorder. PMID- 24405517 TI - Study of the external female genitalia of 14 Rhodnius species (Hemiptera, Reduviidae, Triatominae) using scanning electron microscopy. AB - BACKGROUND: Among the vectors of Chagas disease (Hemiptera: Reduviidae:Triatominae), there are eighteen Rhodnius species described and some are difficult to identify. The aim of this article is to contribute to the specific identification of fourteen Rhodnius spp. through morphological characters of the external female genitalia. METHODS: Female abdomens were cut transversely. The specimens were then prepared for examination by using scanning electron microscopy. RESULTS: The careful examination of the dorsal, posterior and ventral sides revealed characteristics that allowed the identification of each of the fourteen species. CONCLUSION: The use of external female genitalia as characteristics are proposed as a tool for specifically identifying Rhodnius species, and an identification key for these species is presented. PMID- 24405518 TI - Decisions to withhold or withdraw life-sustaining treatment in a Norwegian intensive care unit. AB - BACKGROUND: To withhold and withdraw treatment are important and difficult decisions made in the intensive care unit (ICU). The aim of this study was to investigate the incidence of withholding or withdrawing treatment, characteristics of the patients, and how these decision processes were handled and documented in a general ICU from 2007 to 2009 in a university hospital in Norway. METHODS: Patient characteristics and outcomes of treatment were prospectively registered. We retrospectively reviewed the medical records for information on limitations in treatment. RESULTS: In total, 1287 patients were admitted to the ICU. The ICU mortality was 208 (16%), and the hospital mortality was 341 (26%). In total, 301 patients (23%) had treatment withheld or withdrawn. Medical and unscheduled surgical patients with limitations in treatment had higher Simplified Acute Physiology Score II (P < 0.001) and were older (P < 0.001) than those without limitations in treatment. The most common main reason for withdrawing treatment was poor prognosis. According to the medical records, the patient was involved in the decision-making regarding withdrawal of treatment in only 2% of the cases, and the patient's relatives were involved in the decision-making in 77% of the cases. In 12% of the cases, type of treatment withdrawn was not documented. CONCLUSION: Withholding or withdrawing treatment in the ICU was common. Medical and unscheduled surgical patients with limitations in treatment were older and more severely ill than patients without limitations. There is a potential for better documentation of the processes regarding withholding or withdrawing life-sustaining intensive care treatment. PMID- 24405519 TI - Major bleeding during secondary prevention of venous thromboembolism in patients who have completed anticoagulation: a systematic review and meta-analysis. AB - BACKGROUND: The risk of major bleeding in patients who have completed anticoagulation therapy for unprovoked venous thromboembolism (VTE) is unknown. OBJECTIVE: To report the major bleeding and fatal bleeding rates in patients randomized to placebo or observation (i.e. no anticoagulation therapy) for the secondary prevention of recurrent VTE. PATIENTS AND METHODS: We performed a systematic review and meta-analysis of the literature to summarize the rates of major bleeding and fatal bleeding in patients randomized to placebo or observation during the secondary prevention of VTE. Unrestricted searches of MEDLINE (January 1, 1950 to August 31, 2013), Embase (January 1, 1980 to August 31, 2013), and the Cochrane Register of Controlled Trials using the OVID interface were conducted. Publications from potentially relevant journals were also searched by hand. We used a random-effects model to pool study results and I(2) testing to assess for heterogeneity. RESULTS: The analysis included 11 studies and 3965 patients who were followed for a median of 24 months. The overall pooled major bleeding rate was 0.45 per 100 patient-years (95% CI 0.29 0.64, I(2) = 0%), and the overall pooled fatal bleeding rate was 0.14 per 100 patient-years (95% CI 0.057-0.26, I(2) = 0%). CONCLUSIONS: Patients not receiving anticoagulant therapy for the secondary prevention of VTE experience major bleeding events, and this may have an impact on recommendations for extended treatment in this patient population. PMID- 24405520 TI - Selective admission into stroke unit and patient outcomes: a tale of four cities. AB - : Care of stroke patients costs considerably more in specialized stroke units (SU) compared to care in general medical wards (GMW) but the technology may be cost effective if it leads to significantly improved outcomes. While randomized control trials show better outcomes for stroke patients admitted to SU, observational studies report mixed findings. In this paper we use individual level data from first-ever stroke patients in four European cities and find evidence of selection by the initial severity of stroke into SU in some cities. In these cases, the impact of admission to SU on outcomes is overestimated by multivariate logit models even after controlling for case-mix. However, when the imbalance in patient characteristics and severity of stroke by admission to SU and GMW is adjusted using propensity score methods, the differences in outcomes are no longer statistically significant in most cases. Our analysis explains why earlier studies using observational data have found mixed results on the benefits of admission to SU. PMID- 24405523 TI - Measuring quantum capacitance in energetically addressable molecular layers. AB - The Fermi level or electrochemical signature of a molecular film containing accessible orbital states is ultimately governed by two measurable series energetic components, an energy loss term related to the charging of appropriately addressable molecular orbitals (resonant or charge transfer resistance), and an energy storage or electrochemical capacitance component. The latter conservative term is further divisible into two series contributions, one being a classic electrostatic term and the other arising from the involvement and charging of quantized molecular orbital states. These can be tuned in and out of resonance with underlying electrode states with an efficiency that governs electron transfer kinetics and an energetic spread dependent on solution dielectric. These features are experimentally resolved by an impedance derived capacitance analysis, a methodology which ultimately enables a convenient spectroscopic mapping of electron transfer efficacy, and of density of states within molecular films. PMID- 24405522 TI - Evaluation of different anti-asthmatic drugs on cooling-induced bronchoconstriction. AB - BACKGROUND: Inhalation of cold air is a well-recognized cause of bronchoconstriction in asthmatics. Sudden changes in weather temperature outdoors and indoors due to the extensive use of air conditioning in Kuwait is an important existing problem. OBJECTIVES: The aim of this study was to determine the most effective anti-asthmatic drugs for preventing or reversing cooling induced contraction (CIC). METHODS: We recorded isometric tension from tracheal strips, and bronchiolar rings were prepared from male Merino sheep in organ baths during stepwise cooling. CIC was tested before and after addition of various standard agents. Disodium cromoglycate (DSG), methyl prednisolone, atropine, aminophylline, isoprenaline and adrenaline were examined in two cases. The first was before cooling and the second was after cooling induced the maximum bronchoconstriction. RESULTS: Cooling to 20 degrees C induced a rapid and reproducible contraction in ovine tracheal and bronchial preparations. On readjustment to 37 degrees C, the tone returned rapidly to basal level. DSG, methyl prednisolone and atropine did not prevent or reverse the CIC. Aminophylline prevented CIC by 70%. It inhibited the peak of cooling response by 70%. beta-agonists (isoprenaline and adrenaline) abolished the CIC, and they also rapidly and totally reversed the cooling effect when added at the peak of bronchoconstriction. CONCLUSIONS: These results proved that beta-agonists are the drugs of choice in preventing the bronchoconstriction before exposure to cold environment and also completely reversing the bronchoconstriction induced after cooling exposure. PMID- 24405524 TI - The perplexing role of autophagy in plant innate immune responses. AB - Autophagy is a major intracellular process for the degradation of cytosolic macromolecules and organelles in the lysosomes or vacuoles for the purposes of regulating cellular homeostasis and protein and organelle quality control. In complex metazoan organisms, autophagy is highly engaged during the immune responses through interfaces either directly with intracellular pathogens or indirectly with immune signalling molecules. Studies over the last decade or so have also revealed a number of important ways in which autophagy shapes plant innate immune responses. First, autophagy promotes defence-associated hypersensitive cell death induced by avirulent or related pathogens, but restricts unnecessary or disease-associated spread of cell death. This elaborate regulation of plant host cell death by autophagy is critical during plant immune responses to the types of plant pathogens that induce cell death, which include avirulent biotrophic pathogens and necrotrophic pathogens. Second, autophagy modulates defence responses regulated by salicylic acid and jasmonic acid, thereby influencing plant basal resistance to both biotrophic and necrotrophic pathogens. Third, there is an emerging role of autophagy in virus-induced RNA silencing, either as an antiviral collaborator for targeted degradation of viral RNA silencing suppressors or an accomplice of viral RNA silencing suppressors for targeted degradation of key components of plant cellular RNA silencing machinery. In this review, we summarize this important progress and discuss the potential significance of the perplexing role of autophagy in plant innate immunity. PMID- 24405525 TI - Measuring the ambiguity tolerance of medical students: a cross-sectional study from the first to sixth academic years. AB - BACKGROUND: Tolerance of ambiguity, or the extent to which ambiguous situations are perceived as desirable, is an important component of the attitudes and behaviors of medical students. However, few studies have compared this trait across the years of medical school. General practitioners are considered to have a higher ambiguity tolerance than specialists. We compared ambiguity tolerance between general practitioners and medical students. METHODS: We designed a cross sectional study to evaluate the ambiguity tolerance of 622 medical students in the first to sixth academic years. We compared this with the ambiguity tolerance of 30 general practitioners. We used the inventory for measuring ambiguity tolerance (IMA) developed by Reis (1997), which includes three measures of ambiguity tolerance: openness to new experiences, social conflicts, and perception of insoluble problems. RESULTS: We obtained a total of 564 complete data sets (return rate 90.1%) from medical students and 29 questionnaires (return rate 96.7%) from general practitioners. In relation to the reference groups defined by Reis (1997), medical students had poor ambiguity tolerance on all three scales. No differences were found between those in the first and the sixth academic years, although we did observe gender-specific differences in ambiguity tolerance. We found no differences in ambiguity tolerance between general practitioners and medical students. CONCLUSIONS: The ambiguity tolerance of the students that we assessed was below average, and appeared to be stable throughout the course of their studies. In contrast to our expectations, the general practitioners did not have a higher level of ambiguity tolerance than the students did. PMID- 24405526 TI - Aldehyde dehydrogenase and ATP binding cassette transporter G2 (ABCG2) functional assays isolate different populations of prostate stem cells where ABCG2 function selects for cells with increased stem cell activity. AB - INTRODUCTION: High expression of aldehyde dehydrogenase1A1 (ALDH1A1) is observed in many organs and tumors and may identify benign and cancer stem cell populations. METHODS: In the current study, the stem cell characteristics were determined in cells isolated from human prostate cell lines and clinical prostate specimens based upon the ALDEFLUORTM assay. Cells isolated based on the ALDEFLUORTM assay were compared to cells isolated based on ATP binding cassette transporter G2 (ABCG2) activity using the side population assay. To test for stem cell characteristics of self-renewal and multipotency, cells with high and low ALDH1A1 activity, based on the ALDEFLUORTM assay (ALDHHi and ALDH Low), were isolated from prostate clinical specimens and were recombined with rat urogenital sinus mesenchyme to induce prostate gland formation. RESULTS: The percentage of ALDH Hi cells in prostate cell lines (RWPE-1, RWPE-2, CWR-R1, and DU-145) was 0.5 to 6%, similarly in non-tumor and tumor clinical specimens the percentage of ALDH Hi cells was 0.6 to 4%. Recombinants using ALDH Hi cells serially generated prostate tissue up to three generations with as few as 250 starting cells. Immunohistochemical analysis of the recombinants using ALDHHi cells contained prostatic glands frequently expressing androgen receptor (AR), p63, chromogranin A, ALDH1A1, ABCG2, and prostate specific antigen (PSA), compared to their ALDH Low counterparts. Inhibition of ALDH resulted in the reduction of sphere formation capabilities in the CWR-R1, but not in the RWPE-2 and DU-145, prostate cell lines. ABCG2 inhibition resulted in a more robust decrease of sphere formation in androgen sensitive cell lines, CWR-R1 and RWPE-2, but not androgen insensitive DU-145. ALDH1A1 expression was enriched in ALDH Hi cells and non-side population cells. ABCG2 expression was only enriched in side population cells. CONCLUSIONS: The percentage of ALDHHi cells in prostate cell lines and prostate tissue was consistently higher compared to cells with high ABCG2 activity, identified with the side population assay. The expression of the stem and differentiation markers indicates the ALDH Hi recombinants contained cells with self-renewal and multipotency activity. When the two assays were directly compared, cells with the side population phenotype demonstrated more stem cell potential in the tissue recombination assay compared to ALDH Hi cells. The increased stem cell potential of side population cells in the tissue recombination assay and the decrease in sphere formation when ABCG2 is inhibited indicates that the side population enriches for prostate stem cells. PMID- 24405527 TI - Farmers' market use is associated with fruit and vegetable consumption in diverse southern rural communities. AB - BACKGROUND: While farmers' markets are a potential strategy to increase access to fruits and vegetables in rural areas, more information is needed regarding use of farmers' markets among rural residents. Thus, this study's purpose was to examine (1) socio-demographic characteristics of participants; (2) barriers and facilitators to farmers' market shopping in southern rural communities; and (3) associations between farmers' market use with fruit and vegetable consumption and body mass index (BMI). METHODS: Cross-sectional surveys were conducted with a purposive sample of farmers' market customers and a representative sample of primary household food shoppers in eastern North Carolina (NC) and the Appalachian region of Kentucky (KY). Customers were interviewed using an intercept survey instrument at farmers' markets. Representative samples of primary food shoppers were identified via random digit dial (RDD) cellular phone and landline methods in counties that had at least one farmers' market. All questionnaires assessed socio-demographic characteristics, food shopping patterns, barriers to and facilitators of farmers' market shopping, fruit and vegetable consumption and self-reported height and weight. The main outcome measures were fruit and vegetable consumption and BMI. Descriptive statistics were used to examine socio-demographic characteristics, food shopping patterns, and barriers and facilitators to farmers' market shopping. Linear regression analyses were used to examine associations between farmers' market use with fruit and vegetable consumption and BMI, controlling for age, race, education, and gender. RESULTS: Among farmers' market customers, 44% and 55% (NC and KY customers, respectively) reported shopping at a farmers' market at least weekly, compared to 16% and 18% of NC and KY RDD respondents. Frequently reported barriers to farmers' market shopping were market days and hours, "only come when I need something", extreme weather, and market location. Among the KY farmers' market customers and NC and KY RDD respondents, fruit and vegetable consumption was positively associated with use of farmers' markets. There were no associations between use of farmers' markets and BMI. CONCLUSIONS: Fruit and vegetable consumption was associated with farmers' market shopping. Thus, farmers' markets may be a viable method to increase population-level produce consumption. PMID- 24405528 TI - Prevalence of musculoskeletal complaints and juvenile idiopathic arthritis in children from a developing country: a school-based study. AB - INTRODUCTION: Musculoskeletal complaints are common in children. Studies from developed countries have found most to be non-inflammatory and juvenile idiopathic arthritis (JIA) to be less than 0.1%. However, there is limited data from developing countries such as India. METHODS: This cross-sectional study was conducted from March 2010 to April 2011 among school children aged 6-17 years in northern India. Prevalence of musculoskeletal complaints and JIA were determined using a questionnaire on musculoskeletal complaints. This was filled either by parents (always in children < 14 years) or children themselves. Subsequently, all children were individually met and responses verified. An abbreviated musculoskeletal examination (GALS) was performed on every child. In cases of suspected inflammatory arthritis, further investigations were performed. RESULTS: Of the 2059 children (851 girls, 1208 boys) who were included in this study, mean (+/- SD) age was 11.5 +/- 2.9 years. Joint pain (more than 1 week) was present in 158 (7.6%), back pain in 63 (3.1%) and heel pain in 62 (3%) of them. Limb pains, suggestive of 'growing pains', were present in 45 (2.1%) children. There were six suspected cases of inflammatory musculoskeletal pain; however, only one child was confirmed as having JIA (enthesitis-related arthritis). The estimated prevalence of JIA was 48/100,000 in Indian children. CONCLUSION: Musculoskeletal complaints were not uncommon in children from a developing country like India. Estimated prevalence of JIA was 48/100,000 (95%CI 10-280). PMID- 24405529 TI - Generation of parthenogenetic goat blastocysts: effects of different activation methods and culture media. AB - The present study was carried out to investigate the effects of different activation methods and culture media on the in vitro development of parthenogenetic goat blastocysts. Calcium (Ca2+) ionophore, ethanol or a combination of the two, used as activating reagents, and embryo development medium (EDM), modified Charles Rosenkrans (mCR2a) medium and research vitro cleave (RVCL) medium were used to evaluate the developmental competence of goat blastocysts. Quantitative expression of apoptosis, stress and developmental competence-related genes were analysed in different stages of embryos. In RVCL medium, the cleavage rate of Ca2+ ionophore-treated oocytes (79.61 +/- 0.86) was significantly (P < 0.05) higher than in ethanol (74.90 +/- 1.51) or in the combination of both Ca2+ ionophore and ethanol. In mCR2a or EDM, hatched blastocyst production rate of Ca2+ ionophore-treated oocytes (8.33 +/- 1.44) was significantly higher than in ethanol (6.46 +/- 0.11) or in the combined treatment (6.70 +/- 0.24). In ethanol, the cleavage, blastocyst and hatched blastocyst production rates in RVCL medium (74.90 +/- 1.51, 18.30 +/- 1.52 and 8.24 +/- 0.15, respectively) were significantly higher than in EDM (67.81 +/- 3.21, 14.59 +/- 0.27 and 5.59 +/- 0.42) or mCR2a medium (65.09 +/- 1.57, 15.36 +/- 0.52 and 6.46 +/- 0.11). The expression of BAX, Oct-4 and GlUT1 transcripts increased gradually from 2-cell stage to blastocyst-stage embryos, whereas the transcript levels of Bcl-2 and MnSOD were significantly lower in blastocysts. In addition, different activation methods and culture media had little effect on the pattern of variation and relative abundance of the above genes in different stages of parthenogenetic activated goat embryos. In conclusion, Ca2+ ionophore as the activating agent, and RVCL as the culture medium are better than other tested options for development of parthenogenetic activated goat blastocysts. PMID- 24405530 TI - The socio-environmental determinants of railway suicide: a systematic review. AB - BACKGROUND: Railway suicide has significant adverse impacts for the victims, their family and friends, witnesses to the incident, general public and train network. There is no previous review on the socio-environmental factors and railway suicide. The research question asked in this review was: 'What socio environmental risk and protective predictors are significantly associated with railway suicide?' METHODS: The review searched Medline, PsycINFO, Web of Science and Scopus for English-language studies that assessed the associations between socio-environmental (i.e. geographical, physical, economic and social) factors and railway suicide from their inception to June 2013. It was reported based on the PRISMA Statement. RESULTS: Eleven studies met the inclusion criteria. They were categorised into railway environments (availability of railways and trains, accessibility to railways and familiarity with trains), population characteristics and impact of media reporting. Findings from ecological studies using population level railway suicide data suggested weak and inconsistent evidence for the first two categories. The evidence on the impact of media reporting was moderately strong, with irresponsible media reporting being associated with an increased risk of railway suicide. CONCLUSIONS: There is a need for further research activity to strengthen evidence about socio environmental risk factors for railway suicide. The focus of this research should be on the factors that determine individuals' decisions of using the railway as a method of suicide, with the consideration of a range of geographical, physical, social, and economic factors. PMID- 24405532 TI - Perventricular device closure of a large residual perimembranous interventricular septal defect after previous surgical correction. AB - A 21 years albanian patient was referred with important residual left to right shunt. He was undergone 7 years before conventional surgical correction of a perimembranous ventricular septal defect (VSD). The patient underwent sternotomy and perventricular device closure of the residual employing a 16 mm multifenestrated atrial septal defect occlude, which was positioned through the anterior wall of the right ventricle. across the defect. The previous autologous pericardial patch was compressed into the double umbrella device. We may conclude that perventricular device closure can employed successfully in patients with residual perimembranous VSD after previous surgical repair as an alternative to the conventional surgery with excellent hemodynamic and postoperative outcome. Such a technique should be part of the surgical armamentarum. PMID- 24405533 TI - [Confusions and considerations in myelodysplastic syndromes]. PMID- 24405531 TI - Using verbal autopsy to measure causes of death: the comparative performance of existing methods. AB - BACKGROUND: Monitoring progress with disease and injury reduction in many populations will require widespread use of verbal autopsy (VA). Multiple methods have been developed for assigning cause of death from a VA but their application is restricted by uncertainty about their reliability. METHODS: We investigated the validity of five automated VA methods for assigning cause of death: InterVA 4, Random Forest (RF), Simplified Symptom Pattern (SSP), Tariff method (Tariff), and King-Lu (KL), in addition to physician review of VA forms (PCVA), based on 12,535 cases from diverse populations for which the true cause of death had been reliably established. For adults, children, neonates and stillbirths, performance was assessed separately for individuals using sensitivity, specificity, Kappa, and chance-corrected concordance (CCC) and for populations using cause specific mortality fraction (CSMF) accuracy, with and without additional diagnostic information from prior contact with health services. A total of 500 train-test splits were used to ensure that results are robust to variation in the underlying cause of death distribution. RESULTS: Three automated diagnostic methods, Tariff, SSP, and RF, but not InterVA-4, performed better than physician review in all age groups, study sites, and for the majority of causes of death studied. For adults, CSMF accuracy ranged from 0.764 to 0.770, compared with 0.680 for PCVA and 0.625 for InterVA; CCC varied from 49.2% to 54.1%, compared with 42.2% for PCVA, and 23.8% for InterVA. For children, CSMF accuracy was 0.783 for Tariff, 0.678 for PCVA, and 0.520 for InterVA; CCC was 52.5% for Tariff, 44.5% for PCVA, and 30.3% for InterVA. For neonates, CSMF accuracy was 0.817 for Tariff, 0.719 for PCVA, and 0.629 for InterVA; CCC varied from 47.3% to 50.3% for the three automated methods, 29.3% for PCVA, and 19.4% for InterVA. The method with the highest sensitivity for a specific cause varied by cause. CONCLUSIONS: Physician review of verbal autopsy questionnaires is less accurate than automated methods in determining both individual and population causes of death. Overall, Tariff performs as well or better than other methods and should be widely applied in routine mortality surveillance systems with poor cause of death certification practices. PMID- 24405534 TI - [More attention should be paid in the diagnosis and treatment of pulmonary hypertension]. PMID- 24405535 TI - [A comparative study of fluorescence in situ hybridization versus conventional cytogenetics in the detection of clonal aberrations in myelodysplastic syndrome]. AB - OBJECTIVE: To compare the results of fluorescence in situ hybridization (FISH) versus conventional cytogenetics (CC) in the detection of common chromosomal abnormalities and evaluate the significance of FISH in myelodysplastic syndrome (MDS) . METHODS: A total of 344 patients with de novo MDS from June 2008 to October 2012 were detected by 6 pairs of probes, including CSF1R/D5S23-D5S721 (5q33) , EGR1/ D5S23-D5S721 (5q31) , D7S486 (7q31) /CSP7, D7S522 (7q31) /CSP7, D20S108/CSP8 (20q12/CSP8) and CSPX/CSPY. The results were compared with those of CC. RESULTS: CC revealed cytogenetic abnormalities in 168/344 cases (48.8%) and the frequency of common aberrations such as +8, 20q-, -7/7q-, -5/5q- and -Y were 18.9% (65/344) , 9.3% (32/344), 8.4% (29/344), 8.4% (29/344) and 2.4% (5/206) respectively. While FISH revealed chromosome abnormalities in 147/344 patients (42.7%) and the frequency of +8, 20q-, -7/7q-, -5/5q- and -Y were 20.9% (72/344), 11.6% (40/344), 11.6% (40/344), 10.2% (35/344) and 2.9% (6/206) respectively. Overall 187/344 patients (54.4%) carried clonal aberrations by a combination of CC and FISH. Among 158 patients with normal karyotype by CC, 14 cases (8.9%) were detected to have clonal aberrations by FISH. FISH also confirmed 4 carriers of clonal aberrations out of 9 patients with non clonal abnormalities by CC. CONCLUSIONS: FISH is effective for improving the probability of detecting chromosome abnormalities in MDS cases with normal karyotypes and karyotype failure. FISH may provide rationales for clonal abnormalities in patients with non clonal aberrations by CC. A combination of FISH and CC shows complementary advantages. PMID- 24405536 TI - [Relationship between clinical characteristics and myelodysplastic syndrome patients with isocitrate dehydrogenase gene mutations]. AB - OBJECTIVE: To assess the prevalence and clinical characteristics of isocitrate dehydrogenase 1 and 2 (IDH 1 and IDH2) gene mutations in myelodysplastic syndrome (MDS) patients. METHODS: Pretreatment bone marrow specimens were enriched for mononuclear cells in 108 adult patients with de novo MDS from January 2006 to August 2012. Genomic DNA was extracted from mononuclear cells. And PCR and direct sequencing were performed to sequence exon 4 of IDH gene. RESULTS: IDH mutations were discovered in 11 MDS patients (10.19%, 11/108) and all were heterozygous. The frequencies of IDH1 and IDH2 mutations were 5.56% (6/108) and 4.63% (5/108) respectively. Only one type of IDH1 mutation (c.394C->, p.R132C) was identified in our cohort. All IDH2 mutations caused the changes of R140 (c.419G->A, p.R140Q). However IDH2 R172 mutation was not detected. The combined mutations of IDH1 and IDH2 were not simultaneously observed in the same patient. The prevalence of IDH mutation was higher in advanced-stage MDS than those early stage MDS patients. Mutated and wild-type groups had significantly difference in bone marrow blast percentage (median 12.5% vs 6.0%, P = 0.013) at diagnosis, but not in white blood cell count, hemoglobin level and platelet count, etc. In the normal karyotype group, the frequencies of IDH mutations were as similar as those in the abnormal karyotype group (10.61% (7/66) vs 10.00% (4/40), P > 0.05). The median follow-up time was 472 d, our data indicated that IDH mutations were correlated with poor overall survival (median time 512 vs 740 d, P = 0.017). IDH mutations were also an inferiorly predictive factor in the intermediate-1 group patients of International Prognostic Scoring System (IPSS) (median survival time 512 d vs not reached, P = 0.038). There was also better efficacies than other treatments in IDH mutation positive patients (median survival time 623 vs 165 d, P = 0.049). CONCLUSIONS: IDH mutation is a vital biomarker for better risk stratification of MDS patients with and improving IPSS. Hypomethylation agents may be effective for treating IDH mutation positive patients. PMID- 24405537 TI - [Impact of induced therapy before allogeneic hematopoietic stem-cell transplantation for higher-risk myelodysplastic syndrome: experience of single centre]. AB - OBJECTIVE: To explore the impact of prior-to-transplantation induction therapy (IT) on patient outcome after allogeneic hematopoietic stem-cell transplantation (Allo-HSCT) for higher-risk myelodysplastic syndromes (MDS). METHODS: A total of 49 consecutive patients underwent Allo-HSCT for MDS between November 2002 and December 2012. Twenty-six lower-risk MDS cases received supportive therapy (ST). And 17/23 cases of higher-risk MDS received IT prior to transplantation while another 6 only with ST. Their survival, relapse rate and incidence of transplantation-related mortality (TRM) were retrospectively analyzed according to International Prognostic Scoring System (IPSS) scores and marrow blast count. RESULTS: The 5-year cumulative overall survival (OS), disease-free survival (DFS), relapse rate and incidence of transplantation related mortality (TRM) were 59.9%, 59.2%, 10.5% and 31.8% during a median follow-up period of 24.4 (6.2-72.0) months. The OS and DFS of higher-risk group with IT, ST and lower-risk group were different (72.1% vs 16.7% vs 68.1%, P = 0.028; 72.1% vs 16.7% vs 67.9%, P = 0.030). And the OS and DFS of higher-risk group with IT were similar to those of lower-risk group (P = 0.526,0.504) . For the higher-risk group, the patients on IT had improved survival than those on ST in terms of OS and DFS (both P = 0.020). Moreover, the OS and DFS of remission group were higher than non remission group in patients on IT (both 100% vs 46.7%, P = 0.049). The number of marrow blasts significantly decreased after IT (P = 0.010) without increased TRM (28.9% vs 33.6%, P = 0.612). CONCLUSION: Induction therapy prior to Allo-HSCT for MDS may reduce clone burden and improve the outcomes of higher-risk MDS without increased TRM. PMID- 24405538 TI - [Lower risk myelodysplastic syndrome patients with transfusion dependent treated by dose-reduced decitabine]. AB - OBJECTIVE: To evaluate the efficacy and safety of dose-reduced decitabine for the lower risk myelodysplastic syndrome (MDS) patients with transfusion dependent. METHODS: Twenty-five cases of lower risk (low or intermediate-1 risk in IPSS risk group) MDS patients with transfusion dependence from November 2009 to September 2012 were treated by dose-reduced decitabine (20 mg/m(2) intravenously once daily for 3 days). And their efficacy, side effects, quality-of-life and survival rate were evaluated. RESULTS: Among them, the responses included complete remission (CR, n = 3, 12%), transfusion independence (n = 4, 16%), hematologic improvement (HI, n = 8, 32%) and stable disease (SD, n = 2, 8%). And the overall response rate (ORR) was 68% (17/25) . Among 11 cases available for cytogenetic evaluation, 1 achieved partial cytogenetic remission (PRc). IV grade hematologic toxicity rate was 48% (12/25) and III-IV grade infection rate 20% (5/25). No severe hematologic toxicity was observed. After treatment, the Karnofsky performance score (KPS) increased from 47 +/- 16 to 66 +/- 22 (P = 0.001); more patients were reclassified as WPSS <= 1 (44%vs 16%, P = 0.031) or MDACC score <= 7 (64% vs 8%, P = 0.022). The median follow-up time was 467(14-881) d. The 100 and 600-day expected survive rates of low and intermediate -1 risk in IPSS risk group were 100% versus 95.2% and 100% versus 90.5%. CONCLUSIONS: Dose-reduced decitabine is well-tolerated and effective in transfusion dependent MDS patients in IPSS-lower risk. There is a low rate of severe hematologic toxicity and early mortality. It may prolong their survival time. PMID- 24405539 TI - [Analysis of clinical characteristics and risk factors associated with prognosis of patients with candidemia]. AB - OBJECTIVE: To explore the microbiological and clinical characteristics of patients with candidemia and analyze their prognostic risk factors. METHODS: A retrospective analysis was conducted for hospitalized patients with candidemia from January 2008 to December 2012 at Affiliated Zhongshan Hospital, Fudan University. Pathogen spectrum, resistance pattern, underlying diseases, therapy received and patient prognosis were collected by chart review. The univariate and multivariate Logistic regression analyses were used to determine the prognostic risk factors of candidemia. RESULTS: A total of 138 inpatients were identified. There were 98 males and 40 females with a mean age of (61.3 +/- 16.6) years. The morbidity rate of candidemia in annual discharged patients was 0.034%-0.051%. The most common pathogens were Candida albicans (n = 72, 52.2%), Candida parapsilosis (n = 29, 21.0%) and Candida tropicalis (n = 16, 11.6%). The antibiotic susceptible rate of azole for Candida was 90.9%-97.4% while 55.6%-83.3% for Candida tropicalis. The overall case fatality rate of candidemia was 39.1% (54/138) while the attributable case fatality rate 31.9% (44/138). Multivariate Logistic regression analysis indicated acute physiology and chronic health evaluation II(APACHE II) score >= 20 points (OR = 8.025, 95%CI: 2.032-31.696, P = 0.003), hypoproteinemia (OR = 6.213, 95%CI: 1.849-20.879, P = 0.003), concurrent bacteremia (OR = 5.541, 95%CI: 1.576-19.487, P = 0.008) and indwelling urethral catheter (OR = 13.776, 95%CI: 1.402-135.352, P = 0.024) were the independent risk factors of candidemia-related mortality, while removal or replacement of central venous catheter (OR = 0.231, 59%CI: 0.075-0.716, P = 0.011) and surgery within 30 days (OR = 0.206, 95%CI: 0.050-0.857, P = 0.030) were the protective factors. CONCLUSIONS: Candida albicans is the most common causative agent. The case fatality rate of candidemia has remained high. APACHE II score >= 20 points, hypoproteinemia, indwelling urethral catheter and concurrent bacteremia are independent risk factors attributing to candidemia-related mortality while removal or replacement of central venous catheter and surgery within 30 days are the protective ones. PMID- 24405541 TI - [Influencing factors of glycemic variability in elderly patients with type 2 diabetes]. AB - OBJECTIVE: To explore the influencing factors of glycemic variability in elderly patients with type 2 diabetes. METHODS: A total of 337 elderly patients received continuous glucose monitoring (CGM) from January 2007 to January 2011. The evaluation variables of glycemic variability included standard deviation of blood glucose (SDBG), mean amplitude of glycemic excursion (MAGE), absolute means of daily differences (MODD) and postprandial glucose excursion (PPGE). The normal reference value of glycemic variability was defined according to the diagnostic criteria of Chinese Diabetes Society guideline. RESULTS: The difference of glycemic variability was compared by gender, age and diabetic duration. The values of SDBG, MAGE, MODD and PPGE in females were all higher than those in males (P < 0.05) and no difference existed between various age groups. The level of glycemic variability increased gradually with the extension of diabetic duration (P < 0.01). Logistic regression analysis showed that gender (MAGE: OR = 0.44, P = 0.023; SDBG: OR = 0.39, P = 0.023), diabetic duration (MAGE: OR = 1.58, P = 0.006; SDBG: OR = 2.42, P < 0.001) and HbA1c (MAGE: OR = 2.44, P < 0.001; SDBG: OR = 2.68, P < 0.001) were significant influencing factors of glycemic variability (MAGE/SDBG) in elderly patients with type 2 diabetes (P < 0.05), but not age, body mass index (BMI) or diabetic neuropathy. CONCLUSION: Gender, diabetic duration and HbA1c are significant influencing factors of glycemic variability while age, BMI or diabetic neuropathy has no association with glycemic variability in elderly patients with type 2 diabetes. PMID- 24405540 TI - [Association of TNF-1031T/C and clinical efficacy of insulin therapy in newly diagnosed type 2 diabetics]. AB - OBJECTIVE: Tumor necrosis factor (TNF ) locus has been a long-standing type 2 diabetes (T2D) candidate gene. Few studies have been conducted on TNF SNP (single nucleotide polymorphism) as rs1799964 (T-1031C), rs1800630 (A-863C) and rs1799724 (C-857T) in T2D. The purpose of this study is to examine the association of TNF SNP and T2D in a case control study and further explore whether these SNPs influence the clinical efficacy of insulin therapy. METHODS: A total of 109 newly diagnosed type 2 diabetics and 168 healthy individuals were recruited. Three tag SNPs (rs1799964 (T-1031C), rs1800630 (A-863C), rs1799724 (C-857T)) were selected across the TNF locus and polymerase chain reaction (PCR) directed sequencing was performed. The patients received Lispro 25 twice daily to achieve glycemic control and they were followed up for 1 year. Plasma glucose level, lipid profile, homeostatic model assessment for insulin resistance (HOMA-IR) and homeostatic model assessment for beta-cell function (HOMA-beta) were compared among groups with different haplotypes of SNPs. RESULTS: Haplotype of TNF-1031C 863C-857C increased the risk of T2D (OR = 2.7, P < 0.05) . Comparing with homozygote of TNF-1031T-863C-857C diabetics (TCC), those carrying CCC allele had higher fasting serum insulin (16.1(12.0-20.3) mU/L) and HOMA-IR (lnHOMA-IR 1.8 +/ 0.4) levels (TCC group: 10.6(8.1-14.3) mU/L and 1.42 +/- 0.54 respectively, P < 0.05)). One-year insulin treatment decreased HbA1c effectively in both TCC and CCC groups (P < 0.05). However, higher HOMA-IR was still observed in CCC group than that of TCC after normoglycemia (lnHOMA-IR: 2.5(0.9-3.9) vs 1.1(0.8-1.8) respectively, P < 0.05) . Moreover HOMA-beta showed no significant improvement in CCC group as it was in TCC group by the endpoint of follow-up. CONCLUSIONS: TNF 1031C-863C-857C is a risk haplotype for T2D. CCC carrying patients failed to achieve HOMA-beta improvement. And it might be due to increased endogenous HbOMA IR level comparing with TCC homozygote. PMID- 24405542 TI - [Association of Cystatin C and metabolic syndrome]. AB - OBJECTIVE: To explore the correlation between serum levels of Cystatin C and metabolic syndrome. METHODS: This study was randomly conducted in 506 persons, including 191 patients with metabolic syndrome (MS), 210 with metabolic disorder (MD) and 105 persons in normal control (NC) group. According to serum levels of Cys C, the clinical data were also divided into 3 groups of lower tertile (T1, n = 165), middle tertile (T2, n = 172) and upper tertile (T3, n = 169). Body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), fasting plasma glucose (FPG), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), high density lipoprotein (HDL), creatinine (Cr), estimated glomerular filtration rate (eGFR), microalbuminuria (MAU), systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) were measured and their mutual relations evaluated. RESULTS: Statistically significant differences (all P < 0.01) existed among T1, T2 and T3 groups in the mean values of BMI, waist circumference, WHR, FPG, LDL-C, TG, Cr, eGFR, MAU, SBP, DBP and PP. As tertile levels of Cys C increased, MS morbidity rates became all remarkably augmented (P < 0.01). The MS component scores had significant statistical differences among the patients of T1, T2 and T3 groups (P < 0.01). As the MS component scores increased, the level of Cys C rose in these patients. The higher MS marks were, the higher serum concentration of Cys C was in these patients. The plasma concentration of Cys C in MS patients was closely related with WC, LDL-C, FBG and blood pressure (all P < 0.05), not related with TG levels and negatively correlated with HDL-C levels (r = -0.352, P = 0.01). WC, Cys C, LDL-C, MAU and PP were significantly associated with MS. And the value of OR between Cys C and MS was 2.943 (95% CI 1.276-3.914). CONCLUSION: Cys C is significantly associated with MS. As MS scores rise, the level of Cys C increases. PMID- 24405543 TI - [Multivariate analysis of risk factors for intra-abdominal infections after radical gastrectomy for gastric cancer]. AB - OBJECTIVE: To explore the major risk factors for intra-abdominal infections after radical gastrectomy in patients with gastric cancer. METHODS: From October 2010 to January 2013, a total of 479 patients undergoing radical gastrectomy at Department of Gastric, Duodenal & Pancreatic Surgery, Hunan Provincial Tumor Hospital were divided into 2 groups according to an onset of postoperative intra abdominal infections (n = 32, 6.68%) or not (n = 447, 93.32%). Their clinicopathological data, such as age, gender, co-morbidities, surgical duration, operative blood loss and pathological stage were retrospectively analyzed by Logistic regressive analysis with a case-control study model. RESULTS: As compared with the control group, the patients had a greater age ((59 +/- 10) vs (53 +/- 11) years, P < 0.01), lower lymphocyte count ((1.4 +/- 0.7) *10(9)/L vs (1.7 +/- 0.6) *10(9)/L, P = 0.02), lower hemoglobin level ( (108 +/- 28) vs (117 +/- 24) g/L, P = 0.04), lower albumin level ((34 +/- 6) vs (37 +/- 5) g/L, P < 0.01) and longer surgical duration ((244 +/- 43) vs (216 +/- 45) min, P < 0.01) in the postoperative intra-abdominal infection group. Univariate Logistic regressive analysis found that a history of abdominal surgery, body mass index (BMI) >25 kg/m(2), co-morbidities, diabetes mellitus, complications due to gastric cancer, lymphocyte count <1.5*10(9)/L, hemoglobin <100 g/L, albumin <30 g/L, ascites, perioperative transfusion, total mastectomy, combined organ resection and surgical duration >240 min were associated with the occurrence of postoperative intra-abdominal infections (all P < 0.05). Further multivariate analysis identified 4 independent risk factors for intra-abdominal infections after radical gastrectomy, including combined multiorgan resection (OR = 3.64, 95%CI: 1.39-9.55), BMI>25 kg/m(2) (OR = 3.04, 95%CI: 1.17-7.92), diabetes mellitus (OR = 3.41, 95%CI: 1.05-11.09) and perioperative transfusion (OR = 2.24, 95%CI: 1.02-5.13). CONCLUSION: A correction of modifiable risk factors may reduce the incidence of intra-abdominal infections after radical gastrectomy, shorten the length of hospital stays and improve outcomes in patients with gastric cancer. PMID- 24405544 TI - [Therapeutic mechanism of diaphragm training at different periods in patients with gastroesophageal reflux disease]. AB - OBJECTIVE: To explore the effects of postprandial diaphragm training (DT) on esophageal acid exposure, esophageal motility and proximal gastric volume at different postprandial periods in patients with gastroesophageal reflux disease (GERD). METHODS: Thirty GERD patients and 9 healthy subjects (HS) with matched demographic characteristics were enrolled from June 2005 to June 2006 at Peking Union Medical College Hospital. Esophageal manometry with a Dent sleeve catheter and simultaneous esophageal pH monitoring were recorded in a 30-min fasting period and a 120-min postprandial period. The GERD patients were divided into 3 groups: 9 patients received diaphragm training at 1(st) hour after meal (group DT1 h) and another 10 at 2(nd) hour after meal (group DT2 h) whereas no diaphragm training after meal in 11 (group NDT). Ultrasonic imaging of proximal gastric volume was undertaken at 0, 30, 60, 90 and 120 min after meal. RESULTS: (1) The percentage time with pH<4 in group DT1 h was lower than that in group NDT in the 120-min postprandial period (0.2% (0-4.1%), 6.6% (2.2%-18.2%), P < 0.05) and no significant difference of esophageal acid exposure was observed between groups DT2 h and NDT (3.7% (0.1%-17.8%), 6.6% (2.2%-18.2%), P > 0.05) . (2) Esophagogastric junction (EGJ) and crural diaphragm pressures at the 1(st) hour after meal in group DT1 h were both significantly higher than those in group NDT during diaphragm training ((44.4 +/- 8.1) vs(16.2 +/- 4.5) mm Hg, (38.2 +/- 4.2) vs (9.8 +/- 4.5) mm Hg, 1 mm Hg = 0.133 kPa, both P < 0.05). EGJ and crural diaphragm pressures at the 2(nd) hour after meal in group DT2 h were significantly higher than those in group N-DT during diaphragm training ((53.2 +/ 7.5) vs (14.0 +/- 3.7) mm Hg, (48.2 +/- 6.3) vs (8.9 +/- 2.7) mm Hg, both P < 0.05). There was no change of lower esophageal sphincter pressure (all P > 0.05). (3) After test meal, the groups DT1 h, DT2 h and N-DT had similar proximal stomach volume (all P > 0.05). CONCLUSIONS: Diaphragm training at the 1(st) hour after meal might reduce the 120-min postprandial esophageal acid exposure in GERD patients. The reduction in esophageal acid exposure may result from enhanced antireflux barrier of EGJ function. Therefore postprandial diaphragm training provides a new approach to conservative treatment of GERD. PMID- 24405545 TI - [Safety of omitting axillary lymph node dissection in primary breast cancer patients with negative sentinel lymph nodes]. AB - OBJECTIVE: To explore the safety of omitting axillary lymph node dissection (ALND) in primary invasive breast cancer patients with negative sentinel lymph nodes (SLN). METHODS: Between June 2005 and June 2011, all SLN negative patients omitting ALND were analyzed retrospectively. They were all primary invasive breast cancer patients without clinic cytological evidence of axillary node involvement. SLN biopsy was performed prior to systemic treatment. And the tracer was (99)Tc(m) labeled Rituximab. RESULTS: A total of 1807 eligible patients were enrolled. Their median age was 50 years (21-87). And the median number of SLN was 2. The patients of T1, T2 and T3 were 1069 (59.2%), 712 (39.4%) and 26 (1.4%) respectively. After a median follow-up of 36 months, 14 (0.77%) cases of ipsilateral axillary recurrence were observed. Among them, 10 (0.55%) had single axillary recurrence. Second primary cancer occurred in 22 patients (1.2%). And distant metastases were found in 26 patients (1.4%). The 3-year axillary recurrence rate was 0.7%, disease-free survival 96.4% (95%CI 95.4%-97.4%) and recurrence-free survival 97.1% (95%CI 96.1%-98.1%). CONCLUSION: The omitting of ALND is safe in breast cancer patients with negative SLN. PMID- 24405546 TI - [Diagnostic value of thyroid microcarcinoma with a taller-than-wide shape in thyroid nodules]. AB - OBJECTIVE: To explore the diagnostic value of thyroid microcarcinoma with a taller-than-wide shape (A/T >= 1) in transverse ultrasonographic planes. METHODS: There were a total of 683 thyroid nodules in 491 patients undergoing consecutive ultrasonography and surgery at our hospital between 2011 and 2012. The ultrasonography examinations of thyroid nodules were routinely performed in the transverse planes. A taller-than-wide shape was defined as a ratio of anteroposterior diameter to transverse diameter in transverse plane >= 1. The sensitivity and specificity for thyroid carcinoma were analyzed. The data of thyroid carcinoma were formulated as follows: group 1, nodules > 1 centimeter; group 2, <= 1 centimeter. Their ratios of A/T were compared. The data were analyzed with SPSS 17.0 statistical software package. RESULTS: Among 683 nodules, 499 were malignant and 184 benign. The sensitivity and specificity for malignancy were 61.5% and 84.2% respectively. There was significant difference (P = 0.000). A taller-than-wide shape (A/T >= 1) was more frequent in criterion 2 than criterion 1 (chi(2) = 4.380, P = 0.036). CONCLUSIONS: A taller-than-wide shape (A/T >= 1) is associated with thyroid malignancy especially thyroid microcarcinoma. And it is a useful ultrasonic feature for predicting thyroid microcarcinoma. PMID- 24405547 TI - [Altered expressions of alkane monooxygenase and hypoxia inducible factor-1alpha expression in lung tissue of rat hypoxic pulmonary hypertension]. AB - OBJECTIVE: To explore the altered expressions of alkane monooxygenase (AlkB) and hypoxia-inducible factor-1alpha (HIF-1alpha) in a rat model of hypoxic pulmonary arterial hypertension. METHODS: Twenty Wistar rats were divided randomly into normal control and hypoxia groups after 1-week adaptive feeding. Hypoxia group was raised in a homemade organic glass tank with a 24-h continuous supply of air and nitrogen atmospheric mixed gas. And the oxygen concentration of (10.0 +/- 0.5)% was controlled by oxygen monitoring control system. The control group was maintained in room air. Both groups stayed in the same room with the same diet. After 8 weeks, the level of mean pulmonary pressure (mPAP) was measured by right heart catheterization, right ventricular hypertrophy index (RVHI) calculated by the ratio of right ventricle to left ventricle plus septum and hypoxic pulmonary vascular remodeling (HPSR) observed under microscope. And the levels of AlkB and HIF-1alpha mRNA and protein in lungs were measured by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot. RESULTS: At 8 weeks post hypoxia, compared with the control group [11.0 +/- 0.7 mm Hg (1 mm Hg = 0.133 kPa), 0.210 +/- 0.035], the levels of mPAP and RVHI in hypoxia group (33.3 +/- 1.3 mm Hg, 0.448 +/- 0.013) increased significantly (both P < 0.05), the expressions of AlkB mRNA and protein in pulmonary tissue decreased significantly (0.338 +/- 0.085 vs 0.688 +/- 0.020, P < 0.01) (0.483 +/- 0.052 vs 0.204 +/- 0.010, P < 0.01), and the expressions of HIF-1alpha mRNA and protein increased significantly (0.790 +/- 0.161 vs 0.422 +/- 0.096, P < 0.01) (0.893 +/- 0.080 vs 0.346 +/- 0.008, P < 0.01). CONCLUSION: The down-regulation of AlkB in lung tissue may increase the activity of HIF-1 to participate in the occurrence and development of pulmonary hypertension. PMID- 24405548 TI - [2-deoxyglucose enhances chemosensitivity of androgen-independent prostate cancer cells to docetaxel]. AB - OBJECTIVE: To explore the antitumor effects of 2-deoxyglucose (2-DG) plus docetaxel (Doc) on PC3 and DU145 cells and its mechanism. METHODS: The proliferation of cells was detected by methyl thiazolyl tetrazolium (MTT) assay. Then propidium iodide (PI) staining measured apoptotic cells on flow cytometry. ATP assay kit was used to detect ATP content. The expressions of proteins ubiquitinated protein (Ub) and Hsp70 were measured by Western blot. RESULTS: 2-DG could inhibit proliferation of PC3 and DU145 cells in a dose- and time-dependent manner. However, it could not induce apoptosis in PC3 or DU145. The inhibition rates for PC3 proliferation at 48 h by Doc with concentrations of 0.1, 0.5, 2.5 nmol/L were 10.71%, 25.32% and 56.46% respectively. The inhibition rates for DU145 cell proliferation at 48h by Doc with concentrations of 0.1, 0.5, 2.5 nmol/L were 12.28%, 23.94% and 63.43% respectively. The inhibition rates for PC3 cell proliferation by Doc plus 2-DG with a concentration of 1.0 g/L were 27.15%, 58.74% and 87.95% respectively and 29.53%, 59.41%, and 90.48% for DU145 respectively. 2-DG could enhance the effectiveness of inhibition to PC3 and DU145 proliferation by Doc with a synergistic manner (all q>1.15). The apoptotic rates for PC3 and DU145 induced by Doc 0.5 nmol/L plus 2-DG 1.0 g/L at 48 h were 46.49% and 53.64% respectively. The apoptotic rates were significantly higher than Doc 0.5 nmol/L alone (21.30% for PC3 and 18.92% for DU145 respectively) (P < 0.05). The ATP relative concentration for PC3 in 2-DG 1.0 g/L at 0, 12, 24, 48, and 72 h were 13.75, 11.23, 10.19, 9.81 and 9.02 and for DU145 15.00, 12.59, 11.38, 10.54 and 10.37 respectively. Simultaneously, Western blot showed that Ub and Hsp70 protein were expressed intensively. CONCLUSIONS: 2-DG can enhance the sensitivity of androgen-independent prostate cancer cells to docetaxel. Its mechanism may be associated with the decrease of proteasome function. PMID- 24405549 TI - The predictive ability of bleeding risk stratification models in very old patients on vitamin K antagonist treatment for venous thromboembolism: results of the prospective collaborative EPICA study: reply. PMID- 24405550 TI - Sensitivity to permethrin in a Dermacentor reticulatus population from eastern Poland in laboratory study. AB - BACKGROUND: The action of chemical compounds on the Palaearctic tick D. reticulatus (Fabricius) (Acari: Amblyomminae) has been poorly investigated so far. Therefore, the effects of application of permethrin on engorged D. reticulatus females have been assessed, and the survival rate for the different developmental stages of the tick species in its non-parasitic phase of the life cycle was determined upon application of the pyrethroid. METHODS: Each engorged D. reticulatus female, egg batch, unfed larvae (50 specimens), or unfed nymphs (10 specimens) were sprayed with 20 MUl of 0.015625%- 0.250% solutions of a Coopex WP preparation, which corresponded to 0.78125- 12.5 MUg of permethrin, respectively. The effect of permethrin in the preoviposition and oviposition periods was assessed based on the length of the egg development period, number of females capable of laying eggs, number and weight of eggs laid by the females, and indicators of female reproductive rate. Delayed effects of the action of the various permethrin doses were determined by quantitative and qualitative analysis of the course of embryonic development and larval hatch. The effect of permethrin on survival of the different tick stages was assessed at a temperature of 25 degrees C and 90% RH 48 hours after application of permethrin to one to three day old D. reticulatus eggs, seven to ten-day-old unfed larvae and nymphs. RESULTS: The investigations demonstrated that at the doses applied permethrin decreased the reproductive rate of females, but only at the dose of 6.25 MUg/1 specimen was the mean number of laid eggs drastically reduced, which may result in a decrease in tick abundance already in the first generation. The embryonic development of the eggs laid by the females treated with 6.25 and 12.5 MUg of permethrin/1 specimen was highly disturbed. Irrespective of the permethrin dose applied, all eggs died within 48 hours after application. 100% of unfed D. reticulatus larvae and nymphs died within 48 hours after application of permethrin doses of 6.25 MUg/50 specimens and 12.5 MUg/10 specimens, respectively. CONCLUSIONS: Permethrin can be recommended for D. reticulatus control, particularly in the case of tick resistance to other chemical substances. PMID- 24405551 TI - Characterization of T cell phenotype and function in a double transgenic (collagen-specific TCR/HLA-DR1) humanized model of arthritis. AB - INTRODUCTION: T cells orchestrate joint inflammation in rheumatoid arthritis (RA), yet they are difficult to study due to the small numbers of antigen specific cells. The goal of this study was to characterize a new humanized model of autoimmune arthritis and to describe the phenotypic and functional changes that occur in autoimmune T cells following the induction of pathological events. METHODS: We developed a double transgenic mouse containing both the HLA-DR1 transgene and an HLA-DR1-restricted collagen-specific TCR in order to obtain large numbers of antigen-specific T cells that can be used for immunologic studies. RESULTS: In vitro, CII-specific T cells from this mouse proliferated vigorously in response to the CII immunodominant peptide A2 and the cells altered their phenotype to become predominately CD62Llow and CD44high "activated" T cells. The response was accompanied by the production of Th1, Th2, and Th17-type cytokines. Following immunization with bovine CII/CFA, these mice develop an accelerated arthritis compared to single transgenic HLA-DR1 mice. On the other hand, when the mice were treated orally with the analog peptide A12, (a suppressive analog of collagen we have previously described), arthritis was significantly suppressed, despite the fact that >90% of the CD4+ T cells express the TCR Tg. In GALT tissues taken from the A12-treated mice, IL-2, IFN-gamma, and IL-17 production to the autoimmune collagen determinant dropped while high levels of IL-10 and IL-4 were produced. CONCLUSIONS: We have developed a humanized model of autoimmune arthritis that will be useful for the study of T cell directed therapies as well as T cell mediated mechanisms of autoimmune diseases. PMID- 24405552 TI - Plasma oxytocin concentrations are lower in depressed vs. healthy control women and are independent of cortisol. AB - The neuropeptide oxytocin (OT) promotes social behavior and attenuates stress responsivity in mammals. Recent clinical evidence suggests OT concentrations may be dysregulated in major depression. This study extends previous research by testing whether: 1) OT concentrations vary systematically in depressive disorders with and without hypercortisolemia, 2) gender differences in OT concentrations are observed in depressed vs. healthy control participants, and 3) OT concentrations are predictive of clinical phenotypes. Plasma OT concentrations of psychotic major depressive (PMD; n = 14: 10 female, 4 male), non-psychotic major depressive (NPMD; n = 17: 12 female, 5 male), and non-depressed, healthy control (n = 19: 11 female, 8 male) participants were assayed at 2000, 2400, 0400, and 0800 h. Plasma cortisol concentrations were quantified at 2300 h, and clinical phenotypes were determined. As expected, PMD participants, compared to NPMD and healthy control participants, showed higher plasma cortisol concentrations. Although both depressed groups showed similar OT concentrations, a significant interaction effect between group and gender was observed. Specifically, depressed females exhibited lower mean OT concentrations than depressed males. Further, depressed vs. healthy control female participants exhibited lower mean OT concentrations, whereas depressed vs. healthy control male participants showed a trend in the opposite direction. OT concentrations were also predictive of desirability, drug dependence, and compulsivity scores as measured by the Million Clinical Multiaxial Inventory-III. All findings were independent of cortisol. These data suggest that OT signaling may provide a mechanism by which to better understand female-biased risk to develop depressive disorders and that plasma OT concentrations may be a useful biomarker of certain clinical phenotypes. PMID- 24405553 TI - President's page: Celebrating our history and preparing for the future. PMID- 24405554 TI - Update on the American Board of Internal Medicine Maintenance of Certification Program: a report of the American College of Cardiology's Educational Quality Review Board. PMID- 24405555 TI - The ACC promise: a three-fold plan for mastering ABIM's new MOC changes. PMID- 24405556 TI - An ecological analysis of infant neglect by adolescent mothers. AB - To inform efforts to prevent child neglect, we investigated a wide range of risk factors that have been largely unexamined in relation to infant neglect, the most commonly occurring form of child maltreatment. Using an ecological model of child neglect, we assessed the influence of characteristics at the level of the child, the mother, the family, and broader childrearing contexts on adolescent mothers' likelihood of being a perpetrator in a substantiated case of neglect against their firstborn infants (n=383, M=12 months). Several factors were associated with infant neglect by young mothers: median block income, low infant birth weight, maternal smoking, maternal childhood history of neglect and of positive care, intimate partner violence (IPV) perpetrated by either the mother or her partner, and maternal use of mental health services. In multivariate models, income, a maternal childhood history of positive care, IPV by either a mother or her partner, and mental health service usage made significant contributions to the odds that a mother neglected her infant. Our findings suggest that these factors have particular salience to policymakers' and practitioners' efforts to identify high risk families and to intervene during the earliest months of life to prevent child neglect. PMID- 24405557 TI - Association between congenital heart defects and severe infections in children with Down syndrome. AB - INTRODUCTION: There is a high prevalence of congenital heart disease (CHD) in Down syndrome (DS) patients. Children with DS and CHD also present greater susceptibility to pulmonary infections than those without CHD. AIM: To investigate the prevalence and types of CHD and their association with severe infections in children with DS in southern Brazil seen in a reference outpatient clinic. METHODS: Children aged between six and 48 months with a diagnosis of DS were included consecutively in the period May 2001 to May 2012, and the presence of CHD and severe infections (pneumonia and sepsis) was investigated, classified and analyzed. RESULTS: A total of 127 patients were included, of whom 89 (70.1%) had some type of CHD, 33 (37.7%) of them requiring surgical correction. Severe infections (pneumonia and sepsis) were seen in 23.6% and 5.5%, respectively. Of the cases of pneumonia, 70% had associated CHD (p=0.001) and of those with sepsis, 85% presented CHD (p=0.001). CONCLUSIONS: Our study showed a high prevalence of CHD and its association with severe infections in children with DS seen in southern Brazil. PMID- 24405558 TI - Non-ST-elevation myocardial infarction with the use of oxymetazoline nasal spray. AB - Oxymetazoline is an alpha-1 adrenergic receptor agonist that is commonly used for nasal decongestion and is readily available without a prescription. We report the case of a 64-year-old woman who developed prolonged chest pain associated with elevation of cardiac biomarkers after using oxymetazoline. PMID- 24405559 TI - Left ventricular systolic dysfunction detected by speckle tracking in hypertensive patients with preserved ejection fraction. AB - INTRODUCTION: The spectrum of hypertensive heart disease is wide, and can include left ventricular dysfunction. The development of echocardiographic parameters to improve patient stratification and to identify early adverse changes could be clinically useful. Aim To identify subclinical left ventricular dysfunction in hypertensive subjects with preserved ejection fraction (>55%), identified by global parameters of myocardial strain on speckle tracking imaging. METHODS: This was a comparative observational study of two groups of individuals: normotensive (n=20, age 59 +/- 7 years, 55% male) and hypertensive (n=229, age 62 +/- 12 years, 57% male). Left ventricular function was assessed by various conventional clinical and echocardiographic parameters and global longitudinal and circumferential myocardial strain. Cut-off values to detect subclinical left ventricular dysfunction were established and applied in the hypertensive group. The Student's t test, Mann-Whitney test and chi-square test were used for the comparative statistical analysis. RESULTS: Most hypertensive subjects (53.7%) had grade I hypertension; blood pressure was controlled in 64.9%, and 54.8% showed left ventricular structural changes. Comparison between the normotensive and hypertensive groups showed no significant differences in parameters of global longitudinal or circumferential systolic strain. Application of the cut-offs to the hypertensive group identified 35 individuals (15.3%) as having subclinical left ventricular systolic dysfunction as assessed by global longitudinal myocardial strain parameters. CONCLUSIONS: In this group of hypertensive patients, global myocardial strain parameters identified a group of individuals with subclinical left ventricular systolic dysfunction despite preserved ejection fraction. The clinical relevance of these findings needs to be assessed in long term follow-up studies. PMID- 24405560 TI - Alcohol septal ablation in obstructive hypertrophic cardiomyopathy: four years of experience at a reference center. AB - INTRODUCTION: We describe our center's initial experience with alcohol septal ablation (ASA) for the treatment of obstructive hypertrophic cardiomyopathy. The procedure, its indications, results and clinical outcomes will be addressed, as will its current position compared to surgical myectomy. OBJECTIVE: To assess the results of ASA in all patients treated in the first four years of activity at our center. METHODS: We retrospectively studied all consecutive and unselected patients treated by ASA between January 2009 and February 2013. RESULTS: In the first four years of experience 40 patients were treated in our center. In three patients (7.5%) the intervention was repeated. Procedural success was 84%. Minor complications occurred in 7.5%. Two patients received a permanent pacemaker for atrioventricular block (6% of those without previous pacemaker). The major complication rate was 5%. There were no in-hospital deaths; during clinical follow-up (22 +/- 14 months) cardiovascular mortality was 2.5% and overall mortality was 5%. DISCUSSION AND CONCLUSION: The results presented reflect the initial experience of our center with ASA. The success rate was high and in line with published results, but with room to improve with better patient selection. ASA was shown to be safe, with a low complication rate and no procedure-related mortality. Our experience confirms ASA as a percutaneous alternative to myectomy for the treatment of symptomatic patients with obstructive hypertrophic cardiomyopathy refractory to medical treatment. PMID- 24405561 TI - Shortening the Work Preference Inventory for use with physician scientists: WPI 10. AB - The Work Preference Inventory (WPI) is a four-factor, 30-item measure that assesses work motivation. Used to help individuals choose appropriate career paths, its length contributes to response burden, especially when combined with other measures. We aimed to develop a shortened, valid, and reliable version of the WPI. Trainees at the University of Pittsburgh's Institute for Clinical Research Education completed the 30-item WPI between 2007 and 2012. We conducted exploratory and confirmatory factor analyses to reduce the number of items. Of the 402 eligible trainees, 371 (92%) provided data for the exploratory factor analysis (EFA), and 134 of the eligible 144 trainees (93%) provided data for the confirmatory factor analysis (CFA). EFA revealed four factors that were roughly equivalent to those of the original. CFA used the three items with the highest loadings on each factor, with two items removed due to low loadings and R squareds, resulting in a 10-item scale. Cronbach's alpha for each of the four factors ranged from 0.68 to 0.76. Factors in the WPI-10 were strongly and significantly associated with factors in the original WPI, indicating strong validity of the shortened measure. The WPI-10 shows evidence for similar validity and reliability to the original instrument while reducing respondent burden. PMID- 24405562 TI - HpaP modulates type III effector secretion in Ralstonia solanacearum and harbours a substrate specificity switch domain essential for virulence. AB - Many pathogenic bacteria have evolved a type III secretion system (T3SS) to successfully invade their host. This extracellular apparatus allows the translocation of proteins, called type III effectors (T3Es), directly into the host cells. T3Es are virulence factors that have been shown to interfere with the host's immunity or to provide nutrients from the host to the bacteria. The Gram negative bacterium Ralstonia solanacearum is a worldwide major crop pest whose virulence strongly relies on the T3SS. In R. solanacearum, transcriptional regulation has been extensively studied. However, very few data are available concerning the role played by type III-associated regulators, such as type III chaperones and T3SS control proteins. Here, we characterized HpaP, a putative type III secretion substrate specificity switch (T3S4) protein of R. solanacearum which is not secreted by the bacterium or translocated in the plant cells. HpaP self-interacts and interacts with the PopP1 T3E. HpaP modulates the secretion of early (HrpY pilin) and late (AvrA and PopP1 T3Es) type III substrates. HpaP is dispensable for the translocation of T3Es into the host cells. Finally, we identified two regions of five amino acids in the T3S4 domain that are essential for efficient PopP1 secretion and for HpaP's role in virulence on tomato and Arabidopsis thaliana, but not required for HpaP-HpaP and HpaP-PopP1 interactions. Taken together, our results indicate that HpaP is a putative R. solanacearum T3S4 protein important for full pathogenicity on several hosts, acting as a helper for PopP1 secretion, and repressing AvrA and HrpY secretion. PMID- 24405563 TI - Molecular rotor-based fluorescent probe for selective recognition of hybrid G quadruplex and as a K+ sensor. AB - This work demonstrates the significant fluorescence enhancement of thioflavin T (ThT) when binding to G-quadruplexes possessing hybrid structures by using UV-vis absorption spectra, fluorescence spectra, and Tm experiments to confirm the binding events. ThT binding does not disturb native G-quadruplex structures preformed in Na(+) and K(+) solutions. The fluorescence enhancement is caused by the rotation restriction of benzothiazole (BZT) and dimethylaminobenzene (DMAB) rings in the ThT excited state upon its G-quadruplex binding. This molecular rotor mechanism as a means of fluorescence enhancement is confirmed using a nonrotor analogue of ThT. Hydroxylation and electrolyte experiments demonstrate that ThT stacks on the tetrad of the hybrid G-quadruplexes, whereas electrostatic forces contribute more to ThT binding for other G-quadruplex structures. By stacking on the tetrad, the ThT binding favors selective identification of DNA hybrid G-quadruplex structures with enhanced fluorescence and can serve as a conformation probe to monitor G-quadruplex structure conversion between hybrid and other structures. Using these properties, we developed a selective and label free fluorescent K(+) sensor with a detection limit of 1 mM for K(+) in the presence of 100 mM Na(+). The coexistence of other metal ions produces a fluorescence response comparable to K(+) alone. We believe that ThT can potentially provide structure identification of hybrid G-quadruplexes and aid in the construction of G-quadruplex-based sensors. PMID- 24405564 TI - Incarceration among street-involved youth in a Canadian study: implications for health and policy interventions. AB - BACKGROUND: Risk factors for incarceration have been well described among adult drug using populations; however, less is known about incarceration among at-risk youth. This study examines the prevalence and correlates of incarceration among street-involved youth in a Canadian setting. METHODS: From September 2005 to May 2012, data were collected from the At-Risk Youth Study, a prospective cohort of street-involved youth aged 14-26 who use illicit drugs. Generalized estimating equation (GEE) logistic regression was used to identify factors associated with recent incarceration defined as incarceration in the previous six months. RESULTS: Among 1019 participants, 362 (36%) reported having been recently incarcerated during the study period. In multivariate GEE analysis, homelessness (adjusted odds ratio [AOR]=1.60), daily crystal methamphetamine use (AOR=1.56), public injecting (AOR=1.33), drug dealing (AOR=1.48) and being a victim of violence (AOR=1.68) were independently associated with incarceration (all p<0.05). Conversely, female gender (AOR=0.48), lesbian, gay, bisexual, transgender or two-spirited (LGBTT) identification (AOR=0.47) and increasing age of first hard drug use (AOR=0.96) were negatively associated with incarceration (all p<0.05). CONCLUSION: Incarceration was common among our study sample. Youth who were homeless, used crystal methamphetamine, and engaged in risky behaviors including public injection and drug dealing were significantly more likely to have been recently incarcerated. Structural interventions including expanding addiction treatment and supportive housing for at-risk youth may help reduce criminal justice involvement among this population and associated health, social and fiscal costs. PMID- 24405565 TI - Phase I dose-escalation study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in Japanese patients with advanced solid tumors. AB - Buparlisib (BKM120) is an oral pan-phosphatidylinositol 3-kinase inhibitor, targeting all four isoforms of class I PI3K (alpha, beta, gamma and delta). This open-label Phase I dose-escalation study was conducted to determine the maximum tolerated dose of continuous daily buparlisib in Japanese patients with advanced solid tumors. Secondary objectives included safety and tolerability, pharmacokinetics, antitumor activity and pharmacodynamic marker changes. Fifteen patients were treated at 25 mg/day (n = 3), 50 mg/day (n = 3) and 100 mg/day (n = 9) dose levels. One dose-limiting toxicity of Grade 4 abnormal liver function occurred at 100 mg/day. Considering the safety profile and the maximum tolerated dose in the first-in-man study of buparlisib in non-Japanese patients, further dose escalation was stopped and 100 mg/day was declared the recommended dose. The most common treatment-related adverse events were rash, abnormal hepatic function (including increased transaminase levels), increased blood insulin levels and increased eosinophil count. Hyperglycemia was experienced by two patients, one Grade 1 and one Grade 4, and mood alterations were experienced by three patients, two Grade 1 and one Grade 2. Pharmacokinetic results showed that buparlisib was rapidly absorbed in a dose-proportional manner. Best overall response was stable disease for six patients, including one unconfirmed partial response. In these Japanese patients with advanced solid tumors, buparlisib had a manageable safety profile, with similar pharmacokinetics to non-Japanese patients. The recommended dose of 100 mg/day will be used in future studies of buparlisib in Japanese patients. PMID- 24405566 TI - Influence of loading rate on patellar tendon mechanical properties in vivo. AB - BACKGROUND: Rate-dependent properties of tendons have consistently been observed in vitro but in vivo studies comparing the effects of loading duration on this feature remain conflicting. The main purpose of the present study was to evaluate whether tendon loading rate per se would affect in vivo tendon mechanical properties. METHODS: Twenty-two physically active male subjects were recruited. Patellar tendon deformation was recorded with ultrasonography under voluntary isometric contractions at rates of 50, 80 and 110Nm/s, controlled via visual feedback. FINDINGS: Subjects were able to accurately generate all three loading rates (Accuracy=2% to 15%), with a greater steadiness at 50 (CV=12.4%) and 110Nm/s (CV=13.1%) than at 80Nm/s (CV=22.9%). Loading rate did not appreciably affect strain or stress. However, stiffness (np(2)=0.555) and Youngs's Modulus (np(2)=0.670) were significantly higher at 80Nm/s (21.4% and 21.6%, respectively) and at 110Nm/s (32.5% and 32.0%, respectively) than at 50Nm/s. Similarly, stiffness and Young's modulus were 9.9% and 8.8% higher, respectively, at 110Nm/s than at 80Nm/s. INTERPRETATION: These results indicate that in vivo measurements of patellar tendon mechanics are influenced by loading rate. Moreover, they bear important methodological implications for in vivo assessment of mechanical properties of this tendon and possibly other human tendons. PMID- 24405567 TI - An animal model to evaluate skin-implant-bone integration and gait with a prosthesis directly attached to the residual limb. AB - BACKGROUND: Despite the number of advantages of bone-anchored prostheses, their use in patients is limited due to the lack of complete skin-implant integration. The objective of the present study was to develop an animal model that would permit both detailed investigations of gait with a bone-anchored limb prosthesis and histological analysis of the skin-implant-bone interface after physiological loading of the implant during standing and walking. METHODS: Full-body mechanics of walking in two cats were recorded and analyzed before and after implantation of a percutaneous porous titanium pylon into the right tibia and attachment of a prosthesis. The rehabilitation procedures included initial limb casting, progressively increasing loading on the implant, and standing and locomotor training. Detailed histological analysis of bone and skin ingrowth into implant was performed at the end of the study. FINDINGS: The two animals adopted the bone anchored prosthesis for standing and locomotion, although loads on the prosthetic limb during walking decreased by 22% and 62%, respectively, 4months after implantation. The animals shifted body weight to the contralateral side and increased propulsion forces by the contralateral hindlimb. Histological analysis of the limb implants demonstrated bone and skin ingrowth. INTERPRETATION: The developed animal model to study prosthetic gait and tissue integration with the implant demonstrated that porous titanium implants may permit bone and skin integration and prosthetic gait with a bone-anchored prosthesis. Future studies with this model will help optimize the implant and prosthesis properties. PMID- 24405568 TI - Effects of walking with loads above the ankle on gait parameters of persons with hemiparesis after stroke. AB - BACKGROUND: Walking with a load at the ankle during gait training is a simple way to resist lower limb movements to induce functional muscle strengthening. This study investigated the effects of walking with different loads attached above the paretic ankle on biomechanical gait parameters during over ground walking in post stroke participants. METHODS: Ten participants with moderate chronic hemiparesis were evaluated while walking over ground with three different loads (0.5, 1.0, and 1.5kg) attached above the paretic ankle. Gait speed, cadence, step lengths as well as hip and knee angular displacements, joint moments and power of the paretic limb were compared while walking with and without loads. FINDINGS: Walking with a load led to an increased in gait speed (+0.03-0.05m/s), and in step length of the paretic leg (+5.6 to 9.4% step length, effect size=0.49-0.63), but not of the non-paretic leg. The proportion of the stance and swing phases did not change. Maximal joint moments (+20 to 48%, effect size=0.26-0.55) and power (+20 to 114%, effect size=0.30-0.57) increases varied across participants but were mostly affected in early stance at the hip and during the late swing phase at the knee. Mean angular displacement changes were less than 4 degrees . INTERPRETATION: Post-stroke participants are able to increase hip and knee power bursts to meet the increased mechanical demand of added loads attached to the paretic ankle, while preserving the basic pattern of walking. Further study is needed before using loading to functionally strengthen paretic muscles. PMID- 24405570 TI - The effectiveness of sexual health interventions for people with severe mental illness: a systematic review. AB - BACKGROUND: Severe mental illnesses (SMIs), such as schizophrenia and bipolar disorder, persist over time and can cause extensive disability leading to impairments in social and occupational functioning. People with SMI have higher morbidity and mortality due to physical illness than the general population and may be more likely to engage in high-risk sexual behaviour (e.g. unprotected intercourse, having multiple partners, involvement in the sex trade and illicit drug use), putting them at risk of poorer sexual health outcomes including sexually transmitted infections. Sexual health promotion interventions, developed and implemented for people with SMI, may improve participants' knowledge, attitudes, beliefs or behavioural practices and could lead to a reduction in risky sexual behaviour. OBJECTIVES: To evaluate the effectiveness of sexual health interventions for people with SMI compared with usual care and their applicability to the UK NHS setting. DATA SOURCES: Thirteen electronic databases were searched from inception to December 2012. All controlled trials (randomised or non-randomised) that met the following criteria were included: any sexual health promotion intervention or combination of interventions intended to change the knowledge, attitudes, beliefs, behaviours or practices of individuals with SMI (defined as adults aged >= 18 years who have received a diagnosis of schizophrenia or bipolar disorder) living in the community. REVIEW METHODS: A systematic review of the clinical evidence was undertaken following recommended guidelines. Data were tabulated and discussed in a narrative review. RESULTS: Thirteen randomised controlled studies met the inclusion criteria. The methodological quality of the included studies varied considerably, with only a minority of studies (n = 2) being considered as having very few methodological limitations. Despite wide variations in the study populations, interventions, comparators and outcomes, four studies showed significant improvements in all measured sexual risk behaviour outcomes (e.g. human immunodeficiency virus knowledge and behaviour change) in the intervention groups compared with the control groups. In contrast, four studies found significant improvements in the intervention groups for some outcomes only and three studies found significant improvements in certain subgroups only, based on either gender or ethnicity. Finally, two studies reported no significant differences in any sexual risk behaviour outcomes between the intervention and control groups. Moreover, positive findings were not consistently sustained at follow-up in many studies. LIMITATIONS: Little detail was provided in the studies regarding the content of interventions, how they were delivered and by whom, making replication or generalisability difficult. CONCLUSIONS: Owing to the large between-study variability (especially in the populations, interventions, comparators and reported outcomes) and mixed results, there is insufficient evidence to fully support or reject the identified sexual health interventions for people with SMI. In addition, there are considerable uncertainties around the generalisability of these findings to the UK setting. Further research recommendations include well designed, UK-based trials of sexual health interventions for people with SMI as well as training and support for staff implementing sexual health interventions. STUDY REGISTRATION: PROSPERO number CRD42013003674. FUNDING: The National Institute for Health Research Health Technology Assessment Programme. PMID- 24405569 TI - Telomere shortening correlates to dysplasia but not to DNA aneuploidy in longstanding ulcerative colitis. AB - BACKGROUND: Ulcerative colitis (UC) is a chronic, inflammatory bowel disease which may lead to dysplasia and adenocarcinoma in patients when long-lasting. Short telomeres have been reported in mucosal cells of UC patients. Telomeres are repetitive base sequences capping the ends of linear chromosomes, and protect them from erosion and subsequent wrongful recombination and end-to-end joining during cell division. Short telomeres are associated with the development of chromosomal instability and aneuploidy, the latter being risk factors for development of dysplasia and cancer. Specifically, the abrupt shortening of one or more telomeres to a critical length, rather than bulk shortening of telomeres, seems to be associated with chromosomal instability. METHODS: We investigated possible associations between dysplasia, aneuploidy and telomere status in a total of eight lesions from each of ten progressors and four nonprogressors suffering from longstanding UC. We have analyzed mean telomere length by qPCR, as well as the amount of ultra-short telomeres by the Universal STELA method. RESULTS: An increased amount of ultra-short telomeres, as well as general shortening of mean telomere length are significantly associated with dysplasia in longstanding UC. Furthermore, levels of ultra-short telomeres are also significantly increased in progressors (colons harbouring cancer/dysplasia and/or aneuploidy) compared to nonprogressors (without cancer/dysplasia/aneuploidy), whereas general shortening of telomeres did not show such associations. CONCLUSIONS: Our data suggest that ultra-short telomeres may be more tightly linked to colorectal carcinogenesis through development of dysplasia in UC than general telomere shortening. Telomere status was not seen to associate with DNA aneuploidy. PMID- 24405572 TI - Developmental origins of diversity in cerebellar output nuclei. AB - BACKGROUND: The functional integration of the cerebellum into a number of different neural systems is governed by the connection of its output axons. In amniotes, the majority of this output is mediated by an evolutionarily diverse array of cerebellar nuclei that, in mice, are derived from the embryonic rhombic lip. To understand the origins of cerebellar nucleus diversity, we have explored how nucleus development is patterned in birds, which notably lack a dentate-like nucleus output to the dorsal thalamus. RESULTS: Using targeted in ovo electoroporation of green fluorescent protein (GFP) and red fluorescent protein (RFP) in a variety of combinations and with different conditional enhancers, we show that cerebellar nuclei in chicks are produced, as in the mouse, at the rhombic lip. Furthermore, the comparison of fate-mapped neurons with molecular markers reveals a strict temporal sequence of cell fate allocation in establishing the avian lateral and medial cerebellar nuclei. In contrast to the mouse cerebellum, Lhx9 expression is confined to extracerebellar thalamic afferent nuclei corresponding to the absence, in chicks, of a dentate nucleus. Spatiotemporally targeted over-expression of Lhx9 in chick cerebellar nuclei (recapitulating in part the mammalian expression pattern) results in a loss of distinct nuclear boundaries and a change in axon initial trajectories consistent with a role for Lhx9 specifying targeting. CONCLUSIONS: Our results confirm the relationship between cell fate and a fine grain temporal patterning at the rhombic lip. This suggests that the lack of a cerebellar output to the dorsal thalamus of birds corresponds with a restricted expression of the LIM-homeodomain gene Lhx9 to earlier born rhombic lip cohorts when compared to mice. The evolution of cerebellar nucleus diversity in amniotes may hence reflect a heterochronic adaptation of gene expression with respect to the sequential production of rhombic lip derivatives resulting in altered axonal targeting. PMID- 24405571 TI - Habitual fish intake and clinically silent carotid atherosclerosis. AB - BACKGROUND: Fish consumption is recommended as part of a healthy diet. However, there is a paucity of data concerning the relation between fish consumption and carotid atherosclerosis. We investigated the association between habitual fish consumption and asymptomatic carotid atherosclerosis, defined as the presence of plaques and/or increased intima-media thickness (>= 0.90 mm), in non-diabetic participants. METHODS: Nine hundred-sixty-one (range of age: 18-89 yrs; 37.1% males) adult participants without clinically known atherosclerotic disease were randomly recruited among the customers of a shopping mall in Palermo, Italy, and cross-sectionally investigated. Each participant answered a food frequency questionnaire and underwent high-resolution ultrasonographic evaluation of both carotid arteries. Routine laboratory blood measurements were obtained in a subsample of 507 participants. RESULTS: Based on habitual fish consumption, participants were divided into three groups: non-consumers or consumers of less than 1 serving a week (24.0%), consumers of 1 serving a week (38.8%), and consumers of >= 2 servings a week (37.2%). Age-adjusted prevalence of carotid atherosclerosis (presence of plaques or intima media thickness >= 0.9 mm) was higher in the low fish consumption group (13.3%, 12.1% and 6.6%, respectively; P = 0.003). Multivariate analysis evidenced that carotid atherosclerosis was significantly associated with age (OR = 1.12; 95% CI = 1.09-1.14), hypertension on pharmacologic treatment (OR = 1.81; 95% CI = 1.16-2.82), and pulse pressure (OR = 1.03; 95% CI = 1.01-1.04), while consuming >=2 servings of fish weekly was protective compared with the condition of consumption of <1 serving of fish weekly (OR = 0.46; 95% CI = 0.26-0.80). CONCLUSIONS: High habitual fish consumption seems to be associated with less carotid atherosclerosis, though adequate interventional trials are necessary to confirm the role of fish consumption in prevention of cardiovascular disease. PMID- 24405575 TI - All-Wales licensed premises intervention (AWLPI): a randomised controlled trial to reduce alcohol-related violence. AB - BACKGROUND: Alcohol-related violence in and in the vicinity of licensed premises continues to place a considerable burden on the United Kingdom's (UK) health services. Robust interventions targeted at licensed premises are therefore required to reduce the costs of alcohol-related harm. Previous evaluations of interventions in licensed premises have a number of methodological limitations and none have been conducted in the UK. The aim of the trial was to determine the effectiveness of the Safety Management in Licensed Environments intervention designed to reduce alcohol-related violence in licensed premises, delivered by Environmental Health Officers, under their statutory authority to intervene in cases of violence in the workplace. METHODS/DESIGN: A national randomised controlled trial, with licensed premises as the unit of allocation. Premises were identified from all 22 Local Authorities in Wales. Eligible premises were those with identifiable violent incidents on premises, using police recorded violence data. Premises were allocated to intervention or control by optimally balancing by Environmental Health Officer capacity in each Local Authority, number of violent incidents in the 12 months leading up to the start of the project and opening hours. The primary outcome measure is the difference in frequency of violence between intervention and control premises over a 12 month follow-up period, based on a recurrent event model. The trial incorporates an embedded process evaluation to assess intervention implementation, fidelity, reach and reception, and to interpret outcome effects, as well as investigate its economic impact. DISCUSSION: The results of the trial will be applicable to all statutory authorities directly involved with managing violence in the night time economy and will provide the first formal test of Health and Safety policy in this environment. If successful, opportunities for replication and generalisation will be considered. TRIAL REGISTRATION: UKCRN 14077; ISRCTN78924818. PMID- 24405573 TI - Pregnancy-associated breast cancers are driven by differences in adipose stromal cells present during lactation. AB - INTRODUCTION: The prognosis of breast cancer is strongly influenced by the developmental stage of the breast when the tumor is diagnosed. Pregnancy associated breast cancers (PABCs), cancers diagnosed during pregnancy, lactation, or in the first postpartum year, are typically found at an advanced stage, are more aggressive and have a poorer prognosis. Although the systemic and microenvironmental changes that occur during post-partum involution have been best recognized for their role in the pathogenesis of PABCs, epidemiological data indicate that PABCs diagnosed during lactation have an overall poorer prognosis than those diagnosed during involution. Thus, the physiologic and/or biological events during lactation may have a significant and unrecognized role in the pathobiology of PABCs. METHODS: Syngeneic in vivo mouse models of PABC were used to examine the effects of system and stromal factors during pregnancy, lactation and involution on mammary tumorigenesis. Mammary adipose stromal cell (ASC) populations were isolated from mammary glands and examined by using a combination of in vitro and in vivo functional assays, gene expression analysis, and molecular and cellular assays. Specific findings were further investigated by immunohistochemistry in mammary glands of mice as well as in functional studies using ASCs from lactating mammary glands. Additional findings were further investigated using human clinical samples, human stromal cells and using in vivo xenograft assays. RESULTS: ASCs present during lactation (ASC-Ls), but not during other mammary developmental stages, promote the growth of carcinoma cells and angiogenesis. ASCs-Ls are distinguished by their elevated expression of cellular retinoic acid binding protein-1 (crabp1), which regulates their ability to retain lipid. Human breast carcinoma-associated fibroblasts (CAFs) exhibit traits of ASC Ls and express crabp1. Inhibition of crabp1in CAFs or in ASC-Ls abolished their tumor-promoting activity and also restored their ability to accumulate lipid. CONCLUSIONS: These findings imply that (1) PABC is a complex disease, which likely has different etiologies when diagnosed during different stages of pregnancy; (2) both systemic and local factors are important for the pathobiology of PABCs; and (3) the stromal changes during lactation play a distinct and important role in the etiology and pathogenesis of PABCs that differ from those during post-lactational involution. PMID- 24405574 TI - The impact of human hyperekplexia mutations on glycine receptor structure and function. AB - Hyperekplexia is a rare neurological disorder characterized by neonatal hypertonia, exaggerated startle responses to unexpected stimuli and a variable incidence of apnoea, intellectual disability and delays in speech acquisition. The majority of motor defects are successfully treated by clonazepam. Hyperekplexia is caused by hereditary mutations that disrupt the functioning of inhibitory glycinergic synapses in neuromotor pathways of the spinal cord and brainstem. The human glycine receptor alpha1 and beta subunits, which predominate at these synapses, are the major targets of mutations. International genetic screening programs, that together have analysed several hundred probands, have recently generated a clear picture of genotype-phenotype correlations and the prevalence of different categories of hyperekplexia mutations. Focusing largely on this new information, this review seeks to summarise the effects of mutations on glycine receptor structure and function and how these functional alterations lead to hyperekplexia. PMID- 24405577 TI - Only one of the two type VI secretion systems encoded in the Salmonella enterica serotype Dublin genome is involved in colonization of the avian and murine hosts. AB - The type VI secretion system (T6SS) is a virulence factor for many Gram-negative bacteria. Salmonella genus harbors five phylogenetically distinct T6SS loci encoded in Salmonella Pathogenicity Islands (SPIs) SPI-6, SPI-19, SPI-20, SPI-21 and SPI-22, which are differentially distributed among serotypes. The T6SSs encoded in SPI-6 and SPI-19 contribute to pathogenesis of serotypes Typhimurium and Gallinarum in mice and chickens, respectively. Salmonella Dublin is a pathogen restricted to cattle where it causes a systemic disease. Also, it can colonize other hosts such as chickens and mice, which can act as reservoirs of this serotype. Salmonella Dublin harbors the genes for both T6SS(SPI-6) and T6SS(SPI-19). This study has determined the contribution of T6SS(SPI-6) and T6SS(SPI-19) to host-colonization by Salmonella Dublin using avian and murine models of infection. Competitive index experiments showed that, a mutant strain lacking both T6SSs (?T6SS(SPI-6)/?T6SS(SPI-19)) presents a strong colonization defect in cecum of chickens, similar to the defect observed for the ?T6SS(SPI-6) mutant, suggesting that this serotype requires a functional T6SS(SPI-6) for efficient colonization of the avian gastrointestinal tract. Colonization of mice was also defective, although to a lesser extent than in chickens. In contrast, the T6SS(SPI-19) was not necessary for colonization of either chickens or mice. Transfer of T6SS(SPI-6), but not T6SS(SPI-19), restored the ability of the double mutant to colonize both animal hosts. Our data indicate that Salmonella Dublin requires only the T6SS(SPI-6) for efficient colonization of mice and chickens, and that the T6SS(SPI-6) and T6SS(SPI-19) are not functionally redundant. PMID- 24405576 TI - Molecular characterization and in vitro differentiation of feline progenitor-like amniotic epithelial cells. AB - INTRODUCTION: While amniotic mesenchymal cells have been isolated and characterized in different species, amniotic epithelial cells (AECs) have been found only in humans and horses and are recently considered valid candidates in regenerative medicine. The aim of this work is to obtain and characterize, for the first time in the feline species, presumptive stem cells from the epithelial portion of the amnion (AECs) to be used for clinical applications. METHODS: In our study, we molecularly characterized and induced in vitro differentiation of feline AECs, obtained after enzymatic digestion of amnion. RESULTS: AECs displayed a polygonal morphology and the mean doubling time value was 1.94 +/- 0.04 days demonstrating the high proliferating capacity of these cells. By RT PCR, AECs expressed pluripotent (Oct4, Nanog) and some mesenchymal markers (CD166, CD44) suggesting that an epithelial-mesenchymal transition may occur in these cells that lack the hematopoietic marker CD34. Cells also showed the expression of embryonic marker SSEA-4, but not SSEA-3, as demonstrated by immunocytochemistry and flow cytometry. Moreover, the possibility to use feline AECs in cell therapies resides in their low immunogenicity, due to the absence of MHC-II antigen expression. After induction, AECs differentiated into the mesodermic and ectodermic lineages, demonstrating high plasticity. CONCLUSIONS: In conclusion, feline AECs appear to be a readily obtainable, highly proliferative, multipotent and non-immunogenic cell line from a source that may represent a good model system for stem cell biology and be useful in allogenic cell-based therapies in order to treat tissue lesions, especially with loss of substance. PMID- 24405579 TI - People United to Sustain Health (PUSH): a community-based participatory research study. AB - The prevention of weight gain to address the obesity epidemic rather than weight loss involves promoting small changes in food choices and physical activity. People United to Sustain Health (PUSH) was designed to increase fruit and vegetable consumption, physical activity, and food security to prevent weight gain in rural adults. Forty-nine participants were randomized into a treatment group which received access to a "Rolling Store," nutrition education and physical activity, and a control group which received family coping classes. Forty-one (84%) of participants completed the study. At the end of 6 months, weight for all participants was maintained from baseline to completion with no significant differences between the groups. The mean fruit consumption over 6 months for the treatment group increased and was significantly greater than change in the control group (p = 0.01). This community-based participatory research study was considered successful because weight gain was prevented. PMID- 24405578 TI - Neurocognitive and neuroinflammatory correlates of PDYN and OPRK1 mRNA expression in the anterior cingulate in postmortem brain of HIV-infected subjects. AB - Chronic inflammation may contribute to neuropsychological impairments in individuals with HIV, and modulation of this inflammatory response by opiate receptor ligands is important in light of the prevalence of drug use in HIV populations. Exogenous MOR and KOR agonists have differential effects on central nervous system (CNS) immunity and, while some data suggest KOR agonists are immunosuppressive, the KOR agonist dynorphin has been shown to stimulate human monocyte chemotaxis. In this study, we examined mRNA levels of endogenous opioid receptors OPRK1 and OPRM1, prodynorphin (PDYN), macrophage scavenger receptor CD163, and microglia/macrophage marker CD68 in the caudate and anterior cingulate of postmortem brains from HIV-positive and HIV-negative subjects. Brain tissues of HIV-infected (n = 24) and control subjects (n = 15) were obtained from the Manhattan HIV Brain Bank. Quantification of the gene mRNA was performed using SYBR Green RT-PCR. CD68 and CD163 were increased in HIV-positive (HIV+) compared to HIV-negative (HIV-) individuals in both brain regions. There were higher OPRK1 (P <0.005), and lower PDYN mRNA (P <0.005) levels in the anterior cingulate of HIV+ compared to HIV- subjects. This difference between the clinical groups was not found in the caudate. There was no difference in the levels of OPRM1 mRNA between HIV+ and HIV- subjects. Using linear regression analysis, we examined the relationship of OPRK1 and PDYN mRNA levels in the HIV+ subjects with seven cognitive domain T scores of a neuropsychological test battery. Within the HIV+ subjects, there was a positive correlation between anterior cingulate PDYN mRNA levels and better T-scores in the motor domain. Within the HIV+ subjects there were also positive correlations of both OPRK1 and PDYN mRNA levels with the anti inflammatory marker CD163, but not with proinflammatory CD68 levels. In this setting, decreased PDYN mRNA may reflect a homeostatic mechanism to reduce monocyte migration, accompanied by compensatory increases in the cognate receptor (KOR) to dampen pro-inflammatory responses. It is possible that enhanced neuroprotection and better motor performance are associated with higher levels of dynorphin and the recruitment of neuroprotective CD163-positive macrophages. Further studies are needed to test this hypothesis. PMID- 24405580 TI - Transcription factor SCL/TAL1 mediates the phosphorylation of MEK/ERK pathway in umbilical cord blood CD34+ stem cells during hematopoietic differentiation. AB - Transcription factor stem cell leukemia (SCL), also known as the T-cell acute lymphocytic leukemia 1 (TAL1), plays a key role in the regulation of hematopoiesis, but the molecular mechanisms are not well understood. The aim of the present study is to elucidate the effects of the epidermal growth factor receptor (EGFR) signal pathways underlying the biologic activity of SCL/TAL1 on normal hematopoietic development. Lentiviral vectors with up or down-regulation of SCL/TAL1 were transfected into umbilical cord blood CD34 stem cells. EGFR signaling pathways (including MEK/ERK and Akt/mTOR) and surface hematopoietic markers were analyzed in the process of hematopoietic differentiation. The data revealed that up or down-regulation of SCL/TAL1 gene was accompanied positively by the expressions of p-MEK and p-ERK1/2 protein, but the changes of Akt/mTOR were unobvious. MEK/ERK inhibitor U0126 and SCL/TAL1 down-regulation showed similar inhibitory effects on erythroid, myeloid, and megakaryoid differentiation. However, Akt/mTOR pathway altered insignificantly. MEK/ERK inhibitor U0126 could not affect the expression of SCL/TAL1 mRNA or protein. Taken together, these findings fully illustrated that SCL/TAL1 is located in the up-stream of MEK/ERK pathway and partially regulates hematopoiesis by modulating the phosphorylation level of the key proteins in MEK/ERK pathway. PMID- 24405581 TI - Age-related changes in generalized anxiety disorder symptoms. AB - BACKGROUND: Little is known about the effects of age on the symptoms of anxiety disorder. Accordingly, this study sought to investigate age-related differences in the number and kind of symptoms that distinguish between individuals with and without a diagnosis of generalized anxiety disorder (GAD). METHODS: A sample of 3,486 self-reported worriers was derived from Wave 1 of the National Epidemiological Survey of Alcohol and Related Conditions (NESARC), an epidemiological survey of mental health conducted in the U.S.A. in 2001-2002. Participants were stratified into the following age groups (18-29 years, 30-44 years, 45-64 years, 65-98 years), and then divided into diagnostic groups (GAD and non-GAD worriers). RESULTS: Binary logistic regression analyses revealed that four distinct sets of symptoms were associated with GAD in each age group, and that numerically fewer symptoms were associated with GAD in older adults. Moreover, there were graduated changes in the type and number of symptoms associated with GAD in each successive age group. CONCLUSIONS: There are graduated, age-related differences in the phenomenology of GAD that might contribute to challenges in the detection of late-life anxiety. PMID- 24405582 TI - Response to low bone mineral areal density in patients with sickle cell anaemia (SCA) and short stature should be interpreted with caution. PMID- 24405583 TI - Contact activation: important to consider when measuring the contribution of tissue factor-bearing microparticles to thrombin generation using phospholipid containing reagents. AB - BACKGROUND: A commercial MP reagent containing phospholipids is used for thrombin generation (TG) measurements to estimate the procoagulant activity of microparticles (MPs). Previous reports have shown that contact activation affects TG when TF levels are low, and that addition of phospholipids might augment this effect. OBJECTIVES: To quantify the impact of contact activation on TG in the presence of phospholipids and low/no TF, as is the case using a commercially available MP-reagent. METHODS: Thrombin generation was analyzed using MP- or platelet-rich plasma (PRP)-reagent in the presence and absence of corn trypsin inhibitor and anti-TF antibodies, respectively. To quantify the impact of different experimental parameters on contact activation, microparticle-depleted plasma was analyzed in the presence of different concentrations of phospholipids, TF and/or contact activating agents (kaolin). RESULTS: Even with low contact activating blood collection tubes, substantial thrombin generation was observed with the MP-reagent, but this was completely inhibited by addition of corn trypsin inhibitor. Control experiments illustrate that the phospholipids in the reagent play a major role in enhancing TG initiated by FXIIa. Even with the PRP reagent, which is recommended for determining the content of phospholipids from MPs, TG was partly dependent on contact activation. CONCLUSIONS: Contact activation plays a major role in TG when using reagents/samples containing phospholipids but little or no tissue factor. This needs to be considered and accounted for in future clinical studies using TG to assess the procoagulant activity of MPs. PMID- 24405584 TI - Frailty among rural elderly adults. AB - BACKGROUND: This study aimed to estimate the prevalence and associated factors related to frailty, by Fried criteria, in the elderly population in a rural area in the Andes Mountains, and to analyze the relationship of these with comorbidity and disability. METHODS: A cross-sectional study was undertaken involving 1878 participants 60 years of age and older. The frailty syndrome was diagnosed based on the Fried criteria (weakness, low speed, low physical activity, exhaustion, and weight loss). Variables were grouped as theoretical domains and, along with other potential confounders, were placed into five categories: (a) demographic and socioeconomic status, (b) health status, (c) self-reported functional status, (d) physical performance-based measures, and (e) psychosocial factors. Chi square, ANOVA, and multinomial logistic regression analyses were used to test the prognostic value of frailty for the outcomes of interest. RESULTS: The prevalence of frailty was 12.2%. Factors associated with frailty were age, gender, health status variables that included self-perceived health and number of chronic conditions, functional covariate variables that included disability in activities in daily living (ADL), disabilities in instrumental ADL, chair stand time, and psychosocial variables that included depressive symptoms and cognitive impairment. Higher comorbidity and disability was found in frail elderly people. Only a subset of frail elderly people (10%) reported no disease or disability. CONCLUSIONS: A relevant number of elderly persons living in rural areas in the Andes Mountains are frail. The prevalence of frailty is similar to that reported in other populations in the Latin American region. Our results support the use of modified Cardiovascular Health Study criteria to measure frailty in communities other than urban settings. Frailty in this study was strongly associated with comorbidities, and frailty and comorbidity predicted disability. PMID- 24405585 TI - Locomotion in caterpillars. AB - Most species of caterpillar move around by inching or crawling. Their ability to navigate in branching three-dimensional structures makes them particularly interesting biomechanical subjects. The mechanism of inching has not been investigated in detail, but crawling is now well understood from studies on caterpillar neural activity, dynamics and structural mechanics. Early papers describe caterpillar crawling as legged peristalsis, but recent work suggests that caterpillars use a tension-based mechanism that helps them to exploit arboreal niches. Caterpillars are not obligate hydrostats but instead use their strong grip to the substrate to transmit forces, in effect using their environment as a skeleton. In addition, the gut which accounts for a substantial part of the caterpillar's weight, moves independently of the body wall during locomotion and may contribute to crawling dynamics. Work-loop analysis of caterpillar muscles shows that they are likely to act both as actuators and energy dissipaters during crawling. Because caterpillar tissues are pseudo elastic, and locomotion involves large body deformations, moving is energetically inefficient. Possession of a soft body benefits caterpillars by allowing them to grow quickly and to access remote food sources safely. PMID- 24405586 TI - High expression of dihydropyrimidine dehydrogenase in lung adenocarcinoma is associated with mutations in epidermal growth factor receptor: implications for the treatment of non--small-cell lung cancer using 5-fluorouracil. AB - BACKGROUND: It has been shown that 5-fluorouracil (5-FU) sensitivity in patients with non-small-cell lung cancer (NSCLC) is associated with epidermal growth factor receptor (EGFR) mutation status. However, the relationship between dihydropyrimidine dehydrogenase (DPD), a 5-FU degrading enzyme, and EGFR mutation status is unknown. Here, we focus on clinicopathologic factors and in vitro correlations between DPD expression and EGFR mutation status. PATIENTS AND METHODS: EGFR mutations and messenger RNA (mRNA) levels of DPD and thymidylate synthase (TS) were analyzed in 47 resected NSCLC tumors by laser-capture microdissection. In addition, relationships between EGFR mutation status and the immunohistochemical expression of DPD and TS in 49 patients with primary NSCLC who were treated with a 5-FU derivative of S-1 postoperatively were examined. Correlations among clinicopathologic factors were evaluated. The effect of epidermal growth factor on DPD expression was also investigated in vitro in various cell lines. RESULTS: Adenocarcinoma in situ showed significantly higher DPD mRNA levels and more EGFR mutation frequency than other histological types (P < .05). DPD immunopositive cases were more frequently observed in adenocarcinoma, in females, and in nonsmokers. DPD immunopositive cases were correlated with EGFR mutation status (P < .003). The prognoses of wild-type EGFR and mutated EGFR populations were similarly favorable with postoperative S-1 treatment, which overcomes the problem of 5-FU degradation in mutated EGFR. In vitro, EGFR-mutated cell lines showed high DPD mRNA and protein expression. CONCLUSION: High DPD expression was shown to be correlated with EGFR mutation in adenocarcinoma cells and tissues. Clinicians should take this finding into consideration when using 5 FU to treat patients with NSCLC. PMID- 24405587 TI - Changes in the magnitude of social inequality in the uptake of cervical cancer screening in Taiwan, a country implementing a population-based organized screening program. AB - INTRODUCTION: We sought to examine changes in the magnitude of social inequality in the uptake of cervical cancer screening between 2001 and 2009 in Taiwan. METHODS: We used data from the 2001 and 2009 Taiwan National Health Interview Surveys to calculate the absolute (slope of index of inequality, SII) and relative (relative index of inequality, RII) summary measures of social inequality in the uptake of Pap smear tests to indicate the magnitude of social inequality. RESULTS: The prevalence of having had a Pap smear during the previous 3 years increased in each age and socioeconomic group from 2001 to 2009. The SII and RII by urbanization and education level decreased significantly, while the SII and RII by income level increased significantly between the two study years. The largest increase in inequality of prevalence from 2001 to 2009 was between women living in suburban and rural areas with highest income level and women live in metropolitan areas with lowest income level. CONCLUSIONS: The changes in magnitude of social inequality in the uptake of cervical cancer screening differed by indicators of socioeconomic position. Further studies are needed to explore the mechanisms that result in social inequality by different indicators of socioeconomic position. PMID- 24405588 TI - [Construction and expression of a eukaryotic expression vector containing human CR2-Fc fusion protein]. AB - OBJECTIVE: To construct a eukaryotic expression vector containing human complement receptor 2 (CR2)-Fc and express the CR2-Fc fusion protein in Chinese hamster ovary (CHO) cells. METHODS: The extracellular domain of human CR2 and IgG1 Fc were respectively amplified, ligated and inserted into the eukaryotic expression vector PCI-neo. After verified by restriction enzyme digestion and sequencing, the recombinant plasmid was transfected into CHO K1 cells. The ones with stable expression of the fusion protein were obtained by means of G418 selection. The expression of the CR2-Fc fusion protein was detected and confirmed by SDS-PAGE and Western blotting. RESULTS: Restriction enzyme digestion and sequencing demonstrated that the recombinant plasmid was valid. SDS-PAGE showed that relative molecular mass (Mr;) of the purified product was consistent with the expected value. Western blotting further proved the single band at the same position. CONCLUSION: We constructed the eukaryotic expression vector of CR2 Fc/PCI-neo successfully. The obtained fusion protein was active and can be used for the further study of the role in HIV control. PMID- 24405589 TI - [Levo-L-methyl tryptophan induces immune imbalance at maternal-fetal interface in mice]. AB - OBJECTIVE: To investigate which one, 1-methyl-L-tryptophan (1-L-MT) or 1-methyl-D tryptophan (1-D-MT), induces immune imbalance at maternal-fetal interface in mice. METHODS: BALB/c female mice are mated with C57BL/6J male mice, and since pregnancy day 6.5, the pregnant mice were given respectively 1-L-MT, 1-D-MT and organic solvents for 10 d. All the pregnant mice were executed at pregnancy day 16.5. Indoleamine 2, 3-dioxygenase (IDO) activity in the placenta tissue was detected using high performance liquid chromatography (HPLC), IFN-gamma/IL-4 ratio in the decidual tissue was determined by flow cytometry and pregnancy outcome was compared among groups. RESULTS: IDO activity of placenta tissues in 1 L-MT group was obviously lower than that in 1-D-MT group and the control group, and no statistical difference was found between 1-D-MT group and the control group; IFN-gamma/IL-4 ratio of decidual tissues in 1-L-MT group was higher than that in 1-D-MT group and the control group, and there was no statistical difference between 1-D-MT group and the control group; the quantity and weight of fetal mice in 1-L-MT group were significantly lower than those in 1-D-MT group and the control group, and no statistical difference between 1-D-MT group and the control group. CONCLUSION: 1-L-MT but not 1-D-MT induces immune imbalance at maternal-fetal interface in mice by inhibiting activity of IDO. PMID- 24405590 TI - [Expression and significance of FGFR2IIIc in chemoresistant bladder cancer cells]. AB - OBJECTIVE: To investigate the role of fibroblast growth factor receptor-2 (FGFR2) splice variant FGFR2IIIc in the regulation of mesenchymal-epithelial transition (MET) in doxorubicin-resistant bladder cancer cells. METHODS: A doxorubicin resistant human bladder cell line (253J/DOX) was generated from the bladder cancer cell line 253J by being continuously exposed to gradually increasing doses of doxorubicin. Chemosensitivity to doxorubicin was determined by MTT assay. The expressions of P-glycoprotein and FGFR2IIIc were evaluated by Western blotting and real-time RT-PCR, respectively. Changes in E-cadherin and vimentin were detected by Western blot analysis. Migration ability of 253J and 253J/DOX cells was analyzed by in vitro wound healing assay. RESULTS: The resistant cells, 253J/DOX, were more resistant to doxorubicin than the parent cells. Western blotting and RT-PCR analysis indicated the higher levels of P-glycoprotein and FGFR2IIIc in 253J/DOX cells (P<0.05). Additionally, compared with the 253J cells, 253J/DOX cells presented the upregulation of E-cadherin, the downregulation of vimentin and the inhibition of migration ability. CONCLUSION: FGFR2IIIc-induced MET in chemoresistant bladder cancer cells may play an important role in the formation of metastatic lesions. PMID- 24405591 TI - [Inhibition of Fasudil on lipopolysaccharide-induced TNF-alpha and IL-1beta expressions through TLR4 pathway in murine BV-2 cells in vitro]. AB - OBJECTIVE: To evaluate the effects of Fasudil on the production of proinflammatory cytokines in lipopolysaccharide (LPS)-stimulated BV-2 microglia cells. METHODS: The BV-2 cells cultured in vitro were divided into PBS control group, LPS stimulation group and LPS plus Fasudil group. The production of TNF alpha and IL-1beta was measured by ELISA. The release of NO was checked by Griess reagent assay. Toll-like receptor 2 (TLR2) and TLR4 expressions were determined by flow cytometry. RESULTS: The stimulation of LPS significantly increased the production of TNF-alpha, IL-1beta and NO as well as TLR4 protein expression in BV 2 cells. Fasudil attenuated NO production, and reduced the release of TNF-alpha and IL-1beta in LPS-stimulated BV-2 cells. Interestingly, Fasudil also decreased TLR4 expression. CONCLUSION: Fasudil can suppress the production of TNF-alpha, IL 1beta and NO of microglia cells induced by LPS, which may be associated with the down-regulation of TLR4 pathway. PMID- 24405592 TI - [Role of Toll-like receptor 4 in mouse bone marrow-derived dendritic cell maturation induced by beta2GPI]. AB - OBJECTIVE: To investigate the role of Toll-like receptor 4 (TLR4) in mouse bone marrow-derived dendritic cell maturation induced by beta-2-glycoprotein I (beta2GPI). METHODS: The recombinant murine granulocyte-macrophage colony stimulating factor (rmGM-CSF) and interleukin-4 (rmIL-4) were utilized to induce bone marrow cells from TLR4 intact (C3H/HeN) mice and TLR4 defective (C3H/HeJ) mice into immature dendritic cells (iDCs) in vitro. The iDCs were further stimulated by beta2GPI or LPS (as a positive control), and the morphological changes of cells were observed under an inverted light microscope, the expression changes of surface molecules on cells were analyzed with flow cytometry, and the levels of IL-12 and TNF-alpha secreted by cells were detected by ELISA. RESULTS: The DCs from C3H/HeN mice showed more protrusions and displayed more mature in morphology in response to beta2GPI or LPS, compared with those from C3H/HeJ mice. The expressions of surface molecules, CD11c and MHC-II, were higher on DCs from C3H/HeN mice than those from C3H/HeJ mice (P<0.05). And the levels of IL-12 and TNF-alpha secreted by DCs from C3H/HeN mice were also higher than those from C3H/HeJ mice (P<0.01). CONCLUSION: TLR4 plays an important role in the process of mouse bone marrow-derived dendritic cell maturation induced by beta2GPI. PMID- 24405593 TI - [Bone marrow-derived mesenchymal stem cells from estrogen deficiency induced osteoporosis mice regulate T cell migration and apoptosis through expressing MCP 1]. AB - OBJECTIVE: To reveal the role of bone marrow-derived mesenchymal stem cells (BMSCs) in the development of osteoporosis by comparing the differences in monocyte chemoattractant protein-1 (MCP-1) expression and T cells' migration and apoptosis induced by BMSCs from ovariectomy (OVX) group and sham group. METHODS: OVX was performed on C57BL/6 mice to establish the animal models of osteoporosis. Osteoporosis was confirmed by micro-CT. The expression of MCP-1 between OVX group and sham group was examined by ELISA; after exogenous estrogen of different concentrations were given to stimulate BMSCs from OVX group, the expression of MCP-1 was observed again by ELISA. Through co-culturing of BMSCs and T cells, the change of T cells' migration and apoptosis capacity induced by BMSCs was compared between OVX group and sham group. And also, we observed the effects of exogenous estrogen of different concentrations on the T cells' migration and apoptosis capacity. RESULTS: In animal models of osteoporosis induced by estrogen deficiency, BMSCs had a declined inducing effect on the capacity of T cell migration and apoptosis and expressed a decreased level of migration-related gene MCP-1. After the stimulation of estrogen of certain concentration, the declining tendency was revised to some extent. CONCLUSION: Through expressing MCP-1, BMSCs could regulate the capacity of T cell migration and apoptosis, thus leading to the development of osteoporosis. PMID- 24405594 TI - [Mechanism underlying pancreatic cancer cell resistance to mTOR inhibitor RAD001 via c-Raf/ERK1/2 activation]. AB - OBJECTIVE: To investigate the molecular mechanism of pancreatic cancer cell resistance to mammalian target of rapamycin (mTOR) inhibitor RAD001, and explore a feasible therapeutic strategy to overcome the resistance in patients with pancreatic cancer. METHODS: Western blotting was conducted to find out whether RAD001 induced c-Raf-ERK feedback activation and to identify whether RAD001 in combination with c-Raf inhibitor sorafenib could effectively block the feedback activation of c-Raf and downstream proteins. Sulphorhodamine B (SRB) colorimetric assay and colony formation were used to detect the effect of the combination treatment on cell growth and proliferation; finally, the effect on mouse subcutaneous xenografts was examined to confirm the efficacy of the combination treatment in vivo. RESULTS: RAD001 effectively inhibited the expressions of mTORC1 and its downstream proteins, and induced the feedback activation of c-Raf. Whereas, RAD001 combined with c-Raf inhibitor sorafenib eliminated RAD001-induced activation of c-Raf-ERK pathway and reversed pancreatic cancer cell resistance to RAD001; compared with the RAD001 alone, sorafenib had a synergistical inhibitory effect with RAD001. And the tumor growth inhibitory effect of the combination was also proved in mouse subcutaneous xenografts in vivo. CONCLUSION: RAD001-induced c-Raf-ERK feedback activation contributes to pancreatic cancer cell resistance to RAD001. Targeting of c-Raf may improve the therapeutic efficacy of RAD001 in patients with pancreatic cancer. PMID- 24405595 TI - [Construction of miR-508-5P lentiviral vector and its targeted effect on S-phase kinase-associated protein-2 gene]. AB - OBJECTIVE: To construct a lentiviral vector overexpressing miR-508-5p and verify its targeted regulating effect on S-phase kinase-associated protein-2 (SKP2) gene. METHODS: The stem-loop structure RNA of miR-508-5p was obtained by chemical synthesis and cloned into the linearized pSicoR plasmid. The positive recombinants, which had been identified by restriction enzyme digestion and DNA sequencing method, were transfected into HEK293T cells. Meanwhile, the potential target gene of SKP2-3'UTR, which was complementary with miR-508-5p, was obtained and cloned into the linearized pMIR-Report plasmid. The targeted effect of miR 508-5p on SKP2 gene was verified by the relative luciferase activity measurement, Western blotting and real-time PCR. RESULTS: The PCR, restriction enzyme digestion and DNA sequencing analysis demonstrated that the recombinant plasmids of pSicoR-miR-508-5p and pMIR-Report-SKP2 3'-UTR were constructed successfully. And it was showed that over-expression of miR-508-5p suppressed the mRNA and protein expression level of SKP2 significantly (P<0.05); and suppression of miR 508-5p expression increased the mRNA and protein expression level of SKP2 significantly (P<0.05). CONCLUSION: We have successfully constructed the lentiviral vector containing miR-508-5p gene. MiR-508-5p can suppress SKP2 gene expression by targeting the specific sequence of SKP2-3'UTR. PMID- 24405596 TI - [Effects of recombinant human interleukin-24 alone and in combination with cisplatin on the growth of ovarian cancer cells in vitro]. AB - OBJECTIVE: To investigate the inhibitory effects of recombinant human interleukin 24 (rhIL-24) on ovarian cancer cell lines SKOV3 and cisplatin (DDP)-resistant ovarian cancer cell lines SKOV3/DDP in vitro, and to observe the changes in apoptosis and cell cycle of SKOV3 and SKOV3/DDP. METHODS: Cell proliferation was detected by CCK8 assay, and the changes in apoptosis and cell cycle of SKOV3 and SKOV3/DDP were detected by flow cytometry after the treatment with rhIL-24 alone, DDP alone and rhIL-24 combined with DDP, respectively. RESULTS: The treatment with rhIL-24 significantly inhibited the growth of ovarian cancer cell lines SKOV3 and SKOV3/DDP in vitro. RhIL-24 combined with DDP resulted in a 30.7% growth inhibition, which showed a significant difference compared with the 6.5% growth inhibition in DDP alone group. The apoptosis rates detected by flow cytometry in rhIL-24 alone group, DDP alone group and combination group were 14.95%, 12.99% and 16.32%, respectively, which showed a significant difference compared with the apoptosis rate (1.32%) in negative control group. Furthermore, cell cycle detection indicated that the percentage of SKOV3 in G2 and S phases increased in rhIL-24 alone group, as well as in S phase in combination group. The percentage of SKOV3/DDP in G2 phase increased in rhIL-24 alone group, as well as in G1 phase in combination group. CONCLUSION: The treatment with rhIL-24 led to the growth inhibition of ovarian cancer cell lines SKOV3 and SKOV3/DDP, which was caused by apoptosis. And the inhibition effects of DDP could be enhanced after the treatment with combination therapy. rhIL-24 and combination therapy induced cell cycle arrest in G2 phase and G1 phase, respectively. PMID- 24405597 TI - [Effect of over-expressed monocarboxylate transporter on the biological behavior of MDA-MB-231 breast cancer cells]. AB - OBJECTIVE: To investigate the effect of over-expressed monocarboxylate transporter (MCT) on apoptosis, cell cycle, migration and invasion of MDA-MB-231 breast cancer cells. METHODS: Eukaryotic expression plasmid pcDNA3.1/MCT and empty plasmid pcDNA3.1 were respectively transfected into MDA-MB-231 cells. The expression of MCT gene was tested by real-time quantitative PCR (qRT-PCR) and Western blotting. After stained respectively by annexin V-FITC/PI and PI, the apoptosis and cell cycle in the MDA-MB-231 cells over-expressing MCT were detected by flow cytometry. The abilities of invasion and migration in the MDA-MB 231 cells with over-expressed MCT were respectively determined by Transwell(TM); and scratch wound healing assays. RESULTS: In mRNA and protein levels, the expression of MCT was higher in pcDNA3.1/MCT transfected group than in negative control group and untreated group. Over-expression of MCT in the MDA-MB-231 cells enhanced cell apoptosis, reduced the cell number of G2 phase and increased the cell number of S phase. The abilities of invasion and migration in the MDA-MB-231 cells were inhibited significantly. CONCLUSION: Over-expression of MCT in the MDA MB-231 cells promotes apoptosis, regulates G2/M checkpoint and inhibits the abilities of invasion and migration. PMID- 24405598 TI - [Construction and identification of a full-length human secretory antibody library in Pichia pastoris]. AB - OBJECTIVE: To clone and express functional, recombinant full-length human antibodies in partial N-glycoengineered Pichia pastoris yeast. METHODS: We constructed double promoter series expressing the constant regions of the light and heavy chain genes using the secretory expression vector pPICZalphaA; the obtained vector was named pPICZalphaA-CH;-CL;. Human peripheral blood mononuclear cells (PBMCs) were isolated and RT-PCR was performed using 44 pairs of degenerate primers to generate variable region genes of the heavy and light chains (VH; and VL;). Then, they were inserted into the pPICZalphaA-CH;-CL; vector. The full length human antibody library pPICZalphaA-VH;-CH;-VL;-CL; was transformed into partial N-glycoengineered Pichia pastoris, GS115Y, by electroporation. Sequencing analysis of 20 clones was carried out and the Results were submitted to the IgBLAST-imgt website to determine accuracy and diversity of the antibody library. RESULTS: The pPICZalphaA-CH;-CL; vector was sequenced and the expressions of CH; and CL; were determined by immunoblotting. The full-length human antibody library pPICZalphaA-VH;-CH;-VL;-CL; was constructed with a library capability of 10(5);. The IgBLAST-imgt analysis showed that the antibodies were functional as predicted. CONCLUSION: We successfully constructed a full-length human secretory antibody library in N-glycoengineered Pichia pastoris, which allows the screening of functional antibodies. PMID- 24405599 TI - [Expression of chicken pulmonary surfactant protein A and preparation of its polyclonal antibody]. AB - OBJECTIVE: To express chicken pulmonary surfactant protein A (cSP-A) in Escherichia coli and prepare polyclonal antibodies against the recombinant cSP-A. METHODS: The carbohydrate recognition domain (CRD) gene of cSP-A (cSP-A-CRD) was artificially synthesized, subcloned into the prokaryotic expression vector pGEX 6P-1, and expressed in Escherichia coli BL21(DE3). After the expression products were identified by SDS-PAGE, the gel containing the target protein was cut and further purified. Mice were innoculated with the purified recombinant protein to prepare polyclonal antibodies against cSP-A. The antibody titer was determined by ELISA, and the specificity and application scope of the polyclonal antibodies were analyzed by Western blotting, immunohistochemical fluorescence assay and ELISA. RESULTS: The serum against cSP-A was obtained and had an ELISA titer of 1*10(5);. The serum also showed excellent specificity and reactivity as demonstrated by the Western blotting. It could be used to detect the cSP-A in chicken lung epithelial cells by immunohistochemical fluorescence staining and could also be used to detect the hydrosoluble cSP-A in chicken bronchoalveolar lavage fluid by indirect ELISA. CONCLUSION: The recombinant cSP-A was successfully expressed, and its mouse polyclonal antibodies were obtained. PMID- 24405600 TI - [Preparation and characterization of the monoclonal antibodies against human CA15 3 and establishment of a sandwich CLIA system]. AB - OBJECTIVE: To prepare the monoclonal antibodies (mAbs) against human carbohydrate antigen 15-3 (CA15-3) and establish a double-antibody sandwich chemiluminescent immunoassay (CLIA) system for detecting CA15-3 in the human serum. METHODS: BALB/c mice were immunized with human CA15-3 antigen. Spleen cells of the immunized mice were fused with Sp2/0 cells and the positive hybridoma cells were selected and subcloned. The supernatant was taken for purify mAbs using protein A chromatography. The purity, titer, epitope and subtype of the mAbs were characterized and the sandwich CLIA system was established. The system was evaluated in its accuracy, limit of detection, linearity, repetitiveness and specificity. RESULTS: Five hybridoma cell lines named #3-1-3, #5-2-2, #11-2-2, #12-1-3 and #16-1-3 were obtained respectively, which are of strong positive signal and high secretion. The titers of the mAbs secreted by these hydridomas were above 10(-8); g/mL. All of the mAbs expressed kappa light chains, and their heavy chains were as follows: #3-1-3 mAb had IgG2a, #5-2-2 mAb and #12-1-3 mAb had IgG2b, #11-2-2 mAb and #16-1-3 mAb had IgG3. The double-antibody sandwich CLIA system had a good linear relationship between 0.59 U/mL and 300 U/mL. The recovery rate for accuracy was 97.45% and the limit of detection was 0.59 U/mL. The assay was highly linear (correlation coefficient 0.9978) and highly repeatable [coefficient of variation (CV) <10%]. This CLIA system was also highly specific without cross-reactivity to the tumor marker AFP, CEA, CA50, CA19-9 and CA72-4. CONCLUSION: The mAbs against human CA15-3 have been prepared and a sandwich CLIA system for detecting CA15-3 in the human serum has been established successfully, which provides a basis for CA15-3 quantification and clinical application. PMID- 24405601 TI - [Decreased FcgammaRIIb1 translocation to lipid raft signaling domains in activated B lymphocytes from patients with systemic lupus erythematosus]. AB - OBJECTIVE: To observe the changes in FcgammaRIIb1 translocation to lipid raft signaling domains in activated B lymphocytes from patients with systemic lupus erythematosus (SLE). METHODS: The peripheral blood of SLE patients and healthy subjects were collected, and B lymphocytes were isolated. The cells were stimulated with F(ab')2; fragments of anti-MU chain antibodies [F(ab')2; anti-MU, for B cell receptor (BCR) crosslinking] or with whole immunoglobulin G (IgG) anti MU chain antibodies (IgG anti-MU, for BCR and FcgammaRIIb1 co-crosslinking). The lipid rafts in the cell membrane were extracted by density-gradient ultracentrifugation. FcgammaRIIb1 localization, FcgammaRIIb1 tyrosine residue phosphorylation, and SH2-containing inositol phosphatase (SHIP) recruitment to FcgammaRIIb1 in the lipid rafts were detected by immunoprecipitation and Western blotting. RESULTS: After B lymphocyte stimulation with F(ab')2; anti-MU, FcgammaRIIb1 translocation to lipid rafts, as well as tyrosine-phosphorylated FcgammaRIIb1 and SHIP recruitment to FcgammaRIIb1 in the lipid rafts, showed no significant changes in the B lymphocytes from SLE patients compared with those in the healthy control subjects. However, after B lymphocyte stimulation with IgG anti-MU, the above indexes were significantly lower in the B lymphocytes from SLE patients than in the healthy control subjects. CONCLUSION: This study provides evidence for the decreased FcgammaRIIb1 translocation to lipid rafts as well as for the reduced tyrosine-phosphorylated FcgammaRIIb1 and SHIP recruitment to FcgammaRIIb1 in lipid rafts of B lymphocytes from SLE patients after stimulated with IgG anti-MU. PMID- 24405602 TI - [Expression of CD200 in the bone marrow of chronic lymphocytic leukemia patients and its correlations with clinical prognosis]. AB - OBJECTIVE: To explore the expression of CD200 in the bone marrow of chronic lymphocytic leukemia (CLL) patients and its correlations with clinical features, phenotype, chromosome type and prognosis. METHODS: 40 patients with CLL were tested before chemotherapy. The CD200 in the bone marrow samples were detected by the flow cytometry. The expression of CD19(+);CD200(+); was less than 50% in 18 patients, which were assigned into CD200(low) ;group, and the expression was more than or equal to 50% in 22 patients, which were in CD200(high); group. RESULTS: Compared with the CD200(high); group, the CD200(low) ;group had lower mean age, fewer men, lower initial WBC count, lower initial lymphocyte count, lower initial percentage of lymphocyte, lower lymph node incidence and higher initial hemoglobin(P<0.05). The average percentage of CD19(+);, CD19(+);CD23(+);, CD19(+);CD160(+); and the positive rate of Zeta chain-associated protein 70 (ZAP 70) in the CD200(low) ;group were significantly lower than those in the CD200(high); group (P<0.05). In Binet stage classification, the patients of the CD200(low) ;group were mostly in phase A, and the ones of the CD200(high); group were mostly in phase C (P<0.05). In Rai stage classification, the patients of the CD200(low) ;group were mostly in phase I, and the ones of the CD200(high); group were mostly in phase III stage (P<0.05). CONCLUSION: CD200 might be very important for the diagnosis, prognosis, individualized treatment and the longer survival time of CLL patients. PMID- 24405603 TI - [Expressions and clinical significances of iASPP and caspase-9 in esophageal cancer]. AB - OBJECTIVE: To investigate the expressions of inhibitory member of the apoptosis stimulating protein of p53 family (iASPP) and caspase-9 in the esophageal cancer (EC) tissues and their correlations with clinical pathological parameters. METHODS: Using streptavidin-peroxidase (SP) immunohistochemistry and reverse transcription PCR (RT-PCR), the protein and mRNA expressions of iASPP and caspase 9 were detected in 85 EC samples and 30 normal esophagus tissues to analyze their relationships with the clinicopathologic parameters of EC. RESULTS: The positive expression rate of iASPP was significantly higher in EC than that in normal esophagus tissues by SP (72.9% vs 16.7%, P<0.01) and by RT-PCR (0.657+/-0.115 vs 0.321+/-0.065, P<0.01). However, The positive expression rate of caspase-9 was significantly lower in EC than that in normal esophagus tissue by SP method (18.8% vs 76.7%, P<0.01) and by RT-PCR (0.297+/-0.058 vs 0.593+/-0.108, P<0.01). The mRNA expression levels of iASPP and caspase-9 in EC were significantly related to the invasive extent, histological differentiation, TNM stages, and lymphatic metastases (P<0.05), but not related to the age, sex, tumor size and pathological type (P>0.05). The expression of iASPP mRNA was negatively correlated with caspase-9 (r=-0.382, P<0.05). CONCLUSION: The overexpression of iASPP and the low expression of caspase-9 in EC are closely correlated with tumor invasion and metastasis, and iASPP may promote the progression of EC through inhibiting the expression of caspase-9. PMID- 24405604 TI - [Isolation, culture and identification of sheep multinucleated chorionic trophoblast cells]. AB - OBJECTIVE: To develop a set of methods for isolating and culturing sheep multinucleated chorionic trophoblast cells and identify them. METHODS: Trophoblast cells were isolated and cultured by two-step digestion of trypsin and collagenase, and observed under an inverted phase-contrast microscope. They were further identified through conventional HE staining, immunohistochemical staining and transmission electron microscopy. RESULTS: Under an inverted phase-contrast microscope, the obtained trophoblast cells exhibited epithelioid and sheet-like spreading growth with binuclear or multinuclear. The multinucleated trophoblast cytoplasm from the sheep placental cotyledons and the slides of the trophoblast cells were all stained brown and exhibited positive reactivity by immunohistochemical staining with cytokeratin antibodies. Also abundance of microvilli on surface of cells, together with intracytoplasmic vacuoles, microfilament and lipid droplets were observed under a transmission electron microscope. CONCLUSION: Two-step digestion of trypsin and collagenase has been established for the isolation and cultivation of sheep multinucleated trophoblast cells, and using it, we obtained sheep multinucleated chorionic trophoblast cells with a high purity and biological activity. PMID- 24405605 TI - Involvement of prefrontal AMPA receptors in encounter stimulation-induced hyperactivity in isolation-reared mice. AB - We recently showed that social encounter stimulation induces hyperactivity in mice reared in social isolation from early life and this is associated with the transient activation of prefrontal dopaminergic and serotonergic systems. In the present study, we examined the effect of the alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionate (AMPA) receptor antagonist 2, 3-dioxo-6-nitro-1, 2, 3, 4 tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX) on encounter-induced behavioural and neurochemical changes to study the role of the receptor in abnormal behaviours in isolation-reared mice. The encounter to an intruder mouse induced hyperactivity with transient increases in prefrontal dopamine and serotonin levels in isolation-reared mice. NBQX attenuated the encounter-induced hyperactivity and the associated neurochemical changes in isolation-reared mice. In addition, NBQX reduced aggressive behaviour and cognitive impairment in isolation-reared mice, but did not affect depressive-like behaviour or spontaneous hyper-locomotion in these animals. The AMPA receptor agonist (S)-AMPA increased prefrontal dopamine and serotonin release, and this effect was higher in isolation-reared mice than in the group-reared mice, suggesting higher prefrontal AMPA receptor activity in isolation-reared mice. Furthermore, isolation rearing increased the expression of AMPA receptor subunits (GluR1, GluR2 and GluR3) and GluR1 Ser845 phosphorylation in the prefrontal cortex, but not in the hippocampus or nucleus accumbens. Taken together, these results suggest that an increase in AMPA receptor activity in the prefrontal cortex contributes to some, but not all, abnormal behaviours in isolation-reared mice. PMID- 24405606 TI - AT1 receptor-associated protein and septic shock-induced vascular hyporeactivity: another 'magic bullet' in the pipe? AB - Septic shock remains an important issue for critical care physicians. Despite significant advances in the knowledge of its pathophysiology, new effective therapeutic approaches have yet to emerge. Consequently, research on its pathophysiology must be continued. In a recent study, Katharina Mederle and colleagues explored the impact of angiotensin 1 receptor-associated protein 1 (Arap1) deficiency on vascular hyporesponsiveness in an experimental model of septic shock. The authors demonstrate that experimental septic shock downregulates Arap1 expression, which in turn contributes to vascular hyporesponsiveness to angiotensin II. PMID- 24405607 TI - Latent tuberculosis infection in a Malaysian prison: implications for a comprehensive integrated control program in prisons. AB - BACKGROUND: Prisons continue to fuel tuberculosis (TB) epidemics particularly in settings where access to TB screening and prevention services is limited. Malaysia is a middle-income country with a relatively high incarceration rate of 138 per 100,000 population. Despite national TB incidence rate remaining unchanged over the past ten years, data about TB in prisons and its contribution to the overall national rates does not exist. This survey was conducted to address the prevalence of latent TB infection (LTBI) in Malaysia's largest prison. METHODS: From July to December 2010, all HIV-infected and a comparative group of HIV-uninfected prisoners housed separately in Kajang prison were asked to participate in the survey after explaining the study protocol. Subjects providing informed consent were interviewed using a structured questionnaire followed by the placement of tuberculin skin test (TST) with 2 TU of PPD RT-23 to subjects not being treated for active TB. TST was read after 48-72 hours and indurations of >= 5 mm and >= 10 mm were considered positive among HIV-infected and HIV-uninfected subjects, respectively. Additionally, HIV-infected inmates underwent phlebotomy for CD4 lymphocyte count assessment. A logistic regression model was explored to determine factors associated with TST positivity. RESULTS: Overall, 286 subjects (138 HIV-infected and 148 HIV-uninfected) had complete data and TST results. The majority were men (95.1%), less than 40 years old (median age 36.0, SD 7.87), and Malaysians (93.3%). Most (82.5%) had been previously incarcerated and more than half (53.1%) reported sharing needles just prior to their incarceration. TST was positive in 88.8% (84.7% among HIV-infected and 92.5% among HIV-uninfected subjects) and was independently associated with being HIV-uninfected (AOR = 2.97, p = 0.01) and with frequent previous incarcerations (AOR = 1.22 for every one previous incarceration, p = 0.01) after adjusting for other potential confounding factors. CONCLUSIONS: The prevalence of LTBI was extraordinary high in this sample of Malaysian prisoners, regardless of their age or HIV status. This warrants further examination of the size of the problem of TB in other congregate settings and the establishment of an evidence-based TB control program in Malaysian prisons with integrated TB, HIV and substance abuse components. PMID- 24405608 TI - The Rockefeller University Navigation Program: a structured multidisciplinary protocol development and educational program to advance translational research. AB - The development of translational clinical research protocols is complex. To assist investigators, we developed a structured supportive guidance process (Navigation) to expedite protocol development to the standards of good clinical practice (GCP), focusing on research ethics and integrity. Navigation consists of experienced research coordinators leading investigators through a concerted multistep protocol development process from concept initiation to submission of the final protocol. To assess the effectiveness of Navigation, we collect data on the experience of investigators, the intensity of support required for protocol development, IRB review outcomes, and protocol start and completion dates. One hundred forty-four protocols underwent Navigation and achieved IRB approval since the program began in 2007, including 37 led by trainee investigators, 26 led by MDs, 9 by MD/PhDs, 57 by PhDs, and 12 by investigators with other credentials (e.g., RN, MPH). In every year, more than 50% of Navigated protocols were approved by the IRB within 30 days. For trainees who had more than one protocol navigated, the intensity of Navigation support required decreased over time. Navigation can increase access to translational studies for basic scientists, facilitate GCP training for investigators, and accelerate development and approval of protocols of high ethical and scientific quality. PMID- 24405609 TI - Venous thromboembolism during combat operations: a 10-y review. AB - BACKGROUND: This article examines the incidence of venous thromboembolism (VTE) in combat wounded, identifies risk factors for pulmonary embolism (PE), and compares the rate of PE in combat with previously reported civilian data. METHODS: A retrospective review was performed of all U.S. military combat casualties in Operation Enduring Freedom and Operation Iraqi Freedom with a VTE recorded in the Department of Defense Trauma Registry from September 2001 to July 2011. The Military Amputation Database of all U.S. military amputations during the same 10-y period was also reviewed. Demographic data, injury characteristics, and outcomes were evaluated. RESULTS: Among 26,634 subjects, 587 (2.2%) had a VTE. This number included 270 subjects (1.0%) with deep venous thrombosis (DVT), 223 (0.8%) with PE, and 94 (0.4%) with both DVT and PE. Lower extremity amputation was independently associated with PE (odds ratio [OR], 1.70; 95% confidence interval [CI], 1.07-2.69). A total of 1003 subjects suffered a lower extremity amputation, with 174 (17%) having a VTE. Of these, 75 subjects (7.5%) were having DVT, 70 (7.0%) were having PE, and 29 (2.9%) were found to have both a DVT and a PE. Risk factors found to be independently associated with VTE in amputees were multiple amputations (OR, 2; 95% CI, 1.35-3.42) and above the knee amputation (OR, 2.11; 95% CI, 1.3-3.32). CONCLUSIONS: Combat wounded are at a high risk for thromboembolic complications with the highest risk associated with multiple or above the knee amputations. PMID- 24405610 TI - miR-503 regulates metastatic function through Rho guanine nucleotide exchanger factor 19 in hepatocellular carcinoma. AB - BACKGROUND: Our previous work described a metastasis-related microRNAs expression profiling and revealed miR-503 regulating metastatic function in hepatocellular carcinoma (HCC) cells. Here, we investigate to define the mechanism of miR-503 regulating metastasis in HCC. MATERIALS AND METHODS: The expressions of miR-503 in HCC cell lines and clinical tissues with different metastatic potential were investigated. Meanwhile, a metastatic human HCC cell BALB/c nude mice model was used to investigate whether miR-503 regulates metastasis of HCC in vivo. Furthermore, luciferase activity of reporter gene, 3-(4,5-Dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT), fluorescence-activated cell sorting analysis (FACS), and invasion assay were carried out to characterize the mechanism of miR-503 regulating metastasis in HCC. RESULTS: We confirmed the negative correlation between miR-503 expression and metastatic potential of HCC in cell lines and in clinical HCC tissues. We also showed that overexpression of miR-503 resulted in inhibition of proliferation and metastasis of HCC in vivo. Furthermore, we demonstrated that ARHGEF19 is a direct target gene of miR-503. Finally, our results indicated that ARHGEF19 overcomes the suppressive influence of miR-503 in HCC cells. CONCLUSIONS: Our results suggest an important role of miR-503 in inhibiting metastasis of HCC through deregulating ARHGEF19. PMID- 24405611 TI - Insurance status predicts survival for trauma patients undergoing urgent intervention. AB - BACKGROUND: The purpose of this study was to investigate the relationship between insurance status and outcomes for trauma patients presenting without vital signs undergoing urgent intervention. MATERIALS AND METHODS: The National Trauma Data Bank was queried for patients presenting with a systolic blood pressure equal to zero and a Glasgow Coma Scale score of three ("clinically dead"), who underwent urgent thoracotomy and-or laparotomy (UTL). Insured patients were compared with uninsured (INS [-]) patients. RESULTS: There were 18,171 patients presenting clinically dead having a payment source documented. INS (-) patients were more likely to undergo UTL (5.4% [416-7704] versus 2.7% [285-10,467], 1.481 [1.390 1.577], <0.001). Out of 689 patients who underwent UTL and meeting inclusion criteria, 416 (60.4%) were INS (-). Patients with insurance demonstrated a significantly greater survival (9.9% [27-273] versus 1.7% [7-416], 5.878 [2.596 13.307] P < 0.001). Adjusting for mechanism, race, age, injury severity, and comorbidities, insured status was independently associated with survival. CONCLUSIONS: The presence of health insurance is independently associated with survival in trauma patients presenting with cardiovascular collapse who undergo urgent surgical intervention. PMID- 24405612 TI - Endoprosthetic reconstruction for large extremity soft-tissue sarcoma with juxta articular bone involvement: functional and survival outcome. AB - BACKGROUND: Large extracompartmental limb soft-tissue sarcoma with juxta articular bone involvement poses major challenges in disease management. Radical resection of sarcoma frequently requires concomitant bone resection and reconstruction. We describe the clinical outcomes of endoprosthetic reconstruction and the complications associated with this procedure. METHODS: Thirty patients with soft-tissue sarcomas with local juxta-articular bone involvement in an extremity underwent surgery at our center between May 2004 and October 2011, 20 for primary sarcomas and 10 for local recurrences. Clinical data from those patients were analyzed retrospectively. The bone affected included the proximal femur (10 cases), the distal femur (nine cases), the proximal humerus (eight cases), the proximal tibia (two cases), or the total femur (one case). Wide excision of the tumor and the bone tissue involved was performed on every patient, followed by reconstruction of the subsequent defect using tumor endoprosthesis. All patients underwent regular follow-up for an average of 25 (range, 3-84) mo. RESULTS: Three patients had poor wound healing. Implant fractures leading to additional revisions occurred in two cases. Local tumor recurrence developed in four patients. There were 15 patients with lung metastases, and 11 patients died of disseminated metastases. In the latest follow up, 14 patients survived free of disease and five were alive with tumors. The mean Musculoskeletal Tumor Society functional analysis for proximal femur, distal femur, proximal tibia, proximal humerus, and total femur were 90%, 82%, 73%, 71%, and 60%, respectively. The 2- and 5- y survival rates were 61.6% and 30.0%, respectively. CONCLUSIONS: Endoprosthetic reconstruction could yield satisfactory results as a wide excision and limb salvage therapeutic strategy for patients with large extracompartmental soft-tissue sarcomas with juxta-articular bone involvement. Acceptable complications occurred in the present report. PMID- 24405613 TI - Identification and interference of intraoperative distractions and interruptions in operating rooms. AB - BACKGROUND: Intraoperative interruptions potentially interfere with surgical flow, contribute to patient safety risks, and increase stress. This study aimed to observe interruption events in operating rooms (ORs) and to measure surgical team's intraoperative interference from interruptions during surgery. MATERIALS AND METHODS: Sixty-five surgical cases were observed at two surgical clinics in Germany (mainly abdominal and orthopedic surgery). An established observational tool was successfully adapted to German ORs. Various disruptions to surgical work were captured with a predefined coding scheme. In addition, the severity of each observed interruption was rated on behaviorally anchored scale to define the level of OR team involvement. Pilot test supported tools' reliability. RESULTS: Mean intraoperative duration was 1 h, 23 min (standard deviation = 50:55 min). Overall N = 803 intraoperative interruptions and disruption events were observed. Most frequent were people entering or exiting the OR and telephone or beeper calls. On average, OR teams were distracted or interrupted 9.82 times per hour (standard deviation = 3.97). Equipment failures and OR-environment-related disruptions were rated as the highest interference of OR team functioning. The involved OR professions were differently affected by interruption events. Distribution of intraoperative interruptions within the procedure varied significantly; during early stages of the case, significantly more interruptions were observed. CONCLUSIONS: The study demonstrates the high level of interference in ORs. Furthermore, it provides a useful measure for intraoperative workflow disruptions and their interference of OR team functioning. OR environments need to be well designed to reduce unnecessary interruptions and distractions, so that surgical teams can manage their surgical tasks efficiently and safely. PMID- 24405614 TI - Detection of structural DNA variation from next generation sequencing data: a review of informatic approaches. AB - Next generation sequencing (NGS), or massively paralleled sequencing, refers to a collective group of methods in which numerous sequencing reactions take place simultaneously, resulting in enormous amounts of sequencing data for a small fraction of the cost of Sanger sequencing. Typically short (50-250 bp), NGS reads are first mapped to a reference genome, and then variants are called from the mapped data. While most NGS applications focus on the detection of single nucleotide variants (SNVs) or small insertions/deletions (indels), structural variation, including translocations, larger indels, and copy number variation (CNV), can be identified from the same data. Structural variation detection can be performed from whole genome NGS data or "targeted" data including exomes or gene panels. However, while targeted sequencing greatly increases sequencing coverage or depth of particular genes, it may introduce biases in the data that require specialized informatic analyses. In the past several years, there have been considerable advances in methods used to detect structural variation, and a full range of variants from SNVs to balanced translocations to CNV can now be detected with reasonable sensitivity from either whole genome or targeted NGS data. Such methods are being rapidly applied to clinical testing where they can supplement or in some cases replace conventional fluorescence in situ hybridization or array-based testing. Here we review some of the informatics approaches used to detect structural variation from NGS data. PMID- 24405615 TI - Do patients with income-based insurance have access to total joint arthroplasty? AB - The Patient Protection and Affordable Care Act (PPACA) is expected to increase health care availability through Medicaid expansion. The objective of this study was to evaluate potential effects of the PPACA by examining access to total hip arthroplasty in Southern California. 39 orthopaedic surgeons were called to schedule a hip arthroplasty. Insurances used included a Preferred Provider Organization (PPO), Medicare, and three income-based insurances. There was a significant difference in acceptance rate when comparing PPO and Medicare patients with income-based insurances (P < 0.001). This study showed that in Southern California, patients with income-based insurances are limited in the number of surgeons from whom they can receive care. Thus, although the PPACA will increase the number of insured patients, it may not similarly increase access to providers. PMID- 24405616 TI - A comparison of surgical approaches for primary hip arthroplasty: a cohort study of patient reported outcome measures (PROMs) and early revision using linked national databases. AB - The posterior and lateral approaches to primary hip arthroplasty were compared using national data from England and Wales. Specific component combinations of the most commonly used cemented and cementless implant brands were analysed separately. There was no significant difference between the approaches for all cause revision risk (cemented: P = 0.726, cementless: P = 0.295) and revision for dislocation (P = 0.176, P = 0.695) at 12 months following 37,593 procedures, after adjusting for patient and surgical variables. Analysis of 3881 linked episodes found the posterior approach was associated with significantly higher improvement in function (Oxford Hip Score: 20.8 versus 18.9, P < 0.001 (cemented procedures); 21.7 versus 20.2, P = 0.008 (cementless), EQ5D index: 0.416 versus 0.383, P = 0.003; 0.431 versus 0.384, P = 0.003). The posterior approach may offer a functional benefit (albeit small clinically), without increased revision risk. PMID- 24405617 TI - Significantly reduced leg length discrepancy and increased femoral offset by application of a head-neck adapter in revision total hip arthroplasty. AB - Head-neck adapters in total hip arthroplasty (THA) promise the reconstruction of optimal femoral offset and leg length in revision THA while retaining stable implants. Radiological parameters after adapter implantation in THA revision were determined in 37 cases. Significant reduction of leg length discrepancy and improvement of femoral offset (P < 0.001) were found. Clinical endpoints were determined in 20 cases (mean follow-up 4.0 years). Clinical scores were rather poor (median Harris hip score 54, WOMAC score 41) due to age and comorbidities, postoperative dislocation occurred in 3 cases. Only one stable femoral stem had to be revised due to recurrent postoperative dislocation. In conclusion, a head neck adapter can be a valuable tool in certain cases of revision THA with acceptable dislocation rates while allowing the retention of stable implants. PMID- 24405618 TI - Long-term results of porous-coated anatomic total hip arthroplasty for patients with osteoarthritis of the hip. AB - Between 1986 and 1997, 136 porous-coated anatomic (PCA) total hip arthroplasties were performed for patients with osteoarthritis of the hip, and data were available for 60 hips at final follow-up (mean follow-up, 15.2years). Of these, 18 hips had undergone revision: 12 for the acetabular component, 10 for the femoral component, and 4 for both components. Survival rate at 23years postoperatively was 60% for the acetabular component and 82% for the femoral component. Multivariate Cox proportional hazards regression showed that annual polyethylene wear rate, size, and abduction angle of the acetabular component were significantly associated with acetabular component revision surgery, and that annual polyethylene wear rate and filling ratio of the femur were associated with femoral component revision surgery. PMID- 24405619 TI - Mortality following revision total knee arthroplasty: a matched cohort study of septic versus aseptic revisions. AB - We report the medium-term mortality after septic versus aseptic revision total knee arthroplasty (TKA) and factors that can contribute to mortality in revision TKA. Mortality rates of 88 patients undergoing septic revision (septic group) were compared with age- and year of surgery-matched 88 patients of aseptic revision (aseptic group). The overall mortality after revision TKA was 10.7% at a median of 4 years of follow-up (range, 2-7 years). However, the mortality after septic revision (18%, 16/88) was six times higher than that of aseptic revision (3%, 3/88) (P = 0.003). Infections with Staphylococcus aureus and/or methicillin resistance was not associated with higher mortality rates. Multivariate analysis indicated that increased age (P < 0.001), higher ASA class (P = 0.002), and septic revision (P < 0.001) were identified as independent predictors of increased mortality after revision TKA. PMID- 24405620 TI - In vivo movement of femoral flexion axis of a single-radius total knee arthroplasty. AB - The objective of this study was to investigate in vivo femoro-tibial motion using the movement of femoral flexion axis of a single-radius TKA. We examined 20 clinically successful knees with a single-radius posterior stabilized TKA to evaluate the kinematics of deep knee flexion using 2-3-dimensional registration techniques. The mean knee flexion range of motion was 117.8 degrees . The mean rotation of the femoral component was 7.6 degrees external rotation. The mean knee flexion angle at initial post-cam engagement was 55.2 degrees . No paradoxical movement of femoral component was shown until 70 degrees flexion, afterward the femoral component rolled back with flexion. The data showed that the design of this prosthesis might contribute to reduce the paradoxical anterior femoral movement and provide stability in mid-flexion ranges. PMID- 24405621 TI - Similar improvement in gait parameters following direct anterior & posterior approach total hip arthroplasty. AB - We compared gait parameters prior to, at 6 months and 1 year following total hip arthroplasty (THA) performed via direct anterior approach (DAA) and posterior approach (PA) by a single surgeon in 22 patients. A gait analysis system involving reflective markers, infrared cameras and a multicomponent force plate was utilized. Postoperatively, the study cohort demonstrated improvement in flexion/extension range of motion (ROM) (P = 0.001), peak flexion (P = 0.005) and extension (P = 0.002) moments with no differences between groups. Internal/external ROM improved significantly in the DAA group (P = 0.04) with no change in the PA group. THA performed via DAA and PA offers similar improvement in gait parameters with the exception of internal/external ROM which might be related to the release and repair of external rotators during PA THA. PMID- 24405622 TI - Aquacel surgical dressing reduces the rate of acute PJI following total joint arthroplasty: a case-control study. AB - An effort to prevent PJI has led to the development of antimicrobial dressings that support wound healing. We sought to determine whether Aquacel Surgical dressing independently reduces the rate of acute PJI following TJA. A single institution retrospective chart review of 903 consecutive cases who received the Aquacel Surgical dressing and 875 consecutive cases who received standard gauze dressing was conducted to determine the incidence of acute PJI (within 3 months). The incidence of acute PJI is 0.44% in the Aquacel dressing group compared to 1.7% in the standard gauze dressing group (P = 0.005). Multivariate analysis revealed that use of Aquacel dressing was an independent risk factor for reduction of PJI (odds ratio of 0.165, 95% confidence interval: 0.051-0.533). Aquacel Surgical dressing significantly reduces the incidence of acute PJI. PMID- 24405623 TI - Antibiotic prophylaxis for dental procedures at risk of causing bacteremia among post-total joint arthroplasty patients: a survey of Canadian orthopaedic surgeons and dental surgeons. AB - To elicit current practice and attitudes toward use of antibiotic-prophylaxis among TJA patients prior to dental procedures, a cross-sectional survey of practicing Canadian orthopaedic (OS) and dental surgeons (DS) was undertaken. Of respondents, 77% of OS and 71% of DS routinely prescribe antibiotic-prophylaxis, but while 63% of OS advocate lifelong use, only 22% of DS choose to do so (P<0.0001). Both groups nonetheless recognize the importance of treatment within 2-years post-TJA as per AAOS/ADA guidelines. However, greater duration of practice pointed to potential inadequacy of these guidelines based on reported experience with late-hematogenous infection post-TJA. While discrepancies in attitude toward antibiotic-prophylaxis between surgeon groups remain, both groups agreed that the evidence to support decision making regarding antibiotic prophylaxis for TJA patients undergoing dental procedures remains inadequate. PMID- 24405624 TI - Muscle force steadiness in older adults before and after total knee arthroplasty. AB - The ability to control submaximal muscle forces has been shown to be associated with age-related decreases in physical function, such as increased tendency to fall. This study compared quadriceps muscle force steadiness (MFS) in individuals with knee OA before and after total knee arthroplasty (TKA) to an age-matched group of controls. Lower extremity MFS was measured in 13 subjects with knee OA before and at six months after TKA (TKA-GROUP) and compared to an age-matched control group (CONTROL-GROUP). MFS was significantly more impaired in the TKA GROUP at the pre-operative, but not post-operative visit, and significantly improved between the pre-operative and post-operative visits. Further research is warranted to evaluate the relation between this MFS measurement and physical functional performance in those at high risk for falling. PMID- 24405625 TI - Outcome of porous tantalum acetabular components for Paprosky type 3 and 4 acetabular defects. AB - Porous tantalum acetabular implants provide a potential solution for dealing with significant acetabular bone loss. This study reviews 24 acetabular revisions using tantalum implants for Paprosky type 3 and 4 defects. The mean Harris Hip Score improved from 35 +/- 19 (range, 4-71) to 88 +/- 14 (range, 41-100), p < 0.0001. Postoperative radiographs showed radiolucent lines in 14 hips with a mean width of 1.3 +/- 1.0 mm (range, 0.27-4.37 mm). No gaps enlarged and 71% of them disappeared at a mean of 13 +/- 10 months (range, 3-29 months). At a mean follow up of 37 +/- 14 months (range, 24-66 months), 22 reconstructions showed radiograpic evidence of osseointegration (92%). The two failures were secondary to septic loosening. When dealing with severe acetabular bone loss, porous tantalum acetabular components show promising short-term results. PMID- 24405626 TI - Early outcome comparison between the direct anterior approach and the mini incision posterior approach for primary total hip arthroplasty: 150 consecutive cases. AB - This study evaluated early postoperative results of 150 consecutive primary total hip arthroplasties performed by a single surgeon; 50 from mini-incision posterior approach, 50 during the learning curve for the direct anterior approach, and 50 subsequent cases when the approach was routine. The anterior approach groups had significantly reduced hospital length of stays (2.9 and 2.7 days versus 3.9 days for the posterior group; P < 0.0001) and discharge to home versus rehab was more likely (80% and 84% in anterior groups, 56% in posterior group; P = 0.0028). In the anterior groups, there was significantly less use of assistive devices and narcotics at 6 weeks, and pain was significantly lower. Primary total hip arthroplasty using the anterior approach allows for superior recovery in a matched cohort of patients. PMID- 24405627 TI - Associations between presence of handwashing stations and soap in the home and diarrhoea and respiratory illness, in children less than five years old in rural western Kenya. AB - OBJECTIVE: We tested whether soap presence in the home or a designated handwashing station was associated with diarrhoea and respiratory illness in Kenya. METHODS: In April 2009, we observed presence of a handwashing station and soap in households participating in a longitudinal health surveillance system in rural Kenya. Diarrhoea and acute respiratory illness (ARI) in children < 5 years old were identified using parent-reported syndromic surveillance collected January-April 2009. We used multivariate generalised linear regression to estimate differences in prevalence of illness between households with and without the presence of soap in the home and a handwashing station. RESULTS: Among 2547 children, prevalence of diarrhoea and ARI was 2.3 and 11.4 days per 100 child days, respectively. Soap was observed in 97% of households. Children in households with soap had 1.3 fewer days of diarrhoea/100 child-days (95% CI -2.6, -0.1) than children in households without soap. ARI prevalence was not associated with presence of soap. A handwashing station was identified in 1.4% of households and was not associated with a difference in diarrhoea or ARI prevalence. CONCLUSIONS: Soap presence in the home was significantly associated with reduced diarrhoea, but not ARI, in children in rural western Kenya. Whereas most households had soap in the home, almost none had a designated handwashing station, which may prevent handwashing at key times of hand contamination. PMID- 24405628 TI - Docosahexaenoic acid attenuates the early inflammatory response following spinal cord injury in mice: in-vivo and in-vitro studies. AB - BACKGROUND: Two families of polyunsaturated fatty acid (PUFA), omega-3 (omega-3) and omega-6 (omega-6), are required for physiological functions. The long chain omega-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have significant biological effects. In particular, DHA is a major component of cell membranes in the brain. It is also involved in neurotransmission. Spinal cord injury (SCI) is a highly devastating pathology that can lead to catastrophic dysfunction, with a significant reduction in the quality of life. Previous studies have shown that EPA and DHA can exert neuroprotective effects in SCI in mice and rats. The aim of this study was to analyze the mechanism of action of omega-3 PUFAs, such as DHA, in a mouse model of SCI, with a focus on the early pathophysiological processes. METHODS: In this study, SCI was induced in mice by the application of an aneurysm clip onto the dura mater via a four-level T5 to T8 laminectomy. Thirty minutes after compression, animals received a tail vein injection of DHA at a dose of 250 nmol/kg. All animals were killed at 24 h after SCI, to evaluate various parameters implicated in the spread of the injury. RESULTS: Our results in this in-vivo study clearly demonstrate that DHA treatment reduces key factors associated with spinal cord trauma. Treatment with DHA significantly reduced: (1) the degree of spinal cord inflammation and tissue injury, (2) pro-inflammatory cytokine expression (TNF-alpha), (3) nitrotyrosine formation, (4) glial fibrillary acidic protein (GFAP) expression, and (5) apoptosis (Fas-L, Bax, and Bcl-2 expression). Moreover, DHA significantly improved the recovery of limb function.Furthermore, in this study we evaluated the effect of oxidative stress on dorsal root ganglion (DRG) cells using a well characterized in-vitro model. Treatment with DHA ameliorated the effects of oxidative stress on neurite length and branching. CONCLUSIONS: Our results, in vivo and in vitro, clearly demonstrate that DHA treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma. PMID- 24405630 TI - A paradigm shift: healing, quality of life, and a professional choice. PMID- 24405629 TI - Ixmyelocel-T, an expanded multicellular therapy, contains a unique population of M2-like macrophages. AB - INTRODUCTION: M2 macrophages promote tissue repair and regeneration through various mechanisms including immunomodulation and scavenging of tissue debris. Delivering increased numbers of these cells to ischemic tissues may limit tissue injury and promote repair. Ixmyelocel-T is an expanded, autologous multicellular therapy cultured from bone-marrow mononuclear cells (BMMNCs). The purpose of this study was to characterize further a unique expanded population of M2-like macrophages, generated in ixmyelocel-T therapy. METHODS: Approximately 50 ml of whole bone marrow was obtained from healthy donors and shipped overnight. BMMNCs were produced by using density-gradient separation and cultured for approximately 12 days to generate ixmyelocel-T. CD14+ cells were isolated from ixmyelocel-T with positive selection for analysis. Cell-surface phenotype was examined with flow cytometry and immunofluorescence, and expression of cytokines and chemokines was analyzed with enzyme-linked immunosorbent assay (ELISA). Quantitative real time PCR was used to analyze expression of genes in BMMNCs, ixmyelocel-T, the CD14+ population from ixmyelocel-T, and M1 and M2 macrophages. Ixmyelocel-T was cultured with apoptotic BMMNCs, and then visualized under fluorescence microscopy to assess efferocytosis. RESULTS: Macrophages in ixmyelocel-T therapy expressed surface markers of M2 macrophages, CD206, and CD163. These cells were also found to express several M2 markers, and few to no M1 markers. After stimulation with lipopolysaccharide (LPS), they showed minimal secretion of the proinflammatory cytokines interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-alpha) compared with M1 and M2 macrophages. Ixmyelocel-T macrophages efficiently ingested apoptotic BMMNCs. CONCLUSIONS: Ixmyelocel-T therapy contains a unique population of M2-like macrophages that are characterized by expression of M2 markers, decreased secretion of proinflammatory cytokines after inflammatory stimuli, and efficient removal of apoptotic cells. This subpopulation of cells may have a potential role in tissue repair and regeneration. PMID- 24405632 TI - Outcomes of mandible fracture treatment at an academic tertiary hospital: a 5 year analysis. AB - PURPOSE: To analyze the outcomes of mandible fractures treated using open reduction and internal fixation. PATIENTS AND METHODS: We performed a retrospective chart review of the medical records from patients with mandibular fractures treated surgically during a 5-year period for demographics, systemic illness, history of substance abuse, etiology, fracture location, any associated facial injury, type and timing of repair, antibiotic treatment, and interval to repair. The development of complications such as infection, malunion or nonunion, hardware failure, and wound dehiscence were recorded. RESULTS: Of the 560 patients, adequate data were collected for 363 patients. Of the patients, 60% were white. The male/female ratio was 7.4:1. Systemic illness was noted in 10.5% of the cohort. More than 80% of the subjects had sustained their injury because of assault. The mandible angle was the most common site of fracture (56%). Most (64%) of the patients had sustained multiple fractures. When multiple sites were involved, the angle and body were more commonly involved. The overall complication rate was 26.45%. Hardware failure (15.4%) was the most common complication, followed by infection (15.15%). The revision rate was 8.1% in this cohort. Antibiotic usage and the infection rate were not statistically associated with each other. A greater complication rate was noted among smokers (P = .0072) and patients with systemic illness (P = .0495). CONCLUSIONS: A greater rate of hardware failure was noted in our study. The use of antibiotics did not decrease the incidence of infections. Smokers and patients with systemic medical conditions had a greater risk of complications. Finally, a slight delay in surgical repair was not related to an increased complication rate. PMID- 24405633 TI - Endometrial progesterone resistance and PCOS. AB - Polycystic ovary syndrome (PCOS) is a state of altered steroid hormone production and activity. Chronic estrogen exposure or lack of progesterone due to ovarian dysfunction can result in endometrial hyperplasia and carcinoma. A key contributor to our understanding of progesterone as a critical regulator for normal uterine function has been the elucidation of progesterone receptor (PR) expression, regulation, and signaling pathways. Several human studies indicate that PR-mediated signaling pathways in the nucleus are associated with progesterone resistance in women with PCOS. The aim of this review is to provide an overview of endometrial progesterone resistance in women with PCOS; to present the PR structure, its different isoforms, and their expression in the endometrium; to illustrate the possible regulation of PR and PR-mediated signaling in progesterone resistance in women with PCOS; and to discuss current clinical treatments for atypical endometrial hyperplasia and endometrial carcinoma in women with PCOS and accompanying progesterone resistance. PMID- 24405634 TI - Age at menarche, reactions to menarche and attitudes towards menstruation among Mexican adolescent girls. AB - OBJECTIVE: To investigate the relationships between menarcheal timing and both menarcheal experience and attitudes toward menstruation in Mexican girls. DESIGN: Cross-sectional survey. SETTINGS: Sample of adolescents attending 10 different public schools. PARTICIPANTS: Mexican postmenarcheal adolescents, aged 11-16 years. INTERVENTION: Participants answered 1 questionnaire about menarcheal experience and another about attitudes towards menstruation. RESULTS: Early maturers (menarche before 11 years) were more likely than average (menarche at 11 or 12 years) or late maturers (menarche at 13 or more years) to state they had not known what they should do at the moment they got their first period (P < .01), that they had not felt prepared to start menstruating (P < .05), and that they thought they must keep secret the fact of already having had their first period (P < .05). Concerning their emotional reactions to menarche, early maturers were the most likely to have felt scared (P < .05), worried (P < .05) and sad (P < .05) and were the least likely to have felt calm (P < .05). They were also the most likely to show current secretive attitudes towards menstruation (P < .01). Finally, late maturers showed more positive attitudes toward menstruation than their peers (P < .01). CONCLUSIONS: These results could be useful for developing resources to help early maturing girls manage menstruation. Since these girls have limited or in some cases no time for preparation, they need special support. PMID- 24405635 TI - Human papillomavirus vaccination and sexual behavior in young women. AB - STUDY OBJECTIVE: To compare sexual attitudes and behaviors of young women who have received or declined the HPV vaccine. DESIGN: Cross-sectional survey. SETTING: Obstetrics and gynecology and pediatrics clinics at a large, Midwestern, academic health center. PARTICIPANTS: 223 young women (ages 13-24): 153 who had received HPV vaccination and 70 with no prior HPV vaccination. MAIN OUTCOME MEASURES: Sexual behaviors; attitudes toward sexual activity. RESULTS: Vaccinated young women were slightly but significantly younger than unvaccinated (mean age 19.2 vs 20.0). Both groups showed a large percentage of participants engaging in high-risk sexual behavior (75% vs 77%). The mean age at sexual debut was not significantly different between the groups (16.8 vs 17.0) nor was the average number of sexual partners (6.6 for both). Unvaccinated participants were more likely to have been pregnant (20% vs 8.6%, P = .016), although this difference was not significant in multivariate analysis CI [0.902-5.177]. Specific questions regarding high-risk sexual behaviors and attitudes revealed no significant differences between the groups. CONCLUSION: We found that sexual behaviors, including high-risk behaviors, were similar between young women who had and had not received HPV vaccination. Our findings provide no support for suggestions that the vaccine is associated with increased sexual activity. Importantly, we found that young women in our population are sexually active at a young age and are engaged in high-risk behaviors, affirming the importance of early vaccination. PMID- 24405636 TI - Vitamin D and PTH status among adolescent and young females with severe dysmenorrhea. AB - OBJECTIVE: To investigate Vitamin D and parathyroid hormone (PTH) status among adolescent and young females with severe and very severe dysmenorrhea. DESIGN: Cross-sectional study in specific selected sample. SETTING: One Jordanian university. PARTICIPANTS: Fifty-six females, ages between 17 and 24 years, with severe and very severe dysmenorrhea were surveyed regarding demographics, pain with menstruation, and dietary intake of dairy products. Plasma Vitamin D, PTH levels were measured. RESULTS: About 61% of the studied population experience very severe dysmenorrhea. Half of participants had dairy intake less than 1 serving per day. The majority of participants (80%) had insufficient plasma vitamin D and 48% of them had hyperparathyroidism. CONCLUSION: A high prevalence of vitamin D insufficiency and secondary hyperparathyroidism and/or low dietary calcium intake among adolescent and young adult females who experience severe and very severe dysmenorrhea may negatively affect bone metabolism during achievement of peak bone mass at a young age and adverse bone health at older age. PMID- 24405638 TI - The predictive ability of bleeding risk stratification models in very old patients on vitamin K antagonist treatment for venous thromboembolism: results of the prospective collaborative EPICA study: comment. PMID- 24405637 TI - VPAC2 receptor agonist BAY 55-9837 increases SMN protein levels and moderates disease phenotype in severe spinal muscular atrophy mouse models. AB - BACKGROUND: Spinal Muscular Atrophy (SMA) is one of the most common inherited causes of infant death and is caused by the loss of functional survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene. One of the treatment strategies for SMA is to induce the expression of the protein from the homologous SMN2 gene, a rescuing paralog for SMA. METHODS AND RESULTS: Here we demonstrate the promise of pharmacological modulation of SMN2 gene by BAY 55 9837, an agonist of the vasoactive intestinal peptide receptor 2 (VPAC2), a member of G protein coupled receptor family. Treatment with BAY 55-9837 lead to induction of SMN protein levels via activation of MAPK14 or p38 pathway in vitro. Importantly, BAY 55-9837 also ameliorated disease phenotype in severe SMA mouse models. CONCLUSION: Our findings suggest the VPAC2 pathway is a potential SMA therapeutic target. PMID- 24405639 TI - Hypermethylation of the alternative AWT1 promoter in hematological malignancies is a highly specific marker for acute myeloid leukemias despite high expression levels. AB - BACKGROUND: Wilms tumor 1 (WT1) is over-expressed in numerous cancers with respect to normal cells, and has either a tumor suppressor or oncogenic role depending on cellular context. This gene is associated with numerous alternatively spliced transcripts, which initiate from two different unique first exons within the WT1 and the alternative (A)WT1 promoter intervals. Within the hematological system, WT1 expression is restricted to CD34+/CD38- cells and is undetectable after differentiation. Detectable expression of this gene is an excellent marker for minimal residual disease in acute myeloid leukemia (AML), but the underlying epigenetic alterations are unknown. METHODS: To determine the changes in the underlying epigenetic landscape responsible for this expression, we characterized expression, DNA methylation and histone modification profiles in 28 hematological cancer cell lines and confirmed the methylation signature in 356 cytogenetically well-characterized primary hematological malignancies. RESULTS: Despite high expression of WT1 and AWT1 transcripts in AML-derived cell lines, we observe robust hypermethylation of the AWT1 promoter and an epigenetic switch from a permissive to repressive chromatin structure between normal cells and AML cell lines. Subsequent methylation analysis in our primary leukemia and lymphoma cohort revealed that the epigenetic signature identified in cell lines is specific to myeloid-lineage malignancies, irrespective of underlying mutational status or translocation. In addition to being a highly specific marker for AML diagnosis (positive predictive value 100%; sensitivity 86.1%; negative predictive value 89.4%), we show that AWT1 hypermethylation also discriminates patients that relapse from those achieving complete remission after hematopoietic stem cell transplantation, with similar efficiency to WT1 expression profiling. CONCLUSIONS: We describe a methylation signature of the AWT1 promoter CpG island that is a promising marker for classifying myeloid-derived leukemias. In addition AWT1 hypermethylation is ideally suited to monitor the recurrence of disease during remission in patients undergoing allogeneic stem cell transfer. PMID- 24405640 TI - What is missing in the validation of frailty instruments? PMID- 24405641 TI - Effectiveness of mealtime interventions on behavior symptoms of people with dementia living in care homes: a systematic review. AB - OBJECTIVE: Elderly residents with dementia commonly exhibit increased agitation at mealtimes. This interferes with eating and can be distressing for both the individual and fellow residents. This review examines the effectiveness of mealtime interventions aimed at improving behavioral symptoms in elderly people living with dementia in residential care. DESIGN: Systematic review. DATA SOURCES: Medline, PsycINFO, Embase, HMIC, AMED (OvidSP); CDSR, CENTRAL, DARE (Cochrane Library, Wiley); CINAHL (EBSCOhost); British Nursing Index (NHS Evidence); ASSIA (ProQuest); Social Science Citation Index (Web of Knowledge); EThOS (British Library); Social Care Online and OpenGrey from inception to November 2012. Forward and backward citation chases, hand searches of other review articles identified in the search, and key journals. TYPES OF STUDY: All comparative studies were included. Articles were screened for inclusion independently by 2 reviewers. Data extraction and quality appraisal were performed by one reviewer and checked by a second with discrepancies resolved by discussion with a third if necessary. Data were not suitable for meta-analysis so narrative synthesis was carried out. RESULTS: A total of 6118 articles were identified in the original search. Eleven articles were finally included. Mealtime interventions were categorized into 4 types: music, changes to food service, dining environment alteration, and group conversation. Study quality was poor, making it difficult to reach firm conclusions. Although all studies showed a trend in favor of the intervention, only 6 reported a statistically significant improvement in behavioral symptoms. Four studies suggest cumulative or lingering effects of music on agitated and aggressive behaviors. CONCLUSION: There is some evidence to suggest that mealtime interventions improve behavioral symptoms in elderly people with dementia living in residential care, although weak study designs limit the generalizability of the findings. Well designed, controlled trials are needed to further understand the utility of mealtime interventions in this setting. PMID- 24405642 TI - A Dirichlet process model for classifying and forecasting epidemic curves. AB - BACKGROUND: A forecast can be defined as an endeavor to quantitatively estimate a future event or probabilities assigned to a future occurrence. Forecasting stochastic processes such as epidemics is challenging since there are several biological, behavioral, and environmental factors that influence the number of cases observed at each point during an epidemic. However, accurate forecasts of epidemics would impact timely and effective implementation of public health interventions. In this study, we introduce a Dirichlet process (DP) model for classifying and forecasting influenza epidemic curves. METHODS: The DP model is a nonparametric Bayesian approach that enables the matching of current influenza activity to simulated and historical patterns, identifies epidemic curves different from those observed in the past and enables prediction of the expected epidemic peak time. The method was validated using simulated influenza epidemics from an individual-based model and the accuracy was compared to that of the tree based classification technique, Random Forest (RF), which has been shown to achieve high accuracy in the early prediction of epidemic curves using a classification approach. We also applied the method to forecasting influenza outbreaks in the United States from 1997-2013 using influenza-like illness (ILI) data from the Centers for Disease Control and Prevention (CDC). RESULTS: We made the following observations. First, the DP model performed as well as RF in identifying several of the simulated epidemics. Second, the DP model correctly forecasted the peak time several days in advance for most of the simulated epidemics. Third, the accuracy of identifying epidemics different from those already observed improved with additional data, as expected. Fourth, both methods correctly classified epidemics with higher reproduction numbers (R) with a higher accuracy compared to epidemics with lower R values. Lastly, in the classification of seasonal influenza epidemics based on ILI data from the CDC, the methods' performance was comparable. CONCLUSIONS: Although RF requires less computational time compared to the DP model, the algorithm is fully supervised implying that epidemic curves different from those previously observed will always be misclassified. In contrast, the DP model can be unsupervised, semi-supervised or fully supervised. Since both methods have their relative merits, an approach that uses both RF and the DP model could be beneficial. PMID- 24405643 TI - Predicting women at risk for developing obstetric fistula: a fistula index? An observational study comparison of two cohorts. AB - OBJECTIVE: To ascertain if a predictor of obstructed labour and obstetric fistula (OF) occurrence could be devised. DESIGN: Observational study of two cohorts. SETTING: Selian Lutheran Mission Hospital, Arusha, Tanzania and Aberdeen Women's Centre, Freetown, Sierra Leone. POPULATION: All women presenting with OF caused by obstructed labour and all women having a normal vaginal delivery (NVD) at both institutions were eligible for the study. METHODS: All women with OF and those delivering normally had their height in centimetres measured and their intertuberous space measured by the number of examiner's knuckles admitted. The dimensions for OF and normal delivery were examined individually and multiplied to gain a 'fistula index'. MAIN OUTCOMES MEASURES: Dimensions and index were compared statistically between OF and NVD women using t tests. Sensitivity, specificity and predictive values from receiver operating characteristic curves were obtained for predicting OF. RESULTS: There were statistical differences between the groups with OF women being significantly shorter, having a smaller intertuberous space and lower fistula index than those undergoing NVD (each P < 0.001). Sensitivity was high for fistula index <= 507.5 (94.9%, 95% confidence interval 83.1-98.6%) and for intertuberous space of at least three knuckles (92.3%, 95% CI 79.7-97.3%) alone. CONCLUSIONS: A simple antenatal measurement of intertuberous space could screen those women at higher risk of needing medical intervention to prevent OF. PMID- 24405644 TI - Impact of biomass fuels on pregnancy outcomes in central East India. AB - BACKGROUND: Smoke from biomass burning has been linked to reduced birth weight; association with other birth outcomes is poorly understood. Our objective was to evaluate effects of exposure to biomass smoke on birth weight, preterm birth and stillbirth. METHODS: Information on household cooking fuel was available for secondary analysis from two cohorts of pregnant women enrolled at delivery in India (n = 1744). Birth weight was measured and the modified Ballard performed to assess gestational age. Linear and logistic regression models were used to explore associations between fuel and birth outcomes. Effect sizes were adjusted in multivariate models for socio-demographic characteristics using propensity score techniques and for medical/obstetric covariates. RESULTS: Compared to women who use gas (n = 265), women cooking with wood (n = 1306) delivered infants that were on average 112 grams lighter (95% CI -170.1, -54.6) and more likely to be preterm (OR 3.11, 95% CI 2.12, 4.59). Stillbirths were also more common in the wood group (4% versus 0%, p < 0.001). In adjusted models, the association between wood use and birth weight was no longer significant (14 g reduction; 95% CI -93, 66); however, the increased odds for preterm birth persisted (aOR 2.29; 95% CI 1.24, 4.21). Wood fuel use did not increase the risk of delivering either a low birth weight or small for gestational age infant. CONCLUSIONS: The association between wood fuel use and reduced birth weight was insignificant in multivariate models using propensity score techniques to account for socio-demographic differences. In contrast, we demonstrated a persistent adverse impact of wood fuel use on preterm delivery. If prematurity is confirmed as a consequence of antenatal exposure to household air pollution, perinatal morbidity and mortality from household air pollution may be higher than previously appreciated. PMID- 24405645 TI - The impacts of thyroid function on the diagnostic accuracy of cystatin C to detect acute kidney injury in ICU patients: a prospective, observational study. AB - INTRODUCTION: Cystatin C (Cysc) could be affected by thyroid function both in vivo and in vitro and thereby may have limited ability to reflect renal function. We aimed to assess the association between Cysc and thyroid hormones as well as the effect of thyroid function on the diagnostic accuracy of Cysc to detect acute kidney injury (AKI). METHODS: A total of 446 consecutive intensive care unit (ICU) patients were screened for eligibility in this prospective AKI observational study. Serum Cysc, thyroid hormones and serum creatinine (Scr) were measured upon entry to the ICU. We also collected each patient's baseline characteristics including the Acute Physiology and Chronic Health Evaluation II (APACHE-II) score. The diagnostic performance of Cysc was assessed from the area under the receiver operator characteristic curve (AUC) in each quartile of thyroid hormone(s). RESULTS: A total of 114 (25.6%) patients had a clinical diagnosis of AKI upon entry to the ICU. The range of free thyroxine (FT4) value was 4.77 to 39.57 pmol/L. Multivariate linear regression showed that age (standardized beta = 0.128, P < 0.0001), baseline Scr level (standardized beta = 0.290, P < 0.0001), current Scr (standardized beta = 0.453, P < 0.0001), albumin (standardized beta = -0.086, P = 0.006), and FT4 (standardized beta = 0.062, P = 0.039) were related with Cysc. Patients were divided into four quartiles based on FT4 levels. The AUC for Cysc in detecting AKI in each quartile were as follows: 0.712 in quartile I, 0.754 in quartile II, 0.829 in quartile III and 0.797 in quartile IV. There was no significant difference in the AUC between any two groups (all P > 0.05). The optimal cut-off value of Cysc for diagnosing AKI increased across FT4 quartiles (1.15 mg/L in quartile I, 1.15 mg/L in quartile II, 1.35 mg/L in quartile III and 1.45 mg/L in quartile IV). CONCLUSIONS: There was no significant impact of thyroid function on the diagnostic accuracy of Cysc to detect AKI in ICU patients. However, the optimal cut-off value of Cysc to detect AKI could be affected by thyroid function. PMID- 24405647 TI - A new surgical approach to treat medial or low condylar fractures: the minor parotid anterior approach. AB - OBJECTIVE: A new surgical approach, denoted as the minor parotid anterior approach, was designed to treat medial or low mandibular condylar fractures. STUDY DESIGN: Sixty patients (72 sides) with medial or low condylar fractures were treated surgically. Thirty-six patients (42 sides) were treated with the minor parotid anterior approach, and 24 patients (30 sides) were treated with a retromandibular approach. Data on the surgical procedures and complications were recorded. The follow-up period was 3 to 12 months. RESULTS: Four patients suffered facial nerve injury in the group treated with the retromandibular approach. No cases of facial nerve injury occurred in the minor parotid anterior approach group. CONCLUSIONS: The minor parotid anterior approach avoided facial nerve injury, resulted in less visible facial scarring, and required less manipulation time. Therefore, the minor parotid anterior approach is worth application in the clinical setting. PMID- 24405646 TI - State of non-communicable diseases in Nepal. AB - BACKGROUND: The prevalence of Non Communicable Diseases (NCDs) is still unknown in Nepal. The Ministry of Health and Population, Government of Nepal has not yet formulated policy regarding NCDs in the absence of evidence based finding. The study aims to find out the hospital based prevalence of NCDs in Nepal, thus directing the concerned authorities at policy level. METHODS: A cross sectional study was conducted to identify the hospital based prevalence of 4 NCDs (cancer, cardiovascular disease, diabetes mellitus and chronic obstructive pulmonary disease), wherein 400 indoor patients admitted during 2009 were randomly selected from each of the 31 selected health institutions which included all non specialist tertiary level hospitals outside the Kathmandu valley (n = 25), all specialist tertiary level hospitals in the country (n = 3) and 3 non-specialist tertiary level hospitals inside the Kathmandu valley. In case of Kathmandu valley, 3 non-specialist health institutions- one central hospital, one medical college and one private hospital were randomly selected. The main analyses are based on the 28 non-specialist hospitals. Univariate (frequency and percentage) and bivariate (cross-tabulation) analysis were used. RESULTS: In non-specialist institutions, the hospital based NCD prevalence was 31%. Chronic obstructive pulmonary disease (43%) was the most common NCD followed by cardiovascular disease (40%), diabetes mellitus (12%) and cancer (5%). Ovarian (14%), stomach (14%) and lung cancer (10%) were the main cancers accounting for 38% of distribution. Majority of CVD cases were hypertension (47%) followed by cerebrovascular accident (16%), congestive cardiac failure (11%), ischemic heart disease (7%), rheumatic heart disease (5%) and myocardial infarction (2%). CVD was common in younger age groups while COPD in older age groups. Majority among males (42%) and females (45%) were suffering from COPD. CONCLUSIONS: The study was able to reveal that Nepal is also facing the surging burden of NCDs similar to other developing nations in South East Asia. Furthermore, the study has provided a background data on NCDs in Nepal which should prove useful for the concerned organizations to focus and contribute towards the prevention, control and reduction of NCD burden and its risk factors. PMID- 24405648 TI - Parotid lymphoma: a review of clinical presentation and management. AB - Lymphoma of the parotid gland is a relatively rare occurrence among head and neck tumors. Presentation is indistinguishable from other swellings of the parotid gland; therefore, it is important to consider lymphoma in the differential diagnosis when examining parotid swellings. Parotid lymphomas are most likely to be B-cell non-Hodgkin lymphoma of 1 of 3 types, which include follicular, marginal zone, and diffuse large B cell, although other histologic patterns have been described. We present a review of 3 patients with parotid lymphoma who presented to the University of Maryland Medical Center's Department of Oral and Maxillofacial Surgery with facial swelling. Two patients were diagnosed with follicular lymphoma, whereas the third was diagnosed with marginal zone lymphoma. PMID- 24405649 TI - Oral mycosis fungoides: report with immune profile. AB - Mycosis fungoides (MF) is a cutaneous T-cell lymphoma that uncommonly involves the oral mucosa. Oral MF is an indication of systemic progression and is often associated with an unfavorable outcome. Any oral mucosal site may be affected. This report describes a case of MF involving the hard palate of a 64-year-old woman with confirmed skin MF. The histology showed intra- and subepithelial atypical lymphocytes. Immunohistochemistry on the tissue sections showed that the CD4:CD8 ratio was high (5.8:1) and the CD8:CD3 ratio was low (0.16:1). FoxP3(+) (forkhead box P3-positive) regulatory T cells were conspicuous within the infiltrate, but few interleukin-17 cells were observed. This report is the first to describe a detailed immune profile in oral MF. PMID- 24405650 TI - Biodiesel production from waste cooking oil using a heterogeneous catalyst from pyrolyzed rice husk. AB - A solid acid catalyst was prepared by sulfonating pyrolyzed rice husk with concentrated sulfuric acid, and the physical and chemical properties of the catalyst were characterized in detail. The catalyst was then used to simultaneously catalyze esterification and transesterification to produce biodiesel from waste cooking oil (WCO). In the presence of the as-prepared catalyst, the free fatty acid (FFA) conversion reached 98.17% after 3h, and the fatty acid methyl ester (FAME) yield reached 87.57% after 15 h. By contrast, the typical solid acid catalyst Amberlyst-15 obtained only 95.25% and 45.17% FFA conversion and FAME yield, respectively. Thus, the prepared catalyst had a high catalytic activity for simultaneous esterification and transesterification. In addition, the catalyst had excellent stability, thereby having potential use as a heterogeneous catalyst for biodiesel production from WCO with a high FFA content. PMID- 24405651 TI - Alginate-immobilized bentonite clay: adsorption efficacy and reusability for Cu(II) removal from aqueous solution. AB - This study evaluated the use of alginate-immobilized bentonite to remove Cu(II) as an alternative to mitigate clogging problems. The adsorption efficacy (under the influence of time, pH and initial Cu(II) concentration) and reusability of immobilized-bentonite (1% w/v bentonite) was tested against plain alginate beads. Results revealed that immobilized bentonite demonstrated significantly higher sorption efficacy compared to plain alginate beads with 114.70 and 94.04 mg Cu(II) adsorbed g(-1) adsorbent, respectively. Both sorbents were comparable in other aspects where sorption equilibrium was achieved within 6 h, with optimum pH between pH 4 and 5 for adsorption, displayed maximum adsorption capacity at initial Cu(II) concentrations of 400 mg l(-1), and demonstrated excellent reusability potential with desorption greater than 90% throughout three consecutive adsorption-desorption cycles. Both sorbents also conformed to Langmuir isotherm and pseudo-second order kinetic model. Immobilized bentonite is therefore recommended for use in water treatments to remove Cu(II) without clogging the system. PMID- 24405652 TI - Development and evaluation of a new multi-metal binding biosorbent. AB - A novel multi-metal binding biosorbent (MMBB) was developed by combining a group of three from the selective natural lignocellulosic agro-industrial wastes for effectively eliminating lead, cadmium, copper and zinc from aqueous solutions. Four MMBBs with different combinations (MMBB1: tea waste, corncob, sugarcane bagasse; MMBB2: tea waste, corncob and sawdust; MMBB3: tea waste, corncob and apple peel; MMBB4: tea waste, corncob and grape stalk) were evaluated. FTIR analysis for characterizing the MMBB2 explored that the MMBB2 contains more functional groups available for multi-metals binding. Comparing among the MMBBs as well as the single group biosorbents, MMBB2 was the best biosorbent with the maximum biosorption capacities of 41.48, 39.48, 94.00 and 27.23 mg/g for Cd(II), Cu(II), Pb(II) and Zn(II), respectively. After 5 times of desorption with CaCl2, CH3COOH and NaCl as eluent, the MMBB2 still remained excellent biosorptive capacity, so as it could be well regenerated for reuse and possible recovery of metals. PMID- 24405653 TI - Typical lignocellulosic wastes and by-products for biosorption process in water and wastewater treatment: a critical review. AB - Biosorption on lignocellulosic wastes and by-products has been identified as a proper alternative to the existing technologies applied for toxic metal ion and dye removal from wastewater streams. This paper deals with utilization of typical low cost wastes and by-products produced in different food agricultural and agro industries as biosorbent and reviews the current state of studies on a wide variety of cheap biosorbents in natural and modified forms. The efficiency of each biosorbent has been also discussed with respect to the operating conditions (e.g. temperature, hydraulic residence time, initial metal concentration, biosorbent particle size and its dosage), chemical modification on sorption capacity and preparation methods, as well as thermodynamics and kinetics. PMID- 24405654 TI - Biosorption of Hg(II) onto goethite with extracellular polymeric substances. AB - This study characterized the interactions of goethite, EPS from cyanobacterium Chroococcus sp. and Hg(II) using excitation emission matrix (EEM) spectra and adsorption isotherms. Three protein-like fluorescence peaks were noted to quench in the presence of Hg(II). The estimated conditional stability constant (logKa) and the binding constant (logKb) of the studied EPS-Hg(II) systems ranged 3.84 4.24 and 6.99-7.69, respectively. The proteins in EPS formed stable complex with Hg(II). The presence of proteins of Chroococcus sp. enhanced the adsorption capacity of Hg(II) on goethite; therefore, the goethite-EPS soil is a larger Hg(II) sink than goethite alone soil. Biosorption significantly affects the mobility of Hg(II) in goethite soils. PMID- 24405655 TI - Acute bacterial meningitis in the intensive care unit and risk factors for adverse clinical outcomes: retrospective study. AB - BACKGROUND: Bacterial meningitis constitutes a medical emergency. Its burden has driven from childhood to the elderly and the immunocompromised population. However, the admission of patients with bacterial meningitis to the intensive care unit (ICU) has been sparsely approached, as have the prognostic factors associated with an adverse clinical outcome. METHODS: We performed a retrospective analysis during a 7-year period of patients older than 18 years admitted to 2 polyvalent ICUs. Clinical, demographic, and outcome data were collected to evaluate its clinical impact on the outcome of patients with acute bacterial meningitis. RESULTS: We identified 65 patients with the diagnosis of acute bacterial meningitis (mean Acute Physiology and Chronic Health Evaluation II, 23; hospital mortality, 40%). Upon clinical presentation, their most frequent signs were fever (84%), seizures (21.5%), and a low Glasgow Coma Scale (GCS) score (GCS<8; 58.4%). Fifty-five patients (85%) required organ support. A definite microbiological diagnosis was achieved in 45 patients. An adverse clinical outcome was noted in 46 patients (71%). These patients were older (P=.005), had higher Physiology and Chronic Health Evaluation II score (P=.022), and had lower GCS (P=.022). In the multivariate analysis, older age (per year; adjusted odds ratio [aOR], 1.059) was associated with an adverse outcome, whereas a higher GCS (per point; aOR, 0.826) and presence of fever upon admission (aOR, 0.142) increase the chance of a good recovery. CONCLUSIONS: Patients with acute bacterial meningitis admitted to ICU had substantial morbidity and mortality. Those with low GCS or absence of fever have a particularly high risk of an adverse outcome. PMID- 24405656 TI - Recombinant human thrombopoietin improves platelet counts and reduces platelet transfusion possibility among patients with severe sepsis and thrombocytopenia: a prospective study. AB - INTRODUCTION: Thrombocytopenia is prevalent in patients with severe sepsis, and it is associated with mortalities. Effectively adjunctive treatment might be needed to reverse low platelet counts (PCs). With a growing understanding of thrombocytopenia, recombinant human thrombopoietin (rhTPO) is considered a promising beneficial drug. The present study was dedicated to evaluate the efficiency of rhTPO in improving PCs in patients with severe sepsis. MATERIALS AND METHODS: We performed a prospective study in patients with severe sepsis between March 2012 and February 2013. All enrolled patients were divided into rhTPO group and control group, depending on whether rhTPO was prescribed or not. Platelet counts and other parameters were measured initially and in the following 15 days. RESULTS: Totally, 72 patients (38 in the rhTPO group and 34 in the control group) were included. All enrolled parameters exhibited no significant differences between groups at the baseline. Platelet counts showed a significant increase over time in both groups. Faster improvement of PCs in the rhTPO group was observed with a significant difference. Less platelet transfusion occurred in patients who received rhTPO in our study, as well. No drug-related adverse event during the rhTPO therapy was recorded. CONCLUSION: The use of rhTPO in combination with conventional medical therapies could significantly improve the PCs in patients with severe sepsis and thrombocytopenia and effectively reduce the platelet transfusion possibility. PMID- 24405657 TI - Late cortical plasticity in motor and auditory cortex: role of met-allele in BDNF Val66Met polymorphism. AB - The brain-derived neurotropic factor (BDNF) Val66Met polymorphism has been associated with abnormalities of synaptic plasticity in animal models, and abnormalities in motor cortical plasticity have also been described in humans using transcranial direct current stimulation. No study has yet been done on plasticity in non-motor regions, and the effect of two Met alleles (i.e. 'Met dose') is not well understood. We studied the effect of the BDNF Val66Met polymorphism on the after-effects of transcranial direct current stimulation and tetanic auditory stimulation in 65 subjects (23; Val66Val, 22; Val66Met and 20; Met66Met genotypes). In the first session, motor evoked potentials (MEP) were recorded under stereotaxic guidance for 90 min after 9 min of anodal transcranial direct current stimulation (TDCS). In the second session, auditory-evoked potentials (AEP) were recorded before and after 2 min of auditory 13 Hz tetanic stimulation. There was a difference in MEP facilitation post-TDCS comparing Met carriers with non-Met carriers, with Met carriers having a modest late facilitation at 30-90 min. There was no difference in responses between Val66Met genotype and Met66Met genotype subjects. Tetanic auditory stimulation also produced late facilitation of N1-P2 AEP at 25 min, but there was no apparent effect of genetic status. This study indicates that Met66Met carriers behave like Val66Met carriers for TDCS-induced plasticity, and produce a late facilitation of MEPs. Auditory cortical plasticity was not affected by the BDNF Val66Met polymorphism. This study sheds light on the differences between auditory and motor cortical plasticity and the role of the BDNF Val66Met polymorphism. PMID- 24405658 TI - Evidence of T-cell mediated neuronal injury in stiff-person syndrome with anti amphiphysin antibodies. AB - Paraneoplastic stiff-person syndrome (SPS) has been associated with antibodies against amphiphysin. Current evidence supports a pathogenic role for anti amphiphysin antibodies. A 74-year-old female was diagnosed with amphiphysin associated paraneoplastic stiff-person syndrome and associated encephalomyelitis. She had initial response to IVIG, however her symptoms worsened after two months and were resistant to further treatment. Subsequently the patient died and a post mortem was performed. Neuropathology revealed perivascular and parenchymal lymphocytic infiltrates, with neuronophagia mediated by CD8+ T cells and microglia in brainstem, spinal cord, and mesial temporal lobe structures. These findings suggest a pathogenic role of cytotoxic CD8+ T-cells, with potential implication for therapy of future patients. PMID- 24405659 TI - Prevalence of Group A beta-haemolytic Streptococcus isolated from children with acute pharyngotonsillitis in Aden, Yemen. AB - OBJECTIVES: To estimate the prevalence of Group A beta-haemolytic streptococcus (GAS) and non-GAS infections among children with acute pharyngotonsillitis in Aden, Yemen, to evaluate the value of a rapid diagnostic test and the McIsaac score for patient management in this setting and to determine the occurrence of emm genotypes among a subset of GAS isolated from children with acute pharyngotonsillitis and a history of acute rheumatic fever (ARF) or rheumatic heart disease (RHD). METHODS: Group A beta-haemolytic streptococcus infections in school-aged children with acute pharyngotonsillitis in Aden, Yemen, were diagnosed by a rapid GAS antigen detection test (RADT) and/or GAS culture from a throat swab. The RADT value and the McIsaac screening score for patient management were evaluated. The emm genotype of a subset of GAS isolates was determined. RESULTS: Group A beta-haemolytic streptococcus pharyngotonsillitis was diagnosed in 287/691 (41.5%; 95% CI 37.8-45.3) children. Group B, Group C and Group G beta-haemolytic streptococci were isolated from 4.3% children. The RADT had a sensitivity of 238/258 (92.2%) and specificity of 404/423 (95.5%) against GAS culture. A McIsaac score of >=4 had a sensitivity of 93% and a specificity of 82% for confirmed GAS infection. The emm genotypes in 21 GAS isolates from children with pharyngitis and a history of ARF and confirmed RHD were emm87 (11), emm12 (6), emm28 (3) and emm5 (1). CONCLUSION: This study demonstrates a very high prevalence of GAS infections in Yemeni children and the value of the RADT and the McIsaac score in this setting. More extensive emm genotyping is necessary to understand the local epidemiology of circulating strains. PMID- 24405661 TI - Building leadership among laboratory-based and clinical and translational researchers: the University of California, San Francisco experience. AB - In 2005 the University of California, San Francisco (UCSF) implemented the Scientific Leadership and Management (SLM) course, a 2-day leadership training program to assist laboratory-based postdoctoral scholars in their transition to independent researchers managing their own research programs. In 2011, the course was expanded to clinical and translational junior faculty and fellows. The course enrollment was increased from approximate 100 to 123 participants at the same time. Based on course evaluations, the number and percent of women participants appears to have increased over time from 40% (n = 33) in 2007 to 53% (n = 58) in 2011. Course evaluations also indicated that participants found the course to be relevant and valuable in their transition to academic leadership. This paper describes the background, structure, and content of the SLM and reports on participant evaluations of the course offerings from 2007 through 2011. PMID- 24405660 TI - Minocycline, a microglial inhibitor, blocks spinal CCL2-induced heat hyperalgesia and augmentation of glutamatergic transmission in substantia gelatinosa neurons. AB - BACKGROUND: Several lines of evidence suggest that CCL2 could initiate the hyperalgesia of neuropathic pain by causing central sensitization of spinal dorsal horn neurons and facilitating nociceptive transmission in the spinal dorsal horn. The cellular and molecular mechanisms by which CCL2 enhances spinal pain transmission and causes hyperalgesia remain unknown. The substantia gelatinosa (lamina II) of the spinal dorsal horn plays a critical role in nociceptive transmission. An activated spinal microglia, which is believed to release pro-inflammatory cytokines including TNF-alpha, plays an important role in the development of neuropathic pain, and CCL2 is a key mediator for spinal microglia activation. In the present study, we tested the hypothesis that spinal CCL2 causes the central sensitization of substantia gelatinosa neurons and enhances spinal nociceptive transmission by activating the spinal microglia and augmenting glutamatergic transmission in lamina II neurons. METHODS: CCL2 was intrathecally administered to 2-month-old male rats. An intrathecal injection of CCL2 induced heat hyperalgesia, which was assessed using the hot plate test. Whole-cell voltage-clamp recordings substantia gelatinosa neurons in spinal cord slices were performed to record glutamatergic excitatory postsynaptic currents (EPSCs) and GABAergic inhibitory postsynaptic currents (IPSCs). RESULTS: The hot plate test showed that 1 day after the intrathecal injection of CCL2 (1 MUg), the latency of hind-paw withdrawal caused by a heat stimulus was significantly reduced in rats. One day after the intrathecal administration of CCL2, the amplitude of the evoked glutamatergic EPSCs and the frequency of spontaneous glutamatergic miniature EPSCs (mEPSCs) were significantly increased in outer lamina II neurons. Intrathecal co-injection of minocycline, a specific inhibitor of microglial activation, and CCL2 blocked the CCL2-induced reduction in the latency of hind-paw withdrawal and thermal hyperalgesia. Following intrathecal co administration of CCL2 and minocycline, CCL2 failed to increase the frequency of glutamatergic mEPSCs and failed to promote glutamine release in lamina II neurons. Intrathecal co-injection of WP9QY, a selective TNF-alpha antagonist, and CCL2 completely inhibited CCL2-induced heat hyperalgesia and inhibited the increase in the frequency of glutamatergic mEPSCs in substantia gelatinosa neurons. CONCLUSION: In summary, our results suggest that an intrathecal injection of CCL2 causes thermal hyperalgesia by augmenting the excitatory glutamatergic transmission in substantia gelatinosa neurons through a presynaptic mechanism and facilitating nociceptive transmission in the spinal dorsal horn. Further studies show that intrathecal co-administration of minocycline, a specific inhibitor of microglial activation, or WP9QY, a selective TNF-alpha antagonist, completely inhibited CCL2 potentiation of glutamatergic transmission in substantia gelatinosa neurons and CCL2-induced heat hyperalgesia. The results of the present study suggest that peripheral nerve injury-induced upregulation of the spinal CCL2 level causes the central sensitization of substantia gelatinosa neurons by activating spinal microglia and that TNF-alpha mediates CCL2-induced thermal hyperalgesia and augmentation of glutamatergic transmission in lamina II neurons. PMID- 24405662 TI - Potential beneficial effects of ixmyelocel-T in the treatment of atherosclerotic diseases. AB - INTRODUCTION: Advanced atherosclerotic lesions are characterized by lipid accumulation, inflammation, and defective efferocytosis. An ideal therapy should address all aspects of this multifactorial disease. Ixmyelocel-T therapy, an expanded autologous multicellular therapy showing clinical promise in the treatment of diseases associated with advanced atherosclerosis, includes a novel population of M2-like macrophages. Here, we examine the macrophages of ixmyelocel T and determine their ability to influx modified cholesterol in an atheroprotective manner, maintaining cholesterol homeostasis and preventing cellular dysfunction and death, ultimately promoting reverse cholesterol efflux. METHODS: Approximately 50 ml of whole bone marrow was obtained from healthy donors and shipped overnight. Bone marrow mononuclear cells (BMMNCs) were produced by using density gradient separation and cultured for approximately 12 days to generate ixmyelocel-T. CD14+ cells were isolated from ixmyelocel-T via positive selection for analysis. Ixmyelocel-T and human leukemia monocyte (THP-1) cells were loaded with acetylated low-density lipoprotein (Ac-LDL) for analysis. Flow cytometry and immunofluorescence were used to examine Ac-LDL uptake, expression of cytokines was analyzed by enzyme-linked immunofluorescence assay (ELISA), and quantitative real-time PCR was used to analyze expression of cholesterol-transport genes. Both the in vitro cholesterol efflux assay and in vivo reverse cholesterol transport assay were used to examine cholesterol transport. RESULTS: Ixmyelocel-T macrophages take up acetylated low-density lipoprotein and express the scavenger receptors CD36 and scavenger receptor-B1 (SR-B1). Ixmyelocel-T did not become apoptotic or proinflammatory after lipid loading. The cholesterol transporter genes ABAC1 and ABCG1 were both statistically significantly upregulated when ixmyelocel-T macrophages were loaded with cholesterol. Ixmyelocel-T also exhibited enhanced apolipoprotein A-I (ApoAI) mediated cholesterol efflux. In addition, in vivo reverse cholesterol-transport assay demonstrated that ixmyelocel-T was able to efflux cholesterol in this model. CONCLUSIONS: Ixmyelocel-T macrophages influx modified cholesterol, remained anti-inflammatory in the face of lipid loading and inflammatory challenge, and displayed enhanced cholesterol efflux capabilities. These combined features suggest that this autologous multicellular therapy may exert beneficial effects in atherosclerotic diseases. PMID- 24405663 TI - Increased methylation of lung cancer-associated genes in sputum DNA of former smokers with chronic mucous hypersecretion. AB - BACKGROUND: Chronic mucous hypersecretion (CMH) contributes to COPD exacerbations and increased risk for lung cancer. Because methylation of gene promoters in sputum has been shown to be associated with lung cancer risk, we tested whether such methylation was more common in persons with CMH. METHODS: Eleven genes commonly silenced by promoter methylation in lung cancer and associated with cancer risk were selected. Methylation specific PCR (MSP) was used to profile the sputum of 900 individuals in the Lovelace Smokers Cohort (LSC). Replication was performed in 490 individuals from the Pittsburgh Lung Screening Study (PLuSS). RESULTS: CMH was significantly associated with an overall increased number of methylated genes, with SULF2 methylation demonstrating the most consistent association. The association between SULF2 methylation and CMH was significantly increased in males but not in females both in the LSC and PLuSS (OR = 2.72, 95% CI = 1.51-4.91, p = 0.001 and OR = 2.97, 95% CI = 1.48-5.95, p = 0.002, respectively). Further, the association between methylation and CMH was more pronounced among 139 male former smokers with persistent CMH compared to current smokers (SULF2; OR = 3.65, 95% CI = 1.59-8.37, p = 0.002). CONCLUSIONS: These findings demonstrate that especially male former smokers with persistent CMH have markedly increased promoter methylation of lung cancer risk genes and potentially could be at increased risk for lung cancer. PMID- 24405664 TI - Strengthening the enabling environment for women and girls: what is the evidence in social and structural approaches in the HIV response? AB - There is growing interest in expanding public health approaches that address social and structural drivers that affect the environment in which behaviour occurs. Half of those living with HIV infection are women. The sociocultural and political environment in which women live can enable or inhibit their ability to protect themselves from acquiring HIV. This paper examines the evidence related to six key social and structural drivers of HIV for women: transforming gender norms; addressing violence against women; transforming legal norms to empower women; promoting women's employment, income and livelihood opportunities; advancing education for girls and reducing stigma and discrimination. The paper reviews the evidence for successful and promising social and structural interventions related to each driver. This analysis contains peer-reviewed published research and study reports with clear and transparent data on the effectiveness of interventions. Structural interventions to address these key social and structural drivers have led to increasing HIV-protective behaviours, creating more gender-equitable relationships and decreasing violence, improving services for women, increasing widows' ability to cope with HIV and reducing behaviour that increases HIV risk, particularly among young people. PMID- 24405665 TI - Intra-erythrocyte infusion of dexamethasone reduces neurological symptoms in ataxia teleangiectasia patients: results of a phase 2 trial. AB - BACKGROUND: Ataxia Teleangiectasia [AT] is a rare neurodegenerative disease characterized by early onset ataxia, oculocutaneous teleangiectasias, immunodeficiency, recurrent infections, radiosensitivity and proneness to cancer. No therapies are available for this devastating disease. Recent observational studies in few patients showed beneficial effects of short term treatment with betamethasone. To avoid the characteristic side effects of long-term administration of steroids we developed a method for encapsulation of dexamethasone sodium phosphate (DSP) into autologous erythrocytes (EryDex) allowing slow release of dexamethasone for up to one month after dosing. Aims of the study were: the assessment of the effect of EryDex in improving neurological symptoms and adaptive behaviour of AT patients; the safety and tolerability of the therapy. METHODS: Twenty two patients (F:M=1; mean age 11.2 +/- 3.5) with a confirmed diagnosis of AT and a preserved or partially supported gait were enrolled for the study. The subjects underwent for six months a monthly infusion of EryDex. Ataxia was assessed by the International Cooperative Ataxia Rating Scale (ICARS) and the adaptive behavior by Vineland Adaptive Behavior Scales (VABS). Clinical evaluations were performed at baseline and 1, 3, and 6 months. RESULTS: An improvement in ICARS (reduction of the score) was detected in the intention-to-treat (ITT) population (n=22; p=0.02) as well as in patients completing the study (per protocol PP) (n=18; p=0.01), with a mean reduction of 4 points (ITT) or 5.2 points (PP). When compared to baseline, a significant improvement were also found in VABS (increase of the score) (p<0.0001, ITT, RMANOVA), with statistically significant increases at 3 and 6 months (p<0.0001). A large inter-patient variability in the incorporation of DSP into erythrocytes was observed, with an evident positive effect of higher infusion dose on ICARS score decline. Moreover a more marked improvement was found in less neurologically impaired patients. Finally, a 19 month-extension study involving a subgroup of patients suggested that Erydex treatment can possibly delay the natural progression of the disease.EryDex was well tolerated; the most frequent side effects were common AT pathologies. CONCLUSIONS: EryDex treatment led to a significant improvement in neurological symptoms, without association with the typical steroid side effects. TRIAL REGISTRATION: Current Controlled Trial 2010 022315-19SpA. PMID- 24405667 TI - Avian sleep. PMID- 24405668 TI - Mosquitoes. PMID- 24405666 TI - Vascularized composite allograft tolerance across MHC barriers in a large animal model. AB - Vascularized composite allograft (VCA) transplantation can restore form and function following severe craniofacial injuries, extremity amputations or massive tissue loss. The induction of transplant tolerance would eliminate the need for long-term immunosuppression, realigning the risk-benefit ratio for these life enhancing procedures. Skin, a critical component of VCA, has consistently presented the most stringent challenge to transplant tolerance. Here, we demonstrate, in a clinically relevant miniature swine model, induction of immunologic tolerance of VCAs across MHC barriers by induction of stable hematopoietic mixed chimerism. Recipient conditioning consisted of T cell depletion with CD3-immunotoxin, and 100 cGy total body irradiation prior to hematopoietic cell transplantation (HCT) and a 45-day course of cyclosporine A. VCA transplantation was performed either simultaneously to induction of mixed chimerism or into established mixed chimeras 85-150 days later. Following withdrawal of immunosuppression both VCAs transplanted into stable chimeras (n=4), and those transplanted at the time of HCT (n=2) accepted all components, including skin, without evidence of rejection to the experimental end point 115 504 days posttransplant. These data demonstrate that tolerance across MHC mismatches can be induced in a clinically relevant VCA model, providing proof of concept for long-term immunosuppression-free survival. PMID- 24405669 TI - Non-sexual abdominal appendages in adult insects challenge a 300 million year old bauplan. PMID- 24405670 TI - Inhibitory neurons: vip cells hit the brake on inhibition. AB - Recent studies on vasoactive intestinal peptide-expressing inhibitory neurons in the barrel and auditory cortices of the mouse brain have shown that they form a disinhibitory circuitry that affects the excitability of pyramidal neurons. PMID- 24405671 TI - Meiosis: SYP up firmly and cross over evenly. AB - The distribution and number of reciprocal DNA exchange events (crossovers) along meiotic chromosomes is tightly controlled. A recent report shows that unperturbed meiotic chromosome structure is important for this control, and that crossovers in turn modify chromosome structure locally. PMID- 24405672 TI - Cell migration: sinking in a gradient. AB - How chemoattractant gradients form and persist in complex tissues is a key question in cell migration. Two studies now show that CXCR7 acts as a sink in the migrating zebrafish lateral line primordium to generate SDF1 gradients. PMID- 24405673 TI - Circadian clocks: the tissue is the issue. AB - The circadian clock uses a widely expressed pair of clock activators to drive tissue-specific rhythms in target gene expression. A new study sheds light on this tissue specificity by showing that binding of clock activators and tissue specific transcription factors to closely associated target sites enables cooperative activation of target genes in different tissues. PMID- 24405674 TI - Plant biology: gatekeepers of the road to protein perdition. AB - Targeting membrane proteins for degradation requires the sequential action of ESCRT sub-complexes ESCRT-0 to ESCRT-III. Although this machinery is generally conserved among kingdoms, plants lack the essential ESCRT-0 components. A new report closes this gap by identifying a novel protein family that substitutes for ESCRT-0 function in plants. PMID- 24405675 TI - Autism: demise of the innate social orienting hypothesis. AB - Some have suggested that autism may be caused by poor orienting to social stimuli in early infancy, compounded by the resulting failures to learn from, and about, other humans. Recent results contradict this hypothesis, suggesting a need to rethink. PMID- 24405676 TI - Actin dynamics: cell migration takes a new turn with arpin. AB - Accurate cell migration requires intricate control over the actin cytoskeleton. Recent work has identified an Arp2/3-interacting protein called Arpin, which restricts the rate of actin polymerization and is the latest component in the steadily expanding protein repertoire that controls cell migration. PMID- 24405677 TI - Evolution: 'snowed' in with the enemy. AB - Explaining the origins and maintenance of cooperation in nature is a key challenge in evolutionary biology. A recent study demonstrates two novel mechanisms through which the natural ecology of sinking ocean aggregates- colloquially called 'marine snow' - promotes cooperation. PMID- 24405678 TI - Development: facial makeup enhancing our looks. AB - A recent study in mice deciphers the complex genetic regulatory network underlying the morphogenesis of the face. The enhancer landscape underlying craniofacial development provides multiple entry points to understand what makes up the face, in natural variation or pathological conditions. PMID- 24405679 TI - Development: a deep breath for endocrine organ evolution. AB - Developmental biologists have made surprising discoveries on the evolutionary origins of cell types, organs and body plans. Now, an elegant study in Drosophila raises interesting questions about the origin of two major endocrine organs of insects. PMID- 24405681 TI - Maintenance of arytenoid abduction following carbon dioxide laser debridement of the articular cartilage and joint capsule of the cricoarytenoid joint combined with prosthetic laryngoplasty in horses: an in vivo and in vitro study. AB - The objective was to evaluate CO2 laser debridement of the cricoarytenoid joint (CAJ) combined with prosthetic laryngoplasty to prevent post-operative loss of arytenoid abduction in seven horses. Horses were assigned to either laser debridement of the left CAJ and laryngoplasty (laser treated, n=5) or control laryngoplasty (sham, n=2), and were evaluated with endoscopic examinations and measurement of right to left angle quotients (RLQ) to assess maintenance of arytenoid abduction. The animals were euthanased at intervals after surgery and larynges were harvested for post-mortem testing, including determination of translaryngeal flow, pressure, impedance and RLQ. Measurements were obtained under increasing vacuum-generated negative pressure with laryngoplasty sutures intact and with the knot/crimp of the laryngoplasty sutures removed. Following post-mortem testing the cricoarytenoid joints were examined histologically. Post operative endoscopic examinations revealed no significant differences between RLQ measurements calculated for day 1 following surgery to the termination date of the study for the seven horses. Post-mortem RLQ at airflows of 10 and 60 L/s was significantly higher in sham than in laser treated horses both before and after knot/crimp removal. Translaryngeal impedance at 10 and 60 L/s was not statistically different between groups. Histopathology revealed necrosis and loss of articular cartilage in the laser treated horses. The lymphoid cell infiltration subsided but joint capsule and periarticular fibrosis increased over the course of the study. Post-operative loss of arytenoid abduction after laryngoplasty can be minimized with CO2 laser debridement of the CAJ joint. PMID- 24405680 TI - Tools for resolving functional activity and connectivity within intact neural circuits. AB - Mammalian neural circuits are sophisticated biological systems that choreograph behavioral processes vital for survival. While the inherent complexity of discrete neural circuits has proven difficult to decipher, many parallel methodological developments promise to help delineate the function and connectivity of molecularly defined neural circuits. Here, we review recent technological advances designed to precisely monitor and manipulate neural circuit activity. We propose a holistic, multifaceted approach for unraveling how behavioral states are manifested through the cooperative interactions between discrete neurocircuit elements. PMID- 24405682 TI - Biosecurity: making an intangible tangible. PMID- 24405683 TI - A systematic review and meta-analysis of the effects of antibiotic consumption on antibiotic resistance. AB - BACKGROUND: Greater use of antibiotics during the past 50 years has exerted selective pressure on susceptible bacteria and may have favoured the survival of resistant strains. Existing information on antibiotic resistance patterns from pathogens circulating among community-based patients is substantially less than from hospitalized patients on whom guidelines are often based. We therefore chose to assess the relationship between the antibiotic resistance pattern of bacteria circulating in the community and the consumption of antibiotics in the community. METHODS: Both gray literature and published scientific literature in English and other European languages was examined. Multiple regression analysis was used to analyse whether studies found a positive relationship between antibiotic consumption and resistance. A subsequent meta-analysis and meta-regression was conducted for studies for which a common effect size measure (odds ratio) could be calculated. RESULTS: Electronic searches identified 974 studies but only 243 studies were considered eligible for inclusion by the two independent reviewers who extracted the data. A binomial test revealed a positive relationship between antibiotic consumption and resistance (p < .001) but multiple regression modelling did not produce any significant predictors of study outcome. The meta analysis generated a significant pooled odds ratio of 2.3 (95% confidence interval 2.2 to 2.5) with a meta-regression producing several significant predictors (F(10,77) = 5.82, p < .01). Countries in southern Europe produced a stronger link between consumption and resistance than other regions. CONCLUSIONS: Using a large set of studies we found that antibiotic consumption is associated with the development of antibiotic resistance. A subsequent meta-analysis, with a subsample of the studies, generated several significant predictors. Countries in southern Europe produced a stronger link between consumption and resistance than other regions so efforts at reducing antibiotic consumption may need to be strengthened in this area. Increased consumption of antibiotics may not only produce greater resistance at the individual patient level but may also produce greater resistance at the community, country, and regional levels, which can harm individual patients. PMID- 24405684 TI - Developing aptamer probes for acute myelogenous leukemia detection and surface protein biomarker discovery. AB - BACKGROUND: The majority of patients with acute myelogenous leukemia (AML) still die of their disease. In order to improve survival rates in AML patients, new strategies are necessary to discover biomarkers for the detection and targeted therapy of AML. One of the advantages of the aptamer-based technology is the unique cell-based selection process, which allows us to efficiently select for cell-specific aptamers without knowing which target molecules are present on the cell surface. METHODS: The NB4 AML cell line was used as the target cell population for selecting single stranded DNA aptamers. After determining the affinity of selected aptamers to leukocytes, the aptamers were used to phenotype human bone marrow leukocytes and AML cells in clinical specimens. Then a biotin labelled aptamer was used to enrich and identify its target surface protein. RESULTS: Three new aptamers were characterized from the selected aptamer pools (JH6, JH19, and K19). All of them can selectively recognize myeloid cells with Kd in the low nanomole range (2.77 to 12.37 nM). The target of the biotin-labelled K19 aptamer probe was identified as Siglec-5, a surface membrane protein in low abundance whose expression can serve as a biomarker of granulocytic maturation and be used to phenotype AML. More importantly, Siglec-5 expression can be used to detect low concentrations of AML cells in human bone marrow specimens, and functions as a potential target for leukemic therapy. CONCLUSIONS: We have demonstrated a pipeline approach for developing single stranded DNA aptamer probes, phenotyping AML cells in clinical specimens, and then identifying the aptamer-recognized target protein. The developed aptamer probes and identified Siglec-5 protein may potentially be used for leukemic cell detection and therapy in our future clinical practice. PMID- 24405685 TI - The pressure cooker technique for the treatment of brain AVMs. AB - Arteriovenous malformations (AVMs) may be cured by injecting liquid embolic agents such as Onyx. Reflux, however, can sometimes be difficult to control and may jeopardize a complete embolization. The pressure cooker technique (PCT) was designed to create an anti-reflux plug by trapping the detachable part of an Onyx compatible microcatheter with coils and glue in order to obtain wedge-flow conditions, thereby enabling a better understanding of macrofistulous AVMs and a more comprehensive, forceful and controlled Onyx embolization. The PCT might enlarge the range of AVMs amenable to endovascular cure. Three illustrative cases are presented. PMID- 24405686 TI - MRI with DWI helps in depicting rheumatoid meningitis. PMID- 24405687 TI - Transfusion policy after severe postpartum haemorrhage: a randomised non inferiority trial. AB - OBJECTIVE: To assess the effect of red blood cell (RBC) transfusion on quality of life in acutely anaemic women after postpartum haemorrhage. DESIGN: Randomised non-inferiority trial. SETTING: Thirty-seven Dutch university and general hospitals. POPULATION: Women with acute anaemia (haemoglobin 4.8-7.9 g/dl [3.0 4.9 mmol/l] 12-24 hours postpartum) without severe anaemic symptoms or severe comorbidities. METHODS: Women were allocated to RBC transfusion or non intervention. MAIN OUTCOME MEASURES: Primary outcome was physical fatigue 3 days postpartum (Multidimensional Fatigue Inventory, scale 4-20; 20 represents maximal fatigue). Non-inferiority was demonstrated if the physical fatigue difference between study arms was maximal 1.3. Secondary outcomes were health-related quality of life and physical complications. Health-related quality of life questionnaires were completed at five time-points until 6 weeks postpartum. RESULTS: In all, 521 women were randomised to non-intervention (n = 262) or RBC transfusion (n = 259). Mean physical fatigue score at day 3 postpartum, adjusted for baseline and mode of delivery, was 0.8 lower in the RBC transfusion arm (95% confidence interval: 0.1-1.5, P = 0.02) and at 1 week postpartum was 1.06 lower (95% confidence interval: 0.3-1.8, P = 0.01). A median of two RBC units was transfused in the RBC transfusion arm. In the non-intervention arm, 33 women received RBC transfusion, mainly because of anaemic symptoms. Physical complications were comparable. CONCLUSIONS: Statistically, non-inferiority could not be demonstrated as the confidence interval crossed the non-inferiority boundary. Nevertheless, with only a small difference in physical fatigue and no differences in secondary outcomes, implementation of restrictive management seems clinically justified. PMID- 24405688 TI - Implementation of a novel in vitro model of infection of reconstituted human epithelium for expression of virulence genes in methicillin-resistant Staphylococcus aureus strains isolated from catheter-related infections in Mexico. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) are clinically relevant pathogens that cause severe catheter-related nosocomial infections driven by several virulence factors. METHODS: We implemented a novel model of infection in vitro of reconstituted human epithelium (RHE) to analyze the expression patterns of virulence genes in 21 MRSA strains isolated from catheter related infections in Mexican patients undergoing haemodialysis. We also determined the phenotypic and genotypic co-occurrence of antibiotic- and disinfectant-resistance traits in the S. aureus strains, which were also analysed by pulsed-field-gel electrophoresis (PFGE). RESULTS: In this study, MRSA strains isolated from haemodialysis catheter-related infections expressed virulence markers that mediate adhesion to, and invasion of, RHE. The most frequent pattern of expression (present in 47.6% of the strains) was as follows: fnbA, fnbB, spa, clfA, clfB, cna, bbp, ebps, eap, sdrC, sdrD, sdrE, efb, icaA, and agr. Seventy one percent of the strains harboured the antibiotic- and disinfectant-resistance genes ermA, ermB, tet(M), tet(K), blaZ, qacA, qacB, and qacC. PFGE of the isolated MRSA revealed three identical strains and two pairs of identical strains. The strains with identical PFGE patterns showed the same phenotypes and genotypes, including the same spa type (t895), suggesting hospital personnel manipulating the haemodialysis equipment could be the source of catheter contamination. CONCLUSION: These findings help define the prevalence of MRSA virulence factors in catheter-related infections. Some of the products of the expressed genes that we detected in this work may serve as potential antigens for inclusion in a vaccine for the prevention of MRSA-catheter-related infections. PMID- 24405689 TI - Effects of curcumin on chronic, unpredictable, mild, stress-induced depressive like behaviour and structural plasticity in the lateral amygdala of rats. AB - Depression is a neuropsychiatric disease associated with wide ranging disruptions in neuronal plasticity throughout the brain. Curcumin, a natural polyphenolic compound of curcuma loga, has been demonstrated to be effective in the treatment of depressive-like disorders. The present study aimed to investigate the mechanisms underlying the antidepressant-like effects of curcumin in a rat model of chronic, unpredictable, mild, stress (CUMS) -induced depression. The results showed that CUMS produced depressive-like behaviours in rats, which were associated with ultra-structural changes in neurons within the lateral amygdala (LA). In addition, the expression of synapse-associated proteins such as brain derived neurotrophic factor (BDNF), PSD-95 and synaptophysin were significantly decreased in the LA of CUMS-treated rats. Chronic administration of curcumin (40 mg/kg, i.p. 6 wk) before stress exposure significantly prevented these neuronal and biochemical alterations induced by CUMS, and suppressed depressive-like behaviours, suggesting that this neuronal dysregulation may be related to the depressive-like behaviours caused by CUMS. Together with our previous results, the current findings demonstrate that curcumin exhibits neuroprotection and antidepressant-like effects in the CUMS-induced depression model. Furthermore, this antidepressant-like action of curcumin appears to be mediated by modulating synapse-associated proteins within the LA. These findings provide new insights into the underlying mechanisms leading to neural dysfunction in depression and reveal the therapeutic potential for curcumin use in clinical trials. PMID- 24405690 TI - Post-traumatic psoas abscess diagnosed by 18F FDG PET/CT. PMID- 24405691 TI - HERV-W polymorphism in chromosome X is associated with multiple sclerosis risk and with differential expression of MSRV. AB - BACKGROUND: Multiple Sclerosis (MS) is an autoimmune demyelinating disease that occurs more frequently in women than in men. Multiple Sclerosis Associated Retrovirus (MSRV) is a member of HERV-W, a multicopy human endogenous retroviral family repeatedly implicated in MS pathogenesis. MSRV envelope protein is elevated in the serum of MS patients and induces inflammation and demyelination but, in spite of this pathogenic potential, its exact genomic origin and mechanism of generation are unknown. A possible link between the HERV-W copy on chromosome Xq22.3, that contains an almost complete open reading frame, and the gender differential prevalence in MS has been suggested. RESULTS: MSRV transcription levels were higher in MS patients than in controls (U-Mann-Whitney; p = 0.004). Also, they were associated with the clinical forms (Spearman; p = 0.0003) and with the Multiple Sclerosis Severity Score (MSSS) (Spearman; p = 0.016). By mapping a 3 kb region in Xq22.3, including the HERV-W locus, we identified three polymorphisms: rs6622139 (T/C), rs6622140 (G/A) and rs1290413 (G/A). After genotyping 3127 individuals (1669 patients and 1458 controls) from two different Spanish cohorts, we found that in women rs6622139 T/C was associated with MS susceptibility: [chi2; p = 0.004; OR (95% CI) = 0.50 (0.31 0.81)] and severity, since CC women presented lower MSSS scores than CT (U-Mann Whitney; p = 0.039) or TT patients (U-Mann-Whitney; p = 0.031). Concordantly with the susceptibility conferred in women, rs6622139*T was associated with higher MSRV expression (U-Mann-Whitney; p = 0.003). CONCLUSIONS: Our present work supports the hypothesis of a direct involvement of HERV-W/MSRV in MS pathogenesis, identifying a genetic marker on chromosome X that could be one of the causes underlying the gender differences in MS. PMID- 24405692 TI - Pharmacologic inhibition of S-nitrosoglutathione reductase protects against experimental asthma in BALB/c mice through attenuation of both bronchoconstriction and inflammation. AB - BACKGROUND: S-nitrosoglutathione (GSNO) serves as a reservoir for nitric oxide (NO) and thus is a key homeostatic regulator of airway smooth muscle tone and inflammation. Decreased levels of GSNO in the lungs of asthmatics have been attributed to increased GSNO catabolism via GSNO reductase (GSNOR) leading to loss of GSNO- and NO- mediated bronchodilatory and anti-inflammatory actions. GSNOR inhibition with the novel small molecule, N6022, was explored as a therapeutic approach in an experimental model of asthma. METHODS: Female BALB/c mice were sensitized and subsequently challenged with ovalbumin (OVA). Efficacy was determined by measuring both airway hyper-responsiveness (AHR) upon methacholine (MCh) challenge using whole body plethysmography and pulmonary eosinophilia by quantifying the numbers of these cells in the bronchoalveolar lavage fluid (BALF). Several other potential biomarkers of GSNOR inhibition were measured including levels of nitrite, cyclic guanosine monophosphate (cGMP), and inflammatory cytokines, as well as DNA binding activity of nuclear factor kappa B (NFkappaB). The dose response, onset of action, and duration of action of a single intravenous dose of N6022 given from 30 min to 48 h prior to MCh challenge were determined and compared to effects in mice not sensitized to OVA. The direct effect of N6022 on airway smooth muscle tone also was assessed in isolated rat tracheal rings. RESULTS: N6022 attenuated AHR (ED50 of 0.015 +/- 0.002 mg/kg; Mean +/- SEM) and eosinophilia. Effects were observed from 30 min to 48 h after treatment and were comparable to those achieved with three inhaled doses of ipratropium plus albuterol used as the positive control. N6022 increased BALF nitrite and plasma cGMP, while restoring BALF and plasma inflammatory markers toward baseline values. N6022 treatment also attenuated the OVA-induced increase in NFkappaB activation. In rat tracheal rings, N6022 decreased contractile responses to MCh. CONCLUSIONS: The significant bronchodilatory and anti inflammatory actions of N6022 in the airways are consistent with restoration of GSNO levels through GSNOR inhibition. GSNOR inhibition may offer a therapeutic approach for the treatment of asthma and other inflammatory lung diseases. N6022 is currently being evaluated in clinical trials for the treatment of inflammatory lung disease. PMID- 24405694 TI - Characteristics of 18 patients with hepatocellular carcinoma who obtained a complete response after treatment with sorafenib. AB - AIM: Sorafenib, a multi-targeted tyrosine kinase inhibitor, is a first-line systemic treatment for advanced hepatocellular carcinoma (HCC). However, possible predictors of the efficacy of sorafenib treatment in HCC patients remain unclear. METHODS: We conducted a nationwide survey to examine the situation of patients with HCC treated with sorafenib who obtained a complete response (CR) according to the modified response evaluation criteria in solid tumors (mRECIST). The investigation was intended to collect clinical information regarding CR patients and to compare this data with an interim report examining all-patient surveillance for sorafenib use in Japan, which was released in May 2012. RESULTS: Among the 3047 patients who were treated at institutions belonging to the Liver Cancer Study Group of Japan, 18 patients (0.6%) obtained a CR. Significant factors in the CR group were a female sex, a low bodyweight (<59 kg), an early clinical stage and a small initial dose of sorafenib (P < 0.05). Furthermore, specific adverse events (palmar-plantar erythrodysesthesia syndrome, hypertension, diarrhea, alopecia, fatigue, nausea and anorexia) were frequently observed in the CR group (P < 0.05). CONCLUSION: This study identified the characteristics of CR patients during sorafenib treatment. The evaluation of patients receiving sorafenib, including the investigation of biomarkers, warrants further exploration in future clinical studies to identify a population in which sorafenib treatment is remarkably effective. PMID- 24405693 TI - Albumin versus crystalloid solutions in patients with the acute respiratory distress syndrome: a systematic review and meta-analysis. AB - INTRODUCTION: In patients with acute respiratory distress syndrome (ARDS) fluid therapy might be necessary. The aim of this systematic review and meta-analysis is to determine the effects of colloid therapy compared to crystalloids on mortality and oxygenation in adults with ARDS. METHODS: Randomized controlled trials (RCTs) were identified through a systematic literature search of MEDLINE, EMBASE, CENTRAL and LILACS. Articles published up to 15th February 2013 were independently screened, abstracted, and assessed (Cochrane Risk of Bias Tool) to provide evidence-based therapy recommendations. RCTs were eligible if they compared colloid versus crystalloid therapy on lung function, inflammation, damage or mortality in adults with ARDS. Primary outcome parameters were respiratory mechanics, gas exchange lung inflammation and damage as well as hospital mortality. Kidney function, need for renal replacement therapy, hemodynamic stabilization and intensive care unit (ICU) length of stay served as secondary outcomes. RESULTS: A total of 3 RCTs out of 4130 potential trials found in the databases were selected for qualitative and quantitative analysis totaling 206 patients who received either albumin or saline. Overall risk of bias was unclear to high in the identified trials. Calculated pooled risk of death was not statistically significant (albumin 34 of 100 (34.0%) versus 40 of 104 (38.5%), relative risk (RR) = 0.89, 95% confidence interval (CI) 0.62 to 1.28, P = 0.539). Weighted mean difference (WMD) in PaO2/FiO2 (mmHg) improved in the first 48 hours (WMD = 62, 95% CI 47 to 77, P <0.001, I2 = 0%) after therapy start and remained stable after 7 days (WMD = 20, 95% CI 4 to 36, P = 0.017, I2 = 0%). CONCLUSIONS: There is a high need for RCTs investigating the effects of colloids in ARDS patients. Based on the findings of this review, colloid therapy with albumin improved oxygenation but did not affect mortality. PMID- 24405695 TI - Community member and faith leader perspectives on the process of building trusting relationships between communities and researchers. AB - In the first phase of this research, we conducted, audio-recorded, and transcribed seven focus groups with more than 50 English- or Spanish-speaking women of childbearing age. Qualitative analysis revealed the following themes: (1) expectation that participation would involve relationships based on trust that is built over time and impacted by cultural factors; (2) perceived characteristics of research staff that would help facilitate the development of trusting relationships; (3) perceptions about the location of the visits that may affect trust; (4) perceptions of a research study and trust for the institution conducting the study may affect trust; (5) connecting the study to larger communities, including faith communities, could affect trust and willingness to participate. In the second phase of this research, we conducted, recorded, transcribed, and analyzed interviews with leaders from diverse faith communities to explore the potential for research partnerships between researchers and faith communities. In addition to confirming themes identified in focus groups, faith leaders described an openness to research partnerships between the university and faith communities and considerations for the formation of these partnerships. Faith leaders noted the importance of finding common ground with researchers, establishing and maintaining trusting relationships, and committing to open, bidirectional communication. PMID- 24405696 TI - Compensatory proliferation of endogenous chicken primordial germ cells after elimination by busulfan treatment. AB - INTRODUCTION: Primordial germ cells (PGCs) are the major population of cells in the developing bilateral embryonic gonads. Little is known about the cellular responses of PGCs after treatment with toxic chemicals such as busulfan during embryo development. In this study, we investigated the elimination, restorative ability, and cell cycle status of endogenous chicken PGCs after busulfan treatment. METHODS: Busulfan was emulsified in sesame oil by a dispersion emulsifying system and injected into the chick blastoderm (embryonic stage X). Subsequently, we conducted flow cytometry analysis to evaluate changes in the PGC population and cell cycle status, and immunohistochemistry to examine the germ cell proliferation. RESULTS: Results of flow cytometry and immunohistochemistry analyses after busulfan treatment showed that the proportion of male PGCs at embryonic day 9 and female PGCs at embryonic day 7 were increased by approximately 60% when compared with embryonic day 5.5. This result suggests the existence of a compensatory mechanism in PGCs in response to the cytotoxic effects of busulfan. Results of cell cycling analysis showed that the germ cells in the G0/G1 phase were significantly decreased, while S/G2/M-phase germ cells were significantly increased in the treatment group compared with the untreated control group in both 9-day-old male and female embryos. In addition, in the proliferation analysis with 5-ethynyl-2'-deoxyuridine (EdU) incorporation, we found that the proportion of EdU-positive cells among VASA homolog-positive cells in the 9-day embryonic gonads of the busulfan-treated group was significantly higher than in the control group. CONCLUSIONS: We conclude that PGCs enter a restoration pathway by promoting their cell cycle after experiencing a cytotoxic effect. PMID- 24405697 TI - Alternative tacrolimus and sirolimus regimen associated with rapid resolution of posterior reversible encephalopathy syndrome after lung transplantation. AB - BACKGROUND: Neurotoxicity is a significant complication of calcineurin inhibitor use, and posterior reversible encephalopathy syndrome has been reported. Limited data exist on the use of alternative immunosuppression regimens in the management of posterior reversible encephalopathy syndrome in transplant recipients. METHODS: We present the immunosuppression management strategy of a girl who underwent bilateral lung transplantation for cystic fibrosis 6 months earlier, then suddenly developed a grand mal seizure due to posterior reversible encephalopathy syndrome diagnosed by magnetic resonance imaging of the brain. In an effort to reduce her tacrolimus dose, an alternative immunosuppressant regimen combining tacrolimus and sirolimus was used. RESULTS: After the modification of her immunosuppressant regimen, there was rapid clinical improvement with no further seizures. Her brain findings had resolved on magnetic resonance imaging 2 months later. Over the next 6 months, allograft function remained stable and surveillance transbronchial biopsies found no allograft rejection on the combined sirolimus and tacrolimus therapy. CONCLUSIONS: Tacrolimus-associated neurotoxicity resolved in a lung transplant recipient with a combined tacrolimus and sirolimus regimen. This combined therapy appears to be an effective alternative for lung transplant recipients that allow them to receive the benefits of both drugs but at lower doses, which reduces the risk for adverse effects. PMID- 24405698 TI - Vaccination and occurrence of seizures in SCN1A mutation-positive patients: a multicenter Italian study. AB - BACKGROUND: The relation between epileptic seizures and vaccinations is sometimes debated. In the present work, the impact of vaccination on seizure onset and clinical outcome of SCN1A mutation-positive patients is addressed. METHODS: Seventy-two patients diagnosed with Dravet syndrome or generalized epilepsy with febrile seizure plus, carrying SCN1A mutations or not, were included. Details on vaccination type, temporal relationship between vaccination and seizure occurrence, seizure type at onset and during development, cognitive functioning, and vaccination completion was obtained by reviewing clinical records. Patients were divided into two groups based on the temporal window between vaccination and seizure onset (proximate group: <48 hours; distant group: >48 hours). RESULTS: Vaccination-related seizures occurred in 25% of patients with SCN1A mutation and 18% of patients without the mutation (no significant difference). The proximate group showed an earlier age at seizure onset and a higher frequency of status epilepticus during development than did the distant group. No other significant differences were found. Subsequent vaccinations did not significantly alter the evolution of the disease. CONCLUSIONS: Results from this relatively small series provide evidence that vaccinations do not significantly affect clinical and cognitive evolution of Dravet syndrome and generalized epilepsy with febrile seizure plus patients even if they carry SCN1A mutations. PMID- 24405699 TI - Quantitative trait loci mapping and gene network analysis implicate protocadherin 15 as a determinant of brain serotonin transporter expression. AB - Presynaptic serotonin (5-hydroxytryptamine, 5-HT) transporters (SERT) regulate 5 HT signaling via antidepressant-sensitive clearance of released neurotransmitter. Polymorphisms in the human SERT gene (SLC6A4) have been linked to risk for multiple neuropsychiatric disorders, including depression, obsessive-compulsive disorder and autism. Using BXD recombinant inbred mice, a genetic reference population that can support the discovery of novel determinants of complex traits, merging collective trait assessments with bioinformatics approaches, we examine phenotypic and molecular networks associated with SERT gene and protein expression. Correlational analyses revealed a network of genes that significantly associated with SERT mRNA levels. We quantified SERT protein expression levels and identified region- and gender-specific quantitative trait loci (QTLs), one of which associated with male midbrain SERT protein expression, centered on the protocadherin-15 gene (Pcdh15), overlapped with a QTL for midbrain 5-HT levels. Pcdh15 was also the only QTL-associated gene whose midbrain mRNA expression significantly associated with both SERT protein and 5-HT traits, suggesting an unrecognized role of the cell adhesion protein in the development or function of 5-HT neurons. To test this hypothesis, we assessed SERT protein and 5-HT traits in the Pcdh15 functional null line (Pcdh15(av-) (3J) ), studies that revealed a strong, negative influence of Pcdh15 on these phenotypes. Together, our findings illustrate the power of multidimensional profiling of recombinant inbred lines in the analysis of molecular networks that support synaptic signaling, and that, as in the case of Pcdh15, can reveal novel relationships that may underlie risk for mental illness. PMID- 24405700 TI - Quantitative prediction of the effect of genetic variation using hidden Markov models. AB - BACKGROUND: With the development of sequencing technologies, more and more sequence variants are available for investigation. Different classes of variants in the human genome have been identified, including single nucleotide substitutions, insertion and deletion, and large structural variations such as duplications and deletions. Insertion and deletion (indel) variants comprise a major proportion of human genetic variation. However, little is known about their effects on humans. The absence of understanding is largely due to the lack of both biological data and computational resources. RESULTS: This paper presents a new indel functional prediction method HMMvar based on HMM profiles, which capture the conservation information in sequences. The results demonstrate that a scoring strategy based on HMM profiles can achieve good performance in identifying deleterious or neutral variants for different data sets, and can predict the protein functional effects of both single and multiple mutations. CONCLUSIONS: This paper proposed a quantitative prediction method, HMMvar, to predict the effect of genetic variation using hidden Markov models. The HMM based pipeline program implementing the method HMMvar is freely available at https://bioinformatics.cs.vt.edu/zhanglab/hmm. PMID- 24405701 TI - Thiazolopyridone ureas as DNA gyrase B inhibitors: optimization of antitubercular activity and efficacy. AB - Scaffold hopping from the thiazolopyridine ureas led to thiazolopyridone ureas with potent antitubercular activity acting through inhibition of DNA GyrB ATPase activity. Structural diversity was introduced, by extension of substituents from the thiazolopyridone N-4 position, to access hydrophobic interactions in the ribose pocket of the ATP binding region of GyrB. Further optimization of hydrogen bond interactions with arginines in site-2 of GyrB active site pocket led to potent inhibition of the enzyme (IC50 2 nM) along with potent cellular activity (MIC=0.1 MUM) against Mycobacterium tuberculosis (Mtb). Efficacy was demonstrated in an acute mouse model of tuberculosis on oral administration. PMID- 24405702 TI - Biological evaluation of new antitumor taxoids: alteration of substitution at the C-7 and C-10 of docetaxel. AB - A series of new docetaxol analogues have been designed and synthesized. And their cytotoxicities against cancer cells have been evaluated by MTT method. Most of these compounds showed selective inhibitions on human cancer cell lines. Among them, compound 8 exhibited higher inhibitory activity than Paclitaxel (Taxol) against several cancer cell lines. This work indicated that appropriate modification at C-7 and C-10 of docetaxel might be a promising approach for this unique class of anticancer compounds. PMID- 24405703 TI - 4-Bicyclic heteroaryl-piperidine derivatives as potent, orally bioavailable stearoyl-CoA desaturase-1 (SCD1) inhibitors: part 2. Pyridazine-based analogs. AB - Design, synthesis, and biological evaluation of pyridazine-based, 4-bicyclic heteroaryl-piperidine derivatives as potent stearoyl-CoA desaturase-1 (SCD1) inhibitors are described. In a chronic study of selected analog (3e) in Zucker fa/fa (ZF) rat, dose-dependent decrease of body weight gain and plasma fatty acid desaturation index (DI) in both C16 and C18 are also demonstrated. The results indicate that the plasma fatty acid DI may serve as an indicator for direct target engagement and biomarker for SCD1 inhibition. PMID- 24405704 TI - Synthesis and evaluation of 4-(2-pyrimidinylamino) benzamides inhibitors of hedgehog signaling pathway. AB - A novel series of hedgehog signaling pathway inhibitors has been designed based on the 4-(2-pyrimidinylamino) benzamides scaffold. The synthesis and SAR of these compounds are described. Optimization leads to the identification of compound 3c, a potent and orally available agent with improved physicochemical and pharmacokinetic properties. PMID- 24405705 TI - Novel, sulfonamide linked inhibitors of the hepatitis C virus NS3 protease. AB - A sulfonamide replacement of the P2-P3 amide bond in the context of macrocyclic HCV NS3 protease inhibitors was investigated. These analogs displayed good inhibitory potency in the absence of any P3 capping group. The synthesis and preliminary SAR are described. PMID- 24405706 TI - Cytotoxicity and DNA binding property of triphenylethylene-coumarin hybrids with two amino side chains. AB - Novel triphenylethylene-coumarin hybrids containing two amino side chains were designed and synthesized. Some of these 3,4-diphenyl coumarins, 7b-c (the double chains at 4-position on 3-,4-phenyl, respectively), and 13b-f (the double chains at 4-position on 3-phenyl and 7-position, respectively), showed a broad-spectrum and good anti-proliferative activity against five tumor cells and low cytotoxicity in osteoblast. UV-vis, fluorescence, and circular dichroism (CD) spectroscopies and thermal denaturation exhibited that compounds 7b (R=piperidinyl), 7e (R=NEt2), and 7f (R=4-methylpiperazinyl) had significant interactions with Ct-DNA by the intercalative mode of binding. Structure activity relationships (SARs) analysis suggested that the location of the two amino alkyl chains would play an important role both in the compounds against tumor cells proliferation and their interactions with DNA. PMID- 24405707 TI - Identification of potent CNS-penetrant thiazolidinones as novel CGRP receptor antagonists. AB - Calcitonin gene-related peptide (CGRP) has been implicated in acute migraine pathogenesis. In an effort to identify novel CGRP receptor antagonists for the treatment of migraine, we have discovered thiazolidinone 49, a potent (Ki=30 pM, IC50=1 nM), orally bioavailable, CNS-penetrant CGRP antagonist with good pharmacokinetic properties. PMID- 24405709 TI - Role of genetics in diagnosis and therapy of acquired liver disease. AB - By implementation of novel genotyping technologies, progress in delineating the genetic architecture of acquired liver diseases has been achieved in recent years. The rapid dissemination of genome-wide linkage and association studies has paved the way for the identification of genetic variants that cause or modify non viral liver diseases as well as the natural and treatment-related outcomes in chronic viral hepatitis. Invaluable genomic data has recently been derived from additional genome-wide association studies (GWAS) of the archetypical cholestatic liver diseases primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). Beyond providing novel pathobiological insights in need of more sophisticated functional annotation, gene variation might in the future be instrumental in precise risk stratification and the development of genotype-based treatment algorithms. In this regard, the definition of subtypes of acquired liver disease and re-categorization of clinically defined disease phenotypes into a more 'genometype'-based disease classification represents a priority future research direction. PMID- 24405708 TI - BACE1 activity regulates cell surface contactin-2 levels. AB - BACKGROUND: Although BACE1 is a major therapeutic target for Alzheimer's disease (AD), potential side effects of BACE1 inhibition are not well characterized. BACE1 cleaves over 60 putative substrates, however the majority of these cleavages have not been characterized. Here we investigated BACE1-mediated cleavage of human contactin-2, a GPI-anchored cell adhesion molecule. RESULTS: Our initial protein sequence analysis showed that contactin-2 harbors a strong putative BACE1 cleavage site close to its GPI membrane linker domain. When we overexpressed BACE1 in CHO cells stably transfected with human contactin-2, we found increased release of soluble contactin-2 in the conditioned media. Conversely, pharmacological inhibition of BACE1 in CHO cells expressing human contactin-2 and mouse primary neurons decreased soluble contactin-2 secretion. The BACE1 cleavage site mutation 1008MM/AA dramatically impaired soluble contactin-2 release. We then asked whether contactin-2 release induced by BACE1 expression would concomitantly decrease cell surface levels of contactin-2. Using immunofluorescence and surface-biotinylation assays, we showed that BACE1 activity tightly regulates contactin-2 surface levels in CHO cells as well as in mouse primary neurons. Finally, contactin-2 levels were decreased in Alzheimer's disease brain samples correlating inversely with elevated BACE1 levels in the same samples. CONCLUSION: Our results clearly demonstrate that mouse and human contactin-2 are physiological substrates for BACE1. BACE1-mediated contactin-2 cleavage tightly regulates the surface expression of contactin-2 in neuronal cells. Given the role of contactin-2 in cell adhesion, neurite outgrowth and axon guidance, our data suggest that BACE1 may play an important role in these physiological processes by regulating contactin-2 surface levels. PMID- 24405710 TI - Hydrogen-assisted fabrication of spherical gold nanoparticles through sonochemical reduction of tetrachloride gold(III) ions in water. AB - Spherical gold nanoparticles (AuNPs) were selectively synthesized through sonochemical reduction of tetrachloride gold(III) ions ([AuCl4](-)) in an aqueous solution of hydrogen tetrachloroaurate(III) tetrahydrate (HAuCl4 . 4H2O) with the aid of hydrogen (H2) gas in the absence of any additional capping agents. On the other hand, various shaped-AuNPs such as spherical nanoparticles, triangular and hexagonal plates were formed from sonochemical reduction of [AuCl4](-) in argon (Ar)-, nitrogen (N2)- or oxygen (O2)-purged aqueous [AuCl4](-) solutions. The selective fabrication of spherical AuNPs assisted by H2 gas is most likely attributed to the generation of hydrogen radicals (H) promoted by the reaction of H2 introduced and hydrogen oxide radicals (OH) produced by sonolysis of water. PMID- 24405711 TI - RETRACTED: Size-controlled spherical polymer nanoparticles: synthesis with tandem acoustic emulsification followed by soap-free emulsion polymerization and one step fabrication of colloidal crystal films of various colors. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article was retracted at the request of the Editor. The above paper is essentially a duplicate of an original Article in "Size-Controlled Synthesis of Polymer Nanoparticles with Tandem Acoustic Emulsification Followed by Soap-Free Emulsion Polymerization" ACS Macro Lett., 2013, 2 (6), pp 482-484, 10.1021/mz4001817. PMID- 24405712 TI - Ultrasound-based treatment approaches for intrinsic viscosity reduction of polyvinyl pyrrolidone (PVP). AB - The present work deals with achieving viscosity reduction in polymer solutions using ultrasound-based treatment approaches. Use of simple additives such as salts, or surfactants and introduction of air at varying flow rates as process intensifying parameters have been investigated for enhancing the degradation of polyvinyl pyrrolidone (PVP) using ultrasonic irradiation. Sonication is carried out using an ultrasonic horn at 36 kHz frequency at an optimized concentration (1%) of the polymer. The degradation behavior has been characterized in terms of the change in the viscosity of the aqueous solution of PVP. The intrinsic viscosity of the polymer has been shown to decrease to a limiting value, which is dependent on the operating conditions and use of different additives. Similar extent of viscosity reduction has been observed with 1% NaCl or 0.1% TiO2 at optimized depth of horn and 27 degrees C, indicating the superiority of titanium dioxide as an additive. The combination of ultrasound and ultraviolet (UV) irradiation results in a significantly faster viscosity reduction as compared to the individual operations. A kinetic analysis for the degradation of PVP has also been carried out. The work provides a detailed understanding of the role of the operating parameters and additives in deciding the extent of reduction in the intrinsic viscosity of PVP solutions. PMID- 24405713 TI - Periglacial fires and trees in a continental setting of Central Canada, Upper Pleistocene. AB - Fire is a key factor controlling global vegetation patterns and carbon cycling. It mostly occurs under warm periods during which fuel builds up with sufficient moisture, whereas such conditions stimulate fire ignition and spread. Biomass burning increased globally with warming periods since the last glacial era. Data confirming periglacial fires during glacial periods are very sparse because such climates are likely too cold to favour fires. Here, tree occurrence and fires during the Upper Pleistocene glacial periods in Central Canada are inferred from botanical identification and calibrated radiocarbon dates of charcoal fragments. Charcoal fragments were archived in sandy dunes of central Saskatchewan and were dated >50000-26600 cal BP. Fragments were mostly gymnosperms. Parallels between radiocarbon dates and GISP2-delta18O records deciphered relationships between fire and climate. Fires occurred either hundreds to thousands of years after Dansgaard-Oeschger (DO) interstadial warming events (i.e., the time needed to build enough fuel for fire ignition and spread) or at the onset of the DO event. The chronological uncertainties result from the dated material not precisely matching the fires and from the low residual 14C associated with old sample material. Dominance of high-pressure systems and low effective moisture during post-DO coolings likely triggered flammable periglacial ecosystems, while lower moisture and the relative abundance of fuel overshadowed lower temperatures for fire spread. Laurentide ice sheet (LIS) limits during DO events are difficult to assess in Central Canada due to sparse radiocarbon dates. Our radiocarbon data set constrains the extent of LIS. Central Saskatchewan was not covered by LIS throughout the Upper Pleistocene and was not a continental desert. Instead, our results suggest long-lasting periods where fluctuations of the northern tree limits and fires after interstadials occurred persistently. PMID- 24405714 TI - Differentially expressed microRNAs in the serum of cervical squamous cell carcinoma patients before and after surgery. AB - BACKGROUND: The purpose of this study was to detect the serum microRNAs (miRNAs) that are differentially expressed in cervical squamous cell carcinoma (SCC) patients and negative controls, with a focus on the miRNA profiles of the patients before and after surgery. The aim of the study is to evaluate the potential of these miRNAs as novel markers for the post-therapeutic monitoring of cervical SCC patients. RESULTS: A total of 765 serum miRNAs from 10 cervical SCC patients before surgery, 10 cervical SCC patients after surgery, and 10 negative controls were profiled using a TaqMan MicroRNA Array. A set of selected differentially expressed miRNAs were further analyzed in the patients at different perioperative periods, including preoperative, 1 week postoperative, and one month postoperative. The results showed that several serum miRNAs were differentially expressed in the cervical SCC patients compared with the negative controls, including miR-646, miR-141* and miR-542-3p. More importantly, we found that levels of specific serum miRNAs were deregulated in the pre- and postoperative stages, and these miRNAs could be useful for post-therapeutic monitoring of disease progression. Finally, we depicted a regulatory network of differentially expressed serum miRNAs, and many possible target genes were predicted in the estrogen-mediated signal pathways, supporting the hypothesis that cervical SCC is a hormone-associated gynecological disease. CONCLUSIONS: Our study demonstrated that the circulating miRNAs miR-646, miR-141* and miR-542-3p could potentially serve as non-invasive biomarkers for cervical SCC. The levels of these specific miRNAs might be useful for the post-therapeutic monitoring of disease progression. This is the first report showing that circulating miRNAs could serve as biomarkers for the therapeutic intervention of cervical SCC. PMID- 24405715 TI - Differential effects of PDCD4 depletion on protein synthesis in myoblast and myotubes. AB - BACKGROUND: Reduced muscle mass is a hallmark of metabolic diseases like diabetes and cancer. The mammalian (mechanistic) target of rapamycin complex 1/S6 kinase 1 (mTORC1/S6K1) pathway is critical to the regulation of muscle protein synthesis and mass but its mechanism of action is not completely understood. RESULTS: Using L6 myotubes, we characterized the regulation of programmed cell death 4 (PDCD4), a recently described substrate of S6K1. The abundance, but not Ser67 phosphorylation, of PDCD4 was sensitive to amino acid and serum deprivation: values in starved cells were 4.5X of control (P < 0.001). Refeeding had opposite effects. Growth factors, compared to amino acids, appeared more critical in regulating PDCD4 abundance. Furthermore, inhibition of mTORC1 or the proteasome prevented the refeeding-associated decrease in PDCD4 abundance. Amino acid and serum deprivation significantly increased PDCD4 binding to eIF4A (P < 0.05); this was reversed during refeeding. PDCD4 depletion by RNA interference had no significant effect on phenylalanine incorporation into myotube mixed proteins in control cells but further suppressed (30%) this measure in nutrient-deprived cells (P < 0.0005). This was not observed in myoblasts. In starved myotubes, PDCD4 depletion further reduced the association of eIF4G with eIF4E. CONCLUSION: Our data suggest that in myotubes, PDCD4 abundance is sensitive to nutritional manipulation in an mTORC1 and proteasome depended manner. Furthermore, the role of PDCD4 in regulating protein synthesis appears dependent on the developmental state of the cell. PMID- 24405717 TI - Polynomials to model the growth of young bulls in performance tests. AB - The use of polynomial functions to describe the average growth trajectory and covariance functions of Nellore and MA (21/32 Charolais+11/32 Nellore) young bulls in performance tests was studied. The average growth trajectories and additive genetic and permanent environmental covariance functions were fit with Legendre (linear through quintic) and quadratic B-spline (with two to four intervals) polynomials. In general, the Legendre and quadratic B-spline models that included more covariance parameters provided a better fit with the data. When comparing models with the same number of parameters, the quadratic B-spline provided a better fit than the Legendre polynomials. The quadratic B-spline with four intervals provided the best fit for the Nellore and MA groups. The fitting of random regression models with different types of polynomials (Legendre polynomials or B-spline) affected neither the genetic parameters estimates nor the ranking of the Nellore young bulls. However, fitting different type of polynomials affected the genetic parameters estimates and the ranking of the MA young bulls. Parsimonious Legendre or quadratic B-spline models could be used for genetic evaluation of body weight of Nellore young bulls in performance tests, whereas these parsimonious models were less efficient for animals of the MA genetic group owing to limited data at the extreme ages. PMID- 24405716 TI - Amyloid peptides ABri and ADan show differential neurotoxicity in transgenic Drosophila models of familial British and Danish dementia. AB - BACKGROUND: Familial British and Familial Danish dementias (FBD and FDD, respectively) are associated with mutations in the BRI2 gene. Processing of the mutated BRI2 protein leads to the accumulation in the brain of the 34-mer amyloid Bri (ABri) and amyloid Dan (ADan) peptides, accompanied by neurofibrillary tangles. Recently, transgenic mice successfully reproduced different aspects of FDD, while modeling of FBD in vivo has been more difficult. In this work we have modeled FBD and FDD in Drosophila and tested the hypothesis that ABri and ADan are differentially neurotoxic. RESULTS: By using site-directed insertion, we generated transgenic lines carrying ABri, ADan, Bri2-23 (the normal product of wild-type BRI2 processing) and amyloid-beta (Abeta) 1-42 as a well-characterized neurotoxic peptide, alone or with a His-tag. Therefore, we avoided random insertion effects and were able to compare levels of accumulation accurately. Peptides were expressed with the GAL4-Upstream Activating Sequence (UAS) system using specific drivers. Despite low levels of expression, toxicity in the eye was characterized by mild disorganization of ommatidia and amyloid peptides accumulation. The highest toxicity was seen for ADan, followed by Abeta42 and ABri. Pan-neuronal expression in the CNS revealed an age-dependent toxicity of amyloid peptides as determined by the ability of flies to climb in a geotaxis paradigm when compared to Bri2-23. This effect was stronger for ADan, detected at 7 days post-eclosion, and followed by ABri and Abeta42, whose toxicity became evident after 15 and 21 days, respectively. Histological analysis showed mild vacuolization and thioflavine-S-negative deposits of amyloid peptides. In contrast, the over-expression of amyloid peptides in the specific subset of lateral neurons that control circadian locomotor activity showed no toxicity. CONCLUSIONS: Our results support the differential neurotoxicity of ADan and ABri in the Drosophila eye and CNS at low expression levels. Such differences may be partially attributed to rates of aggregation and accumulation. In the CNS, both peptides appear to be more neurotoxic than wild-type Abeta42. These Drosophila models will allow a systematic and unambiguous comparison of differences and similarities in the mechanisms of toxicity of diverse amyloid peptides associated with dementia. PMID- 24405718 TI - CpG sites associated with NRP1, NRXN2 and miR-29b-2 are hypomethylated in monocytes during ageing. AB - BACKGROUND: Ageing affects many components of the immune system, including innate immune cells like monocytes. They are important in the early response to pathogens and for their role to differentiate into macrophages and dendritic cells. Recent studies have revealed significant age-related changes in genomic DNA methylation in peripheral blood mononuclear cells, however information on epigenetic changes in specific leukocyte subsets is still lacking. Here, we aimed to analyse DNA methylation in purified monocyte populations from young and elderly individuals. FINDINGS: We analysed the methylation changes in monocytes purified from young and elderly individuals using the HumanMethylation450 BeadChip array. Interestingly, we found that among 26 differentially methylated CpG sites, the majority of sites were hypomethylated in elderly individuals. The most hypomethylated CpG sites were located in neuropilin 1 (NRP1; cg24892069) and neurexin 2 (NRXN2; cg27209729) genes, and upstream of miR-29b-2 gene (cg10501210). The age-related hypomethylation of these three sites was confirmed in a separate group of young and elderly individuals. CONCLUSIONS: We identified significant age-related hypomethylation in human purified monocytes at CpG sites within the regions of NRP1, NRXN2 and miR-29b-2 genes. PMID- 24405719 TI - Cost-effectiveness of tenofovir gel in urban South Africa: model projections of HIV impact and threshold product prices. AB - BACKGROUND: There is urgent need for effective HIV prevention methods that women can initiate. The CAPRISA 004 trial showed that a tenofovir-based vaginal microbicide had significant impact on HIV incidence among women. This study uses the trial findings to estimate the population-level impact of the gel on HIV and HSV-2 transmission, and price thresholds at which widespread product introduction would be as cost-effective as male circumcision in urban South Africa. METHODS: The estimated 'per sex-act' HIV and HSV-2 efficacies were imputed from CAPRISA 004. A dynamic HIV/STI transmission model, parameterised and fitted to Gauteng (HIV prevalence of 16.9% in 2008), South Africa, was used to estimate the impact of gel use over 15 years. Uptake was assumed to increase linearly to 30% over 10 years, with gel use in 72% of sex-acts. Full economic programme and averted HIV treatment costs were modelled. Cost per DALY averted is estimated and a microbicide price that equalises its cost-effectiveness to that of male circumcision is estimated. RESULTS: Using plausible assumptions about product introduction, we predict that tenofovir gel use could lead to a 12.5% and 4.9% reduction in HIV and HSV-2 incidence respectively, by year 15. Microbicide introduction is predicted to be highly cost-effective (under $300 per DALY averted), though the dose price would need to be just $0.12 to be equally cost effective as male circumcision. A single dose or highly effective (83% HIV efficacy per sex-act) regimen would allow for more realistic threshold prices ($0.25 and $0.33 per dose, respectively). CONCLUSIONS: These findings show that an effective coitally-dependent microbicide could reduce HIV incidence by 12.5% in this setting, if current condom use is maintained. For microbicides to be in the range of the most cost-effective HIV prevention interventions, product costs will need to decrease substantially. PMID- 24405720 TI - Effects of Carbapenem consumption on the prevalence of Acinetobacter infection in intensive care unit patients. AB - BACKGROUND: The consumption of carbapenems has increased worldwide, together with the increase in resistant gram negative bacilli. Subsequently, the prevalence of carbapenem-resistant Acinetobacter infections has increased rapidly and become a significant problem particularly in intensive care unit patients. The aim of the present study was to evaluate the changes in the prevalence of Acinetobacter infection by restricting the consumption of carbapenems in intensive care unit patients. METHODS: This study was conducted between May 1, 2011 and February 28, 2013. The amount of carbapenem consumption and the number of patients with multi drug resistant Acinetobacter baumannii (MDRAB) isolates during the study period were retrospectively obtained from the records of the patients, who were hospitalized in the intensive care unit. The study period was divided into two periods named as: Carbapenem non-restricted period (CNRP) and carbapenem restricted period (CRP). During CNRP, no restrictions were made on the use of carbapenems. During CRP, the use of carbapenems was not allowed if there was an alternative to carbapenems. Primary Endpoint: MDRAB infection after ICU admission. The definition of nosocomial infections related to Acinetobacter spp. was based on the criteria of the Center for Disease Control (CDC). The correlation between the amount of carbapenem consumption and the number of infections with MDRAB strains between the two periods were evaluated. RESULTS: During the study period, a total of 1822 patients' (1053 patients in CNRP and 769 patients in CRP) records were evaluated retrospectively. A total of 10.82 defined daily dose (DDD/100 ICU days) of anti-pseudomonal carbapenem were used in CNRP, and this figure decreased to 6.95 DDD/100 ICU days in CRP. In the 8-month CNRP, 42 (3.98%) MDRAB-related nosocomial infections were detected, and 14 (1.82%) infections were detected in CRP (p = 0.012). CONCLUSION: The prevalence of MDRAB strains isolated in the CNRP was 2.24-fold higher than the prevalence in the CRP. The prevalence of Acinetobacter infections can be reduced by taking strict isolation measures as well as by implementing good antibiotics usage policy. PMID- 24405721 TI - Metformin induces renal medullary interstitial cell apoptosis in type 2 diabetic mice. AB - OBJECTIVE: Metformin is a first-line antidiabetic drug for type 2 diabetes (T2D) with a relatively good safety profile. Metformin activates AMP-activated protein kinase (AMPK), which is crucial in maintaining renal medullary function, with inappropriate AMPK activation facilitating renal medullary interstitial cells (RMICs) apoptosis under hypertonic challenge. The present study was to determine the effects of metformin on RMIC survival in both normal and T2D mice. METHODS: Mice (C57BL/6, db/m, and db/db) were treated with 450 mg/kg metformin for 7 days and subjected to 24-h water restriction (=dehydration) before being killed. Cell apoptosis in the renal medulla was determined by the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL) assay. Cultured RMIC were treated with 10 mmol/L metformin in the presence or absence of hypertonic stress. Cell viability was determined and the underlying mechanisms were investigated. RESULTS: Metformin induced significant apoptosis of RMIC in dehydrated normal mice and both hydrated and dehydrated T2D mice. Hypertonicity increased ATP production and inhibited AMPK phosphorylation in RMIC, which was attenuated by metformin. Metformin augmented hypertonicity induced apoptosis of RMIC, suppressed the nuclear factor-kappaB/cyclo-oxygenase-2 pathway, reduced reactive oxygen species production and inhibited transcriptional activation of tonicity-responsive enhancer binding protein (TonEBP) and its downstream osmoprotective gene expression. CONCLUSIONS: Metformin treatment is associated with increased RMIC apoptosis in both normally hydrated and dehydrated T2D mice. The results confirm AMPK as a critical factor involved in the maintenance of RMIC viability in T2D and raise safety concerns for metformin and other AMPK-activating antidiabetic drugs in dehydrated diabetic patients. PMID- 24405722 TI - Systems dynamics in endocytosis. AB - The endocytic system acts at the crossroads of different cellular activities to play a central role in the regulation of cell signaling and membrane dynamics. An European Molecular Biology Organization (EMBO) conference held in October 2013 in Villars-sur-Ollon gathered researchers from all over the world to present their latest findings on the endolysosomal system and identify major challenges for the future. The conference covered the entire spectrum of research in this rapidly evolving field ranging from the cellular mechanics of endocytosis to the role of proteins and lipids in the biogenesis and function of endolysosomal organelles and the analysis of higher order system properties in multicellular contexts. In particular, the meeting highlighted current efforts to complement the insights that can be gained by biochemical and cell biological approaches with the use of quantitative biophysics, systems biology and animal model systems to achieve an integrated view of the properties of the endomembrane system and its role in cellular information processing. PMID- 24405723 TI - An air-cell-based cushion for pressure ulcer protection remarkably reduces tissue stresses in the seated buttocks with respect to foams: finite element studies. AB - A sitting-acquired pressure ulcer (PU) is a common injury in wheelchair-bound patients. Preventative measures for the post spinal cord injury (SCI) population include prescription of a supportive thick cushion on the wheelchair, in order to better distribute loads between the buttocks and support surface (which are quantifiable using interface pressure measurements), and potentially, to minimize internal soft tissue loads (which are typically unknown). Information about the biomechanical efficacy of commercially-available structured cushion designs such as air-cell-based (ACB) cushions, gel, and honeycomb-like cushions is sparse. Considering the importance of such evaluations to patient safety and quality of life, we studied the biomechanical performances of an ACB cushion in comparison to standard, flat foam cushions with different stiffness properties. Using a set of finite element (FE) model variants, we determined the mechanical stresses in muscle, fat, and skin tissues under the ischial tuberosities during sitting. Tissue stress analyses were conducted in a reference SCI anatomy, incorporating pathoanatomical and pathophysiological changes associated with chronic SCI, including bone shape adaptation, muscle atrophy, and spasms. We found up to 57% greater immersion and 4 orders-of-magnitude lower muscle, fat, and skin tissue stresses for the ACB cushion. We also found the ACB cushion provides better protection against the aforementioned bone shape adaptation, muscle atrophy, and spasms. Hence, theoretically, the use of a suitable ACB cushion should provide longer safe sitting times for SCI patients with respect to standard foam cushions. PMID- 24405724 TI - Pellagra. A challenging differential diagnosis in burn injuries. AB - With this case report we want to emphasize the importance of performing a thorough physical examination of the burn and detailed review of the patient's history. This is a challenging case because it deals with an uncommon disease nowadays, pellagra, which presents lesions with an appearance very similar to burns; on the other hand the management of pellagra is different to the management of the common burns we are used to handling day-to-day. With this case report we will be able to revise the broad list of different injuries that can bring up an issue related to a correct diagnosis, caused by a large diversity of different etiologies with cutaneous expression. We will look over the diagnostic process of pellagra, management, treatment and results in this patient. PMID- 24405725 TI - Are depression, anxiety and poor mental health risk factors for knee pain? A systematic review. AB - BACKGROUND: While it is recognized that psychosocial factors are important in the development and progression of musculoskeletal pain and disability, no systematic review has specifically focused on examining the relationship between psychosocial factors and knee pain. We aimed to systematically review the evidence to determine whether psychosocial factors, specifically depression, anxiety and poor mental health, are risk factors for knee pain. METHODS: Electronic searches of MEDLINE, EMBASE and PsycINFO were performed to identify relevant studies published up to August 2012 using MESH terms and keywords. We included studies that met a set of predefined criteria and two independent reviewers assessed the methodological quality of the selected studies. Due to the heterogeneity of the studies, a best evidence synthesis was performed. RESULTS: Sixteen studies were included in the review, of which 9 were considered high quality. The study populations were heterogeneous in terms of diagnosis of knee pain. We found a strong level of evidence for a relationship between depression and knee pain, limited evidence for no relationship between anxiety and knee pain, and minimal evidence for no relationship between poor mental health and knee pain. CONCLUSIONS: Despite the heterogeneity of the included studies, these data show that depression plays a significant role in knee pain, and that a biopsychosocial approach to the management of this condition is integral to optimising outcomes for knee pain. PMID- 24405726 TI - Evaluation of the introduction of the national Down syndrome screening program in the Netherlands: age-related uptake of prenatal screening and invasive diagnostic testing. AB - OBJECTIVE: To study the effect of different government prenatal screening (PNS) policies on the uptake of PNS and prenatal diagnostic testing (PND) over the periods 2001-2003 (PNS on request), 2004-2006 (permission to offer the first trimester combined test (FCT) to women of advanced maternal age (AMA), with women aged <36 years informed on explicit request) and 2007-2010 (introduction of population screening) and to evaluate whether trends in uptake are related to maternal age. The indication AMA for PND is still warranted, and the costs for FCT are only reimbursed for AMA women. STUDY DESIGN: Analysis of data on the first- and second-trimester screening program (n=41,600) for Down syndrome (DS) and on PND (n=10,795) performed from 2001 to 2010 in the region North-Holland of the Netherlands. To evaluate the actual participation in PNS and PND in different maternal age groups, estimation of the age distribution of women who underwent a fetal anomaly scan in 2009 (n=14,481) was used as a reference population (participation of 85.2%). RESULTS: The overall uptake of FCT was 35.2% in 2010. Over the years the number of FCT in all age groups increased significantly (P<0.001). Overall the number of PND decreased significantly; the number of PND for AMA decreased and the number of PND for increased risk at FCT (in women <36 and >=36 years) increased (P<0.05). Since 2004 significantly more DS cases were detected with FCT in AMA women and fewer with PND for AMA, and since 2007 more DS cases were detected with FCT in women <36 years (P<0.001). CONCLUSION: The effect of the national screening program is limited. Significantly more women opt for PNS but the overall uptake remains low, especially in younger women. A significant number of AMA women still opt for PND for AMA. The choice for FCT and PND for AMA seems dependent on background risk. To accomplish a more effective screening policy, reimbursement of the cost of the test should apply to all women and the indication for PND for AMA should be abolished. PMID- 24405727 TI - In vitro maturation of oocytes is not a risk factor for adult metabolic syndrome of mouse offspring. AB - OBJECTIVE: To evaluate the effect of in vitro maturation (IVM) of oocytes on the serum cholesterol profile, glucose and insulin tolerance, blood pressure, and heart rate of adult mouse offspring. STUDY DESIGN: The serum cholesterol profile, glucose and insulin tolerance, blood pressure, and heart rate of adult offspring born from in vitro matured oocytes were compared with those of adult offspring born from in vivo matured oocytes. RESULTS: Offspring born from in vitro matured oocytes showed a normal serum cholesterol profile. In the glucose tolerance test, glucose levels were consistently elevated in adult offspring born from in vitro matured oocytes compared with those born from in vivo matured oocytes, but the differences did not reach statistical significance. There were no significant differences in insulin tolerance, blood pressure, and heart rate between adult offspring born from in vitro matured oocytes and those from in vivo matured oocytes. CONCLUSION: No alterations were found in the metabolism profile of adult mouse offspring born from in vitro matured oocytes compared with that from in vivo matured oocytes. PMID- 24405728 TI - Calcium concentration response to uterine ischemia: a comparison of uterine fibroid cells and adjacent normal myometrial cells. AB - OBJECTIVE: Uterine artery occlusion by laparoscopy (UAOL) has been used for the treatment of uterine fibroids and beneficial effects to patients have been shown in clinical studies since 2000. Fibroid cells are more susceptible to apoptosis than myometrial cells under hypoxic conditions, but the molecular mechanisms underlying this effect remain unclear. The aim of this study was to investigate the role of intracellular calcium (Ca(2+)) release mediated by Ca(2+) channel inositol 1,4,5 trisphosphate receptor1 (IP3R1)/ryanodine receptor1 (RYR1) in the apoptosis of uterine fibroid cells under hypoxia. STUDY DESIGN: We compared the expressions of IP3R1 and RYR1 in fibroid and surrounding myometrial tissue from 20 patients before UAOL. After 6h treatment under hypoxia (1% O2) with or without Ca(2+) channel blockers (heparin or/and ruthenium red), the intracellular Ca(2+) concentration, cytochrome c (Cytc) protein and cell apoptosis were determined. RESULTS: IP3R1 and RYR1 mRNA and protein levels were significantly higher in fibroid than in myometrial tissues. Under hypoxic conditions, Ca(2+) concentration in fibroid cells was significantly higher than in myometrial cells (Ca(2+): 82.69+/-16.92nmol/L vs 46.14+/-9.11nmol/L, P<0.05), and Cytc increased similarly in fibroid cells. These increases in Ca(2+) concentration, Cytc and cell apoptosis were significantly reversed by calcium blocker in fibroid cells. CONCLUSION: This study demonstrated that intracellular calcium release mediated by IP3R1/RYR1 could induce apoptosis in uterine fibroid cells under hypoxic conditions, and was responsible for the susceptibility to apoptosis of fibroid cells under UAOL. PMID- 24405729 TI - Maternal and perinatal outcomes in spontaneous versus assisted conception twin pregnancies. AB - OBJECTIVE: To compare maternal and perinatal outcomes in twin pregnancies conceived via assisted reproductive techniques (ART) compared with spontaneous twin pregnancies. STUDY DESIGN: This retrospective study examined 345 dichorionic, di-amniotic twin pregnancies (207 conceived spontaneously and 138 conceived via ART), delivered between January 2007 and June 2011 at the San Pietro Fatebenefratelli Hospital, Rome, a tertiary medical centre. Maternal and perinatal outcomes were compared. A multiple logistic regression analysis was performed to calculate risk estimates as odds ratios (OR) adjusted for maternal age, parity and systemic diseases. Patient data were obtained from a computerized database and analyzed using Statistical Package for the Social Sciences Version 17. RESULTS: Gestational age and birth weight were lower in the ART group, and preterm delivery, gestational diabetes and placental abruption were higher in the ART group compared with the spontaneous conception group. The incidence rates of respiratory complications, patent ductus arteriosus and admission to the neonatal intensive care unit were higher among ART newborns. Length of hospital stay for mothers and newborns was longer in the ART group. No differences in mode of delivery, Apgar score at 5min, congenital anomalies, perinatal mortality, and other considered pregnancy and neonatal complications were found between the two groups. Multivariate analysis adjusted for maternal age, parity and systemic diseases revealed that only the rates of placental abruption [OR 7.45, 95% confidence interval (CI) 2.05-26.98] and patent ductus arteriosus (OR 3.39, 95% CI 1.01-11.46) were significantly higher for the ART group. CONCLUSIONS: Twin pregnancies conceived via ART are at greater risk of poorer outcomes than spontaneous twin pregnancies. This may be related to the type of conception and specific negative features of subfertile patients undergoing infertility treatment. PMID- 24405730 TI - A potential novel strategy, inhibition of vasopressin-induced VEGF secretion by relcovaptan, for decreasing the incidence of ovarian hyperstimulation syndrome in the hyperstimulated rat model. AB - OBJECTIVE: To investigate the effects of V1A receptor antagonist through inhibition of vasopressin-induced VEGF secretion in an experimental model. STUDY DESIGN: Thirty rats were randomly divided into five groups. Four groups were given 10IU pregnant mare serum gonadotropin/day (sc) at 8:00-8:30am on days 22-25 of life. They were administered 30IU hCG at 8:00-8:30am on day 26 of life. On days 26 and 27 of life at 8:00am and 4:00pm, (ip) per animal, 50MUg/kg/day GnRH antagonist in the GnRH antagonist group, 0.3mg relcovaptan in the high dose relcovaptan group, and 0.15mg relcovaptan in the low dose relcovaptan group were administered. The control group was given the same dosage of 0.9% saline solution (ip) on days 22-26 day of life. The main outcomes were weight gain, ovarian weights, peritoneal fluid VEGF values, corpus luteum count, and atretic follicle count. RESULTS: Weight gain was highest in the OHSS group; it was almost twice as much in the OHSS group than it was in the control group. Ovarian weights were significantly lower in all treatment groups (p=0.03). There was no statistically significant difference in ovarian weights between the GnRH antagonist and relcovaptan groups (p=0.176). The evaluation of peritoneal fluid VEGF-A levels revealed statistically significant differences between levels in the treatment groups and in the OHSS group (p=0.005). Atretic follicle count in the OHSS group was significantly lower (p=0.048). In all treatment groups, CL counts were prominently lower than they were in the OHSS group (p=0.002). CONCLUSION: Relcovaptan may be a novel strategy for decreasing risk of OHSS by inhibition of vasopressin-induced VEGF secretion through V1A receptor antagonist. PMID- 24405732 TI - Facing the experience of pain: a neuropsychological perspective. AB - Pain is an experience that none of us would like to have but that each one of us is destined to experience in our lives. Despite its pervasiveness, the experience of pain remains problematic and complex in its depth. Pain is a multidimensional experience that involves nociception as well as emotional and cognitive aspects that can modulate its perception. Following a brief discussion of the neurobiological mechanisms underlying pain, the purpose of this review is to discuss the main psychological, neuropsychological, cultural, and existential aspects which are the basis of diverse forms of pain, like the pain of separation from caregivers or from ourselves (e.g., connected to the thought of our death), the suffering that we experience observing other people's pain, the pain of change and the existential pain connected to the temporal dimension of the mind. Finally, after a discussion of how the mind is able to not only create but also alleviate the pain, through mechanisms such as the expectation of the treatment and the hope of healing, we conclude by discussing neuropsychological research data and the attitude promoted by mindfulness meditation in relation to the pain. An attitude in which, instead to avoid and reject the pain, one learns to face mindfully the experience of pain. PMID- 24405733 TI - The effects of oil exposure on peripheral blood leukocytes and splenic melano macrophage centers of Gulf of Mexico fishes. AB - In August and November 2010 we collected and examined peripheral blood and tissues from three species of Gulf of Mexico fish. Findings were compared to non exposed control fish. The leukocyte counts of exposed alligator gar were not significantly different from controls, while exposed Gulf killifish and sea trout had significantly decreased lymphocyte counts. Liver ethoxyresorufin-O-deethylase (EROD) values from sea trout were significantly greater than control sea trout EROD values, suggesting poly aromatic hydrocarbon exposure. Splenic melano macrophage centers (MMCs) from exposed sea trout and Gulf killifish showed a significant increase in number compared to non-exposed fish. Sea trout splenic MMCs were also significantly greater in size. These findings suggest that Gulf fish sampled were exposed to crude oil from the Macondo well and were in a lymphopenic or immuno-compromised state. PMID- 24405734 TI - The effect of continuous versus intermittent renal replacement therapy on the outcome of critically ill patients with acute renal failure (CONVINT): a prospective randomized controlled trial. AB - INTRODUCTION: Acute renal failure (ARF) requiring renal replacement therapy (RRT) occurs frequently in ICU patients and significantly affects mortality rates. Previously, few large clinical trials investigated the impact of RRT modalities on patient outcomes. Here we investigated the effect of two major RRT strategies (intermittent hemodialysis (IHD) and continuous veno-venous hemofiltration (CVVH)) on mortality and renal-related outcome measures. METHODS: This single center prospective randomized controlled trial ("CONVINT") included 252 critically ill patients (159 male; mean age, 61.5 +/- 13.9 years; Acute Physiology and Chronic Health Evaluation (APACHE) II score, 28.6 +/- 8.8) with dialysis-dependent ARF treated in the ICUs of a tertiary care academic center. Patients were randomized to receive either daily IHD or CVVH. The primary outcome measure was survival at 14 days after the end of RRT. Secondary outcome measures included 30-day-, intensive care unit-, and intrahospital mortality, as well as course of disease severity/biomarkers and need for organ-support therapy. RESULTS: At baseline, no differences in disease severity, distributions of age and gender, or suspected reasons for acute renal failure were observed. Survival rates at 14 days after RRT were 39.5% (IHD) versus 43.9% (CVVH) (odds ratio (OR), 0.84; 95% confidence interval (CI), 0.49 to 1.41; P = 0.50). 14-day-, 30-day, and all-cause intrahospital mortality rates were not different between the two groups (all P > 0.5). No differences were observed in days on RRT, vasopressor days, days on ventilator, or ICU-/intrahospital length of stay. CONCLUSIONS: In a monocentric RCT, we observed no statistically significant differences between the investigated treatment modalities regarding mortality, renal-related outcome measures, or survival at 14 days after RRT. Our findings add to mounting data demonstrating that intermittent and continuous RRTs may be considered equivalent approaches for critically ill patients with dialysis-dependent acute renal failure. TRIAL REGISTRATION: NCT01228123, clinicaltrials.gov. PMID- 24405735 TI - The relationship between carotid intima-media thickness and global atherosclerosis. AB - BACKGROUND: The aim of this study was to investigate the relationship between (i) carotid intima-media thickness (CIMT) at baseline as well as (ii) change in CIMT over 5 years (DeltaCIMT) and atherosclerotically induced luminal narrowing in non coronary arterial territories assessed by whole-body magnetic resonance angiography (WBMRA). METHODS AND RESULTS: In subgroups of the Prospective Investigation of Vasculature in Uppsala Seniors (PIVUS) study, US measurements of CIMT in the common carotid arteries were analysed at 70 and 75 years and DeltaCIMT was calculated (n = 272). WBMRA, assessing arterial stenosis in five different territories by which also a total atherosclerotic score (TAS) was calculated, was performed at 70 years (n = 306). RESULTS: Carotid intima-media thickness in the carotid artery at baseline was correlated with TAS (P = 0.0001) when adjusted to a set of traditional risk factors for atherosclerosis, as well as to stenosis in two of the different investigated territories (aorta and lower leg, P = 0.013 and P = 0.004), but there was no significant correlation between DeltaCIMT and TAS (P = 0.41). CONCLUSIONS: In the present study, CIMT, but not DeltaCIMT over 5 years, in the carotid artery was related to overall stenoses in the body, as assessed by WBMRA. These findings support CIMT as a general marker for atherosclerosis. PMID- 24405736 TI - Effect of applied force and blade speed on histopathology of bone during resection by sagittal saw. AB - A sagittal saw is commonly used for resection of bone during joint replacement surgery. During sawing, heat is generated that can lead to an increase in temperature at the resected surface. The aim of this study was to determine the effect of applied thrust force and blade speed on generating heat. The effect of these factors and their interactions on cutting temperature and bone health were investigated with a full factorial Design of Experiments approach for two levels of thrust force, 15 N and 30 N, and for two levels of blade oscillation rate, 12,000 and 18,000 cycles per minute (cpm). In addition, a preliminary study was conducted to eliminate blade wear as a confounding factor. A custom sawing fixture was used to crosscut samples of fresh bovine cortical bone while temperature in the bone was measured by thermocouple (n=40), followed by measurements of the depth of thermal necrosis by histopathological analysis (n=200). An analysis of variance was used to determine the significance of the factor effects on necrotic depth as evidenced by empty lacunae. Both thrust force and blade speed demonstrated a statistically significant effect on the depth of osteonecrosis (p<0.05), while the interaction of thrust force with blade speed was not significant (p=0.22). The minimum necrotic depth observed was 0.50mm, corresponding to a higher level of force and blade speed (30 N, 18,000 cpm). Under these conditions, a maximum temperature of 93 degrees C was measured at 0.3mm from the kerf. With a decrease in both thrust force and blade speed (15N, 12,000 cpm), the temperature in the bone increased to 109 degrees C, corresponding to a nearly 50% increase in depth of the necrotic zone to 0.74 mm. A predictive equation for necrotic depth in terms of thrust force and blade speed was determined through regression analysis and validated by experiment. The histology results imply that an increase in applied thrust force is more effective in reducing the depth of thermal damage to surrounding bone than an increase in blade speed. PMID- 24405737 TI - Smart instrumentation for determination of ligament stiffness and ligament balance in total knee arthroplasty. AB - Ligament balance is an important and subjective task performed during total knee arthroplasty (TKA) procedure. For this reason, it is desirable to develop instruments to quantitatively assess the soft-tissue balance since excessive imbalance can accelerate prosthesis wear and lead to early surgical revision. The instrumented distractor proposed in this study can assist surgeons on performing ligament balance by measuring the distraction gap and applied load. Also the device allows the determination of the ligament stiffness which can contribute a better understanding of the intrinsic mechanical behavior of the knee joint. Instrumentation of the device involved the use of hall-sensors for measuring the distractor displacement and strain gauges to transduce the force. The sensors were calibrated and tested to demonstrate their suitability for surgical use. Results show the distraction gap can be measured reliably with 0.1mm accuracy and the distractive loads could be assessed with an accuracy in the range of 4N. These characteristics are consistent with those have been proposed, in this work, for a device that could assist on performing ligament balance while permitting surgeons evaluation based on his experience. Preliminary results from in vitro tests were in accordance with expected stiffness values for medial collateral ligament (MCL) and lateral collateral ligament (LCL). PMID- 24405738 TI - Silicon balance in human volunteers; a pilot study to establish the variance in silicon excretion versus intake. AB - BACKGROUND: Accumulating evidence suggests a role for silicon in optimal connective tissue health. Further proof of its importance/essentiality may be provided by studies involving imposed depletion followed by 29Si challenge to estimate metabolic balance. Prior to conducting these expensive studies, we first established the variance of estimating normal Si excretion versus intake using a single oral dose of typical dietary Si, orthosilicic acid. METHODS: Healthy volunteers were recruited from Loei Rajabhat University, separated into two matched groups (three males and three females/group) and maintained on a standardized diet for the three study days. One group ingested 500 ml water containing orthosilicic acid (28.9 mg Si) and the other group received 500 ml water alone, all on a fasted stomach. Blood samples and total urine and faeces were collected over the 48 h post-dose period and 24 h before-hand (baseline) and analysed for silicon by inductively coupled plasma optical emission spectrometry. RESULTS: Serum Si analysis confirmed the ready absorption of silicon from the orthosilicic acid solution. Mean total urinary and faecal Si excretions over the 24 h post-dose period accounted for 57 +/- 9.5% and 39 +/- 9.4% of the ingested dose, respectively. Thus in total 96.3 +/- 5.8% of the ingested dose was recovered in faecal plus urinary excretions over the 24 h post-dose period. CONCLUSIONS: We report that in healthy subjects (presumably in Si balance), the ingestion of a soluble dose of dietary Si results in the same quantity (within analytical error) being excreted within 24 h. It is currently not known if this all originated from the dose solution or if there was some exchange with the body Si pool but, given the low variance in these silicon balance data, isotopic studies are now merited. PMID- 24405739 TI - On the relationship between an Asian haplotype on chromosome 6 that reduces androstenone levels in boars and the differential expression of SULT2A1 in the testis. AB - BACKGROUND: Androstenone is one of the major compounds responsible for boar taint, a pronounced urine-like odor produced when cooking boar meat. Several studies have identified quantitative trait loci (QTL) for androstenone level on Sus scrofa chromosome (SSC) 6. For one of the candidate genes in the region SULT2A1, a difference in expression levels in the testis has been shown at the protein and RNA level. RESULTS: Haplotypes were predicted for the QTL region and their effects were estimated showing that haplotype 1 was consistently related with a lower level, and haplotype 2 with a higher level of androstenone. A recombinant haplotype allowed us to narrow down the QTL region from 3.75 Mbp to 1.94 Mbp. An RNA-seq analysis of the liver and testis revealed six genes that were differentially expressed between homozygotes of haplotypes 1 and 2. Genomic sequences of these differentially expressed genes were checked for variations within potential regulatory regions. We identified one variant located within a CpG island that could affect expression of SULT2A1 gene. An allele-specific expression analysis in the testis did not show differential expression between the alleles of SULT2A1 located on the different haplotypes in heterozygous animals. However a synonymous mutation C166T (SSC6: 49,117,861 bp in Sscrofa 10.2; C/T) was identified within the exon 2 of SULT2A1 for which the haplotype 2 only had the C allele which was higher expressed than the T allele, indicating haplotype-independent allelic-imbalanced expression between the two alleles. A phylogenetic analysis for the 1.94 Mbp region revealed that haplotype 1, associated with low androstenone level, originated from Asia. CONCLUSIONS: Differential expression could be observed for six genes by RNA-seq analysis. No difference in the ratio of C:T expression of SULT2A1 for the haplotypes was found by the allele-specific expression analysis, however, a difference in expression between the C over T allele was found for a variation within SULT2A1, showing that the difference in androstenone levels between the haplotypes is not caused by the SNP in exon 2. PMID- 24405741 TI - Assessment of iris surface features and their relationship with iris thickness in Asian eyes. AB - PURPOSE: To assess iris surface features in Asian eyes and examine their associations with iris thickness measured by anterior segment optical coherence tomography (AS OCT). DESIGN: Cross-sectional study. PARTICIPANTS: We recruited 250 subjects from the Singapore Malay Eye Study. METHODS: We obtained standardized slit-lamp photographs and developed a grading system assessing iris crypts (by number and size), furrows (by number and circumferential extent), and color (higher grade denoting darker iris). Vertical and horizontal cross-sections of the anterior chamber were imaged using AS OCT. Intragrader and intergrader agreements in the grading of iris surface were assessed by weighted kappa (kappa(w)) statistic. Associations of the average iris thickness with the grade of iris features were assessed using linear regression analysis. MAIN OUTCOME MEASURES: Frequency and size of iris crypts, furrows, and color; iris thickness at 750 MUm (IT750) and 2000 MUm (IT2000) from the scleral spur; and maximum iris thickness (ITM) averaged from the 4 quarters. RESULTS: Three hundred sixty-four eyes had complete and gradable data for crypts and color; 330 eyes were graded for furrows. The grading scheme showed good intragrader (crypt kappa(w) = 0.919, furrow kappa(w) =0.901, color kappa(w) = 0.925) and intergrader (crypt kappa(w) = 0.775, furrow kappa(w) = 0.836, color kappa(w) = 0.718) agreements. Higher crypt grade was associated independently with thinner IT750 (beta [change in iris thickness per grade higher] = -0.007; P = 0.029), IT2000 (beta = -0.018; P < 0.001), and ITM (beta = -0.012; P < 0.001). More extensive furrows were associated with thicker IT750 (beta = 0.022; P < 0.001). Darker iris was also associated with thicker IT750 (beta = 0.014; P = 0.001). CONCLUSIONS: Iris surface features, assessed and measured from slit-lamp photographs, correlate well with iris thickness. Irises with more crypts are thinner; irises with more extensive furrows and darker color are thicker peripherally. These findings may provide another means to assess angle closure risk based on iris features. PMID- 24405740 TI - Cost-effectiveness of bevacizumab and ranibizumab for newly diagnosed neovascular macular degeneration. AB - PURPOSE: We sought to determine the most cost-effective treatment for patients with newly diagnosed neovascular macular degeneration: monthly or as-needed bevacizumab injections, or monthly or as-needed ranibizumab injections. DESIGN: Cost-effectiveness analysis. PARTICIPANTS: Hypothetical cohort of 80-year-old patients with newly diagnosed neovascular macular degeneration. METHODS: Using a mathematical model with a 20-year time horizon, we compared the incremental cost effectiveness of treating a hypothetical cohort of 80-year-old patients with newly diagnosed neovascular macular degeneration using monthly bevacizumab, as needed bevacizumab, monthly ranibizumab, or as-needed ranibizumab. Data came from the Comparison of Age-related macular degeneration Treatment Trial (CATT), the Medicare Fee Schedule, and the medical literature. MAIN OUTCOME MEASURES: Costs, quality-adjusted life-years (QALYs), and incremental costs per QALY gained. RESULTS: Compared with as-needed bevacizumab, the incremental cost-effectiveness ratio of monthly bevacizumab is $24,2 357/QALY. Monthly ranibizumab gains an additional 0.02 QALYs versus monthly bevacizumab at an incremental cost effectiveness ratio of >$10 million/QALY. As-needed ranibizumab was dominated by monthly bevacizumab, meaning it was more costly and less effective. In sensitivity analyses assuming a willingness to pay of $100,000/QALY, the annual risk of serious vascular events would have to be >=2.5 times higher with bevacizumab than that observed in the CATT trial for as-needed ranibizumab to have an incremental cost-effectiveness ratio of <$100,000/QALY. In another sensitivity analysis, even if every patient receiving bevacizumab experienced declining vision by 1 category (e.g., from 20/25-20/40 to 20/50-20/80) after 2 years but every patient receiving ranibizumab retained their vision level, as needed ranibizumab would have an incremental cost-effectiveness ratio of $97,340/QALY. CONCLUSIONS: Even after considering the potential for differences in risks of serious adverse events and therapeutic effectiveness, bevacizumab confers considerably greater value than ranibizumab for the treatment of neovascular macular degeneration. PMID- 24405742 TI - Proton therapy for uveal melanoma in 43 juvenile patients: long-term results. AB - PURPOSE: To examine the metastatic and survival rates, eye retention probability, and the visual outcomes of juvenile patients after proton beam radiotherapy (PBRT) for uveal melanoma (UM). DESIGN: Retrospective case-factor matched control study. PARTICIPANTS AND CONTROLS: Forty-three patients younger than 21 years treated with PBRT for UM were compared with 129 matched adult control patients. METHODS: Information on patient demographics and clinical characteristics were recorded before and after treatment from patients' files. The control group was composed of adult patients (>21 years) matched for tumor size (largest tumor diameter, +/-2 mm; height, +/-2 mm) and anterior margin location (iris, ciliary body, pre-equatorial or postequatorial choroid). For each juvenile patient, 3 adults were selected. MAIN OUTCOME MEASURES: Comparing outcomes of juvenile and adult patients in terms of metastatic and eye retention rates using the log-rank statistic, relative survival using the Hakulinen method, as well as their visual outcomes. RESULTS: Forty-three juvenile and 129 control cases were reviewed. The metastatic rate at 10 years was significantly lower in juvenile UM patients than in adult controls (11% vs. 34%; P <0.01), with an associated relative survival rate of 93% versus 65% (P = 0.02). Six juvenile patients (14%) demonstrated metastases. One patient underwent enucleation because of a presumed local tumor recurrence and 4 additional patients underwent enucleation because of complications (9.3%). In the adult control group, 27% (n = 35) of matched patients demonstrated metastases, there were 2 cases of local recurrence, and 16% (n = 21) underwent enucleation because of complications. A visual acuity of more than 0.10 was maintained in most cases, without any significant differences before or after treatment observed between both groups. CONCLUSIONS: After PBRT, metastatic and survival rates are significantly better for juvenile than for adult patients with UM. Clinically, juvenile and adult eyes react similarly to PBRT, with patients having a comparable eye retention probability and maintaining a useful level of vision in most cases. This is the largest case-control study of proton therapy in juvenile eyes to date and further validates PBRT as an appropriate conservative treatment for UM in patients younger than 21 years. PMID- 24405743 TI - Seasonal changes in expression of nerve growth factor and its receptors TrkA and p75 in the ovary of wild ground squirrel (Citellus dauricus Brandt). AB - The aim of this study was to investigate the presence of nerve growth factor (NGF) and its receptors tyrosine kinase A (TrkA) and p75 in the ovaries of the wild ground squirrels during the breeding and nonbreeding seasons. In the breeding period, NGF, TrkA and p75 were immunolocalized in granulosa cells, thecal cells, interstitial cells and luteal cells whereas in the nonbreeding period, both of them were detected only in granulosa cells, thecal cells and interstitial cells. Stronger immunostaining of NGF, TrkA and p75 were observed in granulosa cells, thecal cells and interstitial cells in the breeding season compared to the nonbreeding season. Corresponding for the immunohistochemical results, immunoreactivities of NGF and its two receptors were greater in the ovaries of the breeding season then decreased to a relatively low level in the nonbreeding season. The mean mRNA levels of NGF, TrkA and p75 were significantly higher in the breeding season than in the nonbreeding season. In addition, plasma gonadotropins, estradiol-17beta and progesterone concentrations were significantly higher in the breeding season than in the nonbreeding season, suggesting that the expression patterns of NGF, and TrkA and p75 were correlated with changes in plasma gonadotropins, estradiol-17beta and progesterone concentrations. These results indicated that NGF and its receptors, TrkA and p75 may be involved in the regulation of seasonal changes in the ovarian functions of the wild ground squirrel. PMID- 24405744 TI - Autophagy involved in lipopolysaccharide-induced foam cell formation is mediated by adipose differentiation-related protein. AB - BACKGROUND: Autophagy is an essential process for breaking down macromolecules and aged/damaged cellular organelles to maintain cellular energy balance and cellular nutritional status. The idea that autophagy regulates lipid metabolism is an emerging concept with important implications for atherosclerosis. However, the potential role of autophagy and its relationship with lipid metabolism in foam cell formation remains unclear. In this study, we found that autophagy was involved in the lipopolysaccharide (LPS)-induced the formation of foam cells and was at least partially dependent on adipose differentiation-related protein (ADRP). METHOD: Foam cell formation was evaluated by Oil red O staining. Autophagic activity was determined by immunofluorescence and Western blotting. ADRP gene expression of ADRP was examined by real-time PCR (RT-PCR). The protein expression of ADRP and LC3 was measured using Western blotting analysis. Intracellular cholesterol and triglyceride levels in foam cells were quantitatively measured by enzymatic colorimetric assays. RESULTS: LPS promoted foam cell formation by inducing lipid accumulation in macrophages. The activation of autophagy with rapamycin (Rap) decreased intracellular cholesterol and triglyceride levels, whereas the inhibition of autophagy with 3-methyladenine (3MA) enhanced the accumulation of lipid droplets. Overexpression of ADRP alone increased the formation of foam cells and consequently autophagic activity. In contrast, the inhibitory effects of ADRP activity with siRNA suppressed the activation of autophagy. Taken together, we propose a novel role for ADRP in the regulation of macrophage autophagy during LPS stimulation. CONCLUSION: We defined a new molecular pathway in which LPS-induced foam cell formation is regulated through autophagy. These findings facilitate the understanding of the role of autophagy in the development of atherosclerosis. PMID- 24405746 TI - Escherichia coli-derived outer membrane vesicles are genotoxic to human enterocyte-like cells. AB - BACKGROUND: Colorectal cancers are the third most common type in the world. The causes of the disease are poorly understood, but since the discovery of Helicobacter pylori as a causative agent of gastric cancer, attention has turned to bacteria as a possible trigger for colorectal cancer. Recently H. pylori outer membrane vesicles (OMVs) were revealed as potentially genotoxic which can be important first step in carcinogenesis. We therefore investigated whether OMVs from intestinal Escherichia coli could be genotoxic. METHODS: OMVs from the avirulent DH5alpha strain, a pathogenic adherent-invasive E. coli (AIEC) and an enterohaemolytic (EHEC) strain of E. coli were enriched by ultracentrifugation. The effect on the growth and viability of human enterocyte-like Caco-2 cells by OMVs was determined by trypan blue exclusion, MTT and BrdU incorporation assays. The ability of OMVs to induce DNA damage was assayed by single-cell gel electrophoresis, and 8-oxo-dG and gammaH2Ax immunofluorescence staining. Cytopathological changes were assessed by microscopy. The induction of aneuploidy by the OMVs was measured by flow cytometry in Caco-2 and LoVo cells. RESULTS: We found that OMVs derived were internalised by Caco-2 cells, increased cell numbers, induced double-stranded DNA breaks, recruited gammaH2Ax to the nucleus, initiated DNA rereplication, and produced distended multinucleate cells. DH5alpha and AIEC OMVs caused free radical generation as indicated by the reduction of glutathione in cells, leading to the development of mutagenic 8-oxo-dG adducts in DNA. Flow cytometry revealed that DH5alpha and EHEC OMVs increased aneuploidy in p53 mutant Caco-2 cells, but not in p53 wild type LoVo cells. CONCLUSION: We conclude that E. coli derived OMVs, whether from avirulent or pathogenic strains are potentially genotoxic. PMID- 24405747 TI - Nasal swab samples and real-time polymerase chain reaction assays in community based, longitudinal studies of respiratory viruses: the importance of sample integrity and quality control. AB - BACKGROUND: Carefully conducted, community-based, longitudinal studies are required to gain further understanding of the nature and timing of respiratory viruses causing infections in the population. However, such studies pose unique challenges for field specimen collection, including as we have observed the appearance of mould in some nasal swab specimens. We therefore investigated the impact of sample collection quality and the presence of visible mould in samples upon respiratory virus detection by real-time polymerase chain reaction (PCR) assays. METHODS: Anterior nasal swab samples were collected from infants participating in an ongoing community-based, longitudinal, dynamic birth cohort study. The samples were first collected from each infant shortly after birth and weekly thereafter. They were then mailed to the laboratory where they were catalogued, stored at -80 degrees C and later screened by PCR for 17 respiratory viruses. The quality of specimen collection was assessed by screening for human deoxyribonucleic acid (DNA) using endogenous retrovirus 3 (ERV3). The impact of ERV3 load upon respiratory virus detection and the impact of visible mould observed in a subset of swabs reaching the laboratory upon both ERV3 loads and respiratory virus detection was determined. RESULTS: In total, 4933 nasal swabs were received in the laboratory. ERV3 load in nasal swabs was associated with respiratory virus detection. Reduced respiratory virus detection (odds ratio 0.35; 95% confidence interval 0.27-0.44) was observed in samples where the ERV3 could not be identified. Mould was associated with increased time of samples reaching the laboratory and reduced ERV3 loads and respiratory virus detection. CONCLUSION: Suboptimal sample collection and high levels of visible mould can impact negatively upon sample quality. Quality control measures, including monitoring human DNA loads using ERV3 as a marker for epithelial cell components in samples should be undertaken to optimize the validity of real-time PCR results for respiratory virus investigations in community-based studies. PMID- 24405748 TI - The effects of limb dominance and fatigue on running biomechanics. AB - PURPOSE: To establish whether lower extremity limb dominance has an effect on overground running mechanics. BACKGROUND: In attempts to resolve unilateral pathology, physical therapists often use the restoration of symmetry as a clinical milestone. While lower limb dominance has been shown to affect lower extremity mechanics during dynamic tasks such as jump landing, its effect on running gait is poorly understood. Further, despite the role of fatigue in running mechanics and injury, the interaction between fatigue and limb dominance has yet to be examined. METHODS: Three-dimensional kinematic and kinetic data were collected on 20 females during overground running. Data were collected prior to and following a treadmill run to exertion. Dominant and non-dominant limb data were compared in the fresh-state using a paired t-test. A 2-way repeated-measures ANOVA was used to test for an interaction between fatigue and limb dominance. RESULTS: There were no significant differences between the kinematic or kinetic patterns of the dominant and non-dominant lower extremities during fresh-state overground running. Fatigue was not shown to interact with limb dominance. CONCLUSION: Limb dominance did not affect kinematic or kinetic side-to-side differences. Therefore, physical therapists can continue to use resolution of lower extremity symmetry as a goal of therapy without having to account for limb dominance. The lack of an interaction between fatigue and limb dominance indicates that the dominant and non-dominant limbs fatigue at a similar rate. PMID- 24405749 TI - Body-worn sensors capture variability, but not decline, of gait and balance measures in multiple sclerosis over 18 months. AB - Gait and balance deficits are a frequent complaint in MS but poorly captured by stopwatch-timed tests or rating scales. Body-worn accelerometers and gyroscopes are able to detect gait and balance abnormalities in people with MS who have normal walking speeds. Few longitudinal studies exist using this technology to study the evolution of mobility deficits. The purpose of this study was to determine if body-worn sensors detected any decline in gait and balance measures in people with MS over time. Twenty-seven people with MS (13 mildly disabled, self-rated expanded disability status scale 0-3.5; 14 moderately disabled, SR EDSS 4.0-5.5) who had normal walking speeds and 18 matched control subjects underwent gait and balance testing using body-worn sensors every 6 months for 18 months. While no parameter worsened over time, the moderately disabled MS cohort performed more poorly than the mildly disabled MS cohort who, in turn, was worse than control subjects for both objective and subjective walking and balance measures. Furthermore, the moderately disabled MS cohort demonstrated greater variation in between-visit performance than did the less disabled MS cohort or controls (Bonferroni-corrected p<0.05). Variability may be a key indicator of worsening gait and balance disability in MS. PMID- 24405750 TI - CNIH4 interacts with newly synthesized GPCR and controls their export from the endoplasmic reticulum. AB - The molecular mechanisms regulating G protein-coupled receptors (GPCRs) trafficking from their site of synthesis in the endoplasmic reticulum (ER) to their site of function (the cell surface) remain poorly characterized. Using a bioluminescence resonance energy transfer-based proteomic screen, we identified a novel GPCR-interacting protein; the human cornichon homologue 4 (CNIH4). This previously uncharacterized protein is localized in the early secretory pathway where it interacts with members of the 3 family of GPCRs. Both overexpression and knockdown expression of CNIH4 caused the intracellular retention of GPCRs, indicating that this ER-resident protein plays an important role in GPCR export. Overexpression of CNIH4 at low levels rescued the maturation and cell surface expression of an intracellularly retained mutant form of the beta2-adrenergic receptor, further demonstrating a positive role of CNIH4 in GPCR trafficking. Taken with the co-immunoprecipitation of CNIH4 with Sec23 and Sec24, components of the COPII coat complex responsible for ER export, these data suggest that CNIH4 acts as a cargo-sorting receptor, recruiting GPCRs into COPII vesicles. PMID- 24405751 TI - The one year exercise and lifestyle intervention program KLAKS: Effects on anthropometric parameters, cardiometabolic risk factors and glycemic control in childhood obesity. AB - OBJECTIVE: Regular physical exercise within structured lifestyle programs may improve weight status and minimize metabolic risk factors in childhood obesity. The aim of this study was to evaluate the effect of the one-year combined physical exercise/lifestyle program KLAKS on anthropometric and metabolic parameters and glycemic control in childhood obesity. MATERIALS AND METHODS: 142 overweight/obese (BMI>90th percentile) candidates (7-18years) were enrolled, 115 participants completed the program. Anthropometrics and biochemical parameters were obtained at beginning and completion. An oral glucose tolerance test (OGTT) was performed in a subgroup of participants. Course of glucose and insulin levels within OGTT was correlated with several parameters and is reported here for those who completed the program. RESULTS: The mean standard deviation scores (SDS) decreased significantly for BMI, waist circumference, waist-to-height ratio (WHtR) and percentage body fat (all p<=0.01). Improved metabolic risk markers included mean glucose levels within an OGTT at follow-up compared to baseline (p<0.0001) and HbA1c (p=0.05) as well as indications of improvement for gamma glutamyl-transferase and free fatty acids. CONCLUSIONS: The one-year combined exercise/lifestyle program KLAKS significantly improves markers of obesity and glycemic control. Impaired cardiometabolic risk markers, even subclinical, are also favorably influenced by program participation. PMID- 24405753 TI - A simple plaster for screening for diabetic neuropathy: a diagnostic test accuracy systematic review and meta-analysis. AB - OBJECTIVE: Neuropad is an adhesive indicator test applied at the plantar surface of the foot that detects sweating through color change. We examined the diagnostic accuracy of this simple plaster as triage test for screening for clinically relevant diabetic sensorimotor polyneuropathy in adult outpatients with type 1 or type 2 diabetes. MATERIALS/METHODS: Systematic review and meta analysis of diagnostic accuracy studies. We searched Medline, Embase, Cochrane Library, Biosis Previews, Web of Science, Scopus and gray literature without date or language restrictions. We pooled estimates of sensitivity and specificity, and fitted hierarchical models to produce summary receiver operating characteristic curves. We assessed methodological quality of included studies utilizing the Quality Assessment of Diagnostic Accuracy Studies 2 tool. RESULTS: Eighteen studies with 3470 participants met the inclusion criteria. Average sensitivity and specificity were 86% (95% CI 79 to 91) and 65% (95% CI 51 to 76) respectively. Likelihood ratios (LRs) were LR+=2.44 and LR-=0.22. Subgroup analyses per reference standard utilized provided similar estimates. Most studies were at risk of bias for patient selection and use of index or reference test, and had concerns regarding applicability due to patient selection. CONCLUSION: The adhesive indicator test has reasonable sensitivity and could be used for triage of diabetic neuropathy to rule out foot at risk. Patients who tested positive should be referred to specialized care to establish a definite diagnosis. There is insufficient evidence for effectiveness on patient-important outcomes and cost-effectiveness of implementation in the diagnostic pathway compared with the standard clinical examination. PMID- 24405752 TI - Genome-wide association study identifies common loci influencing circulating glycated hemoglobin (HbA1c) levels in non-diabetic subjects: the Long Life Family Study (LLFS). AB - OBJECTIVE: Glycated hemoglobin (HbA1c) is a stable index of chronic glycemic status and hyperglycemia associated with progressive development of insulin resistance and frank diabetes. It is also associated with premature aging and increased mortality. To uncover novel loci for HbA1c that are associated with healthy aging, we conducted a genome-wide association study (GWAS) using non diabetic participants in the Long Life Family Study (LLFS), a study with familial clustering of exceptional longevity in the US and Denmark. METHODS: A total of 4088 non-diabetic subjects from the LLFS were used for GWAS discoveries, and a total of 8231 non-diabetic subjects from the Atherosclerosis Risk in Communities Study (ARIC, in the MAGIC Consortium) and the Health, Aging, and Body Composition Study (HABC) were used for GWAS replications. HbA1c was adjusted for age, sex, centers, 20 principal components, without and with BMI. A linear mixed effects model was used for association testing. RESULTS: Two known loci at GCK rs730497 (or rs2908282) and HK1 rs17476364 were confirmed (p<5e-8). Of 25 suggestive (5e 8 process -> goals. Functionality includes support for: mapping life domains; medication overview; crisis management; coping exercises; secure messaging; and social support. While the types of evidence that can legitimize design decisions are scattered and indirectly relevant, recent trends in recovery research will be used to guide further refinements. DISCUSSION: PsyConnect has undoubtedly become something other than it would have been without careful attention to the views of service users. The tool invites a proactive approach that is likely to challenge treatment cultures that are reactive, disorder-focused and consultation-based. Service user representatives will need to play central roles in training peers and clinicians in order to increase the likelihood of tool usage in line with intentions. Similarly, their influence on tool design has implications for choice of methods for evaluation. CONCLUSIONS: Starting down the path of service user involvement in intervention design fosters commitment to follow through in the remaining implementation and research phases. While this can be time-consuming and less meriting for researchers, it is probably vital to increasing the likelihood of success of person-centered service innovations. PMID- 24405766 TI - Rapid PCR/ESI-MS-based molecular genotyping of Staphylococcus aureus from nasal swabs of emergency department patients. AB - BACKGROUND: A limitation of both culture-based and molecular methods of screening for staphylococcal infection is that current tests determine only the presence or absence of colonization with no information on the colonizing strain type. A technique that couples polymerase chain reaction to mass spectrometry (PCR/ESI MS) has recently been developed and an assay validated to identify and genotype S. aureus and coagulase-negative staphylococci (CoNS). METHODS: This study was conducted to determine the rates, risk factors, and molecular genotypes of colonizing Staphylococcus aureus in adult patients presenting to an inner-city academic emergency department. Participants completed a structured questionnaire to assess hospital and community risks for infection with methicillin-resistant S. aureus (MRSA). Nasal swabs were analyzed by PCR/ESI-MS to identify and genotype S. aureus and CoNS. RESULTS: Of 200 patients evaluated, 59 were colonized with S. aureus; 27 of these were methicillin-resistant strains. Twenty four of the 59 S. aureus carriers were co-colonized with a CoNS and 140 of the 200 patients were colonized exclusively with CoNS. The molecular genotypes of the 59 S. aureus strains were diverse; 21 unique molecular genotypes belonging to seven major clonal complexes were identified. Eighty-five of 200 patients carried strains with high-level mupirocin resistance. Of these eighty-five participants, 4 were colonized exclusively with S. aureus, 16 were co-colonized with S. aureus and CoNS, and 65 were colonized exclusively with CoNS. CONCLUSION: The prevalence of S. aureus and methicillin-resistant S. aureus colonization in a random sample of patients seeking care in Emergency Department was 29.5% and 13.5%, respectively. A substantial fraction of the S. aureus-colonized patients were co colonized with CoNS and high-level mupirocin-resistant CoNS. Determining the molecular genotype of S. aureus during intake screening may prove valuable in the future if certain molecular genotypes become associated with increased infection risk. PMID- 24405767 TI - Metformin usage in type 2 diabetes mellitus: are safety guidelines adhered to? AB - AIM: To (i) evaluate the prescribing patterns of metformin in patients with type 2 diabetes mellitus (T2DM) and determine the prevalence of contraindications to its use, especially renal impairment, and (ii) identify potential cases of lactic acidosis (LA) related to metformin usage. METHOD: This retrospective study reviewed all patients with a diagnosis of T2DM and taking metformin who was admitted to a major teaching hospital over an 8-month period. Data including demographics, medical conditions, medications at admission and discharge, and relevant pathology results were extracted from medical records. RESULTS: A total of 301 patients (209 medical patients, 92 surgical patients) taking metformin were included. According to guidelines, approximately 31% and 21% of patients received metformin inappropriately (in the presence of contraindications or in excessive dosage) at admission and discharge, respectively. At admission, 65 patients (n = 301, 21.6%) on metformin had at least one contraindication to its use, and 42 patients (n = 254, 16.5%) were prescribed an excessive dosage according to their renal function. At discharge, 43 patients (n = 301, 14.3%) continued on metformin with at least one contraindication and 21 patients (n = 191, 11%) received an excessive dosage according to their renal function. Four patients had evidence of LA (plasma lactate concentration > 5.0 mmol/L and pH < 7.35) without clinical diagnosis. CONCLUSION: Metformin was often used in patients with contraindications to its use, or in higher than recommended dosages. Reconsideration of the official prescribing information for metformin may be warranted as the risk of harm appears to be very low. PMID- 24405769 TI - Cystatin C triggers neuronal degeneration in a model of multiple system atrophy. AB - Multiple system atrophy is an intractable neurodegenerative disease caused by alpha-synuclein (alpha-syn) accumulation in oligodendrocytes and neurons. With the use of a transgenic mouse model overexpressing human alpha-syn in oligodendrocytes, we demonstrated that oligodendrocytic alpha-syn inclusions induce neuronal alpha-syn accumulation, resulting in progressive neuronal degeneration. The mechanism through which oligodendrocytic alpha-syn inclusions trigger neuronal alpha-syn accumulation leading to multiple system atrophy is unknown. In this study, we identified cystatin C, an oligodendrocyte-derived secretory protein that triggers alpha-syn up-regulation and insoluble alpha-syn accumulation, in neurons of the mouse central nervous system. Cystatin C was released by mouse oligodendrocytes overexpressing human alpha-syn, and extracellular cystatin C increased the expression of the endogenous alpha-syn gene in wild-type mouse neurons. These neurons then accumulate insoluble alpha syn and may undergo apoptosis. Cystatin C is a potential pathogenic signal triggering neurodegeneration in multiple system atrophy. PMID- 24405770 TI - Peripheral expression of MAPK pathways in Alzheimer's and Parkinson's diseases. AB - Alteration of mitogen-activated protein kinase pathways may cause aberrant protein phosphorylation and enhanced apoptosis in Alzheimer's disease (AD) and Parkinson's disease (PD). Increased susceptibility of lymphocytes to apoptosis has been reported in AD. To our knowledge this is the first study to investigate the expression and phosphorylation status of p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) in peripheral blood lymphocytes of 20 AD and 20 PD patients and 20 healthy controls using western blot analysis. Compared with controls, no significant difference of total p38MAPK or JNK levels were observed in AD and PD patients, whereas phosphorylated p38MAPK and phosphorylated JNK levels were significantly increased in the AD and PD groups (p<0.001). However, the increased levels of the two phosphorylated kinases in AD versus PD patients presented no significant difference. Interestingly, phosphorylated p38MAPK and phosphorylated JNK levels were positively correlated with disease duration (r=0.602, p=0.005 and r=0.561, p=0.010, respectively) and negatively correlated with the Mini Mental State Examination score (r=-0.664, p=0.001 and r=-0.578, p=0.008, respectively) in AD patients. No correlations between protein levels and clinical variables were found in PD patients. Investigation of peripheral changes in the expression of p38MAPK and JNK may lead to the development of innovative biomarkers of neurodegenerative diseases, particularly for AD. PMID- 24405768 TI - Giant axon formation in mice lacking Kell, XK, or Kell and XK: animal models of McLeod neuroacanthocytosis syndrome. AB - McLeod neuroacanthocytosis syndrome (MLS) is a rare X-linked multisystem disease caused by XK gene mutations and characterized by hematological and neurological abnormalities. XK, a putative membrane transporter, is expressed ubiquitously and is covalently linked to Kell, an endothelin-3-converting enzyme (ECE-3). Absence of XK results in reduction of Kell at sites where both proteins are coexpressed. To elucidate the functional roles of XK, Kell, and the XK-Kell complex associated with pathogenesis in MLS, we studied the pathology of the spinal cord, anterior roots, sciatic nerve, and skeletal muscle from knockout mouse models, using Kel( /-), Xk(-/-), Kel(-/-)Xk(-/-), and wild-type mice aged 6 to 18 months. A striking finding was that giant axons were frequently associated with paranodal demyelination. The pathology suggests probable anterograde progression from the spinal cord to the sciatic nerve. The neuropathological abnormalities were found in all three genotypes, but were more marked in the double-knockout Kel(-/-)Xk(-/ ) mice than in either Kel(-/-) or Xk(-/-) mice. Skeletal muscles from Xk(-/-) and Kel(-/-)Xk(-/-) mice showed mild abnormalities, but those from Kel(-/-) mice were similar to the wild type. The more marked neuropathological abnormalities in Kel( /-)Xk(-/-) mice suggest a possible functional association between XK and Kell in nonerythroid tissues. PMID- 24405771 TI - Therapeutic opinion on endovascular repair for mycotic aortic aneurysm. AB - BACKGROUND: Our aim in this study was to assess the feasibility of endovascular repair for mycotic aortic aneurysms (MAAs) and to provide a therapeutic opinion. METHODS: We retrospectively reviewed the records of 12 patients who underwent endovascular repair for MAAs between September 2006 and June 2011. RESULTS: Patients consisted of 9 men and 3 women, with a median age of 64.6 years (range 45-75 years). The aortic aneurysms were in the thoracic/thoracoabdominal aorta in 5 patients, juxtarenal aorta with visceral involvement in 2 patients, and infrarenal abdominal aorta in 5 patients. Blood cultures of 10 patients (83.3%) were positive for bacteria and showed Salmonella species (8 patients), Klebsiella pneumonia (1 patient), and Escherichia coli (1 patients). Eight patients with active sepsis or active bleeding underwent emergent endovascular repair because of unstable hemodynamics. Notably, 2 patients required adjuvant surgery for complete removal of infectious foci. No deaths occurred within 30 days after intervention. We recorded 2 late deaths: 1 patient died of progressive pneumonia on day 39 after intervention and the other died of liver failure on day 58 after intervention. Late complications were observed in 3 patients, 1 of whom needed an aortic revision for late prosthesis infection. The mean follow-up time was 24 +/- 19.7 months. CONCLUSIONS: Endovascular repair is a feasible therapeutic option for MAAs in that it can both stop bleeding and exclude the aneurysms. Although the aortic interventions performed were successful, the patients had an immunocompromised status and a difficult postoperative recovery. "Aggressive" surgical drainage may be necessary in some patients and may lead to a better outcome. PMID- 24405772 TI - Influence of criteria used in determining prevalence of metabolic syndrome (NCEP ATPIII versus IDF) in patients with intermittent claudication. AB - BACKGROUND: In patients with peripheral arterial disease, metabolic syndrome is associated with less favorable evolution of intermittent claudication. METHODS: The aims of this study were to determine the prevalence of metabolic syndrome in claudicant patients using the IDF and the NCEP-ATPIII criteria, and to assess the level of agreement between the two definitions. RESULTS: In this cross-sectional study, 200 consecutive patients with intermittent claudication (65% male) were classified with or without metabolic syndrome according both criteria. The kappa coefficient was used to assess the level of agreement. Prevalence of metabolic syndrome was 60.5% when using the NCEP-ATPIII definition and 66.5% when using the IDF definition (P = 0.088). Among men, the prevalence of MetS was 55.4% according to the NCEP-ATPIII and 63.1% according to the IDF (P = 0.110) and, among women, 70.0% according to the NCEP-ATPIII and 72.9% according to the IDF (P = 0.754). CONCLUSION: Although the prevalence rates were similar, the reliability analysis showed that the agreement was substantial only among women and just moderate in the total population and among men. PMID- 24405773 TI - Predictors of readmission to a psychiatry inpatient unit. AB - OBJECTIVE: To determine predictors of time to readmission to a general psychiatry inpatient unit. METHOD: Data from the Minimum Data Set-Mental Health (MDS-MH), a standardized assessment used to collect demographic and clinical information, were retrospectively reviewed from April 2006 through October 2008. A total of 758 patients were eligible for the study. A set of clinically relevant predictors was generated based on a literature review. A Cox regression model was applied to determine which variables were most predictive of shorter time to readmission, and their respective hazard ratios (HR). RESULTS: Covariates that were significantly associated with readmission (HR [95% CI]) included receiving a pass (3.48 [2.33, 5.17], p <= 0.0005), 1-2 psychiatric admissions in the past two years (15.63 [7.50, 32.55], p <= 0.0005), and more than 3 psychiatric admissions in the past two years (24.15 [11.58, 50.36], p <= 0.0005). Post hoc analysis indicated that those issued passes were more commonly male (57.1% vs. 43.9%, p=0.03), with a longer length of stay (25.4 +/- 21.2 days vs. 18.7 +/- 21.1 days, p=0.008), and higher GAF score (62.8 +/- 11.1 vs. 57.8 +/- 13.9, p=0.003), but were otherwise similar. CONCLUSIONS: The factors that were associated with reduced time to readmission were a history of previous admissions and receipt of a pass prior to discharge. These results suggest that while physicians may be able to identify patients at high risk of early readmission, issuing a pass may not fully mitigate this risk. There is a need for critical research evaluating the potential benefits of passes. PMID- 24405774 TI - Impulse control disorders in elderly patients. AB - OBJECTIVE: There is no epidemiological study on the prevalence of impulse control disorders (ICDs) in the elderly population. The studies on ICDs in elderly patients are limited and some of them are case reports about pathological gambling and kleptomania. The comorbidity of other psychiatric disorders makes diagnosis difficult and has negative effects on both treatment and the prognosis of ICDs. The aim of this study was to determine the prevalence of ICDs among elderly patients and to evaluate the related sociodemographic and clinical features. METHOD: A total of 76 patients aged 60 and over who have been referred to our outpatient clinics in a one-year period were included in the study. A demographic data form was completed. The Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) was used to determine axis I psychiatric disorders. The prevalence of ICDs was investigated by using the modified version of the Minnesota Impulse Disorders Interview (MIDI). Impulsivity was measured with the Barratt Impulsiveness Scale Version 11 (BIS-11). The Mini-Mental State Examination (MMSE) test was performed to evaluate the cognitive status of patients and to exclude the diagnosis of dementia. In addition, all patients completed Symptom Check List-90 (SCL-90). RESULTS: The prevalence rate of at least one comorbid ICD in our sample was 17%. When patients with a diagnosis of ICDs not otherwise specified (ICD-NOS) were included, the prevalence rate increased to 22.4%. The most common ICD was intermittent explosive disorder (15.8%), followed by pathological gambling (9.2%). The majority of the sample was men (54%), married (80%), had a high school education (51%), and mid-level socioeconomic status (79%). The only statistically significant difference between the sociodemographic characteristics of patients with or without ICDs was gender. The lifetime prevalence of ICDs was 34.1% in men and 8.6% in women. The prevalence of childhood conduct disorder was significantly higher in the group with ICD. There was no statistically significant difference in the number of suicide attempts, history of physical illness and family history of psychiatric disorders between the groups with or without ICDs. Comorbidity of alcohol/substance abuse was found to be 17.6% in patients with ICD whereas no cases were found in the group without ICD. CONCLUSION: The result of this study has shown that approximately one fifth of patients over 60years had at least one lifetime ICD comorbidity. The prevalence rates of ICDs seem to decrease with aging. The male gender and childhood conduct disorder are related with higher prevalence rates of ICDs in elderly. PMID- 24405775 TI - Executive functions and basic symptoms in adolescent antisocial behavior: a cross sectional study on an Italian sample of late-onset offenders. AB - Executive cognitive functions (ECFs) and other cognitive impairments, such as lower IQ and verbal deficits, have been associated with the pattern of antisocial and delinquent behavior starting in childhood (early-onset), but not with late onset antisocial behavior. Beyond objective measures of ECF, basic symptoms are prodromal, subjectively experienced cognitive, perceptual, affective, and social disturbances, associated with a range of psychiatric disorders, mainly with psychosis. The goal of the present study was to examine ECF and basic symptoms in a sample of late-onset juvenile delinquents. Two-hundred nine male adolescents (aged 15-20 years) characterized by a pattern of late-onset delinquent behavior with no antecedents of Conduct Disorder, were consecutively recruited from the Social Services of the Department of Juvenile Justice of the city of Messina (Italy), and compared with nonantisocial controls matched for age, educational level, and socio-demographic features on measures for ECF dysfunction and basic symptoms. Significant differences between late-onset offenders (completers=147) and control group (n=150) were found on ECF and basic symptoms measures. Chi square analysis showed that a significantly greater number of late-onset offending participants scored in the clinical range on several ECF measures. Executive cognitive impairment, even subtle and subclinical, along with subjective symptoms of cognitive dysfunction (basic symptom), may be contributing factor in the development and persistence of antisocial behaviors displayed by late-onset adolescent delinquents. The findings also suggest the need for additional research aimed to assess a broader range of cognitive abilities and specific vulnerability and risk factors for late-onset adolescent offenders. PMID- 24405776 TI - Editors reflections on 2013 and plans for new initiatives in 2014. PMID- 24405778 TI - Considerations for pre-clinical models and clinical trials of pluripotent stem cell-derived cardiomyocytes. AB - Pluripotent stem cells (PSCs) represent an appealing source from which to develop cell replacement therapies. Different initiatives have been launched to promote their development toward clinical applications. This article will review the main questions that should be considered before translating PSC-derived cardiomyocytes into clinical investigations, including the development of good manufacturing practice-level PSC lines, the development of efficient protocols to generate pure populations of cardiac myocytes, and the development of techniques to improve the retention and survival rate of transplanted cells. PMID- 24405777 TI - Behavioral changes following PCB 153 exposure in the spontaneously hypertensive rat - an animal model of Attention-Deficit/Hyperactivity Disorder. AB - BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a behavioral disorder affecting 3-5% of children. Although ADHD is highly heritable, environmental factors like exposure during early development to various toxic substances like polychlorinated biphenyls (PCBs) may contribute to the prevalence. PCBs are a group of chemical industrial compounds with adverse effects on neurobiological and cognitive functioning, and may produce behavioral impairments that share significant similarities with ADHD. The present study examined the relation between exposure to PCB 153 and changes in ADHD-like behavior in an animal model of ADHD, the spontaneously hypertensive rats (SHR/NCrl), and in Wistar Kyoto (WKY/NHsd) controls. METHODS: SHR/NCrl and WKY/NHsd, males and females, were orally given PCB 153 dissolved in corn oil at around postnatal day (PND) 8, 14, and 20 at a dosage of 1, 3 or 6 mg/kg bodyweight at each exposure. The control groups were orally administered corn oil only. The animals were behaviorally tested for exposure effects from PND 37 to 64 using an operant procedure. RESULTS: Exposure to PCB 153 was associated with pronounced and long-lasting behavioral changes in SHR/NCrl. Exposure effects in the SHR/NCrl depended on dose, where 1 mg/kg tended to reduce ADHD-like behaviors and produce opposite behavioral effects compared to 3 mg/kg and 6 mg/kg, especially in the females. In the WKY/NHsd controls and for the three doses tested, PCB 153 exposure produced a few specific behavioral changes only in males. The data suggest that PCB 153 exposure interacts with strain and sex, and also indicate a non-linear dose-response relation for the behaviors observed. CONCLUSIONS: Exposure to PCB 153 seems to interact with several variables including strain, sex, dose, and time of testing. To the extent that the present findings can be generalized to humans, exposure effects of PCB 153 on ADHD behavior depends on amount of exposure, where high doses may aggravate ADHD symptoms in genetically vulnerable individuals. In normal controls, exposure may not constitute an environmental risk factor for developing the full range of ADHD symptoms, but can produce specific behavioral changes. PMID- 24405779 TI - The mechanical and inflammatory low back pain (MIL) index: development and validation. AB - BACKGROUND: The purpose of this study was the development of a valid and reliable "Mechanical and Inflammatory Low Back Pain Index" (MIL) for assessment of non specific low back pain (NSLBP). This 7-item tool assists practitioners in determining whether symptoms are predominantly mechanical or inflammatory. METHODS: Participants (n = 170, 96 females, age = 38 +/- 14 years-old) with NSLP were referred to two Spanish physiotherapy clinics and completed the MIL and the following measures: the Roland Morris Questionnaire (RMQ), SF-12 and "Backache Index" (BAI) physical assessment test. For test-retest reliability, 37 consecutive patients were assessed at baseline and three days later during a non treatment period. Face and content validity, practical characteristics, factor analysis, internal consistency, discriminant validity and convergent validity were assessed from the full sample. RESULTS: A total of 27 potential items that had been identified for inclusion were subsequently reduced to 11 by an expert panel. Four items were then removed due to cross-loading under confirmatory factor analysis where a two-factor model yielded a good fit to the data (chi2 = 14.80, df = 13, p = 0.37, CFI = 0.98, and RMSEA = 0.029). The internal consistency was moderate (alpha = 0.68 for MLBP; 0.72 for ILBP), test-retest reliability high (ICC = 0.91; 95%CI = 0.88-0.93) and discriminant validity good for either MLBP (AUC = 0.74) and ILBP (AUC = 0.92). Convergent validity was demonstrated through similar but weak correlations between the ILBP and both the RMQ and BAI (r = 0.34, p < 0.001) and the MLBP and BAI (r = 0.38, p < 0.001). CONCLUSIONS: The MIL is a valid and reliable clinical tool for patients with NSLBP that discriminates between mechanical and inflammatory LBP. PMID- 24405780 TI - Selection for focal therapy: is it too early to judge? PMID- 24405781 TI - Effect of glutathione reductase knockdown in response to UVB-induced oxidative stress in human lung adenocarcinoma. AB - BACKGROUND: Glutathione reductase (GR) plays a critical role in the maintenance of physiological redox status in cells. However, the comprehensive investigations of GR-modulated oxidative stress have not been reported. METHODS: In the present study, we cultured a human lung adenocarcinoma line CL1-0 and its GR-knockdown derivative CL1-0DeltaGR to evaluate their differential responses to UVB irradiation. RESULTS: We identified 18 proteins that showed significant changes under UVB-irradiation in CL1-0DeltaGR cells rather than in CL1-0 cells. Several proteins involving protein folding, metabolism, protein biosynthesis and redox regulation showed significant changes in expression. CONCLUSIONS: In summary, the current study used a comprehensive lung adenocarcinoma-based proteomic approach for the identification of GR-modulated protein expression in response to UVB irradiation. To our knowledge, this is the first global proteomic analysis to investigate the role of GR under UVB-irradiation in mammalian cell model. PMID- 24405782 TI - Isolated cystic duct atresia. PMID- 24405783 TI - Upper abdominal exenteration: a life saving procedure following caustic ingestion. PMID- 24405784 TI - Association between seasonal affective disorder and subjective quality of the sleep/wake cycle in adolescents. AB - The relationship between seasonal affective disorder (SAD) and subjective quality of sleep/wake cycle in adolescents was explored. The Seasonal Pattern Assessment Questionnaire for Children and Adolescents (SPAQ-CA) and Mini Sleep Questionnaire (MSQ) were administered to 345 adolescents living in the city of Cesena (Emilia Romagna region, Italy) (299 females; age range: 14-18 years), to determine SAD and perceived quality of the sleep/wake cycle. The response rate was 92% for females and 90.2% for males. The MSQ includes two factors, sleep and wake, with lower scores corresponding to a lower quality of sleep and wake. The MSQ includes cut-off criteria to detect a good or bad sleep and wake quality. Adolescents with SAD (16 +/- 5.7) scored significantly lower than those not affected on wake factor (19.5 +/- 4.3), while no effect has been observed on sleep factor. SAD was the only one significant predictor of good/bad wake quality, while it did not reach significant level with reference to good/bad sleep quality. Present results are indications of a possible influence of SAD on wake quality and further studies are necessary to confirm them. PMID- 24405785 TI - Two examples of 'cuboid syndrome' with active bone pathology: why did manual therapy help? AB - Cuboid syndrome describes lateral midfoot pain localised to the cuboid bone. Previously reported case studies promoted joint mobilisation or manipulation interventions. The assumed mechanism was correction of a subtle disruption to the calcaneocuboid joint position. There is an absence of evidence for correction of joint position, but there is evidence of neurophysiological mechanisms for pain modulation. This case study reports on a patient who suffered two occurrences of cuboid syndrome on opposite feet, three years apart. With both occurrences, joint mobilisation achieved rapid and lasting resolution of severe pain and functional limitations. This occurred despite the presence of an active bone pathology at the symptomatic cuboid (demonstrated with nuclear imaging), which could represent a stress reaction, transient osteoporosis, ischaemic necrosis, infection or neoplasm. This case contributes three considerations for clinical reasoning and manual therapy research. 1. Active local bone pathology could exist in other patients with pain at the cuboid, and other conditions where symptoms resolve with joint mobilisation. 2. Rapid and lasting symptom resolution fits with a hypothesis that joint mobilisation acted to reverse neurological sensitisation. 3. Lasting symptom resolution may be clinically associated with manual therapy, but mechanisms extending beyond temporary analgesia are yet to be identified. PMID- 24405786 TI - Inter-clinician and intra-clinician reliability of force application during joint mobilization: a systematic review. AB - Joint mobilizations are commonly used by clinicians to decrease pain and restore joint arthrokinematics following musculoskeletal injury. The force applied during a joint mobilization treatment is subjective to the individual clinician but may have an effect on patient outcomes. The purpose of this systematic review was to critically appraise and synthesize the studies which examined the reliability of clinicians' force application during joint mobilization. A systematic search of PubMed and EBSCO Host databases from inception to March 1, 2013 was conducted to identify studies assessing the reliability of force application during joint mobilizations. Two reviewers utilized the Quality Appraisal of Reliability Studies (QAREL) assessment tool to determine the quality of included studies. The relative reliability of the included studies was examined through intraclass correlation coefficients (ICC) to synthesize study findings. All results were collated qualitatively with a level of evidence approach. A total of seven studies met the eligibility and were included. Five studies were included that assessed inter-clinician reliability, and six studies were included that assessed intra-clinician reliability. The overall level of evidence for inter-clinician reliability was strong for poor-to-moderate reliability (ICC = -0.04 to 0.70). The overall level of evidence for intra-clinician reliability was strong for good reliability (ICC = 0.75-0.99). This systematic review indicates there is variability in force application between clinicians but individual clinicians apply forces consistently. The results of this systematic review suggest innovative instructional methods are needed to improve consistency and validate the forces applied during of joint mobilization treatments. This is particularly evident for improving the consistency of force application across clinicians. PMID- 24405787 TI - Differential transcriptional profile of Corynebacterium pseudotuberculosis in response to abiotic stresses. AB - BACKGROUND: The completion of whole-genome sequencing for Corynebacterium pseudotuberculosis strain 1002 has contributed to major advances in research aimed at understanding the biology of this microorganism. This bacterium causes significant loss to goat and sheep farmers because it is the causal agent of the infectious disease caseous lymphadenitis, which may lead to outcomes ranging from skin injury to animal death. In the current study, we simulated the conditions experienced by the bacteria during host infection. By sequencing transcripts using the SOLiDTM 3 Plus platform, we identified new targets expected to potentiate the survival and replication of the pathogen in adverse environments. These results may also identify possible candidates useful for the development of vaccines, diagnostic kits or therapies aimed at the reduction of losses in agribusiness. RESULTS: Under the 3 simulated conditions (acid, osmotic and thermal shock stresses), 474 differentially expressed genes exhibiting at least a 2-fold change in expression levels were identified. Important genes to the infection process were induced, such as those involved in virulence, defence against oxidative stress, adhesion and regulation, and many genes encoded hypothetical proteins, indicating that further investigation of the bacterium is necessary. The data will contribute to a better understanding of the biology of C. pseudotuberculosis and to studies investigating strategies to control the disease. CONCLUSIONS: Despite the veterinary importance of C. pseudotuberculosis, the bacterium is poorly characterised; therefore, effective treatments for caseous lymphadenitis have been difficult to establish. Through the use of RNAseq, these results provide a better biological understanding of this bacterium, shed light on the most likely survival mechanisms used by this microorganism in adverse environments and identify candidates that may help reduce or even eradicate the problems caused by this disease. PMID- 24405788 TI - Subdivision of arthropod cap-n-collar expression domains is restricted to Mandibulata. AB - BACKGROUND: The monophyly of Mandibulata - the division of arthropods uniting pancrustaceans and myriapods - is consistent with several morphological characters, such as the presence of sensory appendages called antennae and the eponymous biting appendage, the mandible. Functional studies have demonstrated that the patterning of the mandible requires the activity of the Hox gene Deformed and the transcription factor cap-n-collar (cnc) in at least two holometabolous insects: the fruit fly Drosophila melanogaster and the beetle Tribolium castaneum. Expression patterns of cnc from two non-holometabolous insects and a millipede have suggested conservation of the labral and mandibular domains within Mandibulata. However, the activity of cnc is unknown in crustaceans and chelicerates, precluding understanding of a complete scenario for the evolution of patterning of this appendage within arthropods. To redress these lacunae, here we investigate the gene expression of the ortholog of cnc in Parhyale hawaiensis, a malacostracan crustacean, and two chelicerates: the harvestman Phalangium opilio, and the scorpion Centruroides sculpturatus. RESULTS: In the crustacean P. hawaiensis, the segmental expression of Ph-cnc is the same as that reported previously in hexapods and myriapods, with two distinct head domains in the labrum and the mandibular segment. In contrast, Po-cnc and Cs cnc expression is not enriched in the labrum of either chelicerate, but instead is expressed at comparable levels in all appendages. In further contrast to mandibulate orthologs, the expression domain of Po-cnc posterior to the labrum is not confined within the expression domain of Po-Dfd. CONCLUSIONS: Expression data from two chelicerate outgroup taxa suggest that the signature two-domain head expression pattern of cnc evolved at the base of Mandibulata. The observation of the archetypal labral and mandibular segment domains in a crustacean exemplar supports the synapomorphic nature of mandibulate cnc expression. The broader expression of Po-cnc with respect to Po-Dfd in chelicerates further suggests that the regulation of cnc by Dfd was also acquired at the base of Mandibulata. To test this hypothesis, future studies examining panarthropod cnc evolution should investigate expression of the cnc ortholog in arthropod outgroups, such as Onychophora and Tardigrada. PMID- 24405790 TI - Prevalence of hepatitis B and hepatitis C infection in Libya: results from a national population based survey. AB - BACKGROUND: Libya is one of the largest countries in Africa and has the longest coast in the Mediterranean basin facing southern Europe. High rates of prevalence of viral hepatitis have been observed in various regions in Africa, but the prevalence in Libya is not well documented. We report on a large-scale nationwide study that evaluated the epidemiology of hepatitis B and hepatitis C in Libya and assessed the risk factors involved. METHODS: A cross-sectional study was carried out in 2008 on 65,761 individuals all over Libya. The country was divided into 12 regions according to the population density and sampling within each region was carried out under the supervision of the National Centre for Prevention of Infectious Diseases. Serum samples were collected from both males and females of all ages in both urban and rural areas and tested for HBsAg for hepatitis B and anti-HCV antibody for hepatitis C. Prevalence rates were determined in regions and in different groups and correlated with different demographic and risk factors involved in the spread of these viruses. RESULTS: The prevalence of hepatitis B and hepatitis C viruses varied regionally across the country. The overall prevalence of hepatitis B was 2.2% (95% CI 2.1%-2.3%) and was higher among males than females (1.4:1.0). Hepatitis C virus (HCV) prevalence was 1.2% (95% CI 1.1-1.3) and it increased gradually after the age of 30 years (0.7-0.9% for < 30 years; 3.6% for >= 60 years). Prevalence of HBsAg was 0.8-0.9% below the age of 10 years, and higher but similar in older age groups (2.3-2.7%). There was an association between literacy and prevalence of hepatitis, particularly for HCV. Hospital admission, surgical operation, blood transfusion, and intravenous drug use were the main risk factors, and they were associated independently with a higher prevalence rate of viral hepatitis. CONCLUSIONS: Libya may be considered an area of low-intermediate endemicity for hepatitis B virus infection, with lower rates in young age groups, and an area of low endemicity for hepatitis C. The prevalence of hepatitis B and C across Libya is not homogeneous, with indications of the effect of the higher rates in some neighbouring countries. Libya should adopt full coverage national plans and guidelines to face the future consequences of viral hepatitis, particularly hepatitis C virus. PMID- 24405791 TI - Repair of large full-thickness cartilage defect by activating endogenous peripheral blood stem cells and autologous periosteum flap transplantation combined with patellofemoral realignment. AB - Minimal-invasive procedure and one-step surgery offer autologous mesenchymal stem cells derived from peripheral blood (PB-MSCs) a promising prospective in the field of cartilage regeneration. We report a case of a 19-year-old male athlete of kickboxing with ICRS grade IV chondral lesions at the 60 degrees region of lateral femoral trochlea, which was repaired by activating endogenous PB-MSCs plus autologous periosteum flap transplantation combined with correcting the patellofemoral malalignment. After a 7.5 year follow-up, the result showed that the patient returned to competitive kickboxing. Second-look under arthroscopy showed a smooth surface at 8 months postoperation. The IKDC 2000 subjective score, Lysholm score and Tegner score were 95, 98 and 9 respectively at the final follow up. CT and MRI evaluations showed a significant improvement compared with those of pre-operation. PMID- 24405792 TI - A novel technique, dynamic intraligamentary stabilization creates optimal conditions for primary ACL healing: a preliminary biomechanical study. AB - BACKGROUND: Anterior cruciate ligament (ACL) rupture is a common lesion. Current treatment emphasizes arthroscopic ACL reconstruction via a graft, although this approach is associated with potential drawbacks. A new method of dynamic intraligamentary stabilization (DIS) was subjected to biomechanical analysis to determine whether it provides the necessary knee stability for optimal ACL healing. METHODS: Six human knees from cadavers were harvested. The patellar tendon, joint capsule and all muscular attachments to the tibia and femur were removed, leaving the collateral and the cruciate ligaments intact. The knees were stabilized and the ACL kinematics analyzed. Anterior-posterior (AP) stability measurements evaluated the knees in the following conditions: (i) intact ACL, (ii) ACL rupture, (iii) ACL rupture with primary stabilization, (iv) primary stabilization after 50 motion cycles, (v) ACL rupture with DIS, and (vi) DIS after 50 motion cycles. RESULTS: After primary suture stabilization, average AP laxity was 3.2 mm, which increased to an average of 11.26 mm after 50 movement cycles. With primary ACL stabilization using DIS, however, average laxity values were consistently lower than those of the intact ligament, increasing from an initial AP laxity of 3.00 mm to just 3.2 mm after 50 movement cycles. CONCLUSIONS: Dynamic intraligamentary stabilization established and maintained close contact between the two ends of the ruptured ACL, thus ensuring optimal conditions for potential healing after primary reconstruction. The present ex vivo findings show that the DIS technique is able to restore AP stability of the knee. PMID- 24405793 TI - Highly resilient coping entails better perceived health, high social support and low morning cortisol levels in parents of children with autism spectrum disorder. AB - The negative consequences of caring for people with developmental disabilities have been widely described. However, the ability to bounce back from the stress derived from care situations has been less studied. Those caregivers who have shown this ability are considered as resilient. This study aims to evaluate the relationship between resilience and self-reported health and cortisol awakening response (CAR) in a sample of caregivers of people with autism spectrum disorders (ASD). It also aims to evaluate the role of social support as a mediator in the association between resilience and health. Caregivers with higher resilience show better perceived health, lower morning cortisol levels, and less area under the curve with respect to ground (AUCg). Social support was positively related to resilience and mediated the relationship between resilience and perceived health. This mediating effect was not found in the association between resilience and CAR. Resilience could be a protective factor that modulates the negative consequences of chronic stress in the care context. Social support could be an important variable mediating the effects of resilience on health outcomes in caregivers. All these results must be considered when implementing effective psychological programs for helping caregivers. PMID- 24405789 TI - Fatty acid synthesis in Escherichia coli and its applications towards the production of fatty acid based biofuels. AB - The idea of renewable and regenerative resources has inspired research for more than a hundred years. Ideally, the only spent energy will replenish itself, like plant material, sunlight, thermal energy or wind. Biodiesel or ethanol are examples, since their production relies mainly on plant material. However, it has become apparent that crop derived biofuels will not be sufficient to satisfy future energy demands. Thus, especially in the last decade a lot of research has focused on the production of next generation biofuels. A major subject of these investigations has been the microbial fatty acid biosynthesis with the aim to produce fatty acids or derivatives for substitution of diesel. As an industrially important organism and with the best studied microbial fatty acid biosynthesis, Escherichia coli has been chosen as producer in many of these studies and several reviews have been published in the fields of E. coli fatty acid biosynthesis or biofuels. However, most reviews discuss only one of these topics in detail, despite the fact, that a profound understanding of the involved enzymes and their regulation is necessary for efficient genetic engineering of the entire pathway. The first part of this review aims at summarizing the knowledge about fatty acid biosynthesis of E. coli and its regulation, and it provides the connection towards the production of fatty acids and related biofuels. The second part gives an overview about the achievements by genetic engineering of the fatty acid biosynthesis towards the production of next generation biofuels. Finally, the actual importance and potential of fatty acid-based biofuels will be discussed. PMID- 24405794 TI - The effectiveness of aripiprazole in the management of problem behaviour in people with intellectual disabilities, developmental disabilities and/or autistic spectrum disorder--a systematic review. AB - The management of problem behaviours (PB) in individuals with intellectual disabilities (ID), developmental disabilities (DD) and/or autistic spectrum disorders (ASD) can be challenging. Antipsychotic medications are commonly prescribed where other strategies have failed. A systematic review (SR) was conducted to establish the research evidence for the efficacy of aripiprazole in the management of PB in adults and children with ID, DD and/or ASD. Although included studies supported the efficacy of aripiprazole for this indication, the overall quality of studies was poor. Of the 20 studies included in this systematic review there were only two randomised controlled trials (RCTs) on children with ASD and/or ID/DD, both of which were conducted by the pharmaceutical company that manufactures aripiprazole, and it is not clear whether a number of same participants were included in both RCTs. One of the RCTs was extended into an open label long term follow up, which showed that aripiprazole's efficacy lasted over 52 weeks and the adverse effects were tolerable. Four studies were open label prospective studies, 11 were retrospective case reports which included four single case reports, and two were prospective case series. Most studies reported adverse effects from aripiprazole in the form of weight gain, increased appetite, sedation, tiredness, drooling and tremor. However, aripiprazole improved serum prolactin level in some participants and overall did not show any adverse effect on QTc interval. There is a need for more carefully designed RCTs into the use of aripiprazole in the management of PB in people with ID/DD and/or ASD, which should be carried out independent of pharmaceutical companies. PMID- 24405795 TI - Counting contraception. PMID- 24405796 TI - Comparison of interventions for pain control with tenaculum placement: a randomized clinical trial. AB - OBJECTIVE: Although previous studies have demonstrated that a variety of local anesthetics are effective to decrease pain associated with tenaculum placement, no studies directly compare an injection with a topical anesthetic. The objective of this study was therefore to compare mean pain scores with tenaculum placement after an intracervical lidocaine injection or topical lidocaine gel. STUDY DESIGN: A randomized, single-blinded trial of women presenting for office gynecologic procedures that required a tenaculum. Women aged 18 years or older were randomized to receive either a 1% lidocaine intracervical injection or topical application of 2% lidocaine gel to the cervix immediately prior to tenaculum placement. The primary outcome was pain at the time of tenaculum placement, measured on a 100 mm Visual Analog Scale. Secondary outcomes included pain with the intervention and satisfaction with tenaculum placement. RESULTS: Seventy-four women were enrolled and randomized; 35 subjects in each group met criteria for analysis. The two groups had similar socio-demographic characteristics. Women who received the injection had lower mean pain levels at tenaculum placement [12.3 mm (S.D. 17.4 mm) versus 36.6 mm (S.D. 23.0 mm), p<.001] but higher mean pain levels with study drug application [20.4 mm (S.D. 19.4 mm) versus 5.9 mm (S.D. 8.6 mm), p<.001]. Satisfaction with tenaculum placement was similar for the two groups. CONCLUSION: Mean pain with tenaculum placement is lower after receiving a lidocaine injection than after receiving a topical lidocaine gel. Satisfaction with tenaculum placement is similar with both interventions. PMID- 24405797 TI - Buccal misoprostol for treatment of fetal death at 14-28 weeks of pregnancy: a double-blind randomized controlled trial. AB - OBJECTIVE: To assess whether buccal misoprostol is effective for the treatment of intrauterine fetal death. STUDY DESIGN: This double-blind randomized trial was conducted at five tertiary-level hospitals in the United States and Vietnam. One hundred fifty-three women with an intrauterine fetal death at 14-28 weeks of pregnancy received either 100 mcg buccal misoprostol or 200 mcg buccal misoprostol every 6 h for a maximum of 8 doses. The main outcome measure was the fetal-placental delivery rate within 48 hours of prostaglandin commencement without any additional intervention. RESULTS: Most of the women (140/153) were recruited at the study site in Vietnam. Expulsion of both fetus and placenta within 48 hours of prostaglandin commencement without any additional interventions occurred in 61.8% (47/76) of women receiving misoprostol 100 mcg and 77.9% (60/77) of women receiving misoprostol 200 mcg. The 200 mcg dose was significantly more effective than the 100 mcg dose at expelling the fetus and placenta within 48 h [RR 0.68 (95% CI: 0.50-0.92; p=.03)]. The mean time to expulsion was significantly shorter using the 200 mcg dose (18.5+/-11.9 h) than the 100 mcg dose (23.9+/-12.5 h) (p=.02). Most women in both groups found the procedure satisfactory or very satisfactory (100 mcg: 76.7% (56/73); 200 mcg: 89.5% (68/76) [RR 0.86 (95% CI: 0.74-1.00)]. CONCLUSION: Buccal misoprostol is an effective method for medical induction of labor after intrauterine fetal demise. A 200 mcg dose is significantly more effective than 100 mcg for evacuating the uterus within 48h. The treatment is highly acceptable to women. IMPLICATIONS: Administration of 200 mcg buccal misoprostol every six hours is an effective and acceptable method to effect the delivery of a demised fetus at 14-28 weeks that can be feasibly implemented in a wide variety of settings. PMID- 24405799 TI - Changes at the BCLA. PMID- 24405798 TI - Reduction in infection-related mortality since modifications in the regimen of medical abortion. AB - BACKGROUND: From 2001 to March 2006 Planned Parenthood health centers throughout the United States provided medical abortion by a regimen of oral mifepristone followed 24-48 h later by vaginal misoprostol. In response to concerns about serious infections, in early 2006 Planned Parenthood changed the route of misoprostol administration to buccal and required either routine antibiotic coverage or universal screening and treatment for chlamydia; in July 2007, Planned Parenthood began requiring routine antibiotic coverage for all medical abortions. METHODS: We performed a retrospective analysis of Planned Parenthood cases assessing the rates of mortality caused by infection following medical abortion during a time period when misoprostol was administered vaginally (2001 through March 2006), as compared with the rate from April 2006 to the end of 2012 after a change to buccal administration of misoprostol and after initiation of new infection-reduction strategies. RESULTS: The mortality rate dropped significantly in the 81-month period after the joint change to (1) buccal misoprostol replacing vaginal misoprostol and (2) either sexually transmitted infection (STI) screening or routine preventative antibiotic coverage (15 month period) or universal routine preventative antibiotic coverage as part of the medical abortion (66-month period), from 1.37/100,000 to 0.00/100,000, P=.013 (difference=1.37/100,000, 95% CI 0.47-4.03 per 100,000). CONCLUSION: The infection-caused mortality rate following medical abortion declined by 100% following a change from vaginal to buccal administration of misoprostol combined with screen-and-treat or, far more commonly, routine antibiotic coverage. SIGNIFICANCE: Deaths from infection following medical abortion declined to zero after a change in the regimen. PMID- 24405800 TI - Adherence and outcomes of patients prescribed dabigatran (Pradaxa) in routine clinical practice. AB - AIM: To explore and detail clinical experiences of dabigatran, a novel anticoagulant, after it became available in New Zealand in July 2011. METHODS: A cohort of patients was recruited from Hutt Hospital and the two largest primary care practices in the Hutt Valley region. They were included if they took at least one dose of dabigatran between July 2011 and April 2012. Participants undertook a questionnaire 3-12 months after starting dabigatran assessing adherence, perceived side-effects and complications. Those presenting due to an adverse event were analysed separately. RESULTS: Of 102 patients identified, 92 were recruited to this study. At a median of 8 months, 70% of participants were still taking dabigatran, significantly lower than in the RE-LY trial at 12 months (P = 0.0002). The commonest reason given for discontinuation was gastrointestinal (GI) side-effects. Rates of serious adverse outcomes on dabigatran therapy were relatively low. Patients expressed polarised comments, both positive and negative, regarding their experiences of dabigatran. CONCLUSIONS: A high rate of discontinuation of dabigatran, mainly due to GI symptoms, was observed. There does not appear to be any specific predictor of dabigatran tolerance. When prescribed according to guidelines, rates of serious adverse events associated with dabigatran appear to be low. PMID- 24405801 TI - Comparative analysis of gene transcripts for cell signaling receptors in bone marrow-derived hematopoietic stem/progenitor cell and mesenchymal stromal cell populations. AB - INTRODUCTION: Knowing the repertoire of cell signaling receptors would provide pivotal insight into the developmental and regenerative capabilities of bone marrow cell (BMC)-derived hematopoietic stem/progenitor cells (HSPCs) and bone marrow mesenchymal stromal cells (BMMSCs). METHODS: Murine HSPCs were enriched from fluorescence-activated cell sorting (FACS)-sorted Lin-c-Kit+Sca-1+ BMCs isolated from the tibia and femoral marrow compartments. Purified BMMSCs (CD73+, CD90+, CD105+, and CD45-, CD34-, CD31-, c-Kit-) with extensive self-renewal potential and multilineage differentiation capacity (into different mesodermal cell lineages including osteocytes, chrondrocytes, adipocytes) were derived from adherent BMC cultures after CD45+ cell depletion. Adherent colony-forming cells were passaged two to three times and FACS analysis was used to assess cell purity and validate cell-specific surface marker phenotype prior to experimentation. Gene transcripts for a number of cell signaling molecules were assessed using a custom quantitative real-time RT-PCR low-density microarray (94 genes; TaqMan(r) technology). RESULTS: We identified 16 mRNA transcripts that were specifically expressed in BMC-derived HSPC (including Ptprc, c-Kit, Csf3r, Csf2rb2, Ccr4, Cxcr3 and Tie-1), and 14 transcripts specifically expressed in BMMSCs (including Pdgfra, Ddr2, Ngfr, Mst1r, Fgfr2, Epha3, and Ephb3). We also identified 27 transcripts that were specifically upregulated (>=2-fold expression) in BMMSCs relative to HSPCs (Axl, Bmpr1a, Met, Pdgfrb, Fgfr1, Mertk, Cmkor1, Egfr, Epha7, and Ephb4), and 19 transcripts that were specifically upregulated in HSPCs relative to BMMSCs (Ccr1, Csf1r, Csf2ra, Epor, IL6ra, and IL7r). Eleven transcripts were equally expressed (<2-fold upregulation) in HSPCs and BMMSCs (Flt1, Insr, Kdr, Jak1, Agtrl1, Ccr3, Ednrb, Il3ra, Hoxb4, Tnfrsf1a, and Abcb1b), whilst another seven transcripts (Epha6, Epha8, Musk, Ntrk2, Ros1, Srms, and Tnk1) were not expressed in either cell population. CONCLUSIONS: We demonstrate that besides their unique immunophenotype and functional differences, BMC-derived HSPCs and BMMSCs have different molecular receptor signaling transcript profiles linked to cell survival, growth, cell differentiation status, growth factor/cytokine production and genes involved in cell migration/trafficking/adhesion that may be critical to maintain their pluripotency, plasticity, and stem cell function. PMID- 24405802 TI - Psychosocial factors as predictors of quality of life in chronic Portuguese patients. AB - BACKGROUND: Chronic illnesses are diseases of long duration and generally of slow progression. They cause significant quality of life impairment. The aim of this study was to analyse psychosocial predictors of quality of life and of subjective well-being in chronic Portuguese patients. METHODS: Chronic disease patients (n = 774) were recruited from central Portuguese Hospitals. Participants completed self-reported questionnaires assessing socio-demographic, clinical, psychosocial and outcome variables: quality of life (HRQL) and subjective well-being (SWB). MANCOVA analyses were used to test psychosocial factors as determinants of HRQL and SWB. RESULTS: After controlling for socio-demographic and clinical variables, results showed that dispositional optimism, positive affect, spirituality, social support and treatment adherence are significant predictors of HRQL and SWB. Similar predictors of quality of life, such as positive affect, treatment adherence and spirituality, were found for subgroups of disease classified by medical condition. CONCLUSIONS: The work identifies psychosocial factors associated with quality of life. The predictors for the entire group of different chronic diseases are similar to the ones found in different chronic disease subgroups: positive affect, social support, treatment adherence and spirituality. Patients with more positive affect, additional social support, an adequate treatment adherence and a feel-good spirituality, felt better with the disease conditions and consequently had a better quality of life. This study contributes to understanding and improving the processes associated with quality of life, which is relevant for health care providers and chronic diseases support. PMID- 24405803 TI - Earth before life. AB - BACKGROUND: A recent study argued, based on data on functional genome size of major phyla, that there is evidence life may have originated significantly prior to the formation of the Earth. RESULTS: Here a more refined regression analysis is performed in which 1) measurement error is systematically taken into account, and 2) interval estimates (e.g., confidence or prediction intervals) are produced. It is shown that such models for which the interval estimate for the time origin of the genome includes the age of the Earth are consistent with observed data. CONCLUSIONS: The appearance of life after the formation of the Earth is consistent with the data set under examination. PMID- 24405804 TI - Rheumatoid arthritis and incident fracture in women: a case-control study. AB - BACKGROUND: To examine fracture incidence in women with rheumatoid arthritis (RA) for an entire geographical region of south-eastern Australia. METHODS: Women aged 35 years and older, resident in the Barwon Statistical Division (BSD) and clinically diagnosed with RA 1994-2001 were eligible for inclusion as cases (n = 1,008). The control population (n = 172,422) comprised the entire female BSD population aged 35 years and older, excluding those individuals identified as cases. Incident fractures were extracted from the prospective Geelong Osteoporosis Study Fracture Grid. We calculated rate ratios (RR) and 95% confidence intervals (CI) to compare the age-adjusted rate of fracture between the RA and non-RA populations, and used a chi-square test to compare proportions of fractures between women with and without RA, and a two-sided Mann-Whitney U test to examine age-differences. RESULTS: Among 1,008 women with RA, 19 (1.9%) sustained a fracture, compared to 1,981 fractures sustained by the 172,422 women without RA (1.2%). Fracture rates showed a trend for being greater among women diagnosed with RA (age-adjusted RR 1.43, 95%CI 0.98-2.09, p = 0.08). Women with RA sustained vertebral fractures at twice the expected frequency, whereas hip fractures were underrepresented in the RA population (p < 0.001). RA status was not associated with the likelihood of sustaining a fracture at sites adjacent to joints most commonly affected by RA (p = 0.22). CONCLUSION: Given that women with RA have a greater risk of fracture compared to women without RA, these patients may be a suitable target population for anti-resorptive agents; however, larger studies are warranted. PMID- 24405806 TI - Cellular sources of pathogenic and protective TNF and experimental strategies based on utilization of TNF humanized mice. AB - Over the years, tumor necrosis factor (TNF) has been implicated in the pathogenesis of various inflammatory conditions and TNF antagonists are highly efficient in treatment of multiple autoimmune diseases. However, it has been shown that various cellular sources of TNF exhibit distinct and non-redundant functions that can be either deleterious or beneficial. This suggests that systemic TNF blockade, in addition to neutralization of pathogenic TNF, may abrogate its protective functions, resulting in adverse effects. Here we review the data on cellular sources of pathogenic and protective TNF and then discuss an experimental system based on humanized mice to study the role of cell-type specific TNF ablation during various disease models for development of cell-type specific TNF blockade. PMID- 24405805 TI - Comparison of human adult stem cells from adipose tissue and bone marrow in the treatment of experimental autoimmune encephalomyelitis. AB - INTRODUCTION: While administration of ex vivo culture-expanded stem cells has been used to study immunosuppressive mechanisms in multiple models of autoimmune diseases, less is known about the uncultured, nonexpanded stromal vascular fraction (SVF)-based therapy. The SVF is composed of a heterogeneous population of cells and has been used clinically to treat acute and chronic diseases, alleviating symptoms in a range of tissues and organs. METHODS: In this study, the ability of human SVF cells was compared with culture-expanded adipose stem cells (ASCs) and bone-derived marrow stromal cells (BMSCs) as a treatment of myelin oligodendrocyte glycoprotein (35-55)-induced experimental autoimmune encephalitis in C57Bl/6J mice, a well-studied multiple sclerosis model (MS). A total of 1*106 BMSCs, ASCs, or SVF cells were administered intraperitoneally concomitantly with the induction of disease. Mice were monitored daily for clinical signs of disease by three independent, blinded investigators and rated on a scale of 0 to 5. Spinal cords were obtained after euthanasia at day 30 and processed for histological staining using luxol fast blue, toluidine blue, and hematoxylin and eosin to measure myelin and infiltrating immune cells. Blood was collected from mice at day 30 and analyzed by enzyme-linked immunosorbent assay to measure serum levels of inflammatory cytokines. RESULTS: The data indicate that intraperitoneal administration of all cell types significantly ameliorates the severity of disease. Furthermore, the data also demonstrate, for the first time, that the SVF was as effective as the more commonly cultured BMSCs and ASCs in an MS model. All cell therapies also demonstrated a similar reduction in tissue damage, inflammatory infiltrates, and sera levels of IFNgamma and IL-12. While IFNgamma levels were reduced to comparable levels between treatment groups, levels of IL-12 were significantly lower in SVF-treated than BMSC-treated or ASC treated mice. CONCLUSIONS: Based on these data, it is evident that SVF cells have relevant therapeutic potential in an animal model of chronic MS and might represent a valuable tool for stem cell-based therapy in chronic inflammatory disease of the central nervous system. SVF offers advantages of direct and rapid isolation procedure in a xenobiotic-free environment. PMID- 24405807 TI - Fibro-osseous pseudotumor of the digit presenting as an ulcerated lesion: a case report. AB - Fibro-osseous pseudotumor of the digit is rare benign lesion of subcutaneous tissue which is thought to be reactive process as a result of repeated trauma. We report a case of an ulcerated lesion of skin of middle finger, clinically thought to be leishmaniasis which after punch biopsy followed by excision turned out to be fibrosseous pseudotumor. Diagnosis of fibro-osseous pseudotumor requires immense precision as it can clinically mimic unungal exostosis and can sometimes be misinterpreted clinically and radiologically as myositis ossificans. We suggested an algorithimic approach for histopathologic assessment of fibro osseous soft tissue lesions with evaluation of both stromal and osseous components. Bland fibroblastic stroma, mature osseous component with prominent osteoblastic rimming and absence of zonation pattern will support the diagnosis of fibro-osseous pseudotumor especially if located at a superficial and distal location. PMID- 24405808 TI - Beyond cleaved small RNA targets: unraveling the complexity of plant RNA degradome data. AB - BACKGROUND: Degradation is essential for RNA maturation, turnover, and quality control. RNA degradome sequencing that integrates a modified 5'-rapid amplification of cDNA ends protocol with next-generation sequencing technologies is a high-throughput approach for profiling the 5'-end of uncapped RNA fragments on a genome-wide scale. The primary application of degradome sequencing has been to identify the truncated transcripts that result from endonucleolytic cleavage guided by microRNAs or small interfering RNAs. As many pathways are involved in RNA degradation, degradome data should contain other RNA species besides the cleavage remnants of small RNA targets. Nevertheless, no systematic approaches have been established to explore the hidden complexity of plant degradome. RESULTS: Through analyzing Arabidopsis and rice RNA degradome data, we recovered 11 short motifs adjacent to predominant and abundant uncapped 5'-ends. Uncapped ends associated with several of these short motifs were more prevalent than those targeted by most miRNA families especially in the 3' untranslated region of transcripts. Through genome-wide analysis, five motifs showed preferential accumulation of uncapped 5'-ends at the same position in Arabidopsis and rice. Moreover, the association of uncapped 5'-ends with a CA-repeat motif and a motif recognized by Pumilio/Fem-3 mRNA binding factor (PUF) proteins was also found in non-plant species, suggesting that common mechanisms are present across species. Based on these motifs, potential sources of RNA ends that constitute degradome data were proposed and further examined. The 5'-end of small nucleolar RNAs could be precisely captured by degradome sequencing. Position-specific enrichment of uncapped 5'-ends was seen upstream of motifs recognized by several RNA binding proteins especially for the binding site of PUF proteins. False uncapped 5'-ends produced from capped transcripts through non-specific PCR amplification were common artifacts among degradome datasets. CONCLUSIONS: The complexity of plant RNA degradome data revealed in this study may contribute to the alternative applications of degradome in RNA research. PMID- 24405809 TI - The pathology of silent otitis media: a predecessor to tympanogenic meningitis in infants. AB - OBJECTIVE: To determine the association of bacteria embedded within a fibrous matrix in the middle and inner ear in infants with tympanogenic meningitis. METHODS: Thirty-one cases with meningitis from the human temporal bone collection at the University of Minnesota were screened to select those with tympanogenic meningitis. Inclusion criteria for tympanogenic meningitis were acute meningitis with histopathological evidence of chronic otitis media, and no other source of infection. The presence of labyrinthitis and pathologic changes such as granulation tissue, fibrosis, cholesterol granuloma, cholesteatoma, tympanic membrane perforation, tympanosclerosis, and the type of effusion were noted. The extent and location of bacteria embedded in a fibrous matrix were also explored. RESULTS: Seventeen temporal bones, from nine cases that included two females and seven males, ranging in age from five to twenty-three months, met our criteria of tympanogenic meningitis. Eighty two percent of these temporal bones had bacteria within the fibrous matrices (BFM). BFM were located in one anatomical region in one temporal bone and multiple anatomic regions in sixteen temporal bones. The most common locations were the areas near the oval and round windows. They were also commonly seen in the epitympanum, facial recess, and supratubal recess. BFM within the inner ear were observed in the scala tympani and modiolus in the middle and basal turns of the cochleae of nine temporal bones. In one of these temporal bones, BFM were seen in the internal auditory canal. Labyrinthitis was seen in all ears. The tympanic membrane was intact in all cases. BFM were not seen in three temporal bones from two patients. In one case only one side was available for study. CONCLUSIONS: Our findings show an association between the presence of BFM in the ear with chronic pathologic changes and tympanogenic meningitis. Potential pathways of bacteria from the middle ear include hematogeous spread and/or direct spread to dura through the tympanic tegmen, and/or to the inner ear through the oval and round windows, and from there to the modiolus and the meninges. Chronic pathologic changes in the middle ear behind an intact tympanic membrane and the lack of ear symptoms may result in potentially serious sequelae and complications in infant age groups. There should be a heightened awareness of this condition. PMID- 24405810 TI - Letter to the editor regarding 'hearing impairment, severe hyperbilirubinemia and heliotherapy'. PMID- 24405811 TI - Characterisation of interleukin-10 expression on different vascular structures in allergic nasal mucosa. AB - BACKGROUND: Interleukin-10 (IL-10) is a negative regulator of immune responses and was previously shown to be expressed by human nasal endothelial cells, while the adhesion molecule MECA-79 plays a role in trans-endothelial migration of immune competent cells. In this study we investigate the relationship between endothelial IL-10 and MECA-79 expression to address the question whether immune competent cells could be affected at the mucosal entry site. METHODS: Nasal turbinate biopsies were taken from house dust mite allergic patients, before and after nasal allergen provocation. Subsequent slides of biopsies were stained for IL10, MECA-79, CD34, and IL10-Receptor. Capillaries, arteries/veins, and sinusoids were evaluated separately. RESULTS: 90% of sinusoids are IL-10 positive and all sinusoids are negative for MECA-79, while 4.8% of capillaries are positive for IL-10, and 2.2% are positive for MECA-79. Although about 47% of arteries/veins are positive for IL-10 and 57.1% are positive for MECA-79, only about 20% are positive for both markers. Furthermore, we showed that the myo fibroblasts surrounding all sinusoids stain positive for IL10R. CONCLUSIONS: IL10 expression on vascular structures is not related to MECA expression for sinusoids and capillaries and only partly related on arteries/veins, however sinusoidal endothelial IL10 expression is always seen in combination with IL-10R expression of sinusoidal myo-fibroblasts. PMID- 24405812 TI - Design, synthesis and ex-vivo release studies of colon-specific polyphosphazene anticancer drug conjugates. AB - Colon-specific azo based polyphosphazene-anticancer drug conjugates (11-18) have been synthesized and evaluated by ex-vivo release studies. The prepared polyphosphazene drug conjugates (11-18) are stable in acidic (pH=1.2) buffer which showed that these polymer drug conjugates are protected from acidic environment which is the primary requirement of colon specific targeted drug delivery. The ex-vivo release profiles of polyphosphazene drug conjugates (11-18) have been performed in the presence as well as in the absence of rat cecal content. The results showed that more than 89% of parent drugs (methotrexate and gemcitabine) are released from polymeric backbone of polyphosphazene drug conjugates (14 and 18) having n-butanol (lipophilic moiety). The in-vitro cytotoxicity assay has also been performed which clearly indicated that these polymeric drug conjugates are active against human colorectal cancer cell lines (HT-29 and COLO 320 DM). The drug release kinetic study demonstrated that Higuchi's equation is found to be best fitted equation which showed that release of drug from polymeric backbone as square root of time dependent process based on non-fickian diffusion. Therefore, the synthesized polyphosphazene azo based drug conjugates of methotrexate and gemcitabine are the potential candidates for colon targeted drug delivery system with minimal undesirable side effects. PMID- 24405813 TI - Synthesis and evaluation of Strychnos alkaloids as MDR reversal agents for cancer cell eradication. AB - Natural products represent the fourth generation of multidrug resistance (MDR) reversal agents that resensitize MDR cancer cells overexpressing P-glycoprotein (Pgp) to cytotoxic agents. We have developed an effective synthetic route to prepare various Strychnos alkaloids and their derivatives. Molecular modeling of these alkaloids docked to a homology model of Pgp was employed to optimize ligand protein interactions and design analogues with increased affinity to Pgp. Moreover, the compounds were evaluated for their (1) binding affinity to Pgp by fluorescence quenching, and (2) MDR reversal activity using a panel of in vitro and cell-based assays and compared to verapamil, a known inhibitor of Pgp activity. Compound 7 revealed the highest affinity to Pgp of all Strychnos congeners (Kd=4.4MUM), the strongest inhibition of Pgp ATPase activity, and the strongest MDR reversal effect in two Pgp-expressing cell lines. Altogether, our findings suggest the clinical potential of these synthesized compounds as viable Pgp modulators justifies further investigation. PMID- 24405814 TI - CCL3L1 copy number, CCR5 genotype and susceptibility to tuberculosis. AB - BACKGROUND: Tuberculosis is a major infectious disease and functional studies have provided evidence that both the chemokine MIP-1alpha and its receptor CCR5 play a role in susceptibility to TB. Thus by measuring copy number variation of CCL3L1, one of the genes that encode MIP-1alpha, and genotyping a functional promoter polymorphism -2459A > G in CCR5 (rs1799987) we investigate the influence of MIP-1alpha and CCR5, independently and combined, in susceptibility to clinically active TB in three populations, a Peruvian population (n = 1132), a !Xhosa population (n = 605) and a South African Coloured population (n = 221). The three populations include patients with clinically diagnosed pulmonary TB, as well as other, less prevalent forms of extrapulmonary TB. METHODS AND RESULTS: Copy number of CCL3L1 was measured using the paralogue ratio test and exhibited ranges between 0-6 copies per diploid genome (pdg) in Peru, between 0-12 pdg in !Xhosa samples and between 0-10 pdg in South African Coloured samples. The CCR5 promoter polymorphism was observed to differ significantly in allele frequency between populations (*A; Peru f = 0.67, !Xhosa f = 0.38, Coloured f = 0.48). CONCLUSIONS: The case-control association studies performed however find, surprisingly, no evidence for an influence of variation in genes coding for MIP 1alpha or CCR5 individually or together in susceptibility to clinically active TB in these populations. PMID- 24405816 TI - White matter integrity in premanifest and early Huntington's disease is related to caudate loss and disease progression. AB - INTRODUCTION: Huntington's disease (HD) is associated with progressive loss of caudate and white matter volume and integrity. Our aim was to systematically assess interactions between these changes and genetic markers of disease progression; we are not aware of previous studies in which this has been explicitly tested. METHODS: Tract-based spatial statistics were used to assess: (a) differences between the white matter diffusion metrics (fractional anisotropy and mean diffusivity) of 17 premanifest and 19 early manifest HD gene carriers and 21 controls, and (b) the relationships between diffusion metrics, caudate and total white matter volume, and disease burden score and CAG repeat length. Caudate and total white matter volumes were quantified using FIRST and SIENAX respectively. Multiple regression analysis was used to assess which of the imaging metrics predicted disease severity in the HD subjects. RESULTS: Diffusion metrics were significantly altered in premanifest and early HD gene carriers in comparison with controls throughout the white matter skeleton. Correlations between diffusion and volumetric metrics and disease progression were also present. Together, caudate volume and mean white matter fractional anisotropy and mean diffusivity predicted disease burden score in the HD subjects. CONCLUSIONS: The diffusion properties of white matter are extensively altered in HD, and are associated with markers of HD severity, and with caudate and white matter volumes. The correlation between diffusion metrics and white matter volume is stronger in HD subjects than in controls, but there is no such significant interaction for the correlation between diffusion and caudate volume: we propose that many of the changes in white matter diffusion in HD occur as a 'normal' physiological response to pathological caudate volume loss. We have defined the extent to which mean white matter fractional anisotropy, white matter volume and caudate volume are associated with disease burden score. PMID- 24405815 TI - Regional white matter microstructure in very preterm infants: predictors and 7 year outcomes. AB - The aims of this study were to investigate regional white matter microstructural differences between very preterm (VPT) (<30 weeks' gestational age and/or <1250 g) and full term (FT) (>=37 weeks' gestational age) infants at term corrected age with diffusion tensor imaging, and to explore perinatal predictors of diffusion measures, and the relationship between regional diffusion measures and neurodevelopmental outcomes at age 7 years in VPT children. Mean (MD) (p = .003), axial (AD) (p = .008), and radial diffusivity (RD) (p = .003) in total white matter were increased in VPT compared with FT infants, with similar fractional anisotropy (FA) in the two groups. There was little evidence that group-wise differences were specific to any of the 8 regions studied for each hemisphere. Perinatal white matter abnormality and intraventricular hemorrhage (grade III or IV) were associated with increased diffusivity in the white matter of VPT infants. Higher white matter diffusivity measures of the inferior occipital and cerebellar region at term-equivalent age were associated with increased risk of impairments in motor and executive function at 7 years in VPT children, but there was little evidence for associations with IQ or memory impairment. In conclusion, myelination is likely disrupted or delayed in VPT infants, especially those with perinatal brain abnormality (BA). Altered diffusivity at term-equivalent age helps explain impaired functioning at 7 years. This study defines the nature of microstructural alterations in VPT infant white matter, assists in understanding the associated risk factors, and is the first study to reveal an important link between inferior occipital and cerebellar white matter disorganization in infancy, and executive and motor functioning 7 years later. PMID- 24405817 TI - Robust segmentation methods with an application to aortic pulse wave velocity calculation. AB - Aortic stiffness has proven to be an important diagnostic and prognostic factor of many cardiovascular diseases, as well as an estimate of overall cardiovascular health. Pulse wave velocity (PWV) represents a good measure of the aortic stiffness, while the aortic distensibility is used as an aortic elasticity index. Obtaining the PWV and the aortic distensibility from magnetic resonance imaging (MRI) data requires diverse segmentation tasks, namely the extraction of the aortic center line and the segmentation of aortic regions, combined with signal processing methods for the analysis of the pulse wave. In our study non contrasted MRI images of abdomen were used in healthy volunteers (22 data sets) for the sake of non-invasive analysis and contrasted magnetic resonance (MR) images were used for the aortic examination of Marfan syndrome patients (8 data sets). In this research we present a novel robust segmentation technique for the PWV and aortic distensibility calculation as a complete image processing toolbox. We introduce a novel graph-based method for the centerline extraction of a thoraco-abdominal aorta for the length calculation from 3-D MRI data, robust to artifacts and noise. Moreover, we design a new projection-based segmentation method for transverse aortic region delineation in cardiac magnetic resonance (CMR) images which is robust to high presence of artifacts. Finally, we propose a novel method for analysis of velocity curves in order to obtain pulse wave propagation times. In order to validate the proposed method we compare the obtained results with manually determined aortic centerlines and a region segmentation by an expert, while the results of the PWV measurement were compared to a validated software (LUMC, Leiden, the Netherlands). The obtained results show high correctness and effectiveness of our method for the aortic PWV and distensibility calculation. PMID- 24405818 TI - Judging the differences between women's attractiveness and health: is there really a difference between judgments made by men and women? AB - Perceived weight in the face and body size have been shown to be significant predictors of both attractiveness and health. Studies looking at the relationship between attractiveness, perceived health, and perceived weight in faces have found that individuals prefer a lower weight for attractiveness than for apparent health. Here, a group of twenty-four Asian participants were allowed to manipulate the apparent body mass indices (BMIs) of full-length photographs of young Malaysian Chinese women to enhance their perceived healthiness and attractiveness. Results showed that both men and women differentiated between attractiveness and health by preferring a lower BMI for attractiveness than health, suggesting a consistency in the preferred ideal BMI for attractiveness and healthy appearance across both sexes. Results also suggested that BMI provides important cues to judgments of attractive and healthy appearance. PMID- 24405820 TI - Evolutionary history of plant microRNAs. AB - microRNAs (miRNAs) are short noncoding regulatory genes that perform important roles in plant development and physiology. With the increasing power of next generation sequencing technologies and the development of bioinformatic tools, there has been a dramatic increase in the number of studies surveying the miRNAomes of plant species, which has led to an explosion in the number of described miRNAs. Unfortunately, very many of these new discoveries have been incompletely annotated and thus fail to discriminate genuine miRNAs from small interfering RNAs (siRNAs), fragments of longer RNAs, and random sequence. We review the published repertoire of plant miRNAs, discriminating those that have been correctly annotated. We use these data to explore prevailing hypotheses on the tempo and mode of miRNA evolution within the plant kingdom. PMID- 24405819 TI - Pleiotropic effects of cancer cells' secreted factors on human stromal (mesenchymal) stem cells. AB - INTRODUCTION: Studying cancer tumors' microenvironment may reveal a novel role in driving cancer progression and metastasis. The biological interaction between stromal (mesenchymal) stem cells (MSCs) and cancer cells remains incompletely understood. Herein, we investigated the effects of tumor cells' secreted factors as represented by a panel of human cancer cell lines (breast (MCF7 and MDA-MB 231); prostate (PC-3); lung (NCI-H522); colon (HT-29) and head & neck (FaDu)) on the biological characteristics of MSCs. METHODS: Morphological changes were assessed using fluorescence microscopy. Changes in gene expression were assessed using Agilent microarray and qRT-PCR. GeneSpring 12.1 and DAVID tools were used for bioinformatic and signaling pathway analyses. Cell migration was assessed using a transwell migration system. SB-431542, PF-573228 and PD98059 were used to inhibit transforming growth factor beta (TGFbeta), focal adhesion kinase (FAK), and mitogen activated protein kinase kinase (MAPKK) pathways, respectively. Interleukin-1beta (IL1beta) was measured using ELISA. RESULTS: MSCs exposed to secreted factors present in conditioned media (CM) from FaDu, MDA-MB-231, PC-3 and NCI-H522, but not from MCF7 and HT-29, developed an elongated, spindle-shaped morphology with bipolar processes. In association with phenotypic changes, genome wide gene expression and bioinformatics analysis revealed an enhanced pro inflammatory response of those MSCs. Pharmacological inhibitions of FAK and MAPKK severely impaired the pro-inflammatory response of MSCs to tumor CM (approximately 80% to 99%, and 55% to 88% inhibition, respectively), while inhibition of the TGFbeta pathway was found to promote the pro-inflammatory response (approximately 3-fold increase). In addition, bioinformatics and pathway analysis of gene expression data from tumor cell lines combined with experimental validation revealed tumor-derived IL1beta as one mediator of the pro-inflammatory phenotype observed in MSCs exposed to tumor CM. CONCLUSIONS: Our data revealed tumor-derived IL1beta as one mediator of the pro-inflammatory response in MSCs exposed to tumor CM, which was found to be positively regulated by FAK and MAPK signaling and negatively regulated by TGFbeta signaling. Thus, our data support a model where MSCs could promote cancer progression through becoming pro inflammatory cells within the cancer stroma. PMID- 24405821 TI - Elderly male complaining of life-threatening oral swelling. PMID- 24405822 TI - Arterial aging impacts on the risk of late-life depressive and cognitive disorders. Is it time for prevention? PMID- 24405823 TI - Sex-related differences in understanding the prognosis of dementia. PMID- 24405824 TI - Elevated inflammatory markers in diabetes-related dementia. PMID- 24405825 TI - No correlation between Alzheimer's disease and risk of hepatocellular carcinoma in older people: an observation in Taiwan. PMID- 24405826 TI - Diaper with cushion buttock. PMID- 24405827 TI - Incident delirium from interdisciplinary team care. PMID- 24405828 TI - Inhibition of mesenchymal stromal cells by pre-activated lymphocytes and their culture media. AB - INTRODUCTION: Despite having a proven immunosuppressive potential in vitro, human mesenchymal stromal cells (MSCs) are reported to display variable efficacy in vivo and, in fact, their proven benefit in the clinical practice is still limited and controversial. METHODS: The interplay between clinical grade MSCs and pre activated donor lymphocytes or selected lymphocyte subsets was studied in vitro. The kinetics of MSC growth and viability was evaluated by adhesion-dependent changes of culture plate impedance and biochemically by a colorimetric assay. Activation of natural killer (NK) cells was assessed as well, using a flow cytometry assay. RESULTS: A strong inhibition of MSC growth was rapidly induced by the addition of pre-activated lymphocytes but not of resting lymphocytes. Inhibition seems not to be attributable to a single cell population, as similar results can be obtained by depleting NK cells or by using either selected CD4+ or CD8+ lymphocytes. In addition, conditioned medium (CM) from activated lymphocytes was able to inhibit MSC growth in a dose-dependent manner. Furthermore, licensing with IFN-gamma partially protected MSCs from pre-activated lymphocytes but not from their CM. These results suggest an inhibitory role of lymphocyte-activation derived substances. However, the identification of a single molecule responsible for MSC inhibition remained elusive, even if preliminary experiments showed that ATP and, to a lesser extent, TNF-alpha might play a role. CONCLUSIONS: These results suggest that survival of MSCs can be affected by soluble mediators released by activated lymphocytes. Thus it can be hypothesized that MSC immunosuppressive action in vivo could be impaired by ongoing immune activation through the release of inflammatory mediators. PMID- 24405830 TI - Short-term changes in median nerve neural tension after a suboccipital muscle inhibition technique in subjects with cervical whiplash: a randomised controlled trial. AB - OBJECTIVES: To assess the immediate effect of a suboccipital muscle inhibition (SMI) technique on: (a) neck pain, (b) elbow extension range of motion during the upper limb neurodynamic test of the median nerve (ULNT-1), and (c) grip strength in subjects with cervical whiplash; and determine the relationships between key variables. DESIGN: Randomised, single-blind, controlled clinical trial. SETTING: Faculty of Nursing, Physiotherapy and Podiatry, University of Seville, Spain. PARTICIPANTS: Forty subjects {mean age 34 years [standard deviation (SD) 3.6]} with Grade I or II cervical whiplash and a positive response to the ULNT-1 were recruited and distributed into two study groups: intervention group (IG) (n=20) and control group (CG) (n=20). INTERVENTIONS: The IG underwent the SMI technique for 4minutes and the CG received a sham (placebo) intervention. Measures were collected immediately after the intervention. MAIN OUTCOME MEASURES: The primary outcome was elbow range of motion during the ULNT-1, measured with a goniometer. The secondary outcomes were self-perceived neck pain (visual analogue scale) and free-pain grip strength, measured with a digital dynamometer. RESULTS: The mean baseline elbow range of motion was 116.0 degrees (SD 10.2) for the CG and 130.1 degrees (SD 7.8) for the IG. The within-group comparison found a significant difference in elbow range of motion for the IG [mean difference -15.4 degrees , 95% confidence interval (CI) -20.1 to -10.6; P=0.01], but not for the CG (mean difference -4.9 degrees , 95% CI -11.8 to 2.0; P=0.15). In the between-group comparison, the difference in elbow range of motion was significant (mean difference -10.5 degrees , 95% CI -18.6 to -2.3; P=0.013), but the differences in grip strength (P=0.06) and neck pain (P=0.38) were not significant. CONCLUSION: The SMI technique has an immediate positive effect on elbow extension in the ULNT 1. No immediate effects on self-perceived cervical pain or grip strength were observed. PMID- 24405829 TI - Small-scale transcriptomics reveals differences among gonadal stages in Asian seabass (Lates calcarifer). AB - BACKGROUND: The Asian seabass (Lates calcarifer) is a protandrous hermaphrodite that typically matures as a male at approximately 2-4 years of age and then changes sex in subsequent years. Although several sexual maturation stages have been described histologically for both testis and ovary, the underlying gene expression profiles remain lacking. The development of a gene expression platform is therefore necessary to improve our understanding of the gonad development of this cultured teleost species. METHODS: Thirty Asian seabass gonads were collected from farms in Singapore, examined histologically and staged according to their sex and gonadal maturation status. Partial coding sequences of 24 sex related genes were cloned using degenerate primers and were sequenced. Additional 13 cDNA sequences were obtained through next-generation sequencing. A real-time qPCR was then performed using the microfluidic-based Fluidigm 48.48 Dynamic arrays. RESULTS: We obtained 17 ovaries and 13 testes at various stages of sexual maturation. Of the 37 genes that were tested, 32 (86%) showed sexually dimorphic expression. These genes included sex-related genes, sox9, wt1, amh, nr5a2, dmrt1 and nr0b1, which showed testis-enhanced expression similar to other vertebrate species. Known male- and female-enhanced germ cells markers, which were established from studies in other species, similarly showed testis- and ovary enhanced expression, respectively, in the Asian seabass. Three pro-Wnt signaling genes were also upregulated in the ovary, consistent with existing studies that suggested the role of Wnt signaling in ovarian differentiation in teleosts and mammals. The expression patterns of genes involved in steroidogenesis, retinoic acid metabolism, apoptosis and NF-kappaB signaling were also described. We were able to classify gonads according to sex and gonadal maturation stages, based on their small-scale transcriptomic profiles, and to uncover a wide variation in expression profiles among individuals of the same sex. CONCLUSIONS: The analysis of a selected set of genes related to reproduction and in sufficient number of individuals using a qPCR array can elucidate new insights into the molecular mechanisms involved in Asian seabass gonad development. Given the conservation of gene expression patterns found in this study, these insights may also help us draw parallels with other teleosts. PMID- 24405831 TI - Whole-genome sequencing of matched primary and metastatic hepatocellular carcinomas. AB - BACKGROUND: To gain biological insights into lung metastases from hepatocellular carcinoma (HCC), we compared the whole-genome sequencing profiles of primary HCC and paired lung metastases. METHODS: We used whole-genome sequencing at 33X-43X coverage to profile somatic mutations in primary HCC (HBV+) and metachronous lung metastases (> 2 years interval). RESULTS: In total, 5,027-13,961 and 5,275-12,624 somatic single-nucleotide variants (SNVs) were detected in primary HCC and lung metastases, respectively. Generally, 38.88-78.49% of SNVs detected in metastases were present in primary tumors. We identified 65-221 structural variations (SVs) in primary tumors and 60-232 SVs in metastases. Comparison of these SVs shows very similar and largely overlapped mutated segments between primary and metastatic tumors. Copy number alterations between primary and metastatic pairs were also found to be closely related. Together, these preservations in genomic profiles from liver primary tumors to metachronous lung metastases indicate that the genomic features during tumorigenesis may be retained during metastasis. CONCLUSIONS: We found very similar genomic alterations between primary and metastatic tumors, with a few mutations found specifically in lung metastases, which may explain the clinical observation that both primary and metastatic tumors are usually sensitive or resistant to the same systemic treatments. PMID- 24405832 TI - Comparison of publication trends in dermatology among Japan, South Korea and Mainland China. AB - BACKGROUND: We previously showed that the number of publications in dermatology is increasing year by year, and positively correlates with improved economic conditions in mainland China, a still developing Asian country. However, the characteristics of publications in dermatology departments in more developed Asian countries such as Japan and South Korea are unknown. METHODS: In the present study, publications from 2003 through 2012 in dermatology in Japan, South Korea and mainland China were characterized. All data were obtained from http://www.pubmed.com. RESULTS: Dermatology departments in Japan published 4,094 papers, while mainland China and South Korea published 1528 and 1,758 articles, respectively. 48% of articles from dermatology in Japan were original research and 36% were case reports; The number of publications in Japan remained stable over time, but the overall impact factors per paper increased linearly over the last 10 year period (p < 0.05). In mainland China, 67% of articles from dermatology were original research, while 19% were case reports; The number of publications and their impact factors per paper increased markedly. In South Korea, 65% of articles from dermatology were original research and 20% were case reports. The impact factors per paper remained unchanged, despite of the fact that the number of publications increased over the last 10 year period (r2 = 0.6820, p = 0.0032). Only mainland China showed a positive correlation of the number of publications with gross domestic product per capita during this study period. CONCLUSIONS: These results suggest that the total number of publications in dermatology correlates with economic conditions only in developing country, but not in more developed countries in Asia. The extent of economic development could determine both the publication quantity and quality. PMID- 24405834 TI - Absence of low back pain in the general population followed fortnightly over one year with automated text messages. AB - BACKGROUND: Over one year, the majority of patients with low back pain (LBP) from the secondary care sector could not report a single week without LBP and few could report a non-episode, defined as at least one month without LBP. Presumably, non-episodes would be more common in the general population. The aim of this study was to assess the usefulness of this definition of '"non-episodes", by studying their presence over one year in the general population. Specifically, we wanted to: 1) determine the prevalence of non-episodes, 2) identify the proportion of study participants who could be classified as being in a non episode at the end of the observation period, and 3) estimate the proportion of participants classified as having at least two separate non-episodes. METHODS: Danes, aged 49/50, who previously participated in a population-based study on LBP received fortnightly automated text (SMS) messages over one year. Each time, participants reported the number of days with LBP in the preceding fortnight. Fortnights with 0 days of LBP were defined as 'zero-fortnights' and two such fortnights in a row (one month) were defined as a 'non-episode'. Estimates are reported as percentages with their 95% confidence intervals in brackets. RESULTS: Two hundred and ninety-three people were invited to participate. Of these, 16 declined participation and 16 were excluded because they failed to return their text message at least 20 of the 26 times, leaving 261 in the current analyses. Of these, 11% (2-22) never reported a zero-fortnight. In all, 83% (78-88) had at least one non-episode throughout the study period and the proportion of participants classified as being in a non-episode at the end of the study was 59% (53-65). The percentage of individuals with at least two non-episodes was 52% (46 58). CONCLUSIONS: It is possible to differentiate people from the general population as having or not having episodes of LBP using the definition of absence of LBP over one month as the measure. Non-episodes were far more common in the general population than in the secondary care sector, suggesting it to be a potentially useful definition in research. PMID- 24405833 TI - A randomised controlled trial of the clinical effectiveness, safety and cost effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis (SYCAMORE Trial). AB - BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA are at risk of inflammation of the uvea in the eye (uveitis). Overall, 20% to 25% of paediatric uveitis is associated with JIA. Major risk factors for development of uveitis in JIA are oligoarticular pattern of arthritis, an age at onset of arthritis of less than seven years of age, and antinuclear antibody positivity. In the initial stages of mild to moderate inflammation the uveitis is asymptomatic. This has led to current practice of screening all children with JIA for uveitis. Approximately 12% to 38% of patients with JIA develop uveitis in seven years following onset of arthritis. In 30% to 50% of children with JIA-associated uveitis structural complications are present at diagnosis. Furthermore about 50% to 75% of those with severe uveitis will eventually develop visual impairment secondary to ocular complications such as cataract and glaucoma. Defining the severity of inflammation and structural complications in uveitis patients is now possible following Standardised Uveitis Nomenclature (SUN) guidelines, and modified to incorporate the consensus of end point and outcome criteria into the design of randomised trials. Despite current screening and therapeutic options (pre biologics) 10% to 15% of children with JIA-associated uveitis may develop bilateral visual impairment and certified legally blind. To date, there remains no controlled trial evidence of benefits of biologic therapy. METHODS/DESIGN: This study will randomise 154 patients aged 2 to 18 years with active JIA associated uveitis (despite methotrexate (MTX) treatment for at least 12 weeks). All participants will be treated for 18 months, with follow up of 3 years from randomisation (continuing on MTX throughout). All participants will receive a stable dose of MTX and in addition either adalimumab (20 mg/0.8 ml for patients<30 kg or 40 mg/0.8 ml for patients weighing 30 kg or more, subcutaneous (s/c) injection every 2 weeks based on body weight), or placebo (0.8 ml as appropriate according to body weight) s/c injection every 2 weeks. DISCUSSION: This is the first randomised controlled trial that will assess the clinical effectiveness, safety and cost effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis. TRIAL REGISTRATION: ISRCTN10065623. PMID- 24405835 TI - Anomalous left anterior descending coronary artery from the pulmonary artery--the role of cardiac MRI. PMID- 24405836 TI - Increased mean platelet volume in patients with coronary artery disease and its seasonal variation. PMID- 24405837 TI - Ablation of premature ventricular contractions originating from the left ventricular septum. PMID- 24405838 TI - Spironolactone, not furosemide, improved insulin resistance in patients with chronic heart failure. AB - BACKGROUND/OBJECTIVES: Insulin resistance plays an important role in the pathophysiology in chronic heart failure (CHF). Diuretics generally have harmful effects on glucose metabolism, however, the effect of mineral corticoid receptor blockers on insulin resistance in CHF is unclear. This study aimed to evaluate the effects of the aldosterone blocker spironolactone, in comparison with furosemide, on insulin resistance in CHF patients. METHODS: The effect of spironolactone (25mg/day) and furosemide (20mg/day) on IR for 16 weeks each was analyzed in 16 CHF patients using a double-blind, placebo-controlled, randomized cross-over study design. RESULTS: Plasma BNP and left ventricular ejection fraction were improved with both treatments (furosemide: p=0.02 and p=0.009, respectively, spironolactone: p=0.03 and p=0.007, respectively). Fasting plasma glucose was not changed; however, plasma insulin levels decreased and insulin sensitivity (by homeostasis model assessment: HOMA-IR) improved with spironolactone as compared to furosemide (p<0.0005). TNF-alpha, IL-6 and MCP-1 decreased with spironolactone (p=0.002, p=0.02 and p=0.02 vs. baseline, respectively), but not with furosemide. Matrix metalloproteinase (MMP)-2 and MMP 9 were decreased with spironolactone (p=0.003 and p=0.04 vs. baseline, respectively), but not furosemide. Changes in TNF-alpha, IL-6 and MCP-1 levels after spironolactone treatment were significantly correlated with changes in HOMA IR (r=0.61, r=0.55 and r=0.65, respectively; p=0.01, p=0.03 and p=0.01, respectively). Furthermore, changes in MMP-2 and MMP-9 levels were significantly correlated with changes in HOMA-IR (r=0.58 and r=0.58, respectively; p=0.02 and p=0.02, respectively). CONCLUSIONS: Spironolactone, not furosemide, improved insulin resistance in CHF patients probably by the inhibition of inflammatory cytokines and MMPs. PMID- 24405839 TI - Partial clip detachment and posterior mitral leaflet perforation after mitraclip implantation. PMID- 24405841 TI - Quantification of GABAA receptors in the rat brain with [(123)I]Iomazenil SPECT from factor analysis-denoised images. AB - PURPOSE: In vivo imaging of GABAA receptors is essential for the comprehension of psychiatric disorders in which the GABAergic system is implicated. Small animal SPECT provides a modality for in vivo imaging of the GABAergic system in rodents using [(123)I]Iomazenil, an antagonist of the GABAA receptor. The goal of this work is to describe and evaluate different quantitative reference tissue methods that enable reliable binding potential (BP) estimations in the rat brain to be obtained. METHODS: Five male Sprague-Dawley rats were used for [(123)I]Iomazenil brain SPECT scans. Binding parameters were obtained with a one-tissue compartment model (1TC), a constrained two-tissue compartment model (2TCc), the two-step Simplified Reference Tissue Model (SRTM2), Logan graphical analysis and analysis of delayed-activity images. In addition, we employed factor analysis (FA) to deal with noise in data. RESULTS: BPND obtained with SRTM2, Logan graphical analysis and delayed-activity analysis was highly correlated with BPF values obtained with 2TCc (r=0.954 and 0.945 respectively, p<0.0001). Equally significant correlations were found between values obtained with 2TCc and SRTM2 in raw and FA-denoised images (r=0.961 and 0.909 respectively, p<0.0001). Scans of at least 100min are required to obtain stable BPND values from raw images while scans of only 70min are sufficient from FA-denoised images. These images are also associated with significantly lower standard errors of 2TCc and SRTM2 BP values. CONCLUSION: Reference tissue methods such as SRTM2 and Logan graphical analysis can provide equally reliable BPND values from rat brain [(123)I]Iomazenil SPECT. Acquisitions, however, can be much less time-consuming either with analysis of delayed activity obtained from a 20-minute scan 50min after tracer injection or with FA-denoising of images. PMID- 24405840 TI - Generation of SNP datasets for orangutan population genomics using improved reduced-representation sequencing and direct comparisons of SNP calling algorithms. AB - BACKGROUND: High-throughput sequencing has opened up exciting possibilities in population and conservation genetics by enabling the assessment of genetic variation at genome-wide scales. One approach to reduce genome complexity, i.e. investigating only parts of the genome, is reduced-representation library (RRL) sequencing. Like similar approaches, RRL sequencing reduces ascertainment bias due to simultaneous discovery and genotyping of single-nucleotide polymorphisms (SNPs) and does not require reference genomes. Yet, generating such datasets remains challenging due to laboratory and bioinformatical issues. In the laboratory, current protocols require improvements with regards to sequencing homologous fragments to reduce the number of missing genotypes. From the bioinformatical perspective, the reliance of most studies on a single SNP caller disregards the possibility that different algorithms may produce disparate SNP datasets. RESULTS: We present an improved RRL (iRRL) protocol that maximizes the generation of homologous DNA sequences, thus achieving improved genotyping-by sequencing efficiency. Our modifications facilitate generation of single-sample libraries, enabling individual genotype assignments instead of pooled-sample analysis. We sequenced ~1% of the orangutan genome with 41-fold median coverage in 31 wild-born individuals from two populations. SNPs and genotypes were called using three different algorithms. We obtained substantially different SNP datasets depending on the SNP caller. Genotype validations revealed that the Unified Genotyper of the Genome Analysis Toolkit and SAMtools performed significantly better than a caller from CLC Genomics Workbench (CLC). Of all conflicting genotype calls, CLC was only correct in 17% of the cases. Furthermore, conflicting genotypes between two algorithms showed a systematic bias in that one caller almost exclusively assigned heterozygotes, while the other one almost exclusively assigned homozygotes. CONCLUSIONS: Our enhanced iRRL approach greatly facilitates genotyping-by-sequencing and thus direct estimates of allele frequencies. Our direct comparison of three commonly used SNP callers emphasizes the need to question the accuracy of SNP and genotype calling, as we obtained considerably different SNP datasets depending on caller algorithms, sequencing depths and filtering criteria. These differences affected scans for signatures of natural selection, but will also exert undue influences on demographic inferences. This study presents the first effort to generate a population genomic dataset for wild-born orangutans with known population provenance. PMID- 24405842 TI - Both Treg cells and Tconv cells are defective in the Myasthenia gravis thymus: roles of IL-17 and TNF-alpha. AB - Myasthenia gravis (MG) is an autoimmune disease in which the thymus frequently presents follicular hyperplasia and signs of inflammation and T cells display a defect in suppressive regulation. Defects in a suppressive assay can indicate either the defective function of Treg cells or the resistance of Tconv cells to suppression by Treg cells. The aim of this study was to determine which cells were responsible for this defect and to address the mechanisms involved. We first performed cross-experiment studies using purified thymic Treg cells and Tconv cells from controls (CTRL) and MG patients. We confirmed that MG Treg cells were defective in suppressing CTRL Tconv proliferation, and we demonstrated for the first time that MG Tconv cells were resistant to Treg cell suppression. The activation of MG Tconv cells triggered a lower upregulation of FoxP3 and a higher upregulation of CD4 and CD25 than CTRL cells. To investigate the factors that could explain these differences, we analyzed the transcriptomes of purified thymic Treg and Tconv cells from MG patients in comparison to CTRL cells. Many of the pathways revealed by this analysis are involved in other autoimmune diseases, and T cells from MG patients exhibit a Th1/Th17/Tfh signature. An increase in IL 17-related genes was only observed in Treg cells, while increases in IFN-gamma, IL-21, and TNF-alpha were observed in both Treg and Tconv cells. These results were confirmed by PCR studies. In addition, the role of TNF-alpha in the defect in Tconv cells from MG patients was further confirmed by functional studies. Altogether, our results indicate that the immunoregulatory defects observed in MG patients are caused by both Treg cell and Tconv cell impairment and involve several pro-inflammatory cytokines, with TNF-alpha playing a key role in this process. The chronic inflammation present in the thymus of MG patients could provide an explanation for the escape of thymic T cells from regulation in the MG thymus. PMID- 24405843 TI - Relationship between parenchymal involvement and obstructive sleep apnea in subjects with sarcoidosis. AB - INTRODUCTION: Increased obstructive sleep apnea (OSA) incidence has been reported in sarcoidosis. However, no research has been conducted to determine the relation between OSA and pulmonary parenchymal involvement in sarcoidosis. OBJECTIVES: We investigated OSA frequency and association between pulmonary parenchymal involvement and OSA in sarcoidosis. Additionally, relationship between lung functions and polysomnography data was assessed. METHODS: The study enrolled sarcoidosis subjects with or without pulmonary parenchymal involvement. Spirometry, diffusion capacity, 6-min walking test, arterial blood gases, chest X ray, Epworth sleepiness scale (ESS) and polysomnography were performed. Subjects with body mass index (BMI) >=30 or significant upper airway pathologies that might cause OSA were excluded. RESULTS: A total of 29 sarcoidosis subjects (15 with, 14 without parenchymal involvement) with mean age 43.8 +/- 9.4 years were analyzed. Twenty-seven of them were female. BMI was 26.8 +/- 4.2 kg/m(2) . Mean forced expiratory volume 1 s (FEV1 ) was 97.89% +/- 20.21%, and forced vital capacity (FVC) was 102.86 +/- 18.14%. ESS score was 4 +/- 1.6. OSA was identified in 51.7% (n = 15) of subjects. Apnea-hypopnea index (AHI) was 16.16 +/- 19/h and oxygen desaturation index (ODI) was 22.3 +/- 25.99 among subjects with OSA. Sleep apnea related with rapid eye movement was present in 40% of OSA subjects. AHI and ODI were higher among sarcoidosis subjects with parenchymal involvement (P = 0.019, P = 0.026). OSA frequency was higher in the group with parenchymal involvement, but the difference was not statistically significant (n = 10/15, %66 vs n = 5/14, %35). FEV1 and FVC were not related with AHI and ODI. CONCLUSION: We found a high rate of OSA in sarcoidosis. There was a trend of high OSA frequency in sarcoidosis subjects with parenchymal involvement. PMID- 24405844 TI - A novel MIP gene mutation associated with autosomal dominant congenital cataracts in a Chinese family. AB - BACKGROUND: The major intrinsic protein gene (MIP), also known as MIP26 or AQP0, is a member of the water-transporting aquaporin family, which plays a critical role in the maintenance of lifelong lens transparency. To date, several mutations in MIP (OMIM 154050) have been linked to hereditary cataracts in humans. However, more pathogenic mutations remain to be identified. In this study, we describe a four-generation Chinese family with a nonsense mutation in MIP associated with an autosomal dominant congenital cataract (ADCC), thus expanding the mutational spectrum of this gene. METHODS: A large four-generation Chinese family affected with typical Y-suture cataracts combined with punctuate cortical opacities and 100 ethnically matched controls were recruited. Genomic DNA was extracted from peripheral blood leukocytes to analyze congenital cataract-related candidate genes. Effects of the sequence change on the structure and function of proteins were predicted by bioinformatics analysis. RESULTS: Direct sequencing of MIP in all affected members revealed a heterozygous nucleotide exchange c.337C>T predicting an arginine to a stop codon exchange (p.R113X). The substitution co segregated well in all the affected individuals in the family and was not found in unaffected members or in the 100 unrelated healthy controls. Bioinformatics analysis predicted that the mutation affects the secondary structure and function of the MIP protein. CONCLUSIONS: We identified a novel mutation of MIP (p.R113X) in a Chinese cataract family. This is the first nonsense mutation of MIP identified thus far. This novel mutation is also the first disease-causing mutation located in the loop C domain of MIP. The results add to the list of mutations of the MIP linked to cataracts. PMID- 24405845 TI - A novel method for efficient delivery of stem cells to the ischemic brain. AB - INTRODUCTION: Rat middle cerebral artery occlusion (MCAO) model is the most commonly used animal model in ischemic stroke studies. In the model, to increase the amount of stem cells or drugs to enter the brain after delivery into the internal carotid artery (ICA), the pterygopalatine artery (PPA) is occluded. However, PPA occlusion is a technically demanding procedure which often causes complications. METHODS: In this study, we developed an ICA injection needle to facilitate easy and efficient delivery of stem cells to the ischemic brain through the ICA without the need of PPA occlusion. We injected methylene blue and fluorescence dye DiI-labeled human mesenchymal stem cells (DiI-hMSCs) into the ICA in rats with the ICA injection needle (without PPA ligation) or the conventional micro-injection needle (with PPA ligation) and assessed their distributions. RESULTS: When methylene blue was injected, evident blue stains were found in the brain of the injection side particularly the middle cerebral artery (MCA)-supplied areas but not in the PPA supplied areas. Similarly, when DiI-hMSCs were injected, the cells largely appeared in the MCA-supplied tissues, which were similar in quantity compared to conventional micro-injection needle injection with PPA occlusion. Moreover, hMSCs injected with the ICA needle or the micro-injection needle similarly improved the functional recovery of the infarcted brain. CONCLUSIONS: Our results indicate that the ICA injection needle is easy to use and efficient in delivering cells to the ischemic brain tissue in rat MCAO model. PMID- 24405847 TI - Ruptured renal arteriovenous malformation successfully treated by catheter embolization: a case report. AB - BACKGROUND: Renal arteriovenous fistula (RAVF) is a comparatively rare malformation. Here, we report a case of ruptured RAVF that was successfully treated by catheter embolization. CASE PRESENTATION: An 89-year-old female was transferred to our institution with massive gross hematuria in March 2011. Plain abdominal computed tomography (CT) revealed dilated left renal pelvis with high density contents. Hematoma was suspected. Subsequent plain abdominal magnetic resonance imaging revealed left hydronephrosis and blood retention in the dilated left renal pelvis. No renal or ureteral cancer was evident. Hematuria was conservatively treated using hemostatic agents but hematuria persisted. Repeated urinary cytology revealed no malignant cells. On day 9, the patient went into septic and/or hemorrhagic shock. Fluid and catecholamine infusion, blood transfusion, and antibacterial drugs were rapidly initiated, and the patient's general condition gradually improved. Contrast-enhanced abdominal CT revealed marked expansion of the hematoma in the renal pelvis and microaneurysms in the segmental arteries of the left kidney. Inflammation improved, and a left double-J stent was inserted. Selective renal angiography revealed RAVF with microaneurysms in the left segmental arteries; therefore, catheter embolization using metallic coils was performed, which resolved hematuria. CONCLUSION: We report a case of ruptured renal arteriovenous malformation, which was successfully treated by catheter embolization. PMID- 24405846 TI - Growing pains and pleasures: how emotional learning guides development. AB - The nervous system promotes adaptive responding to myriad environmental stimuli by ascribing emotion to specific stimulus domains. This affects the salience of different stimuli, facilitates learning, and likely involves the amygdala. Recent studies suggest a strong homology between adaptive responses that result from learning and those that emerge during development. As in motivated learning, developmental studies have found the salience of different classes of stimulus (e.g., peers) undergoes marked fluctuation across maturation and may involve differential amygdala engagement. In this review, by highlighting the importance of particular stimulus categories during sensitive periods of development, we suggest that variability in amygdala response to different stimulus domains has an active and functional role in shaping emerging cortical circuits across development. PMID- 24405848 TI - Sera of overweight people promote in vitro adipocyte differentiation of bone marrow stromal cells. AB - INTRODUCTION: Overweight status should not be considered merely an aesthetic concern; rather, it can incur health risks since it may trigger a cascade of events that produce further fat tissue through altered levels of circulating signaling molecules. METHODS: We decided to investigate the influence of overweight individuals' sera on in vitro MSC proliferation and differentiation. RESULTS: We observed that in vitro incubation of bone marrow stromal cells with the sera of overweight individuals promotes the adipogenic differentiation of MSCs while partially impairing proper osteogenesis. CONCLUSIONS: These results, which represent a pilot study, might suggest that becoming overweight triggers further weight gains by promoting a bias in the differentiation potential of MSCs toward adipogenesis. The circulating factors involved in this phenomenon remain to be determined, since the great majority of the well known pro-inflammatory cytokines and adipocyte-secreted factors we investigated did not show relevant modifications in overweight serum samples compared with controls. PMID- 24405849 TI - The Dutch Health Care Performance Report: seven years of health care performance assessment in the Netherlands. AB - In 2006, the first edition of a monitoring tool for the performance of the Dutch health care system was released: the Dutch Health Care Performance Report (DHCPR). The Netherlands was among the first countries in the world developing such a comprehensive tool for reporting performance on quality, access, and affordability of health care. The tool contains 125 performance indicators; the choice for specific indicators resulted from a dialogue between researchers and policy makers. In the 'policy cycle', the DHCPR can rationally be placed between evaluation (accountability) and agenda-setting (for strategic decision making). In this paper, we reflect on important lessons learned after seven years of health care system performance assessment. These lessons entail the importance of a good conceptual framework for health system performance assessment, the importance of repeated measurement, the strength of combining multiple perspectives (e.g., patient, professional, objective, subjective) on the same issue, the importance of a central role for the patients' perspective in performance assessment, how to deal with the absence of data in relevant domains, the value of international benchmarking and the continuous exchange between researchers and policy makers. PMID- 24405850 TI - Bach and His. AB - This paper examines the career of Johann Sebastian Bach (1685-1750) and the role played by Wilhelm His I (who was, with Albert von Haller, a noted pioneer of physiology) in the exhumation of Bach's remains in 1894. His's examination of these remains allowed the sculptor Carl Seffner to produce the celebrated statue of Bach which stands outside the church of St Thomas in Leipzig, where the composer was employed from 1723 until his death. Modern forensic techniques have recently enabled Bach's image to be reconstructed in even more spectacular detail. PMID- 24405852 TI - A visco-hyperelastic constitutive approach for modeling polyvinyl alcohol sponge. AB - This study proposes the quasi-linear viscoelastic (QLV) model to characterize the time dependent mechanical behavior of poly(vinyl alcohol) (PVA) sponges. The PVA sponges have implications in many viscoelastic soft tissues, including cartilage, liver, and kidney as an implant. However, a critical barrier to the use of the PVA sponge as tissue replacement material is a lack of sufficient study on its viscoelastic mechanical properties. In this study, the nonlinear mechanical behavior of a fabricated PVA sponge is investigated experimentally and computationally using relaxation and stress failure tests as well as finite element (FE) modeling. Hyperelastic strain energy density functions, such as Yeoh and Neo-Hookean, are used to capture the mechanical behavior of PVA sponge at ramp part, and viscoelastic model is used to describe the viscose behavior at hold part. Hyperelastic material constants are obtained and their general prediction ability is verified using FE simulations of PVA tensile experiments. The results of relaxation and stress failure tests revealed that Yeoh material model can define the mechanical behavior of PVA sponge properly compared with Neo Hookean one. FE modeling results are also affirmed the appropriateness of Yeoh model to characterize the mechanical behavior of PVA sponge. Thus, the Yeoh model can be used in future biomechanical simulations of the spongy biomaterials. These results can be utilized to understand the viscoelastic behavior of PVA sponges and has implications for tissue engineering as scaffold. PMID- 24405851 TI - Small-molecule based musculoskeletal regenerative engineering. AB - Clinicians and scientists working in the field of regenerative engineering are actively investigating a wide range of methods to promote musculoskeletal tissue regeneration. Small-molecule-mediated tissue regeneration is emerging as a promising strategy for regenerating various musculoskeletal tissues and a large number of small-molecule compounds have been recently discovered as potential bioactive molecules for musculoskeletal tissue repair and regeneration. In this review, we summarize the recent literature encompassing the past 4 years in the area of small bioactive molecules for promoting repair and regeneration of various musculoskeletal tissues including bone, muscle, cartilage, tendon, and nerve. PMID- 24405853 TI - Characterization of a modified ROCK2 protein that allows use of N6-ATP analogs for the identification of novel substrates. AB - BACKGROUND: The Rho-associated coiled-coil kinase-2 (ROCK2) is an important signaling transducer in the transmission of extracellular signals effecting organization of the actin cytoskeleton. ROCK2 has been implicated in numerous pathologies and the current focus is on understanding the molecular events that couple ROCK2 activity to biological function. To aid in the search for new ROCK2 substrates, we have developed an analog-sensitive (AS) ROCK2 protein that allows the use of selective ATP analogs that are not efficiently utilized by other protein kinases. RESULTS: The analog sensitive protein, M160A ROCK2, was highly active and could phosphorylate proteins from a cellular homogenate with gamma32P N6 (benzyl)ATP. We show the utility of this approach by identifying a putative ROCK2 substrate, elongation initiation factor-1-alpha1. We further show that the major site of ROCK2 phosphorylation of EIF1alpha1 is Thr432. CONCLUSIONS: Our work demonstrates that AS-ROCK2 could be useful in a systematic proteomic approach for identifying novel ROCK2 substrates. PMID- 24405854 TI - The face of equipoise--delivering a structured education programme within a randomized controlled trial: qualitative study. AB - BACKGROUND: In trials of behavioural interventions, the individuals who deliver the intervention are in a position of key influence on the success of the trial. Their fidelity to the intervention is crucial. Yet little is understood about the experiences of this group of trial personnel. This study aimed to investigate the views and experiences of educators who delivered a structured education intervention to people with type 2 diabetes, which incorporated training in self monitoring of either blood glucose (SMBG) or urine glucose (SMUG) as part of a randomized controlled trial (RCT). METHODS: Educators' views were explored through focus groups before and after training (N=18) and approximately 1 year into the trial (N=14), and semi-structured telephone interviews at approximately 2 years (N=7). Analysis was based on the constant comparative method. RESULTS: Educators held preferences regarding the intervention variants; thus, they were not in individual equipoise. Training raised awareness of preferences and their potential to impact on delivery. Educators were confident in their unbiased delivery, but acknowledged the challenges involved. Concealing their preferences was helped by a sense of professionalism, the patient-centred nature of the intervention, and concessions in the trial protocol (enabling participants to swap monitoring methods if needed). Commitment to unbiased delivery was explained through a desire for evidence-based knowledge in the contentious area of SMBG. CONCLUSIONS: The findings provide insight into a previously unexplored group of trial personnel--intervention deliverers in trials of behavioural interventions- which will be useful to those designing and running similar trials. Rather than individual equipoise, it is intervention deliverers' awareness of personal preferences and their potential impact on the trial outcome that facilitates unbiased delivery. Further, awareness of community equipoise, the need for evidence, and relevance to the individual enhance commitment to the RCT. TRIAL REGISTRATION: ISRCTN95696668. PMID- 24405855 TI - Trends in antiviral therapy of adults hospitalized with influenza in Canada since the end of the 2009 pandemic. AB - BACKGROUND: Multiple observational studies have associated antiviral treatment of patients hospitalized with influenza with improved outcome, including reduced mortality. During the 2009-2010 H1N1 pandemic increased use of antiviral treatment of hospital patients was reported. We have carried out prospective surveillance for influenza in patients in a large network of Canadian hospitals since 2006. We wished to assess trends in antiviral use in the two seasons (2010 2011 and 2011-2012) since the end of the pandemic. FINDINGS: Adults (>16 years) testing positive for influenza at the time of or during admission to participating Canadian hospitals were prospectively reviewed. In 2009-2010 there were 1132 confirmed cases, 1107 in 2010-2011 and 631 in 2011-2012. Information on antiviral therapy was available in >95% in each year. Rising to 89.6% in 2009, the proportion of adult patients treated with antiviral therapy fell to 79.9% and 65.7% in the two subsequent seasons (p < 0.001). Oseltamivir was the antiviral agent used in >98% of cases in each year. The median time from onset of symptoms to initiation of antiviral therapy was three days. The treatment proportion fell across all age groups, co-morbid conditions and disease severity. CONCLUSION: Despite evidence for benefit of antiviral therapy, and clinical practice guidelines recommending treatment of this population, antiviral therapy of Canadian adults hospitalized with influenza has progressively fallen in the two seasons since the end of the 2009-2010 influenza pandemic. PMID- 24405856 TI - Masitinib (AB1010), from canine tumor model to human clinical development: where we are? AB - Masitinib mesylate (AB1010) is a novel potent and selective tyrosine kinase inhibitor, targeting mainly wild-type and mutated c-Kit receptor (c-KitR), Platelet Derived Growth Factor Receptor-alfa/beta (PDGFRa/beta), Lymphocyte specific kinase (Lck), Lck/Yes-related protein (LYn), Fibroblast Growth Factor Receptor 3 (FGFR3) and Focal Adhesion Kinase (FAK). It is the first anticancer therapy approved in veterinary medicine for the treatment of unresectable canine mast cell tumors (CMCTs), harboring activating c-KitR mutations, at dose of 12.5mg/kg once daily. Considering its anti-proliferative action, principally given by inhibiting the MCs c-KitR anti-angiogenic pathway that leads cancer progression, and its role as chemosensitizer, masitinib is under clinical investigation in several human malignancies (Gastro-Intestinal Stromal Tumors, acute myeloid leukemia, systemic mastocytosis, pancreatic cancer, multiple myeloma, non-small cell lung cancer, melanoma, ovarian and prostate cancer), which are characterized by similar canine c-KIT proto-oncogene mutations. Here, we analyze masitinib structure activity, its pharmacokinetics compared to imatinib, the c-KitR pathway referring to the most frequent c-KIT mutations sensitive or resistant to this novel drug compared to imatinib, and masitinib safety profile. We, also, explore preclinical and clinical (completed and ongoing) trials with the aim to emphasize as this recent anti-angiogenic therapy, at first approved in CMCTs and, currently in development for the treatment of several human neoplasms, could be represent a milestone in translational oncology, in which the murine experimental model of cancer research could be integrated by canine spontaneous tumor model. PMID- 24405857 TI - An update on molecular biology of thyroid cancers. AB - Differentiated thyroid cancer (DTC) is the most common endocrinological malignancy. There are several histological variants such as papillary and follicular thyroid carcinoma. Many patients with well-differentiated subtypes of DTC are cured by surgery alone or with radioiodine, while poorly differentiated types usually have a worse prognosis. The aggressiveness of thyroid tumors is closely linked to specific gene alterations. Several diagnostic and prognostic molecular markers such as BRAF and RAS point mutations; RET/PTC and PAX8/PPARgamma gene rearrangements; MAPK, PI3K, p53, Wnt-beta catenin, HIF1alpha and NF-kappaB signaling pathways; microRNA profiles and aberrant methylation have been demonstrated in more than 70% of DTC. Diagnostic use of these molecular markers may be optimized for identifying higher risks of mortality, tumor recurrence and metastatic potential. Understanding the molecular biology of thyroid cancers can be an important avenue for diagnosis and treatment of radioiodine-refractory or inoperable DTC patients with novel molecular targeted therapeutic agents. PMID- 24405858 TI - Current management of CML patients: Summary of the Italian Consensus Meeting held in Rome, April 11-12, 2013. AB - Treatment of Chronic Myeloid Leukaemia (CML) has evolved rapidly in the last 10 years. The objectives of this national consensus meeting were to describe the optimal procedures to perform at diagnosis, the most appropriate choice of tyrosine kinase inhibitor (TKI) in the first line setting, the correct monitoring procedures, the appropriate timing for resistance identification allowing a rapid TKI switch, and the future possibility of treatment discontinuation. A panel of experts in CML management were invited for a 2-day workshop. Prior to the conference, the organizing committee selected several topics and assigned them to different physicians divided in four groups. Issues discussed were (1) role of cytogenetic and molecular response monitoring in 2013; (2) frontline treatment of CML in 2013 and therapeutic objectives; (3) how to monitor response and when to change therapy after resistance or non-optimal responses; (4) possible therapy discontinuation after achievement of deep and stable molecular responses. Different national experts reviewed the literature, analyzed levels of evidence for each topic and, after extensive discussions within smaller working groups, presented their conclusions during the meeting. Each consensus aim was then evaluated by a general vote in the plenary sessions. PMID- 24405859 TI - Abstracts of the 16th International Congress: Towards Successful Aging: Harmony of Mental, Physical and Social Life, 1-4 October 2013,Seoul, Korea. PMID- 24405866 TI - Glioblastoma-arteriovenous fistula complex: imaging characteristics and treatment considerations. AB - Although a certain degree of arteriovenous shunting may be expected in glioblastoma, to our knowledge, the coexistence of a glioblastoma and arteriovenous fistula has not been previously reported. In this case report, we present such a lesion and discuss its diagnosis with a multimodal imaging approach. Additionally, we discuss treatment considerations for such a lesion. PMID- 24405865 TI - Characterization of two transketolases encoded on the chromosome and the plasmid pBM19 of the facultative ribulose monophosphate cycle methylotroph Bacillus methanolicus. AB - BACKGROUND: Transketolase (TKT) is a key enzyme of the pentose phosphate pathway (PPP), the Calvin cycle and the ribulose monophosphate (RuMP) cycle. Bacillus methanolicus is a facultative RuMP pathway methylotroph. B. methanolicus MGA3 harbors two genes putatively coding for TKTs; one located on the chromosome (tkt(C)) and one located on the natural occurring plasmid pBM19 (tkt(P)). RESULTS: Both enzymes were produced in recombinant Escherichia coli, purified and shown to share similar biochemical parameters in vitro. They were found to be active as homotetramers and require thiamine pyrophosphate for catalytic activity. The inactive apoform of the TKTs, yielded by dialysis against buffer containing 10 mM EDTA, could be reconstituted most efficiently with Mn(2+) and Mg(2+). Both TKTs were thermo stable at physiological temperature (up to 65 degrees C) with the highest activity at neutral pH. Ni(2+), ATP and ADP significantly inhibited activity of both TKTs. Unlike the recently characterized RuMP pathway enzymes fructose 1,6-bisphosphate aldolase (FBA) and fructose 1,6 bisphosphatase/sedoheptulose 1,7-bisphosphatase (FBPase/SBPase) from B. methanolicus MGA3, both TKTs exhibited similar kinetic parameters although they only share 76% identical amino acids. The kinetic parameters were determined for the reaction with the substrates xylulose 5-phosphate (TKT(C): kcat/KM: 264 s(-1) mM(-1); TKT(P): kcat/KM: 231 s(-1) mM) and ribulose 5-phosphate (TKT(C): kcat/KM: 109 s(-1) mM; TKT(P): kcat/KM: 84 s(-1) mM) as well as for the reaction with the substrates glyceraldehyde 3-phosphate (TKT(C): kcat/KM: 108 s(-1) mM; TKT(P): kcat/KM: 71 s(-1) mM) and fructose 6-phosphate (TKT(C) kcat/KM: 115 s(-1) mM; TKT(P): kcat/KM: 448 s(-1) mM). CONCLUSIONS: Based on the kinetic parameters no major TKT of B. methanolicus could be determined. Increased expression of tkt(P), but not of tkt(C) during growth with methanol [J Bacteriol 188:3063-3072, 2006] argues for TKT(P) being the major TKT relevant in the RuMP pathway. Neither TKT exhibited activity as dihydroxyacetone synthase, as found in methylotrophic yeast, or as the evolutionary related 1-deoxyxylulose-5-phosphate synthase. The biological significance of the two TKTs for B. methanolicus methylotrophy is discussed. PMID- 24405867 TI - Intralobar pulmonary sequestration complicating with cryptococcal infection. AB - INTRODUCTION: Pulmonary sequestration is a rare congenital malformation characterized by accessory lung tissue supplied by an aberrant systemic artery. It often presents with recurrent infections. But fungus infection is exceptional. OBJECTIVES: To help other clinicians deal with patients with pulmonary sequestration complicating with cryptococcal infection. METHODS: We reported a case of pulmonary sequestration complicating with pulmonary and eye cryptococcosis and did literature review. RESULTS: A 20-year-old immunocompetent male patient suffered from eye pain and blurred vision, and received antibiotics and dexamethasone therapy with no improvement. Bacteriology inspection and computerized tomography scan indicated a diagnosis of cryptococcal infection in both eye and lung. Vitrectomy and antifungal agents were administered. Since symptoms fluctuations, lobectomy was operated. The surgery revealed the presence of pulmonary sequestration. Literature review showed that there is no report about pulmonary sequestration complicating with cryptococcal infection so far. CONCLUSIONS: Pulmonary sequestration is a very important but extremely negligent cause for pulmonary cryptococcal infection. PMID- 24405868 TI - The novel p.Cys65Tyr mutation in NR5A1 gene in three 46,XY siblings with normal testosterone levels and their mother with primary ovarian insufficiency. AB - BACKGROUND: Disorders of sex development (DSD) is the term used for congenital conditions in which development of chromosomal, gonadal, or phenotypic sex is atypical. Nuclear receptor subfamily 5, group A, member 1 gene (NR5A1) encodes steroidogenic factor 1 (SF1), a transcription factor that is involved in gonadal development and regulates adrenal steroidogenesis. Mutations in the NR5A1 gene may lead to different 46,XX or 46,XY DSD phenotypes with or without adrenal failure. We report a Brazilian family with a novel NR5A1 mutation causing ambiguous genitalia in 46,XY affected individuals without Mullerian derivatives and apparently normal Leydig function after birth and at puberty, respectively. Their mother, who is also heterozygous for the mutation, presents evidence of primary ovarian insufficiency. CASE PRESENTATION: Three siblings with 46,XY DSD, ambiguous genitalia and normal testosterone production were included in the study. Molecular analyses for AR, SRD5A2 genes did not reveal any mutation. However, NR5A2 sequence analysis indicated that all three siblings were heterozygous for the p.Cys65Tyr mutation which was inherited from their mother. In silico analysis was carried out to elucidate the role of the amino acid change on the protein function. After the mutation was identified, all sibs and the mother had been reevaluated. Basal hormone concentrations were normal except that ACTH levels were slightly elevated. After 1 mcg ACTH stimulation test, only the older sib showed subnormal cortisol response. CONCLUSION: The p.Cys65Tyr mutation located within the second zinc finger of DNA binding domain was considered deleterious upon analysis with predictive algorithms. The identification of heterozygous individuals with this novel mutation may bring additional knowledge on structural modifications that may influence NR5A1 DNA-binding ability, and may also contribute to genotype-phenotype correlations in DSD. The slightly elevated ACTH basal levels in all three patients with 46,XY DSD and the subnormal cortisol response after 1 mcg ACTH stimulation in the older sib indicate that a long-term follow-up for adrenal function is important for these patients. Our data reinforce that NR5A1 analysis must also be performed in 46,XY DSD patients with normal testosterone levels without AR mutations. PMID- 24405870 TI - Is Palmer's point really safe? PMID- 24405869 TI - Sleep duration and plasma leptin concentrations in early pregnancy among lean and overweight/obese women: a cross sectional study. AB - BACKGROUND: Early-pregnancy short sleep duration is predictive of gestational diabetes and preeclampsia; mechanisms for these associations are unknown. Leptin, an adipocyte-derived peptide involved in regulating food intake and energy expenditure, may play a role in these observed associations. Given inconsistent reports linking short sleep duration with leptin, and absence of studies among pregnant women, we examined the association of maternal sleep duration with plasma leptin in early pregnancy. METHODS: This cross-sectional study included 830 pregnant women. Plasma leptin was measured in samples collected around 13 weeks gestation. Sleep duration was categorized as: <=5, 6, 7-8 (reference), and >=9 hours. Differences in leptin concentrations across categories were estimated using linear regression. Analyses were completed for lean and overweight/obese women. RESULTS: Overall, women with long sleep duration had elevated plasma leptin (p-value = 0.04). However, leptin concentrations were not statistically significantly elevated in women with a short sleep duration. There was no association of leptin with sleep duration among lean women. Among overweight/obese women, a U-shaped relation between leptin and sleep duration was observed: Mean leptin was elevated (beta = 21.96 ng/ml, P < 0.001) among women reporting <=5 hour of sleep compared with reference group; and women reporting >=9 hours of sleep also had elevated leptin (beta = 4.29 ng/ml, P = 0.09). CONCLUSIONS: Short sleep duration, and to a lesser extent long sleep duration, were associated with elevated leptin among overweight/obese women. These data add some evidence to help understand mechanistic relationships of sleep duration with pregnancy complications. PMID- 24405871 TI - Groupthink. PMID- 24405872 TI - Isthmocele. PMID- 24405873 TI - In response. PMID- 24405874 TI - What psychological, physical, lifestyle, and knowledge factors are associated with excess or inadequate weight gain during pregnancy? A cross-sectional survey. AB - OBJECTIVE: Excess weight gain during pregnancy is associated with increased risks of overweight and obesity in both women and their children. Conversely, inadequate weight gain can predispose to growth restriction, which is also associated with childhood obesity. Because most pregnant women now gain more weight than is recommended in guidelines and a substantial portion gain less than the recommended amounts, we sought to determine factors associated with inappropriate weight gain, including physical, lifestyle, knowledge, and particularly psychological factors. METHODS: We conducted a self-administered cross-sectional survey of English-speaking women with a live, singleton gestation. Biologically relevant variables significant at P < 0.10 were included in multiple logistic regression. RESULTS: Three hundred thirty women completed the survey, a response rate of 90.7%. Gaining weight above the amount recommended in guidelines was associated with planning to do so (adjusted OR [aOR] 11.18; 95% CI 4.45 to 28.06), bedtime television (aOR 2.38; 95% CI 1.08 to 5.23), and higher emotional instability scores (aOR 1.26; 95% CI 1.10 to 1.44). Inadequate weight gain was associated with less satisfaction with body weight (aOR 4.84; 95% CI 1.56 to 15.02) and bedtime television (aOR 3.92; 95% CI 1.50 to 10.30), while self-efficacy towards healthy weight was protective (aOR 0.91; 95% CI 0.83 to 0.99). CONCLUSION: Planned weight gain was most strongly associated with excess gestational weight gain, followed by bedtime television watching and emotional instability, while inadequate gain was associated with less satisfaction with body weight and bedtime television watching. Better characterization of psychological and other factors that predict inappropriate gain will be critical for providing a basis for interventions. PMID- 24405875 TI - Histological chorioamnionitis associated with preterm prelabour rupture of membranes at Kingston General Hospital: a practice audit. AB - OBJECTIVE: To determine the prevalence of histological chorioamnionitis associated with preterm prelabour rupture of membranes (PPROM) in women following spontaneous onset of labour, urgent delivery or planned delivery after 34 weeks' gestation. METHODS: Charts of all women admitted to Kingston General Hospital with PPROM prior to 34 weeks' gestation over five years were collected. Obstetrical outcomes and histopathology reports were reviewed. RESULTS: Two hundred forty-four women with PPROM were identified and reviewed. The majority of women (169; 69%) went into spontaneous labour and, of those, 24 (14%) had clinical chorioamnionitis and 79 (47%) had histological chorioamnionitis. Of the 45 women (18%) who required urgent delivery, 27 (60%) had clinical chorioamnionitis and 31 (69%) had histological chorioamnionitis. Only 26 of the original 244 women with PPROM (11%) were managed expectantly until 34 weeks' gestation and then had a planned delivery. The prevalence of histological chorioamnionitis in this group whose placentas were sent for histopathologic review was 24%. Overall, the clinical suspicion of chorioamnionitis was found to be specific (91%) but not sensitive (37%) for identifying chorioamnionitis on the basis of histopathology. CONCLUSION: Histological chorioamnionitis complicates almost one half of all cases of PPROM that occur prior to 34 weeks' gestation. Most women will progress to spontaneous labour or require urgent delivery for clinical chorioamnionitis or other complications related to ruptured membranes before reaching 34 weeks' gestation. Only a subset of women remain pregnant long enough to have labour induced, but among those the prevalence of histological chorioamnionitis is lower (24%). PMID- 24405876 TI - Process evaluation of a task-shifting strategy in hormonal contraception: does training translate into practice? AB - OBJECTIVES: Since 2000, the Province of Quebec has experienced a shortage of physicians and a decrease in access to prescription contraceptives. A task shifting strategy was launched in 2007 to allow trained nurses, in collaboration with community pharmacists, to start healthy women on hormonal contraception for a six-month period without a medical consultation. This study examined the proportion of trained nurses effectively involved in this innovative practice to determine which factors are associated with it. METHODS: We performed a cross sectional study in which all nurses who had been trained in hormonal contraception since 2007, who were registered with the College of Nurses of Quebec, and who were employed as nurses in the Quebec Health System were asked to respond to a postal or electronic survey. RESULTS: A total of 3043 nurses were invited to participate in the study. Fifty-seven percent (57.3%) of 745 respondents were involved in this new practice. The major determinant was the adoption of the Collaborative Agreement in Hormonal Contraception by health organizations. The other influential factors were having been trained before 2011, being a permanent employee, working in a youth clinic of a centre for health and social services, and working in a rural or remote area. CONCLUSION: Despite a modest response rate, this study provides support for formalizing the training of nurses in hormonal contraception by integrating it into nursing education at all levels, and for implementing it in other health organizations such as family medicine groups, which are widespread in Quebec. PMID- 24405877 TI - Fetal pharmacotherapy 3: magnesium sulfate. PMID- 24405878 TI - Should couples be allowed to select the sex of their offspring? PMID- 24405879 TI - Female genital cosmetic surgery. AB - OBJECTIVE: To provide Canadian gynaecologists with evidence-based direction for female genital cosmetic surgery in response to increasing requests for, and availability of, vaginal and vulvar surgeries that fall well outside the traditional realm of medically-indicated reconstructions. EVIDENCE: Published literature was retrieved through searches of PubMed or MEDLINE, CINAHL, and The Cochrane Library in 2011 and 2012 using appropriate controlled vocabulary and key words (female genital cosmetic surgery). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to May 2012. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). Recommendations 1. The obstetrician and gynaecologist should play an important role in helping women to understand their anatomy and to respect individual variations. (III-A) 2. For women who present with requests for vaginal cosmetic procedures, a complete medical, sexual, and gynaecologic history should be obtained and the absence of any major sexual or psychological dysfunction should be ascertained. Any possibility of coercion or exploitation should be ruled out. (III-B) 3. Counselling should be a priority for women requesting female genital cosmetic surgery. Topics should include normal variation and physiological changes over the lifespan, as well as the possibility of unintended consequences of cosmetic surgery to the genital area. The lack of evidence regarding outcomes and the lack of data on the impact of subsequent changes during pregnancy or menopause should also be discussed and considered part of the informed consent process. (III-L) 4. There is little evidence to support any of the female genital cosmetic surgeries in terms of improvement to sexual satisfaction or self-image. Physicians choosing to proceed with these cosmetic procedures should not promote these surgeries for the enhancement of sexual function and advertising of female genital cosmetic surgical procedures should be avoided (III-L) 5. Physicians who see adolescents requesting female genital cosmetic surgery require additional expertise in counselling adolescents. Such procedures should not be offered until complete maturity including genital maturity, and parental consent is not required at that time. (III-L) 6. Non medical terms, including but not restricted to vaginal rejuvenation, clitoral resurfacing, and G-spot enhancement, should be recognized as marketing terms only, with no medical origin; therefore they cannot be scientifically evaluated. (III-L). PMID- 24405881 TI - Introduction: Enzyme catalysis and allostery: a century of advances in molecular understanding. PMID- 24405880 TI - Cervical insufficiency and cervical cerclage. AB - OBJECTIVE: The purpose of this guideline is to provide a framework that clinicians can use to determine which women are at greatest risk of having cervical insufficiency and in which set of circumstances a cerclage is of potential value. EVIDENCE: Published literature was retrieved through searches of PubMed or MEDLINE, CINAHL, and The Cochrane Library in 2012 using appropriate controlled vocabulary (e.g., uterine cervical incompetence) and key words (e.g., cervical insufficiency, cerclage, Shirodkar, cerclage, MacDonald, cerclage, abdominal, cervical length, mid-trimester pregnancy loss). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to January 2011. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). Recommendations 1. Women who are pregnant or planning pregnancy should be evaluated for risk factors for cervical insufficiency. A thorough medical history at initial evaluation may alert clinicians to risk factors in a first or index pregnancy. (III-B) 2. Detailed evaluation of risk factors should be undertaken in women following a mid trimester pregnancy loss or early premature delivery, or in cases where such complications have occurred in a preceding pregnancy. (III-B) 3. In women with a history of cervical insufficiency, urinalysis for culture and sensitivity and vaginal cultures for bacterial vaginosis should be taken at the first obstetric visit and any infections so found should be treated. (I-A) 4. Women with a history of three or more second-trimester pregnancy losses or extreme premature deliveries, in whom no specific cause other than potential cervical insufficiency is identified, should be offered elective cerclage at 12 to 14 weeks of gestation. (I-A) 5. In women with a classic history of cervical insufficiency in whom prior vaginal cervical cerclage has been unsuccessful, abdominal cerclage can be considered in the absence of additional mitigating factors. (II-3C) 6. Women who have undergone trachelectomy should have abdominal cerclage placement. (II-3C) 7. Emergency cerclage may be considered in women in whom the cervix has dilated to < 4 cm without contractions before 24 weeks of gestation. (II-3C) 8. Women in whom cerclage is not considered or justified, but whose history suggests a risk for cervical insufficiency (1 or 2 prior mid-trimester losses or extreme premature deliveries), should be offered serial cervical length assessment by ultrasound. (II-2B) 9. Cerclage should be considered in singleton pregnancies in women with a history of spontaneous preterm birth or possible cervical insufficiency if the cervical length is <= 25 mm before 24 weeks of gestation. (I A) 10. There is no benefit to cerclage in a woman with an incidental finding of a short cervix by ultrasound examination but no prior risk factors for preterm birth. (II-1D) 11. Present data do not support the use of elective cerclage in multiple gestations even when there is a history of preterm birth; therefore, this should be avoided. (I-D) 12. The literature does not support the insertion of cerclage in multiple gestations on the basis of cervical length. (II-1D). PMID- 24405882 TI - The association of treatment delay and prognosis in head and neck squamous cell carcinoma (HNSCC) patients in a Dutch comprehensive cancer center. AB - OBJECTIVE: The increasing volume of head and neck squamous cell carcinoma (HNSCC) patients can lead to longer intervals between histopathological diagnosis and primary treatment. This could cause psychological distress to the patient, but more importantly could possibly lead to tumor progression and decreased survival. Accordingly, this study investigates these relationships. METHODS: The correlation of professional delay and clinical characteristics of 2493 patients, treated between 1990 and 2011 with oral, oropharyngeal, hypopharyngeal and laryngeal SCC, was investigated. Patients were divided in two groups based on treatment delay, defined as the interval between histopathological diagnosis and initial treatment. Univariate and multivariate proportional hazards models were used to assess disease specific survival (DSS) and disease free survival (DFS). RESULTS: Year of diagnosis, tumor site and therapy were significantly related to treatment delay. Tumor stage was not related to treatment delay. Multivariate regression models revealed that the group with a delay of more than 30 days had a better DSS (HR .838, CI .697-.922, p=.041) and DFS (HR .816, CI .702-.947), p=.007) than the group treated within 30 days. CONCLUSION: In our study, treatment delay up to 90 days is not related to impaired survival. This argument can be used extremely cautiously to comfort patients who have to wait several weeks for treatment. Although, possible tumor progression during treatment delay could have led to increased morbidity subsequent to more extensive treatment. Also, possible negative psychological impact of delay in treatment should not be underestimated. PMID- 24405883 TI - Alcohol drinking and upper aerodigestive tract cancer mortality: a systematic review and meta-analysis. AB - OBJECTIVES: Upper aerodigestive tract (UADT) cancer is among the most frequent cancer and the most common death causes of cancer in the world. Epidemiological studies have reported an inconsistent relationship between alcohol drinking and UADT cancer mortality. However, no systematic review or meta-analysis has been reported up to now. To quantify the association between alcohol drinking and UADT cancer mortality, we performed this meta-analysis. METHODS: A literature search was carried out in PubMed and ISI Web of Science to identify all relevant epidemiological studies published before June 30, 2013. And the categorical and dose-response meta-analyses were used to evaluate the association between alcohol drinking and UADT cancer mortality. RESULTS: Ten studies involving 2976 UADT cancer deaths were included. Compared with non/occasional drinkers, the pooled relative risks (RRs) of UADT cancer mortality were 2.01 [95% confidence interval (CI)=1.56-2.59] for any, 1.26 (95% CI=0.94-1.67) for light (? 12.5 g/day), 1.79 (95% CI=1.26-2.53) for moderate (12.6-49.9 g/day), and 3.63 (95% CI=2.63-5.00) for heavy (? 50 g/day) drinkers, respectively. Dose-response analysis showed that the increment in daily alcohol consumption was associated with an increased risk of UADT cancer mortality continuously. CONCLUSION: This study provides evidence of a positive association between alcohol drinking and UADT cancer mortality, especially when alcohol consumption reaching moderate-to-heavy level. Thus, public health recommendation on UADT cancer prevention and control should consider limiting the intake of alcoholic beverages. PMID- 24405884 TI - Cost-effectiveness of changes in alcohol taxation in Denmark: a modelling study. AB - INTRODUCTION: Excessive alcohol consumption is a public health problem in many countries including Denmark, where 6% of the burden of disease is due to alcohol consumption, according to the new estimates from the Global Burden of Disease 2010 study. Pricing policies, including tax increases, have been shown to effectively decrease the level of alcohol consumption. METHODS: We analysed the cost-effectiveness of three different scenarios of changed taxation of alcoholic beverages in Denmark (20% and 100% increase and 10% decrease). The lifetime health effects are estimated as the difference in disability-adjusted life years between a Danish population that continues to drink alcohol at current rates and an identical population that changes their alcohol consumption due to changes in taxation. Calculation of cost offsets related to treatment of alcohol-related diseases and injuries, was based on health care system costs from Danish national registers. Cost-effectiveness was evaluated by calculating cost-effectiveness ratios (CERs) compared to current practice. RESULTS: The two scenarios of 20% and 100% increased taxation could avert 20,000 DALY and 95,500 DALY respectively, and yield cost savings of -?119 million and -?575 million, over the life time of the Danish population. Both scenarios are thus cost saving. The tax decrease scenario would lead to 10,100 added DALY and an added cost of ?60 million. For all three interventions the health effects build up and reach their maximum around 15-20 years after implementation of the tax change. CONCLUSION: Our results show that decreased taxation will lead to an increased burden of disease and related increases in health care costs, whereas both a doubling of the current level of alcohol taxation and a scenario where taxation is only increased by 20% can be cost-saving ways to reduce alcohol related morbidity and mortality. Our results support the growing evidence that population strategies are cost-effective and should be considered for policy making and prevention of alcohol abuse. PMID- 24405885 TI - Anti-inflammatory effects of linagliptin in hemodialysis patients with diabetes. AB - Inflammation and glycemic control are important prognosis-related factors for hemodialysis (HD) patients; moreover, inflammation affects insulin secretion. Here, we evaluated the anti-inflammatory effects of monotherapy with linagliptin a dipeptidase-4 inhibitor-in HD patients with type 2 diabetes. We examined 21 diabetic HD patients who were not receiving oral diabetes drugs or insulin therapy and with poor glycemic control (glycated albumin [GA] level, >20%). Linagliptin (5 mg) was administered to the patients daily. The levels of prostaglandin E2 (PGE2), interleukin-6 (IL-6), high-sensitivity C-reactive protein, GA, blood glucose, and active glucagon-like peptide-1 were determined before and 6 months after treatment. Body weight and serum levels of albumin, hemoglobin, total cholesterol, and low-density lipoprotein cholesterol were also recorded before and after treatment. The levels of PGE2 and GA were significantly decreased 1 month after starting linagliptin therapy, whereas the IL-6 levels were significantly decreased 6 months after starting linagliptin therapy. After 6 months of treatment, the PGE2 levels decreased from 188 +/- 50 ng/mL to 26 +/- 5 ng/mL; IL-6 levels, from 1.5 +/- 0.4 pg/mL to 0.6 +/- 0.1 pg/mL; and GA levels, from 21.3% +/- 0.6% to 18.0% +/- 0.6%. Glucagon-like peptide-1 levels increased 2.5-fold during the treatment. Over the 6-month treatment period, body weight and levels of high-sensitivity C-reactive protein, blood glucose, albumin, hemoglobin, and cholesterol did not change; none of the patients exhibited hypoglycemia. The anti-inflammatory effects of linagliptin monotherapy indicate that it may serve as a useful glucose control strategy for HD patients with diabetes. PMID- 24405886 TI - The influences of SE infection on layers' production performance, egg quality and blood biochemical indicators. AB - BACKGROUND: Salmonella enterica serovar Enteritidis (SE), as a major cause of foodborn illness, infects humans mainly through the egg. However, the symptom of laying hens usually is not typical and hard to diagnosis. In the present study, it is studied that the influences of SE infection on layers' performance, egg quality and blood biochemical indicators. It will help us to improve the strategy to control SE infection in commercial layers. One hundred layers at 20 wk of age were divided into 2 groups, 60 hens for experiment and others for control. The experiment group was fed with the dosage of 108 CFU SE per hen. The specific PCR was used to detect the deposition of SE. On the 8 d after SE infection, 10 hens from the control group and 30 hens from the experimental group were slaughtered to detect the SE colonization. The production performance, egg quality and blood biochemical indices were also analyzed. RESULTS: The results showed that the colonization rate of SE was highest in caecum contents (55.17%) and lowest in vagina (17.24%). For the eggs the detection rate of SE was highest on the eggshell (80.00%) and lowest in yolk (18.81%). SE infection had no significant influence on production performance and egg qualities (P > 0.05). The difference of laying rate between the experimental and control groups was less than 0.30%, and both were approximately equal to 82.00%. The blood analysis showed that the aspartic aminotransferase (AST) and alanine aminotransferase (ALT) of experimental group was significantly higher than those of control group (P < 0.05). For experimental and control groups AST values were 236.22 U/l and 211.84 U/l respectively, and ALT values were 32.19 U/l and 24.55 U/l. All of coefficients were less than 20%. The colonization of SE in organs increases the enzyme activities of AST and ALT in blood. CONCLUSIONS: SE in feed could invade the oviduct and infect the forming eggs. It significantly increased the concentration of ALT and AST in blood. However,SE infection was hard to be observed from the appearances of layer and egg. It might be a dangerous risk to human health. PMID- 24405887 TI - Silicon mitigates heavy metal stress by regulating P-type heavy metal ATPases, Oryza sativa low silicon genes, and endogenous phytohormones. AB - BACKGROUND: Silicon (Si) application has been known to enhance the tolerance of plants against abiotic stresses. However, the protective mechanism of Si under heavy metals contamination is poorly understood. The aim of this study was to assess the role of Si in counteracting toxicity due to cadmium (Cd) and copper (Cu) in rice plants (Oryza sativa). RESULTS: Si significantly improved the growth and biomass of rice plants and reduced the toxic effects of Cd/Cu after different stress periods. Si treatment ameliorated root function and structure compared with non-treated rice plants, which suffered severe root damage. In the presence of Si, the Cd/Cu concentration was significantly lower in rice plants, and there was also a reduction in lipid peroxidation and fatty acid desaturation in plant tissues. The reduced uptake of metals in the roots modulated the signaling of phytohormones involved in responses to stress and host defense, such as abscisic acid, jasmonic acid, and salicylic acid. Furthermore, the low concentration of metals significantly down regulated the mRNA expression of enzymes encoding heavy metal transporters (OsHMA2 and OsHMA3) in Si-metal-treated rice plants. Genes responsible for Si transport (OsLSi1 and OsLSi2), showed a significant up regulation of mRNA expression with Si treatment in rice plants. CONCLUSION: The present study supports the active role of Si in the regulation of stresses from heavy metal exposure through changes in root morphology. PMID- 24405889 TI - "Stress entropic load" as a transgenerational epigenetic response trigger. AB - Epigenetic changes are generally based on the switching of alternative functional or structural states and result in the adaptation of cellular expression patterns during proliferation, differentiation or plastic changes in the adult organism, whereas some epigenetic information can be passed on other generations while other is not. Hence, the principal question is: why is some information reset or resolved during the meiosis process and other is passed from one generation to another, or, in other words: what "adaptation trigger" level initiates transgenerationally transmitted epigenome change? Hereto, we propose a theory which states that stress, or, more specifically, the energy cost of an individual's adaptation to stress, represents a viable candidate for the transgenerational transmission trigger of a given acquired trait. It has been reported recently that the higher lifetime entropy generation of a unit's body mass, the higher the entropy stress level (which is a measure of energy released by a unit's organ mass) and the irreversibility within the organ, resulting in faster organ degradation and consequent health problems for the entire biological system. We therefore suggest a new term: "stress entropic load" will reflect the actual energetic cost of an individual's adaptation and may be used to estimate the probability of inducing transgenerational response once characterized or measured. PMID- 24405888 TI - Human umbilical cord mesenchymal stromal cells exhibit immature nucleus pulposus cell phenotype in a laminin-rich pseudo-three-dimensional culture system. AB - INTRODUCTION: Cell supplementation to the herniated or degenerated intervertebral disc (IVD) is a potential strategy to promote tissue regeneration and slow disc pathology. Human umbilical cord mesenchymal stromal cells (HUCMSCs) - originating from the Wharton's jelly - remain an attractive candidate for such endeavors with their ability to differentiate into multiple lineages. Previously, mesenchymal stem cells (MSCs) have been studied as a potential source for disc tissue regeneration. However, no studies have demonstrated that MSCs can regenerate matrix with unique characteristics matching that of immature nucleus pulposus (NP) tissues of the IVD. In our prior work, immature NP cells were found to express specific laminin isoforms and laminin-binding receptors that may serve as phenotypic markers for evaluating MSC differentiation to NP-like cells. The goal of this study is to evaluate these markers and matrix synthesis for HUCMSCs cultured in a laminin-rich pseudo-three-dimensional culture system. METHODS: HUCMSCs were seeded on top of Transwell inserts pre-coated with MatrigelTM, which contained mainly laminin-111. Cells were cultured under hypoxia environment with three differentiation conditions: NP differentiation media (containing 2.5% MatrigelTM solution to provide for a pseudo-three-dimensional laminin culture system) with no serum, or the same media supplemented with either insulin-like growth factor-1 (IGF-1) or transforming growth factor-beta1 (TGF-beta1). Cell clustering behavior, matrix production and the expression of NP-specific laminin and laminin-receptors were evaluated at days 1, 7, 13 and 21 of culture. RESULTS: Data show that a pseudo-three-dimensional culture condition (laminin-1 rich) promoted HUCMSC differentiation under no serum conditions. Starting at day 1, HUCMSCs demonstrated a cell clustering morphology similar to that of immature NP cells in situ and that observed for primary immature NP cells within the similar laminin-rich culture system (prior study). Differentiated HUCMSCs under all conditions were found to contain glycosaminoglycan, expressed extracellular matrix proteins of collagen II and laminin alpha5, and laminin receptors (integrin alpha3 and beta4 subunits). However, neither growth factor treatment generated distinct differences in NP-like phenotype for HUCMSC as compared with no-serum conditions. CONCLUSIONS: HUCMSCs have the potential to differentiate into cells sharing features with immature NP cells in a laminin-rich culture environment and may be useful for IVD cellular therapy. PMID- 24405890 TI - Contraception, punishment and women who use drugs. AB - BACKGROUND: In light of the recent debate on the use of financial incentives to promote long-acting contraception and sterilisation among women who use illicit drugs we discuss attitudes to contraception, pregnancy and parenting among Australian women who inject drugs. METHODS: Qualitative interviews were conducted with 90 women of reproductive age about contraceptive use, preferences, reproductive histories, attitudes to and experiences of parenting. All women were either currently, or had previously injected drugs. The in-depth, semi-structured interviews were compared and contrasted for themes relating to drug use, contraception, pregnancy and parenting. RESULTS: Participants aspired to control their fertility, expressed individual contraceptive preferences and concerns for their children (both born and unborn). Most had tried a number of contraceptive methods interspersed by periods of non-use related to experiences of side effects, being single or abstinent, believing that they were infertile and trying to conceive. Attitudes varied from woman to woman and in the same individual over their life course. Some believed that they were not likely to be capable, but most aspired to be successful mothers. CONCLUSIONS: Women's drug use should not automatically be associated with an inability to make informed health care choices or to care for children. Evidence suggests that women who use drugs do not need to be paid to limit or end their fertility. Rather, programs that aim to reduce barriers to obtaining free, non-discriminating reproductive advice and parenting assistance would better utilise women's agency to improve their own reproductive health. PMID- 24405891 TI - Tailored interventions to implement recommendations for elderly patients with depression in primary care: a study protocol for a pragmatic cluster randomised controlled trial. AB - BACKGROUND: The prevalence of depression is high and the elderly have an increased risk of developing chronic course. International data suggest that depression in the elderly is under-recognised, the latency before clinicians provide a treatment plan is longer and elderly patients with depression are not offered psychotherapy to the same degree as younger patients. Although recommendations for the treatment of elderly patients with depression exist, health-care professionals adhere to these recommendations to a limited degree only. We conducted a systematic review to identify recommendations for managing depression in the elderly and prioritised six recommendations. We identified and prioritised the determinants of practice related to the implementation of these recommendations in primary care, and subsequently discussed and prioritised interventions to address the identified determinants. The objective of this study is to evaluate the effectiveness of these tailored interventions for the six recommendations for the management of elderly patients with depression in primary care. METHODS/DESIGN: We will conduct a pragmatic cluster randomised trial comparing the implementation of the six recommendations using tailored interventions with usual care. We will randomise 80 municipalities into one of two groups: an intervention group, to which we will deliver tailored interventions to implement the six recommendations, and a control group, to which we will not deliver any intervention. We will randomise municipalities rather than patients, individual clinicians or practices, because we will deliver the intervention for the first three recommendations at the municipal level and we want to minimise the risk of contamination across GP practices for the other three recommendations. The primary outcome is the proportion of actions taken by GPs that are consistent with the recommendations. DISCUSSION: This trial will investigate whether a tailored implementation approach is an effective strategy for improving collaborative care in the municipalities and health-care professionals' practice towards elderly patients with depression in primary care. The effectiveness evaluation described in this protocol will be accompanied with a process evaluation exploring why and how the interventions were effective or ineffective. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01913236. PMID- 24405892 TI - Somatostatin analogs: does pharmacology impact antitumor efficacy? AB - Somatostatin is an endogenous inhibitor of secretion and cell proliferation. These features render somatostatin a logical candidate for the management of neuroendocrine tumors that express somatostatin receptors. Synthetic somatostatin analogs (SSAs) have longer half-lives than somatostatin, but have similar activities, and are used for the treatment of these types of disorders. Interest has focused on novel multireceptor analogs with broader affinity to several of the five somatostatin receptors, thereby presenting putatively higher antitumor activities. Recent evidence indicates that SSAs cannot be considered mimics of native somatostatin in regulating signaling pathways downstream of receptors. Here we review this knowledge, discuss the concept of biased agonism, and highlight what considerations need to be taken into account for the optimal clinical use of SSAs. PMID- 24405894 TI - Left retroperitoneal aortic aneurysm repair in patients unsuitable for endovascular treatment. AB - BACKGROUND: This study aims to evaluate the contemporary outcome of left open retroperitoneal (RP) abdominal aortic surgery over a 7-year time period in patients with difficult anatomy unsuitable for endovascular aneurysm repair (EVAR). METHODS: Eighty-four consecutive patients unsuitable for EVAR/FEVAR underwent left RP open aortic surgery. Of these, 44 (52%) required an infrarenal cross-clamp, 17 (20%) a suprarenal cross-clamp and 15 (18%) a supracoeliac cross clamp. Eight (10%) were thoracoabdominal aneurysms. RESULTS: There were four mortalities within 30 days (4.8%). Two occurred in patients with a supracoeliac cross-clamp, one in a suprarenal cross-clamp (total suprarenal mortality 10%) and one in an infrarenal cross-clamp. Four patients required prolonged ventilatory support (>10 days). Three patients (9%) from the suprarenal group developed post operative renal dysfunction, one of these required permanent dialysis. Paralytic ileus occured in two patients (2%) and was secondary to ischaemia in both cases. CONCLUSION: There will always remain a small group of patients best treated by open aortic surgery. By definition, these are complex, difficult cases and are decreasing in number. However, in vascular units regularly performing the RP approach, excellent results can be obtained. This series provides further evidence for centralization of vascular services. PMID- 24405893 TI - miR-138 inhibits proliferation by targeting 3-phosphoinositide-dependent protein kinase-1 in non-small cell lung cancer cells. AB - OBJECTIVE: Underlying mechanisms of non-small cell lung cancer (NSCLC) development remain poorly understood. miR-138 and 3-phosphoinositide-dependent protein kinase-1 (PDK1) have been reported to be involved in the genesis of NSCLC. The aim of this study was to investigate the role and mechanisms of miR 138 and PDK1 in human NSCLC cells. METHODS: The effect of miR-138 on proliferation of A549 lung cancer cells was first examined using 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay. The expression of PDK1 in A549 lung cancer cells was assessed by real-time polymerase chain reaction further. A luciferase reporter activity assay was conducted to confirm target association between miR-138 and 3' untranslated region (3'-UTR) of PDK1. Finally, the role of PDK1 on proliferation of A549 cells was evaluated by transefection of PDK1 small interfering RNA (siRNA). RESULTS: Proliferation of A549 lung cancer cells was suppressed by miR-138 in a concentration-dependent manner. Furthermore, miR-138 can bind to the 3'-UTR of PDK1 and downregulate expression of PDK1 at both mRNA and protein levels. Knockdown of PDK1 by siRNA significantly inhibits the proliferation of A549 lung cancer cells. CONCLUSIONS: These findings suggest that miR-138 as a potential tumor suppressor could inhibit cell proliferation by targeting PDK1 in NSCLC cells, which could be employed as a potential therapeutic target for miRNA-based NSCLC therapy. PMID- 24405895 TI - Syncope: classification and risk stratification. AB - BACKGROUND: Syncope is one of the most common reasons for emergency department and urgent care clinic visits. The management of syncope continues to be a challenging problem for front-line providers inasmuch as there are a multitude of possible causes for syncope ranging from relatively benign conditions to potentially life-threatening ones. In any event, it is important to identify those syncope patients who are at immediate risk of life-threatening events; these individuals require prompt hospitalization and thorough evaluation. Conversely, it is equally important to avoid unnecessary hospitalization of low risk patients since unneeded hospital care adds to the healthcare cost burden. RESULTS: Historically, front-line providers have taken a conservative approach with admission rates as high as 30-50% among syncope patients. A number of studies evaluating both the short- and long-term risk of adverse events in patients with syncope have focused on development of risk-stratification guidelines to assist providers in making a confident and well-informed choice between hospitalization and out-patient referral. In this regard, a much needed consensus on optimal decision-making process has not been developed to date. However, knowledge from various available risk-stratification studies can be helpful. CONCLUSION: This review summarizes the findings of various risk stratification studies and points out key differences between them. While, the existing risk-stratification methods cannot replace critical assessment by an experienced physician, they do provide valuable guidance. In addition, the various risk-assessment schemes highlight the need for careful initial clinical assessment of syncope patients, selective testing, and being mindful of the short and long-term risks. PMID- 24405896 TI - [Risks and benefits of paracetamol in children with fever]. AB - Worldwide, paracetamol is the most commonly used antipyretic for children and the drug of first choice for reducing fever named in the majority of practice guidelines. However, whether or not it is necessary or desirable to treat fever is questionable. The provision of accurate information on the causes and treatment of fever can decrease the help-seeking behaviour of parents. Paracetamol is both effective and advisable when there is a combination of fever and pain. Fever on its own does not require treatment and doctors should therefore show caution about advising paracetamol for children who have just this symptom. The effect of paracetamol on the general well-being of children with fever on its own has not been unequivocally proven. Treatment with paracetamol for the prevention of febrile convulsions has been proven ineffective. There are indications that inhibiting fever through paracetamol can adversely affect the immune response. The use of paracetamol can produce mild side effects and hepatotoxicity. PMID- 24405897 TI - [Multiple epiphyseal dysplasia: skeletal dysplasia presenting as neuromuscular disease]. AB - BACKGROUND: Multiple epiphyseal dysplasia (MED) is a clinically and genetically heterogeneous skeletal dysplasia. MED is usually inherited as a dominant trait, however, in a quarter of patients it is a recessive trait. Common symptoms of MED are pain and stiffness of joints. However, MED also can present as a neuromuscular disorder with hypotonia and muscle weakness, particularly in childhood. CASE DESCRIPTION: We saw a 7-year-old boy with abnormal gait and slight weakness of the upper legs at our outpatient clinic. Because of his short stature and other skeletal anomalies, skeletal dysplasia was considered. The diagnosis of MED was confirmed by DNA analysis. A mutation in the cartilage oligomeric matrix protein (COMP) gene was found. CONCLUSION: Skeletal dysplasia should be included in the differential diagnosis of children with unexplained neuromuscular symptoms. PMID- 24405898 TI - [A women with a swelling on the shoulder]. AB - A 52-year-old women with diffuse cutaneous systemic sclerosis was examined because of a swollen right acromioclavicular joint after surgery 3 years earlier. Joint aspiration showed serosanguinolent fluid with white amorph material. Polarized microscopy revealed calcium deposits. The diagnosis 'calcinosis cutis' was made. PMID- 24405900 TI - [Coats of arms of the Amsterdam Surgeons' Guild in the dome of the Anatomy Theatre]. AB - In 1731, Cornelis Troost (1696-1750) painted three wardens of the surgeons' guild in Amsterdam. We know their names from the family coats of arms shown on the wall behind them. The same coats of arms and names are painted in the dome of the Anatomy Theatre in the 'Waag', the former weighing house at the Nieuwmarkt in Amsterdam, which also housed the board room of the surgeons' guild. The 84 coats of arms in the beautifully restored dome are a testimony of the rich history of the surgeons' guild. PMID- 24405901 TI - Methicillin-resistant Staphylococcus aureus enterocolitis sequentially complicated with septic arthritis: a case report and review of the literature. AB - BACKGROUND: Although most reports describing patients infected with methicillin resistant Staphylococcus aureus enterocolitis have been published in Japan, this concept remains a matter of debate and diagnostic criteria have not yet been defined. CASE PRESENTATION: The general status of a 74-year-old Japanese man referred to our hospital (day 1) with severe community-acquired pneumococcal pneumonia gradually improved with antibiotic therapy. Thereafter, up to 4 L/day of acute watery diarrhea that started on day 19 was refractory to metronidazole but responded immediately to oral vancomycin. Gram staining stool samples was positive for abundant fecal leukocytes from which dominant methicillin-resistant Staphylococcus aureus (10(4) CFU/mL) were isolated, suggesting methicillin resistant Staphylococcus aureus enterocolitis. High fever with methicillin resistant Staphylococcus aureus bacteremia was evident at day 30, and suppurative right hip arthritis developed around day 71. All methicillin-resistant Staphylococcus aureus strains isolated from stools, blood and aspirated synovial fluid separated in the same manner on pulsed-field gel electrophoresis, as well as two other strains isolated from sputum, belonged to the same clone as sequence type (ST) 764 (complex clonal 5), and carried SCCmec type II. CONCLUSION: The clinical, microbiological and molecular biological findings of this patient indicated methicillin-resistant Staphylococcus aureus enterocolitis that led to septic methicillin-resistant Staphylococcus aureus arthritis. PMID- 24405903 TI - Timely event-related synchronization fading and phase de-locking and their defects in migraine. AB - OBJECTIVE: To investigate the characteristics of event-related synchronization (ERS) fading and phase de-locking of alpha waves during passive auditory stimulation (PAS) in the migraine patients. METHODS: The subjects were 16 adult women with migraine and 16 normal controls. Electroencephalographic (EEG) data obtained during PAS with standard (SS) and deviant stimuli (DS) were used. Alpha ERS fading, the phase locking index (PLI) and de-locking index (DLI) were evaluated from the 10 Hz complex Morlet wavelet components at 100 ms (t100) and 300 ms (t300) after PAS. RESULTS: At t100, significant ERS was found with SS and DS in the migraineurs and controls (P=0.000). At t300 in the controls, ERS faded to zero for DS while in the migraineurs there was no fading for DS. In both groups the PLI for SS and DS was significantly reduced, i.e. de-locked, at t300 compared to t100 (P=0.000). In the migraineurs, the DLI for DS was significantly lower than in the controls (P=0.003). CONCLUSION: The alpha ERS fading and phase de-locking are defective in migraineurs during passive auditory cognitive processing. SIGNIFICANCE: The defects in timely alpha ERS fading and in de locking may play a role in the different attention processing in migraine patients. PMID- 24405902 TI - Downregulation of inhibitory SRC homology 2 domain-containing phosphatase-1 (SHP 1) leads to recovery of T cell responses in elderly. AB - BACKGROUND: Immune responses are generally impaired in aged mammals. T cells have been extensively studied in this context due to the initial discovery of their reduced proliferative capacity with aging. The decreased responses involve altered signaling events associated with the early steps of T cell activation. The underlying causes of these changes are not fully understood but point to alterations in assembly of the machinery for T cell activation. Here, we have tested the hypothesis that the T cell pool in elderly subjects displayed reduced functional capacities due to altered negative feedback mechanisms that participate in the regulation of the early steps of T cell activation. Such conditions tip the immune balance in favor of altered T cell activation and a related decreased response in aging. RESULTS: We present evidence that the tyrosine phosphatase SHP-1, a key regulator of T cell signal transduction machinery is, at least in part, responsible for the impaired T cell activation in aging. We used tyrosine-specific mAbs and Western blot analysis to show that a deregulation of the Csk/PAG loop in activated T cells from elderly individuals favored the inactive form of tyrosine-phosphorylated Lck (Y505). Confocal microscopy analysis revealed that the dynamic movements of these regulatory proteins in lipid raft microdomains was altered in T cells of aged individuals. Enzymic assays showed that SHP-1 activity was upregulated in T cells of aged donors, in contrast to young subjects. Pharmacological inhibition of SHP-1 resulted in recovery of TCR/CD28-dependent lymphocyte proliferation and IL-2 production of aged individuals to levels approaching those of young donors. Significant differences in the active (Y394) and inactive (Y505) phosphorylation sites of Lck in response to T cell activation were observed in elderly donors as compared to young subjects, independently of CD45 isoform expression. CONCLUSIONS: Our data suggest that the role of SHP-1 in T cell activation extends to its increased effect in negative feedback in aging. Modulation of SHP-1 activity could be a target to restore altered T cell functions in aging. These observations could have far reaching consequences for improvement of immunosenescence and its clinical consequences such as infections, altered response to vaccination. PMID- 24405904 TI - HIV-positive females show blunted neurophysiological responses in an emotion attention dual task paradigm. AB - OBJECTIVE: Although HIV is associated with decreased emotional and cognitive functioning, the mechanisms through which affective changes can alter cognitive processes in HIV-infected individuals are unknown. We aimed to clarify this question through testing the extent to which emotionally negative stimuli prime attention to a subsequent infrequently occurring auditory tone in HIV+ compared to HIV- females. METHODS: Attention to emotional compared to non-emotional pictures was measured via the LPP ERP. Subsequent attention was indexed through the N1 and late processing negativity ERP. We also assessed mood and cognitive functioning in both groups. RESULTS: In HIV- females, emotionally negative pictures, compared to neutral pictures, resulted in an enhanced LPP to the pictures and an enhanced N1 to subsequent tones. The HIV+ group did not show a difference in the LPP measure between picture categories, and accordingly, did not show a priming effect to the subsequent infrequent tones. CONCLUSIONS: The ERP findings, combined with neuropsychological deficits, suggest that HIV+ females show impairments in attention to emotionally-laden stimuli and that this impairment might be related to a loss of affective priming. SIGNIFICANCE: This study is the first to provide physiological evidence that the LPP, a measure of attention to emotionally-charged visual stimuli, is reduced in HIV-infected individuals. These results set the stage for future work aimed at localizing brain activation to emotional stimuli in HIV+ individuals. PMID- 24405905 TI - Complexity of functional connectivity networks in mild cognitive impairment subjects during a working memory task. AB - OBJECTIVES: The objective is to study the changes of brain activity in patients with mild cognitive impairment (MCI). Using magneto-encephalogram (MEG) signals, the authors investigate differences of complexity of functional connectivity network between MCI and normal elderly subjects during a working memory task. METHODS: MEGs are obtained from 18 right handed patients with MCI and 19 age matched elderly participants without cognitive impairment used as the control group. The brain networks' complexities are measured by Graph Index Complexity (C(r)) and Efficiency Complexity (C(e)). RESULTS: The results obtained by both measurements show complexity of functional networks involved in the working memory function in MCI subjects is reduced at alpha and theta bands compared with subjects with control subjects, and at the theta band this reduction is more pronounced in the whole brain and intra left hemisphere. CONCLUSIONS: C(e) would be a better measurement for showing the global differences between normal and MCI brains compared with C(r). SIGNIFICANCE: The high accuracy of the classification shows C(e) at theta band can be used as an index for assessing deficits associated with working memory, a good biomarker for diagnosis of MCI. PMID- 24405906 TI - Ultrasonic decontamination of prototype fast breeder reactor fuel pins. AB - Fuel pin decontamination is the process of removing particulates of radioactive material from its exterior surface. It is an important process step in nuclear fuel fabrication. It assumes more significance with plutonium bearing fuel known to be highly radio-toxic owing to its relatively longer biological half life and shorter radiological half life. Release of even minute quantity of plutonium oxide powder in the atmosphere during its handling can cause alarming air borne activity and may pose a severe health hazard to personnel working in the vicinity. Decontamination of fuel pins post pellet loading operation is thus mandatory before they are removed from the glove box for further processing and assembly. This paper describes the setting up of ultrasonic decontamination process, installed inside a custom built fume-hood in the production line, comprising of a cleaning tank with transducers, heaters, pin handling device and water filtration system and its application in cleaning of fuel pins for prototype fast breeder reactor. The cleaning process yielded a typical decontamination efficiency of more than 99%. PMID- 24405908 TI - Inverse association between docosahexaenoic acid and mortality in patients on hemodialysis during over 10 years. AB - We have previously conducted a cohort study to investigate n-3 polyunsaturated fatty acids (PUFAs) in red blood cells (RBCs) and risk of all-cause mortality in hemodialysis (HD) patients over 5 years and found that n-3 PUFAs, especially docosahexaenoic acid (DHA), might be an independent predictor of all-cause mortality. In the present study, we extended the study for another 5 years to determine whether DHA levels in RBCs still predict the mortality of HD patients during a 10-year study period. The study cohort consisted of 176 patients (64.1 +/- 12.0 [mean +/- standard deviation] years of age, 96 men and 80 women) under HD treatment. The fatty acid composition of patients' RBCs was analyzed by gas chromatography. During the study period of 10 years, 97 deaths occurred. After adjustment for 10 confounding factors, the hazard ratio of all-cause mortality of the HD patients in the highest DHA tertile (>8.1%) was 0.52 (95% confidence interval 0.30-0.91) compared with those in the lowest DHA tertile (<7.2%). However, other n-3 PUFAs such as eicosapentaenoic acid and docosapentaenoic acid (n-3) did not reveal any significant correlations. The level of DHA in RBCs could be an independent predictor of all-cause mortality in HD patients even during a long period of follow-up. PMID- 24405907 TI - Health information technology (IT) to improve the care of patients with chronic kidney disease (CKD). AB - Several reports show that patients with chronic disease who are empowered with information technology (IT) tools for monitoring, training and self-management have improved outcomes, however there are few such applications employed in kidney disease. This review explores the current and potential uses of health IT platforms to advance kidney disease care by offering innovative solutions to inform, engage and communicate with individuals with CKD. PMID- 24405909 TI - Backwards and forwards.... PMID- 24405910 TI - Scholarship and the clinical teacher. PMID- 24405911 TI - Sense made common: how to add value to early experience. AB - BACKGROUND: Authentic early experiences (AEEs) have become commonplace in medical curricula. There is a wealth of evidence that students enjoy these experiences, despite significant diversity in context, content and intended purpose between different medical schools. Positive evaluations have rarely explained how or why particular outcomes are achieved, or if unpredicted consequences occurred. AEE is a form of experiential learning, but experience alone is not sufficient for useful learning. Students need support to maximise the potential learning from AEE and minimise undesirable consequences. CONTEXT: This article makes practical suggestions for clinical teachers to add value to AEE. It is based on research that used multiple qualitative methods to further understand AEE. The research sought to address two questions: (1) how and why do students construct useful knowledge and meaning-making from AEE; and (2) how and why do students make AEE work for them? The author draws on her perspective and experience as a practising clinician and clinical teacher to interpret and practically apply research findings. INNOVATION: Clinical teachers can add value to AEE through both actions in the workplace and interactions with their local medical school(s). Suggestions are made to: actively manage expectations; deliberately create legitimacy; proactively manage risk; constructively discuss differences; model connectedness; and develop a consensus understanding of what is 'allowed'. IMPLICATIONS: All of these suggestions are about 'making sense common'. Clinical teachers are encouraged to use questions accompanying the main text to make a self-assessment of their current practice and consider potential changes to provide additional value for students during AEE. PMID- 24405912 TI - Evaluating PLATO: postgraduate teaching and learning online. AB - BACKGROUND: The use of the Internet as a teaching medium has increased rapidly over the last decade. PLATO (postgraduate learning and teaching online) was launched in 2008 by the e-learning unit (ELU) of Wales Deanery. Located within Learning@NHSWales, a Moodle virtual learning environment (VLE), it hosts a wide range of freely available courses and resources tailored to support the education, training and continuing professional development (CPD) needs of health care professionals working across the National Health Service (NHS) Wales. The evaluation aimed to identify the costs and benefits of PLATO, report its value as attributed by users, identify potential cost savings and make recommendations. METHODS: Five courses (case studies) were selected, representing the range of available e-learning resources: e-induction; fetal heart monitoring; cervical screening; GP prospective trainers; and tools for trainers. Mixed methods were used: one-to-one qualitative interviews, focus group discussions and surveys explored user views, and identified individual and organisational value. RESULTS: Qualitative findings identified six key areas of value for users: ELU support and guidance; avoidance of duplication and standardisation; central reference; local control; flexibility for learners; and specific features. Survey results (n=72) indicated 72 per cent of consultants reported that PLATO was easy to access and user friendly. E-learning was rated as 'very/important' for CPD by 79 per cent of respondents. Key challenges were: access, navigation, user concerns, awareness and support. DISCUSSION: PLATO supports education and helps deliver UK General Medical Council standards. Future plans should address the suggested recommendations to realise cost savings for NHS Wales and the Wales Deanery. The findings have wider applicability to others developing or using VLEs. PMID- 24405913 TI - Medical students' online learning technology needs. AB - PURPOSE: This study investigated medical students' online learning technology needs at a medical school. The study aimed to provide evidence-based guidance for technology selection and online learning design in medical education. METHODS: The authors developed a 120-item survey in collaboration with the New Technology in Medical Education (NTIME) committee at the Southern Illinois University School of Medicine (SIUSOM). Overall, 123 of 290 medical students (42%) at the medical school participated in the survey. The survey focused on five major areas: students' hardware and software use; perception of educational technology (ET) in general; online behaviours; perception of ET use at the school; and demographic information. RESULTS: Students perceived multimedia tools, scheduling tools, communication tools, collaborative authoring tools, learning management systems and electronic health records useful educational technologies for their learning. They did not consider social networking tools useful for their learning, despite their frequent use. Third-year students were less satisfied with current technology integration in the curriculum, information sharing and collaborative learning than other years. Students in clerkships perceived mobile devices as useful for their learning. Students using a mobile device (i.e. a smartphone) go online, text message, visit social networking sites and are online during classes more frequently than non-users. CONCLUSIONS: Medical students' ET needs differ between preclinical and clinical years. Technology supporting ubiquitous mobile learning and health information technology (HIT) systems at hospitals and out patient clinics can be integrated into clerkship curricula. PMID- 24405914 TI - Attitude to e-learning among newly qualified doctors. AB - BACKGROUND: e-Learning plays an increasingly important role in medical education. Much research has focused on the evaluation of individual modules among medical students or more senior trainee doctors. We studied the attitude of newly qualified foundation level-1 doctors (FY1s) towards a blended learning programme to gain insight into the perceived role of e-learning in relation to classroom and experiential learning. METHOD: The blended learning strategy consisted of weekly 3-hour sessions of lectures and flexible e-learning sessions. A questionnaire survey was conducted among 54 per cent (37/69) of FY1 doctors, towards the end of their first year post qualification. RESULTS: The majority of FY1s had to carry out additional e-learning outside of work. When asked where was best to carry out e-learning, 54 per cent preferred to e-learn both at work and at home, whereas 38 per cent preferred to e-learn outside of work exclusively. An equal preference for a classroom-only strategy and a blended programme was reported. Seventy-three per cent of the FY1s thought that e-learning should not be part of their compulsory weekly teaching programme. Fifty-four per cent of FY1s thought that e-learning had been useful for their education and training in their FY1 year. The e-learning package cited as being most useful was the safe prescribing e-programme, pioneered locally. CONCLUSION: Newly qualified doctors value e-learning as an adjunct to experiential and lecture-based teaching, and most prefer it as part of a blended learning programme at work or at home. Medical educators must place equal emphasis on the delivery and administration of e-learning as well as on the course design. PMID- 24405915 TI - Using simulation for prescribing: an evaluation. AB - BACKGROUND: Drug errors are a major cause of patient morbidity. The UK General Medical Council has highlighted that prescribing teaching should be prioritised. How should medical teachers best teach the practical aspects of prescribing? METHOD: We piloted a set of eight prescribing simulation tutorials for 35 final year undergraduate medical students in Great Western Hospital, Swindon, UK. Students completed baseline questionnaires addressing confidence levels in prescribing. They then prescribed independently for simulated cases of common medical emergencies within tutor-led tutorials (n = 17) or self-directed prescribing tutorials (n = 18). Confidence scores and numbers of drug errors were documented at baseline and following four tutorials. Drug errors were categorised according to potential harm. Students then swapped to receive the alternative tutorial type. RESULTS: Both tutorial types resulted in a statistically significant decrease in the number of unsafe drug errors: from 57 to three in the tutor-led group (p = 0.003) and from 60 to 14 in the self-directed learning group (p = 0.001). Both tutorial types led to statistically significant increases in confidence scores for global prescribing, prescribing in medical emergencies and managing medical emergencies (with a median increase of one point on a modified Likert scale). Confidence using the British National Formulary improved, but reached statistical significance for the self-directed group only. DISCUSSION: Simulating cases and using real drug charts is an effective method for improving students' prescribing ability and confidence in common medical emergencies. Tutorials like these, whether tutor-led or self-directed, could be incorporated into medical curricula. This could help prevent drug errors in practice, thereby improving patient care and safety. PMID- 24405916 TI - Junior doctor-led practical prescribing course. AB - BACKGROUND: Several authors have studied the transition from medical student to junior doctor. There have been several problems identified, one being prescribing. Junior doctors have been found to be the cause of most of the prescription errors in hospitals. These authors suggest improvements in prescribing teaching, and several describe their own innovations seeking to correct these problems. CONTEXT: As junior doctors in a district general hospital in the UK we had the opportunity to provide teaching to small groups of final year medical students. We had recently begun working as Foundation Year 1 doctors, and had fresh experience of the transition from medical student and the problems that we had encountered with prescribing. We were acutely aware of the commonly made mistakes. INNOVATION: We have designed a short, five-session course covering the practical aspects of prescribing. Assuming that theory had been covered elsewhere, we focused on encouraging the students to prescribe on real drugs charts using information available to junior doctors on the wards. We measured the efficacy of the course by asking the students to rate their own confidence in prescribing in each of the scenarios before and after the session. IMPLICATIONS: The intention was to design and deliver a course that would bridge the gap between pharmacological theory and prescribing in practice. Existing prescribing courses are often taught by senior doctors or pharmacists. We believe that the major strength of this course was that it was designed and delivered by junior doctors, under the supervision of a senior doctor. PMID- 24405917 TI - A prescribing e-tutorial for medical students. AB - BACKGROUND: UK medical students' confidence in their prescribing skills is low, and a significant proportion of prescriptions written by foundation year 1 (FY1) doctors contain errors. The Prescribing Safety Assessment (PSA) is a new national examination aimed at ensuring prescribing competence in undergraduates, but few PSA-specific preparatory resources are available to students. METHODS: A needs analysis was performed and an online e-tutorial (Prepare for the PSA) was designed. The e-tutorial consists mainly of a practise exam that closely mirrors the format of the PSA itself. After completing each question the user receives personalised feedback, and is given the opportunity to further their knowledge using interactive learning activities. A facility for users to contribute their own questions is included, and the e-tutorial also explains the rationale underlying the PSA and directs users to further learning resources. Numerous attempts were made to encourage the use of the e-tutorial amongst UK medical students and educators. A total of 248 final-year students at a UK medical school were asked to evaluate the e-tutorial and rate their prescribing confidence before and after completing it. RESULTS: The response rate in the evaluation was 72.7-73.9 per cent. The results show that completing the e-tutorial is associated with highly significant (p < 0.0001) increases in confidence across all prescribing skills. DISCUSSION: Our e-tutorial is effective and meets the needs of medical students. Once the e-tutorial is disseminated more widely and is expanded by user-contributed questions, we hope that it will become established as a national platform for collaborative prescribing education. PMID- 24405918 TI - Practical prescribing course: a student evaluation. AB - BACKGROUND: Prescribing errors occur in up to 10 per cent of junior doctor prescriptions, and medical students feel underprepared for the challenges of prescribing once qualified. A number of studies have looked into the effectiveness of new interventions, in particular pharmacist-taught prescribing courses, but there is little data on how students perceive these new strategies. The aim of this project was to evaluate a teaching programme of practical prescribing skills, conducted by hospital pharmacists, via a series of focus groups. METHODS: A pharmacist-taught course in practical prescribing was introduced to final-year medical students during clinical placements at five different hospitals. A focus group was conducted at each participating hospital and emerging themes were identified. RESULTS: Key emerging themes from the focus group analysis showed that students felt more confident in prescribing after completing the course. Students valued the opportunity to gain practical prescribing experience by using problem-based exercises, which encouraged them to prescribe on real drug charts, or to spot prescribing errors or drug interactions on charts constructed by pharmacists. Pharmacists were felt to be knowledgeable and approachable teachers. Students highlighted controlled drug prescriptions and familiarity with the British National Formulary (BNF) as key topics that hadn't been covered in conventional pharmacology teaching. DISCUSSION: A practical prescribing course can help prepare medical students by giving them the tools to tackle complex prescribing scenarios. Pharmacists as teachers were well received, and specific topics, including controlled drug prescribing and using sample drug charts, should be the focus of these types of courses. PMID- 24405919 TI - A paediatric social responsiveness project in Thailand. AB - BACKGROUND: A 1-month rotation in Social Paediatrics is compulsory for paediatric residency training in Thailand. Since 1985, the resident doctors (residents) taking this rotation at Prince of Songkla University (PSU) have been assigned to do fieldwork at a primary care hospital, and visit eight health service organisations involved with child rights and child protection. CONTEXT: After 25 years of the Social Paediatrics rotation, we felt that this compulsory rotation was not as effective as it could be. In 2010, the Social Responsiveness Project was conducted in the PSU paediatric residency training as an extracurricular activity, with the basic idea being that residents can play an important role in recognising health problems in the community. INNOVATION: During 2010-2011 the residents organised the Social Responsiveness Project by surveying children's health problems in the CV Crowded Community, and visited the community on one weekend every 3-4 months. IMPLICATIONS: After 2 years of the Social Responsiveness Project, all of the participating residents (n = 17) felt that the programme had been of benefit to them, and had a positive effect on the community, and indicated an intention to continue working in social responsiveness projects in their community after finishing their residency training. Hence, the results of this study indicate that the Social Responsiveness Project is useful for both society at large and for residents in helping young doctors to recognise the problems faced by the children in disadvantaged communities, and what they can do as doctors to help improve the situation of these children. PMID- 24405920 TI - West Yorkshire Mentor Scheme: teaching and development. AB - BACKGROUND: The West Yorkshire Mentoring Scheme (WYMS) was created to provide a framework for clinical supervision, teaching and support by foundation year (FY) doctors for final-year medical students. Although established literature highlights the benefits of near-peer teaching, the accompanying mentoring role has little been explored. This study explored the impact of the WYMS for FY doctors and final-year medical students. METHOD: FY1 mentors were individually paired with fifth-year medical students from the University of Leeds. The scheme aims to provide support, teaching and skills development for both mentors and mentees, as students rotate through clinical placements and assistantships. At the end of each academic year, FY1s and medical students are invited to complete an online questionnaire to highlight their experiences. These data were used to explore the impact of the scheme, and thematic analysis was employed to determine the results. RESULTS: Forty-nine medical students and 122 FY1s responded: 98 per cent of mentors and 100 per cent of mentees would recommend the scheme to their peers. Thematic analysis demonstrated that the scheme proved useful in skills development, teaching supervision and increasing preparedness for work. DISCUSSION: WYMS is well received, beneficial and an excellent, local adjunct to clinical placements. It is of significant value to final-year students and their FY mentors, assisting in the development of student assistantships and clinical placement design. For FY doctors, it is a rewarding scheme that develops essential attributes of time management, communication and leadership for mentors and for the junior doctors who organise the scheme. PMID- 24405921 TI - Supervising the highly performing general practice registrar. AB - BACKGROUND: There is extensive literature on the poorly performing learner. In contrast, there is very little written on supervising the highly performing registrar. Outstanding trainees with high-level knowledge and skills can be a challenge for supervisors to supervise and teach. METHODS: Narrative review and discussion. RESULTS: As with all learners, a learning-needs analysis is fundamental to successful supervision. The key to effective teaching of the highly performing registrar is to contextualise clinical knowledge and skills with the wisdom of accumulated experience. Moreover, supervisors must provide a stimulating learning environment, with regular opportunities for intellectual challenge. The provision of specific, constructive feedback is essential. DISCUSSION: There are potential opportunities to extend the highly performing registrar in all domains of general practice, namely communication skills and patient-centred care, applied knowledge and skills, population health, professionalism, and organisation and legal issues. Specific teaching strategies include role-play, video-consultation review, random case analysis, posing hypothetical clinical scenarios, role modelling and teaching other learners. PMID- 24405922 TI - The prescribing skills assessment. PMID- 24405923 TI - Teaching undergraduate medical students: are we hitting a wall? PMID- 24405924 TI - Is patient satisfaction affected by a student? PMID- 24405925 TI - The patient's perspective. PMID- 24405926 TI - Circassian circle: application of dance techniques for small group teaching. PMID- 24405927 TI - Workplace-based assessments: lost in translation? PMID- 24405932 TI - Don't forget the medical students. PMID- 24405933 TI - Metabolic alterations due to IDH1 mutation in glioma: opening for therapeutic opportunities? PMID- 24405934 TI - Physical activity and health-related quality of life among physiotherapists: a cross sectional survey in an Australian hospital and health service. AB - BACKGROUND: Physiotherapists are a professional group with a high rate of attrition and at high risk of musculoskeletal disorders. The purpose of this investigation was to examine the physical activity levels and health-related quality of life of physiotherapists working in metropolitan clinical settings in an Australian hospital and health service. It was hypothesized that practicing physiotherapists would report excellent health-related quality of life and would already be physically active. Such a finding would add weight to a claim that general physical activity conditioning strategies may not be useful for preventing musculoskeletal disorders among active healthy physiotherapists, but rather, future investigations should focus on the development and evaluation of role specific conditioning strategies. METHODS: A questionnaire was completed by 44 physiotherapists from three inpatient units and three ambulatory clinics (63.7% response rate). Physical activity levels were reported using the Active Australia Survey. Health-related quality of life was examined using the EQ-5D instrument. Physical activity and EQ-5D data were examined using conventional descriptive statistics; with domain responses for the EQ-5D presented in a frequency histogram. RESULTS: The majority of physiotherapists in this sample were younger than 30 years of age (n = 25, 56.8%) consistent with the presence of a high attrition rate. Almost all respondents exceeded minimum recommended physical activity guidelines (n = 40, 90.9%). Overall the respondents engaged in more vigorous physical activity (median = 180 minutes) and walking (median = 135 minutes) than moderate exercise (median = 35 minutes) each week. Thirty-seven (84.1%) participants reported no pain or discomfort impacting their health related quality of life, with most (n = 35,79.5%) being in full health. CONCLUSIONS: Physical-conditioning based interventions for the prevention of musculoskeletal disorders among practicing physiotherapists may be better targeted to role or task specific conditioning rather than general physical conditioning among this physically active population. It is plausible that an inherent attrition of physiotherapists may occur among those not as active or healthy as therapists who cope with the physical demands of clinical practice. Extrapolation of findings from this study may be limited due to the sample characteristics. However, this investigation addressed the study objectives and has provided a foundation for larger scale longitudinal investigations in this field. PMID- 24405935 TI - MicroRNA-20b and ERK1/2 pathway independently regulate the expression of tissue factor in hematopoietic and trophoblastic differentiation of human embryonic stem cells. AB - INTRODUCTION: Tissue factor (TF) is expressed in various types of cells. TF expression is essential for many biological processes, such as blood coagulation and embryonic development, while its high expression in stem cells often leads to failure of transplantation. In this study, we used the human embryonic stem cell (hESC) culture system to understand the molecular mechanisms by which TF expression is regulated in hESC-derived hematopoietic and trophoblastic cells. METHODS: hESCs were induced in vitro to differentiate into hematopoietic and trophoblastic cells. TF expression in various types of cells during these differentiation processes was examined by quantitative real-time polymerase chain reaction analysis and western blot analysis. The regulatory mechanisms of TF expression were investigated by miRNA expression analysis, luciferase report assay, TF mRNA and protein analysis, and pathway phosphorylation analysis. RESULTS: We first found that TF was expressed only in trophoblasts and granulocyte-monocyte (G-M) cells differentiated from hESCs; and then demonstrated that miR-20b downregulated and Erk1/2 signaling pathway upregulated the TF expression in trophoblasts and G-M cells. Finally, we found that miR-20b downregulated the TF expression independently of the Erk1/2 signaling pathway. CONCLUSIONS: The miR-20b and Erk1/2 pathway independently regulate expression of TF in trophoblasts and G-M cells differentiated from hESCs. These findings will open an avenue to further illustrate the functions of TF in various biological processes. PMID- 24405936 TI - Objectively measured physical activity in four-year-old British children: a cross sectional analysis of activity patterns segmented across the day. AB - BACKGROUND: Little is known about preschool-aged children's levels of physical activity (PA) over the course of the day. Using time-stamped data, we describe the levels and patterns of PA in a population-based sample of four-year-old British children. METHODS: Within the Southampton Women's Survey the PA levels of 593 4-year-old children (51% female) were measured using (Actiheart) accelerometry for up to 7 days. Three outcome measures: minutes spent sedentary (<20 cpm); in light (LPA: >=20-399 cpm) and in moderate-to-vigorous activity (MVPA: >=400 cpm) were derived. Average daily activity levels were calculated and then segmented across the day (morning, afternoon and evening). MVPA was log transformed. Two-level random intercept models were used to analyse associations between activity level and temporal and demographic factors. RESULTS: Children were active for 67% (mean 568.5 SD 79.5 minutes) of their daily registered time on average, with 88% of active time spent in LPA. All children met current UK guidelines of 180 minutes of daily activity. There were no differences in children's average daily levels of sedentary activity and LPA by temporal and demographic factors: differences did emerge when activity was segmented across the day. Sex differences were largest in the morning, with girls being more sedentary, spending fewer minutes in LPA and 18% less time in MVPA than boys. Children were more sedentary and less active (LPA and MVPA) in the morning if they attended childcare full-time compared to part-time, and on weekend mornings compared to weekdays. The reverse was true for weekend afternoons and evenings. Children with more educated mothers were less active in the evenings. Children were less sedentary and did more MVPA on summer evenings compared to winter evenings. CONCLUSIONS: Preschool-aged children meet current physical activity guidelines, but with the majority of their active time spent in LPA, investigation of the importance of activity intensity in younger children is needed. Activity levels over the day differed by demographic and temporal factors, highlighting the need to consider temporality in future interventions. Increasing girls' morning activity and providing opportunities for daytime activity in winter months may be worthwhile. PMID- 24405938 TI - The protective effects and genetic pathways of thorn grape seeds oil against high glucose-induced apoptosis in pancreatic beta-cells. AB - BACKGROUND: Excessive apoptosis of beta-cell is closely related to diabetes mellitus. Chronic exposure to high glucose causes beta-cell dysfunction and apoptosis in diabetes. Thorn grape (Vitis davidii Foex.) has been used to treat diabetes in Traditional Chinese medicine for many years. In our previous research, thorn grape seeds oil (TGSO) showed promising anti-diabetic effects in animal models. However, it is unknown whether TGSO played an anti-apoptotic role in the anti-diabetic effects and the mechanism regarding signal transduction pathway is unclear either. METHODS: The rattus pancreatic beta-cell line RIN-m5F was treated with/without TGSO which was extracted by supercritical carbon dioxide (CO2) fluid extraction and analyzed by Gas Chromatography/Mass Spectrometry (GC/MS). Cell apoptosis was detected by fluorescence activated cell sorting (FACS), insulin secretion was assayed by Enzyme-Linked Immunosorbent Assay (ELISA), and the apoptosis-related genes expressions were evaluated by quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR). RESULTS: TGSO, containing 87.02% unsaturated fatty acids (UFAs), significantly reduced pancreatic beta-cell apoptosis and protected the insulin secretion impaired by high glucose. The expressions of pro-apoptotic genes such as iNOS, Caspase-3, ATF 3, JNK, p38 and Fas were down-regulated while the anti-apoptotic genes Akt and Bcl-2/Bax were up-regulated. CONCLUSIONS: The results indicated that TGSO protected beta-cells from high glucose-induced apoptosis and its protective activity may be linked to mitochondrial pathway, endoplasmic reticulum (ER) stress pathway and Fas signal pathway, which implied that TGSO might be an effective complementary or alternative medicine to reduce beta-cell apoptosis and dysfunction. PMID- 24405939 TI - Genetic diversity and domestication origin of tea plant Camellia taliensis (Theaceae) as revealed by microsatellite markers. AB - BACKGROUND: Tea is one of the most popular beverages in the world. Many species in the Thea section of the Camellia genus can be processed for drinking and have been domesticated. However, few investigations have focused on the genetic consequence of domestication and geographic origin of landraces on tea plants using credible wild and planted populations of a single species. Here, C. taliensis provides us with a unique opportunity to explore these issues. RESULTS: Fourteen nuclear microsatellite loci were employed to determine the genetic diversity and domestication origin of C. taliensis, which were represented by 587 individuals from 25 wild, planted and recently domesticated populations. C. taliensis showed a moderate high level of overall genetic diversity. The greater reduction of genetic diversity and stronger genetic drift were detected in the wild group than in the recently domesticated group, indicating the loss of genetic diversity of wild populations due to overexploitation and habitat fragmentation. Instead of the endangered wild trees, recently domesticated individuals were used to compare with the planted trees for detecting the genetic consequence of domestication. A little and non-significant reduction in genetic diversity was found during domestication. The long life cycle, selection for leaf traits and gene flow between populations will delay the emergence of bottleneck in planted trees. Both phylogenetic and assignment analyses suggested that planted trees may have been domesticated from the adjacent central forest of western Yunnan and dispersed artificially to distant places. CONCLUSIONS: This study contributes to the knowledge about levels and distribution of genetic diversity of C. taliensis and provides new insights into genetic consequence of domestication and geographic origin of planted trees of this species. As an endemic tea source plant, wild, planted and recently domesticated C. taliensis trees should all be protected for their unique genetic characteristics, which are valuable for tea breeding. PMID- 24405937 TI - The European COPHES/DEMOCOPHES project: towards transnational comparability and reliability of human biomonitoring results. AB - COPHES/DEMOCOPHES has its origins in the European Environment and Health Action Plan of 2004 to "develop a coherent approach on human biomonitoring (HBM) in Europe". Within this twin-project it was targeted to collect specimens from 120 mother-child-pairs in each of the 17 participating European countries. These specimens were investigated for six biomarkers (mercury in hair; creatinine, cotinine, cadmium, phthalate metabolites and bisphenol A in urine). The results for mercury in hair are described in a separate paper. Each participating member state was requested to contract laboratories, for capacity building reasons ideally within its borders, carrying out the chemical analyses. To ensure comparability of analytical data a Quality Assurance Unit (QAU) was established which provided the participating laboratories with standard operating procedures (SOP) and with control material. This material was specially prepared from native, non-spiked, pooled urine samples and was tested for homogeneity and stability. Four external quality assessment exercises were carried out. Highly esteemed laboratories from all over the world served as reference laboratories. Web conferences after each external quality assessment exercise functioned as a new and effective tool to improve analytical performance, to build capacity and to educate less experienced laboratories. Of the 38 laboratories participating in the quality assurance exercises 14 laboratories qualified for cadmium, 14 for creatinine, 9 for cotinine, 7 for phthalate metabolites and 5 for bisphenol A in urine. In the last of the four external quality assessment exercises the laboratories that qualified for DEMOCOPHES performed the determinations in urine with relative standard deviations (low/high concentration) of 18.0/2.1% for cotinine, 14.8/5.1% for cadmium, 4.7/3.4% for creatinine. Relative standard deviations for the newly emerging biomarkers were higher, with values between 13.5 and 20.5% for bisphenol A and between 18.9 and 45.3% for the phthalate metabolites. Plausibility control of the HBM results of all participating countries disclosed analytical shortcomings in the determination of Cd when using certain ICP/MS methods. Results were corrected by reanalyzes. The COPHES/DEMOCOPHES project for the first time succeeded in performing a harmonized pan-European HBM project. All data raised have to be regarded as utmost reliable according to the highest international state of the art, since highly renowned laboratories functioned as reference laboratories. The procedure described here, that has shown its success, can be used as a blueprint for future transnational, multicentre HBM projects. PMID- 24405940 TI - Epilepsy beyond seizure: a population-based study of comorbidities. AB - Comorbid conditions may affect the quality of life in persons with epilepsy (PWE) more than seizures. Using legally mandated healthcare encounter data, somatic, psychiatric, and neurodevelopmental comorbidities in a large population-based cohort of PWE, were compared to persons with migraine (PWM), a similar neurologic condition, and lower extremity fracture (PWLF), otherwise healthy controls. 64,188 PWE, 121,990 PWM, and 89,808 PWLF were identified from inpatient, outpatient, and emergency department from 2000 to 2011. Epilepsy was ascertained with ICD-9-CM code 345; migraine with 346; fracture of the tibia, fibula, and ankle with 823 and 824. Common comorbidities of epilepsy were identified from the literature. Differences in prevalence among PWE, PWM, and PWLF were assessed by comparison of 95% confidence intervals (CI) constructed under the assumption of independence and normal approximation. The association of the comorbid conditions with epilepsy and migraine, compared to lower extremity fracture, were evaluated with polytomous logistic regression controlling for demographic and mortality covariables. PWE had significantly elevated prevalence of comorbidities compared with PWM and PWLF. Compared with PWLF, the adjusted odds ratios (OR) of having both somatic and psychiatric/neurodevelopmental comorbidities were 5.44 (95% CI=5.25-5.63) and 2.49 (95% CI=2.42-2.55) in PWE and PWM, respectively. The association with epilepsy was the strongest for cognitive dysfunction (OR=28.1; 95% CI=23.3-33.8); autism spectrum disorders (OR=22.2; 95% CI=16.8-29.3); intellectual disability (OR=12.9; 95% CI=11.6-14.3); and stroke (OR=4.2; 95% CI=4.1-4.4). The absolute risk increase in PWE compared with PWM for any somatic or psychiatric/neurodevelopmental comorbidity was 58.8% and 94.3%, respectively. Identifying comorbidities that are strongly and consistently associated with seizures, particularly disorders with shared underlying pathophysiology, is critical in identifying specific research and practice goals that may ultimately improve the quality of life for PWE. This study contributes to that effort by providing population-based comorbidity data for PWE compared with PWM and PWLF. PMID- 24405941 TI - Incidence of pulmonary non-epithelial tumors: 18 years' experience at a single institute. AB - Primary and metastatic non-epithelial tumors of the lung and pleura (NETs-LP) are presumed to represent a small proportion of pulmonary neoplasm, and their epidemiologic characterization is lacking. Moreover, classification of pulmonary mesenchymal tumor according to 'WHO Classification of Tumors of Lung and Pleura' (2004) is simple and necessary to give a supplementation like new 'WHO Classification of Tumors of Soft Tissue and Bone' (2013). Non-epithelial tumors of the lung and pleura diagnosed from January 1995 to April 2013 were retrospectively reviewed and classified in accordance with 'WHO Classification of Tumors of Soft Tissue and Bone' (2013). Of 681 cases represented in the study, smooth muscle tumor (13.1%) was most common, and tumor of uncertain differentiation (10.5%) and fibroblastic/myofibroblastic tumor (5.7%) were followed. Smooth muscle tumor (12.6%) was the common primary tumor, whereas chondrogenic or osteogenic tumor (21.6%) was common in metastatic ones. Pulmonary vascular sarcoma (n=15) was the most frequent primary pulmonary sarcoma with following synovial sarcoma (n=9) and malignant type of solitary fibrous tumor (n=9). This study is the first trial of epidemiologic investigation in Korea about NETs-LP, indirectly representing their incidence in Korea and northeast Asia, and we hope that this presentation offers guidance in further study of NETs LP. PMID- 24405942 TI - Dedifferentiated chondrosarcoma mimicking a giant cell tumor. Is this low grade dedifferentiated chondrosarcoma? AB - We report a very rare case of a dedifferentiated chondrosarcoma mimicking a benign giant cell tumor. A 22-year-old male was admitted to our hospital with a history of mild left wrist pain after a skiing trauma. Radiology revealed an extensive meta-epiphyseal osteolytic lesion in the distal ulna, which appeared to be a giant cell tumor. Histological examination showed a biphasic tumor comprising chondroid and non-chondroid areas with a giant cell-rich lesion resembling a conventional giant cell tumor of the bone. Immunohistochemistry showed no expression of p16(INK4a), VEGFR1, KDR (VEGFR2), VEGFR3, cKIT, MDM2 or CDK4. However, high expression of the tyrosine kinases PDGFRA and PDGFRB was observed. Molecular analysis showed no amplification of the cMYC gene and no activating mutations in the cKIT (exons 9 and 11) or PDGFRA (exon 18) genes. He has been on follow-up for ten months, with no evidence of local recurrence or metastatic disease. In summary, this report highlights a very rare case of a dedifferentiated chondrosarcoma in which the dedifferentiated component of the tumor bears histologic resemblance to a conventional giant cell tumor of bone. We suggest that this tumor might be categorized in the group of low-grade dedifferentiated chondrosarcomas. PMID- 24405944 TI - When does ultrasonography influence management in suspected appendicitis? AB - BACKGROUND: Accurate diagnosis of appendicitis is challenging, particularly in children. Moreover, opinion is divided over the role of ultrasonography (US) in its diagnosis and how US may influence management. This study compares the use of US in two tertiary paediatric hospitals and how it influenced the management of suspected appendicitis. METHODS: Data from acute admissions, radiology, histopathology and theatre were cross-referenced to review all children who underwent an appendicectomy (with or without preoperative US) for suspected appendicitis in Christchurch (CH) in New Zealand and Aberdeen (AB) in Scotland in 2009. RESULTS: Five hundred and ninety-nine patients (442 CH; 157 AB) were included, with similar age and gender distributions. US was performed in 23% of patients with an overall appendix visualization rate of 29%. The overall positive and negative predictive values were 67% and 100%, respectively. Females were more likely to have US than males (P < 0.001, chi(2) ). In females with no appendix seen on US, in the presence or absence of other pathology, a normal appendix was confirmed in 50% and 58%, respectively. Visualizing the appendix resulted in a lower rate of normal appendix at operation (20%, 4/20) compared with when the appendix was not visualized (56%, 14/25). CONCLUSION: Identification of a normal appendix on US seems sufficiently accurate to exclude appendicitis with confidence, while positive US should be interpreted in conjunction with the clinical features in influencing the decision to operate. The incidence of a non inflamed appendix at operation could be reduced with an increased rate of appendiceal visualization by sonographers. PMID- 24405945 TI - Cyclin-dependent kinases as therapeutic targets in melanoma. AB - Decades of scientific insights have led to a recent expansion of the therapeutic menu for melanoma. Despite these advances, the current targeted therapies and immune checkpoint agents continue to yield suboptimal response and cure rates. Hitherto, the most effective targeted therapy strategies have centered on effectors in the mitogen-activated protein kinase (MAPK) pathway. This review focuses on the emerging evidence of combinatorial approaches targeting both MAPK signaling and dysregulations in cell-cycle checkpoints. We discuss the prospects and limitations of utilizing strategies that promote cellular senescence, such as inhibition of the interphase cyclin-dependent kinases (CDKs) and highlight the current state of CDK drug discovery in melanoma. PMID- 24405946 TI - Exosomes: an emerging factor in stress-induced immunomodulation. AB - Cells constitutively release small (40-100 nm) vesicles known as exosomes, but their composition and function changes in response to a variety of physiological challenges, such as injury, infection, and disease. Advances in our understanding of the immunological relevance of exosomes have been made, however, few studies have explored their role in stress physiology. Exposure to a variety of acute stressors facilitates the efficacy of innate immune responses, but the mechanisms for these effects are not fully understood. Since exosomes are emerging as important inflammatory mediators, they likely exhibit a similar role when an organism is exposed to an acute stressor. Here, we review our current knowledge of the basic properties and immunological functions of exosomes and provide emerging data supporting the role of stress-modified exosomes in regulating the innate immune response, potentially enabling long-distance cellular communication and obviating the need for direct cell-to-cell contact. PMID- 24405947 TI - Mid-infrared diffuse reflection on ultrafast time scales. AB - This paper describes an instrument capable of studying diffuse reflection of mid infrared (mid-IR) photons on ultrafast time scales. Femtosecond mid-IR pulses are generated by difference frequency mixing the output of an optical parametric amplifier that is pumped using a regeneratively amplified Ti:Sapphire laser. Time resolution is achieved by up-converting the diffusely reflected photons with pulses from the Ti:Sapphire oscillator. Experiments were performed on a series of powdered KBr samples containing varying amounts of carbon black. The results suggest that diffusely reflected mid-IR photons fall into two distinct categories. A small fraction of the photons travel relatively long effective path lengths (1.3-2.3 mm), while the majority traverse a much shorter distance (0.2 0.05 mm). PMID- 24405943 TI - Identification of conserved RNA secondary structures at influenza B and C splice sites reveals similarities and differences between influenza A, B, and C. AB - BACKGROUND: Influenza B and C are single-stranded RNA viruses that cause yearly epidemics and infections. Knowledge of RNA secondary structure generated by influenza B and C will be helpful in further understanding the role of RNA structure in the progression of influenza infection. FINDINGS: All available protein-coding sequences for influenza B and C were analyzed for regions with high potential for functional RNA secondary structure. On the basis of conserved RNA secondary structure with predicted high thermodynamic stability, putative structures were identified that contain splice sites in segment 8 of influenza B and segments 6 and 7 of influenza C. The sequence in segment 6 also contains three unused AUG start codon sites that are sequestered within a hairpin structure. CONCLUSIONS: When added to previous studies on influenza A, the results suggest that influenza splicing may share common structural strategies for regulation of splicing. In particular, influenza 3' splice sites are predicted to form secondary structures that can switch conformation to regulate splicing. Thus, these RNA structures present attractive targets for therapeutics aimed at targeting one or the other conformation. PMID- 24405948 TI - Phase-sensitive detection in modulation excitation spectroscopy applied to potential induced electron transfer in cytochrome c oxidase. AB - Cytochrome c oxidase (CcO) from Rhodobacter sphaeroides was investigated by modulated excitation surface-enhanced infrared-absorption spectroscopy (SEIRAS). Sequential electron transfer (ET) within CcO was initiated by electrochemical excitation. During modulated excitation by periodic potential pulses with frequencies between 20 and 500 Hz, time-resolved infrared spectra were measured by the step-scan technique, with time resolution in the millisecond range. Conformational changes of the protein structure as a result of ET lead to rather complex SEIRA spectra with many overlapping bands embedded in a broad background signal. Phase-sensitive detection (PSD) was used to separate single components within the broad band of overlapping structural bands in the amide I region. PSD is able to extract the periodic response of single components with the same frequency as the excitation from noise or from static background and therefore enhances the signal-to-noise ratio. Moreover, PSD enables validation of the fit model used for the deconvolution of overlapping bands by analyzing phase lags of single components acquired at different stimulation frequencies. Phase lags between the evaluated vibrational components and the modulated excitation increase with increasing excitation frequencies, an inherent prerequisite of this evaluation method. PMID- 24405949 TI - Combining cryogenic fiber optic probes with commercial spectrofluorimeters for the synchronous fluorescence Shpol'skii spectroscopy of high molecular weight polycyclic aromatic hydrocarbons. AB - Cryogenic fiber optic probes are combined for the first time with a commercial spectrofluorometer for Shpol'skii spectroscopy measurements at liquid nitrogen (77 K) and liquid helium (4.2 K) temperatures. Accurate and reproducible acquisition of fluorescence spectra and signal intensities is demonstrated with three well known Shpol'skii systems, namely, anthracene/heptane, pyrene/hexane, and benzo[a]pyrene/octane. The ability to adjust the excitation and emission bandpass of the spectrofluorimeter to reach both site-resolution and analytically valuable signal-to-noise ratios was illustrated with benzo[a]pyrene in n-octane. The analytical potential of 4.2 K synchronous fluorescence Shpol'skii spectroscopy for the analysis of high molecular weight-polycyclic aromatic hydrocarbons was then explored for the first time. The judicious optimization of wavelength offsets permitted the successful determination of dibenzo[a,l]pyrene, dibenzo[a,e]pyrene, dibenzo[a,h]pyrene, dibenzo[a,i]pyrene, and naphtho[2,3 a]pyrene without previous chromatographic separation from a soil extract with complex matrix composition. The simplicity of the experimental procedure, the competitive analytical figures of merit, and the selectivity of analysis turn 4.2 K synchronous fluorescence Shpol'skii spectroscopy into a valuable alternative for screening isomers of high molecular weight polycyclic aromatic hydrocarbons in environmental samples. PMID- 24405950 TI - Analysis of arc emission spectra of stainless steel electric arc furnace slag affected by fluctuating arc voltage. AB - Control of chromium oxidation in the electric arc furnace (EAF) is a significant problem in stainless steel production due to variations of the chemical compositions in the EAF charge. One potential method to control chromium oxidation is to analyze the emission spectrum of the electric arc in order to find indicators of rising chromium content in slag. The purpose of this study was to determine if slag composition can be gained by utilizing electric arc emission spectra in the laboratory environment, despite electric arc voltage fluctuations and varying slag composition. The purpose of inducing voltage fluctuation was to simulate changes in the industrial EAF process. The slag samples were obtained from Outokumpu Stainless Oy Tornio Works, and three different arc currents were used. The correlation analysis showed that the emission spectra offer numerous peak ratios with high correlations to the X-ray fluorescence-measured slag CrO(x)/FeO(x) and MnO/SiO2 ratios. These ratios are useful in determining if the reduction agents have been depleted in the EAF. The results suggest that analysis of laboratory-scale electric arc emission spectra is suitable for indicating the high CrO(x) or MnO content of the slag despite the arc fluctuations. Reliable analysis of other slag components was not successful. PMID- 24405951 TI - Pressure effects in laser-induced plasmas of trinitrotoluene and pyrene by laser induced breakdown spectroscopy (LIBS). AB - The influence of the ambient atmosphere on the dynamics of plasma expansion, besides the interaction between excited plasma and gas molecules, has been studied for specific organic aromatic compounds. To analyze the influence of air on the formation pathways of atomic and molecular species inside the plasma plume, the spectral emissions in laser-induced breakdown spectroscopy (LIBS) of 2,4,6-trinitrotoluene (TNT) and pyrene were compared at different pressure environments, from high vacuum to atmospheric pressure. Pelletized samples of the compounds were introduced in a vacuum chamber for excitation with the fourth harmonic output of an Nd : YAG laser (266 nm). The optical emission signal was collected with an optical fiber connected to a spectrograph fitted with a intensified charge-coupled device detector. Results from LIBS spectra indicate that changes in pressure level affect the kinetics of the characteristic excited species and their spatial distribution inside the plasma plume. PMID- 24405952 TI - In situ monitoring of thermal crystallization of ultrathin tris(8 hydroxyquinoline) aluminum films using surface-enhanced Raman scattering. AB - Thermal crystallization of 3, 10, and 60 nm-thick tris(8 hydroxyquinoline)aluminum (Alq3) films is studied using surface-enhanced Raman scattering with a constant heating rate. An abrupt higher frequency shift of the quinoline-stretching mode is found to be an indication of a phase transition of Alq3 molecules from amorphous to crystalline. While the 60 nm-thick film shows the same crystallization temperature as a bulk sample, the thinner films were found to have a lower crystallization temperature and slower rate of crystallization. Non-isothermal kinetics analysis is performed to quantify kinetic properties such as the Avrami exponent constants and crystallization rates of ultrathin Alq3 films. PMID- 24405953 TI - Raman spectroscopic investigation of thorium dioxide-uranium dioxide (ThO2-UO2) fuel materials. AB - Raman spectroscopic investigations were carried out on proposed nuclear fuel thorium dioxide-uranium dioxide (ThO2-UO2) solid solutions and simulated fuels based on ThO2-UO2. Raman spectra of ThO2-UO2 solid solutions exhibited two-mode behavior in the entire composition range. Variations in mode frequencies and relative intensities of Raman modes enabled estimation of composition, defects, and oxygen stoichiometry in these compounds that are essential for their application. The present study shows that Raman spectroscopy is a simple, promising analytical tool for nondestructive characterization of this important class of nuclear fuel materials. PMID- 24405954 TI - Solution and solid trinitrotoluene (TNT) photochemistry: persistence of TNT-like ultraviolet (UV) resonance Raman bands. AB - We examined the 229 nm deep-ultraviolet resonance Raman (DUVRR) spectra of solution and solid-state trinitrotoluene (TNT) and its solution and solid-state photochemistry. Although TNT photodegrades with a solution quantum yield of phi ~ 0.015, the initial photoproducts show DUVRR spectra extraordinarily similar to pure TNT, due to the similar photoproduct enhancement of the -NO2 stretching vibrations. This results in TNT-like DUVRR spectra even after complete TNT photolysis. These ultraviolet resonance Raman spectral bands enable DUVRR of trace as well as DUVRR standoff TNT detection. We determined the structure of various initial TNT photoproducts by using liquid chromatography-mass spectrometry and tandem mass spectrometry. Similar TNT DUVRR spectra and photoproducts are observed in the solution and solid states. PMID- 24405955 TI - Infrared and Raman imaging for characterizing complex biological materials: a comparative morpho-spectroscopic study of colon tissue. AB - Complementary diagnostic methods to conventional histopathology are currently being investigated for developing rapid and objective molecular-level understanding of various disorders, especially cancers. Spectral histopathology using vibrational spectroscopic imaging has been put in the frontline as potentially promising in this regard as it provides a "spectral fingerprint" of the biochemical composition of cells and tissues. In order to ascertain the feasible conditions of vibrational spectroscopic methods for tissue-imaging analysis, vibrational multimodal imaging (infrared transmission, infrared attenuated total reflection, and Raman imaging) of the same colon tissue has been implemented. The spectral images acquired were subjected to multivariate clustering analysis in order to identify on a molecular level the constituent histological organization of the colon tissue such as the epithelium, connective tissue, etc., by comparing the cluster images with the histological reference images. Based on this study, a comparative analysis of important factors involved in the vibrational multimodal imaging approaches such as image resolution, time constraints, their advantages and limitations, and their applicability to biological tissues has been carried out. Out of the three different vibrational imaging modalities tested, infrared-attenuated total reflection mode of imaging appears to provide a good compromise between the tissue histology and the time constraints in achieving similar image contrast to that of Raman imaging at an approximately 33-fold faster measurement time. The present study demonstrates the advantages, the limitations of the important parameters involved in vibrational multimodal imaging approaches, and their potential application toward imaging of biological tissues. PMID- 24405956 TI - High-throughput operando Raman-quadrupole mass spectrometer (QMS) system to screen catalytic systems. AB - This paper describes the design and setup of a high-throughput Raman system for an array of eight parallel catalytic reactors during reaction conditions. The "operando" methodology combines in situ spectroscopy during catalytic reaction with a simultaneous activity measurement. The high-throughput operando Raman system, multi-operando, is a device that automates this operando methodology for several catalyst samples at the same time, all samples being in the same reaction conditions. We describe how the system is made, how Raman system positions and acquires spectra, and how each reactor outlet gas is selected and analyzed. PMID- 24405957 TI - The identification and differentiation of secondary colorectal cancer in human liver tissue using X-ray fluorescence, coherent scatter spectroscopy, and multivariate analysis. AB - Secondary colorectal liver cancer is the most widespread malignancy in patients with colorectal cancer. The aim of this study is to identify and differentiate between normal liver tissue and malignant secondary colorectal liver cancer tissue using X-ray scattering and X-ray fluorescence spectroscopy to investigate the best combination of data that can be used to enable classification of these two tissue types. X-ray fluorescence (XRF) and coherent scatter data were collected for 24 normal and 24 tumor matched pair tissue samples. The levels of 12 elements (P, S, K, Ca, Cr, Fe, Cu, Zn, As, Se, Br, and Rb) were measured in all samples. When comparisons were made between normal and tumor tissues, statistically significant differences were determined for K (p = 0.046), Ca (p = 0.040), Cr (p = 0.011), Fe, Cu, Zn, Br, and Rb (p < 0.01). However, for P, S, As, and Se, no statistically significant differences were found (p > 0.05). For the coherent scatter spectra collected, three peaks due to adipose, fibrous content, and water content of tissue were observed. The amplitude, full width half maximum, and area under both fibrous content and water content peaks were found to be significantly higher in secondary colorectal liver tumors compared with surrounding normal liver tissue (p < 0.05). However, no significant differences were found for the adipose peak parameters (p > 0.05). Soft independent modeling of class analogy was performed using the XRF, coherent scatter, and elemental ratio data separately, and the accuracy of the classification of 20 unknown samples was found to be 50, 30, and 80%, respectively. Further analysis has shown that using a combination of the XRF and coherent scatter data in a single combined model gave improved normal and tumor liver tissue classification, with an accuracy that was found to be 85%. PMID- 24405958 TI - An attenuated total reflection Fourier transform infrared (ATR FT-IR) spectroscopic study of gas adsorption on colloidal stearate-capped ZnO catalyst substrate. AB - Attenuated total reflection Fourier transform infrared (ATR FT-IR) spectroscopy has been applied in situ to study gas adsorption on a colloidal stearate-capped zinc oxide (ZnO) surface. Infrared spectra of a colloidal stearate-capped ZnO catalyst substrate were assigned at room temperature using zinc stearate as a reference compound. Heating was shown to create a monodentate species that allowed conformational change to occur, leading to altered binding geometry of the stearate ligands upon cooling. CO2 and H2 adsorption measurements demonstrated that the ligand shell was permeable and did not cover the entire surface, allowing adsorption and reaction with at least some portion of the ZnO surface. It has been demonstrated that stearate ligands did not prevent the usual chemisorption processes involved in catalytic reactions on a model ZnO catalyst system, yet the ligand-support system is dynamic under representative reaction conditions. PMID- 24405959 TI - Concentration-based measurement studies of L-tryptophan using terahertz time domain spectroscopy (THz-TDS). AB - L-Tryptophan is an extremely important amino acid for a variety of biological functions in living organisms. In this study we were able to measure changes in the concentration of L-tryptophan when incorporated into pellets with polyethylene as a host. The changes were measured both through the characteristic absorption bands of the C11 and C12 bonds in the low terahertz frequency range and using changes in the refractive index where pellets with higher concentrations of L-tryptophan showed higher refractive indices. The volumetric concentration of L-tryptophan in the polyethylene pellet was accurately determined with a simple model that explains the contribution to the complex refractive index for the resultant sample due to the two constituent materials. These measurements show that terahertz time-domain techniques can be applied to detect variation in concentration of certain amino acids rapidly by examining the relative phase delay and amplitude change of the terahertz transients. PMID- 24405960 TI - Spectroscopic investigation of direct current (DC) plasma electrolytic oxidation of zirconium in citric acid. AB - Plasma electrolytic oxidation of zirconium in citric acid was investigated using optical spectroscopy. A rich emission spectrum consisting of about 360 zirconium and 170 oxygen atomic and ionic lines was identified in the spectral regions 313 320, 340-516, and 626-640 nm. It was shown that the remaining features observed in the spectrum could be ascribed to various molecular species, which involve zirconium, oxygen, hydrogen, and carbon. The temperature of the plasma core (T = 7500 +/- 1000 K) was determined using measured Zr line intensities, and the temperature of peripheral plasma zone (T = 2800 +/- 500 K) was estimated from the intensity distribution within a part of an OH spectrum. The composition of the plasma containing zirconium, oxygen, and hydrogen, under assumption of local thermal equilibrium, was calculated in the temperature range up to 12,000 K and for pressure of 10(5) and 10(7) Pa, in order to explain the appearance of the observed spectral features. PMID- 24405961 TI - Fourier transform infrared (FT-IR) spectromicroscopy to identify cell organelles: correlation with fluorescence staining in MCF-7 breast cancer cells. AB - Biomolecules display specific vibrational signatures in the infrared (IR) range, and organelles that concentrate these biomolecules can be identified by these IR signatures. Subcellular identification and location of cell organelles using IR signatures is attractive as it does not require the use of any specific trackers and is thus non-invasive and non-destructive. We show here that endogenous IR absorptions are relevant to detecting and imaging the nucleus, the cytoplasm, and the Golgi apparatus/endoplasmic reticulum in MCF-7 breast cancer cells, and we compare these results with our previous work on the HeLa cell line. We correlate maps of fixed and dried cells obtained by synchrotron radiation Fourier transform infrared (SR FT-IR) spectromicroscopy with epifluorescence images using fluorescent trackers for Golgi apparatus and nucleus, namely BODIPY TR C5 ceramide complexed to BSA and DAPI, respectively. Interestingly, the ratios of the IR bands CH2 : CH3 (both asymmetric and symmetric) and CO((ester)):amide I were shown to be reliable gauges of the lipidic character of a cellular compartment, the -CH2 and the CO((ester)) absorptions increasing with the presence of inner membranes like in the Golgi apparatus. PMID- 24405962 TI - Design of a simple cryogenic system for ultraviolet-visible absorption spectroscopy with a back-reflectance fiber optic probe. AB - We report a convenient and inexpensive technique for the rapid acquisition of absorption spectra from small samples at cryogenic temperatures using a home built cryostat with novel collection optics. A cylindrical copper block was constructed with a coaxial bore to hold a 4.00 mm diameter electron paramagnetic resonance (EPR) tube and mounted on a copper feed in thermal contact with liquid nitrogen. A 6.35 mm diameter hole was bored into the side of the cylinder so a fiber optic cable bundle could be positioned orthogonally to the EPR tube. The light passing through the sample is reflected off of the opposing surfaces of the EPR tube and surrounding copper, back through the sample. The emergent light is then collected using the fiber optic bundle and analyzed using a dispersive spectrometer. Absorption spectra for KMnO4 were measured between 400 and 700 nm. Absorption intensity at 506, 525, 545, and 567 nm was found to be proportional to concentration, displaying Beer's law-like behavior. The EPR tube had an internal diameter of 3.2 mm; the double pass of the probe beam through the sample affords a central path length of about 6.4 mm. Comparing these measurements with those recorded on a conventional tabletop spectrometer using a cuvette with a 10.00 mm path length, we consistently found a ratio between intensities of 0.58 rather than the anticipated 0.64. These 6% smaller values we attribute to the curvature of the EPR tube and transmission/reflection losses. This system is particularly well-suited to studying the kinetics and dynamics of chemical reactions at cryogenic temperatures. The rapid response (100 ms) and multiplex advantage provided the opportunity of recording simultaneous time courses at several wavelengths following initiation of a chemical reaction with a pulsed laser source. PMID- 24405963 TI - Microchannel-based surface-enhanced Raman spectroscopy for integrated microfluidic analysis. AB - We have demonstrated a microchannel-based, surface-enhanced Raman spectroscopy (SERS) sensing approach for integrated microfluidic analysis developed using standard micro-fabrication technology. Our approach allows high-sensitivity SERS sensing with a comparatively low-excitation optical power intensity and large cross-sectional microchannel for biological cell analysis. Utilizing a microchannel with a cross section of 100 * 70 MUm(2), we achieved a detection limit smaller than 10 nM for rhodamine 6G at an excitation power intensity of 132 W/cm(2), avoiding any possible heating effects on the sample under investigation. There is great potential for further improvement in the sensitivity of this microchannel-based SERS detection. PMID- 24405964 TI - Trust and condom use among young adults in relationships in Dar es Salaam, Tanzania. AB - Young adults in sub-Saharan Africa most often state 'I trust my partner' as the reason for not using condoms consistently. This study assesses the extent to which young adults in Dar es Salaam, Tanzania, trust their partners, how trust influences condom use and whether certain relationship characteristics influence the relationship between trust and condom use. Data were taken from the 2003 Tanzania Trust Survey, and the level of trust reported by 509 male and female young adults aged 15-24 who were in relationships was examined. The analysis showed that reported trust in a partner has the expected negative relationship with consistent condom use. However, this negative association differs by relationship characteristics. To facilitate the interpretation of interactions between marriage and trust, the predicted probabilities of consistent condom use by level of trust were calculated for males and for females by marital status, showing that the negative association is strong among those who are not married, but that there is no association between trust and condom use among young married adults. PMID- 24405965 TI - Reconstructing long-term trends in municipal sewage discharge into a small lake in northern Manitoba, Canada. AB - Ross Lake lies within the City of Flin Flon (Manitoba, Canada), a mining community originally formed by the Hudson Bay Mining and Smelting Company (now Hudbay Minerals Inc.) in 1927. At the time of this investigation, a continuous effluent stream from Hudbay Minerals (approximately 80 years) and a discontinuous and unknown amount of raw and minimally treated municipal sewage (>20 years, likely ending in 1951) was discharged into the north basin of the lake. Maximum concentrations of fecal sterols, such as coprostanol and terrestrial phytosterols, such as: beta-sitosterol, campesterol, stigmastanol were measured in vertical sections of sediment cores, collected from Ross Lake, in the 15-16-cm section, which likely corresponds to the 1930s. Concentrations of coprostanol increased from <1 MUg g(-1) in older sediments, to 252.3 MUg g(-1) organic carbon at the peak. Observed changes in concentrations of sterols, in combination with radiometric dating and changes to sediment physicochemical characteristics, support the conclusion that sediments of a depth of less than 17.5-cm depth were deposited during the post-industrial era from approximately 1930 onwards. Ratios of coprostanol to cholesterol>1, peaking at 3.6 are consistent with anecdotal information that municipal sewage was discharged into Ross Lake during the early years of urbanization, prior to changes in treatment of sewage and discharge practices that began in 1951. Finally, historical concentrations of terrestrial phytosterols followed trends similar to those of coprostanol and cholesterol and may possibly be the result of an increase in the flux of terrestrial organic matter into Ross Lake as the result of regional deforestation due to logging and fire. PMID- 24405966 TI - Kinetics, intermediates and acute toxicity of arsanilic acid photolysis. AB - Arsanilic acid (4-amino phenyl arsenic acid, ASA) is widely used in poultry production as feed additives, while most of ASA in the feed is excreted in the animal manure and released into the environment. However, the environmental behaviors of ASA were not well understood. In the present study, the photolysis behaviors of ASA and the toxicity of its metabolites to luminescent bacterium were studied. The results showed that ASA could be photodegraded and this process was strongly affected by solution pH, humic acid and dissolved oxygen. Upon UV irradiation for 360 min, ASA could be completely eliminated, but the reduction of total organic carbon (TOC) was not significant. In addition, NH4(+) ions and inorganic arsenic including arsenite and arsenate were identified as the predominant end-products. The conversion of ASA included both direct and indirect photolysis involving radicals, and its possible photolysis pathways were proposed on the basis of the identified intermediates. Unfortunately, higher adverse effects of the conversion products of ASA on bacteria were observed during the photolysis reaction. The results of present study might be helpful for assessing the environmental persistence and risks of ASA. PMID- 24405967 TI - Petroleum films exposed to sunlight produce hydroxyl radical. AB - Sunlight exposed oil films on seawater or pure water produced substantial amounts of hydroxyl radical as a result of irradiation. Oil was collected from the surface of the Gulf of Mexico following the Deepwater Horizon spill and exposed to simulated sunlight in thin films over water. Photochemical production of hydroxyl radical was measured with benzoic acid as a selective chemical probe in the aqueous layer. Total hydroxyl radical formation was studied using high benzoic acid concentrations and varying exposure time. The total amount of hydroxyl radical produced in 24 h irradiations of thin oil films over Gulf of Mexico water and pure water were 3.7*10(-7) and 4.2*10(-7) moles respectively. Steady state concentrations of hydroxyl radical were measured using a competition kinetics approach. Hydroxyl radical concentrations of 1.2*10(-16) to 2.4*10(-16) M were observed for seawater and pure water under oil films. Titanium dioxide (TiO2) nanomaterials were added to the system in an effort to determine if the photocatalyst would enhance oil photodegradation. The addition of TiO2 nanoparticles dramatically changed the observed formation rate of hydroxyl radical in the systems with NP water at pH 3, showing increased formation rate in many cases. With photocatalyst, the steady state concentration of radical decreased, predominantly due to an increase in the hydroxyl radical scavenging rate with oxide present. This study illustrates that oil is a strong and important source of hydroxyl radical when exposed to sunlight. The fate of oil and other dissolved species following oil spills will be heavily dependent on the formation and fate of hydroxyl radical. PMID- 24405968 TI - Phosphine-induced physiological and biochemical responses in rice seedlings. AB - Paddy fields have been demonstrated to be one of the major resources of atmospheric phosphine and may have both positive and negative effects on rice plants. To elucidate the physiological and biochemical responses of rice plants to phosphine, rice seedlings (30 d old) were selected as a model plant and were treated with different concentrations of phosphine (0, 1.4, 4.2, and 7.0 mg m( 3)). Antioxidant enzymes, including superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), and lipid peroxidation measured via malondialdehyde (MDA) were determined as indicators of the physiological and biochemical responses of the rice seedlings to phosphine exposure. Increasing concentrations of phosphine treatment enhanced the activity of SOD, POD, and CAT. In addition, the MDA content increased with increasing concentrations of phosphine. These results suggested that antioxidant enzymes played important roles in protecting rice seedlings from ROS damage. Moreover, rice seedlings were able to cope with the oxidative stress induced by low concentrations of phosphine via an increase in antioxidant enzymatic activities. However, oxidative stress may not fully be prevented when the plants were exposed to higher concentrations of phosphine. PMID- 24405969 TI - Evaluating UV/H2O2, UV/percarbonate, and UV/perborate for natural organic matter reduction from alternative water sources. AB - Natural organic matter (NOM) continues to increase in drinking water sources due to many factors, including changes in land use and global climate. Water treatment facilities will need to evaluate the best treatment options to account for these higher NOM levels. The UV/H2O2 advanced oxidation process (AOP) is one treatment option that has shown success at reducing high levels of NOM. As a result, this study evaluated the UV/H2O2 for the reduction of NOM in a high NOM water matrix, the Florida Everglades. In addition to liquid H2O2, sodium percarbonate and sodium perborate were used as oxidants to evaluate their performance as alternatives to liquid H2O2. Results showed that all three oxidants were able to reduce aromatic carbon (UV254) by 46-66% and dissolved organic carbon (DOC) by 11-19% at UV fluences of 2.6-2.7 J cm(-2) and an H2O2 dose of 100 mg L(-1). When the UV fluences were increased to 21.8-26.1 J cm(-2) at an H2O2 dose of 100 mg L(-1), UV254 reduction increased to 79-97% and DOC to 42-82% for all three oxidants. All three oxidants performed statistically similar for UV254 reduction. However, for DOC reduction, H2O2 performed statically better than both percarbonate and perborate, and perborate performed statistically better than percarbonate. While the UV/H2O2 AOP is effective for NOM reduction in high NOM waters, advances in electrical efficiency are needed to make it economically feasible. PMID- 24405970 TI - Anatomical factors associated with left innominate vein stenosis in hemodialysis patients. AB - Central venous stenosis remains a challenge in hemodialysis patients. Venograms have shown that left innominate vein (LIV) stenosis often occurs in front of the trachea, where it crosses the aortic arch, suggesting that there may be an anatomical factor involved, such as iliac vein compression syndrome. The goal of this study was to determine whether LIV stenosis can be attributed to compression. From September 2008 to December 2011, 19 hemodialysis patients (ten women, nine men) with symptomatic venous hypertension of the upper-left extremity were enrolled in this study. Venography and multidetector computed tomography were used to determine the location of the venous stenosis and to assess LIV anatomy. LIV diameter and the space between the sternum and aortic arch were compared between the LIV stenosis (LIVS) group (n = 9) and the non-LIV-stenosis (NLIVS) group (n = 10). The mean age of the cohort was 63 +/- 17.3 years. The mean LIV diameter was 1.69 +/- 1.55 mm in the LIVS group and 8.71 +/- 2.33 mm in the NLIVS group. The space between the aortic arch and sternum was smaller in the LIVS group (4.55 +/- 2.67 mm) than in the NLIVS group (15.25 +/- 6.12 mm, P < 0.001). A contributing factor to LIV stenosis may be due to anatomical compression of the aortic arch behind the sternum. Preoperative noncontrast computed tomography is recommended for hemodialysis patients to exclude extrinsic compression. PMID- 24405971 TI - Prognostic value of red cell distribution width in patients with sarcoidosis. AB - BACKGROUND: Sarcoidosis is a multisystem granulomatous disorder of unknown etiology. There are no data on the indications for specific tests or optimal frequency for monitoring of the disease activity in sarcoidosis. METHODS: Complete blood counts, demographics and pulmonary function data from sarcoidosis patients evaluated between 2006 and 2012 were collated retrospectively. During follow-up, the latest red cell distribution width (RDW) values of the patients were recorded. The prognosis and diagnosis of sarcoidosis was based on according to the guideline. Sarcoidosis progression was classified as follows: remission, stable disease and progreesive disease. RESULTS: The diagnosis was based on histopathological findings in 93 out of 138 (67.4%) patients. In our cohort, the baseline mean RDW levels were 14.1% +/- 1.2. The RDW distribution by stage was as follows: stage I: 14.0% (+/- 1.6), II: 14.2% (+/- 1.5), III: 13.8% (+/- 0.9) and IV: 15.8% (+/- 2.0). In patients with stage IV, baseline and follow-up values of RDW were found to be significantly higher than the other stages. While the mean baseline RDW was 14.8 (+/- 1.4) in the progressive disease, upon follow-up, the mean RDW had increased to 16.5% (+/- 1.4) (P = 0.021), No difference was found between the baseline and follow-up levels of RDW in the regressive and stable groups. CONCLUSIONS: Serial RDW levels may be beneficial marker to predict progression of sarcoidosis. PMID- 24405972 TI - Prioritizing investments in innovations to protect women from the leading causes of maternal death. AB - PATH, an international nonprofit organization, assessed nearly 40 technologies for their potential to reduce maternal mortality from postpartum hemorrhage and preeclampsia and eclampsia in low-resource settings. The evaluation used a new Excel-based prioritization tool covering 22 criteria developed by PATH, the Maternal and Neonatal Directed Assessment of Technology (MANDATE) model, and consultations with experts. It identified five innovations with especially high potential: technologies to improve use of oxytocin, a uterine balloon tamponade, simplified dosing of magnesium sulfate, an improved proteinuria test, and better blood pressure measurement devices. Investments are needed to realize the potential of these technologies to reduce mortality. PMID- 24405973 TI - Population-based analysis of blunt splenic injury management in children: operative rate is an informative quality of care indicator. AB - BACKGROUND: In hemodynamically normal children with blunt splenic injury (BSI), the standard of care is non-operative management. Several studies have reported that non-paediatric and non-trauma centres have higher operative rates in children with BSI compared to paediatric hospitals and trauma centres. We investigate the feasibility of using operative rate for BSI as a quality of care indicator. METHODS: We performed a population-based retrospective cohort study of children (<=18 years) with BSI admitted to all acute-care hospitals in Canada from 2001 to 2010. The main outcome was rate of operative management for BSI. Hierarchical multivariable logistic regression models were constructed to evaluate the relationship between operative rate and different hospital types (paediatric or non-paediatric, trauma or non-trauma). These models also allowed for generation of hospital-level observed to expected (O/E) ratios for rate of operative management. RESULTS: We identified 3122 children with BSI. The majority (74%) were isolated splenic injuries and the grade of splenic injury was specified in 45% of cases (n=1391, 38% grade I or II; 62% grade III, IV, or V). The overall operative rate was 11% (n=315), of which 9% were total splenectomy and 2% were spleen-preserving operations. After adjusting for age, gender, mechanism of injury, splenic injury grade, ISS, and centre volume, admission to non-paediatric hospitals was associated with a higher probability of operative management (OR 7.6, 95% CI 2.4-24.4), whereas there was no significant difference in operative management between trauma and non-trauma centres (OR 1.6, 95% CI 0.8 3.2). Outlier status based on O/E ratio was determined to identify centres with higher or lower than expected operative rates. CONCLUSIONS: The operative rates for children with BSI are significantly higher in non-paediatric hospitals. In these hospitals that do not routinely care for children and have higher than expected operative rates, we have used operative rate for BSI as a quality of care indicator and identified opportunities for quality improvement initiatives. LEVEL OF EVIDENCE: III, Retrospective comparative study. PMID- 24405974 TI - Management of traumatic soft tissue defects with dermal regeneration template: a prospective study. AB - INTRODUCTION: Traumatic soft tissue defect is a common issue for the trauma surgeon. The aim of this study was to evaluate the use of a dermal regeneration template (DRT) associated to a split-thickness skin graft (STSG) to cover severe traumatic wounds involving exposure of deep functional structures. MATERIALS AND METHODS: Patients with severe traumatic defects, either open fractures or full thickness skin wounds involving exposure of tendons without paratenon, bones without periosteum or joints without articular capsule, managed in the authors' trauma centre, were included in a prospective fashion. They were treated by DRT, associated to STSG within a month and followed up to 18 months. The primary outcome was STSG percentage of take at 18 months. The secondary outcomes included complications rate, functional results, scar retraction rate at 18 months and aesthetic results. RESULTS: A total of 15 patients were included, with 100% follow-up at 18 months. The mean age was 44.3 years, with nine men. Eighty percent of the wounds were located on the lower limb. After 18 months, the mean STSG take rate was 99.3%. Between the placement of the template and the STSG procedure, the reported complications were template unsticking, seroma, local infection and local oedema. There was no reported haematoma. In terms of functional outcome, percentages of patients undergoing rehabilitation from the time of the skin graft until the end of the follow-up decreased from 80% to 20%. There was 8.7% of retraction in length, and an 8.2% retraction in width. The Vancouver Scar Scale score constantly decreased until 2.5 at 18 months. The final functional and aesthetic subjective scores showed the marks to be located above the 'Satisfying' threshold, either by the surgeon or by the patients. DISCUSSION AND CONCLUSION: Eighteen months' follow-up demonstrated that DRT reconstruction is a simple, reliable, efficient tool to treat complex traumatic soft tissue defects. PMID- 24405975 TI - Synthesis of iron-doped TiO2 for degradation of reactive Orange16. AB - In this study the optimum conditions for preparing the iron-doped TiO2 nanoparticles were investigated. Samples were synthesized by sol-gel impregnation method. Three effective parameters were optimized using Taguchi method, consisted of: (i) atomic ratios of Fe to Ti; (ii) sintering temperature; (iii) sintering time. The characterization of samples was determined using X-ray diffraction, BET specific surface area, UV- Vis reflectance spectra (DRS) and scanning electron microscope (SEM). The XRD patterns of the samples indicated the existence of anatase crystal phase in structure. UV- Vis reflectance spectra showed an enhancement in light absorbance in the visible region (wavelength > 400 nm) for iron-doped samples. The photocatalytic activity of samples was investigated by the degradation of RO 16 (RO 16) dye under UV irradiation. The results illustrated that the photocatalytic activity of iron-doped TiO2 was more than pure TiO2, because of the smaller crystal size, grater BET surface area and higher light absorption ability. PMID- 24405976 TI - Diagnostic pathology in 2013: facts, thoughts, and perspectives. AB - Herein we analyze the development of the open access, peer reviewed journal Diagnostic Pathology (http://www.diagnosticpathology.org) during the past year and try to forecast its perspectives in 2014. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1562693099114452. PMID- 24405977 TI - Comparison of the free and bound phenolic profiles and cellular antioxidant activities of litchi pulp extracts from different solvents. AB - BACKGROUND: The phenolic contents and antioxidant activities of fruits could be underestimated if the bound phenolic compounds are not considered. In the present study, the extraction efficiencies of various solvents were investigated in terms of the total content of the free and bound phenolic compounds, as well as the phenolic profiles and antioxidant activities of the extracts. METHODS: Five different solvent mixtures were used to extract the free phenolic compounds from litchi pulp. Alkaline and acidic hydrolysis methods were compared for the hydrolysis of bound phenolic compounds from litchi pulp residue. The phenolic compositions of the free and bound fractions from the litchi pulp were identified using HPLC-DAD. The antioxidant activities of the litchi pulp extracts were determined by oxygen radical absorbance capacity (ORAC) and cellular antioxidant activity (CAA) assays. RESULTS: Of the solvents tested, aqueous acetone extracted the largest amount of total free phenolic compounds (210.7 mg GAE/100 g FW) from litchi pulp, followed sequentially by aqueous mixtures of methanol, ethanol and ethyl acetate, and water itself. The acid hydrolysis method released twice as many bound phenolic compounds as the alkaline hydrolysis method. Nine phenolic compounds were detected in the aqueous acetone extract. In contrast, not all of these compounds were found in the other four extracts. The classification and content of the bound phenolic compounds released by the acid hydrolysis method were higher than those achieved by the alkaline hydrolysis. The aqueous acetone extract showing the highest ORAC value (3406.9 MUmol TE/100 g FW) for the free phenolic extracts. For the CAA method, however, the aqueous acetone and methanol extracts (56.7 and 55.1 MUmol QE/100 g FW) showed the highest levels of activity of the five extracts tested. The ORAC and CAA values of the bound phenolic compounds obtained by acid hydrolysis were 2.6- and 1.9-fold higher than those obtained using the alkaline hydrolysis method. CONCLUSIONS: The free and bound phenolic contents and profiles and antioxidant activities of the extracts were found to be dependent on the extraction solvent used. Litchi exhibited good cellular antioxidant activity and could be a potentially useful natural source of antioxidants. PMID- 24405978 TI - On the stability of the Bayenv method in assessing human SNP-environment associations. AB - BACKGROUND: Phenotypic variation along environmental gradients has been documented among and within many species, and in some cases, genetic variation has been shown to be associated with these gradients. Bayenv is a relatively new method developed to detect patterns of polymorphisms associated with environmental gradients. Using a Bayesian Markov Chain Monte Carlo (MCMC) approach, Bayenv evaluates whether a linear model relating population allele frequencies to environmental variables is more probable than a null model based on observed frequencies of neutral markers. Although this method has been used to detect environmental adaptation in a number of species, including humans, plants, fish, and mosquitoes, stability between independent runs of this MCMC algorithm has not been characterized. In this paper, we explore the variability of results between runs and the factors contributing to it. RESULTS: Independent runs of the Bayenv program were carried out using genome-wide single-nucleotide polymorphism (SNP) data from samples from 60 worldwide human populations following previous applications of the Bayenv method. To assess factors contributing to the method's stability, we used varying numbers of MCMC iterations and also analyzed a second modified data set that excluded two Siberian populations with extreme climate variables. Between any two runs, correlations between Bayes factors and the overlap of SNPs in the empirical p value tails were surprisingly low. Enrichments of genic versus non-genic SNPs in the empirical tails were more robust than the empirical p values; however, the significance of the enrichments for some environmental variables still varied among runs, contradicting previously published conclusions. Runs with a greater number of MCMC iterations slightly reduced run-to-run variability, and excluding the Siberian populations did not have a large effect on the stability of the runs. CONCLUSIONS: Because of high run-to-run variability, we advise against making conclusions about genome-wide patterns of adaptation based on only one run of the Bayenv algorithm and recommend caution in interpreting previous studies that have used only one run. Moving forward, we suggest carrying out multiple independent runs of Bayenv and averaging Bayes factors between runs to produce more stable and reliable results. With these modifications, future discoveries of environmental adaptation within species using the Bayenv method will be more accurate, interpretable, and easily compared between studies. PMID- 24405979 TI - Low dose aspirin and low-molecular-weight heparin in the treatment of pregnant Libyan women with recurrent miscarriage. AB - BACKGROUND: Recurrent miscarriage is a major women's health problem. Aspirin and heparin have been shown to have potentially beneficial effects on trophoblast implantation. However, few published data on this issue are available from developing countries. METHODS: An open clinical trial was conducted at the Department of Obstetrics and Gynecology at Misurata Teaching Hospital in Libya from January 2009 to December 2010 to investigate the effects of treatment with low dose aspirin (LDA) versus treatment with low-molecular-weight-heparin (LMWH) in combination with LDA on patients with a history of recurrent miscarriages. A total of 150 women were enrolled in the study. Women were eligible for the study if they had a history of three or more consecutive miscarriages. Participants were randomly assigned to receive either LDA (75 mg daily) alone or a combination of LDA and LMWH (75 women per treatment group). The primary outcomes were the rate of miscarriages and live births for each group. RESULTS: Compared with the group who received LDA alone, the combination group had a significantly lower number of miscarriages (22/75 [29%] vs. 43/75 [47%], P < 0.001) and had a significantly higher number of live births (53/75 [71%] vs. 32/75 [42%], P < 0.001). Two preterm infants in the LDA group and three in the combination group were admitted to the neonatal intensive care unit. There were no significant differences in the mean (SD) birth weights of neonates born in either group (2955.4 +/- 560 vs. 3050 +/- 540 g for the LDA and combination groups, respectively, P = 0.444). There were no congenital abnormalities detected in either group. CONCLUSION: The combination of LDA and LMWH is better than LDA alone for the maintenance of pregnancy in patients with recurrent first trimester miscarriage. TRIAL REGISTRATION: NCT01917799. PMID- 24405982 TI - A systematic review of the psychometric properties of transition readiness assessment tools in adolescents with chronic disease. AB - BACKGROUND: Health care transition of adolescents with chronic conditions may be unsuccessful when patients have not acquired the necessary skills and developmental milestones. It is therefore critical for health care providers to assess the readiness for transition of their adolescent patients. This is currently hindered by the lack of a recognised, well-established transition readiness assessment tool. METHODS: We conducted a systematic review of all transition-readiness tools for adolescents with chronic medical conditions published in peer-reviewed journals. Tools were rated by the methodological quality of the validation studies, and the psychometric measurement qualities of each tool. RESULTS: Ten different assessment tools were identified. Seven targeted specific diseases and 3 tools were generic. Most tools were poorly validated with only one tool, the Transition Readiness Assessment Questionnaire (TRAQ) demonstrating adequate content validity, construct validity, and internal consistency. CONCLUSION: The TRAQ was the best-validated transition-readiness tool, with additional benefits of disease-neutrality. Further research should focus on testing the predictive validity of this tool, and exploring correlation with transition-outcomes, in an international population. PMID- 24405981 TI - Comparison of pregnancy outcomes between women with gestational diabetes and overt diabetes first diagnosed in pregnancy: a retrospective multi-institutional study in Japan. AB - AIMS: To determine differences in pregnancy outcomes including diabetic complications, maternal and perinatal complications between gestational diabetes mellitus and overt diabetes in pregnancy in Japan. METHODS: A multi-institutional retrospective study compared pregnancy outcomes between gestational diabetes mellitus and overt diabetes in pregnancy. We examined pregnant women who met the former criteria for gestational diabetes mellitus and received dietary intervention with self-monitoring of blood glucose with or without insulin. Overt diabetes in pregnancy was defined as >=2 abnormal values on 75-g oral glucose tolerance test, fasting glucose >=126 mg/dl (7.0 mmol/l) and 2-h postprandial glucose >=200 mg/dl (11.1 mmol/l), or glycated hemoglobin levels >=6.5% (48 mmol/mol). RESULTS: Data were collected on 1267 women with gestational diabetes and 348 with overt diabetes in pregnancy. Pregestational body mass index was higher (26.2 +/- 6.1 vs. 24.9 +/- 5.7 kg, P<0.05) and gestational age at delivery was earlier (37.8 +/- 2.5 weeks vs. 38.1 +/- 2.1 weeks, P<0.05) in overt diabetes than in gestational diabetes. Glycated hemoglobin (6.8 +/- 1.1% [51 mmol/mol] vs. 5.8 +/- 0.5% [40 mmol/mol], P<0.05) and glucose on 75-g oral glucose tolerance test and prevalence of retinopathy (1.2% vs. 0%, P<0.05) and pregnancy-induced hypertension (10.1% vs. 6.1%, P<0.05) were higher in overt diabetes than in gestational diabetes. Pregnancy-induced hypertension was associated with pregestational body mass index, gestational weight gain, chronic hypertension, and nulliparity but not with 75-g oral glucose tolerance test. CONCLUSIONS: Overt diabetes in pregnancy is significantly associated with maternal complications such as retinopathy and pregnancy-induced hypertension. PMID- 24405980 TI - Deficient prepulse inhibition in schizophrenia detected by the multi-site COGS. AB - BACKGROUND: Startle inhibition by weak prepulses (PPI) is studied to understand the biology of information processing in schizophrenia patients and healthy comparison subjects (HCS). The Consortium on the Genetics of Schizophrenia (COGS) identified associations between PPI and single nucleotide polymorphisms in schizophrenia probands and unaffected relatives, and linkage analyses extended evidence for the genetics of PPI deficits in schizophrenia in the COGS-1 family study. These findings are being extended in a 5-site "COGS-2" study of 1800 patients and 1200 unrelated HCS to facilitate genetic analyses. We describe a planned interim analysis of COGS-2 PPI data. METHODS: Eyeblink startle was measured in carefully screened HCS and schizophrenia patients (n=1402). Planned analyses of PPI (60 ms intervals) assessed effects of diagnosis, sex and test site, PPI-modifying effects of medications and smoking, and relationships between PPI and neurocognitive measures. RESULTS: 884 subjects met strict inclusion criteria. ANOVA of PPI revealed significant effects of diagnosis (p=0.0005) and sex (p<0.002), and a significant diagnosis*test site interaction. HCS>schizophrenia PPI differences were greatest among patients not taking 2nd generation antipsychotics, and were independent of smoking status. Modest but significant relationships were detected between PPI and performance in specific neurocognitive measures. DISCUSSION: The COGS-2 multi-site study detects schizophrenia-related PPI deficits reported in single-site studies, including patterns related to diagnosis, prepulse interval, sex, medication and other neurocognitive measures. Site differences were detected and explored. The target COGS-2 schizophrenia "endophenotype" of reduced PPI should prove valuable for identifying and confirming schizophrenia risk genes in future analyses. PMID- 24405983 TI - Clinical utility of cytomegalovirus antigenemia assay and blood cytomegalovirus DNA PCR for cytomegaloviral colitis patients with moderate to severe ulcerative colitis. AB - BACKGROUND AND AIMS: Clinical usefulness of cytomegalovirus (CMV) antigenemia assay and blood CMV polymerase chain reaction (PCR) in patients with ulcerative colitis (UC) needs to be evaluated. METHODS: Medical records of moderate to severe UC patients between January 2001 and December 2012 were reviewed retrospectively. Diagnostic performances of CMV antigenemia assay and blood PCR to predict CMV colitis, and clinical outcome according to the results were analyzed. CMV colitis was diagnosed by H&E staining and/or CMV immunohistochemistry. RESULTS: Of the 229 study subjects, 83 patients (36.2%) had CMV colitis. The sensitivity and specificity of CMV antigenemia assay were 47.0% and 81.7%, and those of blood CMV DNA PCR were 44.3% and 87.9%, respectively. If either CMV antigenemia or PCR was positive in the presence of significant ulcers, the sensitivity and specificity of having CMV colitis were 67.3% and 75.7%, respectively, with the area under the receiver operating characteristic curve value of 0.717. Among patients with significant ulcers, positive CMV antigenemia (33/50 [66.0%] vs. 31/102 [30.4%]; p<0.001) and positive blood CMV PCR (25/37 [67.6%] vs. 24/86 [27.9%]; p<0.001) showed significantly higher probability of CMV colitis than blood test-negative patients. UC-CMV colitis patients with positive CMV antigenemia showed significantly higher rate of colectomy than those with negative antigenemia (13/39 [33.3%] vs. 5/44 [11.4%]; p=0.015). CONCLUSIONS: Although CMV antigenemia and blood CMV PCR showed low sensitivity for diagnosing CMV colitis, the specificity values were high. Among UC-CMV colitis patients, CMV antigenemia showed significant association with subsequent colectomy. PMID- 24405984 TI - Bike and run pacing on downhill segments predict Ironman triathlon relative success. AB - OBJECTIVES: Determine if performance and physiological based pacing characteristics over the varied terrain of a triathlon predicted relative bike, run, and/or overall success. Poor self-regulation of intensity during long distance (Full Iron) triathlon can manifest in adverse discontinuities in performance. DESIGN: Observational study of a random sample of Ironman World Championship athletes. High performing and low performing groups were established upon race completion. METHODS: Participants wore global positioning system and heart rate enabled watches during the race. Percentage difference from pre-race disclosed goal pace (%off) and mean HR were calculated for nine segments of the bike and 11 segments of the run. Normalized graded running pace (accounting for changes in elevation) was computed via analysis software. Step-wise regression analyses identified segments predictive of relative success and HP and LP were compared at these segments to confirm importance. RESULTS: %Off of goal velocity during two downhill segments of the bike (HP: -6.8+/-3.2%, -14.2+/-2.6% versus LP: -1.2+/-4.2%, -5.1+/-11.5%; p<0.020) and %off from NGP during one downhill segment of the run (HP: 4.8+/-5.2% versus LP: 33.3+/-38.7%; p=0.033) significantly predicted relative performance. Also, HP displayed more consistency in mean HR (141+/-12 to 138+/-11 bpm) compared to LP (139+/-17 to 131+/-16 bpm; p=0.019) over the climb and descent from the turn-around point during the bike component. CONCLUSIONS: Athletes who maintained faster relative speeds on downhill segments, and who had smaller changes in HR between consecutive up and downhill segments were more successful relative to their goal times. PMID- 24405985 TI - Discovery of novel inhibitors of HIV-1 reverse transcriptase through virtual screening of experimental and theoretical ensembles. AB - Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are potent anti-HIV chemotherapeutics. Although there are FDA-approved NNRTIs, challenges such as the development of resistance have limited their utility. Here, we describe the identification of novel NNRTIs through a combination of computational and experimental approaches. Based on the known plasticity of the NNRTI binding pocket (NNIBP), we adopted an ensemble-based virtual screening strategy: coupling receptor conformations from 10 X-ray crystal structures with 120 snapshots from a total of 480 ns of molecular dynamics (MD) trajectories. A screening library of 2864 National Cancer Institute (NCI) compounds was built and docked against the ensembles in a hierarchical fashion. Sixteen diverse compounds were tested for their ability to block HIV infection in human tissue cultures using a luciferase based reporter assay. Three promising compounds were further characterized, using a HIV-1 RT-based polymerase assay, to determine the specific mechanism of inhibition. We found that 2 of the three compounds inhibited the polymerase activity of RT (with potency similar to the positive control, the FDA-approved drug nevirapine). Through a computational approach, we were able to discover two compounds which inhibit HIV replication and block the activity of RT, thus offering the potential for optimization into mature inhibitors. PMID- 24405986 TI - Prevalence of Met-203 type spaA variant in Erysipelothrix rhusiopathiae isolates and the efficacy of swine erysipelas vaccines in Japan. AB - Since 2009, erysipelas infection among pigs in Japan has been increasing. This study investigated the prevalence, and characteristics of Erysipelothrix rhusiopathiae isolates in Japan from 2008 to 2010 and assessed the efficacy of current commercial erysipelas vaccines. Based on polymorphisms in a 432-bp hypervariable region in the surface protective antigen A (spaA) gene, 34 isolates were classified into three groups: (i) Group 1 with methionine at position 203 (Met-203) and isoleucine at position 257 (Ile-257) (18 isolates of serotype 1a and one untypable isolate). (ii) Group 2 with Ile-257 (12 isolates of serotypes 1a, 1b, 2, 10 and 11), and (iii) Group 3 with alanine at position 195 (Ala-195) and Ile-257 (three isolates of serotype 1a). Isolates with Met-203 were highly pathogenic in mice and pigs, causing death in the pig and LD50 values of 0.45 1.45 CFU per mouse. One live and three inactivated commercial E. rhusiopathiae vaccines were evaluated for efficacy against a Met-203 isolate. Almost all mice and pigs that received vaccine survived, while non-vaccinated controls all died within 5 days of the challenge. This indicates that swine erysipelas vaccines might be still effective in protecting animals against the recently prevalent Met 203 isolates in Japan. PMID- 24405987 TI - Molecular and functional characterization of cold-responsive C-repeat binding factors from Brachypodium distachyon. AB - BACKGROUND: Adverse environmental conditions severely influence various aspects of plant growth and developmental processes, causing worldwide reduction of crop yields. The C-repeat binding factors (CBFs) are critical transcription factors constituting the gene regulatory network that mediates the acclimation process to low temperatures. They regulate a large number of cold-responsive genes, including COLD-REGULATED (COR) genes, via the CBF-COR regulon. Recent studies have shown that the CBF transcription factors also play a role in plant responses to drought and salt stresses. Putative CBF gene homologues and their downstream genes are also present in the genome of Brachypodium distachyon, which is perceived as a monocot model in recent years. However, they have not been functionally characterized at the molecular level. RESULTS: Three CBF genes that are responsive to cold were identified from Brachypodium, designated BdCBF1, BdCBF2, and BdCBF3, and they were functionally characterized by molecular biological and transgenic approaches in Brachypodium and Arabidopsis thaliana. Our results demonstrate that the BdCBF genes contribute to the tolerance response of Brachypodium to cold, drought, and salt stresses by regulating downstream targets, such as DEHYDRIN5.1 (Dhn5.1) and COR genes. The BdCBF genes are induced under the environmental stress conditions. The BdCBF proteins possess transcriptional activation activity and bind directly to the promoters of the target genes. Transgenic Brachypodium plants overexpressing the BdCBF genes exhibited enhanced resistance to drought and salt stresses as well as low temperatures, and accordingly endogenous contents of proline and soluble sugars were significantly elevated in the transgenic plants. The BdCBF transcription factors are also functional in the heterologous system Arabidopsis. Transgenic Arabidopsis plants overexpressing the BdCBF genes were also tolerant to freezing, drought, and salt stresses, and a set of stress-responsive genes was upregulated in the transgenic Arabidopsis plants. CONCLUSIONS: Taken together, our results strongly support that the BdCBF transcription factors are key regulators of cold stress responses in Brachypodium and the CBF-mediated cold stress signaling pathway is conserved in this plant species. We believe that this study would confer great impact on stress biology in monocot species and could be applied to engineer abiotic stress tolerance of bioenergy grass species. PMID- 24405988 TI - Epidemiology of traumatic head injury from a major paediatric trauma centre in New South Wales, Australia. AB - BACKGROUND: Traumatic brain injury (TBI) is common and is a leading cause of presentations to emergency departments. Understanding the epidemiology of TBI can aid in improving overall management and identifying opportunities for prevention. Currently, there is a paucity of data on paediatric TBI in NSW. The purpose of this study was to determine the demographics, causes, treatment and outcome of TBI at The Children's Hospital at Westmead (CHW), a large trauma referral paediatric hospital. METHODS: A retrospective chart review was conducted of patients admitted to CHW emergency from 2006 to 2011 with a TBI. Patients who presented to the emergency department and had a history of TBI with either symptoms of concussion and/or positive computed tomography (CT) findings of head injury were selected. Information regarding demographics, injury pattern, CT findings, treatment and outcome were retrieved. RESULTS: Over the 6-year period, there were 1489 presentations at the CHW. Of these, 65% were male and 35% were female. The mean age was 7 years. A total of 93% were classified as mild, 1.5% as moderate and 5.5% as severe. Sports and recreational injuries accounted for 26% of all TBI presentations, while motor vehicle accidents (MVAs) accounted for 77% of all TBI deaths. Sixty-two per cent of children underwent a CT brain, and of those, 40% were normal. CONCLUSION: The majority of TBI are mild in nature, with younger children and males at greatest risk. There was a low rate of operative intervention and a high rate of good outcomes. Many injuries may be preventable with the adaptation of better public health education programmes, particularly in very young children and those related to MVAs. PMID- 24405989 TI - Heparin-induced thrombocytopenia due to heparin lock in a hemodialysis patient: a case report. AB - Heparin-induced thrombocytopenia (HIT) is a potentially fatal clinical condition which can develop after exposure to unfractionated or low-molecular-weight heparins. Even small doses of heparin such as heparin flushes in hemodialysis catheter can induce the development of HIT. However, the true incidence of heparin lock-related HIT is unknown. We report a 58-year-old woman with acute kidney injury because of obstructive uropathy who developed HIT after heparin free hemodialysis. She was found to have severe thrombocytopenia with deep vein thrombosis of left lower limb and arterial thrombosis of the right anterior and middle cerebral arteries. The heparin-platelet factor 4 antibody was positive and she was put on plasmapharesis. However, her condition further deteriorated and succumbed shortly. Heparin lock solution in the hemodialysis catheter was believed to be the cause of HIT in our patient. PMID- 24405990 TI - Successful medical management of uterocutaneous fistula. PMID- 24405991 TI - Prevalence and complications of gallstone disease among pregnant women in a Nigerian hospital. AB - OBJECTIVE: To determine the prevalence of gallstone disease and its complications among pregnant women in a semi-urban Nigerian setting. METHODS: Consecutive consenting pregnant women presenting at the prenatal clinic of a Nigerian tertiary hospital were recruited over an 18-month period. During routine obstetric ultrasound, the presence of gallstones and/or associated sequelae was investigated. Patients' sociodemographic data and hemoglobin genotype were documented. RESULTS: Overall, 1283 pregnant women (14-43 years of age) were included in the study. Thirty-seven (2.9%) had sonographic evidence of gallstones, 26 (2%) had biliary sludge, and 2 (0.2%) had gallbladder polyps. Twenty-one (56.8%) of the 37 women with gallstones were 30 years of age or younger. Only 1 (1.2%) of 85 selected women in the first trimester of pregnancy with no gallstones who were followed throughout pregnancy developed gallstones in the third trimester. Overall, 3 (0.2%) women had clinical and radiologic evidence of acute calculous cholecystitis, 2 of whom underwent laparoscopic cholecystectomy after delivery. CONCLUSION: The present study demonstrated a low prevalence of gallstone disease and its acute complications among pregnant Nigerian women in a semi-urban setting. PMID- 24405993 TI - Quantifying the sensitivity of scent detection dogs to identify fecal contamination on raw produce. AB - Consumption of raw produce commodities has been associated with foodborne outbreaks in the United States. In a recent Centers for Disease Control and Prevention report outlining the incidence of food-related outbreaks from 1998 to 2008, produce of all kinds were implicated in 46% of illnesses and 23% of deaths. Methods that quickly identify fecal contamination of foods, including produce, will allow prioritization of samples for testing during investigations and perhaps decrease the time required to identify specific brands or lots. We conducted a series of trials to characterize the sensitivity and specificity of scent detection dogs to accurately identify fecal contamination on raw agricultural commodities (romaine lettuce, spinach, cilantro, and roma tomatoes). Both indirect and direct methods of detection were evaluated. For the indirect detection method, two dogs were trained to detect contamination on gauze pads previously exposed to produce contaminated with feces. For the direct detection method, two dogs were trained to identify fecal contamination on fresh produce. The indirect method did not result in acceptable levels of sensitivity except for the highest levels of fecal contamination (25 g of feces). Each dog had more difficulty detecting fecal contamination on cilantro and spinach than on roma tomatoes. For the direct detection method, the dogs exhibited >75% sensitivity for detecting >=0.25 g of feces on leafy greens (cilantro, romaine lettuce, and spinach) and roma tomatoes, with sensitivity declining as the amount of feces dropped below 0.025 g. We determined that use of a scent detection dog to screen samples for testing can increase the probability of detecting >=0.025 g of fecal contamination by 500 to 3,000% when samples with fecal contamination are rare (<=1%). PMID- 24405995 TI - Growth model of Escherichia coli O157:H7 at various storage temperatures on kale treated by thermosonication combined with slightly acidic electrolyzed water. AB - This study was conducted to investigate the disinfection efficacy of hurdle treatments (thermosonication plus slightly acidic electrolyzed water [SAcEW]) and to develop a model for describing the effect of storage temperatures (4, 10, 15, 20, 25, 30, and 35 degrees C) on the growth of Escherichia coli O157:H7 on fresh cut kale treated with or without (control) thermosonication combined with SAcEW. The hurdle treatments of thermosonication plus SAcEW had strong bactericidal effects against E. coli O157:H7 on kale, with approximately 3.3-log reductions. A modified Gompertz model was used to describe growth parameters such as specific growth rate (SGR) and lag time (LT) as a function of storage temperature, with high coefficients of determination (R(2) > 0.98). SGR increased and LT declined with rising temperatures in all samples. A significant difference was found between the SGR values obtained from treated and untreated samples. Secondary models were established for SGR and LT to evaluate the effects of storage temperature on the growth kinetics of E. coli O157:H7 in treated and untreated kale. Statistical evaluation was carried out to validate the performance of the developed models, based on the additional experimental data not used for the model development. The validation step indicated that the overall predictions were inside the acceptable prediction zone and had lower standard errors, indicating that this new growth model can be used to assess the risk of E. coli O157:H7 contamination on kale. PMID- 24405994 TI - Simultaneous Immunomagnetic Separation Method for the Detection of Escherichia coli O26, O111, and O157 from Food Samples. AB - We performed a simultaneous immunomagnetic separation (IMS) assay on Shiga toxin producing Escherichia coli (STEC) serogroups O26, O111, and O157 with immunobeads coated with O26, O111, or O157 antibodies that were simultaneously added to an aliquot of food culture. We also compared the usefulness of CHROMagar STEC medium against various selective isolation agars designed to test for the three serogroups. Samples of sliced beef, ground beef, and radish sprout were artificially contaminated with STEC O26, O111, and O157 strains after incubation in enrichment broth and were subjected to conventional and simultaneous IMS assays. Simultaneous IMS did not affect the sensitivity of target cell detection. For STEC O26, O111, and O157 inoculated into the enriched samples of sliced beef and radish sprout, the detection ability of CHROMagar STEC was similar to or exceeded that of other isolation agars. However for STEC O157 inoculated into ground beef cultures, cefixime tellurite sorbitol MacConkey agar (CT-SMAC) was the superior detection medium. The performance of simultaneous IMS combined with CT-SMAC and CHROMagar STEC detection is similar to that of the Japanese standard method for isolating E. coli O26, O111, and O157. However, the proposed approach involves the same time, materials, and labor costs as the standard E. coli O157 reference procedure but allows detection of three E. coli serotypes rather than a single strain. PMID- 24405996 TI - Inactivation of stressed Escherichia coli O157:H7 cells on the surfaces of rocket salad leaves by chlorine and peroxyacetic acid. AB - Because Escherichia coli O157:H7 has been frequently associated with many foodborne outbreaks caused by consumption of leafy greens (lettuce, spinach, and celery), this study investigated the ability of deionized water, chlorine, and peroxyacetic acid to detach or inactivate stressed and unstressed cells of E. coli O157:H7 contaminating the surfaces of rocket salad leaves. E. coli O157:H7 cells stressed by acid, cold, starvation, or NaCl exposure, as well as unstressed cells, were inoculated on the surfaces of rocket salad leaves at 4 degrees C. The effectiveness of two sanitizers (200 ppm of chlorine and 80 ppm of peroxyacetic acid) and deionized water for decontaminating the leaves treated with stressed and unstressed E. coli O157:H7 were evaluated during storage at 10 or 25 degrees C for 0.5, 1, 3, and 7 days. It was found that washing with 80 ppm of peroxyacetic acid was more effective and reduced unstressed and stressed cells of E. coli O157:H7 by about 1 log CFU per leaf on the leaves. There was no apparent difference in the ability of stressed and unstressed cells to survive surface disinfection with the tested agents. Treatments to reduce viable E. coli O157:H7 cells on rocket leaves stored at 25 degrees C were more effective than when used on those stored at 10 degrees C. Washing with peroxyacetic acid or chlorine solution did not ensure the safety of rocket leaves, but such treatments could reduce the likelihood of water-mediated transfer of E. coli O157:H7 during washing and subsequent processing. PMID- 24405997 TI - Antibiotic resistance and diversity of Salmonella enterica serovars associated with broiler chickens. AB - The objective of this study was to analyze the antibiotic resistance phenotype and genotype of Salmonella isolated from broiler production facilities. A total of 193 Salmonella isolates recovered from commercial farms in British Columbia, Canada, were evaluated. Susceptibility to antibiotics was determined with the Sensititre system. Virulence and antibiotic resistance genes were detected by PCR assay. Genetic diversity was determined by pulse-field gel electrophoresis (PFGE) typing. Seventeen serovars of Salmonella were identified. The most prevalent Salmonella serovars were Kentucky (29.0% of isolates), Typhimurium (23.8%), Enteritidis (13.5%), and Hadar (11.9%); serovars Heidelberg, Brandenburg, and Thompson were identified in 7.7, 4.1, and 3.6% of isolates, respectively. More than 43% of the isolates were simultaneously resistant to ampicillin, amoxicillin clavulanic acid, ceftiofur, cefoxitim, and ceftriaxone. This beta-lactam resistance pattern was observed in 33 (58.9%) of the Salmonella Kentucky isolates; 2 of these isolates were also resistant to chloramphenicol, streptomycin, sulfisoxazole, and tetracycline. Genes associated with resistance to aminoglycosides (aadA1, aadA2, and strA), beta-lactams (blaCMY-2, blaSHV, and blaTEM), tetracycline (tetA and tetB), and sulfonamide (sul1) were detected among corresponding resistant isolates. The invasin gene (invA) and the Salmonella plasmid virulence gene (spvC) were found in 97.9 and 25.9% of the isolates, respectively, with 33 (71.7%) of the 46 Salmonella Typhimurium isolates and 17 (65.4%) of the 26 Salmonella Enteritidis isolates carrying both invA and spvC. PGFE typing revealed that the antibiotic-resistant serovars were genetically diverse. These data confirm that broiler chickens can be colonized by genetically diverse antibiotic-resistant Salmonella isolates harboring virulence determinants. The presence of such strains is highly relevant to food safety and public health. PMID- 24405998 TI - Survival rate of salmonella on cooked pig ear pet treats at refrigerated and ambient temperature storage. AB - Pet treats, including pig ears, have been implicated as vehicles of human salmonellosis, and Salmonella has been isolated on commercially produced pig ears. Therefore, behavior of the pathogen on this very low water activity (aw) pet treat is of interest. The survival of Salmonella serotypes Newport and Typhimurium DT104 was measured on natural (aw 0.256) and smoked (aw 0.306) pig ear pet treat products inoculated at ca. 6.5 log CFU per sample and stored at 4.4 or 22 degrees C for 365 days. Surviving populations of Salmonella were enumerated periodically, and a modified Weibull model was used to fit the inactivation curves for log populations. After 14 days, the decline of Salmonella was significantly (P < 0.05) greater at 22 degrees C than at 4.4 degrees C. By 365 days of storage at 4.4 degrees C, Salmonella Typhimurium DT104 declined by 2.19 log on smoked pig ears and 1.14 log on natural pig ears, while Salmonella Newport declined by 4.20 log on smoked pig ears and 2.08 log on natural pig ears. Populations of Salmonella Typhimurium DT104 on refrigerated natural pig ears rebounded between day 152 (3.21 log CFU per sample) and day 175 (4.79 log CFU per sample) and rose gradually for the duration of the study to 5.28 log CFU per sample. The model fits for survival rate of Salmonella on pig ears at 4.4 degrees C show a rapid initial decline followed by a long tailing effect. Salmonella Typhimurium DT104 on natural pig ears at 4.4 degrees C had the slowest rate of reduction. At 22 degrees C Salmonella declined nonlinearly by >4.5 log for each combination of serotype and pig ear type at 22 degrees C but remained detectable by enrichment. The model parameter for days to first decimal reduction of Salmonella on pig ears was two to three times higher at 4.4 degrees C compared with 22 degrees C, demonstrating that Salmonella slowly declines on very low aw refrigerated pet treats and more rapidly at room temperature. This information may be useful for pet treat safety assessments. PMID- 24405999 TI - Quantification, serovars, and antibiotic resistance of salmonella isolated from retail raw chicken meat in Vietnam. AB - The objectives of this study were to quantify Salmonella counts on retail raw poultry meat in Vietnam and to phenotypically characterize (serovars and antibiotic resistance) the isolates. A total of 300 chicken carcasses were collected from two cities and two provinces in Vietnam. Salmonella counts on the samples were determined according to the most-probable-number (MPN) method of the U.S. Department of Agriculture, Food Safety and Inspection Service (USDA-FSIS). A total of 457 isolates were serotyped and tested for antibiotic susceptibility. Overall, 48.7% of chicken samples were Salmonella positive with a count of 2.0 log MPN per carcass. There were no significant differences (P > 0.05) in log MPN per carcass by the study variables (market type, storage condition, and chicken production system). There was a significant difference (P < 0.05) in Salmonella positive prevalence by chicken production system. Among the 22 Salmonella serovars identified, Albany was the most frequent (34.1%), followed by Agona (15.5%) and Dabou (8.8%). Resistance to at least one antibiotic was common (i.e., 73.3%), with high resistance to tetracycline (59.1%) and ampicillin (41.6%). Resistance to three antibiotics was the most frequently found multidrug resistance profile (17.7%, n = 81); the profile that was resistant to the highest number of drugs was resistant to nine antibiotics (0.7%, n = 3). Only Salmonella Albany posed phenotypic resistance to ceftriaxone (a drug of choice to treat severe cases of salmonellosis). The data revealed that, whereas Salmonella prevalence on raw poultry was high (48.7%), counts were low, which suggests that the exposure risk to Salmonella is low. However, improper storage of raw chicken meat and cross-contamination may increase Salmonella cell counts and pose a greater risk for infection. These data may be helpful in developing risk assessment models and preventing the transmission of foodborne Salmonella from poultry to humans in Vietnam. PMID- 24406000 TI - Effect of the local microenvironment on survival and thermal inactivation of Salmonella in low- and intermediate-moisture multi-ingredient foods. AB - Multi-ingredient foods having low- or intermediate-moisture characteristics may pose a special challenge to process design and validation. Ingredients of these foods can create local microenvironments that may have a distinct impact on pathogen survival and processing requirements. In this study, two model systems, each consisting of 80% commercial peanut butter (P) and 20% nonfat dry milk powder (M), were formulated to be identical in composition, but different in the source of the Salmonella contamination as originating in either the ingredient P or M. Immediately after inoculation, Salmonella showed a 2.0-log reduction when M was the contaminated ingredient compared with a 0.6-log reduction when P was the contaminated ingredient. This pattern of survival was consistent with the single ingredient control containing only M (2.5-log reduction) or only P (0.7-log reduction), suggesting that the immediate proximity of cells is determined by the contaminated ingredient in the model system. After 5 weeks of storage, the survival rates of Salmonella in the two systems remained different, i.e.a 4- and 2-log reduction resulted in the system with M or P as the contaminated ingredient, respectively. Furthermore, thermal inactivation efficacies also differed significantly between the two systems. Fourier transform infrared spectroscopy demonstrated the nonhomogeneous distribution of water, lipid, and protein, indicating that varied local microenvironments were present and likely affected the behavior of the pathogen. The impact of the microenvironment on inactivation and survival of Salmonella was further confirmed in a butter cookie formulation in which Salmonella was inoculated via four different ingredients. This study shows that the local microenvironment in low- and intermediate moisture foods affects Salmonella survival and thermal inactivation. The ingredient source of the contamination should be taken into account for process design and validation to ensure the safety of the product. PMID- 24406001 TI - Use of Enterococcus faecium as a surrogate for Salmonella enterica during extrusion of a balanced carbohydrate-protein meal. AB - Multiple outbreaks of salmonellosis have been associated with the consumption of low-moisture products, including extruded products. Therefore, there is a need for a nonpathogenic, surrogate microorganism that can be used to validate extrusion processes for Salmonella. The objective of this research was to determine if Enterococcus faecium NRRL B-2354 is an adequate surrogate organism for Salmonella during extrusion. Extrusions at different temperatures were done in material contaminated with both organisms. Results indicated that the minimum temperature needed to achieve a 5-log reduction of E. faecium was 73.7 degrees C. Above 80.3 degrees C, the enumeration of E. faecium showed counts below the detectable levels (<10 CFU g(- 1)). Salmonella was reduced by 5 log at 60.6 degrees C, and above 68.0 degrees C the levels of this organism in the product were below the detection limit of the method. The data show that E. faecium is inactivated at higher temperatures than Salmonella, indicating that its use as a surrogate would provide an appropriate margin of error in extrusion processes designed to eliminate this pathogen. Attempting to minimize risk, the industry could validate different formulations, in combination with thermal treatments, using E. faecium as a safer alternative for those validation studies. PMID- 24406002 TI - Survival of methicillin-resistant Staphylococcus aureus during commercial heat treatment of slab bacon and consumer preparation of sliced bacon. AB - With the knowledge that retail pork products may be contaminated with methicillin resistant Staphylococcus aureus (MRSA), the risk of consumers contracting a MRSA infection or foodborne illness from processed meats, especially bacon, is uncertain. Therefore, a study was designed to investigate the survival of MRSA during heat treatment of slab bacon at a commercial process and during cooking of sliced bacon at the consumer level. Fresh pork bellies were injected with a curing solution, inoculated, and heat treated to an internal temperature of 52 degrees C. Three commercial brands of sliced bacon with similar "sell by" dates and fat-to-lean ratios were also inoculated and cooked at a temperature of 177 degrees C for 0, 2, and 5 min on each side. Heat-treated slab bacon showed a log reduction of 1.89, which was significant (P < 0.05) compared with an uncooked inoculated control. Cooked sliced bacon had a reduction of viable MRSA cells of >6.5 log CFU/cm(2), and there was not a significant brand interaction (P > 0.05). PMID- 24406003 TI - Evaluation of the entomopathogenic fungi Beauveria bassiana, Metarhizium anisopliae, and Isaria fumosorosea for control of Sitophilus oryzae. AB - The entomopathogenic fungi Beauveria bassiana, Metarhizium anisopliae, and Isaria fumosorosea were tested against the stored-grain pest Sitophilus oryzae. The fungi were isolated from the soil (from three locations in Attica, Greece: B. bassiana from Tatoion, M. anisopliae from Marathon, and I. fumosorosea from Aghios Stefanos) using larvae of Galleria mellonella as bait. Suspensions of 2.11 * 10(7) and 2.11 * 10(8), 1.77 * 10(7) and 1.77 * 10(8), and 1.81 * 10(7) and 1.81 * 10(8) conidia per ml of B. bassiana, M. anisopliae, and I. fumosorosea, respectively, were applied by three treatments: (i) sprayed on food and set in petri dishes with adults of S. oryzae, (ii) sprayed on adults of S. oryzae and set in petri dishes without food, and (iii) sprayed on adults of S. oryzae and set in petri dishes with food. The observed mortality of S. oryzae adults during the overall exposure period for the lowest, as well as for the highest, concentrations of B. bassiana, M. anisopliae, and I. fumosorosea ranged from 0 to 100%. Concentration was, in most of the cases tested, a critical parameter that determined the "speed of kill" of the exposed insect species for B. bassiana and M. anisopliae. Conversely, concentration was not that critical for I. fumosorosea, and survival was high in some of the combinations tested, even after 14 days of exposure. Both in the highest and the lowest concentrations of fungi, the mortality of S. oryzae adults was higher when the fungi were applied on adults than when they were applied on food. Higher mortality was observed when food was absent than when food was present, in most of the cases tested. The high efficacy levels recorded in the current study indicate that the tested fungi could be effective biocontrol agents against S. oryzae. PMID- 24406004 TI - Timeliness of electronic reporting and acceptability of public health follow-up of routine nonparatyphoidal and nontyphoidal Salmonella infections, London and South East England, 2010 to 2011. AB - Nonparatyphoidal and nontyphoidal Salmonella (NTS) infections are major causes of food poisoning in England. Diagnostic laboratories and clinicians have a statutory responsibility to report NTS infection cases to the Health Protection Agency via various means, with electronic reporting encouraged as the universal method. The Health Protection Agency (Public Health England since 1 April 2013) refers cases to environmental health departments for follow-up. Timeliness of reporting and adequacy of NTS infection case follow-up are key factors in the implementation of public health actions. Laboratories, health protection units, and environmental health departments in London and South East (SE) regions of England completed three surveys between December 2010 and April 2011, collecting data about the NTS infection case reporting methods and the time elapsed between symptom onset and public health actions. The median period between symptom onset and public health investigation was 25 days in London and 23 days in SE when electronic reporting was used and 12 days in London and 11 days in SE when other means of reporting were used. The most common follow-up method was a telephone questionnaire in London (53%) and a postal questionnaire in SE (52%). The telephone questionnaire had the highest response rate (98% in London; 96% in SE). Timeliness and efficiency of electronic NTS infection case reports can be improved by decreasing the electronic laboratory report period and using telephone-administered questionnaires to maximize the public health benefit when following up single cases of NTS infection. PMID- 24406005 TI - Rapid and sensitive detection of Escherichia coli O157:H7 in milk and ground beef using magnetic bead-based immunoassay coupled with tyramide signal amplification. AB - Escherichia coli O157:H7 is a major foodborne pathogen that has posed serious problems for food safety and public health. Recent outbreaks and recalls associated with various foods contaminated by E. coli O157:H7 clearly indicate its deleterious effect on food safety. A rapid and sensitive detection assay is needed for this harmful organism to prevent foodborne illnesses and control outbreaks in a timely manner. We developed a magnetic bead-based immunoassay for detection of E. coli O157:H7 (the most well-known Shiga toxigenic E. coli strain) with a 96-well microplate as an assay platform. Immunomagnetic separation (IMS) and tyramide signal amplification were coupled to the assay to increase its sensitivity and specificity. This immunoassay was able to detect E. coli O157:H7 in pure culture with a detection limit of 50 CFU/ml in less than 3 h without an enrichment step. The detection limit was decreased 10-fold to 5 CFU/ml with addition of a 3-h enrichment step. When this assay was tested with other nontarget foodborne pathogens and common enteric bacteria, no cross-reactivity was found. When tested with artificially contaminated ground beef and milk samples, the assay sensitivity decreased two- to fivefold, with detection limits of 250 and 100 CFU/ml, respectively, probably because of the food matrix effect. The assay results also were compared with those of a sandwich-type enzyme-linked immunosorbent assay (ELISA) and an ELISA coupled with IMS; the developed assay was 25 times and 4 times more sensitive than the standard ELISA and the IMS ELISA, respectively. Tyramide signal amplification combined with IMS can improve sensitivity and specificity for detection of E. coli O157:H7. The developed assay could be easily adapted for other foodborne pathogens and will contribute to improved food safety and public health. PMID- 24406006 TI - Prevalence of Salmonella serovars, Listeria monocytogenes, and Escherichia coli O157:H7 in Mediterranean ready-to-eat meat products in Jordan. AB - The presence of Salmonella, Listeria monocytogenes, and Escherichia coli O157:H7 in ready-to-eat (RTE) meat products is considered a major concern for food control authorities worldwide. The aims of this study were to determine (i) the prevalence of Salmonella, L. monocytogenes, and E. coli O157:H7 in Mediterranean RTE chicken and beef (CB) products sold in Jordanian restaurants and (ii) the susceptibility of the isolates to antibiotics. A total of 1,028 samples of various types of RTE CB products (550 RTE chicken and 478 RTE beef products) were analyzed by methods described by the International Organization for Standardization followed by molecular confirmation of the isolates. The VITEK2 automated system was used for testing antibiotic susceptibility of the isolates. The overall prevalence of Salmonella serovars in RTE CB products was 0.5%, with 0.8 and 0.2% in RTE chicken and RTE beef, respectively. The overall prevalence of L. monocytogenes in RTE CB products was 2%, with 2.7 and 1.5% in RTE chicken and RTE beef products, respectively. E. coli O157:H7 was not isolated from any of the tested samples. Multidrug-resistant Salmonella and L. monocytogenes isolates were found. The majority of Salmonella isolates were sensitive to most of the tested antibiotics, and all of the isolates were resistant to more than one antibiotic. Similarly, more than 85% of L. monocytogenes isolates were sensitive to nine antibiotics, and the majority of L. monocytogenes isolates were resistant to fosfomycin and oxacillin. PMID- 24406007 TI - Characteristics of extended-spectrum cephalosporin-resistant Escherichia coli isolated from Swiss and imported poultry meat. AB - A worrisome phenomenon is the progressive global spread of Enterobacteriaceae in poultry and chicken meat expressing plasmid-mediated enzymes that inactivate beta lactam antibiotics, suggesting that the food chain might play a role in the epidemiology and the transmission of extended-spectrum cephalosporin-resistant Enterobacteriaceae to humans. The aim of the present study was to further characterize 24 extended-spectrum cephalosporin-resistant Enterobacteriaceae isolated from domestic and imported poultry meat by antibiotic susceptibility testing, identification of the blaESBL/blapAmpC genes, conjugation mating experiments and determination of plasmid incompatibility types, multilocus sequence typing, and analysis of the Escherichia coli phylogenetic groups. On account of their resistance patterns, 21 of the total 24 isolates were classified as multidrug resistant. Eleven isolates carried a blaCMY-2 gene, whereas 13 isolates harbored a blaCTX-M-1 gene. All isolates harbored plasmids that were assigned to 8 of the 18 described plasmid incompatibility groups, the most frequent of which were IncI1, IncFIB, IncB/O, and IncFrepB. The blaESBL/blapAmpC genes were harbored mainly by transferable IncI1 and IncB/O plasmids. Multilocus sequence typing as well as E. coli phylogenetic group typing revealed a high heterogenicity even among different isolates of the same sample. PMID- 24406008 TI - Introduction of infected animals to herds is an important route for the spread of Yersinia enterocolitica infection between pig farms. AB - Altogether, 369 pathogenic Yersinia enterocolitica isolates from 1,118 fecal samples collected from 22 pig farms of different production types were characterized by biotyping, serotyping, and genotyping using multiple-locus variable-number tandem repeats analysis. We investigated the distribution of the different genotypes at the farm level and their association with different farm conditions. Pigs were found to carry and transmit Y. enterocolitica between farms, because the same genotypes were found on farms that had previously transported the pigs between them. The purchase of new animals for the farms associated significantly with the number of different multiple-locus variable number tandem repeats analysis types of Y. enterocolitica found within a farm. Some genotypes seemed to persist on farms for years. The results of this study show that pigs purchased from infected herds transmit Y. enterocolitica infection between farms. Certain pig farms may act as long-term sources of infection. PMID- 24406009 TI - Tetracycline residues in porcine stomach after administration via drinking water on a swine farm. AB - Tetracycline is a broad-spectrum antibiotic used to treat infections in swine. The maximum residue levels of tetracycline in pork stomach tissue in Russia, Europe, and the United States are 10, 200, and 2,000 ppb, respectively. This difference in accepted safety levels may be the reason why stomach tissues that the United States exports continue to be residue violators in overseas markets. In this study, 30 pigs at two different stages of production (weanling and finisher) were treated with tetracycline at 22 mg/kg of body weight per day for a total of 5 days via a water medicator. Blood samples were collected at 0, 72, 78, 96, and 102 h after the start of medication. The medication was stopped at 120 h, and blood samples were again collected at 126, 144, 168, 192, and 216 h after exposure. Five animals were slaughtered for stomach tissue 0, 24, 48, 96, and 192 h after the drug was flushed from the water line. All blood and tissue samples were analyzed by high-performance liquid chromatography-UV methods. The tetracycline levels in plasma were below the level of detection after the U.S. labeled withdrawal time of 4 days. The stomach tissue residues averaged 671.72, 330.31, 297.77, 136.36, and 268.08 ppb on withdrawal days 0, 1, 2, 4, and 8, respectively. Using the U.S. Food and Drug Administration tolerance limit method and a population-based pharmacokinetic model with Monte Carlo simulation, a withdrawal interval was estimated. This study demonstrated that tetracycline residues are still detectable in the stomach tissues after the established United States withdrawal time of 4 days. These residue levels may explain why stomach tissues tested in Russia and Europe show positive residues for tetracycline, even though the meat may pass inspection here in the United States prior to export. PMID- 24406010 TI - Influence of modified atmosphere packaging on meat quality parameters of turkey breast muscles. AB - Poultry meat is often stored in modified atmosphere packaging (MAP) or vacuum packaging to improve consumer acceptance and shelf life. The aim of this study was to determine how different packaging conditions influence meat quality. Therefore, in three independent experiments, turkey breast muscle cutlets were packaged either in vacuum or in different modified atmosphere mixtures (80% O2, 20% CO2 [MAP 1]; 80% N2, 20% CO2 [MAP 2]; and 20% O2, 20% CO2, 60% N2 [MAP 3]) and stored for 12 days at 3 degrees C. Color, pH, electrical conductivity, total viable counts, and Pseudomonas species were determined on days 1, 4, 8, and 12 of storage. On the same days, samples were collected for analysis of thiobarbituric acid-reactive substance and total volatile basic nitrogen concentrations. Sensory parameters and liquid loss were determined on days 4, 8, and 12. Vacuum-packaged meat had the highest liquid loss and lowest sensory results. MAP 1-packaged meat showed the highest sensory, redness, and thiobarbituric acid-reactive substance values. MAP 2-packaged meat had lower sensory values. MAP 3-packaged meat had lower redness and sensory values, especially at the end of storage. The study showed an impact of the packaging condition on different quality parameters, with a small advantage for storage of turkey cutlets in high-oxygen packages. PMID- 24406011 TI - Biofilm formation under different temperature conditions by a single genotype of persistent Listeria monocytogenes strains. AB - Some Listeria monocytogenes strains, termed persistent strains, originate from the same processing plant and have the ability to survive and grow over extended periods of time at contamination sources. In order to evaluate biofilm formation by such persistent strains, we isolated the pathogen from chicken samples collected from the same retail shop in repeated visits over 6 months. Strains that were of serotype 1/2b and were assigned to the same genotype by multi virulence-locus sequence typing analysis were isolated on repeated occasions from December 1997 to June 1998 and thus were defined as persistent strains. In the present study, biofilm formation by the persistent strains was evaluated using microplates at 30 and 37 degrees C. The biofilm-forming capability was measured after cells attaching to the microplate well were stained with crystal violet. Comparison of biofilm formation at 30 degrees C among the persistent strains showed that a significantly higher amount of the stain was obtained from the persistent strains isolated from December to March than from those isolated from April to June. However, no significant difference in biofilm formation at 30 degrees C was observed between persistent and nonpersistent groups of L. monocytogenes strains. In contrast, biofilm formation at 37 degrees C was consistent among the persistent strains, and they produced significantly more biofilm at 37 degrees C than did the nonpersistent strains. The persistent strains were also found to change their biofilm-forming ability in a temperature dependent manner, which may suggest that the persistent strains alter their biofilm formation in response to changing environmental factors. PMID- 24406012 TI - Mycobacterium avium subsp. avium in lymph nodes and diaphragms of pigs from one infected herd in the Czech Republic. AB - This study was performed on 40 finished pigs from one herd naturally infected with Mycobacterium avium subsp. avium. The aim was to investigate the presence and amount of M. a. avium in samples of lymph nodes and diaphragm tissues collected during routine postmortem inspection using the triplex quantitative real time PCR (qPCR) method. We collected, in total, 107 samples: various lymph nodes affected by gross tuberculosis (TB)-like lesions from 17 pig carcasses, as well as samples of head and mesenteric lymph nodes from 23 carcasses without TB like lesions. Samples of diaphragm tissues were collected from all carcasses. M. a. avium was detected in one or more tissue samples collected from half of the slaughtered pigs tested. Samples of diaphragm tissues of three pigs with detected TB-like lesions contained M. a. avium (10(2) to 10(3) cells per g of sample); the organism was not detected in diaphragm tissues from pigs without TB-like lesions. The qPCR method may be useful for quantification of M. a. avium in pigs for the purposes of foodborne risk assessment. PMID- 24406013 TI - Effect of bacterial cell-free supernatants on infectivity of norovirus surrogates. AB - Bacterial metabolic products were evaluated for inhibitory effects on viral propagation in cell culture. Cell-free supernatants (CFS) were prepared from growth of Enterococcus faecalis ATCC 19433, Pseudomonas fluorescens ATCC 13525, Escherichia coli 08, Staphylococcus epidermidis ATCC 12228, Bacillus subtilis 168, Bacillus coagulans 185A, B. coagulans 7050, Clostridium sporogenes PA3679, and a commercial probiotic mixture of Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium bifidum, Lactobacillus salivarius, and Streptococcus thermophilus in microbiological medium or milk. The inhibitory effects of CFS on the propagation of murine norovirus 1 and Tulane virus in RAW 264.7 and LLCMK2 cells, respectively, were evaluated in the continuous presence of CFS or after exposure of host cells to CFS. Slight inhibition of viral propagation was observed for murine norovirus and Tulane virus in the continuous presence of CFS of B. subtilis 168 and E. faecalis 19433, respectively. CFS cytotoxicity was also determined by microscopic examination. Virus persisted in the CFS that demonstrated cytotoxic effects, suggesting a lack of direct effect of CFS on virions. The viral propagation indicates a general lack of competitive inhibition by bacterial extracellular products and bears significance in understanding the persistence of virus in food and human systems shared by bacteria that are recognized for their colonization and competitive capabilities. PMID- 24406014 TI - Listeria monocytogenes persistence in food-associated environments: epidemiology, strain characteristics, and implications for public health. AB - Over the last 10 to 15 years, increasing evidence suggests that persistence of Listeria monocytogenes in food processing plants for years or even decades is an important factor in the transmission of this foodborne pathogen and the root cause of a number of human listeriosis outbreaks. L. monocytogenes persistence in other food-associated environments (e.g., farms and retail establishments) may also contribute to food contamination and transmission of the pathogen to humans. Although L. monocytogenes persistence is typically identified through isolation of a specific molecular subtype from samples collected in a given environment over time, formal (statistical) criteria for identification of persistence are undefined. Environmental factors (e.g., facilities and equipment that are difficult to clean) have been identified as key contributors to persistence; however, the mechanisms are less well understood. Although some researchers have reported that persistent strains possess specific characteristics that may facilitate persistence (e.g., biofilm formation and better adaptation to stress conditions), other researchers have not found significant differences between persistent and nonpersistent strains in the phenotypic characteristics that might facilitate persistence. This review includes a discussion of our current knowledge concerning some key issues associated with the persistence of L. monocytogenes, with special focus on (i) persistence in food processing plants and other food-associated environments, (ii) persistence in the general environment, (iii) phenotypic and genetic characteristics of persistent strains, (iv) niches, and (v) public health and economic implications of persistence. Although the available data clearly indicate that L. monocytogenes persistence at various stages of the food chain contributes to contamination of finished products, continued efforts to quantitatively integrate data on L. monocytogenes persistence (e.g., meta-analysis or quantitative microbial risk assessment) will be needed to advance our understanding of persistence of this pathogen and its economic and public health impacts. PMID- 24406015 TI - Global dust Detection Index (GDDI); a new remotely sensed methodology for dust storms detection. AB - Dust storm occurs frequently in arid and semi-arid areas of the world. This natural phenomenon, which is the result of stormy winds, raises a lot of dust from desert surfaces and decreases visibility to less than 1 km. In recent years the temporal frequency of occurrences and their spatial extents has been dramatically increased. West of Iran, especially in spring and summer, suffers from significant increases of these events which cause several social and economic problems. Detecting and recognizing the extent of dust storms is very important issue in designing warning systems, management and decreasing the risk of this phenomenon. As the process of monitoring and prediction are related to detection of this phenomenon and it's separation from other atmospheric phenomena such as cloud, so the main aim of this research is establishing an automated process for detection of dust masses. In this study 20 events of dust happened in western part of Iran during 2000-2011 have been recognized and studied. To the aim of detecting dust events we used satellite images of MODIS sensor. Finally a model based on reflectance and thermal infrared bands has been developed. The efficiency of this method has been checked using dust events. Results show that the model has a good performance in all cases. It also has the ability and robustness to be used in any dust storm forecasting and warning system. PMID- 24406017 TI - The prognostic role of ERG immunopositivity in prostatic acinar adenocarcinoma: a study including 454 cases and review of the literature. AB - TMPRSS2/ERG fusion is among the most frequent genetic anomalies in prostate adenocarcinomas. Although positive immunostaining for ERG has been shown to tightly correlate with ERG fusion status, the clinical and prognostic significance of a positive ERG stain remains undetermined. The significance of ERG immunostaining in 454 consecutive prostate adenocarcinomas from radical prostatectomies (RPs) using tissue microarrays, herein, is evaluated. A separate set of 59 cases of incidental prostate adenocarcinoma detected on transurethral resection of prostate with a Gleason score of 6 was also included. ERG translocation was significantly more common in peripheral zone cancer in comparison with cancer of the transitional zone (33% in RP versus 5% in transurethral resection of prostate specimens). In the RP cohort, although ERG positivity was significantly associated with younger age at presentation and lower prostate-specific antigen values, it showed no association with Gleason score or with pathologic stage. In multivariate analysis, biochemical recurrence was only associated with the final RP Gleason score and elevated prostate specific antigen levels and was unrelated to neither ERG positivity or to its staining intensity. In our hands, ERG positivity was unrelated to either aggressive local tumor characteristics or a worse outcome. Our results, as well as an extensive review of the related literature showing conflicting findings, seem to indicate that ERG immunopositivity cannot be considered as an important prognostic factor in prostate cancer. PMID- 24406016 TI - Acute exposure to ultraviolet-B radiation modulates sex steroid hormones and receptor expression in the skin and may contribute to the sex bias of melanoma in a fish model. AB - Using the Xiphophorus fish melanoma model, we show a strong male bias for sunlight-induced malignant melanoma, consistent with that seen in the human population. To examine underlying factors, we exposed adult X. couchianus fish to a single, sublethal dose of UVB and measured circulating sex steroid hormones and expression of associated hormone receptor genes over a 24-h period. We found that a single exposure had profound effects on circulating levels of steroid hormones with significant decreases for all free sex steroids at 6 and 24 h and increases in conjugated 2-estradiol and 11-ketotestosterone at 6 and 24 h, respectively. Whereas ARalpha expression increased in male and female skin, neither ARbeta nor either of the ERs showed significant responses to UVB in either sex. The rapid response of male androgens and their receptors in the skin after UVB irradiation implicates hormones in the male bias of skin cancer and suggests that the photoendocrine response immediately after UV exposure may be relevant to melanomagenesis. PMID- 24406018 TI - Clinicopathologic characteristics of prefibrotic-early primary myelofibrosis in Chinese patients. AB - The clinicopathologic features of patients with prefibrotic-early primary myelofibrosis (PEPMF) are still uncertain, and the characteristics of PEPMF in Asian patients are rarely reported. This study analyzed the clinicopathologic characteristics of 42 Chinese patients with PMF newly diagnosed according to the 2008 World Health Organization criteria. Some clinical and laboratory features of the patients differed significantly from those of the predominantly white patients in Western countries. Chinese patients with PEPMF were more often male (1.28:1) and younger, less likely to have higher median hemoglobin concentrations (126 g/L), less frequently had palpable spleens (35.7%), and had longer median times between prefibrotic-early and classical PEPMF (64 months). On bone marrow trephine sections, Chinese patients were more likely to have increased granulopoiesis (78.6%) and less frequently had balloon-like megakaryocytes (61.9%), giant and staghorn megakaryocytes (35.7%), or megakaryocytes with hyperchromatic and dysplastic nuclei (40.4%). In conclusion, some clinicopathologic characteristics of PEPMF in Chinese patients in China differ substantially from those seen in predominantly white patients in Western countries, and more clinicopathologic studies involving different ethnic populations and geographic regions of the world should help unfold the characteristics of this disease. PMID- 24406019 TI - Influence of age on manifestation, VC and TLCO values, and bronchoalveolar lavage cell counts of sarcoidosis and extrinsic allergic alveolitis. AB - INTRODUCTION: Immune response probably changes during human life, being influenced by cumulative exposure to environmental factors and individual genetic background. METHODS: Patients investigated for suspected interstitial lung disease were prospectively enrolled. After completing the diagnostic process, 121 patients were diagnosed extrinsic allergic alveolitis (EAA) and 136 sarcoidosis. Three groups according to age were established (<30 years, 30-60 years, >60 years), clinical manifestation, vital capacity (VC), forced expired volume in 1 s (FEV1 ), lung diffusing capacity for carbon monoxide-transfer factor (TLCO ) and bronchoalveolar lavage fluid (BALF) differential cell count were compared among the groups. RESULTS: Age subgroups of EAA patients did not significantly differ in lung functions. In the group above 60 years, non-significantly higher neutrophils and eosinophils counts and CD4/CD8 ratio were observed. Sarcoidosis patients were significantly younger than EAA group and had significantly better lung functions (VC, FEV1 , TLCO ). Patients with sarcoidosis above 60 years of age had significantly higher percentages of neutrophils in BALF compared with younger patients. BALF percentage of neutrophils positively correlated with age. CONCLUSIONS: Presented results may support the hypothesis that reactivity of immune system changes during the life, which may result in different manifestation of interstitial lung diseases according to age. PMID- 24406020 TI - Patients' perceived purpose of clinical informed consent: Mill's individual autonomy model is preferred. AB - BACKGROUND: Although informed consent is an integral part of clinical practice, its current doctrine remains mostly a matter of law and mainstream ethics rather than empirical research. There are scarce empirical data on patients' perceived purpose of informed consent, which may include administrative routine/courtesy gesture, simple honest permission, informed permission, patient-clinician shared decision-making, and enabling patient's self decision-making. Different purposes require different processes. METHODS: We surveyed 488 adults who were planning to undergo or had recently undergone written informed consent-requiring procedures. Perceptions of informed consent purpose (from norm and current practice perspectives) were explored by asking respondents to rank (1 = most reflective) 10 randomly-presented statements: "meaningless routine", "courtesy gesture" "litigation protection", "take away compensation rights", "inform patient', "make sure patient understand", "document patient's decision", "discover patient's preferences", "have shared decision", and "help patient decide". RESULTS: Respondents' mean (SD) age was 38.3 (12.5); 50.4% were males, 56.8% had >= college education, and 37.3% had undergone a procedure. From the norm perspective, the least reflective statement was "meaningless routine" (ranked 1-3 by 2.6% of respondents) and the most reflective statements were "help patient decide", "make sure patient understand", and "inform patient" (ranked 1-3 by 65%, 60%, and 48% of respondents with median [25%,75%] ranking scores of 2 [1,5], 3 [2,4], and 4 [2,5], respectively). Compared to their counterparts, males and pre procedure respondents ranked "help patient decide" better, whereas females and post-procedure respondents ranked "inform patient" better (p = 0.007 to p < 0.001). Age was associated with better ranking of "help patient decide" and "make sure patient understand" statements (p < 0.001 and p = 0.002, respectively), which were ranked 1-3 by only 46% and 42% of respondents from the current practice perspective (median ranking score 4 [2,6], p < 0.001 vs. norm perspective for both). CONCLUSIONS: 1) the informed consent process is important to patients, however, patients vary in their views of its purpose with the dominant view being enabling patients' self decision-making, 2) males, pre procedure, and older patients more favor a self decision-making purpose, whereas females and post-procedure patients more favor an information disclosure purpose, and 3) more self decision-making and more effective information disclosure than is currently practiced are desired. An informed consent process consistent with Mill's individual autonomy model may be suitable for most patients. PMID- 24406021 TI - An association between neighbourhood wealth inequality and HIV prevalence in sub Saharan Africa. AB - This paper investigates whether community-level wealth inequality predicts HIV serostatus using DHS household survey and HIV biomarker data for men and women ages 15-59 pooled from six sub-Saharan African countries with HIV prevalence rates exceeding 5%. The analysis relates the binary dependent variable HIV positive serostatus and two weighted aggregate predictors generated from the DHS Wealth Index: the Gini coefficient, and the ratio of the wealth of households in the top 20% wealth quintile to that of those in the bottom 20%. In separate multilevel logistic regression models, wealth inequality is used to predict HIV prevalence within each statistical enumeration area, controlling for known individual-level demographic predictors of HIV serostatus. Potential individual level sexual behaviour mediating variables are added to assess attenuation, and ordered logit models investigate whether the effect is mediated through extramarital sexual partnerships. Both the cluster-level wealth Gini coefficient and wealth ratio significantly predict positive HIV serostatus: a 1 point increase in the cluster-level Gini coefficient and in the cluster-level wealth ratio is associated with a 2.35 and 1.3 times increased likelihood of being HIV positive, respectively, controlling for individual-level demographic predictors, and associations are stronger in models including only males. Adding sexual behaviour variables attenuates the effects of both inequality measures. Reporting eleven plus lifetime sexual partners increases the odds of being HIV positive over five-fold. The likelihood of having more extramarital partners is significantly higher in clusters with greater wealth inequality measured by the wealth ratio. Disaggregating logit models by sex indicates important risk behaviour differences. Household wealth inequality within DHS clusters predicts HIV serostatus, and the relationship is partially mediated by more extramarital partners. These results emphasize the importance of incorporating higher-level contextual factors, investigating behavioural mediators, and disaggregating by sex in assessing HIV risk in order to uncover potential mechanisms of action and points of preventive intervention. PMID- 24406022 TI - Spatial multi-criteria decision analysis to predict suitability for African swine fever endemicity in Africa. AB - BACKGROUND: African swine fever (ASF) is endemic in several countries of Africa and may pose a risk to all pig producing areas on the continent. Official ASF reporting is often rare and there remains limited awareness of the continent-wide distribution of the disease.In the absence of accurate ASF outbreak data and few quantitative studies on the epidemiology of the disease in Africa, we used spatial multi-criteria decision analysis (MCDA) to derive predictions of the continental distribution of suitability for ASF persistence in domestic pig populations as part of sylvatic or domestic transmission cycles. In order to incorporate the uncertainty in the relative importance of different criteria in defining suitability, we modelled decisions within the MCDA framework using a stochastic approach. The predictive performance of suitability estimates was assessed via a partial ROC analysis using ASF outbreak data reported to the OIE since 2005. RESULTS: Outputs from the spatial MCDA indicate that large areas of sub-Saharan Africa may be suitable for ASF persistence as part of either domestic or sylvatic transmission cycles. Areas with high suitability for pig to pig transmission ('domestic cycles') were estimated to occur throughout sub-Saharan Africa, whilst areas with high suitability for introduction from wildlife reservoirs ('sylvatic cycles') were found predominantly in East, Central and Southern Africa. Based on average AUC ratios from the partial ROC analysis, the predictive ability of suitability estimates for domestic cycles alone was considerably higher than suitability estimates for sylvatic cycles alone, or domestic and sylvatic cycles in combination. CONCLUSIONS: This study provides the first standardised estimates of the distribution of suitability for ASF transmission associated with domestic and sylvatic cycles in Africa. We provide further evidence for the utility of knowledge-driven risk mapping in animal health, particularly in data-sparse environments. PMID- 24406023 TI - Young novice drivers and the risky behaviours of parents and friends during the provisional (intermediate) licence phase: a brief report. AB - PURPOSE: While there is research indicating that many factors influence the young novice driver's increased risk of road crash injury during the earliest stages of their independent driving, there is a need to further understand the relationship between the perceived risky driving behaviour of parents and friends and the risky behaviour of drivers with a Provisional (intermediate) licence. METHOD: As part of a larger research project, 378 drivers aged 17-25 years (M=18.22, SD=1.59, 113 males) with a Provisional licence completed an online survey exploring the perceived riskiness of their parents' and friends' driving, and the extent to which they pattern (i.e. base) their driving behaviour on the driving of their parents and friends. RESULTS: Young drivers who reported patterning their driving on their friends, and who reported they perceived their friends to be risky drivers, reported more risky driving. The risky driving behaviour of young male drivers was associated with the perceived riskiness of their fathers' driving, whilst for female drivers the perceived riskiness of their mothers' driving approached significance. CONCLUSIONS: The development and application of countermeasures targeting the risky behaviour of same-sex parents appears warranted by the robust research findings. In addition, countermeasures need to encourage young people in general to be non-risky drivers; targeting the negative influence of risky peer groups specifically. Social norms interventions may minimise the influence of potentially-overestimated riskiness. PMID- 24406024 TI - Improved reduced representation bisulfite sequencing for epigenomic profiling of clinical samples. AB - BACKGROUND: DNA methylation plays crucial roles in epigenetic gene regulation in normal development and disease pathogenesis. Efficient and accurate quantification of DNA methylation at single base resolution can greatly advance the knowledge of disease mechanisms and be used to identify potential biomarkers. We developed an improved pipeline based on reduced representation bisulfite sequencing (RRBS) for cost-effective genome-wide quantification of DNA methylation at single base resolution. A selection of two restriction enzymes (TaqalphaI and MspI) enables a more unbiased coverage of genomic regions of different CpG densities. We further developed a highly automated software package to analyze bisulfite sequencing results from the Solexa GAIIx system. RESULTS: With two sequencing lanes, we were able to quantify ~1.8 million individual CpG sites at a minimum sequencing depth of 10. Overall, about 76.7% of CpG islands, 54.9% of CpG island shores and 52.2% of core promoters in the human genome were covered with at least 3 CpG sites per region. CONCLUSIONS: With this new pipeline, it is now possible to perform whole-genome DNA methylation analysis at single base resolution for a large number of samples for understanding how DNA methylation and its changes are involved in development, differentiation, and disease pathogenesis. PMID- 24406025 TI - Ondansetron augmentation in patients with obsessive-compulsive disorder who are inadequate responders to serotonin reuptake inhibitors: improvement with treatment and worsening following discontinuation. AB - OBJECT: The aim of this study was to evaluate low-dose ondansetron as an augmentation strategy in patients with obsessive-compulsive disorder (OCD) who do not adequately respond to serotonin reuptake inhibits (SRIs). METHODS: Twenty-one OCD patients who had not responded adequately to an SRI received 12 weeks of single-blind ondansetron augmentation initiated at 0.25mg BID for 2 weeks, and titrated to 0.5mg BID for an additional 10 weeks. Patients were rated every two weeks using the Yale-Brown Obsessive Compulsive Scale (YBOCS) and Clinical Global Impressions Scale (CGI). Treatment response was defined as an additional 25% reduction in YBOCS score from the score at the initiation of ondansetron augmentation, an end of treatment YBOCS score of <= 24 and a CGI-Improvement (CGI I) score of <= 2. Upon completion of treatment course patients were followed for 4 weeks. RESULTS: At week 12, twelve of the 21 (57%) patients were responders. The average reduction in the YBOCS score for the overall group was 27.2%. Responders had an average 44% YBOCS score reduction and 76.9% CGI-I reduction. After discontinuation of ondansetron the YBOCS worsened an average of 15.5% in the entire sample and 38.3% in the responder subsample. No clinically meaningful side effects were reported. CONCLUSION: OCD patients who do not adequately respond to an SRI may benefit from augmentation with a low-dose of ondansetron. This may provide an alternative approach to augmentation with atypical antipsychotic agents, with a more favorable safety profile. PMID- 24406026 TI - Proposed approach to thrombolysis in dabigatran-treated patients presenting with ischemic stroke. AB - BACKGROUND: Acute ischemic stroke thrombolysis in patients taking dabigatran is controversial because of a presumed increased risk of symptomatic hemorrhagic transformation. Using data from our local hematopathology laboratory, we developed a thrombolysis protocol for acute ischemic stroke patients taking dabigatran. METHODS: A local thrombin time (TT)-dabigatran concentration relationship was calculated using dabigatran calibrators. The effect of dabigatran on activated partial thromboplastin time (aPTT) and prothrombin time (PT) (international normalized ratio [INR]) was also measured. A protocol was developed, in which a dabigatran concentration less than 10 ng/mL (corresponding to a TT<38 seconds or a normal aPTT) was selected as the upper limit for thrombolysis. Consecutive patients presenting with acute stroke were then enrolled in this prospective study. RESULTS: In the 8 months after development of the protocol, 13 potential thrombolysis candidates taking dabigatran were assessed at a median (interquartile range) time of 192 (143) minutes. The median National Institutes of Health Stroke Scale score was 18 (20). The mean time from arrival to TT, aPTT, and PT (INR) results were 39+/-4.1 minutes, 21+/-6.5 minutes, and 21+/-6.5 minutes, respectively. Based on TT/aPTT, 4 patients were ineligible for thrombolysis. Six patients were not treated because of minor or resolving symptoms and another presented with intracerebral hemorrhage. Two patients were treated with intravenous tissue plasminogen activator (tPA), without symptomatic hemorrhagic transformation in either case. In 3 patients (42.8%), aPTT was normal, despite a prolonged TT. CONCLUSIONS: Administration of intravenous tPA in dabigatran-treated patients is feasible. Although, the relationship between dabigatran concentrations and coagulation measures varies between laboratories, individual protocols, preferably based on TT, can be developed at acute stroke treatment centers. PMID- 24406027 TI - Early-onset dystonia after supplementary motor area infarction. AB - A 63-year-old patient with the right supplementary motor area infarct developed early-onset dystonia in the left upper extremity. The mechanisms involved in the genesis of focal dystonia are discussed with emphasis on cortical basal ganglia circuit and efferent projections from the supplementary motor area. PMID- 24406028 TI - Kyphopasty and vertebroplasty. AB - Vertebroplasty and balloon kyphoplasty are percutaneous techniques performed under radioscopic control. They were initially developed for tumoral and osteoporotic lesions; indications were later extended to traumatology for the treatment of pure compression fracture. They are an interesting alternative to conventional procedures, which are often very demanding. The benefit of these minimally invasive techniques has been demonstrated in terms of alleviation of pain, functional improvement and reduction in both morbidity and costs for society. The principle of kyphoplasty is to restore vertebral body anatomy gently and progressively by inflating balloons and then reinforcing the anterior column of the vertebra with cement. In vertebroplasty, cement is introduced directly under pressure, without prior balloon inflation. Both techniques can be associated to minimally invasive osteosynthesis in certain indications. In our own practice, we preferably use acrylic cement, for its biomechanical properties and resistance to compression stress. We use calcium phosphate cement in young patients, but only associated to percutaneous osteosynthesis due to the risk of secondary correction loss. The evolution of these techniques depends on improving personnel radioprotection and developing new systems of vertebral expansion. PMID- 24406029 TI - Homology and molecular dynamics models of toll-like receptor 7 protein and its dimerization. AB - Toll-like receptor protein 7 is a transmembrane protein playing a crucial role in the signaling pathways involved in innate immunity. Its crystal structure is not yet available, but there are several proteins possessing domains of sufficiently high homology, which enabled us to build a model of the toll-like receptor protein 7 monomer and gain insights into dimer formation. To obtain a reliable structure prediction, we subjected this model to equilibration using molecular dynamics simulations. Furthermore, the equilibrated monomer structure was used to construct models of dimerization and to predict binding sites for small ligands. Docking studies were performed for some of the known toll-like receptor protein 7 ligands. We determined that a new homology model generated by the LOOPP server provides a good alternative to a previously reported model. Our docking results indicate that the addition of either imiquimod or 1V209 to a toll-like receptor protein 7 dimer changes an unfavorable interaction into a favorable one. We found that eight small molecules docked to two pockets in toll-like receptor protein 7 bind to both pockets at pH 7 and at pH 5.5. This work provides a realistic model that could be used for drug discovery aimed at finding toll-like receptor protein 7 dimerization activators, with potential clinical applications to a host of diseases, including cancer. PMID- 24406030 TI - Insult-dependent effect of bone marrow cell therapy on inflammatory response in a murine model of extrapulmonary acute respiratory distress syndrome. AB - INTRODUCTION: Administration of bone marrow-derived cells produces beneficial effects in experimental extrapulmonary acute respiratory distress syndrome (ARDS). However, there are controversies regarding the effects of timing of cell administration and initial insult severity on inflammatory response. We evaluated the effects of bone marrow-derived mononuclear cells (BMDMC) in two models of extrapulmonary ARDS once lung morphofunctional changes had already been installed. METHODS: BALB/c mice received lipopolysaccharide (LPS) intraperitoneally (5 mg/kg in 0.5 ml saline) or underwent cecal ligation and puncture (CLP). Control mice received saline intraperitoneally (0.5 ml) or underwent sham surgery. At 24 hours, groups were further randomized to receive saline or BMDMC (2 * 10(6)) intravenously. Lung mechanics, histology, and humoral and cellular parameters of lung inflammation and remodeling were analyzed 1, 3 and 7 days after ARDS induction. RESULTS: BMDMC therapy led to improved survival in the CLP group, reduced lung elastance, alveolar collapse, tissue and bronchoalveolar lavage fluid cellularity, collagen fiber content, and interleukin 1beta and increased chemokine (keratinocyte-derived chemokine and monocyte chemotactic protein-1) expression in lung tissue regardless of the experimental ARDS model. Intercellular adhesion molecule-1 and vascular cell adhesion molecule 1 expression in lung tissue increased after cell therapy depending on the insult (LPS or CLP). CONCLUSIONS: BMDMC therapy at day 1 successfully reduced lung inflammation and remodeling, thus contributing to improvement of lung mechanics in both extrapulmonary ARDS models. Nevertheless, the different inflammatory responses induced by LPS and CLP resulted in distinct effects of BMDMC therapy. These data may be useful in the clinical setting, as they suggest that the type of initial insult plays a key role in the outcome of treatment. PMID- 24406031 TI - Cognitive behavioural therapy for the treatment of depression in people with multiple sclerosis: a systematic review and meta-analysis. AB - BACKGROUND: Depression is a common symptom in people with multiple sclerosis. We systematically reviewed published controlled trials on the effectiveness of cognitive behavioural therapy (CBT) for the treatment of depression in people with multiple sclerosis. METHODS: Publications were identified using MEDLINE, PsycINFO and the Cochrane Central Register of Controlled Trials to June/July 2013. We combined thesaurus and free-text terms which were synonyms of the concepts multiple sclerosis, depression and cognitive behavioural therapy. We included published controlled trials which compared individual, group CBT, conducted face-to-face or remotely, to no CBT. Two reviewers extracted data to calculate standardized mean differences (SMD) for self-reported symptoms of depression and weighted mean differences (WMD) for the Multiple Sclerosis Impact Scale (MSIS-29), with 95% Confidence Intervals (CIs). We investigated statistical heterogeneity using I2. RESULTS: Seven eligible studies (n = 433) were identified, which evaluated the effect on depression of CBT delivered individually (3 studies), in a group (3 studies) and by computer (1 study). The summary effect (SMD -0.61, 95% CI -0.96 to -0.26, p=0.0006) was reduced (SMD 0.46, 95% CI -0.75 to -0.17, p=0.002) when an outlying study was removed in a sensitivity analysis to examine statistical heterogeneity. Three studies (n=213) observed a direction of effect using the MSIS-29 which was not statistically significant (WMD -4.36, 95% CI -9.33 to 0.62, p=0.09). There was no between subgroup heterogeneity (I2=0). CONCLUSIONS: CBT can be an effective treatment for depression in MS. Further research should explore optimal durations and modalities of treatment for patients with different characteristics. PMID- 24406033 TI - The effectiveness of a self-efficacy-enhancing intervention for Chinese patients with colorectal cancer: a randomized controlled trial with 6-month follow up. AB - BACKGROUND: Colorectal cancer is a major public health problem. There is growing support for colorectal cancer survivors who are experiencing problems after cancer treatment to engage in self-management programs to reduce symptom distress. However, there is inconclusive evidence as to the effectiveness of such program especially in Asian region. OBJECTIVES: This study tested the effects of a six-month nurse-led self-efficacy-enhancing intervention for patients with colorectal cancer, compared with routine care over a six-month follow up. DESIGN: A randomized controlled trial with repeated measures, two-group design. SETTING: Three teaching hospitals in Guangzhou, China. PARTICIPANTS: One hundred and fifty two Chinese adult patients with a diagnosis of colorectal cancer were recruited. The intervention group (n=76) received self-efficacy-enhancing intervention and the control group (n=76) received standard care. METHOD: The participants were randomized into either intervention or control group after baseline measures. The outcomes of the study (self-efficacy, symptom distress, anxiety, depression and quality of life) were compared at baseline, three and six months after the intervention. RESULTS: Sixty-eight participants in the intervention group and 53 in the control group completed the study. Their mean age was 53 (SD=11.3). Repeated measure MANOVA found that the patients in the intervention group had significant improvement in their self-efficacy (F=7.26, p=0.003) and a reduction of symptom severity (F=5.30, p=0.01), symptom interference (F=4.06, p=0.025), anxiety (F=6.04, p=0.006) and depression (F=6.96, p=0.003) at three and six months, compared with the control group. However, no statistically significant main effect was observed in quality of life perception between the two groups. CONCLUSIONS: The nurse-led self-efficacy enhancing intervention was effective in promoting self-efficacy and psychological well-being in patients with colorectal cancer, compared with standard care. The intervention can be incorporated into routine care. Future empirical work is required to determine the longer term effects of the intervention. PMID- 24406032 TI - Re-organisation of oesophago-gastric cancer services in England and Wales: a follow-up assessment of progress and remaining challenges. AB - BACKGROUND: This study is an update on an earlier article in 2007 to assess the implementation of the Cancer Plan reform strategy in England and Wales. FINDINGS: A national online survey to upper gastro-intestinal leads at network and trust level. The questionnaire was designed based on existing clinical practice guidelines and addressed governing principles and operational procedures related to the delivery of cancer care. It was sent in January 2012 to upper gastro intestinal network and trusts leads at all cancer networks and acute NHS organisations in England and Wales. Responses were received from 100% of Cancer Networks and 91% of NHS organisations. Centralisation of surgery has improved with all but two trusts (5.4%) now meeting the minimum staffing level for oesophago-gastric cancer surgery. This is a substantial improvement since the 2007 survey when 21 trusts (46.7%) did not meet this requirement. The use of formal assessment for nutritional needs has improved, too. In 2007, the involvement of the palliative care team in multi-disciplinary teams was poor. While this has improved, 27 trusts (19.7%) still report that none of the palliative care team members routinely attend the multi-disciplinary team discussion. CONCLUSIONS: The survey demonstrates improved compliance with organisational recommendations since the last assessment in 2007. Centralisation of surgery has improved and is nearly fully compliant with the reform strategy. Areas that require further improvement are nutritional support and inclusion of palliative care in multi-disciplinary team meetings. PMID- 24406034 TI - Student exchange for nursing students: does it raise cultural awareness'? A descriptive, qualitative study. AB - With free movement for citizens within the European Union and with distant parts of our globe becoming more accessible, cultural awareness and cultural competence are becoming important skills for nurses. Internationalisation and raising awareness of other cultural contexts are essential elements in Swedish higher education, thus explaining the variety of student exchange programmes that are available. The aim of this study was to explore Swedish nursing students' perceptions of student exchange and their experiences. Data were collected through group interviews and then analysed following the principles of content analysis. Our analysis resulted in three categories: Preparing to go abroad, Reasons for going abroad and From expectation to experience. Cultural aspects and cultural awareness were emphasised as strong motivational factors, both personal and professional, behind participation in student exchange programmes. Information was also highlighted as a crucial means of reaching potential students as well as the power of knowledge through personal experience. This study highlights the importance of student exchange in expanding the individual student's personal and professional horizons. It also stresses the importance of including a transcultural nursing element in nursing curricula. PMID- 24406035 TI - Management of postpartum pain. AB - Following the physiologic challenge of birth, many women will experience pain during the postpartum period. The goal is to achieve the right complement and dosing schedule of medications and nonpharmacologic comfort measures to successfully relieve pain, while at the same time allowing the woman to remain fully awake and aware to care for her newborn. Many of the common modalities used for nonpharmacologic pain relief in particular are based on anecdotal evidence, cultural ritual, or outdated studies. In this article, the most common sources of postpartum pain are reviewed as well as evidence-based pain management strategies, including both pharmacologic and nonpharmacologic methods. PMID- 24406036 TI - Puerperal infections of the genital tract: a clinical review. AB - Puerperal genital tract infections, although less common in the 21st century, continue to affect maternal mortality and morbidity rates in the United States. Puerperal genital tract infections include endometritis as well as abdominal and perineal wound infections. These infections interrupt postpartum restoration, increase the potential for readmission to a health care facility, and can interfere with maternal-infant bonding. In addition, unrecognized or improperly treated genital tract infection could extend to other sites via venous circulation or the lymphatic system and increase the risk of severe complications or sepsis. Midwives are leaders in education, low rates of intervention, and prompt recognition of deviation from normal. Because puerperal genital tract infection usually begins after discharge, detailed education for women will encourage preventative health care, prompt recognition, and treatment. PMID- 24406037 TI - CenteringParenting: an innovative dyad model for group mother-infant care. AB - CenteringParenting is a group model that brings a cohort of 6 to 7 mothers and infants together for care during the first year of life. During 9 group sessions the clinician provides well-baby care and also attends to the health, development, and safety issues of the mother. Ideally, CenteringParenting provides continuity of care for a cohort of women who have received care in CenteringPregnancy, group prenatal care that is 10 sessions throughout the entire pregnancy and that leads to community building, better health outcomes, and increased satisfaction with prenatal care. The postpartum year affects the entire family, but especially the mother, who is redefining herself and her own personal goals. Issues of weight/body image, breastfeeding, depression, contraception, and relationship issues all may surface. In traditional care, health resources for support and intervention are frequently lacking or unavailable. Women's health clinicians also note the loss of contact with women they have followed during the prenatal period, often not seeing a woman again until she returns for another pregnancy. CenteringParenting recognizes that the health of the mother is tied to the health of the infant and that assessment and interventions are more appropriate and efficient when done in a dyad context. Facilitative leadership, rather than didactic education, encourages women to fully engage in their care, to raise issues of importance to them, and to discuss concerns within an atmosphere that allows for the surfacing of culturally appropriate values and beliefs. Implementing the model calls for system changes that are often significant. It also requires the building of a substantial team relationship among care providers. This overview describes the CenteringParenting mother infant dyad care model with special focus on the mother and reviews the perspectives and experiences of staff from several practice sites. PMID- 24406038 TI - Share with women. Postpartum depression. PMID- 24406040 TI - The optimum conditions for synthesis of Fe3O4/ZnO core/shell magnetic nanoparticles for photodegradation of phenol. AB - The photocatalysis of phenol was studied using Fe3O4/ZnO core/shell magnetic nanoparticles (MNPs). The photocatalysts were synthesized by coating of ZnO onto the magnetite by precipitation method and characterized by XRD, SEM and FTIR measurements. Using the Taguchi method, this study analyzes the effect of parameters such as calcinations time, calcinations temperature and molar ratio of Fe3O4:ZnO on the photo activity of Fe3O4/ZnO MNPs. XRD and FTIR analysis confirm that coating process was done successfully. SEM images show that the average particle size of synthesized Fe3O4/ZnO nanoparticles was about 50 nm. The phenol removal efficiency of 88% can be achieved by using a photocatalyst which is synthesized through the optimum conditions: calcinations temperature of 550 degrees C, calcinations time of 2 hours and molar ratio of 1:10 for Fe3O4:ZnO. PMID- 24406039 TI - Analysis of TTG1 function in Arabis alpina. AB - BACKGROUND: In Arabidopsis thaliana (A. thaliana) the WD40 protein TRANSPARENT TESTA GLABRA1 (TTG1) controls five traits relevant for the adaptation of plants to environmental changes including the production of proanthocyanidin, anthocyanidin, seed coat mucilage, trichomes and root hairs. The analysis of different Brassicaceae species suggests that the function of TTG1 is conserved within the family. RESULTS: In this work, we studied the function of TTG1 in Arabis alpina (A. alpina). A comparison of wild type and two Aattg1 alleles revealed that AaTTG1 is involved in the regulation of all five traits. A detailed analysis of the five traits showed striking phenotypic differences between A. alpina and A. thaliana such that trichome formation occurs also at later stages of leaf development and that root hairs form at non-root hair positions. CONCLUSIONS: The evolutionary conservation of the regulation of the five traits by TTG1 on the one hand and the striking phenotypic differences make A. alpina a very interesting genetic model system to study the evolution of TTG1-dependent gene regulatory networks at a functional level. PMID- 24406041 TI - Cardiopulmonary morbidity of streptococcal infections in a PICU. AB - AIM: The streptococci are important bacteria that cause serious childhood infections. We investigated cardiopulmonary morbidity associated with streptococcal infection and pediatric intensive care unit (PICU) admission. METHODS: A retrospective study between 2002 and 2013 of all children with a laboratory isolation of streptococcus. RESULTS: There were 40 (2.3%) PICU patients with streptococcal isolations including Streptococcus pyogenes (Group A streptococcus, GAS, n = 7), Streptococcus agalactiae (Group B streptococcus, GBS, n = 5), Streptococcus pneumoniae (SP, n = 20), alpha-hemolytic (n = 4), beta hemolytic (n = 2) and gama-hemolytic (n = 2) streptococci. Comparing among GAS, GBS and SP, respiratory isolates were more likely positive for GAS or SP (P = 0.033), whereas cerebrospinal fluid was more likely positive for GBS (P = 0.002). All GAS and GBS, and the majority of SP (90%) were sensitive to penicillin. All SP specimens were sensitive to cefotaxime and vancomycin. These infections were associated with high PICU mortality of 43%, 20% and 25%, respectively. Isolation of streptococci was associated with a 30% mortality and high rates of need for mechanical ventilatory and inotropic supports. Patients with GAS, SP or any streptococcal isolation had relative risks [95% confidence interval (CI), P value] of PICU deaths of 7.5 (CI 3.1-18.1, P < 0.0001), 4.5 (CI 2.0-9.8, P < 0.0002) and 5.7 (CI 3.4-9.5, P < 0.0001), respectively. In SP, older children had significantly higher prevalence of premorbid conditions such as malignancy, mental retardation/cerebral palsy +/- seizure disorders, chromosomal or genetic disorders (P = 0.003) than children <5 years of age. Serotypes were available for some of these specimens that included 19A, 6B, 3 and 6C. There were four SP deaths with multiorgan system failure and hemolytic uremic syndrome (two 19A and two serotype 3). CONCLUSIONS: Severe streptococcal infections are associated with significant morbidity and mortality despite treatment with systemic antibiotics and intensive care unit support. GAS and SP affect the lungs of children, whereas GBS more likely causes meningitis in infants. The expanded coverage of newer polyvalent pneumococcal vaccines can probably prevent infections by serotypes 19A, 19F, 6B and 3. PMID- 24406042 TI - Ran GTPase induces EMT and enhances invasion in non-small cell lung cancer cells through activation of PI3K-AKT pathway. AB - Ras-related nuclear protein (Ran) GTPase is upregulated in non-small cell lung cancer (NSCLC) cells and is required for NSCLC cell survival. However, the effect of Ran on NSCLC cell invasion and epithelial to mesenchymal transition (EMT) remains unclear. This study found that Ran expression was much higher in highly invasive NSCLC cells than in lowly invasive NSCLC cells. Ectopic expression of Ran enhanced invasion and induced EMT in NSCLC cells. Inhibition of the PI3K-AKT pathway by LY294002, but not the MEK-ERK pathway by PD98509, reversed the above effects in these cells induced by Ran overexpression. In conclusion, our findings demonstrate that Ran induces EMT and enhances invasion in NSCLC cells through the activation of PI3K-AKT signaling. Thus, Ran may be a potential target for NSCLC therapeutic intervention. PMID- 24406043 TI - RNAi targeting of CCR2 gene expression induces apoptosis and inhibits the proliferation, migration, and invasion of PC-3M cells. AB - Prostate cancer (PCa) is the second most lethal malignancy in men. It has been reported that chemokines, produced by cancer cells, have linked with tumor progression and metastatic spread. We have proven that chemokine (C-C) motif ligand 2 (CCL2) is involved in the growth and invasion of PCa. In this study, we studied whether CC chemokine receptor 2 (CCR2), the receptor of CCL2, also contributes to PCa progression. We constructed the recombinant plasmid pGCsi-CCR2 and investigated the effects of pGCsi-CCR2 on proliferation, apoptosis, migration, and invasion of PC-3M cells. RT-PCR and Western blot assay showed that transfection with the plasmid pGCsi-CCR2 successfully inhibited the CCR2 expression. The cell proliferation rate was significantly slow, and the apoptotic rate was increased in PC-3M cells treated with CCR2-siRNA, indicated by MTT cell viability and TUNEL assay, respectively. As expected, CCR2 knockdown also reduced the migration and invasion of PC-3M cells, as illustrated through wound-healing assay and Transwell assay. The possible molecular mechanism was the regulation of several signal pathways involved in survival, apoptosis, migration, and metastasis. Altogether, the present finding suggests that CCR2 expression is crucial for CCL2-induced proliferation and invasion of PC-3M cells, and CCR2 could also be a promising molecular target for prevention of PCa growth and metastasis. PMID- 24406044 TI - MiR-138 induces renal carcinoma cell senescence by targeting EZH2 and is downregulated in human clear cell renal cell carcinoma. AB - MiR-138 has been shown to be downregulated in various cancers, including head and neck squamous cell carcinoma (HNSCC) and clear cell renal carcinoma (ccRCC). In the present study, we aimed to reveal the mechanism of miR-138 induction of senescence in renal carcinoma cells and identify its specific target genes. We used qRT-PCR to analyze miR-138 expression levels in renal carcinoma cell lines and ccRCC samples. The activity of beta-galactosidase was measured for functional analysis after miR-138 mimic transfection. To identify the targets of miR-138, we used three types of target prediction software to determine three candidate target genes. Furthermore, a 3'UTR luciferase assay was performed. Western blotting was used to detect the protein expression levels of candidate target genes. Additionally, knockdown of EZH2 by its siRNA was performed. The expression of miR-138 was downregulated in RCC cells lines and in tumor samples compared with their controls. Transfection of miR-138 mimic induced SN-12 cell senescence, decreased the protein expression of EZH2, and increased the protein expression of P16. Furthermore, miR-138 decreased the 3'UTR luciferase activity of EZH2. The knockdown of EZH2 by siRNA induced SN-12 cell senescence, decreased the protein expression level of EZH2, and increased the protein expression of P16. MiR-138 is a tumor-suppressor miRNA in ccRCC that induces SN-12 cell senescence by downregulating EZH2 expression and upregulating P16 expression. PMID- 24406045 TI - Wnt antagonist, secreted frizzled-related protein 4 (sFRP4), increases chemotherapeutic response of glioma stem-like cells. AB - Malignant gliomas have a highly tumorigenic subpopulation, termed cancer stem cells (CSCs), that drives tumor formation and proliferation. CSCs possess inherent resistance mechanisms against radiation- and chemotherapy-induced cancer cell death, enabling them to survive and initiate tumor recurrence. We examined the effect of secreted frizzled-related protein 4 (sFRP4), a Wnt signaling antagonist, in chemosensitizing the glioma cell line U138MG and glioma stem cells (GSCs) enriched from U138MG to chemotherapeutics. We found that sFRP4 alone and in combination with either doxorubicin or cisplatin induced apoptosis. Proliferation decreased substantially in GSC-enriched population as measured by MTT and BrdU assays. JC-1 and caspase-3 assays demonstrated that cell death was through the apoptotic pathway. sFRP4 treatment also decreased neurosphere formation and induced neuronal differentiation. Inhibition by sFRP4 was abolished by Wnt3a, indicating that sFRP4 acts through the frizzled receptor. Further indication that sFRP4 acts through the Wnt beta-catenin pathway was provided by decrease in the beta-catenin protein and decrease in the beta-catenin-stimulated gene cyclin D1 upon sFRP4 induction. By real-time PCR, an increase in apoptotic markers Bax and p21, a decrease in pro-proliferative marker CycD1, and a decrease in the GSC marker CD133 were observed. These observations indicate that sFRP4 is able to sensitize glioma cells and stem cells to chemotherapeutics. We thus identified for the first time that sFRP4 could help to destroy cancer stem cells of glioma cell line, which would lead to effective treatment regimen to combat brain tumors. PMID- 24406046 TI - The insulin-like growth factor-I receptor inhibitor picropodophyllin-induced selective apoptosis of hepatocellular carcinoma cell through a caspase-dependent mitochondrial pathway. AB - The insulin-like growth factor-I receptor (IGF-1R) and its ligands (IGF-I, IGF II) have been shown to be important promoters of cancer development and are frequently overexpressed in most hepatocellular carcinomas (HCCs). The activation of IGF-1R signaling mediates tumorigenesis, proliferation, and metastasis and thus represents a potential target for innovative treatment strategies for HCC. We investigated the potential inhibitory effect and mechanism of the impact of a novel IGF-1R inhibitor, picropodophyllin (PPP), in HCC lines. It was found that PPP selectively induced cell apoptosis in a time- and dose-dependent manner in HCC cells compared to normal hepatocytes. The inhibitory effects had a positive correlation with the expression of IGF-1R. PPP exerted an apoptotic effect in HCC cells in a caspase-dependent manner through the mitochondrial pathway. The release of cytochrome C from the mitochondrion was coupled with activation of caspase-9 and caspase-3. Treatment of PPP in HepG2 cells resulted in a marked elevation of Bax protein, but decreased levels of phosphorylated Akt and Bcl-2 protein. The ratio of Bax/Bcl-2 was increased in a dose-dependent manner. Our study provides strong evidence that the IGF-1R inhibitor PPP selectively inhibits the growth of human hepatocellular cancer cells by inducing the caspase-dependent mitochondrial pathway cell apoptosis pathway with no observed cytotoxicity on normal cells. PMID- 24406047 TI - FOXC2 often overexpressed in glioblastoma enhances proliferation and invasion in glioblastoma cells. AB - Glioblastoma (GBM) is the most common primary brain tumor and the leading cause of tumor-related death in the central nervous system. To date, the mechanisms of GBM genesis remain elusive. Forkhead box protein C2 (FOXC2) is a transcription factor that has been reported in many cancers, but its function in GBM tumorigenesis is not clearly elucidated. This study found that FOXC2 was overexpressed in GBM cell lines and GBM tissues. The proliferation and invasive potential of GBM cells were significantly increased by ectopic expression of FOXC2 but significantly decreased by RNA interference targeting FOXC2. EGFR expression was modulated by FOXC2 both in mRNA and protein levels. EGFR inhibition by siRNA reversed the FOXC2-induced proliferation and invasion. These findings suggested that FOXC2 expressed in GBM has a function in GBM cell proliferation and invasion and may be partly associated with the EGFR overexpression. PMID- 24406048 TI - Clopidogrel high-on-treatment platelet reactivity in acute ischemic stroke patients. AB - BACKGROUND: During the first days following an acute ischemic stroke, a consistently good antiplatelet effect of clopidogrel is important due to the increased risk of recurrent ischemia. However, the platelet inhibitory effectiveness of clopidogrel is variable for multifactorial reasons. We investigated the prevalence and risk factors for clopidogrel high-on-treatment platelet reactivity (clopidogrel-HTPR) in acute ischemic stroke patients. METHODS: Using multiple-electrode impedance aggregometry (MEA), the antiplatelet effectiveness of clopidogrel in patients with acute ischemic stroke was prospectively evaluated. Measurements were performed 48 h after therapy was either initiated or continued after hospital admission. Clopidogrel-HTPR was defined as ADP-induced values>47 U. RESULTS: A total of 159 patients (71.8 +/- 9.8 years, 69 female) were enrolled and 44% (n=70) patients were clopidogrel HTPR. 35 of the clopidogrel-HTPR were retested within one week and 57.1% (n=20) showed a good clopidogrel response during subsequent testing. We identified diabetes mellitus (36.3% vs. 54.4%, p-value=0.003) and higher HbA1c values (6.3% vs. 6.8%, p=0.007) as risk factors for clopidogrel-HTPR. Multivariate regression analysis revealed that diabetes mellitus more than doubled the risk of clopidogrel-HTPR (OR 2.41; 95%-CI 1.19-4.88; p=0.015). CONCLUSIONS: Clopidogrel HTPR was found in 44% of the patients with acute ischemic stroke. Besides time dependency of the clopidogrel effect, major risk factors for clopidogrel-HTPR were diabetes mellitus and higher HbA1c values. Further investigations are required to analyse if a function test guided strategy has the potential to optimize the antiplatelet therapy of acute stroke patients. PMID- 24406049 TI - Fishing for melanoma drivers. PMID- 24406050 TI - Organic-coated silver nanoparticles in biological and environmental conditions: fate, stability and toxicity. AB - This review paper presents the overview of processes involved in transformation of organic-coated silver nanoparticles (AgNPs) in biological systems and in the aquatic environment. The coating on AgNPs greatly influences the fate, stability, and toxicity of AgNPs in aqueous solutions, biological systems, and the environment. Several organic-coated AgNP systems are discussed to understand their stability and toxicity in biological media and natural water. Examples are presented to demonstrate how a transformation of organic-coated AgNPs in an aqueous solution is affected by the type of coating, pH, kind of electrolyte (mono- or divalent), ionic strength, organic ligands (inorganic and organic), organic matter (fulvic and humic acids), redox conditions (oxic and anoxic), and light. Results of cytotoxicity, genotoxicity, and ecotoxicity of coated AgNPs to food chain members (plants, bacteria, and aquatic and terrestrial organisms) are reviewed. Key factors contributing to toxicity are the size, shape, surface coating, surface charge, and conditions of silver ion release. AgNPs may directly damage the cell membranes, disrupt ATP production and DNA replication, alternate gene expressions, release toxic Ag(+) ion, and produce reactive oxygen species to oxidize biological components of the cell. A progress made on understanding the mechanism of organic-coated AgNP toxicity using different analytical techniques is presented. PMID- 24406051 TI - Demand for long-acting and permanent contraceptive methods among Kurdish women in Mahabad, Iran. AB - It is anticipated that the demand for contraceptives in Iran will increase in the near future as the number of women of reproductive age increases and with women wanting smaller families. The aim of this paper was to study the demand for long acting and permanent contraceptive methods (LAPCMs), and its determinants, among Kurdish women in Mahabad city, Iran. Data were taken from the Mahabad Fertility Survey (MFS) conducted on a sample of over 700 households in April 2012. The results show that the demand for LAPCMs was 71.35% at the time of survey, although only 27.7% of women were using these methods. Thus, the number of unintended pregnancies is likely to increase in the future if this gap is not reduced. The multivariate analysis showed significant impacts on the dependent variables of the number of children ever born, perceived contraceptive costs and childbearing intentions. Moreover, women at the end of their reproductive lives and those with higher education were more likely to desire LAPCMs. It is concluded that despite a growing use of contraceptive methods in Iran in recent decades, the development of reproductive health services and promotion of the quality of family planning services remains a necessity. PMID- 24406052 TI - Comparing key characteristics of young adult crack users in and out-of-treatment in Rio de Janeiro, Brazil. AB - BACKGROUND: Crack use is prevalent among street drug users in Brazilian cities, yet despite recent help system reforms and investments, treatment utilization is low. Other studies have identified a variety of - often inconsistent - factors associated with treatment status among crack or other drug users. This study compared socio-economic, drug use, health and service use characteristics between samples of young adult crack users in- and out-of-treatment in Rio de Janeiro, Brazil. FINDINGS: Street-involved crack users (n = 81) were recruited by community-based methods, and privately assessed by way of an anonymous interviewer-administered questionnaire as well as biological methods, following informed consent. In-treatment users (n = 30) were recruited from a public service in-patient treatment facility and assessed based on the same protocol. Key indicators of interest were statistically cross-compared. Not-in-treatment users were less likely to: be white, educated, stably housed, to be involved in drug dealing, to report lifetime marijuana and current alcohol use, to report low mental health status and general health or addiction/mental health care; they were more likely to: be involved in begging and utilize social services, compared to the in-treatment sample (statistical significance for differences set at p < .05). CONCLUSIONS: In-treatment and not-in-treatment crack users differed on several key characteristics. Overall, in-treatment users appeared to be more socio-economically integrated and connected to the health system, yet not acutely needier in terms of health or drug problems. Given overall low treatment utilization but high need, efforts are required to facilitate improved treatment access and use for marginalized crack users in Brazil. PMID- 24406053 TI - The ticks (Acari: Ixodida: Argasidae, Ixodidae) of Bolivia. AB - The tick species reported in Bolivia are reviewed here as (1) endemic or established: Ornithodoros echimys, O. guaporensis, O. hasei, O. kohlsi, O. mimon, O. peropteryx, O. rostratus, Otobius megnini, Amblyomma auricularium, A. cajennense, A. calcaratum, A. coelebs, A. dubitatum, A. humerale, A. incisum, A. longirostre, A. naponense, A. nodosum, A. oblongoguttatum, A. ovale, A. parvitarsum, A. parvum, A. pecarium, A. pseudoconcolor, A. rotundatum, A. scalpturatum, A. tigrinum, A. triste, Dermacentor nitens, Haemaphysalis juxtakochi, H. leporispalustris, I. boliviensis, I. cooleyi, I. luciae, Rhipicephalus microplus, R. sanguineus, and (2) erroneously reported: Ornithodoros puertoricensis, O. talaje, O. turicata, Amblyomma americanum, A. maculatum, A. multipunctum, Ixodes ricinus, I. scapularis, Rhipicephalus annulatus. Many of these records are lacking locality and/or host, and some of them need new findings for confirmation. Some of the species recorded may represent a threat for human and animal health, therefore would be of great value to make a countrywide survey of ticks in order to update the information presented in this work. PMID- 24406055 TI - Information disclosure in clinical informed consent: "reasonable" patient's perception of norm in high-context communication culture. AB - BACKGROUND: The current doctrine of informed consent for clinical care has been developed in cultures characterized by low-context communication and monitoring style coping. There are scarce empirical data on patients' norm perception of information disclosure in other cultures. METHODS: We surveyed 470 adults who were planning to undergo or had recently undergone a written informed consent requiring procedure in a tertiary healthcare hospital in Saudi Arabia. Perceptions of norm and current practice were explored using a 5-point Likert scale (1 = strongly agree with disclosure) and 30 information items in 7 domains: practitioners' details, benefits, risks, complications' management, available alternatives, procedure's description, and post-procedure's issues. RESULTS: Respondents' mean (SD) age was 38.4 (12.5); 50.2% were males, 57.2% had >= college education, and 37.9% had undergone a procedure. According to norm perception, strongly agree/agree responses ranged from 98.0% (major benefits) to 50.5% (assistant/trainee's name). Overall, items related to benefits and post procedure's issues were ranked better (more agreeable) than items related to risks and available alternatives. Ranking scores were better in post-procedure respondents for 4 (13.3%) items (p < 0.001 to 0.001) and in males for 8 (26.7%) items (p = 0.008 to <0.001). Older age was associated with better ranking scores for 3 (10.0%) items and worse for one (p < 0.001 to 0.006). According to current practice perception, strongly agree/agree responses ranged from 93.3% (disclosure of procedure's name) to 13.9% (lead practitioner's training place), ranking scores were worse for all items compared to norm perception (p < 0.001), and post procedure status, younger age, and lower educational level were associated with better ranking scores for 15 (50.0%), 12 (40.0%), and 4 (13.3%) items, respectively (p < 0.001 to 0.009). CONCLUSIONS: 1) even in an overall high context communication culture, extensive and more information than is currently disclosed is perceived as norm, 2) the focus of the desired information is closer to benefits and post-procedure's issues than risks and available alternatives, 3) male, post-procedure, and older patients are in favor of more information disclosure, 4) male, older, and more educated patients may be particularly dissatisfied with current information disclosure. The focus and extent of information disclosure for clinical informed consent may need to be adjusted if a "reasonable" patient's standard is to be met. PMID- 24406056 TI - Removal of dichloromethane from waste gas streams using a hybrid bubble column/biofilter bioreactor. AB - The performance of a hybrid bubble column/biofilter (HBCB) bioreactor for the removal of dichloromethane (DCM) from waste gas streams was studied in continuous mode for several months. The HBCB bioreactor consisted of two compartments: bubble column bioreactor removing DCM from liquid phase and biofilter removing DCM from gas phase. Effect of inlet DCM concentration on the elimination capacity was examined in the DCM concentration range of 34-359 ppm with loading rates ranged from 2.2 to 22.8 g/m3.h and constant total empty bed retention time (EBRT) of 200 s. In the equal loading rates, the elimination capacity and removal efficiency of the biofilter were higher than the corresponding values of the bubble column bioreactor. The maximum elimination capacity of the HBCB bioreactor was determined to be 15.7 g/m3.h occurred in the highest loading rate of 22.8 g/m3.h with removal efficiency of 69%. The overall mineralization portion of the HBCB bioreactor was in the range of 72-79%. The mixed liquor acidic pH especially below 5.5 inhibited microbial activity and decreased the elimination capacity. Inhibitory effect of high ionic strength was initiated in the mixed liquor electrical conductivity of 12.2 mS/cm. This study indicated that the HBCB bioreactor could benefit from advantages of both bubble column and biofilter reactors and could remove DCM from waste gas streams in a better manner. PMID- 24406054 TI - Tracking of stem cells in vivo for cardiovascular applications. AB - In the past ten years, the concept of injecting stem and progenitor cells to assist with rebuilding damaged blood vessels and myocardial tissue after injury in the heart and peripheral vasculature has moved from bench to bedside. Non invasive imaging can not only provide a means to assess cardiac repair and, thereby, cellular therapy efficacy but also a means to confirm cell delivery and engraftment after administration. In this first of a two-part review, we will review the different types of cellular labeling techniques and the application of these techniques in cardiovascular magnetic resonance and ultrasound. In addition, we provide a synopsis of the cardiac cellular clinical trials that have been performed to-date. PMID- 24406057 TI - Anti-IgE therapy to Kimura's disease: a pilot study. AB - Kimura's disease is a chronic disease that is characterized by subcutaneous granuloma of soft tissues in the head and neck region, increased eosinophil counts and high serum IgE levels. It is thought to be an IgE-mediated disease. Omalizumab, a monoclonal antibody, has recently been suggested as a potential new systemic treatment for IgE-mediated diseases, based on its efficacy in treating asthma and allergic rhinitis. We report a study of three patients with Kimura's disease who received anti-IgE (omalizumab) treatment. All patients were treated with a fixed schedule of eight cycles of omalizumab 300mg, administered subcutaneously at intervals of 2 weeks. The size of tumorous regions was evaluated by MRI at base line and after 4 months of treatment. Blood samples were taken every month. In each of the patients, the size of tumorous regions and the peripheral blood eosinophil and basophil counts were all decreased after the treatment. These results suggest that omalizumab may be valuable for treatment of Kimura's disease. PMID- 24406058 TI - The effect of performance-volume limit on the DRG based acute care hospital financing in Hungary. AB - OBJECTIVES: The aim of our paper is to analyse the effect of the so-called performance volume limit (PVL) financing method on acute hospital care. DATA AND METHODS: The data were derived from the nationwide administrative dataset of the National Health Insurance Fund Administration (OEP) covering the period 2003 2008. We analysed the trends in the DRG cost-weights, number of cases, case-mix, and average length of stay. We calculated the average annual reimbursement rate per DRG cost-weight with and without the application of PVL degression according to the hospital type and medical professions. RESULTS: Our results showed that although the national case mix (i.e., the sum of all of the DRG cost-weights produced in one year) did not change between 2003-2006, the trend of the annual number of cases increased, and the average length of stay decreased. During 2007 2008, a significant decline was found in each indicator. The introduction of the PVL resulted in a health insurance budget saving of 1.9% in 2004, 2.6% in 2005, 3.4% in 2006, 5.6% in 2007, and 3.2% in 2008. We found the lowest reimbursement rate per DRG cost-weight at the university medical schools (HUF 138,200 or ? 550) and children's hospitals (HUF 132,547 or ? 528), whereas the highest was at the county hospitals (HUF 143,451 or ? 571) and city hospitals (HUF 142, 082 or ? 565). CONCLUSIONS: The implementation of the PVL reduced the acute care hospital activity and reimbursement. The effect of the PVL was different on the different types of hospitals, and it had a serious disadvantageous effect on the university medical schools and children's hospitals. PMID- 24406059 TI - Association of epicardial fat with left ventricular diastolic function in subjects with metabolic syndrome: assessment using 2-dimensional echocardiography. AB - BACKGROUND: Metabolic syndrome (MetS) is related with left ventricular diastolic dysfunction (LVDD) and poor cardiovascular outcome. Epicardial adipose tissue (EAT) thickness, measured by echocardiography, is increased in subjects with MetS. However, the association of EAT with LV diastolic function has not been evaluated in subjects with MetS. METHODS: In this retrospective study, EAT thickness was measured in 1,486 consecutive asymptomatic patients with no known heart disease who had transthoracic echocardiography during a self-referred healthcare exam. Subjects with a history of ischemic heart disease, cardiomyopathy or significant valvular heart disease were excluded. LVDD was defined as E/e' ratio >= 15. Subjects were grouped into two groups, those with MetS and those without. RESULTS: MetS was present in 346 subjects. There was no difference in LV systolic function between the two groups. However compared to patients without MetS, patients with MetS had larger left atrium (LA) size and higher E/e' ratio (38 +/- 5 versus 35 +/- 5 mm for LA and 10.0 +/- 3.3 versus 8.7 +/- 2.7 for E/e' ratio in subjects with versus without MetS both p < 0.001). LVDD was found in 27 (7.8%) subjects with MetS, compared to 30 (2.6%) subjects without MetS (p < 0.001). In subjects with MetS, EAT was significantly correlated with LVDD, even after adjusting for other cardiometabolic risk factors such as age, systolic blood pressure, BMI, blood glucose and LDL cholesterol (OR 1.845, 95% CI 1.153-2.951, p = 0.011). CONCLUSION: Greater EAT is found in subjects with MetS. EAT is significantly associated with LVDD in subjects with MetS, even after adjusting for other risk factors. PMID- 24406060 TI - In search of potent 5-HT6 receptor inverse agonists. AB - A series of non-sulfonamide/non-sulfone derived potent 5-HT6 receptor inverse agonists has been disclosed. Representative compound 9 (Ki = 14 nm) displayed selectivity against a set of family members as well as brain permeability 6 h post-oral administration. In addition, the separated enantiomers of compound 9 displayed difference in activity indicating the influence of chirality on potency. PMID- 24406062 TI - Clinical implications of drug-drug interactions with P2Y12 receptor inhibitors. AB - Polypharmacy in patients undergoing coronary artery stenting or in those presenting with an acute coronary syndrome is common. Nevertheless, the risk of drug-drug interactions in patients treated simultaneously with P2Y12 receptor inhibitors is less well considered in routine clinical practice. Whereas the irreversible P2Y12 receptor inhibitors clopidogrel and prasugrel are prodrugs requiring cytochrome P450 (CYP) enzymes for metabolic activation, such activation is not necessary for the direct-acting reversible P2Y12 receptor inhibitor ticagrelor. Several drugs frequently used in cardiology have been shown to interact with the metabolism of P2Y12 receptor inhibitors in pharmacodynamic studies. Whereas several drug-drug interactions have been described for clopidogrel and ticagrelor, prasugrel seems to have a low potential for drug-drug interactions. The clinical implications of these interactions have raised concern. In general, concomitant administration of P2Y12 receptor antagonists and strong inhibitors or inducers of CYP3A/CYP2C19 should be performed with caution in patients treated with clopidogrel/ticagrelor. Under most circumstances, clinicians have the option of prescribing alternative drugs with less risk of drug-drug interactions when used concomitantly with P2Y12 receptor inhibitors. PMID- 24406063 TI - Association between thrombophilia and the post-thrombotic syndrome: a systematic review and meta-analysis. AB - BACKGROUND: The postthrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT), occurring in 20-40% of patients. Identifying risk factors for PTS may be useful to provide patients with prognostic information and target prevention strategies. OBJECTIVE: To conduct a systematic review to assess whether, among patients with DVT, inherited and acquired thrombophilias are associated with a risk of PTS. METHODS: We searched the electronic databases PubMed, EMBASE, Scopus, and Web of Science for studies published from 1990 to 2013 that assessed any thrombophilia in adult DVT patients and its association with the development of PTS. We calculated odds ratios and 95% confidence intervals for PTS according to the presence of thrombophilia. Meta-analysis was performed using the random-effects model. RESULTS: Sixteen studies were included: 13 assessed factor V Leiden (FVL), 10 assessed prothrombin mutation, five assessed protein S and C deficiencies, three assessed antithrombin deficiency, four assessed elevated FVIII levels, and six assessed antiphospholipid antibodies. None of the meta-analyses identified any thrombophilia to be predictive of PTS. Both FVL and prothrombin mutation appeared protective among studies including patients with both first and recurrent DVT and studies in which more than 50% of patients had an unprovoked DVT. CONCLUSIONS: Our meta-analysis did not demonstrate a significant association between any of the thrombophilias assessed and the risk of PTS in DVT patients. Other biomarkers in the pathophysiological pathway may be more predictive of PTS. PMID- 24406064 TI - The O-linked glycans of human von Willebrand factor modulate its interaction with ADAMTS-13. AB - BACKGROUND: O-linked glycans (OLGs) are clustered on either side of the von Willebrand factor (VWF) A1 domain and modulate its interaction with platelets; however, their influence on the VWF interaction with ADAMTS-13 is unknown. OBJECTIVES: To assess the role of the OLGs in VWF susceptibility to ADAMTS-13 proteolysis, which would help to explain their specific distribution. METHODS: OLG sites were mutated individually and as clusters on either and both sides of the A1 domain, and expressed in HEK293T cells. First, their proteolysis by ADAMTS 13 was assayed in the presence of urea. Next, a parallel-flow chamber was used to analyze VWF-mediated platelet capture on collagen in the presence and absence of ADAMTS-13 under a shear stress of 1500 s(-1) . The decrease in platelet capture in the presence ADAMTS-13 was used as a measure of VWF proteolysis. RESULTS: Initially, we found that, under denaturing conditions, the C-terminal S1486A and Cluster 2 and double cluster (DC) variants were less susceptible to ADAMTS-13 proteolysis than wild-type VWF. Next, we showed that addition of ADAMTS-13 diminished VWF-mediated platelet capture on collagen under flow; surprisingly, this was more pronounced with the S1486A, Cluster 2 and DC variants than with wild-type VWF, indicating that these are proteolyzed more rapidly under shear flow. CONCLUSIONS: OLGs provide rigidity to peptide backbones, and our findings suggest that OLG in the A1-A2 linker region regulates VWF conformational changes under shear. Importantly, the impact of OLGs on ADAMTS-13 cleavage under shear stress is the opposite of that under denaturing conditions, highlighting the non physiologic nature of in vitro cleavage assays. PMID- 24406065 TI - Analysis of inter-subunit contacts reveals the structural malleability of extracellular domains in platelet glycoprotein Ib-IX complex. AB - BACKGROUND: The glycoprotein (GP)Ib-IX complex is critical to hemostasis and thrombosis. Its proper assembly is closely correlated with its surface expression level and requires cooperative interactions among extracellular and transmembrane domains of Ibalpha, Ibbeta and IX subunits. Two interfaces have been previously identified between the extracellular domains of Ibbeta and IX. OBJECTIVE: To understand how extracellular domains interact in GPIb-IX. METHODS: The Ibbeta extracellular domain (IbbetaE ) or the IX counterpart (IXE ) in GPIb-IX was replaced with a well-folded IbbetaE /IXE chimera called IbbetaEabc , and the effect of domain replacement on assembly and expression of the receptor complex in transiently transfected Chinese hamster ovary cells was analyzed. RESULTS: Replacing IXE with IbbetaEabc in GPIb-IX retained interface 1 but not interface 2 between the extracellular domains. While this domain replacement preserved complex integrity, the expression levels of Ibbeta and Ibalpha were significantly reduced. Additional domain replacement with IbbetaEabc or IbbetaE in GPIb-IX produced the complex at disparate expression levels that cannot be simply explained by two separate interfaces. In particular, when IbbetaE in GPIb-IX was replaced by IbbetaEabc , Ibalpha and IX were expressed at approximately 70% of the wild-type level. Their levels were not reduced when IXE was changed further to IbbetaE . CONCLUSIONS: Our results demonstrate the importance of the association between Ibbeta and IX extracellular domains for complex assembly and efficient expression, and provide evidence for the structural malleability of these domains that may accommodate and propagate conformational changes therein. PMID- 24406067 TI - Desmopressin response in hemophilia A patients with FVIII:C < 0.10 IU mL(-1.). PMID- 24406066 TI - Gain in translation: heme oxygenase-1 induced by activated protein C promotes thrombus resolution. PMID- 24406068 TI - Membrane topology for human vitamin K epoxide reductase. PMID- 24406069 TI - Management of challenging cases of patients with cancer-associated thrombosis including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH: a reply to a rebuttal. PMID- 24406070 TI - Microarrayed dog, cat, and horse allergens show weak correlation between allergen specific IgE and IgG responses. PMID- 24406071 TI - A common single nucleotide polymorphism impairs B-cell activating factor receptor's multimerization, contributing to common variable immunodeficiency. PMID- 24406072 TI - Theophylline inhibits the cough reflex through a novel mechanism of action. AB - BACKGROUND: Theophylline has been used in the treatment of asthma and chronic obstructive pulmonary disease for more than 80 years. In addition to bronchodilator and anti-inflammatory activity, clinical studies have suggested that theophylline acts as an antitussive agent. Cough is the most frequent reason for consultation with a family doctor, and treatment options are limited. Determining how theophylline inhibits cough might lead to the development of optimized compounds. OBJECTIVE: We sought to investigate the inhibitory activity of theophylline on vagal sensory nerve activity and the cough reflex. METHODS: Using a range of techniques, we investigated the effect of theophylline on human and guinea pig vagal sensory nerve activity in vitro and on the cough reflex in guinea pig challenge models. RESULTS: Theophylline was antitussive in a guinea pig model, inhibited activation of single C-fiber afferents in vivo and depolarization of human and guinea pig vagus in vitro, and inhibited calcium influx in airway-specific neurons in vitro. A sequence of pharmacological studies on the isolated vagus and patch clamp and single-channel inside-out experiments showed that the effect of theophylline was due to an increase in the open probability of calcium-activated potassium channels. Finally, we demonstrated the antitussive activity of theophylline in a cigarette smoke exposure model that exhibited enhanced tussive responses to capsaicin. CONCLUSION: Theophylline inhibits capsaicin-induced cough under both normal and "disease" conditions by decreasing the excitability of sensory nerves through activation of small- and intermediate-conductance calcium-activated potassium channels. These findings could lead to the development of optimized antitussive compounds with a reduced side effect potential. PMID- 24406074 TI - Human syndromes of immunodeficiency and dysregulation are characterized by distinct defects in T-cell receptor repertoire development. AB - BACKGROUND: Human immunodeficiencies characterized by hypomorphic mutations in critical developmental and signaling pathway genes allow for the dissection of the role of these genes in the development of the T-cell receptor (TCR) repertoire and the correlation of alterations of the TCR repertoire with diverse clinical phenotypes. OBJECTIVE: The presence of T cells in patients with Omenn syndrome (OS) and patients with atypical presentations of severe combined immunodeficiency gene mutations presents an opportunity to study the effects of the causal genes on TCR repertoires and provides a window into the clinical heterogeneity observed. METHODS: We performed deep sequencing of TCRbeta complementarity-determining region 3 (CDR3) regions in subjects with a series of immune dysregulatory conditions caused by mutations in recombination activating gene 1/2 (RAG 1/2), IL-2 receptor gamma (IL2RG), and zeta chain-associated protein kinase 70 (ZAP70); a patient with atypical DiGeorge syndrome; and healthy control subjects. RESULTS: We found that patients with OS had marked reductions in TCRbeta diversity compared with control subjects, as expected. Patients with atypical presentations of RAG or IL2RG mutations associated with autoimmunity and granulomatous disease did not have altered overall diversity but instead had skewed V-J pairing and skewed CDR3 amino acid use. Although germline TCRs were more abundant and clonally expanded in patients with OS, nongermline sequences were expanded as well. TCRbeta from patients with RAG mutations had less junctional diversity and smaller CDR3s than patients with OS caused by other gene mutations and healthy control subjects but relatively similar CDR3 amino acid use. CONCLUSIONS: High-throughput TCR sequencing of rare immune disorders has demonstrated that quantitative TCR diversity can appear normal despite qualitative changes in repertoire and strongly suggests that in human subjects RAG enzymatic function might be necessary for normal CDR3 junctional diversity. PMID- 24406073 TI - Genome-wide association study and admixture mapping identify different asthma associated loci in Latinos: the Genes-environments & Admixture in Latino Americans study. AB - BACKGROUND: Asthma is a complex disease with both genetic and environmental causes. Genome-wide association studies of asthma have mostly involved European populations, and replication of positive associations has been inconsistent. OBJECTIVE: We sought to identify asthma-associated genes in a large Latino population with genome-wide association analysis and admixture mapping. METHODS: Latino children with asthma (n = 1893) and healthy control subjects (n = 1881) were recruited from 5 sites in the United States: Puerto Rico, New York, Chicago, Houston, and the San Francisco Bay Area. Subjects were genotyped on an Affymetrix World Array IV chip. We performed genome-wide association and admixture mapping to identify asthma-associated loci. RESULTS: We identified a significant association between ancestry and asthma at 6p21 (lowest P value: rs2523924, P < 5 * 10(-6)). This association replicates in a meta-analysis of the EVE Asthma Consortium (P = .01). Fine mapping of the region in this study and the EVE Asthma Consortium suggests an association between PSORS1C1 and asthma. We confirmed the strong allelic association between SNPs in the 17q21 region and asthma in Latinos (IKZF3, lowest P value: rs90792, odds ratio, 0.67; 95% CI, 0.61-0.75; P = 6 * 10( 13)) and replicated associations in several genes that had previously been associated with asthma in genome-wide association studies. CONCLUSIONS: Admixture mapping and genome-wide association are complementary techniques that provide evidence for multiple asthma-associated loci in Latinos. Admixture mapping identifies a novel locus on 6p21 that replicates in a meta-analysis of several Latino populations, whereas genome-wide association confirms the previously identified locus on 17q21. PMID- 24406075 TI - Epidemiological study on Schistosoma mansoni infection in Sanja area, Amhara region, Ethiopia. AB - BACKGROUND: The epidemiology of schistosomiasis is well documented and its geographic distribution has been mapped and there is an ongoing mapping in Ethiopia. Nevertheless, new transmission foci have been discovered in different parts of the country. The objective of this study was to assess the establishment of transmission and determine the prevalence of Schistosoma mansoni infection in school children from Sanja Town, northwest Ethiopia. METHODS: A cross-sectional parasitological survey involving 384 school children in two primary schools of Sanja Town was conducted between February and April 2013. Stool specimens were collected and microscopically examined using Kato-Katz and Sodium acetate-acetic acid-formalin (SAF) concentration methods. Malacological survey was also carried out to identify snail intermediate hosts and larval infection rate in the snail. The snails collected were checked for trematode infection by shedding. Observation was also made on water contact habits of the study population. RESULTS: The prevalence of Schistosoma mansoni infection using Kato-Katz method was high among male (79.5%) children in Sanja Primary school while it was high among female (75%) children in Ewket Amba Primary school. The prevalence of Schistosoma mansoni infection among Sanja Primary school children in the age groups 5-9 and 10-14 years were 84.6% and 75.2%, respectively while in Ewket Amba Primary school, the prevalence was 66% and 77.9% in the age groups 5-9 and 10-14 years respectively. The prevalence of schistosome infection in Biomphalaria pfeifferi was 16.9% and 0.027% during February and April, respectively. S. mansoni infection was successfully established in laboratory mice and adult worms were harvested after six weeks of laboratory maintenance. Observations made on water contact activities showed swimming, bathing and washing in the river and the stream as the high risk activities for Schistosoma mansoni infection. CONCLUSION: The study has shown establishment of transmission of schistosomiasis mansoni in Sanja Town. Therefore, appropriate integrated control measures need to be introduced to reduce morbidity in the population and also to control the transmission of schistosomiasis in the study area. PMID- 24406076 TI - Human amniotic epithelial cells can differentiate into granulosa cells and restore folliculogenesis in a mouse model of chemotherapy-induced premature ovarian failure. AB - INTRODUCTION: Ovarian dysfunction frequently occurs in female cancer patients after chemotherapy, but human amniotic epithelial cells (hAECs) that can differentiate into cell types that arise from all three germ layers may offer promise for restoration of such dysfunction. Previous studies confirmed that hAECs could differentiate into cells that express germ cell-specific markers, but at this time hAECs have not been shown to restore ovarian function. METHODS: To model premature ovarian failure, hAECs infected with lenti-virus carrying green fluorescent protein were injected into the tail vein of mice sterilized with cyclophosphamide and busulphan. hAECs migrated to the mouse ovaries and overall ovarian function was measured using immunohistochemical techniques. RESULTS: Seven days to two months after hAECs transplantation, ovarian cells were morphologically restored in sterilized mice. Hemotoxylin and eosin staining revealed that restored ovarian cells developed follicles at all stages. No follicles were observed in control mice at the same time period. Immunostaining with anti-human antigen antibodies and pre-transplantation labeling with green fluorescent protein (GFP) revealed that the grafted hAECs survived and migrated to mouse ovary, differentiating into granulosa cells. Furthermore, the ovarian function marker, anti-Mullerian hormone, was evident in treated mouse ovaries after hAEC transplantation. CONCLUSIONS: Intravenously injected hAECs reached the ovaries of chemotherapy-treated mice and restored folliculogenesis, data which suggest promise for hAECs for promoting reproductive health and improving the quality of life for female cancer survivors. PMID- 24406077 TI - Moderate hemoptysis: recurrent hemoptysis and mortality according to bronchial artery embolization. AB - INTRODUCTION: The studies on hemoptysis have focused mainly on hemoptysis causes and massive or life-threatening hemoptysis. And there is a limited data that non massive hemoptysis, especially moderate hemoptysis. OBJECTIVES: We analyzed the prognosis and severity of bleeding on flexible bronchoscopy (FB) between moderate and massive hemoptysis. METHODS: We reviewed total 852 subjects (59.9 +/- 16.0 years) identified with hemoptysis. Reviewed database included severity of subjective hemoptysis, bleeding on FB, comorbid conditions, time from admission to bronchial artery embolization (BAE), recurrent hemoptysis and mortality. RESULTS: In subjective hemoptysis, recurrent hemoptysis occurred in mild 8.0%, moderate 40.7%, massive hemoptysis 33.8%, and mortality was 4.7%, 13.4% and 13.5%. Especially, no statistical difference was shown in recurrent hemoptysis [hazard ratio (HR) = 0.795; 95% confidence interval (CI) 0.562-1.125, P = 0.196] and mortality (HR = 1.054; 95% CI 0.596-1.864, P = 0.856) between moderate and massive hemoptysis. In moderate hemoptysis patients, oozing or active bleeding on FB took up 83.3%. In this review, recurrent hemoptysis was more in oozing bleeding than active bleeding (HR = 1.781; 95% CI 1.214-2.431, P = 0.002), but mortality was similar (HR = 1.611; 95% CI 0.930-2.790, P = 0.089). Recurrent hemoptysis significantly decreased in the group with BAE performed within 24 h (HR = 0.308; 95% CI 0.149-0.637, P = 0.001) in moderate hemoptysis. Also, recurrent hemoptysis and mortality were significantly increased in the patients with smoking (>=40 pack-years), oozing or active bleeding on FB, and hypertension. CONCLUSION: Moderate hemoptysis has shown similar prognosis of recurrent hemoptysis and mortality to massive hemoptysis. Therefore, the more aggressive FB and BAE should be considered in moderate hemoptysis. PMID- 24406079 TI - Pleural fluid mononuclear cells (PFMCs) from tuberculous pleurisy can migrate in vitro in response to CXCL10. AB - We recently reported that pleural fluid mononuclear cells (PFMCs) from tuberculous pleurisy stimulated with Bacillus Calmette-Guerin (BCG) or TB antigens produced high levels of cytokines. However, it was still unclear what mechanism of the PFMCs used to migrate into the pleural fluids in TB infection. In the present study, we found that CD3(+)CD4(+) and CD3(+)CD8(+) T cells from PFMCs expressed significantly high levels of CXCR3 compared to PBMCs. In addition, the levels of CXCL10 (the ligand for CXCR3) in pleural fluids were significantly higher than those in normal serum and cancerous fluids. After stimulation with BCG, PFMCs produced high levels of CXCL10. Importantly, the synthesis of CXCL10 was mainly dependent on the BCG-induced production of IFNs, because the neutralization of endogenous IFN-alpha or IFN-gamma with mAbs significantly reduced the production of CXCL10 from BCG-stimulated PFMCs. In addition, the tubercular pleural fluid (TBPF) or exogenous CXCL10 induced the migration of PFMCs, indicating that IFN-alpha or IFN-gamma modulated the immune response through the expression of CXCL10 to aid the recruitment and selective homing of activated/effector cells to the site of Mycobacterium tuberculosis (M.tb) infection. Taken together, the levels of CXCL10 in pleural fluids were high and BCG-stimulated PFMCs expressed high levels of CXCL10, and CXCL10 induced the migration of PFMCs into the pleural fluids in TB infection. PMID- 24406078 TI - MITF E318K's effect on melanoma risk independent of, but modified by, other risk factors. AB - A rare germline variant in the microphthalmia-associated transcription factor (MITF) gene, E318K, has been reported as associated with melanoma. We confirmed its independent association with melanoma [odds ratio (OR) 1.7, 95% confidence interval (CI) = 1.1, 2.7, P = 0.03]; adjusted for age, sex, center, age * sex interaction, pigmentation characteristics, family history of melanoma, and nevus density). In stratified analyses, carriage of MITF E318K was associated with melanoma more strongly in people with dark hair than fair hair (P for interaction, 0.03) and in those with no moles than some or many moles (P for interaction, <0.01). There was no evidence of interaction between MC1R 'red hair variants' and MITF E318K. Moreover, risk of melanoma among carriers with 'low risk' phenotypes was as great or greater than among those with 'at risk' phenotypes with few exceptions. PMID- 24406081 TI - Occupancy of serotonin transporters in the amygdala by paroxetine in association with attenuation of left amygdala activation by negative faces in major depressive disorder. AB - Amygdala hyperactivation in major depressive disorder (MDD) might be attenuated by selective serotonin reuptake inhibitors (SSRIs), but the working mechanism remains unclear. We hypothesized that higher amygdala serotonin transporter (SERT) occupancy by paroxetine results in greater attenuation of amygdala activation by negative facial expressions in MDD patients. We treated fifteen MDD patients (22-55 years) with paroxetine 20-50mg/day. After 6 and 12 weeks, we quantified (1) clinical response (>=50% decrease in Hamilton Depression Rating Scale (HDRS), (2) SERT occupancy in both amygdala measured by repeated [123I]beta CIT single photon emission computed tomography (SPECT), and (3) amygdala activation when viewing fearful and angry (negative) faces with repeated functional MRI scans. Response rates were 4/15 and 9/15 at 6 and 12 weeks, respectively. Attenuation of left amygdala activation was associated with amygdala SERT occupancy (P=0.006) and response (P=0.015). This association may provide a rationale for decreased limbic activity seen during treatment of MDD. It might also explain the rapid decrease in negative attentional bias and amygdala activation caused by SSRIs. PMID- 24406080 TI - PD-1/PD-Ls pathways between CD4(+) T cells and pleural mesothelial cells in human tuberculous pleurisy. AB - Programmed death 1 (PD-1), PD-ligand 1 (PD-L1), and PD-L2 have been demonstrated to be involved in tuberculosis immunity, however, the expression and regulation of PD-1/PD-Ls pathways in pleural mesothelial cells (PMCs) and CD4(+) T cells in tuberculous pleural effusion (TPE) have not been investigated. Expression of PD-1 on CD4(+) T cells and expressions of PD-L1 and PD-L2 on PMCs in TPE were determined. The impacts of PD-1/PD-Ls pathways on proliferation, apoptosis, adhesion, and migration of CD4(+) T cells were explored. Concentrations of soluble PD-l, but not of soluble PD-Ls, were much higher in TPE than in serum. Expressions of PD-1 on CD4(+) T cells in TPE were significantly higher than those in blood. Expressions of PD-Ls were much higher on PMCs from TPE when compared with those from transudative effusion. Interferon-gamma not only upregulated the expression of PD-1 on CD4(+) T cells, but also upregulated the expressions of PD Ls on PMCs. Blockage PD-1/PD-Ls pathways abolished the inhibitory effects on proliferation and adhesion activity of CD4(+) T cells induced by PMCs. PD-1/PD-Ls pathways on PMCs inhibited proliferation and adhesion activity of CD4(+) T cells, suggesting that Mycobacterium tuberculosis might exploit PD-1/PD-Ls pathways to evade host cell immune response in human. PMID- 24406082 TI - Pre-operative considerations in aesthetic facial surgery. AB - This article reviews the common pitfalls in the complex process of pre-operative assessment for facial plastic surgery. Legal guidelines and best practice are discussed, and attention is directed mainly towards the consenting and psychological issues surrounding this area of surgery. PMID- 24406083 TI - Reply to the editor:. PMID- 24406084 TI - Regarding: cardiovascular risk-factor knowledge and risk perception among HIV infected adults. PMID- 24406085 TI - No difference in dose distribution in organs at risk in postmastectomy radiotherapy with or without breast implant reconstruction. AB - The aim of this study was to quantify the variation in doses to organs at risk (ipsilateral lung and heart) and the clinical target volume (CTV) in the presence of breast implants. In this retrospective cohort study, patients were identified through the National Breast Cancer Register. Consecutive breast cancer patients undergoing mastectomy between 2009 and 2011 and completing a full course of postmastectomy radiotherapy (PMRT) were eligible. All included patients (n = 818) were identified in the ARIA(c) oncology information system and further stratified for immediate breast reconstruction (IBR+, n = 162) and no immediate breast reconstruction (IBR-, n = 656). Dose statistics for ipsilateral lung, heart and CTV were retrieved from the system. Radiation plans for patients with chest wall (CW) only (n = 242) and CW plus lymph nodes (n = 576) irradiation were studied separately.The outcome variables were dichotomized as follows: lung, V(20Gy) <= 30% vs. V(20Gy) > 30%; heart, D(mean) <= 5 Gy vs. D(mean) > 5 Gy; CTV, V95% >= median vs. V95% < median.In the univariate and multivariate regression models no correlation between potential confounders (i.e. breast reconstruction, side of PMRT, CW index) and the outcome variables was found. Multivariate analysis of CW plus lymph nodes radiation plans, for example, showed no association of breast reconstruction with dosimetric outcomes in neither lung nor heart- lung V(20Gy) (odds ratio [OR]: 0.6, 95%CI, 0.4 to 1.0, p = 0.07) or heart D(mean) (OR: 1.2, 95%CI, 0.5 to 3.1, p = 0.72), respectively.CTV was statistically significantly larger in the IBR+ group (i.e. included breast implant), but no correlation between the implant type and dosimetric characteristics of the organs at risk was revealed.In the current study, the presence of breast implants during postmastectomy radiotherapy was not associated with increased doses to ipsilateral lung and heart, but CTV definition and its dosimetric characteristics urge further evaluation. PMID- 24406086 TI - Saliva secretion in engrafted mouse bioengineered salivary glands using taste stimulation. AB - PURPOSE: The aim of this study was to compare saliva flow and protein composition induced using five basic taste stimulations between natural and bioengineered salivary glands. MATERIALS AND METHODS: We developed a mouse saliva secretion model using taste stimulation and analyzed the saliva secretion from natural and bioengineered salivary glands using an assay. The protein components and alpha amylase in the natural and bioengineered saliva were analyzed by gel electrophoresis and Western blotting. RESULTS: The salivary flow responses induced by sour (citric acid) and bitter (quinine-HCl) stimuli were significantly high in the natural and bioengineered salivary glands. Although the protein concentrations in the natural and bioengineered saliva induced using five basic taste stimulations were similar, the protein composition and the amylase concentration in the natural saliva after taste stimulation had different profiles. Sympathetic and non-sympathetic nerves were observed around the acini and ducts in the natural and bioengineered salivary glands. However, the frequency of neuropeptide Y-positive sympathetic nerves in the bioengineered gland was relatively high compared to that in the natural gland. CONCLUSIONS: These results suggest that the signal balance between the sympathetic and parasympathetic components of the efferent nerves in an engrafted bioengineered salivary gland may differ from that in a natural salivary gland. PMID- 24406087 TI - Bariatric surgery and psoriasis. AB - Obesity is associated with psoriasis and poses a significant obstacle to psoriasis management. Bariatric surgery is an effective procedure for weight loss, and some reports suggest that it may improve psoriasis. However, more evidence is needed before definitive conclusions can be drawn. Bariatric surgery procedures, in particular the Roux-en-Y gastric bypass, may one day be a viable option for obese patients with refractory psoriasis. PMID- 24406088 TI - Factors that influence perforator thrombosis and predict healing with perforator sclerotherapy for venous ulceration without axial reflux. AB - OBJECTIVE: Refluxing perforators contribute to venous ulceration. We sought to describe patient characteristics and procedural factors that (1) impact rates of incompetent perforator vein (IPV) thrombosis with ultrasound-guided sclerotherapy (UGS) and (2) impact the healing of venous ulcers (CEAP 6) without axial reflux. METHODS: A retrospective review of UGS of IPV injections from January 2010 to November 2012 identified 73 treated venous ulcers in 62 patients. Patients had no other superficial or axial reflux and were treated with standard wound care and compression. Ultrasound imaging was used to screen for refluxing perforators near ulcer(s). These were injected with sodium tetradecyl sulfate or polidocanol foam and assessed for thrombosis at 2 weeks. Demographic data, comorbidities, treatment details, and outcomes were analyzed. Univariate and multivariable modeling was performed to determine covariates predicting IPV thrombosis and ulcer healing. RESULTS: There were 62 patients (55% male; average age, 57.1 years) with active ulcers for an average of 28 months with compression therapy before perforator treatment, and 36% had a history of deep venous thrombosis and 30% had deep venous reflux. At a mean follow-up of 30.2 months, ulcers healed in 32 patients (52%) and did not heal in 30 patients (48%). Ulcers were treated with 189 injections, with an average thrombosis rate of 54%. Of 73 ulcers, 43 ulcers (59%) healed, and 30 (41%) did not heal. The IPV thrombosis rate was 69% in patients whose ulcers healed vs 38% in patients whose ulcers did not heal (P < .001). Multivariate models demonstrated male gender (P = .03) and warfarin use (P = .01) negatively predicted thrombosis of IPVs. A multivariate model for ulcer healing found complete IPV thrombosis was a positive predictor (P = .02), whereas a large initial ulcer area was a negative predictor (P = .08). Increased age was associated with fewer ulcer recurrences (P = .05). Predictors of increased ulcer recurrences were hypertension (P = .04) and increased follow-up time (P = .02). Calf vein thrombosis occurred after 3% (six of 189) of injections. CONCLUSIONS: Thrombosis of IPVs with UGS increases venous ulcer healing in a difficult patient population. Complete closure of all IPVs in an ulcerated limb was the only predictor of ulcer healing. Men and patients taking warfarin have decreased rates of IPV thrombosis with UGS. PMID- 24406089 TI - Impact of amputation level and comorbidities on functional status of nursing home residents after lower extremity amputation. AB - OBJECTIVE: The ability of nursing home residents to function independently is associated with their quality of life. The impact of amputations on functional status in this population remains unclear. This analysis evaluated the effect of amputations-transmetatarsal (TM), below-knee (BK), and above-knee (AK)--on the ability of residents to perform self-care activities. METHODS: Medicare inpatient claims were linked with nursing home assessment data to identify admissions for amputation. The Minimum Data Set Activities of Daily Living Long Form Score (0 28; higher numbers indicating greater impairment), based on seven activities of daily living, was calculated before and after amputation. Hierarchical modeling determined the effect of the surgery on postamputation function of residents. Controlling for comorbidity, cognition, and prehospital function allowed for evaluation of Activities of Daily Living trajectories over time. RESULTS: In total, 4965 residents underwent amputation: 490 TM, 1596 BK, and 2879 AK. Mean age was 81 years, and 54% of the patients were women. Most were white (67%) or black (26.5%). Comorbidities before amputation included diabetes mellitus (70.7%), coronary heart disease (57.1%), chronic kidney disease (53.6%), and/or congestive heart failure (52.1%). Mortality within 30 days of hospital discharge was 9.0%, and hospital readmission was 27.7%. Stroke, end-stage renal disease, and poor baseline cognitive function were associated with the poorest functional outcome after amputation. Compared with residents who received TM amputation, those who had BK or AK amputation recovered more slowly and failed to return to baseline function by 6 months. BK was found to have a superior functional trajectory compared with AK. CONCLUSIONS: Elderly nursing home residents undergoing BK or AK amputation failed to return to their functional baseline within 6 months. Among frail elderly nursing home residents, higher amputation level, stroke, end-stage renal disease, poor baseline cognitive scores, and female sex were associated with inferior functional status after amputation. These factors should be strongly assessed to maintain activities of daily living and quality of life in the nursing home population. PMID- 24406090 TI - Digital obstructive arterial disease can be detected by laser Doppler measurements with high sensitivity and specificity. AB - OBJECTIVE: This study was conducted to determine the sensitivity and specificity of laser Doppler flowmetry (LDF) measurements for digital obstructive arterial disease (DOAD) using angiography as the reference standard and to compare the accuracy of different classical tests used to assess DOAD. Diagnosis of vascular abnormalities at the digital level is challenging. Angiography is the gold standard for assessment of DOAD but is invasive and expensive to perform. METHODS: We performed a retrospective analysis of consecutive patients referred at Mayo Clinic (Rochester, Minn) for upper extremity arterial assessment during a 27-month period. Finger-brachial index, skin blood flow (in arbitrary units [a.u.]), and skin temperature (in degrees Celsius) were recorded in each digit on the pulp at baseline and after a thermal challenge test (hand placed in a thermal box at 47.0 degrees C for 15 minutes). Angiogram analysis was blinded and performed by a radiologist using a vascularization scale ranging from 0 (no vessel) to 4 (normal). The receiver operating characteristic curve was used to define a specific cutoff point to detect DOAD. Twenty-two patients had LDF measurements and complete angiograms. RESULTS: A total of 185 digits were analyzed because some patients had only analysis of one hand. The best area under the curve (AUC) was 0.98 (range, 0.94-0.99) for postwarming skin blood flow, with a cutoff point of <=206 a.u. This AUC was statistically different from AUCs of all the other tests (P < .01). Sensitivity and specificity were 93% (95% confidence interval, 85%-97%) and 96% (95% confidence interval, 90%-99%), respectively. CONCLUSIONS: LDF combined with a thermal challenge is highly accurate, safe, and noninvasive means to detect DOAD. PMID- 24406091 TI - Discussion. PMID- 24406092 TI - The mobilizing action toward community health partnership study: multisector partnerships in US counties with improving health metrics. AB - INTRODUCTION: Multisector partnerships are promoted as a mechanism to improve population health. This study explored the types and salient features of multisector partnerships in US counties with improving population health metrics. METHODS: We used the "Framework for Understanding Cross-Sector Collaborations" proposed by Bryson, Crosby, and Stone to guide data collection and interpretation. Comparative case studies were conducted in 4 counties selected on the basis of population, geographic region, an age-adjusted mortality decline better than the US average, and stable per capita income. Data were collected through website and report reviews and through in-depth interviews with key informants (N = 59) representing multiple sectors. County reports were developed and cross-case themes related to partnership types and salient features were derived. RESULTS: Multisector collaboration was common in all 4 counties despite substantial variations in population, geographic size, demographic diversity, and other characteristics. Most partnerships were formed by professionals and organizations to improve delivery of health and social services to vulnerable populations or to generate policy, system, and environment changes. Multisector collaboration was valued in all cases. Outcomes attributed to partnerships included short- and long-term effects that contributed to improved population health. CONCLUSION: The Bryson, Crosby, and Stone model is a useful framework for conducting case study research on multisector partnerships. Outcomes attributed to the multisector partnerships have the potential to contribute to improvement in population health. Further study is needed to confirm whether multisector partnerships are necessary for improving population health within counties and to understand which partnership characteristics are critical for success. PMID- 24406093 TI - Obesity prevalence by occupation in Washington State, Behavioral Risk Factor Surveillance System. AB - INTRODUCTION: Data that estimate the prevalence of and risk factors for worker obesity by occupation are generally unavailable and could inform the prioritization of workplace wellness programs. The aims of this study were to estimate the prevalence of obesity by occupation, examine the association of occupational physical activity and a range of health behaviors with obesity, and identify occupations in which workers are at high risk of obesity in Washington State. METHODS: We conducted descriptive and multivariable analyses among 37,626 employed Washington State respondents using the Behavioral Risk Factor Surveillance System in odd numbered years, from 2003 through 2009. We estimated prevalence and prevalence ratios (PRs) by occupational groups adjusting for demographics, occupational physical activity level, smoking, fruit and vegetable consumption, and leisure-time physical activity (LPTA). RESULTS: Overall obesity prevalence was 24.6% (95% confidence interval [CI], 24.0-25.1). Workers in protective services were 2.46 (95% CI, 1.72-3.50) times as likely to be obese as workers in health diagnosing occupations. Compared with their counterparts, workers who consumed adequate amounts of fruits and vegetables and had adequate LTPA were significantly less likely to be obese (PR = 0.91; 95% CI, 0.86-0.97 and PR = 0.63; 95% CI, 0.60-0.67, respectively). Workers with physically demanding occupational physical activity had a lower PR of obesity (PR = 0.83; 95% CI, 0.78 0.88) than those with nonphysically demanding occupational physical activity. CONCLUSION: Obesity prevalence and health risk behaviors vary substantially by occupation. Employers, policy makers, and health promotion practitioners can use our results to target and prioritize workplace obesity prevention and health behavior promotion programs. PMID- 24406094 TI - Online grocery store coupons and unhealthy foods, United States. PMID- 24406096 TI - Guiding properties of asymmetric hybrid plasmonic waveguides on dielectric substrates. AB - We proposed an asymmetric hybrid plasmonic waveguide which is placed on a substrate for practical applications by introducing an asymmetry into a symmetric hybrid plasmonic waveguide. The guiding properties of the asymmetric hybrid plasmonic waveguide are investigated using finite element method. The results show that, with proper waveguide sizes, the proposed waveguide can eliminate the influence of the substrate on its guiding properties and restore its broken symmetric mode. We obtained the maximum propagation length of 2.49 * 103 MUm. It is approximately equal to that of the symmetric hybrid plasmonic waveguide embedded in air cladding with comparable nanoscale confinement. PMID- 24406095 TI - Use of secondary prevention pharmacotherapy after first myocardial infarction in patients with diabetes mellitus. AB - BACKGROUND: Despite recommended pharmacotherapies the use of secondary prevention therapy after myocardial infarction (MI) remains suboptimal. Patients with diabetes mellitus (DM) have worse prognosis after MI compared to patients without DM and aggressive secondary prevention pharmacotherapy in this population is therefore warranted. We examined the changes in use of evidence-based secondary prevention pharmacotherapy in patients with and without DM discharged after first MI. METHODS: All patients aged 30 years or older admitted with first MI in Denmark during 1997-2006 were identified by individual-level linkage of nationwide registries of hospitalizations. Univariate and multivariate logistic regression models were used to identify patient characteristics associated with initiation of acetylsalicylic acid, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, and clopidogrel within 90 days, and statins within 180 days of discharge, respectively. RESULTS: A total of 78,230 patients were included, the mean age was 68.3 years (SD 13.0), 63.5% were men and 9,797 (12.5%) had diabetes. Comparison of claimed prescriptions in the period 1997-2002 and 2003-2006 showed significant (p < 0.001) increases in claims for acetylsalicylic acid (38.9% vs. 69.7%), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (38.7% vs. 50.4%), beta-blockers (69.2% vs. 77.9%), clopidogrel (16.7% vs. 66.3%), and statins (41.3% vs. 77.3%). During 2003 2006, patients with DM claimed significantly less acetylsalicylic acid (odds ratio [OR] 0.81 [95% confidence interval [CI] 0.74-0.88) and clopidogrel (OR 0.91 [95% CI 0.83-1.00]) than patients without DM. CONCLUSIONS: Despite sizeable increase in use of evidence-based secondary prevention pharmacotherapy after MI from 1997 to 2006, these drugs are not used in a substantial proportion of subjects and patients with DM received significantly less antiplatelet therapy than patients without DM. Increased focus on initiation of secondary prevention pharmacotherapy after MI is warranted, especially in patients with DM. PMID- 24406097 TI - Psychometric evaluation of the French version of the questionnaire attitudes towards morphine use; a cross-sectional study in Valais, Switzerland. AB - BACKGROUND: In Switzerland, nurses are allowed to prescribe and administer morphine in emergency situations without a doctor. Still, nurses and other health professionals are often reluctant to prescribe and administer morphine for pain management in patients. No valid French-speaking instrument is available in Switzerland to assess the attitudes of nurses and other health professionals towards the prescription and administration of morphine. In this study, we evaluated the psychometric properties of the French version of the questionnaire "Attitudes towards morphine use". METHODS: The instrument was derived from an Italian version. Forward and back translations of the questionnaire were performed. Item analysis and construct validity were assessed between April and December 2010 in a cross sectional study including five Swiss hospitals in a sample of 588 health professionals (533 nurses, mean age 38.3 +/- 10.2 years). Thirty subjects participated in test-retest reliability. RESULTS: The time to complete the instrument ranged between 12 and 15 minutes and neither floor nor ceiling effect were found. The initial 24-item instrument showed an intraclass correlation (ICC) of 0.69 (95% CI: 0.64 to 0.73, P < 0.001), and a Cronbach's alpha of 0.700. Factor analysis led to a six-component solution explaining 52.4% of the total variance. After excluding five items, the shortened version showed an ICC of 0.74 (95% CI, 0.70 to 0.77, P < 0.001) and a Cronbach's alpha of 0.741. Factor analysis led to a five-component solution explaining 54.3% of the total variance. The five components were named "risk of addiction/dependence"; "operational reasons for not using morphine"; "risk of escalation"; "other (non dependence) risks" and "external (non-operational) reasons". In test-retest, the shortened instrument showed an ICC of 0.797 (95% CI, 0.630 to 0.911, P < 0.001) and a Cronbach's alpha of 0.797. CONCLUSIONS: The 19-item shortened instrument assessing attitudes towards the prescription and administration of morphine showed adequate content and construct validity. PMID- 24406098 TI - Mental health problems in the 10th grade and non-completion of upper secondary school: the mediating role of grades in a population-based longitudinal study. AB - BACKGROUND: School drop-out is a problem all over the world with adverse life course consequences. The aim of this paper is to study how internalising and externalising problems in the 10th grade are associated with non-completion of upper secondary school, and to examine the mediating role of grade points in the 10th grade across general academic and vocational tracks in upper secondary school. We also study the impact of health behaviour. METHODS: Population-based health surveys were linked with Norwegian registries on education and sociodemographic factors (n = 10 931). Mental health was assessed by the self report Strengths and Difficulties Questionnaire. Logistic regression was used to analyse the relations between mental health and health behaviour in 10th grade and non-completion of upper secondary school. The mediating effect of grade points was studied by causal mediation analysis. RESULTS: Adolescents not completing upper secondary school reported more externalising problems and girls more internalising problems in the 10th grade, after adjustments. Smoking and physical inactivity increased the odds of non-completion of upper secondary school. Causal mediation analyses showed that a reduction in externalising problems of 10 percentage points led to lower rates of non-completion of 4-5 percentage points, and about three-quarters of this total effect was mediated by grades. For internalising problems the total effect was significant only for girls (1 percentage point), and the mediated effect of grades was about 30%. The effect of mental health problems on school dropout was mainly the same in both vocational and general tracks. CONCLUSIONS: Assuming a causal relationship from mental health problems to school performance, this study suggests that externalising problems impair educational attainment. A reduction of such problems may improve school performance, reduce school drop-out and reduce the adverse life-course consequences. PMID- 24406100 TI - In vitro analysis of localized aneurysm rupture. AB - In this study, bulge inflation tests were used to characterize the failure response of 15 layers of human ascending thoracic aortic aneurysms (ATAA). Full field displacement data were collected during each of the mechanical tests using a digital image stereo-correlation (DIS-C) system. Using the collected displacement data, the local stress fields at burst were derived and the thickness evolution was estimated during the inflation tests. It was shown that rupture of the ATAA does not systematically occur at the location of maximum stress, but in a weakened zone of the tissue where the measured fields show strain localization and localized thinning of the wall. Our results are the first to show the existence of weakened zones in the aneurysmal tissue when rupture is imminent. An understanding these local rupture mechanics is necessary to improve clinical assessments of aneurysm rupture risk. Further studies must be performed to determine if these weakened zones can be detected in vivo using non-invasive techniques. PMID- 24406099 TI - Interaction of lubricin with type II collagen surfaces: adsorption, friction, and normal forces. AB - One of the major constituents of the synovial fluid that is thought to be responsible for chondroprotection and boundary lubrication is the glycoprotein lubricin (PRG4); however, the molecular mechanisms by which lubricin carries out its critical functions still remain largely unknown. We hypothesized that the interaction of lubricin with type II collagen, the main component of the cartilage extracellular matrix, results in enhanced tribological and wear properties. In this study, we examined: (i) the molecular details by which lubricin interacts with type II collagen and how binding is related to boundary lubrication and adhesive interactions; and (ii) whether collagen structure can affect lubricin adsorption and its chondroprotective properties. We found that lubricin adsorbs strongly onto denatured, amorphous, and fibrillar collagen surfaces. Furthermore, we found large repulsive interactions between the collagen surfaces in presence of lubricin, which increased with increasing lubricin concentration. Lubricin attenuated the large friction and also the long-range adhesion between fibrillar collagen surfaces. Interestingly, lubricin adsorbed onto and mediated the frictional response between the denatured and native amorphous collagen surfaces equally and showed no preference on the supramolecular architecture of collagen. However, the coefficient of friction was lowest on fibrillar collagen in the presence of lubricin. We speculate that an important role of lubricin in mediating interactions at the cartilage surface is to attach to the cartilage surface and provide a protective coating that maintains the contacting surfaces in a sterically repulsive state. PMID- 24406101 TI - Advances in studies of disease-navigating webs: Sarcoptes scabiei as a case study. AB - The discipline of epidemiology is the study of the patterns, causes and effects of health and disease conditions in defined anima populations. It is the key to evidence-based medicine, which is one of the cornerstones of public health. One of the important facets of epidemiology is disease-navigating webs (disease-NW) through which zoonotic and multi-host parasites in general move from one host to another. Epidemiology in this context includes (i) classical epidemiological approaches based on the statistical analysis of disease prevalence and distribution and, more recently, (ii) genetic approaches with approximations of disease-agent population genetics. Both approaches, classical epidemiology and population genetics, are useful for studying disease-NW. However, both have strengths and weaknesses when applied separately, which, unfortunately, is too often current practice. In this paper, we use Sarcoptes scabiei mite epidemiology as a case study to show how important an integrated approach can be in understanding disease-NW and subsequent disease control. PMID- 24406102 TI - The role of extracellular vesicles in Plasmodium and other protozoan parasites. AB - Protozoan parasites and other microorganisms use various pathways to communicate within their own populations and to manipulate their outside environments, with the ultimate goal of balancing the rate of growth and transmission. In higher eukaryotes, including humans, circulating extracellular vesicles are increasingly recognized as key mediators of physiological and pathological processes. Recent evidence suggests that protozoan parasites, including those responsible for major human diseases such as malaria and Chagas disease, use similar machinery. Indeed, intracellular and extracellular protozoan parasites secrete extracellular vesicles to promote growth and induce transmission, to evade the host immune system, and to manipulate the microenvironment. In this review we will discuss the general pathways of extracellular vesicle biogenesis and their functions in protozoan infections. PMID- 24406103 TI - Effects of novel diarylpentanoid analogues of curcumin on secretory phospholipase A2 , cyclooxygenases, lipo-oxygenase, and microsomal prostaglandin E synthase-1. AB - Arachidonic acid and its metabolites have generated a heightened interest due to their significant role in inflammation. Inhibiting the enzymes involved in arachidonic acid metabolism has been considered as the synergistic anti inflammatory effect. A series of novel curcumin diarylpentanoid analogues were synthesized and evaluated for their inhibitory effects on activity of secretory phospholipase A2 , cyclooxygenases, soybean lipo-oxygenase as well as microsomal prostaglandin E synthase-1. Among the curcumin analogues, compounds 3, 6, 9, 12, and 17 exhibited strong inhibition of secretory phospholipase A2 activity, with IC50 values ranging from 5.89 to 11.02 MUm. Seven curcumin analogues 1, 3, 6, 7, 9, 11, and 12 showed inhibition of cyclooxygenases-2 with IC50 values in the range of 46.11 to 94.86 MUm, which were lower than that of curcumin. Compounds 3, 6, 7, 12, and 17 showed strong inhibition of lipo-oxygenase enzyme activity. Preliminary screening of diarylpentanoid curcumin analogues for microsomal prostaglandin E synthase-1 activity revealed that four diarylpentanoid curcumin analogues 5, 6, 7, and 13 demonstrated higher inhibition of microsomal prostaglandin E synthase-1 activity with IC50 ranging from 2.41 to 4.48 MUm, which was less than that of curcumin. The present results suggest that some of these diarylpentanoid analogues were able to inhibit the activity of these enzymes. This raises the possibility that diarylpentanoid analogues of curcumin might serve as useful starting point for the design of improved anti-inflammatory agents. PMID- 24406105 TI - Radiation-induced alterations of histone post-translational modification levels in lymphoblastoid cell lines. AB - BACKGROUND: Radiation-induced alterations in posttranslational histone modifications (PTMs) may affect the cellular response to radiation damage in the DNA. If not reverted appropriately, altered PTM patterns may cause long-term alterations in gene expression regulation and thus lead to cancer. It is therefore important to characterize radiation-induced alterations in PTM patterns and the factors affecting them. METHODS: A lymphoblastoid cell line established from a normal donor was used to screen for alterations in methylation levels at H3K4, H3K9, H3K27, and H4K20, as well as acetylation at H3K9, H3K56, H4K5, and H4K16, by quantitative Western Blot analysis at 15 min, 1 h and 24 h after irradiation with 2 Gy and 10 Gy. The variability of alterations in acetylation marks was in addition investigated in a panel of lymphoblastoid cell lines with differing radiosensitivity established from lung cancer patients. RESULTS: The screening procedure demonstrated consistent hypomethylation at H3K4me3 and hypoacetylation at all acetylation marks tested. In the panel of lymphoblastoid cell lines, however, a high degree of inter-individual variability became apparent. Radiosensitive cell lines showed more pronounced and longer lasting H4K16 hypoacetylation than radioresistant lines, which correlates with higher levels of residual gamma-H2AX foci after 24 h. CONCLUSION: So far, the factors affecting extent and duration of radiation-induced histone alterations are poorly defined. The present work hints at a high degree of inter-individual variability and a potential correlation of DNA damage repair capacity and alterations in PTM levels. PMID- 24406106 TI - Dietary cholesterol, heart disease risk and cognitive dissonance. AB - In the 1960s, the thesis that dietary cholesterol contributes to blood cholesterol and heart disease risk was a rational conclusion based on the available science at that time. Fifty years later the research evidence no longer supports this hypothesis yet changing the dietary recommendation to limit dietary cholesterol has been a slow and at times contentious process. The preponderance of the clinical and epidemiological data accumulated since the original dietary cholesterol restrictions were formulated indicate that: (1) dietary cholesterol has a small effect on the plasma cholesterol levels with an increase in the cholesterol content of the LDL particle and an increase in HDL cholesterol, with little effect on the LDL:HDL ratio, a significant indicator of heart disease risk, and (2) the lack of a significant relationship between cholesterol intake and heart disease incidence reported from numerous epidemiological surveys. Over the last decade, many countries and health promotion groups have modified their dietary recommendations to reflect the current evidence and to address a now recognised negative consequence of ineffective dietary cholesterol restrictions (such as inadequate choline intake). In contrast, health promotion groups in some countries appear to suffer from cognitive dissonance and continue to promote an outdated and potentially hazardous dietary recommendation based on an invalidated hypothesis. This review evaluates the evidence for and against dietary cholesterol restrictions and the potential consequences of such restrictions. PMID- 24406104 TI - Mesenchymal stem cells from umbilical cord matrix, adipose tissue and bone marrow exhibit different capability to suppress peripheral blood B, natural killer and T cells. AB - INTRODUCTION: The ability to self-renew, be easily expanded in vitro and differentiate into different mesenchymal tissues, render mesenchymal stem cells (MSCs) an attractive therapeutic method for degenerative diseases. The subsequent discovery of their immunosuppressive ability encouraged clinical trials in graft versus-host disease and auto-immune diseases. Despite sharing several immunophenotypic characteristics and functional capabilities, the differences between MSCs arising from different tissues are still unclear and the published data are conflicting. METHODS: Here, we evaluate the influence of human MSCs derived from umbilical cord matrix (UCM), bone marrow (BM) and adipose tissue (AT), co-cultured with phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (MNC), on T, B and natural killer (NK) cell activation; T and B cells' ability to acquire lymphoblast characteristics; mRNA expression of interleukin-2 (IL-2), forkhead box P3 (FoxP3), T-bet and GATA binding protein 3 (GATA3), on purified T cells, and tumor necrosis factor-alpha (TNF-alpha), perforin and granzyme B on purified NK cells. RESULTS: MSCs derived from all three tissues were able to prevent CD4+ and CD8+ T cell activation and acquisition of lymphoblast characteristics and CD56 dim NK cell activation, wherein AT-MSCs showed a stronger inhibitory effect. Moreover, AT-MSCs blocked the T cell activation process in an earlier phase than BM- or UCM-MSCs, yielding a greater proportion of T cells in the non-activated state. Concerning B cells and CD56 bright NK cells, UCM-MSCs did not influence either their activation kinetics or PHA-induced lymphoblast characteristics, conversely to BM- and AT MSCs which displayed an inhibitory effect. Besides, when co-cultured with PHA stimulated MNC, MSCs seem to promote Treg and Th1 polarization, estimated by the increased expression of FoxP3 and T-bet mRNA within purified activated T cells, and to reduce TNF-alpha and perforin production by activated NK cells. CONCLUSIONS: Overall, UCM-, BM- and AT-derived MSCs hamper T cell, B cell and NK cell-mediated immune response by preventing their acquisition of lymphoblast characteristics, activation and changing the expression profile of proteins with an important role in immune function, except UCM-MSCs showed no inhibitory effect on B cells under these experimental conditions. Despite the similarities between the three types of MSCs evaluated, we detect important differences that should be taken into account when choosing the MSC source for research or therapeutic purposes. PMID- 24406107 TI - Influence of the extent of coronary atherosclerotic disease on ST-segment changes induced by ST elevation myocardial infarction. AB - The accuracy of the admission electrocardiogram (ECG) in predicting the site of acute coronary artery occlusion in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease is not well known. This study aimed to assess whether the presence of multivessel coronary artery disease (CAD) modifies the artery-related ST-segment changes in patients with acute coronary artery occlusion. We reviewed the admission ECG, clinical records, and coronary angiography of 289 patients with STEMI caused by acute occlusion of left anterior descending (LAD; n = 140), right (n = 118), or left circumflex (LCx; n = 31) coronary arteries. All patients underwent primary percutaneous coronary reperfusion during the first 12 hours. The magnitude and distribution of artery related ST-segment patterns were comparable in patients with single (n = 149) and multivessel (n = 140) CAD. Occlusion of proximal (n = 55) or mid-distal (n = 85) LAD artery induced ST-segment elevation in leads V1 to V5, but only the proximal occlusion induced reciprocal ST-segment depression in leads II, III, and aVF (p <0.001). Proximal and mid-distal occlusion of right (n = 45 and 73, respectively) or LCx (n = 15 and 16) coronary artery always induced ST-segment elevation in leads II, III, and aVF and reciprocal ST-segment depression in leads V2 and V3. ST-segment elevation in lead V6 >0.1 mV predicted LCx artery occlusion. In conclusion, patients with STEMI with single or multivessel CAD have concordant artery-related ST-segment patterns on the admission ECG; in both groups, reciprocal ST-segment depression in LAD artery occlusion predicts a large infarct. Subendocardial ischemia at a distance is not a requisite for the genesis of reciprocal ST-segment changes. PMID- 24406108 TI - Comparison of endovascular versus epicardial lead placement for resynchronization therapy. AB - Cardiac resynchronization therapy (CRT) has been shown to improve survival and symptoms in patients with severe left ventricular (LV) dysfunction, congestive heart failure, and prolonged QRS duration. LV lead placement is achieved by placing the lead in the coronary sinus, an endovascular approach, or by a minimally invasive robotic-assisted thoracoscopic epicardial approach. There are no data directly comparing the 2 methods. Patients eligible for CRT were randomized to the endovascular and epicardial arms. Coronary sinus lead placement was achieved using the standard technique, and epicardial leads were placed using a minimally invasive robotic-assisted thoracoscopic approach. The primary end point was a decrease in LV end-systolic volume index at 6 months. The secondary end points included 30-day mortality rate, measures of clinical improvement, 1 year electrical lead performance, and 1-year survival rate. The relative improvement of LV end-systolic volume index from baseline to 6 months was similar between the arms (28.8% for the transvenous [n = 12] vs 30.5% for the epicardial (n = 9) arm, p = 0.93). There were no significant differences in the secondary end points between the 2 groups. In conclusion, there were no differences in echocardiographic and clinical outcomes comparing a conventional endovascular approach versus robotic-assisted surgical epicardial LV lead placement for CRT in patients with heart failure. Surgical approaches are still a viable alternative when a transvenous procedure has failed or is not technically feasible. PMID- 24406109 TI - Comparison of the frequency of atrial fibrillation in young obese versus young nonobese men undergoing examination for fitness for military service. AB - The association between body mass index (BMI) in young adulthood and long-term risk of atrial fibrillation (AF) has not yet been examined for men. We conducted a population-based 36-year cohort study to examine the BMI-associated risk of AF in 12,850 young men who had BMI measured at their examination of fitness for military service. AF was identified from the Danish National Registry of Patients, covering all Danish hospitals since 1977. We began follow-up on the twenty-second birthday of each subject and continued until the occurrence of AF, emigration, death, or December 31, 2012. We used Cox regression to compute hazard ratios (HRs) with 95% confidence intervals (CIs), adjusting for education and height. The cohort contributed a total of 375,888 person-years of follow-up and the median follow-up time was 26 years (mean 29 years). The incidence of AF per 100,000 person-years was 53 for men of normal weight (BMI: 18.5 to 24.9 kg/m(2)), 54 for underweight men (BMI <18.5 kg/m(2)), 106 for overweight men (BMI: 25.0 to 24.9 kg/m(2)), and 144 for obese men (BMI >=30 kg/m(2)). With normal weight as the reference group, the adjusted HR for AF was 0.99 (95% CI 0.52 to 1.87) for underweight men, 2.08 (95% CI 1.48 to 2.92) for overweight men, and 2.87 (95% CI 1.46 to 5.62) for obese men. The adjusted HR associating 1 unit increase in BMI with AF was 1.12 (95% CI 1.07 to 1.16). In conclusion, overweight and obese young men had more than twice the risk of AF compared with young men of normal weight. PMID- 24406110 TI - Relation of albuminuria to coronary microvascular function in patients with chronic kidney disease. AB - The relation between albuminuria and coronary microvascular function in patients with chronic kidney disease (CKD) has not been fully investigated. Therefore, we sought to assess whether albuminuria is associated with coronary flow velocity reserve (CFVR) impairment in patients with CKD. Coronary flow study was prospectively performed in 175 patients with CKD. CFVR of the left anterior descending artery was measured to evaluate coronary microvascular function using transthoracic echocardiography. We divided the patients into 5 groups according to the stages of CKD and analyzed the effect of albuminuria. CFVR gradually decreased with an increase in CKD stages. CFVR in patients with albuminuria was lower than those without albuminuria. In groups with CKD stages 2 and 3, the patients with albuminuria showed lower CFVR than those without albuminuria. Multiple logistic regression analysis revealed that albuminuria, age, and gender were independently associated with CFVR impairment. Of these factors, albuminuria was the most powerful predictor with the risk ratio of 12.4 for CFVR impairment. In conclusion, the more the CKD stages progressed, the more severe CFVR was impaired. Albuminuria was associated with CFVR impairment in patients with CKD; even in mild-to-moderate CKD, patients with albuminuria showed further reduced coronary vasodilator capacity. PMID- 24406111 TI - Impact of triiodothyronine and N-terminal pro-B-type natriuretic peptide on the long-term survival of critically ill patients with acute heart failure. AB - We assessed the prognostic implications of low triiodothyronine (T3) and N terminal pro-B-type natriuretic peptide (NT-proBNP) levels in critically ill patients with acute heart failure. We acquired data for 144 critical care patients with acute decompensated heart failure, of which 106 were included in this study. Plasma thyroid hormones and NT-proBNP levels were determined within 48 hours of admission. We assessed these measures for predicting all-cause and cardiac mortalities. At a mean follow-up period of 25 +/- 31 months, the all cause mortality rate was 51% (54 of 106) and the cardiac mortality rate was 70% (38 of 54). A multivariate Cox regression model showed that log-transformed NT proBNP levels (log NT-proBNP; hazard ratio [HR] 2.90, 95% confidence interval [CI] 1.38 to 6.08, p = 0.005) and T3 levels (HR 0.98, 95% CI 0.96 to 0.99, p = 0.008) were associated with all-cause mortality, and log NT-proBNP (HR 3.70, 95% CI 1.28 to 10.71, p = 0.02) and T3 (HR 0.98, 95% CI 0.96 to 0.99, p = 0.01) were associated with cardiac mortality. Based on cut-off values for NT-proBNP (10,685 pg/ml) and T3 (52.3 ng/dl), Kaplan-Meier analyses provided significant prognostic information with the highest risk for all-cause mortality in the low T3 (<=52.3 ng/dl)/high NT-proBNP (>10,685 pg/ml) group (HR 8.54, 95% CI 4.19 to 17.40, p <0.0001). In conclusion, T3 levels appear to be independent predictors for both all-cause and cardiac mortalities among critical ill patients with heart failure, and high NT-proBNP and low T3 levels predict a worse long-term outcome. PMID- 24406112 TI - Effects of left ventricular geometry and obesity on mortality in women with normal ejection fraction. AB - Left ventricular (LV) geometry is an independent predictor of cardiovascular morbidity and mortality. Although obesity is a known risk factor for cardiovascular diseases, studies have suggested a paradoxical relation between obesity and prognosis. We retrospectively assessed 26,126 female patients with normal LV ejection fraction to determine the impact of LV geometry, including normal structure, concentric remodeling, and eccentric or concentric LV hypertrophy, and obesity on mortality during an average follow-up of 1.7 years. Abnormal LV geometry occurred more commonly in obese (body mass index >=30 kg/m(2), n = 10,465) compared with nonobese (body mass index <30 kg/m(2), n = 15,661) patients (56% vs 47%, respectively, p <0.0001). Overall mortality, however, was considerably less in obese compared with nonobese patients (5.6% vs 8.7%, respectively, p <0.0001). In both groups, progressive increases in mortality were observed from normal structure to concentric remodeling and then to eccentric and concentric LV hypertrophy (obese patients 2.9%, 6.5%, 6.7%, and 11.1%, respectively, and nonobese patients 5.3%, 10.6%, 11.4%, and 16.8%, respectively, p <0.0001 for trend). In conclusion, although an obesity paradox exists, in that obesity in women is associated with abnormal LV geometry but less mortality, our data demonstrate that abnormal LV geometric patterns are highly prevalent in both obese and nonobese female patients with normal ejection fraction and are associated with greater mortality. PMID- 24406113 TI - Genomewide RNAi screen identifies protein kinase Cb and new members of mitogen activated protein kinase pathway as regulators of melanoma cell growth and metastasis. AB - A large-scale RNAi screen was performed for eight different melanoma cell lines using a pooled whole-genome lentiviral shRNA library. shRNAs affecting proliferation of transduced melanoma cells were negatively selected during 10 days of culture. Overall, 617 shRNAs were identified by microarray hybridization. Pathway analyses identified mitogen-activated protein kinase (MAPK) pathway members such as ERK1/2, JNK1/2 and MAP3K7 and protein kinase C beta (PKCbeta) as candidate genes. Knockdown of PKCbeta most consistently reduced cellular proliferation, colony formation and migratory capacity of melanoma cells and was selected for further validation. PKCbeta showed enhanced expression in human primary melanomas and distant metastases as compared with benign melanocytic nevi. Moreover, treatment of melanoma cells with PKCbeta-specific inhibitor enzastaurin reduced melanoma cell growth but had only small effects on benign fibroblasts. Finally, PKCbeta-shRNA significantly reduced lung colonization capacity of stably transduced melanoma cells in mice. Taken together, this study identified new candidate genes for melanoma cell growth and proliferation. PKCbeta seems to play an important role in these processes and might serve as a new target for the treatment of metastatic melanoma. PMID- 24406114 TI - A retrospective approach to assess human health risks associated with growing air pollution in urbanized area of Thar Desert, western Rajasthan, India. AB - : Air pollution has been a matter of great concern globally because of the associated health risks to individuals. The situation is getting worse in developing countries with more urbanization, industrialization and more importantly the rapidly growing population posing a threat to human life in the form of pulmonary, cardiovascular, carcinogenic or asthmatic diseases by accumulating toxic pollutants, harmful gases, metals, hydrocarbons etc. OBJECTIVE: The present study was undertaken to assess the magnitude of ambient air pollutants and their human health risks like respiratory ailments, infectious diseases, cardiovascular diseases and cancer using a Retrospective Approach of Bart Ostra. METHODOLOGY: The parameters PM2.5, PM10, NOx, SO2, NH3 and O3 were monitored at all selected study sites monitored through a high volume sampler (APM 451 Envirotech, Envirotech Instruments Pvt. Ltd., New Delhi, India). Retrospective Approach was used for assessment of risk factors and disease burden of respiratory and cardiopulmonary health problems. RESULTS: Environmental burden of disease showed that the problem of health related to air pollution is a main concern particularly in the growing cities of India. High to critical level of air pollution including PM10, PM2.5, NOx, SO2, NH3 and O3 was observed in all seasons at traffic intersections and commercial sites. The respiratory infections (25% incidence in population exposed to indoor smoke problems) and a prevalence of asthma/COPD (4.4%) in households exposed to high vehicular pollution along with signs of coronary artery/heart disease and/or hypertension and cancers (37.9 52.2%), were reported requiring preventive measures. CONCLUSION: The study reflects a great concern for the mankind with the need of having streamline ways to limit air pollution and emphasize upon efficiently determining the risk of illness upon exposure to air pollution. PMID- 24406115 TI - Differential patterns of expression of neuropeptide Y throughout abstinence in outbred Swiss mice classified as susceptible or resistant to ethanol-induced locomotor sensitization. AB - Several studies have focused on the negative emotional state associated with drug abstinence. The peptide NPY plays an important role given its involvement in drug addiction, anxiety, and mood disorders. Interestingly, it is well established that outbred Swiss mice exhibit a prominent behavioral variability to ethanol induced locomotor sensitization. Here, we investigated whether mice that were either susceptible or resistant to ethanol sensitization differed in their NPY expression during abstinence. The mice were treated daily with ethanol (2 g/kg, i.p.) or saline for 21 days. According to the locomotor activity after the last injection, the ethanol group was classified as sensitized (EtOH_High) or non sensitized (EtOH_Low). To evaluate NPY expression, some of the mice were sacrificed at 18 h or 5 days of abstinence, and others were challenged at the 5th day of abstinence with ethanol (1.4 g/kg) and sacrificed after 1.5 h. At 5 days of abstinence, NPY expression increased in the orbital cortex, dorsomedial striatum, and dentate gyrus in the EtOH_High mice. These changes were counteracted by the ethanol challenge. In the EtOH_Low mice, NPY expression increased in the dentate gyrus only after 18 h of abstinence. Lastly, a decreased level of NPY was found in the prelimbic cortex of the EtOH_Low mice at 5 days of abstinence, and this was reversed by ethanol challenge. Therefore, behavioral variability in ethanol sensitization confers differential neurochemical features during the subsequent abstinence, including distinct patterns of NPY expression. PMID- 24406117 TI - An alternative technique to define and visualize columellar and nasal tip vectors. Improvement of mestizo nose. AB - BACKGROUND: With some frequency, in mestizo rhinoplasty, we focus much of our attention on the nasal tip. This work also highlights the importance of obtaining a proper balance of the columella, achieving a pleasing visual effect of the vector lines that make up the nasal profile (columella and nasal tip vectors). METHODS: We performed a complete medical history in all patients and developed a surgical plan after nasal anatomy analysis. Pre- and postoperative photographs were obtained for medium and long term control. RESULTS: We treated 112 patients with this surgical technique, 77 with an open approach and 35 with a closed approach. The results were documented in the short and long term with a range of 6 months to 5 years. CONCLUSIONS: We feel that the use of an angulated extended columellar graft is highly polyfunctional, providing length, definition and support to nasal tip grafts. Because of the graft design, it is possible to predetermine the new columella length/tip, thus visualizing the columella and nasal tip vectors of the nasal profile. The angulated extension prevents cephalic lateral-caudal displacements of the tip graft, and to some degree it is possible to increase or decrease nasal length depending on the angularity of the extension. PMID- 24406118 TI - The effect of caffeine on hearing in a guinea pig model of acoustic trauma. AB - OBJECTIVE: Caffeine is a widely consumed substance affecting the metabolism of adenosine and cellular metabolism of calcium. Noise also affects these metabolic pathways while inducing hearing loss. The aim of this study was to determine the effect of daily intake of caffeine on hearing loss after an episode of acoustic trauma in guinea pigs. MATERIALS AND METHODS: In this pilot study, forty guinea pigs were randomly divided into four groups: group I (control, n=10) received intraperitoneal saline, group II (n=10) received intraperitoneal caffeine (120 mg/kg/day) for 14 days, group III (n=10) was exposed to noise (tone of 6 kHz at 120 dB for one hour) and group IV (n=10) was exposed to noise as group III and received caffeine as group II. Auditory brainstem responses were measured at four different frequencies (8, 16, 20, and 25 kHz) prior to and at intervals of 1h, 3 days, 10 days, and 14 days after the initial treatment. On day 14, morphological analysis was performed to assess the effects of caffeine on acoustic trauma. RESULTS: Aggravated hearing loss was observed in group IV after 10 days of follow up. After 14 days, one of the four frequencies (8 kHz) tested showed statistically significant greater impairment in hearing (8.2 +/- 3.6 dB, p=0.026). Auditory hair cells showed no difference while spiral ganglion cell counts were diminished in group IV (p<0.05). CONCLUSION: These findings indicate that caffeine may have a detrimental effect on hearing recovery after a single event of acoustic trauma. PMID- 24406119 TI - Effectiveness of radiofrequency cryptolysis for the treatment of halitosis due to caseums. AB - OBJECTIVE: To evaluate the effectiveness of radiofrequency (RF) cryptolysis for caseum-induced halitosis. STUDY DESIGN: Clinical retrospective study. SETTING: Otorhinolaryngology Head and Neck Surgery Department of Konya Training and Research Hospital in Turkey. SUBJECTS AND METHODS: Thirty-four patients with caseum-induced halitosis were included. Eight were male (23.5%) and 26 were female (76.5%). Their mean age was 28.29 +/- 9.3 (range: 17-48) years. The mean duration of complaint of halitosis before RF cryptolysis was 53.41 +/- 42.6 months (range: 6-182 months). The Finkelstein test, organoleptic measurements, and visual analog scale (VAS) were performed before and 12 months after RF cryptolysis. RESULTS: Before RF cryptolysis, all patients had a positive Finkelstein's test result, organoleptic measurements revealed that three (8.82%) had serious halitosis, 24 (70.58%) had average halitosis, and seven (20.58%) had mild halitosis, and the mean VAS score was 6.82 +/- 1.45. The follow-up period after RF cryptolysis was 12 months. After the single RF cryptolysis session, 26 patients (76.47%) were negative for Finkelstein's test, organoleptic assessments revealed that 26 (76.47%), six (17.64%), and two (5.88%) showed complete, partial, and no recovery, respectively, (p<0.001), and the mean VAS score was significantly better at 1.88 +/- 2.5 (p<0.001). Thirty-two patients (94.1%) exhibited a decrease in VAS score. CONCLUSION: RF cryptolysis is a cost effective, safe, and easily applicable modality for the treatment of halitosis due to caseums in the crypts of the palatine tonsils. PMID- 24406120 TI - Reverse shoulder arthroplasty for acute proximal humerus fractures: a systematic review. AB - BACKGROUND: Proximal humerus fractures are one of the most common fractures among elderly patients. We performed a systematic review to detail the demographics, outcomes, and complications of patients who undergo reverse shoulder arthroplasty for complex proximal humerus fractures. METHODS: A systematic review of the literature was performed. Two reviewers assessed and confirmed the methodical quality of each study. Studies that met our criteria were assessed for pertinent data, and when available, similar outcomes were combined to generate frequency weighted means. RESULTS: Nine studies met the inclusion and exclusion criteria for this review. The frequency weighted mean age was 77.5 years and the mean follow up was 43.2 months. Females comprised 90.4% of the patient population. Four-part fractures were most commonly encountered. The frequency weighted mean constant's score was 55.9. Frequency weighted mean active forward flexion, abduction, and external rotation at neutral were 122 degrees , 97 degrees , and 18 degrees , respectively. Tuberosity repair was associated with significantly higher external rotation compared to no repair (24 degrees vs 15 degrees ; P = .0003). The most common complication was scapular notching (32%) while the impact of this finding remains unknown. CONCLUSION: Pooled data and frequency weighted mean outcomes showed that RSA patients tend to be elderly women and still have postoperative dysfunction despite well-controlled pain. Repair of the greater tuberosity allows greater range of motion in patients. PMID- 24406121 TI - Correction of acquired glenoid bone loss in osteoarthritis with a standard versus an augmented glenoid component. AB - BACKGROUND: The magnitude and anatomic consequences of pathologic acquired glenoid retroversion and posterior bone loss that can be surgically corrected with a standard versus an augmented glenoid component have not been studied extensively in a surgical patient population. MATERIALS AND METHODS: Twenty-nine patients with glenohumeral osteoarthritis, acquired posterior bone loss, and increased retroversion were studied by use of a three-dimensional computer surgical simulation. For each case, amount of medialization was measured as the linear distance from the lateral aspect of the glenoid vault model to the center of the articular implant surface. Simulation of implant placement at 0 degrees or 6 degrees was performed with use of a standard glenoid having a uniform thickness and an asymmetric thickness augmented component. RESULTS: An increased amount of medialization was seen with the standard glenoid, 8.3 +/- 4.1 mm, compared with 3.8 +/- 3.3 mm with use of the augmented glenoid implant (P < .001). When glenoid retroversion was corrected to 0 degrees , pathologic version was shown to have strong and significant relationship to the amount of medialization for both the standard (R(2) = 0.825) and augmented (R(2) = -0.68) glenoid implant. There was an increased ability to correct greater amounts of pathologic version with less medialization by use of an augmented step glenoid compared with a standard anchor peg glenoid. DISCUSSION: Correction of moderate to severe glenoid retroversion by asymmetric reaming cannot always be done with use of a standard component, and if it is done, it will result in greater medialization of the joint line. Use of an augmented component can allow complete correction of retroversion and minimize the effect of medialization. PMID- 24406122 TI - Celebrating the 40th anniversary of the Japan Shoulder Society. PMID- 24406124 TI - Does the presence of glenoid bone loss influence coracoid bone graft osteolysis after the Latarjet procedure? A computed tomography scan study in 2 groups of patients with and without glenoid bone loss. AB - BACKGROUND: Coracoid bone graft osteolysis and fibrous union are the principal causes of failure in patients treated with the Latarjet procedure. This study aims to investigate the hypothesis that coracoid bone graft osteolysis is more pronounced in cases without glenoid bone loss, which may be due to a diminished mechanotransduction effect at the bone healing site. METHODS: We prospectively followed up 34 patients, treated with a mini-plate Latarjet procedure, divided into 2 groups (group A patients had glenoid bone loss >15% and group B patients had no glenoid bone loss). A computed tomography scan evaluation with 3 dimensional reconstruction was then performed on all patients to evaluate coracoid bone graft osteolysis according to our coracoid bone graft osteolysis classification. RESULTS: The computed tomography scan analysis showed a different distribution of osteolysis between group A and group B. The statistical analysis showed a significant difference (P < .01, Bonferroni test) between groups A and B for the following sections: proximal/lateral/superficial, proximal/medial/deep, distal/lateral/superficial, and distal/lateral/deep. On average, the coracoid grafts in group A patients showed less osteolysis than the coracoid grafts in group B patients (39.6% vs 65.1%). DISCUSSION: The coracoid bone graft underwent much less osteolysis in patients with significant glenoid bone loss (>15%) than in those without it. Because factors of blood supply, compression, and surgical technique were the same for both groups, we believe that the mechanotransduction effect from the humeral head on the graft influences its remodeling. CONCLUSION: The results of this study suggest that the bone graft part of the Latarjet procedure plays a role in patients with significant coracoid bone loss but much less so when there is no bone loss. PMID- 24406123 TI - Evaluation of shoulder-specific patient-reported outcome measures: a systematic and standardized comparison of available evidence. AB - BACKGROUND: The aim of this study was to perform a standardized and systematic evaluation of the available evidence on multi-item shoulder-specific patient reported outcome measures that are applicable to a wide spectrum of disorders. MATERIALS AND METHODS: A systematic review was conducted in PubMed to identify articles with information regarding the development process, metric properties, and administration issues of shoulder-specific patient-reported outcome measures. Two experts independently reviewed all the articles identified for one instrument and applied the EMPRO (Evaluating Measures of Patient Reported Outcomes) tool, which was designed to assess the quality of attributes in a standardized way. An overall EMPRO score and 6 attribute-specific scores were calculated (range, 0 100) to describe the quality of instrument performance. RESULTS: We identified 11 instruments and 112 articles (2-30 articles per instrument). The American Shoulder and Elbow Surgeons (ASES) shoulder assessment, Simple Shoulder Test (SST), and Oxford Shoulder Score (OSS) were the best rated, with overall scores of 77.4 points, 72.6 points, and 69.7 points, respectively. They have been shown to be valid, reliable, and responsive, with a low administration burden. Acceptable results were also found for the Flexilevel Scale of Shoulder Function, Shoulder Pain and Disability Index, and Dutch Shoulder Disability Questionnaire, but some of their attributes need further evaluation. CONCLUSIONS: Current evidence supports the use of the ASES, SST, or OSS. We recommend the SST for longitudinal studies or clinical trials, the Dutch Shoulder Disability Questionnaire for clinical practice to minimize administration burden, and the ASES or OSS to discriminate among patients' or groups' evaluations at one point of time. PMID- 24406125 TI - [Menopause:old concept, real problem]. PMID- 24406126 TI - [Survey on characteristics of menopause of Chinese women with the age of 40-60 years at gynecological clinic from 14 hospitals]. AB - OBJECTIVE: To investigate the characteristics of menopause of Chinese women with the age of 40-60 years concerning gynecologic clinics in China. METHODS: From Mar.2008 to Sept.2008, a face-to-face questionnaire was conducted in gynecological clinic in perimenopausal and postmenopausal women in 14 hospitals in China, which included general demographic data, menstrual change process, climacteric symptoms and knowledge about menopause. Modified Kupperman index were used to evaluate climacteric symptoms during the recent week and awareness of hormonal replacement therapy were studied. RESULTS: A total of 1641 women were investigated. The ages of onset of menopause transition, climacteric symptoms and natural menopause were (47 +/- 4), (46 +/- 4), (49 +/- 3) years old respectively. Climacteric symptoms could be found in 78.43% (1287/1641) women during menopausal transition, which were mainly mild to moderate symptoms. The top 5 symptoms were fatigue and weakness (71.48%, 1173/1641), irritability (68.68%, 1127/1641), insomnia (67.65%, 1110/1641), muscle and joint pain (64.11%, 1052/1641) and hot flush (57.90%, 950/1641). The climacteric symptoms were not constant during menopausal transition, usually more severe in late transition and postmenopausal periods, during which the moderate and severe symptoms were 59.1% (189/320) and 51.1% (291/570) respectively. Although most symptoms primarily appeared along with menstruation change, there are about 17.5% (172/981) patients experienced climacteric symptoms before menstruation change occurrence. There were 56.39% (733/1300) women had ever heard (mostly from gynecologist) about hormone replacement therapy from Obstetrician and Gynecologist. CONCLUSIONS: Most of the women during menopausal transition had climacteric symptoms, usually mild and moderate ones. Although most symptoms primarily appeared along with menstruation change, there are other patients' experienced climacteric symptoms before menstruation change occurrence. PMID- 24406127 TI - [Survey on epidemiologic factors associated with the age of natural menopause and menopausal symptoms in Jiangsu women]. AB - OBJECTIVE: To investigate the epidemiologic factors associated with the age of natural menopause and menopausal symptoms in a large population at age of 40 to 65 years in Jiangsu Province. METHODS: From May 2010 to Oct.2011, a total of 20 275 women (40 to 65 years) attending health examination in Jiangsu Province were enrolled in this cross-sectional study. A structured questionnaire was used to collect data of demographics, menopausal status, chronic diseases, reproductive history. Also the menopausal symptoms were evaluated by Kupperman menopause index (KMI). Cox proportional hazards regression model and Logistic regression were performed to identify risk factors for earlier age of natural menopause and menopausal symptoms, respectively. RESULTS: The overall median age at natural menopause in Jiangsu women was 50 years.Lower educational level, poor economic status, lower body mass index (BMI), age at menarche less than 14 years, nulliparity and smoking were associated with earlier onset of natural menopause (P < 0.05). The most frequently symptoms in perimenopausal women were fatigue (46.84%, 1880/4014), insomnia (44.67%, 1793/4014) and muscle/joint pain (43.80%, 1758/4014), while sexual problems (57.06%, 3463/6070), muscle/joint pain (53.30%, 3235/6070) and insomnia (51.03%, 3097/6070) were predominant symptoms in postmenopausal women. After adjusting for confounding factors, it was revealed that women with poor educational background, low income, divorce, higher BMI, higher parity, and smoking presented positive correlation with menopausal symptoms (P < 0.05). CONCLUSIONS: The study suggested that an estimate of median age at natural menopause were 50 years in Jiangsu women. The main factors contributing to earlier onset of menopause and menopausal symptoms were lower educational level, poor economic status, and smoking. Moreover, there were different menopausal symptoms between perimenopausal and postmenopausal women, which provided the important insights for physicians to prevent and treat menopause symptoms in their clinical practice. PMID- 24406128 TI - [Study on risk factors of cardiovascular disease and the status of bone mineral density in women with hypoestrogenism]. AB - OBJECTIVE: To study risk factors of cardiovascular disease (CVD) and status of bone mineral density (BMD) in women with hypoestrogenism. METHODS: From Jul 2011 to April 2013, a total of 256 women with hypoestrogenism in the First Affiliated Hospital of Shanxi Medical University were enrolled in this retrospective study, which were divided into four groups:133 women in ppausal group, 25 women in premature ovarian failure (POF) group, 67 women in menopausal transition group and 31 women in premature ovarian failure transition group.General statue, CVD risk factors and BMD were compared among four groups.General statue include menopausal period, menopausal symptoms (Kupperman Index), CVD risk factors include body mass index, blood pressure, waist circumference, waist-hip ratio, blood lipids and glucose, BMD include left hip, lumbar spine bone mineral density and T or Z value. RESULTS: (1) The median menopausal period were 3.4 years in postmenopausal group and 3.6 years in premature ovarian failure group, which did not show no statistical difference (P > 0.05).Kupperman Index in four groups were 12 in postmenopausal group, 9 in POF group, 9 in menopausal transition group and 8 in premature ovarian failure transition group, which reached statistical difference (P < 0.05).(2) The difference of body mass index (BMI), waist circumference, waist-hip ratio, diastolic blood pressure were no statistically significant among four groups(P > 0.05); the systolic blood pressure in four groups were 120, 110, 110, 110 mm Hg (1 mm Hg = 0.133 kPa), their differences were statistically significance (P < 0.05); the high-density lipoprotein (HDL-C) was 1.6 mmol/L in postmenopausal group, and 1.3 mmol/L in premature ovarian failure transition group, their differences were all statistically significance (P < 0.05); the difference of the fasting plasma glucose (FPG) was not statistically different in 4 groups (P > 0.05).(3) The abnormal rate of lower bone mass in lumbar spine were 57% (46/81) postmenopausal group, 8/15 in POF group, 32% (9/28) in menopausal transition group, 12/19 in premature ovarian failure transition group, and osteoporosis was 9% (7/81), 3/15, 1% (3/28) and 0 respectively , their differences were statistically different (P < 0.05); the abnormal rate of BMD of left hip and lumbar spine of 11/15 and 12/16 in POF group was higher than 65% (53/81) in postmenopausal group. In the mean time, the abnormal rate of BMD of left hip and lumbar spine were, 12/19 and 10/20 in premature ovarian failure transition group, which were significantly higher than 43% (12/28) and 39% (12/31) in the menopausal transition group. CONCLUSIONS: The menopausal symptoms resulting from hypoestrogenism in natural postmenopausal women are mostly remarkable. The decrease of BMD in lumbar spine is more significant than that of left hip among postmenopausal women.Women with earlier menopause was prone to cause the changes of blood fat and abnormal of BMD, especially HDL-C decreased significantly compared with those natural postmenopause, it is more likely to cause CVD and osteoporosis. PMID- 24406129 TI - [Study on relationship between endogenous androgens and insulin resistance at the different stages of postmenopause]. AB - OBJECTIVE: To investigate the relationship between insulin resistance and endogenous androgens at early and late phase of postmenopause. METHODS: A total of 105 women with early postmenopause ( <= 5 years since menopause) and 107 women with late postmenopause ( >= 10 years since menopause) were enrolled in this study.In the mean time, those women were classified into normal weight[body mass index (BMI), BMI <24 kg/m(2)] group and overweight (BMI >= 24 kg/m(2)) group.Sex hormone-binding globulin (SHBG), testosterone (T) , dehydroepiandrosterone sulfate (DHEA-S) , fasting blood glucose(FBG), fasting insulin (FINS) levels were measured and then calculated free androgen index (FAI) and homeostatic model assessment of insulin resistance (HOMA-IR) . The relationship between sex hormones and insulin resistance was analyzed by partial correlation and multiple linear regression analyses. RESULTS: Compared to early postmenopausal women, late postmenopausal women had higher FINS [(7.9 +/- 6.6) mU/L versus (6.6 +/- 4.0) mU/L] and HOMA-IR(2.1 +/- 1.9 versus 1.7 +/- 1.1), but they had lower DHEA-S[(0.9 +/- 0.5) mg/L versus (1.1 +/- 0.5) mg/L, all P < 0.05) ]. Both in early postmenopausal and late postmenopausal groups, overweight women had higher HOMA IR (early group, 2.2 +/- 1.0 versus 1.2 +/- 0.9;late group, 2.8 +/- 2.6 versus 1.6 +/- 1.1) and FINS early group[(6.9 +/- 2.9) mU/L versus (4.6 +/- 2.0) mU/L];late group[(10.2 +/- 9.3) mU/L versus (6.4 +/- 3.6) mU/L] than those at women with normal weight group (all P < 0.05) .In early postmenopausal group, overweight women had lower SHBG[ (52 +/- 37) nmol/L versus (71 +/- 37) nmol/L] and higher FAI (2.5 +/- 2.1) versus (1.3 +/- 1.1) than those at normal weight women group (all P < 0.05) .In late postmenopausal group, overweight women had higher DHEA-S (1.0 +/- 0.5) mg/L versus (0.8 +/- 0.4) mg/L (P < 0.05) . The analyses suggested that in early postmenopausal group, SHBG was correlated negatively with FINS and HOMA-IR (beta = -0.386, P < 0.05;beta = -0.553, P < 0.05) , DHEA-S was correlated positively with FBG (beta = 0.348, P < 0.05) in early postmenopausal group.FAI was correlated positively with FBG in late postmenopausal group (beta = 0.505, P < 0.05) . CONCLUSIONS: The increased androgenic activities are associated with insulin resistance after of menopause. These correlations are different at different stages of postmenopause, which SHBG levels correlate with high risk of insulin resistance and DHEA-S levels correlates with high blood glucose levels at early postmenopause and FAI correlates with high blood glucose levels at late postmenopause. PMID- 24406130 TI - [Protective effects of caloric restriction on ovarian function]. AB - OBJECTIVE: To study the protective effects on ovarian function by caloric restriction (CR) and its mechanism. METHODS: Thirty female C57BL/6 mice of 8 weeks old were randomly divided into two groups, including ad libitum (AL) group and caloric restriction (CR) group. The general situation and ovarian function of those mice were compared and evaluated.Ovarian follicles were counted by hematoxylin-eosin staining. Anti-Miillerian Hormone(AMH) mRNA expression of the ovary were detected by using real-time PCR. The concentrations of serum estradiol, progesterone of the mice were measured by ELISA. And the fertility of mice by mating trials were evaluated, SIRT3, Hypoxia inducible factor 1alpha (HIF 1alpha) and catalase (CAT) mRNA expression of the mice ovaries were detected by Real-Time PCR. RESULTS: The total follicles were 546 in CR mice and 286 in AL mice. The proportion of primordial follicles were 38.6% (211/546) in ovaries of CR mice and 29.4% (84/286) in ovaries of AL mice, which reached statistical difference. The proportion of atretic follicles 5.3% (29/546) in ovaries of CR mice, compared with 16.8% (48/286) in AL mice, was significantly decreased (P < 0.05). The AMH mRNA expression in CR mice ovaries was 3.37 times of that of AL mice (P < 0.05). The serum concentration of estradiol in CR mice was up to (5.3 +/- 1.6) pmol/L, which was much higher than (3.6 +/- 1.6) pmol/L in AL mice. While, the progesterone concentration of (0.4 +/- 0.3) nmol/L in CR mice was lower than (1.4 +/- 0.8) nmol/L in AL mice (P < 0.05).Fertility and survival of offsprings were both improved in CR mice. The expression level of SIRT3 mRNA in CR mice ovary was 1.39 times, CAT was 1.55 times and HIF-1alpha was 0.31 times of those in AL mice (P < 0.05). CONCLUSIONS: Caloric restriction can delay the ovary aging process through reduce follicle depletion by suppressing follicle recruitment and ovulation. The function of ovarian reserve and reproductive endocrine was effectively protected. Caloric restriction can reduce the incidence of follicular atresia, its mechanism might be associated with anti-oxidative stress. PMID- 24406131 TI - [Umbilical cord ligation in the fetocide of complicated monochorionic multiple gestations]. AB - OBJECTIVE: To evaluate the clinical effect and safety of umbilical cord ligation in the fetocide of complicated monochorionic multiple gestations. METHODS: From January 2009 to December 2012, clinical data of 18 women with complicated monochorionic multiple gestations who experienced intrauterine percutaneous umbilical cord ligation in Peking University Third Hospital were collected. Among the patients, 6 were selective intrauterine growth restriction (1 with type I, 4 with type II, 1 with type III); 4 were acrania or hydropic twins; 4 were acardiac twins, 2 were complicated triplet gestation; 1 was twin-twin transfusion syndrome with right ventricular dysplasia and 1 was monochorionic diamniotic (MCDA) with caesarean section history. The procedure was performed under both endoscopic and sonographic guidance. The gestational age at the time of the procedure were 17 27(+6) weeks. The procedure and perinatal outcome were analyzed. RESULTS: (1) The procedure was performed successfully in all the 18 cases. The average duration of the procedure was 63 min (24-156 min). The blood loss was 7.6 ml (5-20 ml). The mean gestational age at the time of the procedure was 20 weeks (17-27(+) weeks). The average birth weight of the neonates was 2441 g (1000-3400 g) .(2) There were 206 fetuses survived. Two fetuses had cardiac anomalies and were terminated in the following 2-3 weeks.Intrauterus fetal demise occured in 3 twin reverse arterial perfusion syndrome (TRAP) cases 3-14 weeks after the procedure.1 case delivered as early preterm birth at 28 weeks and the neonate died of respiratory distress syndrome (RDS) and hypoxie-ischemicen-cephalopathy (HIE) .Fourteen neonates were in healthy and normal development by 3-51 months' follow-up.(3) Fourteen cases delivered at more than 28 weeks (28-38 weeks, averagely 33(+1) weeks). The gestational weeks were prolonged by 5-21 weeks (averagely 13(+4) weeks). Among them, 3 case were early preterm birth (28-33 weeks) and 3 were late preterm birth (34-36 weeks). CONCLUSION: Percutaneous umbilical cord ligation is a reliable technique for the fetocide of complicated monochrionic mutilple gestations, especially for monochronic monoamniotic pregnancies. PMID- 24406132 TI - [Expression of KLF-8 and MMP-9 in placentas and their relationship with the pathogenesis of preeclampsia]. AB - OBJECTIVE: To evaluate the expression of Kruppel-like factor 8 (KLF-8) and matrix metalloproteinase 9 (MMP-9) in placentas and their relationship with the pathogenesis of preeclampsia (PE). METHODS: Twenty-two women with PE(mild PE:4 cases; severe PE:18 cases) who received cesarean sections in the First Affiliated Hospital of Chongqing Medical University from September 2011 to March 2012 were recruited as the PE group (n = 22). And twenty women who received elective term cesarean section without perinatal complications were chosen as the control group (n = 20). Placentas were collected and immunohistochemical SP method were employed to detect the localization of KLF-8 protein.KLF-8 mRNA level was determined by quantitative real-time PCR technique and western blot analysis was used to quantify KLF-8 and MMP-9 protein levels. RESULTS: (1) There was no difference of KLF-8 protein distribution in placentas of the PE group and the control group.It was mainly located in the nuclear and cytoplasm of syncytiotrophoblasts.KLF-8 immunostaining was apparently decreased in the placentas of preeclamptic women when compared with the control group.(2)The KLF-8 mRNA levels were significantly decreased in placentas of the PE group (0.69 +/- 0.08) compared to those of the control group (1.14 +/- 0.09, P < 0.01). (3) KLF-8 and MMP-9 protein levels significantly decreased in the PE placentas (0.68 +/- 0.05 and 0.21 +/- 0.03) when compared to the control group (0.94 +/- 0.06 and 0.34 +/- 0.03, respectively, P < 0.01).(4) There was a positive correlation between the expression of KLF-8 and MMP-9 protein in the placentas from PE and normal pregnancies (r = 0.64, P < 0.01). CONCLUSIONS: KLF-8 mRNA and protein levels were decreased in placentas of PE patients compared to those of normotensive women.KLF-8 protein was primarily located in the invasion-related trophoblast cells and its expression had a positive correlation with MMP-9 levels.KLF-8 might have an important role in the pathogenesis of PE by regulation of trophoblast invasion. PMID- 24406133 TI - [Effects and mechanisms of trophoblast cells autophagy in preeclampsia]. AB - OBJECTIVE: To investigate the occurrence law of autophagy in trophoblast cells from preeclampsia and its underlying mechanisms. METHODS: Twenty cases of placenta tissues were collected from women suffered from preeclampsia and normal pregnant women respectively. Autophagosome of trophoblast cells were observed by transmission electron microscope. The expressions of LC3-II/I and Atg4B in placenta tissues were detected by western blot and real-time PCR. RESULTS: Compared with the control group, typical autophagosomes of trophoblast cells were observed by transmission electron microscope. The ratio of LC3-II/I in placenta of PE patients was increased (1.43 +/- 0.23) compared with control group (0.59 +/ 0.12), and the expression of Atg4B was up-regulated in both mRNA [(1.73 +/- 0.16) folds] and protein levels (0.71 +/- 0.13) compared with control group (P < 0.05). CONCLUSIONS: Autophagy was significantly up-regulated in trophoblast cells from patients suffered from preeclampsia. Thus, all the data suggest that autophagy might be involved in the generation of preeclampsia. PMID- 24406134 TI - [Comparison of two different chemotherapy regimens for concurrent chemoradiotherapy in stage Ib2 to IVa squamous cell carcinoma of the uterine cervix]. AB - OBJECTIVE: To compare the clinical efficacy and safety of two chemotherapy regimens for concurrent chemoradiotherapy in patients with stage Ib2 to IVa squamous cell carcinoma of the uterine cervix. METHODS: Between November 2007 and November 2011, 146 patients with stage Ib2 to IVa squamous cell carcinoma of the uterine cervix who received concurrent chemoradiotherapy in Peking University Cancer Hospital were analyzed. All cases were divided into two groups according to the different chemotherapy regimens during radiation therapy, the group receiving radiotherapy concomitant with weekly cisplatin or nedaplatin alone (platinum alone group, n = 59), the group receiving radiotherapy concomitant with cisplatin plus fluorouracil or nedaplatin plus tegafur every 3 weeks (combined group, n = 87). There were no statistical difference in the clinical and pathological characteristics between the two groups. RESULTS: Patients were evaluated by pelvic examination and pelvic MRI after chemoradiotherapy for 3 months according to WHO criteria. The response rate were respectively 97% (57/59) and 93% (81/87) in platinum alone group and combined group, in which there was no significant difference (P = 0.249). The five-year overall survival and the five year progression-free survival of platinum alone group and combined group were respectively 61.2% versus 69.5% (P > 0.05) and 43.3% versus 24.4% (P > 0.05). There were also no statistically significant differences between platinum alone group and combined group in the five-year local recurrence rate and five-year distant metastasis (11.8% versus 9.8%, 29.4% versus 38.7%; all P > 0.05). Acute gastrointestinal toxicities (nausea and vomiting) in combined group were exactly higher than that in the other group [78% (68/87) versus 51% (30/59), P < 0.01]. Moreover, anaemia was slightly more common in combined group [53% (46/87) versus 25% (15/59), P = 0.019]. However, the occurrence rate of the acute or late proctitis and cystitis did not reveal difference between two groups (P > 0.05). CONCLUSIONS: Both concurrent chemoradiotherapy regimens had similar efficacy on cervical cancer patients with stage Ib2 to IVa. But the toxicity was lower in patients with weekly platinum than those with platinum-based combined regimens during radiation therapy. PMID- 24406135 TI - [Study of claudin-4 in the diagnosis and treatment of endometrial carcinoma]. AB - OBJECTIVE: To clarify the role of claudin-4 in endometrial tumorigenesis and explore claudin-4 be as potentially useful agent in the treatment of endometrial carcinoma. METHODS: The expression of claudin-4 in 62 endometrioid endometrial carcinoma (EEC), 30 atypical hyperplasia endometrial tissue and 60 human normal endometrium was determined using immunohistochemistry and real-time PCR. Ninety female BALB/c mice were transplanted with Ishikawa endometrial cancer cells, which were divided into three groups with different intraperitoneal treatments with cisplatin, paclitaxel and saline solution. After the observation period, the tumors were extracted and stained with monoclonal antibody against claudin-4. The messenger RNA expression of claudin-4 was also detected using real-time PCR. RESULTS: Among the EEC samples, 34% (21/62) showed medium staining for claudin-4 and 66% (41/62) showed intense staining. In atypical hyperplasia group, 27% (8/30) showed weak staining, 53% (16/30) showed medium staining and 20% (6/30) showed intense staining for claudin-4. Of the normal endometrial tissue, 47% (28/60) showed weak staining and 53% (32/60) showed no staining for claudin-4. According to real-time PCR, the relative quantity of claudin-4 was 170 +/- 12 in EEC group, 89 +/- 15 in atypical hyperplasia group and 18 +/- 3 in normal endometrium. Compared with those in atypical hyperplasia group and normal endometrium group, the protein and mRNA expression of claudin-4 were significantly increased in the group of EEC (all P < 0.05). In the study of Ishikawa xenografts, no significant changes in tumor volume and claudin-4 expression were shown in paclitaxel group compared with that in the control group. Nevertheless, a significant reduction of the tumor growth and a significant decrease in claudin-4 expression were observed in cisplatin group. After cisplatin treatment, the tumor volume was significantly decreased [(0.51 +/ 0.21) versus (0.73 +/- 0.12) cm(3)], and the mRNA expression of claudin-4 was also significantly decreased (153 +/- 35 versus 273 +/- 27). CONCLUSION: These results demonstrate that claudin-4 is strongly expressed in EEC, which may be a useful biomarker to monitor the effects of chemotherapy in patients with endometrial carcinoma. PMID- 24406136 TI - [Study of mechanism of medroxyprogesterone 17-acetate on the cancer stem cell like properties of human endometrial cancer]. AB - OBJECTIVE: To explore the mechanism resistance of medroxyprogesterone 17 acetate(MPA) on the endometrial cancer side-population(SP) cells. METHODS: (1) Ishikawa-SP cells from endometrial cancer cell lines Ishikawa were be separated by Hoechst 33342 dyeing method and flow cytometry analysis. The clone formation efficiency between Ishikawa-SP cells and Ishikawa-non-SP cells were performed by clone formation assay. Breast cancer resistance protein (BCRP) was examined by immunocytochemistry method. (2) Ishikawa, Ishikawa-SP, Ishikawa-non-SP cells were treated with various concentrations of MPA at 5, 10, 15, 20 umol/L. After cultured for 24, 48, and 72 hours, cells growth were measured by methanethiosulfomate (MTS) assay. (3) The groups of Ishikawa, Ishikawa-SP, Ishikawa-non-SP cells incubated with MPA at the half maximal inhibitory concentration (IC50) were selected for cell apoptosis assay by using flow cytometry. After MPA treatment, the expression of caspase-3 was examined by immunocytochemistry method. RESULTS: (1) There were few proportion of Ishikawa-SP cells in Ishikawa endometrial carcinoma, which were 2.7%. There were stronger clone formation efficiency for Ishikawa-SP cells than that for Ishikawa-non-SP cells in Ishikawa [(6.02 +/- 1.17)% vs.(0.53 +/- 0.20)%, P = 0.001]. And there were higher level expression of BCRP (P = 0.001) and also more resistant Taxol and radiation between Ishikawa-SP cells and Ishikawa-non-SP cells. (2) The inhibitory effect of MPA was concentration-dependent and time-dependent. (3)After MPA treatment, the apoptosis rates of Ishikawa-SP, Ishikawa-non-SP,Ishikawa were (4.01 +/- 0.43) %, (9.30 +/- 0.67) %, and (4.64 +/- 0.18) %, respectively(P < 0.05). The level expression of caspase-3 in Ishikawa group after MPA treated were higher than that in Ishikawa-SP group. CONCLUSION: MPA may be inhibit the growth of endometrial cancer, Ishikawa-SP and Ishikawa-non-SP cells, while Ishikawa-SP may be more resistant to MPA than Ishikawa-non-SP, which mechanism of resistance on MPA may be related to the properties of cancer stem-like cells and cell apoptosis. PMID- 24406137 TI - [Effect and mechanism of gene therapy of lentivirus mediated RhoA shRNA on ovarian cancer xenograft in vivo]. AB - OBJECTIVE: To investigate treatment effects of lentivirus mediated RhoA short hairpin RNA (shRNA) on xenograft tumor of ovarian cancer in nude mice in vivo and the underlying mechanism. METHODS: Human ovarian cancer cell line HO8910 were inoculated to establish subcutaneous xenograft model of human ovarian cancer. Tumor-bearing nude mice were assigned randomizely to three groups: Lenti-RhoA-sh group, Lenti- negative control (NC) group and phosphate buffered saline (PBS) group.lentivirus mediated RhoA shRNA, negative control lentivirus and PBS were respectively injected in the three groups. Effects of treatment were observed by tumor growth curve, tumor volume, tumor weight, and tumor inhibition rate. Xenograft tissues and liver, spleen, lung, and renal tissues were examined by hematoxylin and eosin (HE) staining or were detected by streptavidin perosidase(SP)immunochemical method. The changes of RhoA gene expression in xenograft tissues after lentivirus mediated RhoA shRNA treated were also detected by real-time qPCR, immunochemistry and Western blot assay. Cell apoptosis in xenograft tissues were examined by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method and apoptotic index (AI) were counted. RESULTS: Compared with Lenti-NC group and PBS group, the growth speed of xenograft in Lenti-RhoA-sh group delayed significantly after injection 9 days (P < 0.01) . Tumor volume (338 +/- 114) mm(3) decreased significantly in the Lenti RhoA-sh group when compared with those in Lenti-NC group (1190 +/- 332) mm(3) and PBS group (1101 +/- 396) mm(3) (P < 0.01) . Tumor weight (0.23 +/- 0.11) g decreased significantly in the Lenti-RhoA-sh group when compared with Lenti-NC group (0.79 +/- 0.19) g and PBS group (0.74 +/- 0.17) g (P < 0.01) . Real-time qPCR result shown that the expression of RhoA mRNA (0.30 +/- 0.05) decreased significantly in the Lenti-RhoA-sh group compared with Lenti-NC group (0.95 +/- 0.06) and PBS group(1.00 +/- 0.11; P < 0.01) .Western blot result showed that the expression level of RhoA protein decreased significantly in the Lenti-RhoA-sh group (0.14 +/- 0.06) compared with those in Lenti-NC group(0.78 +/- 0.14) and PBS group (0.75 +/- 0.13;P < 0.01). TUNEL staining displayed that AI significantly increased in the Lenti-RhoA-sh group (20.9 +/- 3.4) % compared with those in Lenti-NC group (5.2 +/- 2.0) % and PBS group (6.0 +/- 2.1) % (P < 0.01). CONCLUSION: Lentivirus mediated RhoA shRNA may be effectively down-regulate of the expression of RhoA, inhibit the growth of subcutaneous xenograft tumor of ovarian cancer in nude mice by increasing the cell apoptosis. PMID- 24406138 TI - Characteristics and outcomes of chronic pulmonary aspergillosis: a retrospective analysis of a tertiary hospital registry. AB - INTRODUCTION: Our objective was to investigate characteristics risk factors and outcomes of patients with chronic pulmonary aspergillosis (CPA). METHODS: The Aspergillosis Committee prospectively collected Aspergillus notifications from January 2000 to December 2011. A retrospective analysis of data was performed. RESULTS: Among 1614 notifications registered, 44 cases of CPA in non immunocompromised patients were identified. The median age was 65 years (Q1-Q3: 54-75), the median body mass index (BMI) was 20 kg/m(2) (Q1-Q3: 16-22) and 15 had chronic obstructive pulmonary disease. All patients had a positive specific serum precipitin antibody titer. Radiological presentations were: cavitations [single n = 31 (70%); multiple n = 12 (27%)] containing mycetomas [n = 18 (41%)], consolidations [n = 19 (43%)], emphysema [n = 15 (34%)] and sequelae of mycobacterial infection [n = 10 (23%)]. The median duration of follow-up was 30 months (Q1-Q3: 14-55). The median duration of antifungal treatment was 6 months (Q1-Q3: 3-12). Outcomes were unfavorable in 14 patients, and 12 (27%) died. Analysis by multivariate Cox regression model with bootstrapping showed that a higher BMI and a lower Charlson index score were predictive of favorable evolution, hazard ratio (95% confidence interval): BMI (+1) = 0.83 (0.71-0.97), Charlson (+1) = 1.37 (1.01-1.85). When analyses were restricted to chronic CPA and chronic necrotizing pulmonary aspergillosis, the multivariate Cox regression model showed that both BMI and Charlson index score were not statistically significant. CONCLUSION: Our results provide data on clinical characteristics and outcomes of CPA emphasizing the role of preexisting chronic respiratory conditions and protective effect of preserved BMI and lower Charlson index score. PMID- 24406139 TI - Financial stress in late adulthood and diverse risks of incident cardiovascular disease and all-cause mortality in women and men. AB - BACKGROUND: Financial stress may have adverse health effects. The main aim of this study was to investigate whether having a cash margin and living alone or cohabiting is associated with incident cardiovascular disease (CVD) and all-cause mortality. METHODS: Representative population-based prospective cohort study of 60-year-old women (n = 2065) and men (n = 1939) in Stockholm County, Sweden. National registers were used to identify cases of incident CVD (n = 375) and all cause mortality (n = 385). The presence of a cash margin was determined in the questionnaire with the following question: Would you, if an unexpected situation occurred, be able to raise 10,000 SEK within a week? (This was equivalent to US$ 1250 in 1998). RESULTS: Compared with cohabiting women with a cash margin, the risk of all-cause mortality was higher among cohabiting women without a cash margin, with hazard ratios (HRs) of 1.97 (95% confidence interval (CI) 1.06 3.66). Using cohabiting men with cash margin as referent, single men without a cash margin were at an increased risk of both incident CVD and all-cause mortality: HR 2.84 (95% CI 1.61-4.99) and 2.78 (95% CI 1.69-4.56), respectively. Single men with cash margins still had an increased risk of all-cause mortality when compared with cohabiting men with a cash margin: HR 1.67 (95% CI 1.22-2.28). CONCLUSIONS: Financial stress may increase the risks of incident CVD and all cause mortality, especially among men. Furthermore these risks are likely to be greater in men living in single households and in women without cash margins. Living with a partner seems to protect men, but not women, from ill-health associated with financial stress due to the lack of a cash margin. PMID- 24406140 TI - On the improvement of blood sample collection at clinical laboratories. AB - BACKGROUND: Blood samples are usually collected daily from different collection points, such hospitals and health centers, and transported to a core laboratory for testing. This paper presents a project to improve the collection routes of two of the largest clinical laboratories in Spain. These routes must be designed in a cost-efficient manner while satisfying two important constraints: (i) two hour time windows between collection and delivery, and (ii) vehicle capacity. METHODS: A heuristic method based on a genetic algorithm has been designed to solve the problem of blood sample collection. The user enters the following information for each collection point: postal address, average collecting time, and average demand (in thermal containers). After implementing the algorithm using C programming, this is run and, in few seconds, it obtains optimal (or near optimal) collection routes that specify the collection sequence for each vehicle. Different scenarios using various types of vehicles have been considered. Unless new collection points are added or problem parameters are changed substantially, routes need to be designed only once. RESULTS: The two laboratories in this study previously planned routes manually for 43 and 74 collection points, respectively. These routes were covered by an external carrier company. With the implementation of this algorithm, the number of routes could be reduced from ten to seven in one laboratory and from twelve to nine in the other, which represents significant annual savings in transportation costs. CONCLUSIONS: The algorithm presented can be easily implemented in other laboratories that face this type of problem, and it is particularly interesting and useful as the number of collection points increases. The method designs blood collection routes with reduced costs that meet the time and capacity constraints of the problem. PMID- 24406141 TI - A high-resolution peak fractionation approach for streamlined screening of nuclear-factor-E2-related factor-2 activators in Salvia miltiorrhiza. AB - Generation of a high-purity fraction library for efficiently screening active compounds from natural products is challenging because of their chemical diversity and complex matrices. In this work, a strategy combining high resolution peak fractionation (HRPF) with a cell-based assay was proposed for target screening of bioactive constituents from natural products. In this approach, peak fractionation was conducted under chromatographic conditions optimized for high-resolution separation of the natural product extract. The HRPF approach was automatically performed according to the predefinition of certain peaks based on their retention times from a reference chromatographic profile. The corresponding HRPF database was collected with a parallel mass spectrometer to ensure purity and characterize the structures of compounds in the various fractions. Using this approach, a set of 75 peak fractions on the microgram scale was generated from 4mg of the extract of Salvia miltiorrhiza. After screening by an ARE-luciferase reporter gene assay, 20 diterpene quinones were selected and identified, and 16 of these compounds were reported to possess novel Nrf2 activation activity. Compared with conventional fixed-time interval fractionation, the HRPF approach could significantly improve the efficiency of bioactive compound discovery and facilitate the uncovering of minor active components. PMID- 24406142 TI - Aromatic ligands for plasmid deoxyribonucleic acid chromatographic analysis and purification: an overview. AB - The aromatic ring systems are among the most stable chemical structures known and in combination with many other chemical groups, they can originate an extraordinary variety of molecules, with interesting chemical and physical properties. Many aromatic molecules have been applied for the purification of various biomolecules, such as proteins, carbohydrates and nucleic acids. Combining aromatic chromatography with optimized production, extraction and clarification procedures, can offer a number of advantages for pharmaceutical plasmid DNA (pDNA) purification. This review focuses on pDNA chromatographic purification and analysis using aromatic ligands. The goal is to give an updated view of all existing aromatic ligands, their main characteristics, applicability and technical features of the chromatographic methods in which they have been applied. Also, a critical assessment of each method is performed as well as a comparison of the different procedures, their key features and limitations. PMID- 24406143 TI - Avidity of influenza virus: model-based identification of adsorption kinetics from surface plasmon resonance experiments. AB - Affinity chromatography and membrane adsorption are highly promising methods for the downstream processing of cell culture-derived influenza virus. For the optimization of this separation process, it is desirable to quantify the kinetics of virus adsorption. For this reason, the adsorption kinetics of the influenza A virus (Puerto Rico/8/34 (H1N1)) on a surface with the immobilized ligand Euronymus europaeus lectin (EEL) was investigated. The adsorption kinetics was experimentally monitored in a microfluidic flow cell by surface plasmon resonance (SPR) spectroscopy. The boundary layer theory was applied to analyze the convective and diffusive mass transport of the virus particles in the SPR flow cell. A multi-site kinetic adsorption model was found to describe the experimentally recorded adsorption curves adequately. According to the proposed model, under the applied experimental conditions, the number of sites (galactose residuals) binding one single virus particle to the EEL surface is in the range of 300 to 460, which is in average about 4% of the total number of sites available on the virus surface. The avidity of individual virus particles to the EEL surface was estimated to be in the order of magnitude of 10(6)M(-1)s(-1). PMID- 24406144 TI - Development and evaluation of plunger-in-needle liquid-phase microextraction. AB - In this work, a novel, simple and fast one-step liquid-phase microextraction (LPME) approach, termed plunger-in-needle LPME was developed. In this method, the stainless steel plunger wire of a commercially available plunger-in-needle microsyringe was simply etched by immersion in hydrofluoric acid to form a microporous structure, and was used as the extractant solvent holder. The extractant solvent could be easily held within the pores created by the etching. When the plunger wire with the extractant solvent was exposed to the sample solution, analytes directly diffused from the sample solution to the solvent. After extraction, the plunger wire was directly introduced into the injection port of a gas chromatography-mass spectrometry (GC-MS) system for analysis of the analytes after thermal desorption. Polycyclic aromatic hydrocarbons (PAHs) were used as model analytes to evaluate the extraction performance of this new approach to LPME. Parameters affecting the extraction efficiency were investigated in detail. Under the optimized conditions, the method detection limits for 10PAHs were in the range of 0.003 and 0.136MUg/L (at a signal/noise ratio of 3), with relative standard deviations of between 2.9% and 9.6% on the same etched plunger wire. The linearities of the calibration plots were from 0.05 to 50 or from 1 to 50MUg/L, depending on the PAHs. When this method was applied for the spiked river water sample, the relative recoveries ranged from 70.1% to 106.4%. The proposed method integrates the extraction and extract introduction into one device, without extraneous sorbent needed, which makes the procedure fast and simple. It is also an environmentally friendly approach as the organic solvent consumed is almost negligible. PMID- 24406146 TI - Triptolide improves nerve regeneration and functional recovery following crush injury to rat sciatic nerve. AB - Recently, accumulating data have demonstrated that triptolide exhibits neurotrophic and neuroprotective properties. However, the role of triptolide in repair and regeneration of peripheral nerve injury (PNI) has rarely been performed. The current study was designed to observe the possible beneficial effect of triptolide on promoting peripheral nerve regeneration in rats. Rats with sciatic nerve crush injury were administered daily with triptolide for 7 days. Axonal regeneration was evaluated by morphometric analysis and Fluoro-gold retrograde tracing. Motor functional recovery was evaluated by walking track analysis, electrophysiological assessment and histological appearance of target muscles. Levels of pro-inflammatory cytokines within injured nerves were also determined. The results demonstrated that triptolide was capable of promoting peripheral nerve regeneration. Additionally, triptolide significantly decreased the levels of pro-inflammatory cytokines within injured nerves. These findings indicate the possibility of developing triptolide as a therapeutic agent for PNI. The neuroprotective effects of triptolide might be associated with its anti inflammatory properties. PMID- 24406147 TI - Enhancement of oscillatory activity in the endopiriform nucleus of rats raised under abnormal oral conditions. AB - Endopiriform nucleus (EPN) is located deep to the piriform cortex, and has neural connections with not only neighboring sensory areas but also subcortical areas where emotional and nociceptive information is processed. Well-balanced oral condition might play an important role in stability of brain activities. When the oral condition is impaired, several areas in the brain might be affected. In the present study, we investigated whether abnormal conditions of oral region influence neural activities in the EPN. Orthodontic appliance that generates continuous force and chronic pain-related stress was fixed to maxillary incisors of rats, and raised. Field potential recordings were made from the EPN of brain slices. We previously reported that the EPN has an ability to generate membrane potential oscillation. In the present study, we have applied the same methods to assess activities of neuron clusters in the EPN. In the case of normal rats, stable field potential oscillations were induced in the EPN by application of low frequency electrical stimulation under the medium with caffeine. In the case of rats with the orthodontic appliance, stable field potential oscillations were also induced, but both duration of oscillatory activities and wavelet number were increased. The enhanced oscillations were depressed by blockade of NMDA receptors. Thus, impairment of oral health under application of continuous orthodontic force and chronic pain-related stress enhanced neural activities in the EPN, in which up-regulation of NMDA receptors may be concerned. These findings suggest that the EPN might be involved in information processing with regard to abnormal conditions of oral region. PMID- 24406148 TI - Strain differences in stress-induced changes in central CRF1 receptor expression. AB - The Wistar Kyoto (WKY) rat is genetically predisposed to increased sensitivity to psychological and physical stressors. Evidence points towards the importance of corticotropin-releasing factor (CRF), a peptide secreted by the paraventricular nucleus of the hypothalamus, in this strain's aberrant response to stress. CRF binds to CRF1 and 2 receptors (CRFR1 and CRFR2) which are expressed in both hypothalamic and extra-hypothalamic brain regions. Phosphorylation of the signal transduction molecule, extracellular signal regulated kinase (ERK)1/2 has been linked with stress and the actions of CRF. Western blotting techniques were employed to examine changes in protein expression of CRFR1 and phosphorylated ERK1/2 in hypothalamic and extra-hypothalamic brain regions of open field stressed Sprague Dawley (SD) and WKY rats. Stress exposure resulted in increased hypothalamic ERK1/2 phosphorylation and subsequent increases in CRFR1 expression in SD but not WKY rats. In extra-hypothalamic brain regions, the stressor caused decreased or unchanged ERK 1/2 phosphorylation in both strains. A potentiated increase in CRFR1 expression was noted in the frontal cortex of WKY rats following the stressor and expression of CRFR1 was reduced in the hippocampus of WKY rats. These data demonstrate region-specific differences in stress-induced changes in expression of CRF receptors and intracellular signaling molecules in stress-sensitive WKY rats and stress-resilient SD rats. PMID- 24406145 TI - Perinatally acquired HIV infection in adolescents from sub-Saharan Africa: a review of emerging challenges. AB - Worldwide, more than three million children are infected with HIV, 90% of whom live in sub-Saharan Africa. As the HIV epidemic matures and antiretroviral treatment is scaled up, children with HIV are reaching adolescence in large numbers. The growing population of adolescents with perinatally acquired HIV infection living within this region presents not only unprecedented challenges but also opportunities to learn about the pathogenesis of HIV infection. In this Review, we discuss the changing epidemiology of paediatric HIV and the particular features of HIV infection in adolescents in sub-Saharan Africa. Longstanding HIV infection acquired when the immune system is not developed results in distinctive chronic clinical complications that cause severe morbidity. As well as dealing with chronic illness, HIV-infected adolescents have to confront psychosocial issues, maintain adherence to drugs, and learn to negotiate sexual relationships, while undergoing rapid physical and psychological development. Context-specific strategies for early identification of HIV infection in children and prompt linkage to care need to be developed. Clinical HIV care should integrate age appropriate sexual and reproductive health and psychological, educational, and social services. Health-care workers will need to be trained to recognise and manage the needs of these young people so that the increasing numbers of children surviving to adolescence can access quality care beyond specialist services at low-level health-care facilities. PMID- 24406149 TI - Sevoflurane induced amnesia inhibits hippocampal Arc expression partially through 5-hydroxytryptamine-7 receptors in the bilateral basolateral amygdala in rats. AB - This study aimed to investigate whether the regulation of 5-hydroxytryptamine-7 (5-HT7) receptors in the bilateral basolateral amygdala (BLA) could alter the amnesic effects of sevoflurane and change the hippocampal expression of Arc and neural apoptosis. Male Sprague-Dawley rats were randomized into ten groups. First, the animals received bilateral injection of SB269970 (20, 50, or 100 pmol/0.2 MUl) or saline (0.2 MUl) or AS-19 (2, 10, or 50 pmol/0.2 MUl), followed by inhalation of 2% sevoflurane or air for 2h. Then, fear conditioning training was carried out, and the percentage of freezing was detected 24h later. Furthermore, hippocampal Arc protein level and neural apoptosis were measured. Pre-training inhalation of sevoflurane reduced the extent of freezing, and hippocampal Arc expression. The largest dose of SB269970 (100 pmol) could block sevoflurane-induced amnesia and reverse the inhibitive effect of sevoflurane on Arc expression, while the maximal dose of AS-19 could exacerbate the amnesic effect, and further inhibit Arc expression. Furthermore, pre-training inhalation of 2% sevoflurane for 6h could not induce neural apoptosis in the hippocampus. The amnesic effect of sevoflurane might partly attribute to its impairment of memory formation in the hippocampus via activation of 5-HT7 receptors in the BLA. PMID- 24406150 TI - Autophagy-related gene16L2, a potential serum biomarker of multiple sclerosis evaluated by bead-based proteomic technology. AB - Multiple sclerosis (MS) is an autoimmune disease characterized by neuroinflammation and demyelination that are mediated by T cells. The prolonged survival of autoreactive T cells acts as a primary event to trigger an inflammatory cascade that mediates myelin loss and clinical relapse in MS. Recently, T cell survival has been shown to be modulated by the autophagy-related gene (Atg). In the present study, we performed bead fractionation/matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry analyses using serum from 54 MS patients and 55 healthy controls. Eleven peptides were significantly different between the two groups with one being identified as a fragment of Atg16L2. Then the decreased levels of Atg16L2 peptides in MS patients were validated by immunoblotting and real-time PCR. As the Atg12-Atg5.Atg16 multimeric complex plays an essential role in autophagy, our results suggest that Atg16L2 may play an important role in autophagy of T cells and serve as a potential biomarker to predict clinical relapse of MS. PMID- 24406151 TI - Melatonin, selective and non-selective MT1/MT2 receptors agonists: differential effects on the 24-h vigilance states. AB - Melatonin (MLT) is a neurohormone implicated in several physiological processes such as sleep. Contrasting results have been produced on whether or not it may act as a hypnotic agent, and the neurobiological mechanism through which it controls the vigilance states has not yet been elucidated. In this study we investigated the effect of MLT (40 mg/kg), a non-selective MT1/MT2 receptor agonist (UCM793, 40 mg/kg), and a selective MT2 partial agonist (UCM924, 40 mg/kg) on the 24-h vigilance states. EEG and EMG sleep-wake patterns were registered across the 24-h light-dark cycle in adult Sprague-Dawley male rats. MLT decreased (-37%) the latency to the first episode of non rapid eye movement sleep (NREMS), enhanced the power of NREMS delta band (+33%), but did not alter the duration of any of the three vigilance states. Differently, UCM793 increased the number of episodes (+52%) and decreased the length of the episodes (-38%) of wakefulness but did not alter the 24-h duration of wakefulness, NREMS and REMS. UCM924 instead reduced the latency (-56%) and increased (+31%) the duration of NREMS. Moreover, it raised the number of REMS episodes (+57%) but did not affect REMS duration. Taken together, these findings show that MLT and non-selective MT1/MT2 receptor agonists do not increase the quantity of sleep but differently influence the three vigilance states. In addition, they support the evidence that selective MT2 receptor agonists increase NREMS duration compared to MLT and non selective MT1/MT2 agonists. PMID- 24406152 TI - An evidence for lack of pseudoneglect in patients with schizophrenia: an ERP study. AB - Studies have reported an altered expression of pseudoneglect in patients with schizophrenia, but no study has examined pseudoneglect in schizophrenia at the neural level. We investigated pseudoneglect using the visual P3 event-related potential and the mental number bisection (MNB) task in 21 patients and 25 controls. Using an oddball task, participants were asked to discriminate an infrequent ('one' or 'nine') from a frequent written number ('five'). The P3 ERP components were delayed to the targets on the right of the MNL ('nine') compared to the targets on the left ('one') in controls. The effect of number magnitude on the P3 latency was not observed in the patients. In MNB task, the patients did not show the normal leftward bias observed in healthy individuals. Our findings indicate a lack of pseudoneglect and the presence of an anomalous brain asymmetry in schizophrenia. PMID- 24406153 TI - The dual role of astrocyte activation and reactive gliosis. AB - Astrocyte activation and reactive gliosis accompany most of the pathologies in the brain, spinal cord, and retina. Reactive gliosis has been described as constitutive, graded, multi-stage, and evolutionary conserved defensive astroglial reaction [Verkhratsky and Butt (2013) In: Glial Physiology and Pathophysiology]. A well- known feature of astrocyte activation and reactive gliosis are the increased production of intermediate filament proteins (also known as nanofilament proteins) and remodeling of the intermediate filament system of astrocytes. Activation of astrocytes is associated with changes in the expression of many genes and characteristic morphological hallmarks, and has important functional consequences in situations such as stroke, trauma, epilepsy, Alzheimer's disease (AD), and other neurodegenerative diseases. The impact of astrocyte activation and reactive gliosis on the pathogenesis of different neurological disorders is not yet fully understood but the available experimental evidence points to many beneficial aspects of astrocyte activation and reactive gliosis that range from isolation and sequestration of the affected region of the central nervous system (CNS) from the neighboring tissue that limits the lesion size to active neuroprotection and regulation of the CNS homeostasis in times of acute ischemic, osmotic, or other kinds of stress. The available experimental data from selected CNS pathologies suggest that if not resolved in time, reactive gliosis can exert inhibitory effects on several aspects of neuroplasticity and CNS regeneration and thus might become a target for future therapeutic interventions. PMID- 24406154 TI - The interaction between tropomyosin-related kinase B receptors and serine kinases modulates acetylcholine release in adult neuromuscular junctions. AB - We conducted an electrophysiological study of the functional link between the tropomyosin-related kinase B (trkB) receptor signaling mechanism and serine threonine kinases, both protein kinase C (PKC) and protein kinase A (PKA). We describe their coordinated role in transmitter release at the neuromuscular junction (NMJ) of the Levator auris longus muscle of the adult mouse. The trkB receptor normally seems to be coupled to stimulate ACh release because inhibiting the trkB receptor with K-252a results in a significant reduction in the size of EPPs. We found that the intracellular PKC pathway can operate as in basal conditions (to potentiate ACh release) without the involvement of the trkB receptor function, although the trkB pathway needs an operative PKC pathway if it is to couple to the release mechanism and potentiate it. To actively stimulate PKA (which also results in ACh release potentiation), the operativity of trkB is a necessary condition, and one effect of trkB may be PKA stimulation. PMID- 24406155 TI - The effects of circulating testosterone and pubertal maturation on risk for disordered eating symptoms in adolescent males. AB - BACKGROUND: Testosterone may be a biological factor that protects males against eating disorders. Elevated prenatal testosterone exposure is linked to lower levels of disordered eating symptoms, but effects emerge only after mid-puberty. Whether circulating levels of testosterone account for decreased risk for disordered eating in boys after mid-puberty is currently unknown; however, animal data support this possibility. In rodents, prenatal testosterone's masculinizing effects on sex-differentiated behaviors emerge during puberty when circulating levels of testosterone increase and 'activate' the expression of masculinized phenotypes. This study investigated whether higher levels of circulating testosterone predict lower levels of disordered eating symptoms in adolescent boys, and in particular whether effects are associated with advancing pubertal maturation. METHOD: Participants were 213 male twins from the Michigan State University Twin Registry. The Minnesota Eating Behavior Survey and Eating Disorder Examination Questionnaire assessed several disordered eating symptoms. The Pubertal Development Scale assessed pubertal status. Afternoon saliva samples were assayed for testosterone using enzyme immunoassays. RESULTS: Consistent with animal data, higher levels of circulating testosterone predicted lower levels of disordered eating symptoms in adolescent boys and effects emerged with advancing puberty. Results were not accounted for by several important covariates, including age, adiposity, or mood/anxiety symptoms. CONCLUSIONS: Findings suggest that elevated circulating testosterone may be protective and underlie decreased risk for eating pathology in males during/after puberty, whereas lower levels of testosterone may increase risk and explain why some, albeit relatively few, males develop eating disorders. PMID- 24406158 TI - Effect of bioaugmentation to enhance phytoremediation for removal of phenanthrene and pyrene from soil with Sorghum and Onobrychis sativa. AB - The use of plants to remove Poly-aromatic-hydrocarbons (PAHs) from soil (phytoremediation) is emerging as a cost-effective method. Phytoremediation of contaminated soils can be promoted by the use of adding microorganisms with the potential of pollution biodegradation (bioaugmentation). In the present work, the effect of bacterial consortium was studied on the capability of Sorghum and Onobrychis sativa for the phytoremediation of soils contaminated with phenanthrene and pyrene. 1.5 kg of the contaminated soil in the ratio of 100 and 300 mg phenanthrene and/or pyrene per kg of dry soil was then transferred into each pot (nine modes). The removal efficiency of natural, phytoremediation and bioaugmentation, separately and combined, were evaluated. The samples were kept under field conditions, and the remaining concentrations of pyrene and phenanthrene were determined after 120 days. The rhizosphere as well as the microbial population of the soil was also determined. Results indicated that both plants were able to significantly remove pyrene and phenanthrene from the contaminated soil samples. Phytoremediation alone had the removal efficiency of about 63% and 74.5% for pyrene and phenanthrene respectively. In the combined mode, the removal efficiency dramatically increased, leading to pyrene and phenanthrene removal efficiencies of 74.1% and 85.02% for Onobrychis sativa and 73.84% and 85.2% for sorghum, respectively. According to the results from the present work, it can be concluded that Onobrychis sativa and sorghum are both efficient in removing pyrene and phenanthrene from contamination and bioaugmentation can significantly enhance the phytoremediation of soils contaminated with pyrene and phenanthrene by 22% and 16% respectively. PMID- 24406157 TI - Broad-based visual benefits from training with an integrated perceptual-learning video game. AB - Perception is the window through which we understand all information about our environment, and therefore deficits in perception due to disease, injury, stroke or aging can have significant negative impacts on individuals' lives. Research in the field of perceptual learning has demonstrated that vision can be improved in both normally seeing and visually impaired individuals, however, a limitation of most perceptual learning approaches is their emphasis on isolating particular mechanisms. In the current study, we adopted an integrative approach where the goal is not to achieve highly specific learning but instead to achieve general improvements to vision. We combined multiple perceptual learning approaches that have individually contributed to increasing the speed, magnitude and generality of learning into a perceptual-learning based video-game. Our results demonstrate broad-based benefits of vision in a healthy adult population. Transfer from the game includes; improvements in acuity (measured with self-paced standard eye charts), improvement along the full contrast sensitivity function, and improvements in peripheral acuity and contrast thresholds. The use of this type of this custom video game framework built up from psychophysical approaches takes advantage of the benefits found from video game training while maintaining a tight link to psychophysical designs that enable understanding of mechanisms of perceptual learning and has great potential both as a scientific tool and as therapy to help improve vision. PMID- 24406159 TI - AKR1B10, a good prognostic indicator in gastric cancer. AB - BACKGROUND AND OBJECTIVES: The aim of the study was to investigate the correlation between AKR1B10 expression and clinicopathological features of gastric cancer (GC). METHODS: Real-time polymerase chain reaction (RT-PCR) was performed to determine AKR1B10 mRNA expression. AKR1B10 protein levels were measured by immunohistochemistry. RESULTS: RT-PCR analysis confirmed that AKR1B10 was significantly down-regulated in gastric cancer compared with paired, normal mucosa. Immunohistochemistry revealed that the percentage of AKR1B10-positive specimens was lower in gastric carcinoma compared with normal specimens. The frequency of AKR1B10-positive GC specimens was higher in patients with tumor size <5 cm, no lymph node metastasis, no distant metastasis and lower tumor stages The mean survival time for patients in the AKR1B10-positive group was significantly higher compared with the AKR1B1-negative group. The 5-year survival rate for the AKR1B10-positive group was also significantly higher than for the AKR1B1-negative group. Cox regression analysis revealed that AKR1B10 expression is an independent prognostic factor of GC. CONCLUSIONS: Expression of AKR1B10 in gastric cancer was significantly associated with tumor size, lymph node metastasis, distance metastasis and TNM stage, and AKR1B10 may be a good prognostic indicator in gastric cancer. PMID- 24406160 TI - Inhibition of lysine-specific demethylase 1 by the acyclic diterpenoid geranylgeranoic acid and its derivatives. AB - Lysine-specific demethylase 1 (LSD1) is upregulated in many cancers, especially neuroblastoma. We set out to explore whether geranylgeranoic acid (GGA) inhibits LSD1 activity by using recombinant human LSD1. GGA inhibited LSD1 activity with IC50 similar to that of the clinically used drug tranylcypromine. In human neuroblastoma SH-SY5Y cells, GGA induced NTRK2 gene expression alongside upregulation of histone H3 with dimethylated lysine-4 in the regulatory regions of the NTRK2 gene. Dihydrogenation of GGA reinforced the LSD1-inhibitory effect in a position-dependent manner. The inhibitory effects of dihydro-derivatives of GGA on recombinant LSD1 strongly correlated with the induction of NTRK2 gene expression in SH-SY5Y cells. These data demonstrate for the first time the efficient LSD1-inhibitor activity of GGA and its derivatives, providing a novel prospect of preventing cancer onset by using GGA to regulate epigenetic modification. PMID- 24406161 TI - Mitochondria are required for ATM activation by extranuclear oxidative stress in cultured human hepatoblastoma cell line Hep G2 cells. AB - Ataxia-telangiectasia mutated (ATM) is a serine/threonine protein kinase that plays a central role in DNA damage response (DDR). A recent study reported that oxidized ATM can be active in the absence of DDR. However, the issue of where ATM is activated by oxidative stress remains unclear. Regarding the localization of ATM, two possible locations, namely, mitochondria and peroxisomes are possible. We report herein that ATM can be activated when exposed to hydrogen peroxide without inducing nuclear DDR in Hep G2 cells, and the oxidized cells could be subjected to subcellular fractionation. The first detergent-based fractionation experiment revealed that active, phosphorylated ATM was located in the second fraction, which also contained both mitochondria and peroxisomes. An alternative fractionation method involving homogenization and differential centrifugation, which permits the light membrane fraction containing peroxisomes to be produced, but not mitochondria, revealed that the light membrane fraction contained only traces of ATM. In contrast, the heavy membrane fraction, which mainly contained mitochondrial components, was enriched in ATM and active ATM, suggesting that the oxidative activation of ATM occurs in mitochondria and not in peroxisomes. In Rho 0-Hep G2 cells, which lack mitochondrial DNA and functional mitochondria, ATM failed to respond to hydrogen peroxide, indicating that mitochondria are required for the oxidative activation of ATM. These findings strongly suggest that ATM can be activated in response to oxidative stress in mitochondria and that this occurs in a DDR-independent manner. PMID- 24406163 TI - The novel steroidal alkaloids dendrogenin A and B promote proliferation of adult neural stem cells. AB - Dendrogenin A (DDA) and dendrogenin B (DDB) are new aminoalkyl oxysterols which display re-differentiation of tumor cells of neuronal origin at nanomolar concentrations. We analyzed the influence of dendrogenins on adult mice neural stem cell proliferation, sphere formation and differentiation. DDA and DDB were found to have potent proliferative effects in neural stem cells. Additionally, they induce neuronal outgrowth from neurospheres during in vitro cultivation. Taken together, our results demonstrate a novel role for dendrogenins A and B in neural stem cell proliferation and differentiation which further increases their likely importance to compensate for neuronal cell loss in the brain. PMID- 24406162 TI - The ABCA1 domain responsible for interaction with HIV-1 Nef is conformational and not linear. AB - HIV-1 Nef is an accessory protein responsible for inactivation of a number of host cell proteins essential for anti-viral immune responses. In most cases, Nef binds to the target protein and directs it to a degradation pathway. Our previous studies demonstrated that Nef impairs activity of the cellular cholesterol transporter, ABCA1, and that Nef interacts with ABCA1. Mutation of the (2226)DDDHLK motif in the C-terminal cytoplasmic tail of ABCA1 disrupted interaction with Nef. Here, we tested Nef interaction with the ABCA1 C-terminal cytoplasmic fragment using yeast 2-hybrid system assay and co-immunoprecipitation analysis in human cells. Surprisingly, analysis in a yeast 2-hybrid system did not reveal any interaction between Nef and the C-terminal cytoplasmic fragment of ABCA1. Using co-immunoprecipitation from HEK 293T cells expressing these polypeptides, only a very weak interaction could be detected. The (2226)DDDHLK motif in the C-terminal cytoplasmic tail of ABCA1 found previously to be essential for interaction between ABCA1 and Nef is insufficient to bestow strong binding to Nef. Molecular modeling suggested that interaction with Nef may be mediated by a conformational epitope composed of the sequences within the cytoplasmic loop of ABCA1 and the C-terminal cytoplasmic domain. Studies are now underway to characterize this epitope. PMID- 24406164 TI - Long-term electrophysiological activity and pharmacological response of a human induced pluripotent stem cell-derived neuron and astrocyte co-culture. AB - Human induced pluripotent stem cell (hiPSC)-derived neurons may be effectively used for drug discovery and cell-based therapy. However, the immaturity of cultured human iPSC-derived neurons and the lack of established functional evaluation methods are problematic. We here used a multi-electrode array (MEA) system to investigate the effects of the co-culture of rat astrocytes with hiPSC derived neurons on the long-term culture, spontaneous firing activity, and drug responsiveness effects. The co-culture facilitated the long-term culture of hiPSC derived neurons for >3 months and long-term spontaneous firing activity was also observed. After >3 months of culture, we observed synchronous burst firing activity due to synapse transmission within neuronal networks. Compared with rat neurons, hiPSC-derived neurons required longer time to mature functionally. Furthermore, addition of the synapse antagonists bicuculline and 6-cyano-7 nitroquinoxaline-2,3-dione induced significant changes in the firing rate. In conclusion, we used a MEA system to demonstrate that the co-culture of hiPSC derived neurons with rat astrocytes is an effective method for studying the function of human neuronal cells, which could be used for drug screening. PMID- 24406165 TI - Sportomics: building a new concept in metabolic studies and exercise science. AB - For more than a decade, we have used alternative approaches to understand metabolic responses to physical stress. In addition to classic laboratory studies (cell and animal models), we have used elite athletes and sports to examine metabolic stress. Our central question involves the ability of the body to protect the central nervous system from high and toxic ammonemia during acute and chronic exercise. Information about this problem can aid in understanding important signaling pathways, which may yield better ways to protect people who suffer from diseases that lead to hyperammonemia, such as liver failure, or to hypermetabolic states, such as cancer or thermal injury. We proposed a Sportomics approach to mimic the real challenges and conditions that are faced during sports training and competition. Sportomics is non-hypothesis-driven research on an individual's metabolite changes during sports and exercise. It is similar to metabolomics and other "-omics" approaches, but Sportomics focuses on sports as a metabolic challenge. Our study is holistic and top-down; we treat the data systematically and have generated a large computer-searchable database. We also propose that in-field metabolic analyses are important for understanding, supporting and training elite athletes. In this review, we discuss Sportomics history, problems, benefits and results. We included different weather conditions, such as temperature, wind and humidity, and diverse metabolic responses due to uneven sleep and eating behaviors near the time of the experiment. We are currently generating databases as well as data-mining principles and procedures to improve metabolomics and proteomics studies as well as adding genomics and transcriptomics studies to the Sportomics approach. We believe that this approach can fill a methodological gap between systems biology and translational medicine similar as a bench to the field approach. PMID- 24406166 TI - Bile acid synthesis precursors in familial combined hyperlipidemia: the oxysterols 24S-hydroxycholesterol and 27-hydroxycholesterol. AB - Familial combined hyperlipidemia (FCHL), the most common inherited disorder of lipid metabolism is characterized by increasing cholesterol synthesis precursors due to hepatic overproduction of cholesterol. The bile acids synthesis pathway has not been previously studied in FCHL. The aim of this work was to study the oxysterol levels which are involved in the bile acids synthesis from cholesterol in FCHL. Clinical parameters and subclinical atherosclerosis were studied in a total of 107 FCHL patients and 126 normolipidemic controls. Non cholesterol sterols (desmosterol and lanosterol) and oxysterols (27-hydroxycholesterol and 24S-hydroxycholesterol) were measured by high performance liquid chromatography tandem mass spectrometry. Desmosterol and lanosterol, markers of cholesterol synthesis, had a positive correlation with BMI and apo B. However, no correlation was found for 24S-hydroxycholesterol and 27-hydroxycholesterol, precursors of bile acids, with these clinical parameters. Only 27-hydroxycholesterol had a positive correlation with apo B, rho=0.204 (P=0.037). All oxysterol levels were higher in FHCL as compared to normal controls. A total of 59 FCHL subjects (59%) presented values of 24S-hydroxycholesterol above the 95th percentile of this oxysterol in the control population. All oxysterols showed no association with fat mass in contrast with non-cholesterol sterols. FCHL subjects with oxysterol overproduction had less carotid intima media thickness (cIMT), which suggests less atherosclerosis in these subjects. In summary, our data indicate that high oxysterol levels might be good markers of FCHL, unrelated to fat mass, and may exert a protective mechanism for cholesterol accumulation. PMID- 24406168 TI - Regulation of mIkappaBNS stability through PEST-mediated degradation by proteasome. AB - Negative regulatory proteins in a cytokine signaling play a critical role in restricting unwanted excess activation of the signaling pathway. At the same time, negative regulatory proteins need to be removed rapidly from cells to respond properly to the next incoming signal. A nuclear IkappaB protein called IkappaBNS is known to inhibit a subset of NF-kappaB target genes upon its expression by NF-kappaB activation. Here, we show a mechanism to control the stability of mIkappaBNS which might be important for cells to prepare the next round signaling. We found that mIkappaBNS is a short-lived protein of which the stability is controlled by proteasome, independent of ubiquitylation process. We identified that the N-terminal PEST sequence in mIkappaBNS was critical for the regulation of stability. PMID- 24406167 TI - Direct interaction between EFL1 and SBDS is mediated by an intrinsically disordered insertion domain. AB - Removal of anti-association factor, Tif6 (eIF6), by elongation factor-like 1 (EFL1) and Shwachman-Bodian-Diamond syndrome (SBDS) protein is a critical step in the late stage of ribosome maturation. Although EFL1 is known to have GTPase activity that is stimulated by SBDS, how they cooperatively trigger dissociation of Tif6 from the ribosome remains to be elucidated. In the present study, the interaction between EFL1 and SBDS was analyzed by size exclusion chromatography, gel shift assay, and isothermal titration calorimetry (ITC). The results showed that EFL1 interacted directly with SBDS. ITC experiments using domain-truncated mutants showed that the interaction between EFL1 and SBDS is governed by the insertion domain of EFL1 and domains II-III of SBDS. Circular dichroism spectroscopy showed that the insertion domain of EFL1 has a random structure in the absence of SBDS, whereas the disadvantageous entropy change observed on ITC suggested a fixed conformation coupled with complex formation with SBDS. Based on these observations together with those reported previously, we propose roles of EFL1 and SBDS in ribosomal maturation. PMID- 24406169 TI - PCDH10 is required for the tumorigenicity of glioblastoma cells. AB - Protocadherin10 (PCDH10)/OL-protocadherin is a cadherin-related transmembrane protein that has multiple roles in the brain, including facilitating specific cell-cell connections, cell migration and axon guidance. It has recently been reported that PCDH10 functions as a tumor suppressor and that its overexpression inhibits proliferation or invasion of multiple tumor cells. However, the function of PCDH10 in glioblastoma cells has not been elucidated. In contrast to previous reports on other tumors, we show here that suppression of the expression of PCDH10 by RNA interference (RNAi) induces the growth arrest and apoptosis of glioblastoma cells in vitro. Furthermore, we demonstrate that knockdown of PCDH10 inhibits the growth of glioblastoma cells xenografted into immunocompromised mice. These results suggest that PCDH10 is required for the proliferation and tumorigenicity of glioblastoma cells. We speculate that PCDH10 may be a promising target for the therapy of glioblastoma. PMID- 24406171 TI - Boosting response inhibition neural network with rTMS may improve dyskinesias in Parkinson's disease. PMID- 24406172 TI - Feeding associated neonatal necrotizing enterocolitis (Primary NEC) is an inflammatory bowel disease. AB - Neonatal necrotizing enterocolitis which develops after feeding preterm infants is characterized by severe intestinal inflammation and profound systemic metabolic acidosis. The fermentation of undigested dietary carbohydrate by colonic flora yields gases (CO2 and H2) and short chain organic acids. These organic acids can disrupt the intestinal mucosa and initiate inflammation driven predominantly by resident mast cells and by granulocytes which are recruited from blood. A systemic acidosis ensues derived from intestinal acids, not classic lactic acidosis produced from anaerobic metabolism. The systemic acidosis further compromises inflamed bowel leading to bowel necrosis. PMID- 24406170 TI - PeptiSite: a structural database of peptide binding sites in 4D. AB - We developed PeptiSite, a comprehensive and reliable database of biologically and structurally characterized peptide-binding sites, in which each site is represented by an ensemble of its complexes with protein, peptide and small molecule partners. The unique features of the database include: (1) the ensemble site representation that provides a fourth dimension to the otherwise three dimensional data, (2) comprehensive characterization of the binding site architecture that may consist of a multimeric protein assembly with cofactors and metal ions and (3) analysis of consensus interaction motifs within the ensembles and identification of conserved determinants of these interactions. Currently the database contains 585 proteins with 650 peptide-binding sites. http://peptisite.ucsd.edu/ link allows searching for the sites of interest and interactive visualization of the ensembles using the ActiveICM web-browser plugin. This structural database for protein-peptide interactions enables understanding of structural principles of these interactions and may assist the development of an efficient peptide docking benchmark. PMID- 24406173 TI - [Facial nerve function and hearing preservation experience in middle fossa approach removal of small acoustic tumor surgery]. AB - OBJECTIVE: The aim of this study was to investigate the hearing and facial nerve preservation in the middle fossa approach surgery for the removal of small acoustic tumor (vestibular schwannomas, VS). METHODS: A prospective database was established, and data were retrospectively reviewed. Between January 2004 and February 2013, 13 patients with acoustic tumor underwent surgery via middle fossa approach for hearing preservation. The patients consisted of six men and seven women with a mean age of 48 years. Tumor size ranged from 0.8 cm to 1.5 cm. Hearing loss was categorized as American Academy of Otolaryngology Head and Neck Surgery (AAO-HNS) class A, class B, class C and class D. Facial nerve function was evaluated according to House-Brackmann (HB) Grade I-VI. RESULTS: Gross-total resection was accomplished in 12 of 13 patients. Preoperative hearing as class A in ten, class B in two, and class C in one patient respectively. Postoperatively, hearing was graded as class A in eight patients, class B in 3, and class C in 2 patients. Facial nerve function was House-Brackmann (HB) grade I in twelve patients, grade II in one patient preoperatively. Postoperatively, facial nerve function was HB Grade I in twelve patients and Grade III in one patient. The overall hearing preservation rate was at least 80% (8/10) and HB Grade I facial nerve outcome of 100% (12/12) . All cases were followed up for 0.5 to 5 years, no complications were observed. CONCLUSIONS: The middle fossa approach for the resection of small VS with hearing preservation is a viable and relatively option. It should be considered among the various options available for the management of small and growing VS. PMID- 24406174 TI - [Prevention and treatment of skin complications following BAHA implantation]. AB - OBJECTIVE: To discuss the skin complications of 16 cases received bone-anchored hearing aid (BAHA) implantations, and the clinical experience for prevention and treatment skin complications following BAHA. METHODS: Retrospective review 16 patients who received BAHA implantation from December 2010 to March 2013, and summarize the complications and treatment. RESULTS: Four patients (1/4) suffered from skin complications. According to Holgers classification, two patients (1/8) had a Holgers Grade 1-2 skin reaction and cured by local application of antibiotics. Two patients (1/8) experienced Holgers Grade 3 skin reaction received revision surgeries for excessive soft tissue growth. One patient replaced the BAHA abutment with a longer 9.0mm one. CONCLUSIONS: Infection and skin overgrowth around the abutment was the common complications of BAHA implantation. Standardize the peri-operative managements, and clean the skin regularly would prevent the skin complication. Additional surgical intervention should be applied timely in the cases of severe complications. PMID- 24406175 TI - [Removal of Schwannoma in the pterygopalatine and infratemporal fossa via endoscopic prelacrimal recess approach]. AB - OBJECTIVE: To sum up and analyze the results of surgical removal of Schwannoma in the pterygopalatine and infratemporal fossa (PPF and ITF) through postero-lateral wall via prelacrimal recess approach (PLRA). The surgical technique and indications were presented and discussed. METHODS: Six patients aged from 29-59 year-old with Schwannoma in the PPF and ITF, who received the tumor resection via PLRA under endoscope, were enrolled in this paper. Three were female and 3 were male. All of them received preoperative CT and MRI. The PPF and ITF were approached via prelacrimal recess endoscopically under general anesthesia. Schwannoma was histopathologically confirmed after surgery. The postoperative periodical CT and MRI follow up was conducted. RESULTS: The tumors were removed completely in these 6 patients. No recurrence was found during 19.3 months follow up on the average. Three patients had obvious numbness in the V2 innervation area 1 or 2 weeks after operation and disappeared afterwards. Only 1 patient had mild altercation numbness at the end of follow up. CONCLUSIONS: Schwannoma involved PPF and ITF can be removed endoscopically via PLRA. The lateral wall of nasal cavity might be kept intact. It is a novel minimally transnasal invasive approach to PPF and ITF with less damage and complications. PMID- 24406176 TI - [Early experience of resection of meningiomas in anterior skull base with intra extracranial extension via a pure endoscopic endonasal approach]. AB - OBJECTIVE: The early experience of treating anterior skull base meningiomas with intra-extracranial extension via pure endoscopic endonasal approach (EEA) was presented, the safety, feasibility and preliminary treatment outcomes were investigated. METHODS: Eight patients with intra-extradural meningiomas who were admitted from October 2006 to October 2010 were operated on via EEA in one stage in Xuanwu hospital. In this study, the operative technique was described, the degree of resection, complications and the early clinical outcomes were discussed. RESULTS: The complete resection of meningiomas with intra-extracranial extension was achieved in all patients using EEA in one stage. Preoperative visual symptoms were improved or resolved in all cases who presented with preoperative visual complaints. No patient in our series experienced a new neurological deficit after surgery or recurrence and death related meningiomas in the follow-up period (33-75 months). One patient experienced postoperative cerebrospinal fluid leak, delayed meningitis and secondary hydrocephalus which responded to therapy. After treatment, the patient was cure. CONCLUSION: Our limited experience indicates that EEA is feasible and safe for the complete resection of anterior skull base meningiomas with intra- and extracranial extension in one stage in selected cases. PMID- 24406177 TI - [Nasal cavity computer fluid dynamics analysis on 60 healthy Chinese adults]. AB - OBJECTIVES: To investigate the aerodynamics characteristics of nasal cavity in inspiration phase from 60 healthy Chinese people and provide the reference values for future computational fluid dynamics (CFD) research. METHODS: CFD was used for numerical simulation. The indices of main airflow passage, total nasal airway resistance, maximal velocity, maximal wall shear stress, nasal mucosa area, nasal volume and surface area-to-volume ratio were extracted from CFD analysis results. SPSS 16.0 software was used to analyze the data. RESULTS: The main airflow passage in nasal cavity was common meatus, the mean total nasal airway resistance was (0.211 +/- 0.085) kPa.s.L(-1), the mean maximal velocity was (12.01 +/- 2.79) m/s, the mean maximal wall shear stress was (2.50 +/- 0.89) Pa, the mean nasal mucosa area was (161.2 +/- 34.7) mm(2), the mean nasal volume was (31.7 +/- 8.1) ml and the mean surface area-to-volume ratio was (0.58 +/- 0.09) mm(-1). No significant difference was detected in aerodynamics indices between male and female people. CONCLUSIONS: The main airflow passage is located in common meatus. The nasal valve area is the key constrictive plane in nasal cavity. There are no gender differences of main airflow characteristics in nasal cavity. The normal ranges of aerodynamics indices could be used for reference values for future CFD research. PMID- 24406178 TI - [Clinical application of modified endoscopic thyroidectomy]. AB - OBJECTIVE: To compare clinical outcomes of endoscopic thyroidectomy via mammary areola approach and conventional via chest wall and breasts approach. METHODS: A total of 480 cases undergoing endoscopic thyroidectomy for thyroid nodules between September 2002 and September 2012 were reviewed, including 280 cases via the chest wall and breasts approach between September 2002 and August 2009 and 190 cases via mammary areola approach between September 2002 and September 2012. The mean operation time, the location and diameter of the puncture pore, intraoperative bleeding volume, the mean hospital stay after surgery, postoperative pain score scaled by visual analog scores (VAS) were compared between groups. After 3-month follow-up, long term post-surgical complications, the recurrence rates of nodules and scar cosmetic satisfaction evaluation were also compared. Statistical methods including chi(2) test, Students' test and ANOVA analysis were applied. RESULTS: Two groups were followed for 12 months. The differences between groups were statistically obvious in variables of diameters of the puncture pore (15.5 mm +/- 4.9 mm vs. 20.6 mm +/- 7.6 mm, t = 2.42, P = 0.046) , intraoperative bleeding volume (16.2 ml +/- 4.5 ml vs. 30.5 ml +/- 11.4 ml, t = 2.53, P = 0.032) , pain score on the first day after operation (1.5 +/- 0.4) and (1.0 +/- 0.2), (t = 4.68, P = 0.020) , scar cosmetic satisfaction evaluation 3 months after operation (chi(2) = 6.20, P < 0.05) , chest wall numbness (0 vs. 72.4%,chi(2) = 380, P = 0.000) . But there were no significant differences in the mean operation time, the mean hospital stay after surgery, and the recurrence rates of nodules between two groups. CONCLUSION: Minimally invasive endoscopic thyroidectomy via mammary areola approach is a safe and effective method for the surgery of thyroid nodules with good aesthetic outcome. PMID- 24406179 TI - [Primary mechanism of the role of dual oxidase-1 causing airway allergic diseases in human bronchial epithelium]. AB - OBJECTIVE: To investigate the role of dual oxidase-1 (DUOX-1) inducing airway hyperresponsiveness in human bronchial epithelium. METHODS: The human bronchial epithelial cells were divided into several groups: control group, tumor necrosis factor-alpha (TNF-alpha) group, methyl-beta-cyclodextrin (M-beta-CD)+TNF-alpha group, desipramine (DES)+ TNF-alpha group, diphenylene iodonium (DPI) + TNF-alpha group and apocynin (APO)+TNF-alpha group. Fractionation was performed by sucrose gradient centrifugation and the protein DUOX-1 was measured by western blotting. The lipid raft clusters and its colocalization with DUOX-1 were confocal analysed. The intracellular reactive oxygen species (ROS) accumulation was measured by fluorescence of reactive oxygen probe of intracellular measurement. Sigmastat 3.02 software was used to analyze the data. RESULTS: (1) Detection of ROS, control group: 1.00 +/- 0.00; TNF-alpha group: 1.95 +/- 0.16; M-beta-CD+TNF alpha group: 0.91 +/- 0.16; DES+TNF-alpha group: 1.49 +/- 0.20; DPI+TNF-alpha group: 1.03 +/- 0.16; APO+TNF-alpha group: 1.47 +/- 0.26. The difference was statistically significant (F = 3.83, P < 0.05). (2) Extracts in rafts to lipid rafts region represents the ratio of total protein, protein content DUOX-1 each group, control group: 0.21 +/- 0.02; TNF-alpha group: 0.49 +/- 0.04; M-beta CD+TNF-alpha group: 0.08 +/- 0.02; DES+TNF-alpha group: 0.09 +/- 0.03; the difference was statistically significant (F = 3.96, P < 0.05). (3) DUOX-1 protein fluorescence values, control group: 1.72 +/- 0.21; TNF-alpha group: 8.11 +/- 1.23; M-beta-CD+TNF-alpha group: 1.51 +/- 0.32; DES+TNF-alpha group: 1.43 +/- 0.11; the difference was statistically significant (F = 4.87, P < 0.05). (4) DUOX 1 gene detection, control group: 1.00 +/- 0.00 ScrRNA+TNF-alpha group: 1.75 +/- 0.04; DUOX-1siRNA+TNF-alphagroup: 1.15 +/- 0.02; the difference was statistically significant (F = 4.19, P < 0.05). CONCLUSION: TNF-alpha can induce DUOX-1 expression increasing in lipid raft, then the DUOX-1 can be activated to increase reactive oxygen species level; acidic sphingomyelinase inhibitor desipramine can inhibit this process, the results disclose that the process will depend on the ceramide of lipid raft. PMID- 24406180 TI - [Clinical observation of placement of tympanostomy microtube to treat middle ear atelectasis]. AB - OBJECTIVE: To investigate the treatment efficacy of tympanostomy microtube placement surgery for middle ear atelectasis. METHODS: A retrospective analysis was conducted on 26 patients (28 ears) with middle ear atelectasis, who complained fullness or pressure in the ears.Otoscope showed tympanic membrane invagination, scattered or disappeared cone of light, tympanic membrane was pale and dull. The pure tone audiometry air-bone gap >10 dB. Acoustic immittance showed tympanic negative pressure. All the ears had atelectasis of I-III grade. Patients were performed tympanic membrane microtube placement under local anesthesia, and were followed up for 6-12 months. RESULTS: Twenty-five ears recovered from the fullness after operation, in which, 23 ears reverted from type "C" to type "A" in acoustic immittance tests and the pure-tone average (PTA) of hearing thresholds were decreasing from 5 to 20 dB, while 2 ears relapse after removal of the microtube. Three ears with middle ear atelectasis of III grade were ineffectiveness. All the 26 cases had no complications including middle ear infection, tympanosclerosis, and permanent perforation after removal of the microtubes. CONCLUSIONS: The placement of tympanostomy microtube can be used to treat middle ear atelectasis, especially to the patients with middle ear atelectasis of I-II grade as it is effective on elimination of middle ear negative pressure and remission of fullness. PMID- 24406181 TI - [Comparison of recurrence and complication by different thyroidectomy in the treatment of differentiated thyroid carcinoma as initial treatment: a meta analysis]. AB - OBJECTIVE: To compare the total thyroidectomy or subtotal resection and gland lobe and isthmus lobectomy as initial treatment to TNM stage I and II differentiated thyroid cancer. The difference between recurrence rate and surgical complications were analysed. METHODS: The literatures published between 1972-2012 were searched in Pubmed, Medline, Wanfang database, Chinese Biomedical Literature Database, Chinese scientific Journals database and China National Knowledge Infrastructure. According to the inclusion and deletion criteria, 17 articles were included to compare the postoperative recurrence and complications in randomized controlled or case-control studies, involving 13 articles in recurrence rate and 11 articles in complications.RevMan5.0 software package was used to perform meta-analysis. RESULTS: Thirteen articles involved with the recurrence rate, the total case number was 3511. Among these cases, 414 recurred, overall recurrence rate was 11.59%, of which, 150 recurred cases in total or subtotal resection group (experimental group), the recurrence rate was 6.51%; 264 recurred cases in gland lobe lobectomy plus isthmus group (control group), the recurrence rate was 21.83%. Comparing the two groups, the odds ratio (OR) and their 95% confidence interval (95%CI) was 0.26 [0.21,0.33], Z value was 11.33, P < 0.01, which showed that the recurrence rate in experimental group was significantly lower than that in control group.Eleven articles involved with the complications, the total case number was 2388, 166 cases had postoperative complications. The complication rate was 6.95%, of which, 109 cases in experimental group, the complication rate was 8.52%; 57 cases in control group, the complication rate was 5.15%. Compared with the two groups, OR values and their 95%CI was 3.63 [2.47, 5.33], Z was 6.58, P < 0.01, the experimental group had significantly higher incidence of complications. CONCLUSION: For I and II differentiated thyroid cancer, total thyroidectomy or subtotal resection may reduce the chance of recurrence, but the postoperative complications is higher; while gland lobe and isthmus lobectomy has lower postoperative complications, but may increase the risk of relapse. PMID- 24406182 TI - [Necrotizing otitis external with cerebral infarction: a case report]. PMID- 24406183 TI - [One case of meningioma of middle and posterior fossae and skull base: as monaural secretory otitis media for the first performance]. PMID- 24406184 TI - [Intralesional bleomycin injection treatment for 44 cases of pharyngolaryngeal haemangioma]. PMID- 24406185 TI - [Twenty-nine cases of intranasal endoscopic open surgery on the frontal process of maxilla fracture reduction]. PMID- 24406186 TI - [One case of rare tracheobronchial foreign body (fusiform magnet) successfully removed through bronchoscopy in a child]. PMID- 24406187 TI - [One case of intracranial mucormycosis infection following endoscopic repair of cerebrospinal fluid rhinorrhea]. PMID- 24406188 TI - [One case of epithelioid angiosarcoma of the middle ear]. PMID- 24406189 TI - [Acute myeloid leukemia in remission with external auditory canal granulocytic sarcoma: a case report]. PMID- 24406190 TI - [Middle ear papilloma: a case report]. PMID- 24406191 TI - [Fourth branchial cleft cyst with purulent inflammation caused by suppurative thyroid it is in a case]. PMID- 24406192 TI - [Conference summary of academic meeting to commemorate the 60th universally of the Chinese Journal of Otorhinolaryngology Head and Neck Surgery and the first meeting of the 10th editorial board]. PMID- 24406193 TI - [Epidemiological investigation of vertigo]. PMID- 24406194 TI - [Application of three-dimensional display techniques in endoscopic skull base surgery]. PMID- 24406195 TI - [Introduction to 2011 American clinical practice guideline: polysomnography for sleep disordered breathing prior to tonsillectomy in children]. PMID- 24406196 TI - Discrimination of bladder cancer cells from normal urothelial cells with high specificity and sensitivity: combined application of atomic force microscopy and modulated Raman spectroscopy. AB - Atomic force microscopy (AFM) and modulated Raman spectroscopy (MRS) were used to discriminate between living normal human urothelial cells (SV-HUC-1) and bladder tumour cells (MGH-U1) with high specificity and sensitivity. MGH-U1 cells were 1.5-fold smaller, 1.7-fold thicker and 1.4-fold rougher than normal SV-HUC-1 cells. The adhesion energy was 2.6-fold higher in the MGH-U1 cells compared to normal SV-HUC-1 cells, which possibly indicates that bladder tumour cells are more deformable than normal cells. The elastic modulus of MGH-U1 cells was 12 fold lower than SV-HUC-1 cells, suggesting a higher elasticity of the bladder cancer cell membranes. The biochemical fingerprints of cancer cells displayed a higher DNA and lipid content, probably due to an increase in the nuclear to cytoplasm ratio. Normal cells were characterized by higher protein contents. AFM studies revealed a decrease in the lateral dimensions and an increase in thickness of cancer cells compared to normal cells; these studies authenticate the observations from MRS. Nanostructural, nanomechanical and biochemical profiles of bladder cells provide qualitative and quantitative markers to differentiate between normal and cancerous cells at the single cellular level. AFM and MRS allow discrimination between adhesion energy, elasticity and Raman spectra of SV-HUC-1 and MGH-U1 cells with high specificity (83, 98 and 95%) and sensitivity (97, 93 and 98%). Such single-cell-level studies could have a pivotal impact on the development of AFM-Raman combined methodologies for cancer profiling and screening with translational significance. PMID- 24406197 TI - Hierarchically structured nerve guidance channels based on poly-3-hydroxybutyrate enhance oriented axonal outgrowth. AB - Traumatic peripheral nerve lesions can cause local anesthesia, paralysis and loss of autonomic control. Reconstruction using engineered nerve guidance conduits (NGCs) is rarely successful due to the sub-optimal characteristics of the conduits. To address the demands of clinical practice, we developed a hierarchically structured NGC from slowly resorbing poly(3-hydroxybutyric acid) (P3HB). The NGC consists of a permeable single-lumen tube and melt-spun fibrillar lumen fillers. Permeable tubes were constructed from P3HB/poly(E-caprolactone) (PCL) blends or poly(3-hydroxybutyric acid-co-4-hydroxybutyric acid) (P(3HB-co 4HB)). Polyvinylpyrrolidone was used as a porogen in solvent-free thermoplastic processing, followed by selective polymer leaching. All tested material compositions showed hydrolytic degradation after 16weeks in phosphate buffered saline, whereas P3HB/PCL tubes maintained mechanical strength compared to (P(3HB co-4HB)). The porous scaffolds allowed diffusion of large molecules (~70kDa). In vitro studies demonstrated that mouse fibroblasts survived and proliferated inside closed porous tubes. An in vitro model of axonal regeneration using dorsal root ganglia and sympathetic cervical ganglia demonstrated that the NGCs successfully supported neuron survival and neurite outgrowth. The introduction of fibrillar lumen fillers promoted oriented neurite growth and coating with extracellular matrix proteins further increased ganglia attachment and cell migration. In this study we show that P3HB-based NGCs scaffolds have potential in long gap peripheral nerve repair strategies. PMID- 24406198 TI - Development of photosynthetic biomaterials for in vitro tissue engineering. AB - Tissue engineering has opened a new therapeutic avenue that promises a revolution in regenerative medicine. To date, however, the translation of engineered tissues into clinical settings has been highly limited and the clinical results are often disappointing. Despite decades of research, the appropriate delivery of oxygen into three-dimensional cultures still remains one of the biggest unresolved problems for in vitro tissue engineering. In this work, we propose an alternative source of oxygen delivery by introducing photosynthetic scaffolds. Here we demonstrate that the unicellular and photosynthetic microalga Chlamydomonas reinhardtii can be cultured in scaffolds for tissue repair; this microalga shows high biocompatibility and photosynthetic activity. Moreover, Chlamydomonas can be co-cultured with fibroblasts, decreasing the hypoxic response under low oxygen culture conditions. Finally, results showed that photosynthetic scaffolds are capable of producing enough oxygen to be independent of external supply in vitro. The results of this study represent the first step towards engineering photosynthetic autotrophic tissues. PMID- 24406199 TI - Oligopeptide-terminated poly(beta-amino ester)s for highly efficient gene delivery and intracellular localization. AB - The main limitation of gene therapy towards clinics is the lack of robust, safe and efficient gene delivery vectors. This paper describes new polycations for gene delivery based on poly(beta-amino ester)s (pBAE) containing terminal oligopeptides. The authors developed oligopeptide-modified pBAE-pDNA nanoparticles that achieve better cellular viability and higher transfection efficacy than other end-modified pBAE and commercial transfection agents. Gene expression in highly permissive cell lines was remarkably high, but transfection efficiency in less-permissive cell lines was highly dependent on oligopeptide composition and nanoparticle formulation. Moreover, the use of selected oligopeptides in the pBAE formulation led to preferential intracellular localization of the particles. Particle analysis of highly efficient pBAE formulations revealed different particle sizes and charge features, which indicates chemical pseudotyping of the particle surface, related to the oligopeptide chemical nature. In conclusion, chemical modification at the termini of pBAE with amine-rich oligopeptides is a powerful strategy for developing delivery systems for future gene therapy applications. PMID- 24406200 TI - Foreign body response to subcutaneous biomaterial implants in a mast cell deficient Kit(w-Sh) murine model. AB - Mast cells (MCs)_are recognized for their functional role in wound-healing and allergic and inflammatory responses - host responses that are frequently detrimental to implanted biomaterials if extended beyond acute reactivity. These tissue reactions impact especially on the performance of sensing implants such as continuous glucose monitoring (CGM) devices. Our hypothesis that effective blockade of MC activity around implants could alter the host foreign body response (FBR) and enhance the in vivo lifetime of these implantable devices motivated this study. Stem cell factor and its ligand c-KIT receptor are critically important for MC survival, differentiation and degranulation. Therefore, an MC-deficient sash mouse model was used to assess MC relationships to the in vivo performance of CGM implants. Additionally, local delivery of a tyrosine kinase inhibitor (TKI) that inhibits c-KIT activity was also used to evaluate the role of MCs in modulating the FBR. Model sensor implants comprising polyester fibers coated with a rapidly dissolving polymer coating containing drug releasing degradable microspheres were implanted subcutaneously in sash mice for various time points, and the FBR was evaluated for chronic inflammation and fibrous capsule formation around the implants. No significant differences were observed in the foreign body capsule formation between control and drug-releasing implant groups in MC-deficient mice. However, fibrous encapsulation was significantly greater around the drug-releasing implants in sash mice compared to drug-releasing implants in wild-type (e.g. MC-competent) mice. These results provide insights into the role of MCs in the FBR, suggesting that MC deficiency provides alternative pathways for host inflammatory responses to implanted biomaterials. PMID- 24406202 TI - Skeletonema marinoi (Bacillariophyceae) sensitivity to herbicides and effects of temperature increase on cellular responses to terbuthylazine exposure. AB - The North East area of Italy is an intensively farmed area, where the use of herbicides has increased dramatically during the last years. Some of the most detected herbicides are triazine compounds, such as: simazine (SIM), terbuthylazine (TBA), its degradation product desethyl-terbuthylazine (D-TBA) and other herbicides, such as metolachlor (MET). In this paper, the sensitivity of the diatom Skeletonema marinoi to the most detected herbicides (TBA, D-TBA, SIM and MET) was preliminarily studied. All the pollutants tested significantly inhibited the diatom growth and photosynthetic efficiency (from the concentration of 15 MUg L(-1)) with the exception of TBA which had the strongest effects on S. marinoi starting from the concentration of 5 MUg L(-1). Consequently, cellular physiological responses to TBA exposure (1, 5, 10, 20 and 30 MUg L(-1)) were further studied at increasing temperature conditions (15, 20 and 25 degrees C). Inhibition of growth rate and photosynthetic efficiency was observed earlier and determined by lower TBA levels than those affecting cell growth. These responses were significantly enhanced at increasing temperature conditions when growth rates were higher than those measured at 15 degrees C. Carbon cell content increased in the cultures exposed to high concentrations of TBA (from 20 MUg L( 1)) compared to the controls, especially at high temperatures. Cell chlorophyll significantly increased from the added concentration of 10 MUg L(-1) of TBA at all the temperatures and, as a consequence, also the Chl:C ratio significantly increased. The C:N ratio followed the pattern of nitrate uptake and was characterized, at all the temperatures, by low values during the lag phase in cultures with 20 and 30 MUg L(-1) of TBA; in these conditions, in fact, the nutrient in the medium was exhausted later then in the controls. Only cultures exposed to 30 MUg L(-1) of TBA at 25 degrees C, which stopped to take up nutrients earlier and could not increase chlorophyll levels, did not display any growth capacity. This study shows that S. marinoi is affected by TBA concentrations lower than those affecting some harmful flagellate species frequently observed in the Adriatic Sea. Thus, it raises the question of the combined effects of herbicides pollution and high temperature pressures on phytoplankton composition. PMID- 24406201 TI - Whole body tracking of superparamagnetic iron oxide nanoparticle-labelled cells- a rheumatoid arthritis mouse model. AB - INTRODUCTION: The application of mesenchymal stem cells (MSCs) in treating rheumatoid arthritis (RA) has been made possible by the immunosuppressive and differentiation abilities of these cells. A non-invasive means of assessing cell integration and bio-distribution is fundamental in evaluating the risks and success of this therapy, thereby enabling clinical translation. This paper defines the use of superparamagnetic iron oxide nanoparticles (SPIONs) in conjunction with magnetic resonance imaging (MRI) to image and track MSCs in vivo within a murine model of RA. METHODS: Murine MSCs (mMSCs) were isolated, expanded and labelled with SiMAG, a commercially available particle. In vitro MRI visibility thresholds were investigated by labelling mMSCs with SiMAG with concentrations ranging from 0 to 10 MUg/ml and resuspending varying cell doses (10930 to 5 * 10950 cells) in 2 mg/ml collagen prior to MR-imaging. Similarly, in vivo detection thresholds were identified by implanting 3 * 10950 mMSCs labelled with 0 to 10 MUg/ml SiMAG within the synovial cavity of a mouse and MR-imaging. Upon RA induction, 300,000 mMSCs labelled with SiMAG (10 MUg/ml) were implanted via intra-articular injection and joint swelling monitored as an indication of RA development over seven days. Furthermore, the effect of SiMAG on cell viability, proliferation and differentiation was investigated. RESULTS: A minimum particle concentration of 1 MUg/ml (300,000 cells) and cell dose of 100,000 cells (5 and 10 MUg/ml) were identified as the in vitro MRI detection threshold. Cell viability, proliferation and differentiation capabilities were not affected, with labelled populations undergoing successful differentiation down osteogenic and adipogenic lineages. A significant decrease (P < 0.01) in joint swelling was measured in groups containing SiMAG-labelled and unlabelled mMSCs implying that the presence of SPIONs does not affect the immunomodulating properties of the cells. In vivo MRI scans demonstrated good contrast and the identification of SiMAG-labelled populations within the synovial joint up to 7 days post implantation. This was further confirmed using histological analysis. CONCLUSIONS: We have been able to monitor and track the migration of stem cell populations within the rheumatic joint in a non-invasive manner. This manuscript goes further to highlight the key characteristics (biocompatible and the ability to create significant contrast at realistic doses within a clinical relevant system) demonstrated by SiMAG that should be incorporated into the design of a new clinically approved tracking agent. PMID- 24406203 TI - Differential regulation of peripheral IL-1beta-induced mechanical allodynia and thermal hyperalgesia in rats. AB - This study examined the differential mechanisms of mechanical allodynia and thermal hyperalgesia after injection of interleukin (IL) 1beta into the orofacial area of male Sprague-Dawley rats. The subcutaneous administration of IL-1beta produced both mechanical allodynia and thermal hyperalgesia. Although a pretreatment with iodoresiniferatoxin (IRTX), a transient receptor potential vanilloid 1 (TRPV1) antagonist, did not affect IL-1beta-induced mechanical allodynia, it significantly abolished IL-1beta-induced thermal hyperalgesia. On the other hand, a pretreatment with D-AP5, an N-methyl-d-aspartate (NMDA) receptor antagonist, and NBQX, an alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor antagonist, blocked IL-1beta-induced mechanical allodynia. Pretreatment with H89, a protein kinase A (PKA) inhibitor, blocked IL-1beta-induced mechanical allodynia but not thermal hyperalgesia. In contrast, pretreatment with chelerythrine, a protein kinase C (PKC) inhibitor, inhibited IL-1beta-induced thermal hyperalgesia. Subcutaneous injections of 2% lidocaine, a local anesthetic agent, blocked IL-1beta-induced thermal hyperalgesia but not IL-1beta-induced mechanical allodynia. In the resiniferatoxin (RTX)-pretreated rats, a subcutaneous injection of IL-1beta did not produce thermal hyperalgesia due to the depletion of TRPV1 in the primary afferent fibers. Double immunofluorescence revealed the colocalization of PKA with neurofilament 200 (NF200) and of PKC with the calcitonin gene-related peptide (CGRP) in the trigeminal ganglion. Furthermore, NMDA receptor 1 (NR1) and TRPV1 predominantly colocalize with PKA and PKC, respectively, in the trigeminal ganglion. These results suggest that IL-1beta-induced mechanical allodynia is mediated by sensitized peripheral NMDA/AMPA receptors through PKA-mediated signaling in the large-diameter primary afferent nerve fibers, whereas IL-1beta induced thermal hyperalgesia is mediated by sensitized peripheral TRPV1 receptors through PKC-mediated signaling in the small-diameter primary afferent nerve fibers. PMID- 24406204 TI - Mast cell numbers negatively correlate with fibrosis in cryptorchid testes. AB - PURPOSE: Mast cells have been found to play a role in fibrotic processes in multiple organ systems and are increased in number in the testes of infertile men. We have reviewed the literature and to date have found no studies investigating the role of mast cells in fibrosis of undescended testis. We examined the expression of mast cells in human cryptorchid testes and compared mast cell expression with testicular fibrosis in these testes. METHODS: Testicular biopsies from cryptorchid testis were collected over 2 years. Biopsies from 78 patients were retrospectively sectioned, stained, and reviewed for the amount of fibrosis (graded 0-3) as well as mast cell number (MCN). MCNs were quantified by tryptase staining, and the average MCN per high-powered field (HPF) was determined. Statistical analysis was performed using a one-way ANOVA with a Kruskal-Wallis test and post hoc analysis with the Dunn test when significant. RESULTS: Larger MCNs were significantly associated with lower fibrotic indices at the time of orchidopexy. The average MCNs were 2.06, 0.86, 0.37, and 0.58 for fibrotic indices of 0, 1, 2, and 3, respectively. MCNs were significantly higher in biopsies with a fibrotic index of 0 than all other groups (p < 0.05). CONCLUSION: Mast cell expression correlates inversely with testicular fibrosis in cryptorchid testes. Further studies correlating mast cell expression with testicular function in boys with cryptorchidism are warranted. PMID- 24406205 TI - Peering through the mist: systematic review of what the chemistry of contaminants in electronic cigarettes tells us about health risks. AB - BACKGROUND: Electronic cigarettes (e-cigarettes) are generally recognized as a safer alternative to combusted tobacco products, but there are conflicting claims about the degree to which these products warrant concern for the health of the vapers (e-cigarette users). This paper reviews available data on chemistry of aerosols and liquids of electronic cigarettes and compares modeled exposure of vapers with occupational safety standards. METHODS: Both peer-reviewed and "grey" literature were accessed and more than 9,000 observations of highly variable quality were extracted. Comparisons to the most universally recognized workplace exposure standards, Threshold Limit Values (TLVs), were conducted under "worst case" assumptions about both chemical content of aerosol and liquids as well as behavior of vapers. RESULTS: There was no evidence of potential for exposures of e-cigarette users to contaminants that are associated with risk to health at a level that would warrant attention if it were an involuntary workplace exposures. The vast majority of predicted exposures are < <1% of TLV. Predicted exposures to acrolein and formaldehyde are typically <5% TLV. Considering exposure to the aerosol as a mixture of contaminants did not indicate that exceeding half of TLV for mixtures was plausible. Only exposures to the declared major ingredients- propylene glycol and glycerin--warrant attention because of precautionary nature of TLVs for exposures to hydrocarbons with no established toxicity. CONCLUSIONS: Current state of knowledge about chemistry of liquids and aerosols associated with electronic cigarettes indicates that there is no evidence that vaping produces inhalable exposures to contaminants of the aerosol that would warrant health concerns by the standards that are used to ensure safety of workplaces. However, the aerosol generated during vaping as a whole (contaminants plus declared ingredients) creates personal exposures that would justify surveillance of health among exposed persons in conjunction with investigation of means to keep any adverse health effects as low as reasonably achievable. Exposures of bystanders are likely to be orders of magnitude less, and thus pose no apparent concern. PMID- 24406206 TI - Electrophysiology study without intracardiac catheters. The value of proper Holter interpretation: a case report. AB - This case report presents the case of a 55-year-old male patient with a long standing history of palpitations. A 24-h Holter monitor revealed an incessant form of long-RP supraventricular tachycardia. The differential diagnosis is presented and discussed. In a stepwise approach, it is explained how the exact mechanism of the tachycardia can be inferred through careful examination of the multiple onsets, terminations and response to spontaneous monomorphic premature ventricular contractions. PMID- 24406208 TI - Refining the deceleration capacity index in phase-rectified signal averaging to assess physical conditioning level. AB - BACKGROUND: Deceleration capacity (DC) of heart rate is a measure of cardiac vagal modulation. This study introduced a DC adaptation (Modified Index) that measured the velocity of change in the phase-rectified signal averaging curve, and assessed its ability to discriminate athletes from controls. MATERIALS AND METHODS: The Modified Index was compared to Standard DC approach in a prospective case-control study. Subjects were classified according to maximal metabolic equivalents as the control group (CG) and athlete group (AG). The Modified Index was compared to Standard DC and classical approaches (RMSSD and HF) by the area under receiver operating characteristic curve (AUC) using 10,000 bootstraps. RESULTS: In Standard DC and Modified Index bootstrap median values were (ms), respectively, 11.80 and 17.94 (p<0.01) in CG, and 25.98 and 45.62 in AG (p<0.01). AUC (mean+/-SD) was 0.70+/-0.12 for Standard DC and 0.96+/-0.04 for Modified Index (p<0.01). CONCLUSIONS: Modified Index appropriately discriminates athletes from healthy sedentary subjects. PMID- 24406207 TI - Determinants of developing widened spatial QRS-T angle in HIV-infected individuals: results from the Strategies for Management of Antiretroviral Therapy [SMART] Study. AB - BACKGROUND: A widened electrocardiographic spatial QRS-T angle has been shown to be predictive of cardiovascular disease in HIV-infected individuals. However, determinants and risk factors of developing widened QRS-T angle over time in this population remain unknown. METHODS AND RESULTS: Spatial QRS-T angle was automatically measured from standard electrocardiogram of 1444 HIV-infected individuals without baseline widened spatial QRS-T angle from the Strategies for Management of Antiretroviral Therapy [SMART], a clinical trial comparing two antiretroviral treatment strategies [Drug Conservation (DC) vs. Viral Suppression (VS)]. Conditional logistic regression analysis was used to examine the association between baseline characteristics and incident widened spatial QRS-T angle (a new angle>93 degrees in males and>74 degrees in females). During 2544 person-years of follow-up, 199 participants developed widened angle at a rate of 7.8 per 100 person-years. In unadjusted models, female sex, black race (vs. white), DC treatment strategy, current and past smokers (vs. never), history of alcohol abuse, greater body mass index, history of diabetes and higher levels of hs-C-reactive protein were associated with incident widened spatial QRS-T angle. When these variables were entered together in the same model with adjustment for demographics and treatment strategy, DC treatment strategy [OR (95% CI): 1.50 (1.09, 2.07)], female gender [1.69 (1.17, 2.45)], current and past smoking (vs. never) [2.49 (1.63, 3.81) and 1.93 (1.21, 3.09), respectively], and diabetes [2.28 (1.33, 3.91)] predicted incident widened spatial QRS-T angle. CONCLUSIONS: Drug conservation treatment strategy, female gender, smoking, and diabetes are independently predictive of incident widened spatial QRS-T angle in HIV-infected individuals. PMID- 24406209 TI - Regulation of the anti-tumour immune response by cancer-associated fibroblasts. AB - The microenvironment of established tumours is often immunosuppressed, and this allows tumours to grow and disseminate without being eliminated by the patient's immune system. The recent FDA approval of immunotherapies such as ipilimumab and sipuleucel-T that directly activate the adaptive and innate immune responses has triggered interest in developing other novel anti-cancer approaches that modulate the immune system. Understanding how the different constituents of the tumour microenvironment influence the immune system is thus crucial and is expected to generate a plethora of factors that can be targeted to boost immunity and trigger long lasting anti-tumour efficacy. Cancer associated fibroblasts (CAFs) are a crucial component of the tumour microenvironment. Through secretion of multiple growth factors, cytokines and proteases, CAFs are known to be key effectors for tumour progression and can promote cancer cell growth, invasiveness and angiogenesis. However, recent publications have also linked CAF biology to innate and adaptive immune cell recruitment and regulation. Here, we review recent findings on how CAFs can influence the immune status of tumours through direct and indirect interaction with immune cells and other key components of the tumour microenvironment. PMID- 24406210 TI - Carcinoma-associated fibroblasts provide operational flexibility in metastasis. AB - Malignant cancer cells do not act as lone wolves to achieve metastasis, as they exist within a complex ecosystem consisting of an extracellular matrix scaffold populated by carcinoma-associated fibroblasts (CAFs), endothelial cells and immune cells. We recognize local (primary tumor) and distant ecosystems (metastasis). CAFs, also termed myofibroblasts, may have other functions in the primary tumor versus the metastasis. Cellular origin and tumor heterogeneity lead to the expression of specific markers. The molecular characteristics of a CAF remain in evolution since CAFs show operational flexibility. CAFs respond dynamically to a cancer cell's fluctuating demands by shifting profitable signals necessary in metastasis. Local, tissue-resident fibroblasts and mesenchymal stem cells (MSCs) coming from reservoir sites such as bone marrow and adipose tissue are the main progenitor cells of CAFs. CAFs may induce awakening from metastatic dormancy, a major cause of cancer-specific death. Cancer management protocols influence CAF precursor recruitment and CAF activation. Since CAF signatures represent early changes in metastasis, including formation of pre-metastatic niches, we discuss whether liquid biopsies, including exosomes, may detect and monitor CAF reactions allowing optimized prognosis of cancer patients. PMID- 24406211 TI - The role of reactive oxygen species and metabolism on cancer cells and their microenvironment. AB - Compelling evidence show that reactive oxygen species (ROS) levels are finely regulated in the cell and can act as "second messengers" in response to diverse stimuli. In tumor epithelial cells, ROS accumulate abnormally and induce signaling cascades that mediate the oncogenic phenotype. In addition to their impact on tumor epithelial cells, ROS also affect the surrounding cells that constitute the tumor microenvironment. Indeed, ROS production increases tumor angiogenesis, drives the onset of inflammation and promotes conversion of fibroblast into myofibroblasts. These cells, initially identified upon wound healing, exhibit similar properties to those observed in fibroblasts associated with aggressive adenocarcinomas. Indeed, analyses of tumors with distinct severity revealed the existence of multiple distinct co-existing subtypes of carcinoma-associated fibroblasts (CAFs), with specific marker protein profiling. Chronic oxidative stress deeply modifies the proportion of these different fibroblast subtypes, further supporting tumor growth and metastatic dissemination. At last, ROS have been implicated in the metabolic reprogramming of both cancer cells and CAFs, allowing an adaptation to oxidative stress that ultimately promotes tumorigenesis and chemoresistance. In this review, we discuss the role of ROS in cancer cells and CAFs and their impact on tumor initiation, progression, and metastasis. PMID- 24406212 TI - p53 orchestrates between normal differentiation and cancer. AB - During recent years, it is becoming more and more evident that there is a tight connection between abnormal differentiation processes and cancer. While cancer and stem cells are very different, especially in terms of maintaining genomic integrity, these cell types also share many similar properties. In this review, we aim to provide an over-view of the roles of the key tumor suppressor, p53, in regulating normal differentiation and function of both stem cells and adult cells. When these functions are disrupted, undifferentiated cells may become transformed. Understanding the function of p53 in stem cells and its role in maintaining the balance between differentiation and malignant transformation can help shed light on cancer initiation and propagation, and hopefully also on cancer prevention and therapy. PMID- 24406213 TI - Implantable controlled release devices for BMP-7 delivery and suppression of glioblastoma initiating cells. AB - Designing therapeutic devices capable of manipulating glioblastoma initiating cells (GICs) is critical to stop tumor recurrence and its associated mortality. Previous studies have indicated that bone morphogenetic protein-7 (BMP-7) acts as an endogenous suppressor of GICs, and thus, it could become a treatment for this cancer. In this work, we engineer an implantable microsphere system optimized for the controlled release of BMP-7 as a bioinspired therapeutic device against GICs. This microsphere delivery system is based on the formation of a heparin-BMP-7 nanocomplex, first coated with Tetronic((r)) and further entrapped in a biodegradable polyester matrix. The obtained microspheres can efficiently encapsulate BMP-7, and release it in a controlled manner with minimum burst effect for over two months while maintaining protein bioactivity. Released BMP-7 showed a remarkable capacity to stop tumor formation in a GICs cell culture model, an effect that could be mediated by forced reprogramming of tumorigenic cells towards a non-tumorigenic astroglial lineage. PMID- 24406214 TI - Dual-modal upconversion fluorescent/X-ray imaging using ligand-free hexagonal phase NaLuF4:Gd/Yb/Er nanorods for blood vessel visualization. AB - Visualization of blood vessel of lung can improve the detection of the lung and pulmonary vascular diseases. However, research on visualization of blood vessel of lung using the new generation upconversion nanoprobes is still scarce. Herein, high quality hexagonal phase NaLuF4:Gd/Yb/Er nanorods were synthesized by a simple hydrothermal method through doping Gd(3+). Doping Gd can not only promote the phase transformation from cubic to hexagonal and the shape evolution from microtube to rod-like, but also provide an additional magnetic properties for biomedical application. The as-prepared nanorods were further converted to water solubility by treating with HCl for eliminating the capped oleic acid. The ligand free nanorods were successfully used for high-contrast upconversion fluorescent bioimaging of HeLa cells. Moreover, the in vivo synergistic upconversion fluorescent and X-ray imaging of nude mice were demonstrated by subcutaneously and intravenously administrated the ligand-free nanorods. The X-ray signals were matched well with the upconversion signal, indicating the successfully synergistic bioimaging. The ex-vivo X-ray and upconversion fluorescent imaging of various organs revealed that the nanorods were mainly accumulated in liver and lung. More importantly, the blood vessel of the lung can be readily visualized when these ligand-free nanorods are intravenously injected. Apart from the synergistic X-ray and upconversion bioimaging, the ligand-free nanorods can also possess excellent paramagnetic property for potential magnetic resonance imaging contrast agent. Our results have demonstrated the enhanced visualization of blood vessel of lung performed by dual-modal bioimaging of X-ray and upconversion fluorescence, revealing the great promise of these nanoprobes in angiography imaging. Such a new technique enables the integration of the two bioimaging techniques by combining their collective strengths and minimizing their shortcomings. PMID- 24406215 TI - Promotion of dentin regeneration via CCN3 modulation on Notch and BMP signaling pathways. AB - Dentin regeneration remains a great challenge in clinic. Dental pulp stem cells (DPSCs) actively contribute to dentinogenesis, which is orchestrated by a spectrum of signaling factors. However, the exact mechanism underlying the reparative dentin regeneration process is largely unknown and the application of DPSCs in the repair of dentin defect is thus limited. Here, using a rat reparative dentin regeneration model, we observed that DPSCs underwent a proliferation phase followed by a differentiation phase after dental injury. A transient elevation of nephroblastoma overexpressed (NOV, or CCN3) expression correlated with this progressive dental tissue restoration process. Further studies revealed that over-expression of CCN3 promoted human DPSCs proliferation via activation of Notch. Moreover, using cocultured cells (DPSCs/CCN3 and DPSCs) in vitro and the cocultured cells-poly (lactic-co-glycolic acid) (PLGA) scaffold complex in vivo, we demonstrated that CCN3 was capable of promoting mineralization in a non-cell autonomous manner through promoting secretion of BMP2. CCN3 can promote dentinogenesis by coordinating proliferation and odontoblastic differentiation of DPSCs via modulating Notch and BMP2 signaling pathways and CCN3 is a promising therapeutic target in dentin tissue engineering. PMID- 24406216 TI - Synergistic effects of self-assembling peptide and neural stem/progenitor cells to promote tissue repair and forelimb functional recovery in cervical spinal cord injury. AB - While neural stem/progenitor cells (NPCs) show promise for traumatic spinal cord injury (SCI), their efficacy in cervical SCI remains to be established. Moreover, their application to SCI is limited by the challenges posed by the lesion including the glial scar and the post-traumatic cavitation. Given this background, we sought to examine the synergistic effect of self-assembling peptide (SAP) molecules, designed to optimize the post-traumatic CNS microenvironment, and NSCs in a clinically-relevant model of contusive/compressive cervical SCI. We injected K2(QL)6K2 (QL6) SAPs into the lesion epicenter 14 days after bilateral clip compression-induced cervical SCI in rats, combined with simultaneous transplantation of neural stem/progenitor cells (NPCs) intraspinally adjacent to the lesion epicenter. The QL6 SAPs reduced the volume of cystic cavitation in the spinal cord lesion. Simultaneously engrafted NPCs preserved motor neurons and attenuated perilesional inflammation. The combination of QL6 and NPCs promoted forelimb neurobehavioral recovery and was associated with significant improvement in forelimb print area and stride length. In summary, we report for the first time histologic and functional benefits in a clinically-relevant model of cervical SCI through the synergistic effects of combined SAP and NPCs. PMID- 24406217 TI - Dextran derivative-based pH-sensitive liposomes for cancer immunotherapy. AB - pH-Sensitive dextran derivatives having 3-methylglutarylated residues (MGlu-Dex) were prepared by reacting dextran with 3-methyl-glutaric anhydride. MGlu-Dex changed the protonation state and their characteristics from hydrophilic to hydrophobic in neutral and acidic pH regions. Surface modification of egg yolk phosphatidylcholine liposomes with MGlu-Dex produced highly pH-sensitive liposomes that were stable at neutral pH but which were destabilized strongly in the weakly acidic pH region. MGlu-Dex-modified liposomes were taken up efficiently by dendritic cells and delivered entrapped ovalbumin (OVA) molecules into the cytosol. When MGlu-Dex-modified liposomes loaded with OVA were administered subcutaneously to mice, the antigen-specific humoral and cellular immunity was induced more effectively than the unmodified liposomes loaded with OVA. Furthermore, administration of MGlu-Dex-modified liposomes loaded with OVA to mice bearing E.G7-OVA tumor significantly suppressed tumor growth and extended the mice survival. Results suggest that MGlu-Dex-modified liposomes are promising for the production of safe and potent antigen delivery systems that contribute to the establishment of efficient cancer immunotherapy. PMID- 24406218 TI - Nanofibrous scaffolds releasing a small molecule BDNF-mimetic for the re direction of endogenous neuroblast migration in the brain. AB - Brain tissue engineering has the potential to harness existing elements of neurogenesis within the adult brain to overcome a microenvironment that is otherwise inhibitory to regeneration, especially following severe tissue damage. This study investigates the ability of electrospun poly epsilon-caprolactone (PCL) to re-direct the migratory pathway of endogenous neuroblasts from the disrupted subventricular zone (SVZ). A small molecule non-peptide ligand (BDNF mimetic) that mimicked the trophic properties of brain-derived neurotrophic factor (BDNF) was incorporated into electrospun PCL scaffolds to improve neuroblast survival and promote neuroblast migration towards the implant. PCL scaffolds were able to support neuroblast infiltration and migration along the implant tract. In the presence of the BDNF-mimetic, neuroblasts were able to migrate towards the implant via the parenchyma, and their persistence within the implants was prolonged. In addition, the BDNF-mimetic improved implant integration and increased local neuronal plasticity by increasing neurite sprouting at the tissue-implant interface. SMI32+ neurites were observed inside scaffolds at 21 days but not 8 days post implantation, indicating that at least some of the infiltrated neuroblasts had differentiated into neurons. PMID- 24406219 TI - Suppression of orthotopically implanted hepatocarcinoma in mice by umbilical cord derived mesenchymal stem cells with sTRAIL gene expression driven by AFP promoter. AB - Mesenchymal stem cells (MSCs) are promising vehicles for delivering therapeutic agents in tumor therapy. Human umbilical cord-derived mesenchymal stem cells (HUMSCs) resemble bone marrow-derived MSCs with respect to hepatic differentiation potential in injured livers in animals, while their hepatic differentiation under the hepatocarcinoma microenvironment is unclear. In this study, HUMSCs were isolated and transduced by lentiviral vectors coding the soluble human tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) gene driven by alpha-fetoprotein (AFP) promoter to investigate the therapeutic effects of these HUMSC against orthotopically implanted hepatocarcinoma in mice. We showed that HUMSCs can be transduced by lentivirus efficiently. HUMSCs developed cuboidal morphology, and expressed AFP and albumin in a two-step protocol. HUMSCs were capable of migrating to hepatocarcinoma in vitro as well as in vivo. In the orthotopical hepatocarcinoma microenvironment, the AFP promoter was activated during the early hepatic differentiation of HUMSCs. After intravenous injected, MSC.AFPILZ-sTRAIL expressed sTRAIL exclusively at the tumor site, and exhibited significant antitumor activity. This effect was stronger when in combination with 5-FU. The treatment was tolerated well in mice. Collectively, our results provide a potential strategy for targeted tumor therapy relying on the use of the tumor tropism and specific differentiation of HUMSCs as vehicles. PMID- 24406221 TI - [Additional comments on community-acquired pneumonia in children]. PMID- 24406220 TI - High prevalence of asymptomatic malaria in south-eastern Bangladesh. AB - BACKGROUND: The WHO has reported that RDT and microscopy-confirmed malaria cases have declined in recent years. However, it is still unclear if this reflects a real decrease in incidence in Bangladesh, as particularly the hilly and forested areas of the Chittagong Hill Tract (CHT) Districts report more than 80% of all cases and deaths. surveillance and epidemiological data on malaria from the CHT are limited; existing data report Plasmodium falciparum and Plasmodium vivax as the dominant species. METHODS: A cross-sectional survey was conducted in the District of Bandarban, the southernmost of the three Hill Tracts Districts, to collect district-wide malaria prevalence data from one of the regions with the highest malaria endemicity in Bangladesh. A multistage cluster sampling technique was used to collect blood samples from febrile and afebrile participants and malaria microscopy and standardized nested PCR for diagnosis were performed. Demographic data, vital signs and splenomegaly were recorded. RESULTS: Malaria prevalence across all subdistricts in the monsoon season was 30.7% (95% CI: 28.3 33.2) and 14.2% (95% CI: 12.5-16.2) by PCR and microscopy, respectively. Plasmodium falciparum mono-infections accounted for 58.9%, P. vivax mono infections for 13.6%, Plasmodium malariae for 1.8%, and Plasmodium ovale for 1.4% of all positive cases. In 24.4% of all cases mixed infections were identified by PCR. The proportion of asymptomatic infections among PCR-confirmed cases was 77.0%, oligosymptomatic and symptomatic cases accounted for only 19.8 and 3.2%, respectively. Significantly (p < 0.01) more asymptomatic cases were recorded among participants older than 15 years as compared to younger participants, whereas prevalence and parasite density were significantly (p < 0.01) higher in patients younger than 15 years. Spleen rate and malaria prevalence in two to nine year olds were 18.6 and 34.6%, respectively. No significant difference in malaria prevalence and parasite density was observed between dry and rainy season. CONCLUSIONS: A large proportion of asymptomatic plasmodial infections was found which likely act as a reservoir of transmission. This has major implications for ongoing malaria control programmes that are based on the treatment of symptomatic patients. These findings highlight the need for new intervention strategies targeting asymptomatic carriers. PMID- 24406222 TI - [Rational management of refractory Mycoplasma pneumoniae pneumonia]. PMID- 24406223 TI - [Third nationwide survey of childhood asthma in urban areas of China]. AB - OBJECTIVE: Asthma is the most common chronic respiratory disease among children. In recent years, the prevalence of childhood asthma was rising in most countries around the world. This nationwide study was conducted to investigate the prevalence of childhood asthma in urban areas of large cities in China, and to find the characteristics of attacks, the diagnosis and treatment status, and provide scientific data for improving the prevention and management of asthma in children. METHOD: This nationalwide, cross-sectional survey was organized by the National Cooperative Group on Childhood Asthma, and conducted in 43 cities all over the country, including 27 capital cities of provinces or autonomous regions, 4 municipalities, from September 2009 to August 2010. Children born from July 1st 1995 to June 30th 2010 were enrolled in the survey, consisting of children who had been living in the surveyed cities and those born outside the city but had lived in the cities for over 6 months. Schools, kindergartens and communities in each city were selected by phased stratified random cluster sampling. Standardized preliminary questionnaire was used for screening out possible patients in the survey. Diagnosis of asthma was confirmed by enquiry of history, together with review of previous record and tests, physical examination in suspected asthmatic children. Asthmatic children were further asked for past diagnosis, treatment and concomitant allergic diseases. Double entry and validation was adopted for all data using Epi-Info software, and analysis was carried out by SPSS V19.0. RESULT: Totally 463 982 children were investigated for the survey. Asthma was diagnosed in 13 992 children, 12 634 children with classical asthma (90.3%) and 1358 children with cough variant asthma (9.7%); 4387 cases (31.4%) were newly diagnosed in all asthmatic children. The total asthma incidence rate was 3.02% (95%CI:2.97%-3.06%), with classical asthma at 2.72% (95%CI:2.68%-2.77%) and cough variant asthma at 0.29% (95%CI:0.28%-0.31%). The prevalence in last two-year (2009-2010) was 2.32% (95%CI:2.28%-2.37%). The prevalence of asthma in male and female children was 3.51% (8495/241 811) and 2.29% (5089/222 160) respectively with significant difference (chi(2) = 608.7, P < 0.01). Preschool children (3-5 years old) had the highest prevalence of asthma (4.15%), which was significantly higher than that of school-age children (6-14 years old, 2.82%) and infants (0-2 years old, 1.77%).In different regions of the country, the highest rate was found in East China (4.23%), and the lowest rate in North-east China (2.00%). Among different cities, highest rate was found in Shanghai (7.57%) and the lowest rate in Lasa (0.48%).Family allergic history was reported in 45.2% (n = 6321) , personal history of allergy reported in 72.5% (n = 10 143) , and allergic rhinitis reported in 50.1% (n = 7010) asthmatic children. Respiratory tract infection (87.9%, n = 12 299) and changes of weather condition/inhaling cold air (51.5%, n = 7204) were the most common triggers of asthma exacerbation. The common clinical manifestations of asthma were cough (91.3%, n = 12 771) and wheezing (76.2%, n = 10 659). Dysphasia (3.1%, n = 438), orthopnea (6.5%, n = 905), cyanosis (3.8%, n = 528) or sweating (5.0%, n = 696) was relatively less often seen during exacerbation. In last year, more than half (61.4%, 4826/12 518) of the patients experienced asthma attack, 32.1% (4028/12 530) went to emergency room once, and 16.3% (2039/12 514) were hospitalized for treatment. Bronchodilators were used in 71.4% (n = 9986), inhaled corticosteroid in 58.7% (n = 8209), antibiotics in 75.1% (n = 10 504) of asthmatic children. Peak flow meter was used in 14.3% (1449/10 145) of asthmatic children 5 years and older for monitoring. CONCLUSION: The total asthma incidence of childhood asthma aged 0-14 year old in cities in China was 3.02% and prevalence in last two years was 2.32%. The asthma prevalence was significantly different among regions, cities, ages, and genders. Nearly one third of patients with asthma was not diagnosed in early stage or diagnosed correctly. The treatment and management of asthma in children awaits improvement as well. PMID- 24406224 TI - [Relationship between bronchoalveolar lavage mycoplasma load and clinical characteristics in children with Mycoplasma pneumoniae pneumonia]. AB - OBJECTIVE: Mycoplasma pneumoniae (MP) is an important pathogen for community acquired pneumonia in children. MP infection was considered to be self-limited, but many severe refractory MP pneumonia cases have been reported in recent years. The reason for variation in severity of MP pneumonia remains unclear. MP virulence including drug-resistance and host immunologic function are important influencing factors. The present study aimed to clarify relationship between local MP load and severity of MP pneumonia. METHOD: MP DNA was quantitatively detected by fluorescent real-time PCR in bronchoalveolar lavage fluid (BALF) from 77 children with MP pneumonia. They were classified into groups of low MP load ( < 10(3)/ml, n = 14) , moderate MP load (10(3)-10(6)/ml, n = 22) and high MP load ( > 10(6)/ml, n = 41) . Clinical symptoms, main laboratory and imaging results of children among the three groups were compared. RESULT: When compared with low load group and moderate load group, high load group had longer fever duration (7 d, 10 d vs. 12 d) , longer time to normalization of temperature with macrolide administration (4 d, 8 d vs. 10 d) , more patients with high fever (50.0%, 68.2% vs. 87.8%) and longer duration of fever than 10 d (35.7%, 50.0% vs. 73.2%).Statistically significant difference existed in CRP among the three groups (1.0 mg/L, 11.5 mg/L, 34 mg/L). Large field of consolidation or atelectasis were found in 58.5% of high load patients, much higher than 22.7% in moderate load and 14.3% in low load patients. Bilateral or massive pleural effusion was not found in low load group, while in moderate load and high load group, they were 13.6% and 24.4%. However, no significant difference was found in symptoms and main laboratory and imaging results among different age groups in high load patients. CONCLUSION: There is a close relationship between MP load in BALF and clinical characteristics in children with MP pneumonia. Those with high MP load have a more severe process. PMID- 24406225 TI - [Long-term efficacy of sublingual immunotherapy with Dermatophagoides Farianae Drops in children with allergic asthma sensitized to dust mites]. AB - OBJECTIVE: To observe the efficacy of sublingual immunotherapy (SLIT) in children with allergic asthma during the treatment and 1 year after the treatment. METHOD: This is an open and retrospective study; 80 children with mild-moderate allergic asthma between 4 and 14 years of age were chosen from the Department of Respiratory Medicine, Nanjing Children's Hospital Affiliated to Nanjing Medical University from May to August, 2009. All children were sensitized to Dermatophagoides Farianae and/or Dermatophagoides Pteronyssinus and have received anti-asthma drug therapy for 3 months (baseline). Thirty-nine children in SLIT group underwent 2-year SLIT and combined with anti-asthma drug, these children were then followed up for 1 year. Forty-one children in drug group only received anti-asthma drug and were followed up for 3 years. The scores of asthma symptom, scores of asthma medication and the number of discontinuation of anti-asthma drug were compared between the SLIT group and drug group for the baseline, end of the 2nd year and 3rd year treatment. The frequency of acute attack of asthma was also compared between the two groups for 1 year before the treatment and the 3rd year treatment. RESULT: (1) At baseline, the asthma symptom scores, the medication scores and the frequency of acute attack of asthma in 1 year before the treatment of the two groups showed no significant difference. (2) After 2-year SLIT, the daytime asthma symptom scores of SLIT group were lower than the drug group (0.18 +/- 0.06,0.93 +/- 0.12,Z = -4.873, P < 0.05), the night asthma symptom scores of the two groups showed no significant difference. One year after SLIT, the daytime and night asthma symptom scores of SLIT group were both lower than those of the drug group (daytime SLIT group vs. Drug group: 0.18 +/- 0.06 vs. 1.46 +/- 0.72,Z = -5.082, P < 0.05;night SLIT group vs. Drug group: 0.05 +/- 0.04 vs. 0.66 +/- 0.14,Z = -4.019, P < 0.05). (3) At the end of SLIT and 1 year after SLIT, the medication scores of SLIT group were both lower than those of the drug group (End of SLIT SLIT group vs. Drug group: 0.31 +/- 0.07 vs. 0.75 +/- 0.12,Z = -2.813, P < 0.05;1 year after SLIT SLIT group vs. Drug group: 0.17 +/- 0.06 vs. 0.87 +/- 0.17,Z = -4.106, P < 0.05), the number of discontinuation of anti-asthma drug of SLIT group were both more than the drug group (End of SLIT SLIT group vs. Drug group: 20 vs. 10,chi(2) = 6.167, P < 0.05;1 year after SLIT SLIT group vs. Drug group: 29 vs.13,chi(2) = 14.581, P < 0.05).(4) In the 3rd year, the frequency of acute attack of asthma in SLIT group was significantly lower than that of drug group (0.69 +/- 1.20, 1.20 +/- 1.44,Z = -1.968, P < 0.05) . CONCLUSION: SLIT can significantly improve the symptoms of asthma, reduce the use of anti-asthma drug and reduce the frequency of the acute attack of asthma. Meanwhile, the efficacy could still maintain 1 year after the SLIT treatment. PMID- 24406226 TI - [Guidelines for management of community acquired pneumonia in children (the revised edition of 2013) (I)]. PMID- 24406227 TI - [Obstructive sleep-disordered breathing in infants]. PMID- 24406228 TI - [Application of bi-level positive airway pressure ventilation in treatment of respiratory distress syndrome in premature infants]. PMID- 24406229 TI - [Growth curves for breastfed infants in rural areas]. AB - OBJECTIVE: To construct the growth percentile curves of weight, length and head circumference-for-age for breastfeed infants in rural areas, and take them as the reference standards to evaluate growth of breastfed infants in rural areas. METHOD: The data collected in the Longitudinal Study of Chinese Breastfed Infants Growth and Development from birth to 12 months of age in 6 well-being rural areas were used. The MLwiN2.25 was selected to construct the multilevel model to estimate the predicted values, and fit the percentiles reference curves (P3, P15, P50, P85, and P97) of weight, length and head circumference-for-age. The results of this study were compared with those of the Nine-city growth reference percentiles curves in China and with WHO growth reference percentiles curves. RESULT: The percentiles reference curves of weight, length and head circumference for-age for breastfeeding infants aged 0-12 months in rural areas were developed. Compared with the Nine-city growth reference, the P3 curves of weight-for-age and girls' length-for-age were higher by 0.02-0.39 kg, 0-0.42 kg and 0.27-1.15 cm. Compared with the WHO growth reference, the P3 curves of boys and girls were both at a high level.It was estimated that using Nine-city growth reference percentiles curves to evaluate the infants in rural areas could reduce the rates of underweight and girls' stunting; and using WHO growth reference percentiles curves could reduce all infants' underweight rates. CONCLUSION: The growth percentiles reference curves which were constructed by the longitudinal observational data and scientific method would have great significance in reflecting the development of breastfed infants, evaluating and guiding infants' growth in rural areas. PMID- 24406230 TI - [Early prediction of acute kidney injury in infants and young children after cardiopulmonary bypass surgery]. AB - OBJECTIVE: To understand the incidence of acute kidney injury (AKI) in infants and toddlers and evaluate the possibility of predicting AKI with urine neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), N-acetyl-beta-D glucosaminidase (NAG), microalbumin (MA) and alpha1-microglobulin (alpha1-MG) after surgeries for congenital heart diseases with cardiopulmonary bypass (CPB). METHOD: Fifty-eight children (ages <= 3 years) who had undergone surgery for congenital heart diseases with CPB were enrolled. Urinary samples were collected before and 4 h, 6 h, 12 h, 24 h post CPB to detect the concentration of NGAL, IL 18, NAG, MA and alpha1-MG. RESULT: The AKI group had 29 cases, none AKI group also had 29 cases. Urinary concentration of NGAL 4, 6, and 12 h post CPB were significantly higher in AKI group (2820 ug/g, 905.7 ug/g, 76.1 ug/g separately) than in none AKI group (27.6 ug/g, 19.5 ug/g, 16.0 ug/g separately, P < 0.01). Urinary concentration of IL-18 4, 6, 12 and 24 h post CPB were significantly higher in AKI group than in none AKI group (P < 0.05). Urinary concentration of NAG 4 h and 6 h post CPB were significantly higher in AKI group than in none AKI group (P < 0.01). Urinary concentration of MA/UCr post CPB 4 h, 6 h and 12 h were significantly higher in AKI group than in none AKI group (P < 0.05). Urinary concentration of alpha1-MG/UCr post CPB 4 h, 6 h and 12 h were significantly higher in AKI group than in none AKI group (P < 0.01). All the five biomarkers had predictive abilities at 4-hour after surgery. CONCLUSION: Urine biomarkers NGAL, IL-18, NAG, MA and alpha1-MG were valuable early predictors of AKI after CPB surgery. PMID- 24406231 TI - [Argon plasma coagulation combined with cryotherapy via bronchoscopy for the treatment of one child with severe post-intubation tracheal stenosis and literature review]. AB - OBJECTIVE: To observe the short term effect of argon plasma coagulation (APC) combined with cryotherapy via bronchoscopy for treatment of severe post intubation tracheal stenosis in a child. METHOD: A 3-year old boy was admitted for cephalothorax abdominal compound trauma and dyspnea, who had severe post incubation tracheal stenosis. The agreement about the operation risk was signed by the parents. Endotracheal APC procedure was performed with a bronchoscope under general anesthesia. The APC probe was put into the working channel of the bronchoscope. The stenotic lesion was endoscopically visualized and then coagulated by argon plasma. Such coagulation was carried out several times at the stenotic site until it gradually became dilated. The devitalized tissue was mechanically removed with grasping forceps. Thereafter, bronchoscopic cryosurgery was repeatedly performed at the stenotic site. Clinical symptoms, signs and bronchoscopic manifestations were observed right after operation, after 1 day, 10 days, 1 month and 6 months separately. RESULT: Tracheal tissue hyperplasia and cyanosis disappeared, laryngeal stridor and dyspnea improved obviously right after the operation. General condition of the patient was well, there was no laryngeal stridor and dyspnea 10 days after operation. The mucosa of the surgical site was smooth and no tracheostenosis was seen under bronchoscope at 1 month and 6 months after the operation. CONCLUSION: Argon plasma coagulation combined with cryotherapy via bronchoscope is an effective method to treat tracheal stenosis of children, which needs further exploration for the application. PMID- 24406232 TI - [Clinical features of four atypical pediatric cases of endemic typhus with pneumonia]. AB - OBJECTIVE: To analyze clinical manifestations, treatment and prognosis of 4 cases with endemic typhus. METHOD: The clinical data of four endemic typhus patients in prognosis were retrospectively analyzed. These four atypical cases of endemic typhus with pneumonia were treated in our department from October 2011 to March 2012. They were all male, with an age range of 15 months to 7 years. The four patients had long history, mild respiratory symptom and no improvement was found after treatment with cephalosporins. There were no evidences of bacterial, viral, or fungal infections and we thought they might have infection with other pathogen. Three were from rural areas. Routine blood tests, Weil-Felix reaction, blood smear (Giemsa staining) , and indirect immunofluorescence assay were performed. RESULT: Blood smear and IFA tests showed evidences for endemic typhus. The clinical presentations were atypical, the patients had no headache, but all had fever, rash, and pneumonia of varying severity. None of the patients had a severe cough, but bronchial casts were observed in one case. Recurrent fever was reported in three cases. Physical examinations showed no eschars, but one patient had a subconjunctival hemorrhage, and one had skin scratches, cervical lymphadenopathy, pleural effusion, pericardial effusion, and cardiac dilatation. Two patients had remarkably increased peripheral blood leukocyte counts; both these patients also had high alanine aminotransferase (ALT) levels and one had a high C-reactive protein (CRP) level. Weil-Felix testing was negative or the OX19 titer was low. The peripheral blood smear (Giemsa stain) showed intracellular pathogens in all four cases. After combined therapy with doxycycline and macrolide antibiotics, all four patients recovered well. CONCLUSION: The endemic typhus children often come from rural areas. The clinical presentations were atypical, they usually have no headache, but have fever (often Periodic fever) , rash, and pneumonia of varying severity in these four cases. Combined therapy with doxycycline and macrolide antibiotics was effective in all four patients. PMID- 24406233 TI - [Alterations of SP-A, SP-D and KL-6 in serum and bronchoalveolar lavage fluid in children with Mycoplasma pneumoniae pneumonia]. AB - OBJECTIVE: To study the alterations and relationship of surfactant protein (SP) A, SP-D and KL-6 in serum and bronchoalveolar lavage fluids (BALF) in children with Mycoplasma pneumoniae pneumonia (MPP). METHOD: Self-control method was used for the study on SP-A, SP-D and KL-6 in serum, infected and non-infected BALFs in 32 MMP children with only one side of MPP. RESULT: The contents of SP-A, SP-D and KL-6 in infected BALF were [mg/L;M (IQR) ]: 243 (90-468) , 187 (43-333) , 148 (47 426) ;104 (37-257) , 56 (25-131) , 35 (12-147) in non-infected BALF; 35 (25-69) , 33 (9-149) and 24 (15-62) in serum. The correlation coefficient of KL-6 between serum and infected BALF were -0.534 and -0.378 (P < 0.05). CONCLUSION: There were significant correlation between the alterations of SP-A, SP-D and KL-6 in serum and lung infection in children with CAP. KL-6 in serum may be more sensitive than SP-A and SP-D. PMID- 24406234 TI - [Mutation analysis of a family with 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency]. AB - OBJECTIVE: The aim of this study was to explore the genetic features of a family with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (MHBDD) which may provide the basis for the diagnosis and genetic counseling. METHOD: Clinical data of the proband was collected, total RNA and genomic DNA were extracted from the peripheral blood. The whole coding region of the ACAT1 gene was amplified by RT PCR. 5' noncoding region of the ACAT1 gene and all 6 exons and flanking intron regions of the HADH2 gene were amplified by PCR. All amplification products were directly sequenced and compared with the reference sequence. RESULT: (1) The patient was a one-year-old boy who presented with psychomotor retardation and astasia when he was admitted to the hospital. Biochemical test revealed slight hyperlactatemia (3.19 mmol/L) and magnetic resonance imaging showed delayed myelination. 2-Methylacetoacetyl-CoA thiolase deficiency was suggested by gas chromatography-mass spectrometry. (2) There was no mutation in the ACAT1 gene and a hemizygous missense mutation c.388C > T was found in the 4 exon of the HADH2 gene which resulted in p. R130C. Proband's mother was the heterozygote and the father was normal. CONCLUSION: This is the first report on MHBDD patient and HADH2 mutation in China. p.R130C is responsible for the pathogenesis of the disease in the infant. PMID- 24406235 TI - [Observation on virus shedding periods of enterovirus-71 and coxsackievirus A 16 monitored by nucleic acids determination in stool samples of children with hand, foot and mouth disease]. AB - OBJECTIVE: To observe the duration of enterovirus-71 (EV71) and coxsackievirus A 16 (CoxA16) viral shedding in stool samples of children with hand, foot and mouth disease (HFMD) infected with EV71 and CoxA16 and to explore the relationship between the duration of intestinal virus shedding and the severity of illness of children with HFMD. METHOD: Totally 113 laboratory-confirmed cases of children with HFMD infected with EV71 and CoxA16 were followed up. The stool samples were collected with the interval of 4 to7 days and the viral nucleic acids were detected by fluorescent PCR until the stool viral nucleic acids of infected children turned to be negative. The cases in EV71 group were further divided into "ordinary EV71 group" and "severe EV71 group" according to the severity of the illness. The positive rates of viral nucleic acid and the differences of distribution among different groups were analyzed by Kaplan-Meier survival analysis during the follow-up period. RESULT: The 113 cases of infected children were grouped as follows: 65 cases of EV71 positive children, 44 cases of CoxA16 positive children, 4 cases of EV71/CoxA16 mixed infection. The median duration of the stool viral nucleic acids turning to negative was 26 (18.25-32.50) days in EV71 group and 27 (14.50-33.75) days in CoxA16 group (Z = 1.51, P > 0.05). At 1, 4, 6 and 10 weeks, the positive rates of stool viral nucleic acid of children with HFMD in EV71 group were 100%, 48.1%, 17.2% and 0 respectively. At 1, 4 and 6 weeks, the positive rates of stool viral nucleic acid of children with HFMD in CoxA16 group were 95.5%, 53.8% and 0 respectively (chi(2) = 0.18, P > 0.05). At 1, 4 and 6 weeks, the positive rates of stool viral nucleic acid of children with HFMD in ordinary EV71 group were 100%, 23.5% and 0 respectively, while at 1, 4, 6 and 10 weeks, the positive rates of stool viral nucleic acid of children with HFMD in severe EV71 group were 100%, 62.4%, 26.0% and 0 respectively (chi(2) = 5.689, P < 0.05). CONCLUSION: The duration of enterovirus shedding in stool samples of children with HFMD lasted for a long period. The maximum duration of EV71 and CoxA16 in stool of children with HFMD was 10 weeks and 6 weeks, respectively. The duration of intestinal virus shedding of children with HFMD infected with EV71 was related with the severity of the illness. PMID- 24406236 TI - [Effect of clinical pathway management on pediatric pneumonia]. AB - OBJECTIVE: To investigate effect of clinical pathway management on pediatric pneumonia. METHOD: Data were colleted from children hospitalizated with bronchial pneumonia, bronchiolitis, mycoplasma pneumonia in Center of Respiratory Disorders in Children's Hospital of Chongqing Medical University from January 2011 to December 2012. According to implement of clinical pathway management, all patients were divided into pathway management group (n = 405) and non-pathway management group (n = 503). Length of stay, costs of hospitalization, clinical effect and use of antibiotics were compared in these two groups. RESULT: In pathway management group, average length of stay of children with bronchial pneumonia and bronchiolitis was (6.1 +/- 1.6) d and (6.2 +/- 1.5) d respectively. While in non-pathway management group, length of stay was (7.2 +/- 1.9) d and (7.3 +/- 1.5) d (P = 0.000). There was no significant difference in length of stay between these two groups of children with mycoplasma pneumonia [ (6.9 +/- 1.8) d vs.(7.7 +/- 2.5) d] (P = 0.198). Costs of auxiliary tests in pathway management group was slightly higher than that in non-pathway management group. While other costs in pathway management group were significantly lower than those in non-pathway management group. Total costs of hospitalization of patients with these three diseases in pathway management group and non-pathway management group were Y(4609 +/- 1225) vs Y (5629 +/- 1813) , Y (5006 +/- 1250) vs. Y (5686 +/- 1337), Y (4946 +/- 1259) vs. Y (6488 +/- 3032) respectively. There was a significant difference (P < 0.05). Percentages of antibiotics use in two groups were 70.9% vs.99.4%, 45.7% vs.93.4% and 96.2% vs.100.0%. Antibiotics related indicators such as mean number of day of use, ratio of combination and grade of antibiotics were significantly higher in pathway management group compared to non pathway management group (P < 0.01). There was no significant difference in other indicators like clinical effect and unscheduled readmission in 30 days between two groups (P > 0.05). CONCLUSION: Clinical pathway management can regulate medical behaviors through reduction of medical costs, avoidance of excessive laboratory tests and therapy, and regulation of antibiotic use. PMID- 24406237 TI - [Benign neonatal sleep myoclonus-three cases report]. PMID- 24406239 TI - Comparison of graft patency between off-pump and on-pump coronary artery bypass grafting: an updated meta-analysis. AB - BACKGROUND: Currently, off-pump coronary artery bypass grafting (OPCAB) and on pump coronary artery bypass grafting (ONCAB) are 2 well-established therapeutic strategies for patients with coronary artery disease, and debate regarding which strategy provides superior graft patency is ongoing. The current study is a meta analysis of randomized controlled trials that compared the graft patency between OPCAB and ONCAB. METHODS: Data sources were PubMed, the Cochrane Library, Google Scholar, and ISI Web of Knowledge (1966-2013). We identified studies comparing graft patency after the 2 procedures as the primary intervention for patients with multivessel coronary artery disease and conducted a meta-analysis of randomized controlled trials on graft patency. RESULTS: A literature search yielded 12 randomized controlled trials, for a total of 3,894 and 4,137 grafts performed during OPCAB and ONCAB procedures, respectively. Meta-analysis of these studies showed an increased risk of occlusion of all grafts (risk ratio [RR], 1.35; 95% confidence interval [CI], 1.16-1.57) and saphenous vein grafts (SVGs) (RR, 1.41; 95% CI, 1.24-1.60) in the OPCAB group, whereas there was no significant difference in graft occlusion of left internal mammary artery (LIMA) (RR, 1.15; 95% CI, 0.83-1.59) and radial artery (RR, 1.37; 95% CI, 0.76-2.47) grafts between OPCAB and ONCAB. CONCLUSIONS: Meta-analysis of currently available randomized controlled trials on graft patency shows that ONCAB reduces the incidence of SVG graft occlusion significantly but does not affect LIMA and radial artery graft patency compared with OPCAB. PMID- 24406240 TI - Left ventricular end-diastolic pressure predicts survival in coronary artery bypass graft surgery patients. AB - BACKGROUND: There is a known association between a depressed left ventricular ejection fraction (LVEF < 0.35) and increased mortality in patients undergoing coronary artery bypass graft (CABG) operations. Recent studies show that elevated preoperative LV end-diastolic pressure (LVEDP) is an independent predictor of operative death for patients undergoing CABG. Therefore, the purpose of this study was to define the long-term predictive value of elevated LVEDP in CABG and its relationship to LVEF. METHODS: Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH), a clinical data collection initiative capturing all patients undergoing isolated CABG in Alberta, Canada, was used to identify 6,735 consecutive patients who had LVEDP and LVEF data recorded by catheterization undergoing isolated CABG between 1996 and 2011. Patients were divided into four groups based on LVEF and LVEDP: group 1 (LVEF>=0.35, LVEDP<18 mm Hg), group 2 (LVEF<0.35, LVEDP<18 mm Hg), group 3 (LVEF>=0.35, LVEDP>=18 mm Hg), and group 4 (LVEF<0.35, LVEDP>=18 mm Hg). RESULTS: Patients with an LVEF>0.35 had improved long-term survival compared with patients with depressed LVEF (LVEF<0.35, p<0.001). In patients with a depressed LVEF, an elevated LVEDP was associated with decreased long-term survival (group 2 vs 4, p<0.001). Other significant independent predictors for death were age, chronic obstructive pulmonary disease, peripheral vascular disease, dialysis dependence, and congestive heart failure (p<0.001). Isolated elevated LVEDP was not an independent risk factor for long-term mortality. CONCLUSIONS: In patients with a depressed LVEF, an elevated LVEDP is associated with poor long-term survival. These data support the added value of long-term prognostic value of LVEDP in patients with depressed LVEF undergoing CABG. PMID- 24406241 TI - Thoracic empyema caused by Prevotella spp. diagnosed using 16S rDNA sequence analysis. AB - We describe a case of thoracic empyema in a 76-year-old male with complication of diabetes mellitus and hypertension. His chief complaints were fever and chest pain. The patient was diagnosed as pleural infection according to the pulmonary computed tomography (CT) scan and laboratory results. The patient had persistent fever after the treatment of continuous percutaneous drainage and 1 week of intravenous moxifloxacin. He was then misdiagnosed as tuberculous pleuritis and still had fever after the treatment of 2 weeks' antituberculosis drugs. Repeated cultures of sputum, blood, bronchoalveolar lavage fluid and pleural fluid were all negative. A gram-negative bacillus was found in the pleural pus Gram stain, and it was identified as Prevotella spp. by 16S ribosomal DNA (rDNA) sequence analysis. The patient recovered after further treatment, including CT-induced pleural drain and intravenous imipenem. Totally, he received 2-week imipenem and 1-month metronidazole therapy from the day he was diagnosed with empyema to the termination of treatment. On the subsequent 2-month and 6-month follow-up visits, no recurrence has been reported for this patient. Routine microbiological methods are important in diagnosis of pleural infection, but they have limitations in some cases, especially for anaerobe. Molecular assay based on 16S rDNA is helpful in detecting causative organisms of thoracic empyema. PMID- 24406242 TI - Efficient expansion of human keratinocyte stem/progenitor cells carrying a transgene with lentiviral vector. AB - INTRODUCTION: The development of an appropriate procedure for lentiviral gene transduction into keratinocyte stem cells is crucial for stem cell biology and regenerative medicine for genetic disorders of the skin. However, there is little information available on the efficiency of lentiviral transduction into human keratinocyte stem/progenitor cells and the effects of gene transduction procedures on growth potential of the stem cells by systematic assessment. METHODS: In this study, we explored the conditions for efficient expansion of human keratinocyte stem/progenitor cells carrying a transgene with a lentiviral vector, by using the culture of keratinocytes on a feeder layer of 3 T3 mouse fibroblasts. The gene transduction and expansion of keratinocytes carrying a transgene were analyzed by Western blotting, quantitative PCR, and flow cytometry. RESULTS: Polybrene (hexadiamine bromide) markedly enhanced the efficiency of lentiviral gene transduction, but negatively affected the maintenance of the keratinocyte stem/progenitor cells at a concentration higher than 5 MUg/ml. Rho-assiciated kinase (ROCK) inhibitor Y-27632, a small molecule which enhanced keratinocyte proliferation, significantly interfered with the lentiviral transduction into cultured human keratinocytes. However, a suitable combination of polybrene and Y-27632 effectively expanded keratinocytes carrying a transgene. CONCLUSIONS: This study provides information for effective expansion of cultured human keratinocyte stem/progenitor cells carrying a transgene. This point is particularly significant for the application of genetically modified keratinocyte stem/progenitor stem cells in regenerative medicine. PMID- 24406243 TI - Level of asthma control and health care utilization in Asia-Pacific countries. AB - BACKGROUND: Data on the impact of asthma in many countries in the Asia-Pacific region is limited. This study investigated whether partly- and uncontrolled asthma were associated with increased medication use/healthcare utilization and productivity loss among a population of asthma patients from nine Asia-Pacific countries. METHODS: We used cross-sectional data from 3630 asthma patients >=12 years from the 2011 Asia-Pacific Asthma Insights and Management (AP-AIM) survey. Using Global Initiative for Asthma (GINA) guidelines, patients were categorized as having well-controlled, partly- controlled, or uncontrolled asthma. Chi-square tests were used to assess the relation of degree of asthma control with utilization of asthma medications, health services, productivity, and mood. RESULTS: Overall, 7.6% of the patients surveyed had asthma that was well controlled, with the highest proportions in Singapore (14%) and the lowest in India (0%) and China (2%). Patients whose asthma was not well-controlled reported greater use of asthma medications, more emergency healthcare visits or hospitalizations for their asthma, and more interference of their mood due to asthma. They also reported significant decreases in productivity due to asthma. CONCLUSIONS: Patients who did not have well-controlled asthma had greater utilization rates of asthma medications and healthcare services and were more likely to report missing multiple days of work/school compared to patients whose asthma was well-controlled. These associations suggest that emphasis on improving asthma control could have dramatic effects on patient well-being and utilization of healthcare resources. PMID- 24406244 TI - Asthma control in patients on fixed dose combination evaluated with mannitol challenge test. AB - Asthma is often difficult to control and it is likely that not all patients are optimally treated. This study aimed to explore asthma control in adults receiving fixed dose combination (FDC) therapy. Control of asthma was assessed using the mannitol challenge test as a monitoring tool to see if this would give additional information compared to the asthma control test (ACT). The study was an open label, prospective study on 98 adults prescribed with FDC therapies for at least three months. 74 patients considered that their asthma was well controlled. However, 60 patients had a positive mannitol challenge test (PD15 < 635 mg), and when those with a positive response to the short-acting beta2-agonist (>=15%) after the mannitol challenge test were included, this increased to 64 patients (65%). Exploratory analysis determined that the spirometry parameters; FEV1/FVC and FEV1% of predicted, were statistically significant predictors of a positive mannitol challenge test. Co-morbid conditions such as concomitant upper airway involvement or eczema did not predict mannitol reactivity. Although most patients rated their asthma as well controlled, many provided a positive mannitol challenge test, suggesting the presence of underlying inflammation, despite treatment with fixed dose combination therapy. PMID- 24406245 TI - Therapeutic approaches against common structural features of toxic oligomers shared by multiple amyloidogenic proteins. AB - Impaired proteostasis is one of the main features of all amyloid diseases, which are associated with the formation of insoluble aggregates from amyloidogenic proteins. The aggregation process can be caused by overproduction or poor clearance of these proteins. However, numerous reports suggest that amyloid oligomers are the most toxic species, rather than insoluble fibrillar material, in Alzheimer's, Parkinson's, and Prion diseases, among others. Although the exact protein that aggregates varies between amyloid disorders, they all share common structural features that can be used as therapeutic targets. In this review, we focus on therapeutic approaches against shared features of toxic oligomeric structures and future directions. PMID- 24406246 TI - Transport of estradiol-17beta-glucuronide, estrone-3-sulfate and taurocholate across the endoplasmic reticulum membrane: evidence for different transport systems. AB - Important reactions of drug metabolism, including UGT mediated glucuronidation and steroidsulfatase mediated hydrolysis of sulfates, take place in the endoplasmic reticulum (ER) of hepatocytes. Consequently, UGT generated glucuronides, like estradiol-17beta-glucuronide, have to be translocated back into the cytoplasm to reach their site of excretion. Also steroidsulfatase substrates, including estrone-3-sulfate, have to cross the ER membrane to reach their site of hydrolysis. Based on their physicochemical properties such compounds are not favored for passive diffusion and therefore likely necessitate transport system(s) to cross the ER membrane in either direction. The current study aims to investigate the transport of taurocholate, estradiol-17beta glucuronide, and estrone-3-sulfate in smooth (SER) and rough (RER) endoplasmic reticulum membrane vesicles isolated from Wistar and TR(-) rat liver. Time dependent and bidirectional transport was demonstrated for taurocholate, showing higher uptake rates in SER than RER vesicles. For estradiol-17beta-glucuronide a fast time-dependent efflux with similar efficiencies from SER and RER but no clear protein-mediated uptake was shown, indicating an asymmetric transport system for this substrate. Estrone-3-sulfate uptake was time-dependent and higher in SER than in RER vesicles. Inhibition of steroidsulfatase mediated estrone-3 sulfate hydrolysis decreased estrone-3-sulfate uptake but had no effect on taurocholate or estradiol-17beta-glucuronide transport. Based on inhibition studies and transport characteristics, three different transport mechanisms are suggested to be involved in the transport of taurocholate, estrone-3-sulfate and estradiol-17beta-glucuronide across the ER membrane. PMID- 24406247 TI - 1,4-Naphthoquinone, a pro-oxidant, suppresses immune responses via KEAP-1 glutathionylation. AB - Low levels of oxidative stress have been shown to activate Nrf-2, an important anti-inflammatory transcription factor, by us and also by several other investigators. Earlier we showed that pro-oxidants protect normal lymphocytes against radiation injury by activating Nrf-2. In the present study, we have investigated the effect of oxidative stress on immune responses and delineated the underlying mechanism. Hydrogen peroxide, tert-butylhydroquinone and 1,4 naphthoquinone (NQ) inhibited mitogen induced proliferation of lymphocytes. NQ also inhibited mitogen (Concanavalin A) induced cytokine secretion by murine T cells and lipopolysaccharide induced release of cytokines, nitric oxide and cyclooxygenase-2 expression by macrophages. NQ modulated cellular redox by decreasing GSH/GSSG ratio and the immunosuppressive effects of NQ were significantly abrogated by thiol containing antioxidants and not by non-thiol antioxidants. This redox perturbation led to activation of Nrf-2 pathway and inhibition of NF-kappaB. NQ treatment increased total protein S-thiolation, induced glutathionylation of KEAP-1 protein and decreased IKKbeta levels in lymphocytes. Molecular docking studies revealed that NQ can disrupt KEAP-1/Nrf-2 interaction by directly blocking the binding site of Nrf-2 in the KEAP-1 protein. Further, inhibitors of Nrf-2 and HO-1 abrogated the anti-inflammatory effects of NQ. T cells isolated from spleen and gut associated lymphoid tissue of NQ administered mice also showed suppression of NF-kappaB activation and were hyporesponsive to mitogenic stimulation. These results demonstrate that pro oxidants modulate inflammatory and immune responses via oxidative stress mediated KEAP-1 glutathionylation and IKKbeta degradation. PMID- 24406248 TI - Reactive oxygen species-regulated glycogen synthase kinase-3beta activation contributes to all-trans retinoic acid-induced apoptosis in granulocyte differentiated HL60 cells. AB - All-trans retionic acid (ATRA) treatment confers disease remission in acute promyelocytic leukemia (APL) patients by inducing granulocytic differentiation, which is followed by cell apoptosis. Although glycogen synthase kinase (GSK) 3beta is known to be required for spontaneous cell death in neutrophils, the requirement of GSK-3beta activation for the apoptotic effects remains unknown. This question is addressed in the present study using a model of ATRA-induced granulocytic differentiation and apoptosis in APL HL60 cells. ATRA at a therapeutic concentration (1 MUM) induced granulocytic differentiation, followed by apoptosis. ATRA treatment caused decreased Mcl-1, caspase-3 activation, and PARP cleavage following the inactivation of phosphatidylinositol 3-kinase/AKT and the activation of GSK-3beta. Pharmacologically and genetically inhibiting GSK 3beta effectively retarded ATRA-induced Mcl-1 degradation and apoptosis. Additional differentiation inducers, phorbol 12-myristate 13-acetate and dimethyl sulfoxide, also triggered GSK-3beta-dependent apoptosis. Mechanistically, ATRA caused the generation of reactive oxygen species (ROS) through increased expression of NADPH oxidase subunits (p47(phox) and p67(phox)) to facilitate ATRA induced GSK-3beta activation and cell apoptosis. This study indicates that ROS initiate GSK-3beta-dependent apoptosis in granulocyte-differentiated cells after long-term ATRA treatment. PMID- 24406249 TI - The novel pyrrolo-1,5-benzoxazepine, PBOX-6, synergistically enhances the apoptotic effects of carboplatin in drug sensitive and multidrug resistant neuroblastoma cells. AB - Neuroblastoma, a malignancy of neuroectoderrmal origin, accounts for 15% of childhood cancer deaths. Despite advances in understanding the biology, it remains one of the most difficult paediatric cancers to treat. A major obstacle in the effective treatment of neuroblastoma is the development of multidrug resistance (MDR). There is thus a compelling demand for new treatment strategies for this cancer that can bypass such resistance mechanisms. The pyrrolo-1,5 benzoxazepine (PBOX) compounds are a series of novel microtubule-targeting agents that potently induce apoptosis in various cancer cell lines, ex vivo patient samples and in vivo cancer models. In this study we examined the ability of two members, PBOX-6 and -15, to exhibit anti-cancer effects in a panel of drug sensitive and MDR neuroblastoma cell lines. The PBOX compounds potently reduced the viability of all neuroblastoma cells examined and exhibited a lower fold resistance in MDR cells when compared to standard chemotherapeutics. In addition, the PBOX compounds synergistically enhanced apoptosis induced by etoposide, carboplatin and doxorubicin. Exposure of drug sensitive and resistant cell lines to PBOX-6/carboplatin induced cleavage of Bcl-2, a downregulation of Mcl-1 and a concomitant increase in Bak. Furthermore, activation of caspase-3, -8 and -9 was demonstrated. Finally, gene silencing of Mcl-1 by siRNA was shown to sensitise both drug sensitive and multidrug resistant cells to carboplatin-induced apoptosis demonstrating the importance of Mcl-1 downregulation in the apoptotic pathway mediated by the PBOX compounds in neuroblastoma. In conclusion, our findings indicate the potential of the PBOX compounds in enhancing chemosensitivity in neuroblastoma. PMID- 24406250 TI - Developing physician consensus on the reporting of patients with mild cognitive impairment and mild dementia to transportation authorities in a region with mandatory reporting legislation. AB - OBJECTIVE: To establish consensus among dementia experts about which patients with mild cognitive impairment (MCI) or mild dementia should be reported to transportation authorities. METHODS: We conducted a literature review of predictors of driving safety in patients with dementia and combined these into 26 case scenarios. Using a modified Delphi technique, case scenarios were reviewed by 38 dementia experts (geriatric psychiatrists, geriatricians, cognitive neurologists and family physicians with expertise in elder care) who indicated whether or not they would report the patient in each scenario to regional transportation authorities and recommend a specialized on-road driving test. Scenarios were presented up to five times to achieve consensus, defined as 85% agreement, and discrepancies were discussed anonymously online. RESULTS: By the end of the fifth iteration, there was cumulative consensus on 18 scenarios (69%). The strongest predictors of decision to report were the combination of caregiver concern about the patient's driving and abnormal Clock Drawing Test, which accounted for 62% of the variance in decision to report at the same time as or without a road test (p <0.01). Based on these data, an algorithm was developed to guide physician decision-making about reporting patients with MCI or mild dementia to transportation authorities. CONCLUSION: This study supports existing international guidelines that recommend specialized on-road testing when driving safety is uncertain for patients with MCI and emphasizes the importance of assessing executive dysfunction and caregiver concern about driving. PMID- 24406251 TI - Memantine for Lewy body disorders: systematic review and meta-analysis. AB - OBJECTIVE: To clarify whether memantine is more efficacious in several outcomes and safer than placebo in patients with Lewy body disorders, we performed a meta analysis of memantine in patients with Lewy body disorders. METHODS: The meta analysis included randomized controlled trials of memantine for Lewy body disorders in all patients with Lewy body disorders. Motor function, activities of daily living, Neuropsychiatric Inventory, Mini-Mental State Exam, discontinuation rate, and individual side effects were evaluated. RESULTS: No significant effects of memantine on motor function scores, Mini-Mental State Exam scores, Neuropsychiatric Inventory scores, and activity of daily living scores were found. However, memantine was superior to placebo in Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change scores (standardized mean difference: -0.26; 95% confidence interval: -0.51 to -0.02; z = 2.08; p = 0.04; two studies; N = 258). Dropout due to all causes, inefficacy, or adverse events were similar in both groups. Moreover, no significant differences in serious adverse events, somnolence/tiredness, stroke, dizziness/vertigo, and confusion were found between the groups. CONCLUSION: Our results suggest that memantine did not have a benefit for the treatment of Lewy body disorders in cognition and motor function. However, memantine may be superior to placebo for the overall impression of the disorders. Further, memantine is well tolerated. PMID- 24406252 TI - Apoptosis of regulatory T cells in Crohn's disease. PMID- 24406254 TI - Family caregivers in public tertiary care hospitals in Bangladesh: risks and opportunities for infection control. AB - BACKGROUND: Family caregivers are integral to patient care in Bangladeshi public hospitals. This study explored family caregivers' activities and their perceptions and practices related to disease transmission and prevention in public hospitals. METHODS: Trained qualitative researchers conducted a total of 48 hours of observation in 3 public tertiary care hospitals and 12 in-depth interviews with family caregivers. RESULTS: Family caregivers provided care 24 hours a day, including bedside nursing, cleaning care, and psychologic support. During observations, family members provided 2,065 episodes of care giving, 75% (1,544) of which involved close contact with patients. We observed family caregivers washing their hands with soap on only 4 occasions. The majority of respondents said diseases are transmitted through physical contact with surfaces and objects that have been contaminated with patient secretions and excretions, and avoiding contact with these contaminated objects would help prevent disease. CONCLUSION: Family caregivers are at risk for hospital-acquired infection from their repeated exposure to infectious agents combined with their inadequate hand hygiene and knowledge about disease transmission. Future research should explore potential strategies to improve family caregivers' knowledge about disease transmission and reduce family caregiver exposures, which may be accomplished by improving care provided by health care workers. PMID- 24406255 TI - Duration of colonization with methicillin-resistant Staphylococcus aureus in an acute care facility: a study to assess epidemiologic features. AB - BACKGROUND: Patients with a history of methicillin-resistant Staphylococcus aureus (MRSA) colonization or infection are often presumed to remain colonized when they are readmitted to the hospital. This assumption underlies the hospital practice that flags MRSA-positive patients so that these patients can be placed in contact isolation at hospital admission and, when necessary, be given the appropriate empirical therapy and/or antibiotic prophylaxis. METHODS: To determine the duration of and factors associated with MRSA colonization among patients following discharge, we designed a cohort study of patients hospitalized between October 1, 2007, and July 31, 2009, at the Atlanta Veterans Affairs Medical Center, a 128-bed acute care facility. We defined 3 cohorts: cohort A; patients with both a MRSA infection during hospitalization and nasal colonization at discharge; cohort B; patients with a MRSA infection but no nasal colonization at discharge; and cohort C; patients only nasally colonized at discharge. We collected information on demographic characteristics, underlying conditions, infections, and antibiotic use. We cultured nasal swabs obtained from patients at home. We calculated hazard ratios (HR), comparing cohorts A, B, and C after controlling for other factors. RESULTS: We obtained 231 swabs (23 in cohort A, 34 in cohort B, and 174 in cohort C). We documented MRSA colonization in 92 (39.9%) of the 231 patients who returned swabs. The median duration of colonization was 33.3 months. Factors significantly associated with persistent MRSA colonization were (1) total duration of hospital stay from previous admissions prior to study entry and (2) a member of cohort A who had a longer duration of colonization compared with cohorts B and C (P < .001). CONCLUSION: Our data suggest that higher initial inocula of bacteria may be an important determinant of persistent colonization with MRSA. PMID- 24406253 TI - Cockayne Syndrome group B protein stimulates NEIL2 DNA glycosylase activity. AB - Cockayne Syndrome is a segmental premature aging syndrome, which can be caused by loss of function of the CSB protein. CSB is essential for genome maintenance and has numerous interaction partners with established roles in different DNA repair pathways including transcription coupled nucleotide excision repair and base excision repair. Here, we describe a new interaction partner for CSB, the DNA glycosylase NEIL2. Using both cell extracts and recombinant proteins, CSB and NEIL2 were found to physically interact independently of DNA. We further found that CSB is able to stimulate NEIL2 glycosylase activity on a 5-hydroxyl uracil lesion in a DNA bubble structure substrate in vitro. A novel 4,6-diamino-5 formamidopyrimidine (FapyA) specific incision activity of NEIL2 was also stimulated by CSB. To further elucidate the biological role of the interaction, immunofluorescence studies were performed, showing an increase in cytoplasmic CSB and NEIL2 co-localization after oxidative stress. Additionally, stalling of the progression of the transcription bubble with alpha-amanitin resulted in increased co-localization of CSB and NEIL2. Finally, CSB knockdown resulted in reduced incision of 8-hydroxyguanine in a DNA bubble structure using whole cell extracts. Taken together, our data supports a biological role for CSB and NEIL2 in transcription associated base excision repair. PMID- 24406256 TI - Evaluation of two organosilane products for sustained antimicrobial activity on high-touch surfaces in patient rooms. AB - A controlled trial of applying 2 organosilane-based products with antimicrobial properties to high-touch surfaces was conducted in 9 patient rooms. Cultures of surfaces obtained before daily cleaning with a quaternary ammonium disinfectant showed no significant residual antimicrobial activity of the organosilane products, although a modest reduction could not be excluded. PMID- 24406257 TI - Prevention of Clostridium difficile infection in rural hospitals. AB - BACKGROUND: Prevention of Clostridium difficile infection (CDI) remains challenging across the spectrum of health care. There are limited data on prevention practices for CDI in the rural health care setting. METHODS: An electronic survey was administered to 21 rural facilities in Wisconsin, part of the Rural Wisconsin Health Cooperative. Data were collected on hospital characteristics and practices to prevent endemic CDI. RESULTS: Fifteen facilities responded (71%). Nearly all respondent facilities reported regular use of dedicated patient care items, use of gown and gloves, private patient rooms, hand hygiene, and room cleaning. Facilities in which the infection preventionist thought the support of his/her leadership to be "Very good" or "Excellent" employed significantly more CDI practices (13.3 +/- 2.4 [standard deviation]) compared with infection preventionists who thought there was less support from leadership (9.8 +/- 3.0, P = .033). Surveillance for CDI was highly variable. The most frequent barriers to implementation of CDI prevention practices included lack of adequate resources, lack of a physician champion, and difficulty keeping up with new recommendations. CONCLUSION: Although most rural facilities in our survey reported using evidence-based practices for prevention of CDI, surveillance practices were highly variable, and data regarding the impact of these practices on CDI rates were limited. Future efforts that correlate CDI prevention initiatives and CDI incidence will help develop evidence-based practices in these resource-limited settings. PMID- 24406258 TI - Assessing surgical site infection risk factors using electronic medical records and text mining. AB - Text mining techniques to detect surgical site infections (SSI) in unstructured clinical notes were used to improve SSI detection. In conjuction with data from an integrated electronic medical record, all of the 22 SSIs detected by traditional hospital-based surveillance were found using text mining, along with an additional 37 SSIs not detected by traditional surveillance. PMID- 24406259 TI - Knowledge, perceptions, and practices of methicillin-resistant Staphylococcus aureus transmission prevention among health care workers in acute-care settings. AB - BACKGROUND: Health care workers (HCWs) play a critical role in prevention of health care-associated infections such as methicillin-resistant Staphylococcus aureus (MRSA), but glove and gown contact precautions and hand hygiene may not be consistently used with vulnerable patients. METHODS: A cross-sectional survey of MRSA knowledge, attitudes/perceptions, and practices among 276 medical, nursing, allied health, and support services staff at an acute-care hospital in the eastern United States was completed in 2012. Additionally, blinded observations of hand hygiene behaviors of 104 HCWs were conducted. RESULTS: HCWs strongly agreed that preventive behaviors reduce the spread of MRSA. The vast majority reported that they almost always engage in preventive practices, but observations of hand hygiene found lower rates of adherence among nearly all HCW groups. HCWs who reported greater comfort with telling others to take action to prevent MRSA transmission were significantly more likely to self-report adherence to recommended practices. CONCLUSIONS: It is important to reduce barriers to adherence with preventive behaviors and to help all HCWs, including support staff who do not have direct patient care responsibilities, to translate knowledge about MRSA transmission prevention methods into consistent adherence of themselves and their coworkers to prevention guidelines. PMID- 24406260 TI - Assessment of injection practice in primary health care facilities of Shiraz, Iran. AB - BACKGROUND: Occupational risk for several bloodborne viruses is attributable to unsafe injection practices. To understand injection frequency and safety, we surveyed injection rates and factors influencing injection prescription in primary health care facilities and associated health clinics in Shiraz, Iran. METHODS: We used both quantitative and qualitative approaches to study the frequency and safety of injections delivered in 27 primary health care facilities. We used observations and 3 data collecting tools. Patterns of 600 general practice physicians' (GPs) prescriptions were also reviewed. In-depth interviews to elicit the factors contributing to injection prescriptions were conducted. RESULTS: The annual per capita injection rate was 3.12. Corticosteroids were prescribed more frequently than antibiotics (P < .001). Knowledge of participants concerning transmission risks for 3 of the most common bloodborne infections (BBIs) was less than 75%. Factors affecting use of injections by GPs included strong patient preference for injections over oral medications and financial benefit for GPs, especially those in private practice settings. CONCLUSION: Frequency of therapeutic injections in the participating facilities in Shiraz was high. Sociocultural factors in the patient community and their beliefs in the effectiveness of injections exerted influence on GP prescribing practices. Programs for appropriate and safe injection practices should target GP and injection providers, as well as patients, informing them about alternative treatments and possible complications of unnecessary and unsafe injections. PMID- 24406261 TI - Influenza detection from emergency department reports using natural language processing and Bayesian network classifiers. AB - OBJECTIVES: To evaluate factors affecting performance of influenza detection, including accuracy of natural language processing (NLP), discriminative ability of Bayesian network (BN) classifiers, and feature selection. METHODS: We derived a testing dataset of 124 influenza patients and 87 non-influenza (shigellosis) patients. To assess NLP finding-extraction performance, we measured the overall accuracy, recall, and precision of Topaz and MedLEE parsers for 31 influenza related findings against a reference standard established by three physician reviewers. To elucidate the relative contribution of NLP and BN classifier to classification performance, we compared the discriminative ability of nine combinations of finding-extraction methods (expert, Topaz, and MedLEE) and classifiers (one human-parameterized BN and two machine-parameterized BNs). To assess the effects of feature selection, we conducted secondary analyses of discriminative ability using the most influential findings defined by their likelihood ratios. RESULTS: The overall accuracy of Topaz was significantly better than MedLEE (with post-processing) (0.78 vs 0.71, p<0.0001). Classifiers using human-annotated findings were superior to classifiers using Topaz/MedLEE extracted findings (average area under the receiver operating characteristic (AUROC): 0.75 vs 0.68, p=0.0113), and machine-parameterized classifiers were superior to the human-parameterized classifier (average AUROC: 0.73 vs 0.66, p=0.0059). The classifiers using the 17 'most influential' findings were more accurate than classifiers using all 31 subject-matter expert-identified findings (average AUROC: 0.76>0.70, p<0.05). CONCLUSIONS: Using a three-component evaluation method we demonstrated how one could elucidate the relative contributions of components under an integrated framework. To improve classification performance, this study encourages researchers to improve NLP accuracy, use a machine-parameterized classifier, and apply feature selection methods. PMID- 24406262 TI - Critical appraisal of organ procurement under Maastricht 3 condition. AB - The ethics committee of the French Society of Anesthesia and Intensive Care (Sfar) has been requested by the French Biomedical Agency to consider the issue of organ donation in patients after the decision to withdraw life-supportive therapies has been taken. This type of organ donation is performed in the USA, Canada, the United Kingdom, the Netherlands and Belgium. The three former countries have published recommendations formalizing procedures and operations. The French Society of Anesthesia and Intensive Care (Societe francaise d'anesthesie et de reanimation [Sfar]) ethics committee has considered this issue and envisioned the different aspects of the whole process. Consequently, it sounded a note of caution regarding the applicability of this type of organ procurement in unselected patients following a decision to withdraw life supportive therapies. According to French regulations concerning organ procurement in brain-dead patients, the committee stresses the need to restrict this specific way of procurement to severely brain-injured patients, once confirmatory investigations predicting a catastrophic prognosis have been performed. This suggests that the nature of the confirmatory investigation required should be formalized by the French Biomedical Agency on behalf of the French parliamentarians, which should help preserve population trust regarding organ procurement and provide a framework for medical decision. This text has been endorsed by the Sfar. PMID- 24406263 TI - Readmissions following elective radical total gastrectomy for early gastric cancer: a case-controlled study. AB - BACKGROUND: Readmission after gastrectomy is one of the factors that reflect quality of life. Therefore, we analyzed the several factors related to readmissions after total gastrectomy for early gastric cancer. METHODS: From January 2002 through December 2009, 102 consecutive patients who underwent radical total gastrectomy for early gastric cancer were enrolled in this study. We evaluated the incidence, cause, time point, and type of treatment for readmission after discharge; we compared the readmission and non-readmission groups in regard to clinicopathologic features and postoperative outcomes. RESULTS: The readmission rate during the five years after total gastrectomy was 22 of 102 (21.6%). The most common cause for readmission was esophagojejunostomy stricture (5 cases). The treatment given for 31 readmissions included 23 conservative therapies, 3 radiologic or endoscopic interventions, and 5 re operations. No significant differences were detected in the clinicopathologic feature, postoperative outcomes, or 5-year survival rates between the readmission and non-readmission group. No specific risk factor was found to be associated with readmission. CONCLUSION: Although we could not determine a specific risk factor associated with readmission after radical total gastrectomy, prevention of readmission by evaluating the causes and treatments after radical total gastrectomy can improve the patient's quality of life. PMID- 24406264 TI - Comparison of tissue effects in rabbit muscle of surgical dissection devices. AB - While some energy-based surgical dissection and coagulation modalities may offer excellent cutting and coagulation abilities, the impact on healing may differ among devices. We compared the tissue effects of three of these modalities with those of the standard surgical scalpel in rabbit muscle at 24 h and 14 days after surgery by evaluating radiographic and histological data. Linear incisions were made with each device in the dorsal lumbar musculature of rabbits using monopolar electrocautery in cut mode (MPE-Cut) and coagulation mode (MPE-Coag), a ferromagnetic induction loop (FMI), and a traditional scalpel. Magnetic resonance imaging scans and histological sampling were done at 24 h and 14 days. Subjective cutting and coagulation characteristics for each device were also recorded during surgery. The scalpel and FMI appeared to cause the least tissue damage adjacent to the incisions in rabbit dorsal lumbar musculature. The scalpel showed the best healing, while the FMI and MPE-Cut demonstrated good healing. The MPE-Coag showed the worst tissue healing. The scalpel, FMI, and MPE-Cut all exhibited favorable subjective characteristics during surgery. It appears that the FMI may be a better choice for surgical dissection and coagulation in muscle tissue than the MPE coagulation mode because it shows less tissue damage and offers better tissue healing. PMID- 24406265 TI - Can we fix it? Evaluating the potential of placental stem cells for the treatment of pregnancy disorders. AB - In pregnancy disorders such as pre-eclampsia, intrauterine growth restriction (IUGR) and recurrent miscarriage a poorly functioning placenta is thought to be a major component of the disease process. However, despite their prevalence, we currently have no way to fix dysfunctional placentae or directly treat these disorders. Over the past two decades our understanding of the role that stem cells play in organ development and regeneration has expanded rapidly, and over the past 5 years the therapeutic use of stem cells to both regenerate damaged tissues, and act as potent modulators of diseased microenvironments, has become a reality in many organs including the heart, kidney, liver, skin and eye. Over its short lifespan the placenta undergoes rapid and continuous growth and differentiation, meaning that placental 'organogenesis' only truly ends at delivery, and thus stem cells are likely to play important roles in placental function for the duration of pregnancy. Two populations of stem cells exist in the placenta that contribute to this on-going growth and differentiation: trophoblast stem cells and mesenchymal stem cells. This review will address our current understanding of how each of these stem cell populations contributes to successful placental function, how epithelial and mesenchymal stem cell populations are being translated to the clinic in other fields, and whether these advances can teach us anything about how placental stem cells could be used to fix faulty placentae in the future. PMID- 24406266 TI - Influence of speed of sample processing on placental energetics and signalling pathways: implications for tissue collection. AB - INTRODUCTION: The placenta is metabolically highly active due to extensive endocrine and active transport functions. Hence, placental tissues soon become ischaemic after separation from the maternal blood supply. Ischaemia rapidly depletes intracellular ATP, and leads to activation of stress-response pathways aimed at reducing metabolic demands and conserving energy resources for vital functions. Therefore, this study aimed to elucidate the effects of ischaemia ex vivo as may occur during tissue collection on phosphorylation of placental proteins and kinases involved in growth and cell survival, and on mitochondrial complexes. METHODS: Eight term placentas obtained from normotensive non-laboured elective caesarean sections were kept at room-temperature and sampled at 10, 20, 30 and 45 min after delivery. Samples were analyzed by Western blotting. RESULTS: Between 10 and 45 min the survival signalling pathway intermediates, P-AKT, P GSK3alpha and beta, P-4E-BP1 and P-p70S6K were reduced by 30-65%. Stress signalling intermediates, P-eIF2alpha increased almost 3 fold after 45 min. However, other endoplasmic reticulum stress markers and the Heat Shock Proteins, HSP27, HSP70 and HSP90, did not change. Phosphorylation of AMPK, an energy sensor, was elevated 2 fold after 45 min. Contemporaneously, there was an ~25% reduction in mitochondrial complex IV subunit I. DISCUSSION AND CONCLUSIONS: These results suggest that for placental signalling studies, samples should be taken and processed within 10 min of caesarean delivery to minimize the impact of ischaemia on protein phosphorylation. PMID- 24406267 TI - The contribution of familial internalizing and externalizing liability factors to borderline personality disorder. AB - BACKGROUND: Individuals with borderline personality disorder (BPD) frequently display co-morbid mental disorders. These disorders include 'internalizing' disorders (such as major depressive disorder and anxiety disorders) and 'externalizing' disorders (such as substance use disorders and antisocial personality disorder). It is hypothesized that these disorders may arise from latent 'internalizing' and 'externalizing' liability factors. Factor analytic studies suggest that internalizing and externalizing factors both contribute to BPD, but the extent to which such contributions are familial is unknown. METHOD: Participants were 368 probands (132 with BPD; 134 without BPD; and 102 with major depressive disorder) and 885 siblings and parents of probands. Participants were administered the Diagnostic Interview for DSM-IV Personality Disorders, the Revised Diagnostic Interview for Borderlines, and the Structured Clinical Interview for DSM-IV. RESULTS: On confirmatory factor analysis of within-person associations of disorders, BPD loaded moderately on internalizing (factor loading 0.53, S.E. = 0.10, p < 0.001) and externalizing latent variables (0.48, S.E. = 0.10, p < 0.001). Within-family associations were assessed using structural equation models of familial and non-familial factors for BPD, internalizing disorders, and externalizing disorders. In a Cholesky decomposition model, 84% (S.E. = 17%, p < 0.001) of the association of BPD with internalizing and externalizing factors was accounted for by familial contributions. CONCLUSIONS: Familial internalizing and externalizing liability factors are both associated with, and therefore may mutually contribute to, BPD. These familial contributions account largely for the pattern of co-morbidity between BPD and internalizing and externalizing disorders. PMID- 24406268 TI - Prevalence and correlates of food insecurity among students attending a midsize rural university in Oregon. AB - OBJECTIVE: To examine the prevalence and identify correlates of food insecurity among students attending a rural university in Oregon. METHODS: Cross-sectional nonprobability survey of 354 students attending a midsize rural university in Oregon during May, 2011. The main outcome was food insecurity measured using the US Department of Agriculture Household Food Security Survey Module: 6-Item Short Form. Socioeconomic and demographic variables were included in multivariate logistic regression models. RESULTS: Over half of students (59%) were food insecure at some point during the previous year. Having fair/poor health (odds ratio [OR], 2.08; 95% confidence interval [CI], 1.07-4.63), being employed (OR, 1.73; 95% CI, 1.04-2.88), and having an income < $15,000/y (OR, 2.23; 95% CI, 1.07-4.63) were associated with food insecurity. In turn, good academic performance (grade point average of >= 3.1) was inversely associated with food insecurity. CONCLUSIONS: Food insecurity seems to be a significant issue for college students. It is necessary to expand research on different campus settings and further strengthen support systems to increase access to nutritious foods for this population. PMID- 24406269 TI - Barriers and supports to implementing a nutrition and physical activity intervention in child care: directors' perspectives. AB - OBJECTIVE: To explore the experiences of child care centers implementing a nutrition and physical activity (PA) program and identify supports and barriers as reported by center directors. DESIGN: Semi-structured interviews with 20 child care center directors following program implementation. SETTING: Twenty-two child care centers serving low-income children in Georgia. PARTICIPANTS: Twenty child care center directors who led program implementation at their respective centers. INTERVENTION: The program focused on introducing wellness policies to centers and on providing training and technical assistance to support implementation. PHENOMENON OF INTEREST: Center directors' perceptions, attitudes, and reflections on the process of implementing changes to nutrition and PA practices. ANALYSIS: Qualitative analysis of interview transcripts was conducted using NVivo 9 software. Researchers employed 2 levels of coding; 4 predominant themes emerged. RESULTS: Directors' insights included the importance of hands-on activities and printable materials to engage children in nutrition and PA education and healthy behaviors; challenges and supports to engaging parents in child wellness; recognition that children readily accept nutrition and PA changes; and the need for program implementation efforts to prioritize the provision of support for directors and staff in modifying nutrition and PA practices. CONCLUSION AND IMPLICATIONS: Directors consider nutrition and PA policy changes to be beneficial to the child care environment. This study highlights important considerations for efforts to promote healthy weight environments in the early care setting. PMID- 24406270 TI - Functional interactions of varenicline and nicotine with nAChR subtypes implicated in cardiovascular control. AB - INTRODUCTION: It has been suggested that varenicline-induced activation of nicotinic acetylcholine receptors (nAChRs) could play a role in the cardiovascular (CV) safety of varenicline. However, since preclinical studies showed that therapeutic varenicline concentrations have no effect in models of CV function, this study examined in vitro profiles of varenicline and nicotine at nAChR subtypes possibly involved in CV control. METHODS: Concentration-dependent functional effects of varenicline and nicotine at human alpha3beta4, alpha3alpha5beta4, alpha7, and alpha4beta2 nAChRs expressed in oocytes were determined by electrophysiology. The proportion of nAChRs predicted to be activated and inhibited by concentrations of varenicline (1mg b.i.d.) and of nicotine in smokers was derived from activation-inhibition curves for each nAChR subtype. RESULTS: Human varenicline and nicotine concentrations can desensitize and inhibit nAChRs but cause only low-level activation of alpha3beta4, alpha4beta2 (<2%), alpha7 (<0.05%), and alpha3alpha5beta4 (<0.01%) nAChRs, which is consistent with literature data. Nicotine concentrations in smokers are predicted to inhibit larger fractions of alpha3beta4 (48%) and alpha3alpha5beta4 (10%) nAChRs than therapeutic varenicline concentrations (11% and 0.6%, respectively) and to inhibit comparable fractions of alpha4beta2 nAChRs (42%-56%) and alpha7 nAChRs (16%) as varenicline. CONCLUSIONS: Nicotine and varenicline concentrations in patients and smokers are predicted to cause minimal activation of ganglionic alpha3beta4* nAChRs, while their functional profiles at alpha3beta4, alpha3alpha5beta4, alpha7, and alpha4beta2 nAChRs cannot explain that substituting nicotine from tobacco with varenicline would cause CV adverse events in smokers who try to quit. Other pharmacological properties that could mediate varenicline-induced CV effects have not been identified. PMID- 24406271 TI - Assessment of immunosuppressive activity of human mesenchymal stem cells using murine antigen specific CD4 and CD8 T cells in vitro. AB - INTRODUCTION: Mesenchymal stem cells (MSCs) have immunosuppressive activity. They do not induce allospecific T cell responses, making them promising tools for reducing the severity of graft versus host disease (GVHD) as well as treating various immune diseases. Currently, there is a need in the MSC field to develop a robust in vitro bioassay which can characterize the immunosuppressive function of MSCs. METHODS: Murine clonal CD4 and CD8 T cells were stimulated with cognate peptide antigen and antigen presenting cells (APCs) in the absence or presence of human MSCs, different aspects of T cell activation were monitored and analyzed using flow cytometry, real time RT-PCR and cytokine measurement. RESULTS: Human MSCs (hMSCs) can alter multiple aspects of murine T cell activation induced by stimulation with specific antigen, including: reduced proliferation, inhibited or stimulated cell surface marker expression (CD25, CD69, CD44 and CD62L), inhibited mRNA expression of transcription factors (T-bet and GATA-3) and decreased cytokine expression (interferon-gamma, interleukin-10). Disappearance of activation-induced cluster formation and decreased apoptosis of CD8 T cells were also observed. Moreover, the effects are specific to MSCs; incubating the T cells with non-MSC control cell lines had no effect on T cell proliferation and activation. CONCLUSIONS: Clonal murine T cells can be used to measure, characterize, and quantify the in vitro immunosuppressive activity of human MSCs, representing a promising approach to improve bioassays for immunosuppression. PMID- 24406272 TI - A comparison study of haemolysis production in three contemporary centrifugal pumps. AB - One challenge in providing extracorporeal circulation is to supply optimal flow while minimising adverse effects, such as haemolysis. To determine if the recent generation constrained vortex pumps with their inherent design improvements would lead to reduced red cell trauma, we undertook a study comparing three devices. Utilizing a simulated short-term ventricular assist circuit primed with whole human blood, we examined changes in plasma free haemoglobin values over a six-day period. The three pumps investigated were the Maquet Rotaflow, the Levitronix PediVAS and the Medos Deltastream DP3.This study demonstrated that all three pumps produced low levels of haemolysis and are suitable for use in a clinical environment. The Levitronix PediVAS was significantly less haemolytic than either the Rotaflow (p<0.05) or the DP3 (p<0.05). There was no significant difference in plasma free haemoglobin between the Rotaflow and the DP3 (p=0.71). PMID- 24406274 TI - One-month strawberry-rich anthocyanin supplementation ameliorates cardiovascular risk, oxidative stress markers and platelet activation in humans. AB - Strawberries are an important fruit in the Mediterranean diet because of their high content of essential nutrients and beneficial phytochemicals, which seem to exert beneficial effects in human health. Healthy volunteers were supplemented daily with 500 g of strawberries for 1 month. Plasma lipid profile, circulating and cellular markers of antioxidant status, oxidative stress and platelet function were evaluated at baseline, after 30 days of strawberry consumption and 15 days after the end of the study. A high concentration of vitamin C and anthocyanins was found in the fruits. Strawberry consumption beneficially influenced the lipid profile by significantly reducing total cholesterol, low density lipoprotein cholesterol and triglycerides levels (-8.78%, -13.72% and 20.80%, respectively; P<.05) compared with baseline period, while high-density lipoprotein cholesterol remained unchanged. Strawberry supplementation also significant decreased serum malondialdehyde, urinary 8-OHdG and isoprostanes levels (-31.40%, -29.67%, -27.90%, respectively; P<.05). All the parameters returned to baseline values after the washout period. A significant increase in plasma total antioxidant capacity measured by both ferric reducing ability of plasma and oxygen radical absorbance capacity assays and vitamin C levels (+24.97%, +41.18%, +41.36%, respectively; P<.05) was observed after strawberry consumption. Moreover, the spontaneous and oxidative hemolysis were significant reduced (-31.7% and -39.03%, respectively; P<.05), compared to the baseline point, which remained stable after the washout period. Finally, strawberry intake significant decrease (P<.05) the number of activated platelets, compared to both baseline and washout values. Strawberries consumption improves plasma lipids profile, biomarkers of antioxidant status, antihemolytic defenses and platelet function in healthy subjects, encouraging further evaluation on a population with higher cardiovascular disease risk. PMID- 24406275 TI - Peculiar observations in measuring testosterone in women treated with oral contraceptives supplemented with dehydroepiandrosterone (DHEA). AB - Total testosterone is considered to be decreased during the use of combined oral contraceptives. There is, however, considerable concern about the quality of testosterone assays, especially at low levels. We aimed to confirm testosterone levels measured by direct radioimmunoassay in a recent clinical trial with a state-of-the-art LC-MSMS method. Surplus specimens with known testosterone levels collected during the study (Clinical Trial Registration number ISRCTN06414473) were reanalyzed with an LC-MSMS method. This method was compared to another LC MSMS method that had shown to concur excellently to a reference method. Follow-up experiments were designed to explain the results. In contrast to our expectation, LC-MSMS measurements did not corroborate the data obtained by radioimmunoassay. Subsequent experiments showed that this could be attributed to a strong dependency of the radioimmunoassay on SHBG. Testosterone results (n = 198) obtained by direct radioimmunoassay showed a negative correlation to SHBG levels (r = -0.676; p<0.001). By contrast, testosterone results obtained by LC-MSMS were not related to SHBG (r = 0.100; NS). In conclusion, our results indicate that total testosterone measurements during oral contraceptive use are unreliable when performed with assays sensitive to the SHBG concentration. The discrepancy with the literature can most likely be explained by the sensitivity of the immunoassay used to SHBG. Given the sharp increase in SHBG during the use of many oral contraceptives, total testosterone may not decrease, whereas its bioavailability, estimated by free testosterone levels, will be diminished. Studies aiming at restoration of testosterone homeostasis during oral contraception need to take this into account. PMID- 24406276 TI - DNA from buccal swab is suitable for rapid genotyping of angiotensin-converting enzyme insertion/deletion (I/D) polymorphism. AB - BACKGROUND: Plasma angiotensin-converting enzyme (ACE) variability between individuals is the results of an insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene. The I and D alleles differ for the presence or absence of a 288 bp Alu sequence DNA fragment. METHODS: The present paper regards the development of a single-tube High Resolution Melting Analysis (HRMA), applied to DNA extracted by buccal swabs, for determining three ACE I/I, I/D, D/D genotypes, in order to obtain a rapid and high throughput method. This method takes advantage of the presence of the 288 bp DNA fragment. Primer design was performed taking into account the possible different efficiency of allele I amplification compared to allele D, avoiding the misclassification of I/D with D/D genotypes. RESULTS: 50 samples previously genotyped by "conventional" PCR protocol already published in literature were 100% concordant with the HRMA results, showing high reproducibility, sensitivity and specificity. ACE genotypes were distinguished by normalized temperature melting curves and by derivate fluorescence plots. CONCLUSIONS: HRMA was confirmed as particularly suitable for the identification of ACE I/D polymorphism. Simple setup and rapidity of the analysis (about 1.5 h for 96 samples, including data interpretation) are other important advantages along with low-costs, making this technique useful in clinical research and diagnostics. PMID- 24406273 TI - Application of nanotechnology in improving bioavailability and bioactivity of diet-derived phytochemicals. AB - Nanotechnology is an innovative approach that has potential applications in nutraceutical research. Phytochemicals have promising potential for maintaining and promoting health, as well as preventing and potentially treating some diseases. However, the generally low solubility, stability, bioavailability and target specificity, together with the side effects seen when used at high levels, have limited their application. Indeed, nanoparticles can increase solubility and stability of phytochemicals, enhance their absorption, protect them from premature degradation in the body and prolong their circulation time. Moreover, these nanoparticles exhibit high differential uptake efficiency in the target cells (or tissue) over normal cells (or tissue) through preventing them from prematurely interacting with the biological environment, enhanced permeation and retention effect in disease tissues and improving their cellular uptake, resulting in decreased toxicity, In this review, we outline the commonly used biocompatible and biodegradable nanoparticles including liposomes, emulsions, solid lipid nanoparticles, nanostructured lipid carriers, micelles and poly(lactic-co-glycolic acid) nanoparticles. We then summarize studies that have used these nanoparticles as carriers for epigallocatechin gallate, quercetin, resveratrol and curcumin administration to enhance their aqueous solubility, stability, bioavailability, target specificity and bioactivities. PMID- 24406277 TI - Stabilization of proximal interphalangeal joint in lesser toe deformities with an angulated intramedullary implant. AB - BACKGROUND: Hammertoe and claw toe are among the most common foot deformities. Proximal interphalangeal (PIP) joint realignment can be performed using specifically designed intramedullary implants. The aim of this study was to assess the clinical outcome of patients with lesser toes deformities undergoing PIP joint realignment using an intramedullary implant. METHODS: Patients requiring PIP joint realignment were included in this prospective multicenter observational study and followed for 12 months. A total of 156 toes, in 117 patients were implanted with the implants. Complications and radiological and functional outcome were assessed. RESULTS: The proportion of joints fused on X rays was 83.8% (95% CI: 77.8, 89.7) after 1 year. American Orthopaedic Foot and Ankle Society lesser metatarsophalangeal-interphalangeal scale (AOFAS-LMIS) improved from 40.4 (SD = 18.3) preoperatively to 85.5 (SD = 9.2) after 1 year. The proportion of patients with pain was 15.5% after 6 weeks and decreased to 4.7% after 1 year. Of the patients, 98% were satisfied about the operation. In patients with incomplete fusion of the PIP joint after 1 year, AOFAS-LMIS improved from 36.7 (SD = 18.9) preoperatively to 84.2 (SD = 10.1) 1 year postoperatively, while pain was reported by 2 patients (8.3%) after 1 year. Toe malalignment and lack of toe pulp-contact were reported slightly more frequently than for the whole group of patients, but not for the majority of the cases. Overall, complications were reported intraoperatively in 1.3% of the patients (2 cases) and postoperatively in 3.2% (5 cases). Revision was required in 1 case. Mallet toe deformity was found in 2.0% of the patients after 1 year. CONCLUSION: This study showed that the use of an intramedullary implant for PIP realignment led to a high rate of fusion and a good outcome. No need of reoperation was reported for patients with incomplete joint fusion who had a stable joint with no pain. LEVEL OF EVIDENCE: Level IV, prospective case series. PMID- 24406278 TI - A comparative study of clinicopathological features between simple bone cysts of the calcaneus and the long bone. AB - BACKGROUND: The potential unrevealed clinicopathological differences between simple bone cysts situated in the calcaneus (calcaneal bone cysts) and those situated in long bones (long bone cysts) were investigated in the present study. METHODS: A total of 41 cysts from 41 patients who underwent operative treatment were evaluated: 16 cysts in the calcaneus, 17 in the humerus, 7 in the femur, and 1 in the tibia. The clinical course, radiological findings, and histological features were retrospectively reviewed. RESULTS: The mean patient age was 11.5 years (range, 3 to 25 years), and the mean follow-up was 33.0 months (range, 12 to 77 months). The mean patient age was significantly higher in patients with calcaneal bone cysts (13.5 years; long bone cysts, 10.2 years, P < .05). No treatment failure was seen for patients with calcaneal bone cysts, while 7 long bone cysts required reoperation. In H&E-stained specimens of the cyst wall, cholesterol clefts were identified in 10 of the 16 calcaneal bone cysts (62.5%), whereas none were identified in long bone cysts (0%; P < .0001). CONCLUSION: Our study elucidates the different clinicopathological features existing between calcaneal bone cysts and long bone cysts. Cholesterol clefting is most likely due to hemorrhaging and the subsequent breakdown of blood in the cyst. The significance of these differences between long bone and calcaneal cysts is still open to conjecture. LEVEL OF EVIDENCE: Level III, retrospective comparative series. PMID- 24406279 TI - Pharmacogenetic potential biomarkers for carbamazepine adverse drug reactions and clinical response. AB - Carbamazepine (CBZ) is a first-line widely used anticonvulsant. It has a narrow therapeutic index and exhibits considerable interindividual and interethnic variability in clinical efficacy and adverse drug reactions including potentially life-threatening hypersensitivity reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. The most important pharmacogenetic finding is related to the association of CBZ-induced hypersensitivity with human leukocyte antigens (HLA class I and II alleles). Moreover, genotyping for HLA-B*15:02 allele is required prior to initiating CBZ in Asians and Asian ancestry patients, demonstrating the usefulness of biomarkers to avoid adverse drug reactions. On the other hand, in order to explain the differences in the clinical response to CBZ, genetic polymorphisms in phase I (CYP3A4, CYP3A5 and EPHX1) and phase II (UGT2B7) metabolising enzymes have been assessed; additionally, the influence of transporters (ABCB1 and ABCC2), receptors (PXR) and other drug targets (voltage- gated Na+ channels) in CBZ clinical response has been evaluated. To date, these studies are controversial and require further investigations to clarify the functional role of these polymorphisms as potential biomarkers in regard to CBZ therapy. PMID- 24406280 TI - Evaluation of clinical cases in External Quality Assessment Scheme (EQAS) for the urinary sediment. AB - BACKGROUND: The few available External Quality Assessment (EQA) programs on urinary sediment rarely include an evaluation of clinical cases. The present paper provides a descriptive analysis of clinical cases included in the Italian EQA program on urinary sediment. METHODS: Ten cases were presented over a 5-year period (2007-2011). Each clinical case included a brief clinical history, some key laboratory data and four key urinary sediment particles obtained by phase contrast microscopy. The clinical diagnoses indicated by participants, chosen among four or five proposed, were evaluated only for those who had been able to correctly identify all four urinary sediment particles. The results of each survey were then evaluated, scored and commented on. RESULTS: The numbers of participants for the 10 surveys ranged from 268 to 325. Throughout surveys, only 63.9%+/-17.0% (range 39.6%-88.7%) of participants achieved access to clinical diagnosis. Of these, 90.2%+/-8.5% (range 73.7%-98.1%) were able to indicate the correct diagnosis. CONCLUSIONS: Our findings demonstrate that once the correct identification of urinary sediment particles is obtained, most participants are able to associate urinary findings with the respective clinical conditions, thus establishing the correct diagnosis. PMID- 24406281 TI - The in vitro stability of novel cardiovascular and sepsis biomarkers at ambient temperature. AB - BACKGROUND: The in vitro stability of a biomarker can determine whether it should be used in clinical practice where long delays between sampling and assay are common. We measured the in vitro stability of five novel biomarkers that are being evaluated for their diagnostic and/or prognostic utility in patients with heart failure: mid-regional pro-atrial natriuretic peptide (MR-proANP), mid regional pro-adreno-medullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET 1), C-terminal pro-arginine vasopressin (copeptin) and ultrasensitive procalcitonin (PCT). METHODS: Peripheral venous blood samples were obtained from 19 patients with chronic heart failure into four EDTA tubes. The first tubes were centrifuged immediately at 4 degrees C with the other tubes stored at 20 degrees C for 4, 24 or 72 hours (h) before centrifuging. Supernatant plasma was frozen and stored at -80 degrees C until assay. The levels of analyte in samples processed with and without delay were compared using correlation analysis, paired t-tests and Bland-Altman plots. RESULTS: Copeptin and PCT were stable up to 72 h at 20 degrees C in whole blood and MR-proANP and MR-proADM up to 24 h. However, CT-proET-1 showed some signs of degradation after only 4 h with 94% of analyte recovered after 24 h, dropping to 80% after 72 h. CONCLUSIONS: MR-proANP, MR proADM, copeptin and PCT are stable biomarkers and therefore suitable for introduction into routine clinical practice in a primary or secondary care setting where delays in sample preparation and assay are likely. Ideally, samples for measurement of CT-proET-1 should be centrifuged soon after venepuncture but the analyte is stable enough for most routine clinical purposes. PMID- 24406282 TI - N Latex FLC serum free light-chain assays in patients with renal impairment. AB - BACKGROUND: The aim of this study was to establish ranges for N Latex free light chain (FLC) monoclonal-based nephelometric assays in patients with renal impairment. METHODS: In this retrospective study, serum samples from 284 patients with chronic kidney disease (CKD) stages 1-5 were measured with N Latex and Freelite FLC reagents on the Siemens BNII system and compared with controls without renal impairment. RESULTS: Both kappaFLC and lambdaFLC concentrations increased with the N Latex FLC and the Freelite assays with each increment in CKD stage. No difference was found in FLC kappa concentrations between the two methods. In patients with renal failure, N Latex FLC detected higher concentrations of lambdaFLC (CKD5 median, 128 mg/L; 95% range, 43-302) compared with Freelite (89.5 mg/L, 35-197) (p<0.0001). This resulted in significantly different kappa/lambda ratios in patients with CKD for the two tests. The Freelite kappa/lambda ratio in the CKD5 group (median, 1.22; min-max, 0.22-2.70) was significantly increased compared with healthy controls (p<0.0001), and several individual samples were outside the reference range for healthy controls (0.26-1.65). In contrast, none of the 284 patients with CKD had an FLC kappa/lambda ratio exceeding the N Latex reference limits for healthy controls (0.31-1.56). The N Latex FLC kappa/lambda ratio in the CKD5 group (0.69, 0.32 1.54) was significantly lower compared with the control group (p<0.0001). CONCLUSIONS: These findings demonstrate that the N Latex FLC kappa/lambda ratio in patients with renal failure did not differ from the reference limits for healthy controls. PMID- 24406283 TI - Serum melatonin levels in psoriasis and associated depressive symptoms. PMID- 24406284 TI - Better blood collection tubes for plasma glucose: ready for prime time? PMID- 24406285 TI - 25-Hydroxy vitamin D levels in chronic urticaria and its correlation with disease severity from a tertiary care centre in South India. PMID- 24406286 TI - Stat testing utilization in clinical laboratories. National survey of Italian Society of Clinical Biochemistry and Molecular Biology (SIBioC). PMID- 24406288 TI - Validation of a point-of-care (POC) lactate testing device for fetal scalp blood sampling during labor: clinical considerations, practicalities and realities. AB - BACKGROUND: Although fetal blood sampling for pH is well established the use of lactate has not been widely adopted. This study validated the performance and utility of a handheld point-of-care (POC) lactate device in comparison with the lactate and pH values obtained by the ABL 800 blood gas analyzer. METHODS: The clinical performance and influences on accuracy and decision-making criteria were assessed with freshly taken fetal blood scalp samples (n=57) and umbilical cord samples (n=310). Bland-Altman plot was used for data plotting and analyzing the agreement between the two measurement devices and correlation coefficients (R2) were determined using Passing-Bablok regression analysis. RESULTS: Sample processing errors were much lower in the testing device (22.8% vs. 0.5%). Following a preclinical assessment and calibration offset alignment (0.5 mmol/L) the test POC device showed good correlation with the reference method for lactate FBS (R2=0.977, p<0.0001, 95% CI 0.9 59-0.988), arterial cord blood (R2=0.976, p<0.0001, 95% CI 0.967-0.983) and venous cord blood (R2=0.977, p<0.0001, 95% CI 0.968-0.984). CONCLUSIONS: A POC device which allows for a calibration adjustment to be made following preclinical testing can provide results that will correlate closely to an incumbent lactate method such as a blood gas analyzer. The use of a POC lactate device can address the impracticality and reality of pH sample collection and testing failures experienced in day to day clinical practice. For the StatStrip Lactate meter we suggest using a lactate cut-off of 5.1 mmol/L for predicting fetal acidosis (pH<7.20). PMID- 24406287 TI - Evaluation of INK4A promoter methylation using pyrosequencing and circulating cell-free DNA from patients with hepatocellular carcinoma. AB - BACKGROUND: Hyper-methylation of CpG dinucleotides in the promoter region of inhibitor of cyclin-dependent kinase 4A (INK4A) has been reported in 60%-80% of hepatocellular carcinoma (HCC). As INK4A promoter hypermethylation event occurs early in HCC progression, the quantification of INK4A promoter methylation in blood sample may represent a useful biomarker for non-invasive diagnosis and prediction of response to therapy. METHODS: We examined INK4A promoter methylation using circulating cell-free DNA (ccfDNA) in a total of 109 serum specimens, including 66 HCC and 43 benign chronic liver diseases. Methylation of the individual seven CpG sites was examined using pyrosequencing. RESULTS: Our results showed that there were significantly higher levels of methylated INK4A in HCC specimens than controls and that the seven CpG sites had different levels of methylation and might exist in different PCR amplicons. The area under receiver operating characteristic (ROC) curve was 0.82, with 65.3% sensitivity and 87.2% specificity at 5% (LOD), 39.0% sensitivity and 96.5% specificity at 7% LOD, and 20.3% sensitivity and 98.8% specificity at 10% LOD, respectively. CONCLUSIONS: Our results support additional studies incorporating INK4A methylation testing of ccfDNA to further validate the diagnostic, predictive, and prognostic characteristics of this biomarker in HCC patients. The knowledge of the existence of epi-alleles should help improve assay design to maximize detection. PMID- 24406289 TI - Dabigatran, rivaroxaban, apixaban, argatroban and fondaparinux and their effects on coagulation POC and platelet function tests. AB - BACKGROUND: In recent years, several selectively acting anticoagulants, including the direct thrombin inhibitors (DTI; argatroban, dabigatran) and the factor Xa inhibitors (rivaroxaban, apixaban, fondaparinux), have been developed. With their clinical application increasing, it is of interest to evaluate their interference with classical haemostaseological point-of-care tests. Additionally, the effect of the investigated anticoagulants on platelet function tests will come increasingly more into focus for monitoring not only hereditary platelet dysfunction, but also antiplatelet therapy. METHODS: Blood samples from healthy volunteers were spiked with therapeutic and supratherapeutic concentrations of the drugs listed above and investigated with regard to their effects on the following POCTs: activated clotting time (ACT), thromboelastometry with ROTEM, PFA and Multiplate. Light-transmission aggregometry (LTA) was used for a platelet function assay. RESULTS: At supratherapeutic concentrations, ACT and ROTEM analysis were always influenced after administration of the drugs listed above (except fondaparinux in EXTEM-CT). Therapeutic concentrations showed differential effects on these assays. LTA measurements revealed a distinct decrease in alpha thrombin-induced platelet aggregation for both DTIs (therapeutic and supratherapeutic concentrations), while argatroban reduced platelet function in supratherapeutic concentrations. None of the drugs seemed to have any influence on PFA or Multiplate. CONCLUSIONS: Selective thrombin and factor Xa inhibitors exhibit distinct effects on POCTs and platelet function tests. This must be considered in assessing assay results when taking medical decisions. PMID- 24406290 TI - Effect of storage conditions and freeze/thaw cycles on serum and plasma levels of anti-acetylcholine receptor (AChR) antibody. PMID- 24406292 TI - Printable temperature-responsive hybrid hydrogels with photoluminescent carbon nanodots. AB - Smart ink-like hybrid hydrogels that simultaneously possess semi-interpenetrating network structure, strong photoluminescence and temperature sensitivity are successfully fabricated based on the crosslink of poly(acrylamide) (PAAm) in the presence of poly(N-isopropylacrylamide) (PNIPAM) and carbon nanodots (CNDs) at room temperature. The resulting hybrid hydrogels were highly photoluminescent. The photoluminescence was sensitive to external temperature stimuli and reversible. Moreover, the hybrid hydrogels were applied as fluorescent inks for patterning using gravure printing, which may open a door towards developing smart CND based thermosensitive photoluminescent markers and sensors. PMID- 24406291 TI - Gynecologic cancer disparities: a report from the Health Disparities Taskforce of the Society of Gynecologic Oncology. AB - OBJECTIVES: To review the extent of health disparities in gynecologic cancer care and outcomes and to propose recommendations to help counteract the disparities. METHODS: We searched the electronic databases PubMed and the Cochrane Library. We included studies demonstrating quantifiable differences by race and ethnicity in the incidence, treatment, and survival of gynecologic cancers in the United States (US). Most studies relied on retrospective data. We focused on differences between Black and White women, because of the limited number of studies on non Black women. RESULTS: White women have a higher incidence of ovarian cancer compared to Black women. However, the all-cause ovarian cancer mortality in Black women is 1.3 times higher than that of White women. Endometrial and cervical cancer mortality in Black women is twice that of White women. The etiology of these disparities is multifaceted. However, much of the evidence suggests that equal care leads to equal outcomes for Black women diagnosed with gynecologic cancers. Underlying molecular factors may play an additional role in aggressive tumor biology and endometrial cancer disparities. CONCLUSION: Gynecologic cancer disparities exist between Black and White women. The literature is limited by the lack of large prospective trials and adequate numbers of non-Black racial and ethnic groups. We conclude with recommendations for continued research and a multifaceted approach to eliminate gynecologic cancer disparities. PMID- 24406293 TI - Impairment of the immune system in GH-overexpressing transgenic zebrafish (Danio rerio). AB - Growth hormone (GH) is an important regulator of immune functions in vertebrates, and it has been intensively reported a series of stimulatory actions of this hormone over on the immune system. Within aquaculture, overexpression of GH has been considered a promising alternative for promoting higher growth rates in organisms of commercial interest. Considering the various pleiotropic effects of GH, there are still few studies that aim to understand the consequences of the excess of GH on the physiological systems. In this context, our goal was to present the effects of the overexpression of GH on immune parameters using a model of zebrafish (Danio rerio) that overexpress this hormone. The results showed that GH transgenic zebrafish had 100% of mortality when immunosuppressed with dexamethasone, revealing a prior weakening of the immune system in this lineage. Morphometric analysis of thymus and head kidney revealed a reduction in the area of these structures in transgenic zebrafish. Moreover, the phenotypic expression of CD3 and CD4 thymocytes was also depreciated in transgenic zebrafish. Furthermore, a decrease was noted in the expression of genes RAG-1 (60%), IKAROS (50%), IL-1beta (55%), CD4 (60%) and CD247 (40%), indicating that development parameters, of innate and acquired immunity, are being harmed. Based on these results, it can be concluded that the excess of GH impairs the immune functions in GH transgenic zebrafish, indicating that the maintenance of normal levels of this hormone is essential for the functioning of immunological activities. PMID- 24406294 TI - Cholesterol sensitises the transient receptor potential channel TRPV3 to lower temperatures and activator concentrations. AB - TRPV3, a thermosensitive cation channel, is predominantly expressed in keratinocytes. It contributes to physiological processes such as thermosensation, nociception, and skin development. TRPV3 is polymodally regulated by chemical agonists, innocuous heat, intracellular acidification or by membrane depolarization. By manipulating the content of plasma membrane cholesterol, a key modulator of the physicochemical properties of biological membranes, we here addressed the question, how the lipid environment influences TRPV3. Cholesterol supplementation robustly potentiated TRPV3 channel activity by sensitising it to lower concentrations of chemical activators. In addition, the thermal activation of TRPV3 is significantly shifted to lower temperatures in cholesterol-enriched cells. The sensitising effect of cholesterol was not caused by an increased plasma membrane targeting of the channel. In HaCaT keratinocytes, which natively express TRPV3, a cholesterol-mediated sensitisation of TRPV3-like responses was reproduced. The cholesterol-dependent modulation of TRPV3 activity may provide a molecular mechanism to interpret its involvement in keratinocyte differentiation. PMID- 24406295 TI - Do androgen deprivation drugs affect the immune cross-talk between mononuclear and prostate cancer cells? AB - The aim of the study was to examine the effect of androgen deprivation drugs, i.e. leuprolide and bicalutamide on the immune cross-talk between human peripheral blood mononuclear cells (PBMC) and cells from PC-3 and LNCaP human prostate cancer lines. PBMC, PC-3 and LNCaP were separately incubated without and with two androgen-deprivation drugs, i.e. leuprolide and bicalutamide, and the secretion of IL-1beta, IL-6, IL-1ra and IL-10 was examined. In addition, the effect of both drugs on the production of those cytokines was carried out after 24 hours incubation of PBMC with both types of cancer cells. Leuprolide or bicalutamide did not affect the production of the cytokines by PBMC or by the prostate cancer cells from the two lines. Incubation of PBMC with PC-3 or LNCaP cells caused increased production of IL-1beta, IL-6 and IL-10 as compared with PBMC incubated without malignant cells. While 10(-7) M and 10(-8) M of leuprolide caused a decreased secretion of IL-1beta by PBMC previously incubated with prostate cancer cells without the drug, bicalutamide did not affect this PBMC activity at any drug concentration. This observation suggests the existence of an additional mechanism explaining the effect of androgen deprivation therapy in prostate cancer patients. PMID- 24406296 TI - Rho kinase inhibition by fasudil suppresses lipopolysaccharide-induced apoptosis of rat pulmonary microvascular endothelial cells via JNK and p38 MAPK pathway. AB - Apoptosis of microvascular endothelial cells plays a crucial role in the progression of various lung diseases and triggers microcirculatory disorder and organ dysfunction. LPS, an outer membrane component of Gram-negative bacteria, is one of the major virulence factors for lung diseases. Recent studies have shown that the Rho/Rho kinase (ROCK) pathway plays an important role in the regulation of apoptosis, inflammatory cell migration and chemokine production in various cell types and animal models. We therefore undertake this study to investigate the inhibitory effect of fasudil, a potent and selective inhibitor of ROCK, on LPS-induced apoptosis of rat pulmonary microvascular endothelial cells (PMVECs). The results suggested that fasudil effectively prevented LPS-induced injury of rat PMVECs, as determined by MTT assay, LDH activity assay, apoptosis and western blot analysis of apoptosis-related proteins Bcl-2 and Bax. Furthermore, the mechanisms underlying the protective effect were evaluated. We found that LPS induced MYPT-1 phosphorylation was markedly suppressed by fasudil. Moreover, fasudil pretreatment obviously inhibited the activation of JNK and p38 MAPKs induced by LPS, whereas that of ERK1/2 was not affected by fasudil. In addition, inhibiting the JNK and p38 pathways by SP600125 and SB203580 respectively attenuated the LPS-induced apoptosis and regulated the expression of apoptosis related proteins Bcl-2 and Bax. Taken together, these results demonstrate that fasudil exerts an anti-apoptotic effect in rat PMVECs, which is mediated by the inhibition of Rho/ROCK and its downstream JNK and p38 MAPKs. PMID- 24406297 TI - Proteome variance differences within populations of European whitefish (Coregonus lavaretus) originating from contrasting salinity environments. AB - Variation in gene expression is an important component of the phenotypic differences observed in nature. Gene expression variance across biological groups and environmental conditions has been studied extensively and has revealed specific genes and molecular mechanisms of interest. However, little is known regarding the importance of within-population gene expression variation to environmental adaptation. To address this issue, we quantified the proteomes of individuals of European whitefish (Coregonus lavaretus) from populations that have previously been shown to have adapted during early development to freshwater and brackishwater salinity environments. Using MS-based label-free proteomics, we studied 955 proteins in eight hatch-stage fish embryos from each population that had been reared in either freshwater or brackishwater salinity conditions. By comparing the levels of within-population protein expression variance over individuals and per protein between populations, we found that fish embryos from the population less affected by salinity level had also markedly higher levels of expression variance. Gene Ontologies and molecular pathways associated with osmoregulation showed the most significant difference of within-population proteome variance between populations. Several new candidate genes for salinity adaptation were identified, emphasising the added value of combining assessments of within-population gene expression variation with standard gene expression analysis practices for better understanding the mechanisms of environmental adaptation. BIOLOGICAL SIGNIFICANCE: We demonstrate the benefits of studying within-population gene expression variance together with more typical methods of gene expression profiling. Proteome variance differences within European whitefish populations originating from different salinity environments allowed us to identify several new candidate genes for salinity adaptation in teleost fish and generate many further hypotheses to be tested. This article is part of a Special Issue entitled: Proteomics of non-model organisms. PMID- 24406298 TI - Comparative proteomics unveils cross species variations in Anabaena under salt stress. AB - The present study compares protein diversity within three Anabaena species (Anabaena doliolum, Anabaena sp.PCC 7120 and Anabaena L31). 2-DE based analysis of 256 protein spots in control and 1, 3, 5, and 7days of salt treatment resulted into 96 proteins arching across fourteen functional categories were assigned to biochemical pathways using KOBAS 2.0. While 52.34% of the evaluated protein spots were common across three species, the remaining 47.66% fraction mainly comprised of the hypothetical and unknown proteins. PSORTb, CDD, Motifscan and Pfam revealed function and subcellular localization for 27 of the 31 hypothetical and unknown proteins. The differences in high salt tolerance (LC50) of A. doliolum over A. L31 was reflected by (i) many fold accumulation (as spot volumes) of Alr3090, Alr0803, peptidyl prolyl cis-trans isomerase and modulator of DNA gyrase proteins, and (ii) a better photosynthesis and energy homeostasis as indicated through photosystem activity, respiration, ATP and NADPH contents. Some common noteworthy salt effects include (i) photosystem damage, (ii) DNA damage repair, (iii) upregulated protein synthesis, (iv) enhanced sulphur metabolism, and (v) upregulated pentose phosphate pathway. 34 of the identified protein spots are novel entries to the Anabaena salt proteome. This study reveals the existence of separate strategies even within species to combat stress. BIOLOGICAL SIGNIFICANCE: This study for the first time enumerates protein diversity in three Anabaena species employing their presence/absence and relative abundance. Proteomics integrated with physiology and bioinformatics deciphers differential salt tolerance among the studied species and is the first of its kind to predict the function of hypothetical and unknown proteins. Salt-induced proteomic alterations clearly demonstrate significant metabolic shifts and existence of separate molecular phenome among the species investigated. This may be responsible for niche specificity limiting their application as biofertilizer. Of the 96 identified proteins, a large chunk are new entries to the Anabaena salt proteome while some protein genes may be used as potential candidates for engineering salt tolerant cyanobacteria. PMID- 24406299 TI - Delineating the effect of host environmental signals on a fully virulent strain of Bacillus anthracis using an integrated transcriptomics and proteomics approach. AB - Pathogenic bacteria sense the host environment and regulate expression of virulence-related genes. Environmental signals like temperature, bicarbonate/CO2 and glucose induce toxin production in Bacillus anthracis, but the mechanisms by which these signals contribute to virulence and overall physiological adaptation remains elusive. An integrated, systems level investigation using transcriptomics and iTRAQ-based proteomics was done to assess the effect of temperature, bicarbonate/CO2 and glucose on B. anthracis. Significant changes observed in amino acid, carbohydrate, energy and nucleotide metabolism indicates events of metabolic readjustments by environmental factors. Directed induction of genes involved in polyamine biosynthesis and iron metabolism revealed the redirection of cellular metabolite pool towards iron uptake. Protein levels of glycolytic enzymes, ptsH and Ldh along with transcripts involved in immune evasion (mprF, bNOS, Phospholipases and asnA), cell surface remodeling (rfbABCD, antABCD, and cls) and utilization of lactate (lutABC) and inositol showed constant repression under environmental perturbations. Discrepancies observed in mRNA/protein level of genes involved in glycolysis, protein synthesis, stress response and nucleotide metabolism hinted at the existence of additional regulatory layers and illustrated the utility of an integrated approach. The above findings might assist in the identification of novel adaptive strategies of B. anthracis during host associated survival and pathogenesis. BIOLOGICAL SIGNIFICANCE: In this study, the changes observed at both transcript and protein level were quantified and integrated to understand the effect of host environmental factors (host temperature, bicarbonate and glucose) in shaping the physiology and adaptive strategies of a fully virulent strain of B. anthracis for efficient survival and virulence in its host. Perturbations affecting toxin production were found to concordantly affect vital metabolic pathways and several known as well as novel virulence factors. These changes act as a valuable asset for generating testable hypotheses that can be further verified by detailed molecular and mutant studies to identify novel adaptive strategies of B. anthracis during infection. Adaptation of an integrated transcriptomics and proteomics approach also led to the identification of discrepancies between mRNA/protein levels among genes across major functional categories. Few of these discrepancies have been previously reported in literature for model organisms. However their existence in B. anthracis and that too as a result of growth perturbations have not been reported till date. These findings demonstrate a substantial role of regulatory processes post mRNA synthesis via post transcriptional, translational or protein degradation mechanisms. This article is part of a Special Issue entitled: Proteomics of non-model organisms. PMID- 24406300 TI - Biobanking 3.0: evidence based and customer focused biobanking. AB - Biobanking is a new and very dynamic field. To achieve long term financial sustainability of biobank infrastructures we propose that a new focus is needed on activities, products and services provided by the biobank that relate to the external stakeholder: biobanking 3.0. Earlier stages of biobanking are biobanking 1.0 (primary focus on the number of biospecimens and data) and biobanking 2.0 (primary focus on the quality of biospecimens and data). Both stages 1.0 and 2.0 are predominantly product oriented areas and have required a mostly internal focus on operational development within the biobank itself. In this paper we will introduce our concept of biobanking 3.0 which capitalizes on the earlier stages but dictates a shift in focus to enhancing the value and impact for the three major sets of external stakeholders (people/patients, funders, and research customers) and creating a path to balanced and planned investment in biobank infrastructure and the sustainability of biobanking. Biobanking 3.0 will improve real understanding as well as perceptions of value across different stakeholders. Patients and donors will appreciate seeing how their biospecimens and data are effectively used for research. Funders will value the ability to plan efficient targeting of funding and to monitor the impact of their support. Researchers will capitalize on the ability to translate their ideas into effective knowledge. Ultimately adoption of biobanking 3.0 will impact on the sustainability in the three main dimensions relevant to biobanking: social sustainability (acceptability), operational sustainability (efficiency), and financial sustainability (accomplishment). PMID- 24406301 TI - Evaluation of NM-BAPTA method for plasma total calcium measurement on Cobas 8000(r). AB - OBJECTIVES: A new method was developed by Roche for the measurement of plasma calcium using the chromophore 5-nitro-5'-methyl-(1,2-bis(o-aminophenoxy)ethan N,N,N',N'-tetraacetic acid (NM-BAPTA) which could have several advantages over the CPC method. The aim of our study was to evaluate the analytical performances of the NM-BAPTA assay from Roche on c701/Cobas 8000(r) and to perform a comparison study of calcium values with CPC and Arsenazo III methods. METHODS: The analytical performance including imprecision study, linearity, and stability of the NM-BAPTA assay was tested on the c701/Cobas 8000(r)analyzer. The most frequent interferences such as magnesium and gadolinium-based contrast agents (Gd CAs) were examined with spiked human plasma on the selected method. The calcium Arsenazo III method from Horiba (Montpellier, France) installed on ABX Pentra 400(r) was used as a reference method. Linear regression analysis was performed to compare data from the different methods. RESULTS: The CV of the NM-BAPTA assay showed good analytical performances with CV <1.5%, in agreement with the proposed and interim European biologic goals. We found no interference neither with gadobenate dimeglumine nor with gadoteric acid considering significant findings as interference greater than 5%. In the analytical range from 0.85 to 3.80 mmol/L, the NM-BAPTA method was closely correlated to the Arsenazo III method. CONCLUSIONS: Our data demonstrate that this new calcium NM-BAPTA method developed by Roche analyzers perform as well as the conventional method, especially for the outermost values. Thus, this new colorimetric assay could substitute the CPC method on Roche analyzers. PMID- 24406302 TI - Rasch analysis of the Iowa Level of Assistance Scale in patients with total hip and knee arthroplasty. AB - The aim of this study was to carry out a psychometric analysis, using both Classical Test Theory and Rasch analysis (RA) methods, of the Iowa Level of Assistance Scale (ILAS) administered in patients with recent total hip arthroplasty (THA) or total knee arthroplasty, to examine its metric properties and provide insights for a refined version. A total of 203 patients who had undergone THA or total knee arthroplasty were assessed using the ILAS for assistance needed during functional activities (ILAS-funct) and need for assistive devices (ILAS-dev) before discharge from the orthopedic ward. The responses were psychometrically analyzed using the Classical Test Theory and RA. Cronbach's alpha was adequate only for group comparisons (ILAS-funct, 0.82; ILAS dev, 0.79). The two domains (ILAS-funct and ILAS-dev) showed a good correlation. According to RA rating scale diagnostics, ILAS-funct showed two disordered response category thresholds: of the seven different response levels of 'assistance', only five were appreciably discernible. All five ILAS-funct items fitted the model and did not show either local dependence or differential item functioning across age groups or sex. ILAS-dev presented two unused response categories, which precluded Rasch calibration and subsequent analyses. ILAS-funct showed sound psychometric properties, but the rating system of ILAS-funct could be simplified, at least collapsing the response categories 5 (failed) and 6 (not tested). In ILAS-dev, the presence of unused response categories calls for a reconsideration of its scaling options and methods. PMID- 24406303 TI - Alterations of the microvascular network in the sclerotic hippocampus of patients with temporal lobe epilepsy. AB - Hippocampal sclerosis is the most frequent pathology encountered in resected tissue obtained from patients with temporal lobe epilepsy. The main hallmarks of hippocampal sclerosis are neuronal loss and gliosis. Several authors have proposed that an increase in blood vessel density is a further indicator, based on interpretations from staining of markers related to both blood-brain barrier disruption and the formation of new blood vessels. However, previous studies performed in our laboratory using correlative light and electron microscopy revealed that many of these "blood vessels" are in fact atrophic vascular structures with a reduced or virtually absent lumen and are often filled with processes of reactive astrocytes. Thus, "normal" vasculature within the sclerotic CA1 field is drastically reduced. Since this decrease is consistently observed in the human sclerotic CA1, this feature can be considered another key pathological indicator of hippocampal sclerosis associated with temporal lobe epilepsy. PMID- 24406304 TI - Identification and functional characterization of the goldfish (Carassius auratus L.) high mobility group box 1 (HMGB1) chromatin-binding protein. AB - We report on the identification and functional characterization of HMGB1 of the goldfish. Quantitative analysis indicated the highest expression of goldfish HMGB1 in the brain, with lower mRNA levels in spleen, intestine, kidney, gill and heart. HMGB1 was also differentially expressed in goldfish immune cell populations with highest mRNA levels present in splenocytes and neutrophils. We generated and functionally characterized the recombinant HMGB1 (rgHMGB1). The rgHMGB1 primed the respiratory burst response in monocytes and induced nitric oxide production of primary goldfish macrophages. Treatment of goldfish macrophages with heat-killed Mycobacterium marinum and Aeromonas salmonicida elevated the expression of HMGB1 and resulted in higher HMGB1 protein levels. The rgHMGB1 induced a dose-dependent production of TNFalpha-2 and IL-1beta1 of goldfish macrophages. Furthermore, the dual luciferase reporter assay revealed that goldfish HMGB1 induced the activation of the NF-kappaB signaling pathway. Our results indicate that goldfish HMGB1 is a critical regulatory cytokine of inflammatory and antimicrobial response of the goldfish. PMID- 24406305 TI - Preparative separation of polyphenols from the flowers of Paeonia lactiflora Pall. by high-speed counter-current chromatography. AB - High-speed counter-current chromatography was used to separate and purify polyphenols for the first time from the flowers of Paeonia lactiflora Pall. with two solvent systems as follows: petroleum ether-ethyl acetate-H2O (1:9:10, v/v/v/v) and petroleum ether-ethyl acetate-butanol-H2O (1:9:0.5:10, v/v/v/v). Eight compounds were separated successfully in single run which were identified as quercetin-3-O-(6"-O-galloyl)-glucoside (I, 41.5 mg), 1,2,3,4,6-trigalloyl-beta D-glucose (II, 106.2mg), quercetin-3-O-beta-D-glucoside (III, 42.3 mg), kaempferol-3-O-(6"-O-galloyl)-glucoside (IV, 23.5 mg), isohamnetin-3-O-beta-D glucoside (V, 34.1 mg), kaempferol (VI, 14.8 mg), kaempferol-3-O-beta-D-glucoside (VII, 32.6 mg), kaempferol-7-O-beta-D-glucoside (VIII, 23.8 mg) by electrospray ionization-mass spectrometry (ESI-MS) and nuclear magnetic resonance (NMR). The purities of compounds I-VIII were all over 97.0% as determined by HPLC. PMID- 24406306 TI - The relationship between meteorological variables and sporadic cases of Legionnaires' disease in residents of England and Wales. AB - We studied the timing of occurrence of 1676 sporadic, community-acquired cases of Legionnaires' disease in England and Wales between 1993 and 2008, in relation to temperature, relative humidity, rainfall, windspeed and ultraviolet light using a fixed-stratum case-crossover approach. The analysis was conducted using conditional logistic regression, with consideration of appropriate lag periods. There was evidence of an association between the risk of Legionnaires' disease and temperature with an apparently long time lag of 1-9 weeks [odds of disease at 95th vs. 75th centiles: 3.91, 95% confidence interval (CI) 2.06-7.40], and with rainfall at short time lags (of 2-10 days) (odds of disease at 75th vs. 50th centiles: 1.78, 95% CI 1.50-2.13). There was some evidence that the risk of disease in relation to high temperatures was greater at high relative humidities. A higher risk of Legionnaires' disease may be indicated by preceding periods of warmer wetter weather. PMID- 24406307 TI - The macrophage migration inhibitory factor (MIF)-homologue D-dopachrome tautomerase is a therapeutic target in a murine melanoma model. AB - The macrophage migration inhibitory factor (MIF)-homologue D-dopachrome tautomerase (D-DT) recently has been described to have similar functions as MIF. However, the role of D-DT, as opposed to MIF, in tumor biology remains unknown. We hypothesized that D-DT could represent a target for therapeutic interventions in cancer. We analyzed the production of D-DT in the murine melanoma model B16F10 and the murine breast cancer model 4T1 by western blot and ELISA. D-DT was released by tumor cells both in vitro and in vivo. RT-PCR revealed the expression of the D-DT receptor CD74 on both tumor cell lines. Tumor bearing mice had higher serum levels of D-DT compared to healthy controls. Remarkably, knock-down of D-DT by siRNA reduced proliferation of B16F10 cells in BrDU-assay and rendered them more prone to apoptosis induction, as shown by flow cytometry. In vivo neutralization of D-DT by antibodies reduced tumor progression in the B16F10 subcutaneous syngeneic tumor model. In summary, we could show that D-DT and its receptor are expressed in the murine tumors B16F10 and 4T1. Knock-down of D-DT through siRNA or blocking by antibodies reduced proliferation of B16F10 tumor cells. This qualifies D-DT for further evaluation as a therapeutic target. PMID- 24406308 TI - Effectiveness of an Indian-made attenuated influenza A(H1N1)pdm 2009 vaccine: a case control study. AB - A live attenuated influenza A(H1N1)pdm 2009 vaccine was developed and distributed in India in 2010. We estimated the vaccine effectiveness (VE) against laboratory confirmed pandemic H1N1 (pH1N1) infections in patients with influenza-like illness who visited five tertiary care hospitals in Pune, India during June December 2010. Swab specimens were analyzed for influenza pH1N1 by reverse transcriptase polymerase chain reaction (RT-PCR). VE was estimated using the test negative case-control study design and logistic regression. A total of 784 patients (253 cases, 531 controls) were analyzed. The unadjusted overall VE was 75.5% (95% confidence interval [CI] 42.1-89.7), while the adjusted VE was 76% (95% CI 42.1-89.7). We conclude that the live attenuated influenza A(H1N1)pdm 2009 vaccine was effective in our study population, which has opened prospects for using this platform for trivalent formulations. PMID- 24406309 TI - White matter microstructure throughout the brain correlates with visual imagery in grapheme-color synesthesia. AB - In this study we show, for the first time, a correlation between the neuroanatomy of the synesthetic brain and a metric that measures behavior not exclusive to the synesthetic experience. Grapheme-color synesthetes (n=20), who experience colors triggered by viewing or thinking of specific letters or numbers, showed altered white matter microstructure, as measured using diffusion tensor imaging, compared with carefully matched non-synesthetic controls. Synesthetes had lower fractional anisotropy and higher perpendicular diffusivity when compared to non-synesthetic controls. An analysis of the mode of anisotropy suggested that these differences were likely due to the presence of more crossing pathways in the brains of synesthetes. Additionally, these differences in white matter microstructure correlated negatively, and only for synesthetes, with a measure of the vividness of their visual imagery. Synesthetes who reported the most vivid visual imagery had the lowest fractional anisotropy and highest perpendicular diffusivity. We conclude that synesthetes as a population vary along a continuum while showing categorical differences in neuroanatomy and behavior compared to non-synesthetes. PMID- 24406310 TI - Social networking policies in nursing education. AB - Social networking use has increased exponentially in the past few years. A literature review related to social networking and nursing revealed a research gap between nursing practice and education. Although there was information available on the appropriate use of social networking sites, there was limited research on the use of social networking policies within nursing education. The purpose of this study was to identify current use of social media by faculty and students and a need for policies within nursing education at one institution. A survey was developed and administered to nursing students (n = 273) and nursing faculty (n = 33). Inferential statistics included chi2, Fisher exact test, t test, and General Linear Model. Cronbach's alpha was used to assess internal consistency of social media scales. The chi2 result indicates that there were associations with the group and several social media items. t Test results indicate significant differences between student and faculty for average of policies are good (P = .0127), policies and discipline (P = .0315), and policy at the study school (P = .0013). General Linear Model analyses revealed significant differences for "friend" a patient with a bond, unprofessional posts, policy, and nursing with class level. Results showed that students and faculty supported the development of a social networking policy. PMID- 24406311 TI - Synthesis of multi-functional large pore mesoporous silica nanoparticles as gene carriers. AB - The development of functional nanocarriers that can enhance the cellular delivery of a variety of nucleic acid agents is important in many biomedical applications such as siRNA therapy. We report the synthesis of large pore mesoporous silica nanoparticles (LPMSN) loaded with iron oxide and covalently modified by polyethyleneimine (denoted PEI-Fe-LPMSN) as carriers for gene delivery. The LPMSN have a particle size of ~200 nm and a large pore size of 11 nm. The large pore size is essential for the formation of large iron oxide nanoparticles to increase the magnetic properties and the adsorption capacity of siRNA molecules. The magnetic property facilitates the cellular uptake of nanocarriers under an external magnetic field. PEI is covalently grafted on the silica surface to enhance the nanocarriers' affinity against siRNA molecules and to improve gene silencing performance. The PEI-Fe-LPMSN delivered siRNA-PLK1 effectively into osteosarcoma cancer cells, leading to cell viability inhibition of 80%, higher compared to the 50% reduction when the same dose of siRNA was delivered by a commercial product, oligofectamine. PMID- 24406312 TI - [Hydrocycarbamide induced fever: four cases and literature review]. AB - PURPOSE: Hydroxyurea (HU) or hydroxycarbamide is an antimetabolite chemotherapy frequently used in the treatment of chronic myeloproliferative disorders. This treatment is usually well tolerated but a few cases of fever induced by the molecule have been reported in the literature. The aim of the study was to describe the clinical and biological characteristics of HU induced fever. METHODS: We performed a cross sectional study of patients treated with HU and followed-up in an internal medicine department between 2006 and 2012. We added our cases of HU induced fever with those reported in the literature (Pubmed and Cochrane databases) since 1981. RESULTS: We identified 38 cases of HU induced fever, including our 4 cases. The mean age was 65+/-10.9 years and the sex-ratio 1/2. The fever appeared after a median duration of treatment of 21 days and was usually high (40 degrees C) but clinically well tolerated. A biological inflammatory syndrome (CRP: 131+/-92 mg/L) was constant and one third of the patients also presented with hepatitis or lung disease. A probabilistic antibiotic treatment was introduced for 34% of the patients. For the half of the patients, HU-reintroduction test was performed, and was positive for all the patients but one. As soon as HU was withdrawn, the fever disappeared in a median of 24 hours. CONCLUSION: HU induced fever is unusual. Clinical presentation is very stereotyped. When this adverse effect is suspected, an infectious disease must first be ruled out. If infection is excluded, HU has to be stopped. PMID- 24406313 TI - [What are the indications for vena cava filters in 2014?]. PMID- 24406314 TI - [Non-cirrhotic ascites: pathophysiology, diagnosis and etiology]. AB - Ascites, in 20% of cases, is not linked to liver cirrhosis. The pathophysiology is most often different. The understanding of these pathophysiological mechanisms can lead to etiologic diagnosis. The diagnostic approach is mainly based on the biological study of ascites, especially protein concentration and albumin gradient between serum and ascites. In Western countries, tumors and heart diseases are the predominant causes, while developing countries are mainly concerned by infectious diseases, among which tuberculosis is the leading cause. Other uncommon causes must be recognized, as ascites may be the presenting feature of the disease. Their knowledge will facilitate the therapeutic approach. PMID- 24406315 TI - Consumer reporting of adverse events following immunization (AEFI): identifying predictors of reporting an AEFI. AB - Passive reporting of adverse events following immunization (AEFI) by consumers or healthcare professionals is the primary mechanism for post-marketing surveillance of vaccine safety. Although recent initiatives have promoted consumer reporting, there is a lack of research concerning consumer reporters. Computer assisted telephone interviews (CATI) were conducted in 2011 of a cross-sectional, random, general population sample of 191 South Australian parents who stated that their children had previously experienced an AEFI. We compared awareness of surveillance, vaccine safety opinions, and demographics of parents reporting an AEFI to either healthcare professionals or surveillance authorities with those who did not report their children's AEFI. Multivariate regression analyses measured: the association between reporting and safety views; and demographic predictors of reporting an AEFI. Reporting an AEFI to a healthcare professional or a surveillance authority was not significantly associated with awareness of a surveillance system. AEFI reporters, when compared with non-reporters, were more likely to be Australian-born (OR = 4.58, [1.64, 12.78], P = 0.004); were associated with the perception that a serious reaction was more likely to occur at their children's last immunization (OR = 2.54 [95%CI 1.22, 5.30], P = 0.013); and were less accepting of the risk of febrile convulsion, (OR = 3.59 [95%CI 1.50, 8.57], P = 0.004). Although reporting an AEFI was not associated with awareness of surveillance or most socio-demographics, the results suggest some difference in safety opinions. Further studies are required to ascertain if these differences pre-date the occurrence of an AEFI or are a consequence of the AEFI and how consumers can contribute further to vaccine safety surveillance. PMID- 24406316 TI - Collective autoionization in multiply-excited systems: a novel ionization process observed in helium nanodroplets. AB - Free electron lasers (FELs) offer the unprecedented capability to study reaction dynamics and image the structure of complex systems. When multiple photons are absorbed in complex systems, a plasma-like state is formed where many atoms are ionized on a femtosecond timescale. If multiphoton absorption is resonantly enhanced, the system becomes electronically-excited prior to plasma formation, with subsequent decay paths which have been scarcely investigated to date. Here, we show using helium nanodroplets as an example that these systems can decay by a new type of process, named collective autoionization. In addition, we show that this process is surprisingly efficient, leading to ion abundances much greater than that of direct single-photon ionization. This novel collective ionization process is expected to be important in many other complex systems, e.g. macromolecules and nanoparticles, exposed to high intensity radiation fields. PMID- 24406318 TI - The gap gene Kruppel of Rhodnius prolixus is required for segmentation and for repression of the homeotic gene sex comb-reduced. AB - The establishment of the anterior-posterior segmentation in insects requires the concerted action of a hierarchical gene network. Here, we study the orthologue of Kruppel gap gene in the hemipteran Rhodnius prolixus (Rp-Kr). We characterized its structure, expression pattern and function. The genomic sequence upstream of the Rp-Kr transcriptional unit shows a putative regulatory region conserved in the orthologue genes from Drosophila melanogaster and Tribolium castaneum. Rp-Kr expression is zygotic and it is expressed in the anterior half of the embryo (the posterior half of the egg) during the blastoderm stage and germ band formation; later, during germ band extension, it is expressed in a central domain, from T2 to A3. The Rp-Kr loss of function phenotypes shows disrupted thoracic and abdominal segmentation. Embryos with weak segmentation phenotypes show homeotic transformations, in which an ectopic tibial comb, typical of T1 leg, appears in T2, which correlates with the ectopic expression of Rp-sex-comb reduced in this leg. PMID- 24406319 TI - Mesenchymal stem cells reciprocally regulate the M1/M2 balance in mouse bone marrow-derived macrophages. AB - Mesenchymal stem cells (MSCs) have been widely studied for their applications in stem cell-based regeneration. During myocardial infarction (MI), infiltrated macrophages have pivotal roles in inflammation, angiogenesis and cardiac remodeling. We hypothesized that MSCs may modulate the immunologic environment to accelerate regeneration. This study was designed to assess the functional relationship between the macrophage phenotype and MSCs. MSCs isolated from bone marrow and bone marrow-derived macrophages (BMDMs) underwent differentiation induced by macrophage colony-stimulating factor. To determine the macrophage phenotype, classical M1 markers and alternative M2 markers were analyzed with or without co-culturing with MSCs in a transwell system. For animal studies, MI was induced by the ligation of the rat coronary artery. MSCs were injected within the infarct myocardium, and we analyzed the phenotype of the infiltrated macrophages by immunostaining. In the MSC-injected myocardium, the macrophages adjacent to the MSCs showed strong expression of arginase-1 (Arg1), an M2 marker. In BMDMs co cultured with MSCs, the M1 markers such as interleukin-6 (IL-6), IL-1beta, monocyte chemoattractant protein-1 and inducible nitric oxide synthase (iNOS) were significantly reduced. In contrast, the M2 markers such as IL-10, IL-4, CD206 and Arg1 were markedly increased by co-culturing with MSCs. Specifically, the ratio of iNOS to Arg1 in BMDMs was notably downregulated by co-culturing with MSCs. These results suggest that the preferential shift of the macrophage phenotype from M1 to M2 may be related to the immune-modulating characteristics of MSCs that contribute to cardiac repair. PMID- 24406321 TI - Staged hybrid treatment for contained rupture of a large right coronary artery aneurysm. AB - We describe a staged approach to the management of a rare acute condition- contained rupture of a large right coronary artery aneurysm. A covered stent was deployed percutaneously to isolate the aneurysm at presentation followed by planned coronary bypass grafting. Treatment interval was complicated by new-onset pulmonary tuberculosis and subacute thrombosis of the covered stent leading to nonfatal inferior myocardial infarction. Coronary surgery was performed after complete antitubercular treatment and resolution of the acute pericarditis/thrombosis as a consequence of the contained rupture. The advantages of this staged approach included the following: (a) The covered stent prevented both acute myocardial infarction and progressive pseudoaneurysm expansion in the acute phase. (b) Deferred surgery was rendered technically less hazardous while avoiding the undesirable option of having to exclude an extremely calcified dominant right coronary artery. The patient made an excellent postoperative recovery with complete resolution of her symptoms at 6 weeks' follow-up. PMID- 24406322 TI - Contact with animals and risk of oesophageal squamous cell carcinoma: outcome of a case-control study from Kashmir, a high-risk region. AB - BACKGROUND: Several studies have reported association between animal contact and some cancer types, including lymphohaematopoietic, colon, pancreatic and neurological malignancies. We aimed to investigate the association between animal contact and risk of oesophageal squamous cell carcinoma (ESCC) in a case-control study in Kashmir, India, area with a relatively high incidence of ESCC. METHODS: We recruited 703 histologically confirmed ESCC cases and 1664 controls individually matched to the cases for age, sex and district of residence. Information, including on animal contact, was obtained in face-to-face interviews using a structured questionnaire. Conditional logistic regression models were used to calculate ORs and 95% CIs. RESULTS: As compared with no contact with animals, daily close contact was associated with an increased risk of ESCC (OR 5.99; 95% CI 3.86 to 9.31) in models adjusted for several potential confounding factors, including multiple indicators of socioeconomic status. This association persisted in subgroups following stratification by a composite wealth score and occupation. Irregular contact with animals was not associated with ESCC risk. The association between duration of animal contact and ESCC risk was mixed; however, contact for more than 50 years was associated with an increased risk (OR 3.10; 95% CI 1.53 to 6.26). Frequency (p for trend, 0.001) and duration (p for trend, <0.001) of animal contact showed dose-response association with ESCC risk. CONCLUSIONS: Our results suggest an association between long-term and daily close contact with animals and ESCC. This association needs to be investigated in further studies. PMID- 24406320 TI - Exogenous rhTRX reduces lipid accumulation under LPS-induced inflammation. AB - Redox-regulating molecule, recombinant human thioredoxin (rhTRX) which shows anti inflammatory, and anti-oxidative effects against lipopolysaccharide (LPS) stimulated inflammation and regulate protein expression levels. LPS-induced reactive oxygen intermediates (ROI) and NO production were inhibited by exogenous rhTRX. We identified up/downregulated intracellular proteins under the LPS treated condition in exogenous rhTRX-treated A375 cells compared with non-LPS treated cells via 2-DE proteomic analysis. Also, we quantitatively measured cytokines of in vivo mouse inflammation models using cytometry bead array. Exogenous rhTRX inhibited LPS-stimulated production of ROI and NO levels. TIP47 and ATP synthase may influence the inflammation-related lipid accumulation by affecting lipid metabolism. The modulation of skin redox environments during inflammation is most likely to prevent alterations in lipid metabolism through upregulation of TIP47 and ATP synthase and downregulation of inflammatory cytokines. Our results demonstrate that exogenous rhTRX has anti-inflammatory properties and intracellular regulatory activity in vivo and in vitro. Monitoring of LPS-stimulated pro-inflammatory conditions treated with rhTRX in A375 cells could be useful for diagnosis and follow-up of inflammation reduction related with candidate proteins. These results have a therapeutic role in skin inflammation therapy. PMID- 24406323 TI - WITHDRAWN: Manipulating cognition and behavior with microstimulation, implications for cognitive prostheses. PMID- 24406324 TI - Species-dependent effects of biochar amendment on bioaccumulation of atrazine in earthworms. AB - We observed that at a contamination level of 4.25 mg-atrazine/kg-soil, the biota soil accumulation factor (BSAF) for the anecic M. guillelmi is approximately 5 times that for the epigeic E. foetida. This is attributable to the fact that bio uptake by E. foetida is mainly through dermal absorption, whereas bio-uptake by M. guillelmi is largely affected by the gut processes, through which the physical grinding and surfactant-like materials facilitate the desorption of atrazine from soil. Strikingly, biochar amendment resulted in much greater reduction in BSAF for M. guillelmi than for E. foetida. At a biochar dose of 0.5% (wt:wt) the difference in BSAF between the two species became much smaller, and at a dose of 2% no statistical difference was observed. A likely explanation is that gut processes by M. guillelmi were much less effective in extracting atrazine from the biochar (the predominant phase wherein atrazine resided) than from soil particles. PMID- 24406326 TI - Detection of single-digit foodborne pathogens with the naked eye using carbon nanotube-based multiple cycle signal amplification. AB - A carbon nanotube (CNT)-based multiple cycle signal amplification strategy has been demonstrated for detection of single-digit foodborne pathogens with the naked eye. In the present design, CNTs are used as carriers for loading numerous horseradish peroxidase (HRP) and concanavalin A (ConA) tags, and multiple cycle signal amplification is achieved through the biotinylated anti-HRP antibody and avidin-HRP. PMID- 24406327 TI - Emergency CT helps unravel an unusual problem! PMID- 24406325 TI - X-marks the spot: X-chromosome identification during dosage compensation. AB - Dosage compensation is the essential process that equalizes the dosage of X linked genes between the sexes in heterogametic species. Because all of the genes along the length of a single chromosome are co-regulated, dosage compensation serves as a model system for understanding how domains of coordinate gene regulation are established. Dosage compensation has been best studied in mammals, flies and worms. Although dosage compensation systems are seemingly diverse across species, there are key shared principles of nucleation and spreading that are critical for accurate targeting of the dosage compensation complex to the X chromosome(s). We will highlight the mechanisms by which long non-coding RNAs function together with DNA sequence elements to tether dosage compensation complexes to the X-chromosome. This article is part of a Special Issue entitled: Chromatin and epigenetic regulation of animal development. PMID- 24406328 TI - Impact of a GP-led walk-in centre on NHS emergency departments. AB - OBJECTIVE: To determine the impact of the GP-led walk-in centre (WIC) in Sheffield (England) on the demand for emergency department (ED) care. METHODS: A survey of patients visiting the Sheffield GP WIC was conducted over 3 weeks during September and October 2011. A short, postvisit questionnaire was also sent to those who agreed to determine if the patient had used another NHS service for the same problem. Routine data were obtained from the adult and children's EDs and minor injuries unit in Sheffield, 1 year before and 1 year after the opening of the GP WIC. A linear model of the number of minor daytime attendances (GP type) per month was used to estimate the impact of opening the GP WIC, after controlling for seasonal variation and a linear time trend. RESULTS: A total of 529 patients responded to the survey (response rate 51%). Based on their self reported intentions, 64 of these patients (53 adults and 11 children) were diverted from going to ED in the 3-week survey period as a result of the establishment of the GP WIC. From this we would have expected around a 26% monthly reduction in GP-type attendances at adult ED, and 7% reduction at children's ED. However, routine data only showed an 8% (95% CI 1% to 16%) reduction at the adult ED. Reductions in GP-type attendances at the children's ED and the minor injury unit at the time of the opening of the GP WIC were also found, but were not statistically significant. The estimated impact on children's ED was a 14% reduction (95% CI -38% to 8%), and for minor injuries unit (MIU) a 4% reduction (95% CI -18 to 9%). CONCLUSIONS: There was a statistically significant reduction in GP-type daytime attendances at the adult ED after the opening of the GP WIC. Since this reduction was not mirrored in changes in night time attendances (when the GP WIC was closed), and our survey responses suggested some people were diverted from going to the ED, it is possible that the opening of the GP WIC caused this reduction. PMID- 24406329 TI - A novel multipatient intranasal diamorphine spray for use in acute pain in children: pharmacovigilance data from an observational study. AB - OBJECTIVES: To establish the safety of an intranasal diamorphine (IND) spray in children. DESIGN: An open-label, single-dose pharmacovigilance trial. SETTING: Emergency departments in eight UK hospitals. PARTICIPANTS: Children aged 2-16 years with a fracture or other trauma. OUTCOME MEASURES: Adverse events (AE) specifically related to nasal irritation, respiratory and central nervous system depression. RESULTS: 226 patients received 0.1 mg/kg IND. No serious or severe AEs occurred. The incidence of treatment-emergent AEs (TEAEs) was 26.5% (95% CI 20.9% to 32.8%), 93% being mild. 89% were related to treatment, all being known effects of the drug or route of administration except for three events in two patients. 20.4% (95% CI 15.3% to 26.2%) patients reported nasal irritation, all mild except one moderate and one 'unknown' severity. No respiratory depression was reported. Three AEs related to reduced Glasgow Coma Score (GCS) occurred, all mild. CONCLUSIONS: There were no safety concerns raised during the conduct of the study. In addition to expected side effects, IND can cause mild nasal irritation in a proportion of patients. EUROPEAN UNION DRUG REGULATING AUTHORITIES CLINICAL TRIAL NO: 2009-014982-16. PMID- 24406330 TI - Lung torsion. PMID- 24406331 TI - Family background of modern health worries, somatosensory amplification, and health anxiety: A questionnaire study. AB - In the development of somatosensory amplification, health anxiety, and modern health worries, environmental factors seem more important than genetic background. Parental attitudes might represent a major source of learning. In total, 186 adolescents and their parents completed a questionnaire assessing modern health worries, somatosensory amplification, health anxiety, and somatic symptoms. Adolescents' modern health worries, somatosensory amplification, and health anxiety were positively related to respective parental characteristics in regression analyses even after controlling for sociodemographic variables and somatic symptoms. Parental beliefs may play a role in the development of these characteristics. PMID- 24406332 TI - Roles of Hox genes in the patterning of the central nervous system of Drosophila. AB - One of the key aspects of functional nervous systems is the restriction of particular neural subtypes to specific regions, which permits the establishment of differential segment-specific neuromuscular networks. Although Hox genes play a major role in shaping the anterior-posterior body axis during animal development, our understanding of how they act in individual cells to determine particular traits at precise developmental stages is rudimentary. We have used the abdominal leucokinergic neurons (ABLKs) to address this issue. These neurons are generated during both embryonic and postembryonic neurogenesis by the same progenitor neuroblast, and are designated embryonic and postembryonic ABLKs, respectively. We report that the genes of the Bithorax-Complex, Ultrabithorax (Ubx) and abdominal-A (abd-A) are redundantly required to specify the embryonic ABLKs. Moreover, the segment-specific pattern of the postembryonic ABLKs, which are restricted to the most anterior abdominal segments, is controlled by the absence of Abdominal-B (Abd-B), which we found was able to repress the expression of the neuropeptide leucokinin. We discuss this and other examples of how Hox genes generate diversity within the central nervous system of Drosophila. PMID- 24406333 TI - Diverse roles for the Drosophila fructose sensor Gr43a. AB - The detection of nutrients, both in food and within the body, is crucial for the regulation of feeding behavior, growth, and metabolism. While the molecular basis for sensing food chemicals by the taste system has been firmly linked to specific taste receptors, relatively little is known about the molecular nature of the sensors that monitor nutrients internally. Recent reports of taste receptors expressed in other organ systems, foremost in the gastrointestinal tract of mammals and insects, has led to the proposition that some taste receptors may also be used as sensors of internal nutrients. Indeed, we provided direct evidence that the Drosophila gustatory receptor 43a (Gr43a) plays a critical role in sensing internal fructose levels in the fly brain. In addition to the brain and the taste system, Gr43a is also expressed in neurons of the proventricular ganglion and the uterus. Here, we discuss the multiple potential roles of Gr43a in the fly. We also provide evidence that its activation in the brain is likely mediated by the neuropeptide Corazonin. Finally, we posit that Gr43a may represent only a precedent for other taste receptors that sense internal nutrients, not only in flies but, quite possibly, in other animals, including mammals. PMID- 24406334 TI - Bridging the divide: illuminating the path of intercellular exchange through ring canals. AB - Ring canals are made from arrested cleavage furrows, and provide direct cytoplasmic connections among sibling cells. They are well documented for their participation in Drosophila oogenesis, but little is known about their role in several somatic tissues in which they are also found. Using a variety of genetic tools in live and fixed tissue, we recently demonstrated that rapid intercellular exchange occurs through somatic ring canals by diffusion, and presented evidence that ring canals permit equilibration of protein among transcriptionally mosaic cells. We also used a novel combination of markers to evaluate the extent of protein movement within and across mitotic clones in follicle cells and imaginal discs, providing evidence of robust movement of GFP between the 2 sides of mitotic clones and frequently into non-recombined cells. These data suggest that, depending on the experimental setup and proteins of interest, inter-clonal diffusion of protein may alter the interpretation of clonal data in follicle cells. Here, we discuss these results and provide additional insight into the impact of ring canals in Drosophila somatic tissues. PMID- 24406335 TI - Multiple roles of Nrf2-Keap1 signaling: regulation of development and xenobiotic response using distinct mechanisms. AB - Xenobiotic and oxidative responses protect cells from external and internal toxicities. Nrf2 and Keap1 are central factors that mediate these responses, and are closely related with many human diseases. In a recent study, we revealed novel developmental function and regulatory mechanism of Nrf2 and Keap1 by investigating their Drosophila homolog CncC and dKeap1. We found that CncC and dKeap1 control metamorphosis through regulations of ecdysone biosynthetic genes and ecdysone response genes in different tissues. CncC and dKeap1 cooperatively activate these developmental genes, in contrast to their conserved antagonizing effect to xenobiotic response transcription. In addition, interactions between CncC and Ras signaling in metamorphosis and in transcriptional regulation were established. Here I discuss the implications that place these classic xenobiotic response factors into a broader network that potentially control development and oncogenesis using mechanisms other than those mediating xenobiotic response. PMID- 24406336 TI - Hedgehog and extramacrochaetae in the Drosophila eye: an irresistible force meets an immovable object. AB - During the third and final larval instar stage, thousands of pluripotent cells within the Drosophila eye imaginal disc are transformed into a near perfect neurocrystalline lattice of 800 unit eyes called ommatidia. This transformation begins with the initiation of the morphogenetic furrow at the posterior margin of the eye field. The furrow, which marks the leading edge of a wave of differentiation, passes across the epithelium transforming unpatterned and undifferentiated cells into rows of periodically spaced clusters of photoreceptor neurons. As cells enter and exit the furrow they undergo dramatic alterations in cellular architecture and gene expression, many of which are required to propel the furrow forward and for proper cell fate specification. The Decapentaplegic (Dpp) and Hedgehog (Hh) signaling pathways are required for the initiation and progression of the furrow, respectively. Consistent with a role in furrow progression, the loss of Hh pathway activity results in a "furrow stop" phenotype. In contrast, reductions in levels of the helix-loop-helix transcription factor, Extramacrochaetae (Emc), lead to the polar opposite phenotype--the furrow accelerates. Recently, we demonstrated that the furrow stop and furrow acceleration phenotypes are molecularly connected. Emc appears to serve as a brake on the furrow by dampening the activity of the Hh pathway. Loss of Emc leads to an upsurge in Hh pathway activity and a faster moving furrow. The acceleration of the furrow appears to be due to an increase in levels of the full length isoform of Cubitus Interruptus (Ci (155)) and Suppressor of Fused [Su(fu)]. Here we will briefly review the mechanisms by which Hh drives and Emc impedes the progression of the furrow across the developing retina. PMID- 24406337 TI - Mind the gap: cells respond to tissue damage by changing orientation of cell divisions. AB - Nature presents plenty of examples of cellular behavior that determines the shape of an organ during development, such as epithelial polarity and cell division orientation. Little is known, however, about how organs regenerate or how cellular behavior affects regeneration. One of the most exciting aspects of regeneration biology is understanding how proliferation and patterning are coordinated, since it means that cells not only have to proliferate but also have to do so in an ordered manner so that organs are reconstructed proportionally. Drosophila wing imaginal discs and adult wings are models used in different approaches to investigate this issue; they have recently been used to reveal that, after localized cell death, neighboring cells change their cell division orientation toward the damaged zone. During this process, cell polarity and spindle orientation operate in coordination with cell proliferation to regenerate proper organ size and shape. PMID- 24406338 TI - FOXP3 over-expression inhibits melanoma tumorigenesis via effects on proliferation and apoptosis. AB - The Forkhead box P3 (FOXP3) transcription factor is the key driver of regulatory T cell (Treg cells) differentiation and immunosuppressive function. In addition, FOXP3 has been reported to be expressed in many tumors, including melanoma. However, its role in tumorigenesis is conflicting, with both tumor suppressive and tumor promoting functions described. The aim of the current study was to characterize the expression and function of FOXP3 in melanoma. FOXP3 expression was detected by immunohistochemistry (IHC) in 12% (18/146) of stage III and IV melanomas. However expression was confined to fewer than 1% of cells in these tumors. Stable over-expression of FOXP3 in the SK-MEL-28 melanoma cell line reduced cell proliferation and clonogenicity in vitro, and reduced xenograft growth in vivo. FOXP3 over-expression also increased pigmentation and the rate of apoptosis of SK-MEL-28 cells. Based on its infrequent expression in human melanoma, and its growth inhibitory and pro-apoptotic effect in over-expressing melanoma cells, we conclude that FOXP3 is not likely to be a key tumor suppressor or promoter in melanoma. PMID- 24406339 TI - Effect of sitagliptin treatment on metabolism and cardiac function in genetic diabetic mice. AB - To investigate the chronic effect of sitagliptin (7-[(3R)-3-amino-1-oxo-4-(2,4,5 trifluorophenyl)butyl]-5,6,7,8-tetrahydro-(3-(trifluoromethyl)-1,2,4-triazolo[4,3 a]pyrazine phosphate (1:1) monohydrate, SIT) on metabolism and cardiac function in genetic diabetic Akita mice, 10 weeks old Akita mice were either exposed for 4 months to a high fat and high cholesterol (HF-HC) diet, with or without 10mg/kg/day SIT, or were fed for 3 months with the same diet with or without 50mg/kg/day SIT. SIT treatment of Akita mice at either a low or high dose did not affect body or liver weight. A significant increase in subcutaneous and gonadal fat mass was only observed for the 50mg/kg/day dose of SIT. Furthermore, only the 50mg/kg/day SIT dose resulted in an improvement of glycemic control, as evidenced by a decrease in fasting blood HbA1c levels and an increase in plasma adiponectin levels. Echocardiographic analysis revealed that Akita mice kept on the HF-HC diet with 10mg/kg/day of SIT for 4 months showed an increase in ejection fraction and fractional shortening, whereas the higher dose (50mg/kg/day) had no effect on these parameters, but instead induced left ventricular (LV) hypertrophy as evidenced by an enlarged LV internal diameter, volume and mass. Thus, in the diabetic Akita mouse SIT is cardioprotective at a low dose (10mg/kg/day), whereas improvement of glycemic control requires a higher dose (50mg/kg/day) which, however, induces LV hypertrophy. This mouse model may thus be useful to study the safety of anti-diabetic drugs. PMID- 24406340 TI - A new role for STAT3 as a regulator of chromatin topology. PMID- 24406341 TI - Unique role of SRSF2 in transcription activation and diverse functions of the SR and hnRNP proteins in gene expression regulation. AB - Transcription pause release from gene promoters has been recognized to be a critical point for transcriptional regulation in higher eukaryotes. Recent studies suggest that regulatory RNAs are extensively involved in transcriptional control, which may enlist various RNA binding proteins. We recently showed a key role of SRSF2, a member of the SR family of splicing regulators, in binding to promoter-associated small RNA to mediate transcription pause release, a regulatory strategy akin to the function of the HIV Tat protein via binding to the TAR element in nascent RNA to activate transcription. In this report, we further dissect the structural requirement for SRSF2 to function as a transcription activator and extend the analysis to multiple SR and hnRNP proteins by using the MS2 tethering strategy. Our results reveal that SRSF2 is a unique SR protein that activates transcription in a position-dependent manner while three other SR proteins enhance translation in a position-independent fashion. In contrast, multiple hnRNP proteins appear to negatively influence mRNA levels, especially when tethered in the gene body. These findings suggest broad participation of RNA binding proteins in diverse aspects of regulated gene expression at both the transcriptional and posttranscriptional levels in mammalian cells. PMID- 24406343 TI - Nuclear actin polymerization from faster growing ends in the initial activation of Hox gene transcription are nuclear speckles involved? AB - The HoxB cluster expression is activated by retinoic acid and transcribed in a collinear manner. The DNA-binding Pknox1-Pbx1 complex modulates Hox protein activity. Here, NT2-D1 teratocarcinoma cells -a model of Hox gene expression- were used to show that upon retinoic acid induction, Pknox1 co-localizes with polymeric nuclear actin. We have found that globular actin aggregates, polymeric actin, the elongating RNA polymerase II and THOC match euchromatic regions corresponding to nuclear speckles. Moreover, RNA polymerase II, N-WASP, and transcription/splicing factors p54(nrb) and PSF were validated as Pknox1 interactors by tandem affinity purification. PSF pulled down with THOC and nuclear actin, both of which co-localize in nuclear speckles. Although latrunculin A slightly decreases the general level of HoxB gene expression, inhibition of nuclear actin polymerization by cytochalasin D blocks the expression of HoxB transcripts in a collinear manner. Thus, our results support the hypothesis that nuclear actin polymerization is involved in the activation of HoxB gene expression by means of nuclear speckles. PMID- 24406347 TI - Exchange bias effect in Au-Fe3O4 nanocomposites. AB - We report exchange bias (EB) effect in the Au-Fe3O4 composite nanoparticle system, where one or more Fe3O4 nanoparticles are attached to an Au seed particle forming 'dimer' and 'cluster' morphologies, with the clusters showing much stronger EB in comparison with the dimers. The EB effect develops due to the presence of stress at the Au-Fe3O4 interface which leads to the generation of highly disordered, anisotropic surface spins in the Fe3O4 particle. The EB effect is lost with the removal of the interfacial stress. Our atomistic Monte Carlo studies are in excellent agreement with the experimental results. These results show a new path towards tuning EB in nanostructures, namely controllably creating interfacial stress, and opens up the possibility of tuning the anisotropic properties of biocompatible nanoparticles via a controllable exchange coupling mechanism. PMID- 24406348 TI - Self-aggregation mechanisms of N-alkyl derivatives of urea and thiourea. AB - The mechanisms of self-aggregation of N-alkyl and N,N'-dialkyl derivatives of urea and thiourea in weakly polar solvents (chloroform and 1,2-dichloroethane) were examined. The C-H...O or C-H...S hydrogen bonds formed with these two acidic solvents compete with the N-H...O or N-H...S hydrogen bonds formed between solute molecules, influencing the self-aggregation of urea derivatives in a particular solvent. The peculiarities of the solvent interactions were discussed and the stronger interaction of chloroform was noted. Aggregation of the N-alkyl derivatives was followed using IR spectroscopy, with two gradual aggregation constants (K1 and K2) determined. The average molecular weight and dipole moments were shown to depend on the concentration, and the form of aggregation was analyzed through the study of the dipole moments. All of the urea derivatives demonstrated an increase in dipole moment with increased concentration, resulting in stronger NH2...O hydrogen bond interactions and leading to linear-type aggregation. Contrastingly, the dipole moments of the mono-N-alkyl-substituted thioureas decreased with concentration. Density-functional theory calculation of these processes showed that reliable results could only be obtained if solvent interactions were considered, with a specific combination of local and bulk effects. It was also shown that going from N,N'-disubstituted to N-monoalkyl derivatives the ability to aggregate increases, which is related to a diminished steric hindrance to hydrogen bonding. Finally, it was demonstrated that the mechanisms of self-aggregation depend on the acid-base properties of the solute, hydrogen bonding to the solvent molecules, and steric interactions of the aliphatic chains. PMID- 24406349 TI - [The impact factor, the h index and other bibliometric indicators]. PMID- 24406350 TI - [The need to redirect oneself facing the challenge of chronicity]. PMID- 24406351 TI - [Towards a "sustainable caregiving family"]. PMID- 24406352 TI - [Characteristics and epidemiological changes for patients with community-acquired pneumonia in hospital emergency departments]. AB - BACKGROUND: The aim of this paper is to determine both the prevalence of community-acquired pneumonia (CAP) in the A & E Department and the most relevant epidemiological changes in the last decade, as well as the profile and management of these patients. METHODS: Descriptive cross-sectional analysis at 49 Spanish A & E Departments during 12 months. All patients with infections, respiratory infection or CAP diagnosis were included. All patients attended to in A & E during the study were recorded as well. RESULTS: CAP has increased its prevalence among patients in the A & E Departments in the past decade (0.85% to 1.35%, p <0.001). Fifty-one per cent were over 70 years old. Sixty-nine point eight per cent had some underlying disease and 17.8% had risk factors. Eleven point seven per cent met sepsis criteria, 4.6% severe sepsis and 3% septic shock. Thirty seven per cent of patients were directly discharged from the A & E Departments. CONCLUSIONS: The impact and prevalence of CAP in A & E Departments has increased in the last decade. It is the most common cause of sepsis, severe sepsis and septic shock, admission to intensive care units and death due to infectious disease. PMID- 24406353 TI - [Legibility analysis of drug package leaflets using Flesch-Sszigriszt index and Inflesz score]. AB - BACKGROUND: To measure and evaluate the legibility of a sample of informative leaflets about common drugs. METHODS: A descriptive cross-sectional study was performed, using a representative sample of package leaflets corresponding to the 30 most widely consumed drugs in Spain. The Flesch-Szigriszt Index was used as a measuring tool and the INFLESZ score to evaluate the legibility of leaflets of medicinal products. Documents with a Flesch-Szigriszt Index value >=55 were considered legible. RESULTS: The mean Flesch-Szigriszt Index value was 52.62 (standard deviation: 4.67). This score is classified as "a bit difficult" on the INFLESZ score. Only 10 of 30 leaflets obtained an acceptable level of legibility. The sections of the leaflets with higher grammatical complexity were "what it is and what it is used for" (indications), "before taking the medication" (contraindications) and "adverse effects". CONCLUSIONS: The legibility of the package leaflets analyzed could be improved: grammatical structures are usually convoluted, and their comprehension by ordinary citizens belonging to the general public is difficult. The involvement of health care professionals in resolving doubts and giving information to users about the consumption of drugs may be essential for a correct treatment. PMID- 24406354 TI - [Development and validation of a scale of healthcare professional attitudes to the liberation from restraint use with dependent people]. AB - BACKGROUND: There are studies on the prevalence and use of restraints but not a measuring instrument to eliminate subjectivity in evaluation of their use in clinical practice and research in our environment. OBJECTIVE: Design and validation of a scale of measurement of attitudes of health care professionals towards the use of physical and pharmacological restraints. METHODS: Descriptive and correlational study for scale validation. Following a literature review, we developed a list of items that were subjected to a validity analysis: validity of content through judges, validity of criterion through external variable contrast, and validity of construct using exploratory factor analysis. Reliability was analysed using the Cronbach alpha coefficient. RESULTS: Two hundred and seventy six people answered the questionnaire, 82.4% (224) women and 17.6% (48) men, average age 38.65 years. The 40 item scale provided a Cronbach alpha of 0.897. Four dimensions were obtained explaining 46.758% of the total variance. The factors were named: Autonomy (15.084% of the variance), safety (12.228%), environment (8.463%) and avoidance (6.062%). Except for the last one, all the subscales obtained an alpha superior to 0.717. There were differences due to the experience in Alzheimer care. Staff with experience score significantly lower in Factor 1 and Factor 3, and higher in Factor 2, but there is no difference in the overall computation. Moreover, by gender, women scored higher in Factor 1. CONCLUSIONS: This scale is a significant step forward in the study of the attitudes of health care professionals as it enquires into underlying causes. PMID- 24406355 TI - High crossectomy without vascular sectioning vs classic saphenectomy. Randomized clinical trial: analysis of recurrent varicose veins. AB - BACKGROUND: This study was designed with the aim of defining a new surgical procedure for varicose veins and for comparison with classic crossectomy in terms of reducing the recurrence rate of varicose veins. MATERIAL AND METHODS: Double blind randomized clinical trial. For easy access, we selected 150 patients who came to the Phlebology Consultation Unit meeting inclusion criteria. With their informed consent, they were included in a study group using random table numbers. Group 1: (CS) Classic saphenectomy, 75 patients. Group 2: (HCWVS) High crossectomy without vascular sectioning. Both groups were monitorised at 12 and 24 months by Eco-Doppler study. RESULTS: The incidence of varicose vein recurrence at 12 month follow-up was 69.3% in the group of patients undergoing CS, while in the group receiving HCWVS it was 29.3% (p <0.0001). These differences, though minor, remained statistically significant at 24 months of evolution (76% vs. 48%, p = 0.0004). The most common recurrence type was type I, with statistically significant differences at 12 and 24 months. CONCLUSIONS: We believe that saphenectomy with crossectomy without vascular sectioning is the appropriate procedure to treat varicose veins, reducing type 1 or reticular relapse rate and maintaining the principles of classic surgery to reduce type 2 or truncular recurrence rate. This technique should be implemented with procedures based on saphenous sclerosis with foam art the saphenous femoral junction, in order to assess the recurrence rate of type 2 or truncular varicose veins. PMID- 24406356 TI - [Prevalence and costs of chronicity and multimorbidity in the population covered by the Basque public telecare service]. AB - BACKGROUND: The public telecare service in the Basque Autonomous Community (betiON) is a service offered by the Department of Employment and Social Policy of the Basque Government and offers telephone support to elderly and disabled populations, providing communication with an assistance centre. This connection with health care devices makes it possible to implement shared information systems with health and social data, which enable a characterization of the population attended to and the development of integrated models for health and social provision. OBJECTIVE: To describe the distribution of chronic diseases and multimorbidity among users of betiON, to estimate the cost of their health care and to compare these indicators with those of the general population. METHODS: We extracted information from betiON and public healthcare databases. We characterized the telecare population above 65 years (N = 23.742) and compared it with the total population in the Basque Autonomous Community (N = 2.262.707) with respect to variables in demography socio-economic burden, costs and ambulatory care conditions. RESULTS: In the telecare population, the average age is 83 years, 80% are women, 55.1% live alone and reside in poorer neighbourhoods. Forty two point five per cent of males and 36.5% of women are affected by five or more chronic conditions, averaging 4.06 pathologies per person. They also show higher healthcare costs than the general population. CONCLUSIONS: Telecare users have a higher disease burden, greater need for healthcare and unfavourable social conditions. Telecare provides an opportunity for innovation and intervention, through the coordination of social and healthcare services. PMID- 24406357 TI - [Influence of rural or urban environment on perception of the supports and needs of caregivers in hospitals]. AB - BACKGROUND: After the Functional Plan was implemented with support measures for caregivers in hospitals of Granada (Spain), the effectiveness and impact of environment on the perception and needs of caregivers was analysed. MATERIALS AND METHODS: A qualitative, phenomenological study was made through semi-structured interviews. A total of 45 caregivers included in the Functional Plan took part. In addition, perceived social support, family functioning, and anxiety level were measured, respectively, through the Duke-UNC, Apgar Family, and Goldberg Scale questionnaires. The data were qualitatively analysed by open, axial, and selective coding, and the questionnaires by descriptive statistics. RESULTS: The caregivers of the urban setting valued the support that made their life easier in hospital and the social support received at home more highly, while caregivers in rural settings valued hospital support oriented towards education in care for life after returning home, all linked to the personalization of care. Personal disturbances due to care occurred in all settings, although differences appeared in psychic repercussions and in the type of drugs and their consumption. There were differences in terms of support needed and the difficulties encountered. CONCLUSIONS: The setting where caregivers live determines their perceptions of care and some of their needs in the hospital. The measures questioned in the Functional Plan should be reviewed and some priorities should be redefined, including additional measures, depending on the family situation of the caregivers. PMID- 24406358 TI - [A reflection group's experience in handling difficult clinical encounters]. AB - BACKGROUND: We present the experience of a reflection group to evaluate whether the methodology carried out helps health professionals to understand difficult encounters and improve their professional satisfaction and communication with the patient. METHOD: We followed a cognitive restructuring methodology with a written record in order to analyze difficult encounters with patients, first individually and then followed by comments in the reflection group. RESULTS: Difficult encounters mainly involved: requests felt to be inappropriate, questioning of professional competence, and unexpected change of doctor. The emotions arising, before and after "rethinking", changed in intensity in a significant way (p<0.001). Irrational thoughts were grouped in 9 types of cognitive distortions, with the most frequent being "emotional reasoning" and "control fallacies". The majority of constructive explanatory patterns that emerged after "rethinking" were related to the need for improving communication. The group recognized many positive contributions. Neither the surveys used to evaluate occupational burnout, nor the survey designed for the evaluation showed significant differences, comparing the beginning and end of the work. CONCLUSIONS: The joint use of a cognitive-behavioral methodology in the framework of a reflection group is mutually complementary, and enables group work without the need for professional direction. Written reflection and work with irrational thoughts and "rethinking" with the perspective of group comment is an experience that is applicable in the context of Primary Care and helps in handling difficult encounters. PMID- 24406359 TI - [Impact of the inclusion of articles written in English in multilingual Spanish biomedical journals]. AB - OBJECTIVES: To analyze the impact of articles published in English compared to those published in Spanish in multilingual Spanish biomedical journals. METHODOLOGY: We analyzed the language of publication, the number of original articles, the nationality of the authors, the citations received, the citing article and the nationality of the citing authors among the articles published from 2008-2012 in 5 multilingual Spanish biomedical journals. RESULTS: The study included 4,296 documents, 85 of which were published in English (2%). The percentage of original articles and of non-Spanish authorship was significantly higher among these latter articles and they also achieved more citations and more citing articles per article published. CONCLUSIONS: The proportion of articles published in English by multilingual Spanish biomedical journals is low and they are more often originals signed exclusively by foreign authors and receive more citations than those published in Spanish, which are also more frequently made by foreign authors. PMID- 24406360 TI - [Evaluation of patient safety culture among family and community medicine residents in a hospital A& E department]. AB - BACKGROUND: Improving patient safety is a priority in all health care centres. It does not appear as a specific area of training in specialty programs. The aim of this study is to evaluate the safety culture of Family Medicine residents (MIR - Medico Interno Residente/Medical Internship and Residency). METHODS: Transversal descriptive study. The Spanish version of the "Hospital Survey on Patient Safety" questionnaire was used. Strengths and opportunities for improving the service of the A & E Department were determined. RESULTS: The most highly valued dimension was teamwork in the A & E Department. The worst qualified were "staffing" and "management support". None of those surveyed had notified any incidents in the unit. CONCLUSIONS: Amongst the MIR surveyed there is a lack of knowledge about the channels for notifying adverse events, as well as a training deficiency in safety culture. This should be strengthened in the training of specialists in Family and Community Medicine. PMID- 24406361 TI - [Use of ocular drugs in pregnancy]. AB - The information available on the safety of medicines in pregnant women is limited and must be suitably channeled. Medication that is applied topically or as eye drops can present relevant systemic absorption and cross the placenta barrier or enter maternal milk. We have reviewed ophthalmic medicines according to the fetal risk categories proposed by the classification of the Food and Drug Administration (FDA). We evaluate the medicines of choice in the most frequent ophthalmic pathologies, as well as the medicines that must be avoided. PMID- 24406362 TI - [Patients' self-management of type 2 diabetes: a narrative review]. AB - According to the World Health Organization, the number of people with diabetes mellitus in 2030 will be 366 millions in the whole world, with diabetes mellitus type 2 having the highest prevalence. The current National Chronicity and Diabetes Strategies advocate patients' self-management programs and/or interventions. Nevertheless, lack of knowledge and inadequate attitudes hinder the associative relationship between patients and professionals that is required in these programs. This literature review aims to show the outstanding needs of type 2 diabetes mellitus patients when it comes to managing the illness. Thus, results from this literature review could lay the foundations for the development of effective future programs, helping professionals focus on patients' needs. PMID- 24406363 TI - [Emergent drugs (III): hallucinogenic plants and mushrooms]. AB - An increase in the consumption of vegetable substances with a hallucinogenic effect has been observed. Some of these substances are associated with ancestral religious ceremonies, while many of them are legal or are partially regulated. Salvia divinorum is a powerful kappa receptor agonist, with dissociative and hallucinogenic properties, which start quickly and have a short duration. Kratom (Mytragyna speciosa) has mitragynine as its principal alkaloid, with stimulating effects at low doses (coke-like effect), and sedative effects (opiate-like effect) at high doses. Several deaths from its consumption have been detected. The consumption of hallucinogenic mushrooms appears in cyclic form, although there has been increase in their online offer. They are consumed in search of their hallucinogenic effects, above all those belonging to the family of psilocybes, which contain tryptamines with a hallucinogenic effect similar to LSD. Peyote (Lophophora psilocybes), a cactus rich in mescaline (trimetoxifeniletilamina), produces hallucinations of the five senses, and forms part of the religious culture of the North American Indians. Daturas, which are ubiquitous, produce anticholinergic symptoms and effects on the central nervous system (delirium, hallucinations, etc.), due to their high atropine and scopolamine content. Other substances used for their hallucinogenic effects include the drink known as ayahuasca, and seeds for preparing infusions like Ololiuqui, Morning Glory (Ipomoea violacea), Hawaian Baby Woodrose (Argyreia nervosa), Syrian Rue (Peganum harmala) and Iboga Rootbark (Tabernanthe iboga). PMID- 24406364 TI - [Specialized dendritic cells in cross-presentation of exogenous antigens to cytotoxic T lymphocytes]. AB - Dendritic cells (DC) are cells of hematopoietic origin, which constitutively express MHC class I and II, and are functionally the most potent inducers of T lymphocyte activation and proliferation. CD8+ T lymphocytes proliferate and acquire cytotoxic functions upon recognition of their cognate antigen on the surface of one or various dendritic cells with which they interact. However, only some DC subsets are able to present antigen to cytotoxic T cell precursors as taken up from extracellular sources. This function is termed cross-presentation (in Spanish, presentacion cruzada or presentacion subrogada) and requires shuttle mechanisms from phagosomes to the cytosol for antigen processing. It has been demonstrated that the differentiation of DC with these capabilities is dependent on FLT-3L and the transcription factor BATF3. They express peculiar functions and differentiation markers. These cells are distinguished in mice by surface CD8 features, while CD141 (BDCA-3) marks these cells in the human. These subpopulations are capable of selective internalization of necrotic cell debris by means of their CLEC9A lectin which is a receptor for extracellular polymerized actin. Expression of the chemokine receptor XCR1 favours contact with CD8+ T cells. Therapeutic vaccination with tumour antigens using DC is a strategy under development for the treatment of cancer. The use of DC subsets with more prominent capabilities for cross-presentation would mimic the natural mechanisms of immunization to induce cytolitic T lymphocytes. In vivo targeting of antigens with monoclonal antibodies against DEC-205 or CLEC9A attains very robust immune responses and is a strategy undergoing clinical trials for chronic viral diseases and malignancies. PMID- 24406365 TI - [Medication administration errors in emergency departments]. PMID- 24406366 TI - [Medication administration errors in emergency services]. PMID- 24406367 TI - [Methylphenidate in patiens receiving palliative care. At what stage of the investigation we are?]. PMID- 24406368 TI - [Methylphenidate in patients receiving palliative care. A what stage of the investigation are we?]. PMID- 24406369 TI - [Progress in health assessment through questionnaires]. PMID- 24406370 TI - [Candida esophagitis in an immunocompetent women. A case report]. AB - Candida esophagitis (CE) is one of the invasive infections caused by Candida albicans (CA). Its prevalence diagnosed by upper endoscopy ranges between 0.77 2.4%. Its main cause is CA. CE more often affects immunocompromised people, however it may affect healthy people too. CE requires systemic antifungal therapy. We report a case of a CE in a healthy woman who presented good response to prescribed treatment. Omeprazole might be involved in the development of her CE. PMID- 24406371 TI - [Cutaneous metastases of rectal cancer]. AB - Colorectal carcinoma is a tumour that very infrequently gives rise to cutaneous metastases and when it does so, it is rarely via the haematogenous route. We present the case of a 55-year old male diagnosed with an adenocarcinoma of the rectum (lower third), clinical stage T3N2M0. Initially treated with neoadjuvant radiochemotherapy, he was operated on eight weeks later, with an extended abdominoperineal amputation. The anatomopathological result was mucinous adenocarcinoma of the rectum, clinical stage ypT3bN1. Following a postoperative period without complications, the patient received chemotherapeutic treatment with capecitabine. Eighteen months later the patient reported the progressive appearance of subcutaneous nodules in different localizations. In the computerized tomography test multiple images were objectivized suggesting metastasis at the hepatic and pulmonary levels, as well as subcutaneous lesions. The biopsy-excision of one of the subcutaneous nodules corroborated the suspicion of metastasis of the adenocarcinoma of the rectum. Chemotherapy treatment was considered for the patient, which was not administered due to the rapid deterioration of the patient leading to his death. PMID- 24406372 TI - [Ectopic acromegaly due to a bronchial carcinoid]. AB - Tumours that cause ectopic acromegaly can do so through the secretion of GH or GHRH. One hundred cases of ectopic acromegaly due to secretion of GHRH have been described. Given the rarity of this pathology, we present a clinical case with the aim of contributing our diagnostic-therapeutic experience and the subsequent follow-up. We present the case of a patient with acromegaloid physical features that had evolved over several years. Concomitantly, he also presented other accompanying symptoms that were suggestive of a possible bronchial origin. Facing the clinical suspicion of acromegaly, we opted to confirm it biochemically and subsequently through image study. A hypophysary origin was ruled out, so we carried out screening for a bronchial neuroendocrine and/or gastrointestinal tumor as they are the most frequent localizations. The treatment of choice was surgical resection. PMID- 24406373 TI - [Cholestasis and listeriosis in the third trimester of pregnancy]. AB - Listeriosis is an infection produced by Listeria monocytogenes. It is infrequent and affects people at extreme ages, pregnant women, immunocompromised people and, occasionally, healthy people. Its incidence has increased in recent years and shows a certain tendency to seasonality, increasing in summer. It can appear sporadically or as outbreaks. In pregnant women the infection is most frequently produced in the third trimester and the symptoms are usually light. Nonetheless, the infection of the fetus is severe, and can produce miscarriages, fetal deaths, corioamnionitis and premature births with the newborn infected, manifested in the form of granulomatosis infantiseptica with abscesses and scattered granulomas or at a later stage , as meningitis or sepsis. Intrahepatic cholestasis is a reversible form of cholestasis, its cause is unknown, it is specific to pregnancy and is more frequent in multiparous women, in the third trimester and rarely before the 26th week. It disappears following childbirth and is the second cause of jaundice in pregnancy, after hepatitis. The diagnosis of cholestasis is basically clinical. It appears as palmoplantar pruritus but can also produce nausea, vomiting and abdominal discomfort localized in the right hypochondrium. Given that listeriosis and cholestasis can have a shared symptomology, the possibility of listeriosis must be borne in mind in order for early implementation of the mechanisms of diagnostic confirmation (cultivation of sterile fluids or tissues: blood, neonatal CSF, amniotic liquid or placenta) and specific treatment. We present a case of cholestasis and listeriosis in the third trimester with a good maternofetal result. PMID- 24406374 TI - Morphology of melanocytic lesions in situ. AB - Melanoma is a solid tumour with its own specificity from the biological and morphological viewpoint. On one hand, numerous mutations are already known affecting different pathways. They usually concern proliferation rate, apoptosis, cell senescence and cell behaviour. On the other hand, several visual criteria at the tissue level are used by physicians in order to diagnose skin lesions. Nevertheless, the mechanisms between the changes from the mutations at the cell level to the morphology exhibited at the tissue level are still not fully understood. Using physical tools, we develop a simple model. We demonstrate analytically that it contains the necessary ingredients to understand several specificities of melanoma such as the presence of microstructures inside a skin lesion or the absence of a necrotic core. We also explain the importance of senescence for growth arrest in benign skin lesions. Thanks to numerical simulations, we successfully compare this model to biological data. PMID- 24406376 TI - Pitfalls in clinical assessment of neurotoxic diseases: negative effects of repeated diagnostic evaluation, illustrated by a clinical case. AB - Exposure to different toxic substances can have acute and chronic neurological and neuropsychiatric health effects on humans. Patients often report impaired concentration and memory, irritability, fatigue, instability of affect and difficulties in impulse control. The diagnostic process for neurotoxic diseases is complex and relies heavily on the exclusion of differential diagnosis and substantiating the cognitive complaints by neuropsychological assessment. Diagnostic evaluations have the purpose to help the patient by finding an explanation for the symptoms to guide treatment strategy or prevent further deterioration. But what if the diagnostic process in itself leads to problems that can be quite persistent and difficult to manage? The iatrogenic, or sick making, side effects of the diagnostic process are the main focus of this case study. PMID- 24406375 TI - Exposure to prenatal life events stress is associated with masculinized play behavior in girls. AB - Previous research has shown that prenatal exposure to endocrine-disrupting chemicals can alter children's neurodevelopment, including sex-typed behavior, and that it can do so in different ways in males and females. Non-chemical exposures, including psychosocial stress, may disrupt the prenatal hormonal milieu as well. To date, only one published study has prospectively examined the relationship between exposure to prenatal stress and gender-specific play behavior during childhood, finding masculinized play behavior in girls who experienced high prenatal life events stress, but no associations in boys. Here we examine this question in a second prospective cohort from the Study for Future Families. Pregnant women completed questionnaires on stressful life events during pregnancy, and those who reported one or more events were considered "stressed". Families were recontacted several years later (mean age of index child: 4.9 years), and mothers completed a questionnaire including the validated Preschool Activities Inventory (PSAI), which measures sexually dimorphic play behavior. In sex-stratified analyses, after adjusting for child's age, parental attitudes toward gender-atypical play, age and sex of siblings, and other relevant covariates, girls (n=72) exposed to prenatal life events stress had higher scores on the PSAI masculine sub-scale (beta=3.48, p=0.006) and showed a trend toward higher (more masculine) composite scores (beta=2.63, p=0.08). By contrast, in males (n=74), there was a trend toward an association between prenatal stress and higher PSAI feminine sub-scale scores (beta=2.23, p=0.10), but no association with masculine or composite scores. These data confirm previous findings in humans and animal models suggesting that prenatal stress is a non-chemical endocrine disruptor that may have androgenic effects on female fetuses and anti androgenic effects on male fetuses. PMID- 24406378 TI - Bus accident analysis of routes with/without bus priority. AB - This paper summarises findings on road safety performance and bus-involved accidents in Melbourne along roads where bus priority measures had been applied. Results from an empirical analysis of the accident types revealed significant reduction in the proportion of accidents involving buses hitting stationary objects and vehicles, which suggests the effect of bus priority in addressing manoeuvrability issues for buses. A mixed-effects negative binomial (MENB) regression and back-propagation neural network (BPNN) modelling of bus accidents considering wider influences on accident rates at a route section level also revealed significant safety benefits when bus priority is provided. Sensitivity analyses done on the BPNN model showed general agreement in the predicted accident frequency between both models. The slightly better performance recorded by the MENB model results suggests merits in adopting a mixed effects modelling approach for accident count prediction in practice given its capability to account for unobserved location and time-specific factors. A major implication of this research is that bus priority in Melbourne's context acts to improve road safety and should be a major consideration for road management agencies when implementing bus priority and road schemes. PMID- 24406379 TI - Supporting patients during their breast cancer journey: the informational role of clinical nurse specialists. AB - BACKGROUND: Research evidence suggests that a multidisciplinary team approach improves the outcomes of patients with breast cancer. However, limited attention has examined the extent to which the clinical nurse specialist's (CNS's) role can impact Irish patients' care, particularly given the novelty of this role in Ireland. OBJECTIVE: The objective of this study was to examine the informational role of CNSs in supporting Irish patients during their breast cancer journey and the extent of its impact on their care. METHODS: Three Irish breast cancer teams were investigated. A Picker questionnaire was administered to more than 100 patients per team who had completed treatment. Questions focused on the patients' journey from diagnosis through to treatment completion. Follow-up interviews with the teams' CNSs were conducted to achieve a deeper understanding of the care received. RESULTS: While patients reported an overall positive impression of their care, they were least satisfied with the amount of information and emotional support they received during their chemotherapy. Clinical nurse specialists commented that there is insufficient staffing in medical oncology to address this need in part because the ill-defined job description makes it difficult to quantify the impact of this role. CONCLUSIONS: The informational role of the CNS is inadequately recognized and is thus not currently able to fully address patients' care needs. IMPLICATIONS FOR PRACTICE: Clarification of the CNS's role description in oncology care in Ireland is needed as is sufficient CNS staffing to maintain the vital informational role of CNSs throughout the patients' breast cancer journey. PMID- 24406377 TI - The neurodegenerative effects of selenium are inhibited by FOXO and PINK1/PTEN regulation of insulin/insulin-like growth factor signaling in Caenorhabditis elegans. AB - Exposures to high levels of environmental selenium have been associated with motor neuron disease in both animals and humans and high levels of selenite have been identified in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis (ALS). We have shown previously that exposures to high levels of sodium selenite in the environment of Caenorhabditis elegans adult animals can induce neurodegeneration and cell loss resulting in motor deficits and death and that this is at least partially caused by a reduction in cholinergic signaling across the neuromuscular junction. Here we provide evidence that reduction in insulin/insulin-like (IIS) signaling alters response to high dose levels of environmental selenium which in turn can regulate the IIS pathway. Most specifically we show that nuclear localization and thus activation of the DAF 16/forkhead box transcription factor occurs in response to selenium exposure although this was not observed in motor neurons of the ventral cord. Yet, tissue specific expression and generalized overexpression of DAF-16 can partially rescue the neurodegenerative and behavioral deficits observed with high dose selenium exposures in not only the cholinergic, but also the GABAergic motor neurons. In addition, two modifiers of IIS signaling, PTEN (phosphatase and tensin homolog, deleted on chromosome 10) and PINK1 (PTEN-induced putative kinase 1) are required for the cellular antioxidant reduced glutathione to mitigate the selenium-induced movement deficits. Studies have suggested that environmental exposures can lead to ALS or other neurological diseases and this model of selenium-induced neurodegeneration developed in a genetically tractable organism provides a tool for examining the combined roles of genetics and environment in the neuro pathologic disease process. PMID- 24406380 TI - The everyday life of the young child shortly after receiving a cancer diagnosis, from both children's and parent's perspectives. AB - BACKGROUND: Providing qualified, evidence-based healthcare to children requires increased knowledge of how cancer affects the young child's life. There is a dearth of research focusing on the young child's experience of everyday life. OBJECTIVE: The purpose of this study was to explore young children's and their parents' perceptions of how cancer affects the child's health and everyday life shortly after diagnosis. METHODS: Thirteen children with newly diagnosed cancer aged 1 to 6 years and their parents, connected to a pediatric oncology unit in Southern Sweden, participated in this study through semistructured interviews. Child and parent data were analyzed as a family unit, using qualitative content analysis. RESULTS: Everyday life was spent at hospital or at home waiting to go back to hospital. Analysis led to the following categories: feeling like a stranger, feeling powerless, and feeling isolated. CONCLUSIONS: The child wants to be seen as a competent individual requiring information and participation in care. Parents need to be a safe haven for their child and not feel forced to legitimize painful and traumatic procedures by assisting with them. Nurses play a major role in the lives of children. Research with and on the young child is necessary and a way of making them visible and promoting their health and well being. IMPLICATIONS FOR PRACTICE: Nurses need to reevaluate the newly diagnosed child's care routines so as to shift focus from the illness to the child. This requires competent nurses, secure in their caring role. PMID- 24406381 TI - "Injustice! That is the cause": a qualitative study of the social, economic, and structural determinants of late diagnosis and treatment of breast cancer in Egypt. AB - BACKGROUND: In developing countries, breast cancer is generally diagnosed late. Two companion quantitative studies found that health system shortages were a major cause of delayed diagnosis together with poor health literacy. Yet, patients' perceptions regarding the delays were missing. OBJECTIVE: We conducted a qualitative study to deepen our understanding of women's experiences with diagnosis and treatment delays and highlight nuances not identifiable in the quantitative studies. INTERVENTIONS/METHODS: Fifteen women recruited from the quantitative study were interviewed. Information on diagnosis/treatment delays collected in the quantitative study constituted the basis for the selection of participants, the aim being to ensure a maximum of variability in the types of delays. RESULTS: In addition to women's health literacy challenges, which likely resulted from the interactions of individual, interpersonal, and systemic factors, barriers attributable to healthcare system weaknesses and financial constraints were revealed to be key factors. CONCLUSIONS: To reduce late-stage diagnosis, tackling women's "lack of breast cancer awareness" is far from sufficient. Although the majority of health professionals are not in a position to address structural and policy barriers, it is nonetheless important for them to be cognizant of these barriers so that they can better advise and guide their patients. IMPLICATIONS FOR PRACTICE: Our study aimed to provide a deeper understanding of the social, cultural, and structural barriers patients face in Egypt. Such knowledge should help nurses and other health professionals develop a nonjudgmental, compassionate, and perceptive approach to care. PMID- 24406382 TI - Supportive care needs for women with gynecological cancer and their relatives during the prediagnostic period. AB - BACKGROUND: The prediagnostic process for gynecological cancer has become quite rapid. It gives the woman limited time to handle new information about her illness and make decisions. The existing support initiatives in Denmark focus on aftercare rather than on needs for support in the prediagnostic period. OBJECTIVE: The purpose of this study was to investigate the need for supportive care among women with gynecological cancer and their relatives during the prediagnostic period. METHOD: A qualitative descriptive method was applied to semistructured interviews. We interviewed, at different times in the prediagnostic period, 16 women with gynecological cancer and 16 relatives. Participants were recruited at 1 hospital during a 3-month period. RESULTS: Women in the prediagnostic period require an overview of the treatment process supplemented with information, involvement, and help to prepare themselves for treatment. Relatives need involvement, someone to talk to, an overview of the prediagnostic period, and advice on communication about cancer with children and teenagers in the family. CONCLUSIONS: Women with gynecological cancer should be encouraged to let their relatives get involved in the prediagnostic period. Information about the prediagnostic period should be readily accessible at a time when the women and their relatives need this. Internet-based information could be a relevant solution in the prediagnostic period. IMPLICATIONS FOR PRACTICE: Issues concerning support of the relatives and needs among families with children should be spotted in the early diagnostic phase of patients with gynecological cancer. More knowledge about the prediagnostic period should be made available as eHealth solutions. PMID- 24406384 TI - Reporting quality for abstracts of randomized controlled trials in cancer nursing research. AB - BACKGROUND: Abstracts are often used to screen a journal article. Little is known about the reporting quality for abstracts of randomized controlled trials (RCTs) in cancer nursing. OBJECTIVE: This study evaluated the quality of abstracts reporting published RCTs in cancer nursing and examined factors contributing to better reporting quality. METHODS: This is a literature review study. Searches were conducted in PubMed and Cumulative Index to Nursing and Allied Health Literature for English-language RCTs involving cancer nursing. Quality of abstract reporting was assessed and scored based on the Consolidated Standards of Reporting Trial statement for Abstracts (CONSORT for Abstracts). Descriptive statistics, univariate, and multivariate analyses were used to identify predictors of better quality of abstracts. RESULTS: A total of 227 eligible articles published between 1984 and 2010 from 68 journals were identified. On average 46% of the items in the CONSORT for Abstracts were reported. More than 80% of the studies addressed only 6 of the 17 items from the CONSORT for Abstracts. Items concerning randomization, blinding, and intent-to-treat analysis were reported by fewer than 30% of the studies. Publication year, word count, impact factor, number of institutes, corresponding author's country, and funding accounted for 31.6% to 33.2% of the variance of the quality of abstracts based on a multiple regression model. CONCLUSIONS: The reporting quality score of cancer nursing RCT abstracts was suboptimal. IMPLICATIONS FOR PRACTICE: Strategies to improve abstract reporting quality are needed. To ensure that essential RCT information can be reported in the abstract, journal editors may need to reassess word count limits. PMID- 24406383 TI - Transition from patient to survivor in African American breast cancer survivors. AB - BACKGROUND: Breast cancer is the most common cancer among African American (AA) women, with a survival rate of 79%, lower than for other ethnic and racial groups in the United States. Minorities experience disparities in timeliness of care, delivery of culturally sensitive care, and outcomes. Transition from active treatment to survivorship presents an opportunity for exploration. PURPOSE/OBJECTIVES: This qualitative, grounded theory study examined the experiences and coping of AA women as they transition from being a breast cancer patient to being a breast cancer survivor. METHODS: This study included 15 community-based AA women aged 35 to 75 years in Charleston, South Carolina, and Buffalo, New York, who had completed treatment for primary breast cancer between 6 and 18 months prior. A semistructured interview explored experiences as they finished treatment, support from family, role of spirituality, physical and emotional concerns, needs of the survivor, as well as suggestions for possible interventions for other survivors. Two investigators reviewed transcripts and coding to confirm and refine the findings. RESULTS: Four main themes were identified: perseverance through struggles supported by reliance on faith, persistent physical issues, anticipatory guidance needed after treatment, and emotional needs as important as physical. CONCLUSIONS: The transition from cancer patient to survivor is a pervasive time filled with stress, loss of safety net, and significant coping measures. Participants expressed the need to have support from another AA breast cancer survivor as they complete treatment. IMPLICATIONS FOR PRACTICE: Nurses and providers can assess and address stressors in transition. Nurses should design patient-centered interventions using peers as direct support to promote effective coping strategies. PMID- 24406385 TI - Cardiorenal syndrome: understanding the connections between cardiac and renal disease. AB - Renal and cardiac diseases are nearly ubiquitous in hospitalized patients and common causes of morbidity in outpatients. Although the connection between the heart and kidneys is relatively well known in the medical community, a more formal classification for the clinical interplay of the two systems has been developed only recently. Cardiorenal syndrome was described by Italian nephrologist Claudio Ronco in 2008. This classification allows for justification of management strategies in these complex patients and will guide further research studies. PMID- 24406386 TI - Subfoveal choroidal thickness in retinal angiomatous proliferation. AB - PURPOSE: To investigate the subfoveal choroidal thickness in patients with retinal angiomatous proliferation (RAP). METHODS: In consecutive patients with RAP, subfoveal choroidal thickness was retrospectively measured by the use of enhanced depth imaging spectral domain optical coherence tomography in comparison with age-matched control subjects. RESULTS: Nineteen eyes of 19 patients with RAP and 32 eyes of 32 control subjects were included in this study. No significant differences were found between the eyes with RAP and the control eyes regarding age, gender, spherical equivalent, and axial length. Mean subfoveal choroidal thickness in 19 eyes with RAP was significantly less than that in the control eyes (129.5 +/- 35.8 MUm vs. 201.3 +/- 55.0 MUm, P < 0.0001). The difference in mean subfoveal choroidal thickness between eyes with Stage 2 RAP (132.8 +/- 38.2 MUm) and eyes with Stage 3 RAP (126.4 +/- 36.6 MUm) was not significant, though each measurement was significantly less than that in the control eyes (P < 0.001 and P = 0.002, respectively). CONCLUSION: Eyes with RAP had a significantly thinner subfoveal choroid compared with normal eyes. Such morphologic features may be related to the pathologic mechanism of RAP. PMID- 24406387 TI - Quantification of metamorphopsia in chronic central serous chorioretinopathy after half-dose verteporfin photodynamic therapy. AB - PURPOSE: To determine the degree of metamorphopsia before and 1 year after half dose verteporfin photodynamic therapy in eyes with chronic central serous chorioretinopathy. METHODS: This was a retrospective, noncomparative, interventional case series. Forty-five eyes of 45 consecutive patients with chronic central serous chorioretinopathy were evaluated. The degree of metamorphopsia was measured with M-CHARTS before and at 1, 3, 6, 9, and 12 months after half-dose verteporfin photodynamic therapy. The best-corrected visual acuity was also measured. RESULTS: Forty of the 45 eyes had a complete resolution of the serous retinal detachment at 1 month, 1 eye at 3 months, and 3 eyes at 6 months. The serous retinal detachment in one eye persisted throughout the follow up period. The mean horizontal metamorphopsia score improved significantly from 0.61 +/- 0.52 degrees at baseline to 0.49 +/- 0.56 degrees at 12 months (P = 0.04). The vertical metamorphopsia score improved significantly from 0.52 +/- 0.53 degrees at baseline to 0.33 +/- 0.46 degrees at 12 months (P = 0.005). CONCLUSION: Half-dose verteporfin photodynamic therapy for chronic central serous chorioretinopathy results in significant improvements of metamorphopsia at 1 year, especially in eyes with good best-corrected visual acuity at the baseline. Half-dose verteporfin photodynamic therapy can be a therapeutic option for patients with good visual acuity who complain of metamorphopsia. PMID- 24406388 TI - Our experiences suggest that the technique described by Wong may be further simplified while preserving successful outcomes. PMID- 24406389 TI - Sensitivity of fluid detection in patients with neovascular amd using spectral domain optical coherence tomography high-definition line scans. AB - PURPOSE: To determine the sensitivity of the Cirrus high-definition (HD) 5-line raster scans for detecting retinal fluid in neovascular age-related macular degeneration when using the spectral domain optical coherence tomography macular cubes as a gold standard. METHODS: Patients were retrospectively identified from their initial follow-up visit after being newly diagnosed with neovascular age related macular degeneration in at least one eye. Patients were imaged with Cirrus spectral domain optical coherence tomography using the 512 * 128 macular cube scan and HD 5-line raster scan settings. Patients with other diseases that cause subretinal or intraretinal fluid, or who had an epiretinal membrane causing macular traction were excluded from the analysis. We recorded the presence or absence of subretinal or intraretinal fluid in the macular cube and on the HD 5 line raster scans. RESULTS: Seventy-nine patients met the study requirements. Of the 63 patients who had fluid present on the macular cube, 1 did not seem to have fluid on the HD 5-line raster scans. Taking the macular cube as a gold standard, the sensitivity of the HD 5-line raster scans for detecting retinal fluid in this cohort was 98.4%. CONCLUSION: The Cirrus HD 5-line raster scans have a high sensitivity for detecting fluid in the macular cube in patients with neovascular age-related macular degeneration. PMID- 24406390 TI - Efficient lysis of epithelial ovarian cancer cells by MAGE-A3-induced cytotoxic T lymphocytes using rAAV-6 capsid mutant vector. AB - MAGE-A3 is highly expressed in epithelial ovarian cancer (EOC), making it a promising candidate for immunotherapy. We investigated whether dendritic cells (DCs) transduced with a rAAV-6 capsid mutant vector Y445F could elicit effective MAGE-A3-specific anti-tumor cytotoxic T lymphocyte (CTL) responses in vitro. MAGE A3 was cloned and rAAV-6-MAGE-A3 purified, followed by proviral genome detection using real-time PCR. Immunofluorescence detection of rAAV-6-Y445F-MAGE-A3 transduced DCs demonstrated 60% transduction efficiency. Fluorescent in situ hybridization analysis confirmed chromosomal integration of rAAV vectors. Flow cytometric analysis of transduced DCs showed unaltered expression of critical monocyte-derived surface molecules with retention of allo-stimulatory activity. Co-culture of autologous T lymphocytes with MAGE-A3-expressing DCs produced CTLs that secreted IFN-gamma, and efficiently killed MAGE-A3+ EOC cells. This form of rAAV-based DC immunotherapy, either alone or more likely in combination with other immune-enhancing protocols, may prove useful in the clinical setting for management of EOC. PMID- 24406391 TI - A cohort event monitoring to determine the adverse events following administration of mouse brain derived, inactivated Japanese Encephalitis vaccine in an endemic district in Sri Lanka. AB - Introduction of human immunization reduced Japanese Encephalitis (JE) cases dramatically in Sri Lanka. However, the increased reporting of adverse events following immunization (AEFI) affected vaccine acceptance by the community. Against this background, we describe the incidence of overall AEFI and incidence and profile of AEFI, thought to be causally related to the mouse-brain derived JE vaccine. A follow-up of 9798 vaccine recipients was performed for a period of two weeks post-vaccination. Parents self-recorded observed signs and symptoms. The self-records were collected by trained supervisors. All monitored children who manifested symptom/s were investigated in details by medical officers experienced in AEFI investigations within two weeks after ending the follow-up period. Using the results of the investigation, the causality assessment was performed. The estimated cumulative incidence rate of overall AEFI was 8.6 children per 100 immunizations. The same for observed AEFI consistent with causal association to the inactivated JE vaccine was 4.3 children (95% CI-3.9-4.7%) per 100 immunizations. The most frequent AEFI was fever (81%). The frequency of high fever (>102 degrees F) was 26%. Other major AEFI were body ache (22%) vomiting (21%), urticaria (19%), pruritus (5%), and headache (5%). Though 83% of children with AEFI thought to be causally related to the vaccine sought medical care, only 6.6% required hospitalizations. The incidence rate of AEFI in the cohort event monitoring was several-fold higher than that reported through the national AEFI surveillance system. The incidence rate of allergic manifestations among Sri Lankan children approached what was reported for non-endemic settings and was higher than in other JE endemic populations elsewhere. Contrary to the belief of medical practitioners and the general public, incidence of seizures was low and vaccine related other neurological manifestations were absent. PMID- 24406392 TI - Comparison of two commercial vaccines against visceral leishmaniasis in dogs from endemic areas: IgG, and subclasses, parasitism, and parasite transmission by xenodiagnosis. AB - BACKGROUND: The incidence of zoonotic canine visceral leishmaniasis (CVL) would decrease if dogs were effectively vaccinated; however, additional data on the efficacy of canine vaccines are required for their approved preventative use. PURPOSE: To prospectively evaluate vaccination outcomes using two products commercially available in Brazil, with respect to adverse reactions (reactogenicity), humoral response, disease signs, parasitism, and parasite infectiousness in naturally exposed pet dogs in an endemic area of visceral leishmaniasis (VL). METHODS: From 2010 to 2012, healthy dogs were vaccinated with Leishmune((r)) (50 animals) or Leish-Tec((r)) (50 animals). Each dog was examined to identify clinical signs during peri- and post-vaccination procedures every 2 months for 11 months to identify the presence of parasites or parasite DNA in splenic samples using culturing or PCR, respectively. Levels of anti-Leishmania IgG, IgG1, and IgG2 were quantified in sera by ELISA and infectiousness was assessed by xenodiagnosis. RESULTS: Adverse effects occurred in 2.2% (1/45) and 13.0% (6/46) of the animals in the Leishmune((r)) and Leish-Tec((r)) groups, respectively. IgG levels peaked on the 21st day following the first dose of Leishmune((r)) and on the 21st day after the second dose of Leish-Tec((r)). The final seropositivity rate for IgG was 32.5% (13/40) and 30.9% (13/42) in the Leishmune((r)) and Leish-Tec((r)) groups, respectively. The Leishmune((r)) group presented higher levels of IgG1 and IgG2 compared to the Leish-Tec((r)) group (p<0.001), and ELISA reactivity in both vaccinated groups was significantly lower (p<0.001) than in infected positive control dogs. Parasitism was observed in 12.2% (5/41) of the Leishmune((r)) group, and 7.9% (3/38) of the Leish-Tec((r)) group, with xenodiagnostic transmission rates of Leishmania to Lutzomyia longipalpis of 5.1% (2/39), and 5.4% (2/37), respectively. CONCLUSIONS: No significant differences were observed in dogs vaccinated with Leishmune((r)) or Leish-Tec((r)), with respect to LVC clinical aspects, parasitism, IgG seropositivity, or dog infectiousness. The Leishmune((r))-vaccinated animals presented higher levels of IgG, IgG1, and IgG2. The animals vaccinated with Leish Tec((r)) exhibited adverse reactions with greater frequency and severity. PMID- 24406393 TI - Generation of a safety enhanced Salmonella Gallinarum ghost using antibiotic resistance free plasmid and its potential as an effective inactivated vaccine candidate against fowl typhoid. AB - A safety enhanced Salmonella Gallinarum (SG) ghost was constructed using an antibiotic resistance gene free plasmid and evaluated its potential as fowl typhoid (FT) vaccine candidate. The antibiotic resistance free pYA3342 plasmid possesses aspartate semialdehyde dehydrogenase gene which is complimentary to the deletion of the chromosomal asd gene in the bacterial host. This plasmid was incorporated with a ghost cassette containing the bacteriophage PhiX174 lysis gene E, designated as pJHL101. The plasmid pJHL101 was transformed into a two virulence genes-deleted SG. The SG ghosts with tunnel formation and loss of cytoplasmic contents were observed by scanning electron microscopy and transmission electron microscopy. The cell viability of the culture solution was decreased to 0% at 24h after the induction of gene E expression by an increase in temperature from 37 degrees C to 42 degrees C. The safety and protective efficacy of the SG ghost vaccine was further examined in chickens which were divided into three groups: group A (non-immunized control), group B (orally immunized), and group C (intramuscularly immunized). The birds were immunized at 7d of age. No clinical symptoms associated with FT such as anorexia, depression and greenish diarrhea were observed in the immunized chickens. Upon challenge with a virulent SG strain at 3 week post-immunization, the chickens immunized with the SG ghost via various routes were efficiently protected, as shown by significantly lower mortality and post-mortem lesions in comparison with control group. In addition, all the immunized chickens showed significantly higher antibody responses accompanied by a potent antigen-specific lymphocyte proliferative response along with significantly increased numbers of CD4+ and CD8+ T lymphocytes. Overall, our results provide a promising approach of generating SG ghosts using the antibiotic resistance free plasmid in order to prepare a non-living bacterial vaccine candidate which could be environmentally safe yet efficient to prevent FT in chickens. PMID- 24406394 TI - Molecular dynamics simulation of the partitioning of benzocaine and phenytoin into a lipid bilayer. AB - Molecular dynamics simulations were used to examine the partitioning behaviour of the local anaesthetic benzocaine and the anti-epileptic phenytoin into lipid bilayers, a factor that is critical to their mode of action. Free energy methods are used to quantify the thermodynamics of drug movement between water and octanol as well as for permeation across a POPC membrane. Both drugs are shown to favourably partition into the lipid bilayer from water and are likely to accumulate just inside the lipid headgroups where they may alter bilayer properties or interact with target proteins. Phenytoin experiences a large barrier to cross the centre of the bilayer due to less favourable energetic interactions in this less dense region of the bilayer. Remarkably, in our simulations both drugs are able to pull water into the bilayer, creating water chains that extend back to bulk, and which may modify the local bilayer properties. We find that the choice of atomic partial charges can have a significant impact on the quantitative results, meaning that careful validation of parameters for new drugs, such as performed here, should be performed prior to their use in biomolecular simulations. PMID- 24406395 TI - "Please tap the shape, anywhere you like": Shape skeletons in human vision revealed by an exceedingly simple measure. AB - A major challenge for visual recognition is to describe shapes flexibly enough to allow generalization over different views. Computer vision models have championed a potential solution in medial-axis shape skeletons-hierarchically arranged geometric structures that are robust to deformations like bending and stretching. In the experiments reported here, we exploited an old, unheralded, and exceptionally simple paradigm to reveal the presence and nature of shape skeletons in human vision. When participants independently viewed a shape on a touch-sensitive tablet computer and simply tapped the shape anywhere they wished, the aggregated touches formed the shape's medial-axis skeleton. This pattern held across several shape variations, demonstrating profound and predictable influences of even subtle border perturbations and amodally filled-in regions. This phenomenon reveals novel properties of shape representation and demonstrates (in an unusually direct way) how deep and otherwise-hidden visual processes can directly control simple behaviors, even while observers are completely unaware of their existence. PMID- 24406396 TI - Improvement in spatial imagery following sight onset late in childhood. AB - The factors contributing to the development of spatial imagery skills are not well understood. Here, we consider whether visual experience shapes these skills. Although differences in spatial imagery between sighted and blind individuals have been reported, it is unclear whether these differences are truly due to visual deprivation or instead are due to extraneous factors, such as reduced opportunities for the blind to interact with their environment. A direct way of assessing vision's contribution to the development of spatial imagery is to determine whether spatial imagery skills change soon after the onset of sight in congenitally blind individuals. We tested 10 children who gained sight after several years of congenital blindness and found significant improvements in their spatial imagery skills following sight-restoring surgeries. These results provide evidence of vision's contribution to spatial imagery and also have implications for the nature of internal spatial representations. PMID- 24406397 TI - Matrikines from basement membrane collagens: a new anti-cancer strategy. AB - BACKGROUND: Tumor microenvironment is a complex system composed of a largely altered extracellular matrix with different cell types that determine angiogenic responses and tumor progression. Upon the influence of hypoxia, tumor cells secrete cytokines that activate stromal cells to produce proteases and angiogenic factors. In addition to stromal ECM breakdown, proteases exert various pro- or anti-tumorigenic functions and participate in the release of various ECM fragments, named matrikines or matricryptins, capable to act as endogenous angiogenesis inhibitors and to limit tumor progression. SCOPE OF REVIEW: We will focus on the matrikines derived from the NC1 domains of the different constitutive chains of basement membrane-associated collagens and mainly collagen IV. MAJOR CONCLUSIONS: The putative targets of the matrikine control are the proliferation and invasive properties of tumor or inflammatory cells, and the angiogenic and lymphangiogenic responses. Collagen-derived matrikines such as canstatin, tumstatin or tetrastatin for example, decrease tumor growth in various cancer models. Their anti-cancer activities comprise anti-proliferative effects on tumor or endothelial cells by induction of apoptosis or cell cycle blockade and the induction of a loss of their migratory phenotype. They were used in various preclinical therapeutic strategies: i) induction of their overexpression by cancer cells or by the host cells, ii) use of recombinant proteins or synthetic peptides or structural analogues designed from the structure of the active sequences, iii) used in combined therapies with conventional chemotherapy or radiotherapy. GENERAL SIGNIFICANCE: Collagen-derived matrikines strongly inhibited tumor growth in many preclinical cancer models in mouse. They constitute a new family of anti-cancer agents able to limit cancer progression. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties. PMID- 24406398 TI - Tyrosine phosphorylation of 3BP2 is indispensable for the interaction with VAV3 in chicken DT40 cells. AB - Adaptor protein c-Abl SH3 domain-binding protein-2 (3BP2) is known to play regulatory roles in immunoreceptor-mediated signal transduction. We have previously demonstrated that Tyr(174), Tyr(183) and Tyr(446) in mouse 3BP2 are predominantly phosphorylated by Syk, and the phosphorylation of Tyr(183) and the Src homology 2 (SH2) domain of mouse 3BP2 are critical for B cell receptor (BCR) induced activation of nuclear factor of activated T cells (NFAT) in human B cells. In this report, we have shown that Syk, but not Abl family protein tyrosine kinases, is critical for BCR-mediated tyrosine phosphorylation of 3BP2 in chicken DT40 cells. Mutational analysis showed that Tyr(174), Tyr(183) and Tyr(426) of chicken 3BP2 are the major phosphorylation sites by Syk and the SH2 domain of 3BP2 is critical for tyrosine phosphorylation. In addition, phosphorylation of Tyr(426) is required for the inducible interaction with the SH2 domain of Vav3. Moreover, the expression of the mutant form of 3BP2 in which Tyr(426) was substituted to Phe resulted in the reduction in BCR-mediated Rac1 activation, when compared with the case of wild-type. Altogether, these data suggest that 3BP2 is involved in the activation of Rac1 through the regulation of Vav3 by Syk-dependent phosphorylation of Tyr(426) following BCR stimulation. PMID- 24406399 TI - A simple and economical method of electrode fabrication for brain self stimulation in rats. AB - INTRODUCTION: Intracranial self-stimulation (ICSS) is an operant paradigm in which rodents self-administer rewarding electrical stimulation through electrodes implanted into the brain. We describe a simple, inexpensive and reliable method to fabricate monopolar and bipolar electrodes, along with the swivel system, for delivery of electric pulses at the targeted sites in the brain of rat. METHODS: The system consists of an insulated stainless steel wire(s) (diameter: 0.25 mm), plastic base, pedestal and connector attached to a swivel via a stimulating cable, which is connected to the stimulator. We provide the specifications, source of each component, and the method of fabrication in details. RESULTS: In house fabricated monopolar or bipolar electrodes were subjected to rigorous tests. We implanted the electrode into the medial forebrain bundle (MFB) and rat was trained to press the lever for electrical self-stimulation in operant chamber for 60 min each day. In about 3-4 days, the animal gave a consistent response (~40 presses/min) and was considered as conditioned. For evaluation of reinforcement behavior, the number of lever pressings of conditioned rat with or without electrical stimulation was assessed for a period of 30 min each day for 10 weeks. The rewarding frequency sustained for the entire duration. In addition, we compared the lever pressing data of the groups of rats implanted with in-house fabricated versus with those with commercial electrodes; no significant differences were encountered. DISCUSSION: The required components for the electrode fabrication are easily available. With some practice, the system can be easily assembled in the laboratory and costs less than a dollar. We suggest that the electrodes, fabricated using this method, may serve as an economical and reliable tool in neuropharmacological and neurobehavioral studies. PMID- 24406400 TI - Effective catalytic disproportionation of aqueous H2O2 with di- and mono-nuclear manganese(II) complexes containing pyridine alcohol ligands. AB - The two novel manganese(II) complexes with 2-hydroxymethylpyridine (2-CH2OHpy) {[Mn2(MU-Cl)2(2-CH2OHpy)4]Cl2.2H2O (1)} and 2-hydroxyethylpyridine (2-(CH2)2OHpy) {[Mn(2-(CH2)2OHpy)2(NCS)2] (2)} were synthesized and characterized by means of X ray diffraction, IR, EPR, HF EPR spectroscopy, magnetic and TG/DTG data. The complexes show catalase-like activity in neutral aqueous solution since they were able to disproportionate H2O2 to harmless H2O and O2. Both complexes act as true catalysts since they reverted to their original form after depleting all the H2O2, as suggested by the operando resonant inelastic X-ray spectroscopy (RIXS) measurements. PMID- 24406401 TI - Use of the h-index to measure the quality of the output of health services researchers. AB - OBJECTIVE: To assess the use of the h-index to measure the quality of the output of health services researchers. METHOD: Online survey, with bibliometric analysis of a convenience volunteer sample of researchers mainly in the UK, North America and Australasia. Self-reported from Google Scholar: h-index; number of papers; number of citations; number of papers with >= 10 citations. RESULTS: There were complete responses from 532 health services researchers of whom 371 (70%) were from the UK. Of the bibliometric measures, the h-index appeared to be the best discriminator between other measures of quality (e.g. seniority; entry into the last UK Research Assessment Exercise). The median h-index was 12, with 90th and 95th quantiles of 40 and 52, respectively. Statisticians had the highest h-index with qualitative researchers the lowest (median 16 and 7, respectively). The h index was predicted to increase by approximately 1 point annually with the biggest increase in statisticians and smallest in qualitative researchers when estimated by quantile regression. CONCLUSIONS: The h-index is a useful summary measure of output and quality of health services researchers. However, any accurate interpretation of bibliometric measures needs to take into account a person's research discipline. PMID- 24406402 TI - Capsular neovascularisation: case report and review of literature. PMID- 24406403 TI - Dante and asthenopia: a modern visual problem described during the Middle Ages. PMID- 24406404 TI - B-scan ultrasonography following open globe repair. AB - PURPOSE: To examine the accuracy and predictive ability of B-scan ultrasonography in the post-repair assessment of an open globe injury. METHODS: In all, 965 open globe injuries treated at the Massachusetts Eye and Ear Infirmary between 1 January 2000 and 1 June 2010 were retrospectively reviewed. A total of 427 ultrasound reports on 210 patients were analyzed. Ultrasound reports were examined for the following characteristics: vitreous hemorrhage, vitreous tag, retinal tear, RD (including subcategories total RD, partial RD, closed funnel RD, open funnel RD, and chronic RD), vitreous traction, vitreous debris, serous choroidal detachment, hemorrhagic choroidal detachment, kissing choroidal detachment, dislocated crystalline lens, dislocated intraocular lens (IOL), disrupted crystalline lens, intraocular foreign body (IOFB), intraocular air, irregular posterior globe contour, disorganized posterior intraocular contents, posterior vitreous detachment, choroidal vs retinal detachment, vitreal membranes, and choroidal thickening. The main outcome measure was visual outcome at final follow-up. RESULTS: Among 427 B-scan reports, there were a total of 57 retinal detachments, 19 retinal tears, 18 vitreous traction, 59 serous choroidal detachments, 47 hemorrhagic choroidal detachments, and 10 kissing choroidal detachments. Of patients with multiple studies, 26% developed retinal detachments or retinal tears on subsequent scans. Ultrasound had 100% positive predictive value for diagnosing retinal detachment and IOFB. The diagnoses of retinal detachment, disorganized posterior contents, hemorrhagic choroidal detachment, kissing choroidal detachment, and irregular posterior contour were associated with worse visual acuity at final follow-up. Disorganized posterior contents correlated with particularly poor outcomes. CONCLUSIONS: B-scan ultrasonography is a proven, cost-effective imaging modality in the management of an open globe injury. This tool can offer both diagnostic and prognostic information, useful for both surgical planning and further medical management. PMID- 24406405 TI - Reply to Kivela et al. PMID- 24406406 TI - Blebitis with scleral abscess in a case of operated trabeculectomy with mitomycin C and a subcunjunctival ologen implant. PMID- 24406407 TI - Severe intraocular pressure rise following intravitreal triamcinolone: a national survey to estimate incidence and describe case profiles. AB - PURPOSE: The objective of this study is to estimate the incidence of steroid induced severe intraocular pressure (IOP) rise following intravitreal triamcinolone acetonide (IVTA) injection and to describe case profiles of the patients affected within the United Kingdom. PATIENTS AND METHODS: A national survey was carried out to identify cases that had developed severe IOP rise requiring laser or surgery following IVTA through the British Ophthalmic Surveillance Unit. Respondents were mailed a questionnaire and with a follow-up questionnaire 1 year later, to ascertain characteristics of the patients identified. We also carried out a midpoint survey to ascertain national practice of IVTA at the time. RESULTS: There were 29 confirmed reports of severe IOP rise after IVTA in the 13-month period of surveillance. All the cases were unilateral and the mean time between the IVTA and the maximum recorded IOP was 16 weeks. Six of these patients had pre-existing glaucoma or ocular hypertension, and a further two were known to be 'steroid responders'. Using the adjusted denominators, obtained from our national survey, the estimated annual incidence would be between 3.6 and 9.5 per 1000 injections. CONCLUSIONS: These results confirm that severe IOP rise after IVTA is an uncommon but serious complication. Data obtained from this national study should aid clinicians in choosing the treatment best suited to their patients. PMID- 24406408 TI - Enhanced depth imaging as an adjunctive tool in the diagnosis of decalcified choroidal osteoma. PMID- 24406409 TI - Plasma and vitreous fluid levels of Dickkopf-1 in patients with diabetic retinopathy. AB - PURPOSE: Dickkopf-1 (DKK-1) is a secreted inhibitor of the Wnt/beta-catenin signaling pathway, which plays a pathogenic role in diabetic retinopathy (DR). We aimed to investigate whether DKK-1 levels in the plasma and the vitreous are associated with DR in type 2 diabetes mellitus (DM) patients. METHODS: Case control study: plasma samples were collected from 125 type 2 DM including 81 DR (29 non-proliferative DR (NPDR) and 52 proliferative DR (PDR)), 44 non-DR patients (NDR), and 100 non-diabetic controls. Undiluted vitreous fluid samples were obtained from 30 PDR and 25 non-diabetic patients. DKK-1 concentrations in samples were determined using enzyme-linked immunosorbent assay. Variables were compared with the Kruskal-Wallis H test, Mann-Whitney U-test, and chi(2)-test, when appropriate. RESULTS: Plasma DKK-1 levels were significantly lower in DR patients (median: 465.77 pg/ml, range: 137.11-1190.31) than in non-diabetic controls (656.83 pg/ml, 171.63-1795.08; P<0.001) and NDR patients (693.04 pg/ml, 305.43-1218.35; P<0.001). Furthermore, DKK-1 levels were lower in PDR patients (425.21 pg/ml, 137.10-1077.32) compared with NPDR patients (594.86 pg/ml, 256.36 1393.27; P=0.003). Vitreous absolute DKK-1 levels in PDR patients (259.04 pg/ml, 104.44-596.96) were higher than in non-diabetic controls (138.26 pg/ml, 18.69 239.52; P<0.001). After normalizing by total vitreous protein concentrations, however, there was no significant difference between the groups. DKK-1 levels in vitreous were lower than those in plasma in both groups (P<0.001 for controls; P=0.002 for PDR patients). CONCLUSIONS: Decreased plasma DKK-1 levels, which may contribute to the Wnt pathway activation, are associated with the presence and progression of DR, and have potential to become a biomarker for DR. PMID- 24406410 TI - Myopic macular retinoschisis with microvascular anomalies. PMID- 24406411 TI - Emmetropisation and the aetiology of refractive errors. AB - The distribution of human refractive errors displays features that are not commonly seen in other biological variables. Compared with the more typical Gaussian distribution, adult refraction within a population typically has a negative skew and increased kurtosis (ie is leptokurtotic). This distribution arises from two apparently conflicting tendencies, first, the existence of a mechanism to control eye growth during infancy so as to bring refraction towards emmetropia/low hyperopia (ie emmetropisation) and second, the tendency of many human populations to develop myopia during later childhood and into adulthood. The distribution of refraction therefore changes significantly with age. Analysis of the processes involved in shaping refractive development allows for the creation of a life course model of refractive development. Monte Carlo simulations based on such a model can recreate the variation of refractive distributions seen from birth to adulthood and the impact of increasing myopia prevalence on refractive error distributions in Asia. PMID- 24406413 TI - Reply to Dr Grzybowski. PMID- 24406412 TI - Epidemiology of myopia. AB - Myopia is one of the most prevalent disorders of the eye. Higher myopia is associated with comorbidities that increase risks of severe and irreversible loss of vision, such as retinal detachment, subretinal neovascularization, dense cataract, and glaucoma. In recent years, reports from population-based prevalence studies carried out in various geographical areas now give a clear picture of the current distribution of refractive error. The scarcity of data from well-designed longitudinal cohort studies is still yet to be addressed. These studies have confirmed the previous data indicating that prevalence of refractive error varies according to ethnicity and geographic regions, and also point to an increase in myopia prevalence over the past half-century. The problem is particularly pronounced in affluent, industrialised areas of East Asia. Environmental risk factors for myopia related to socioeconomic status and lifestyle have been identified. The past decade has seen a greater understanding of the molecular biological mechanisms that determine refractive error, giving further support to the belief that myopia is the result of a complex interaction between genetic predisposition and environmental exposures. This review summarizes data on the prevalence, incidence, progression, associations, risk factors, and impact from recent epidemiological studies on myopia. PMID- 24406414 TI - Early surgery for epiretinal membrane preserves more vision for patients. AB - PURPOSE: To establish whether early vitrectomy for epiretinal membrane (ERM) is preferable to delayed surgery. METHODS: We carried out a retrospective study of 120 eyes from 120 patients with pre-operative visual acuity (VA) of 6/60 or better. Pre-operative logMAR score was considered to act as an appropriate proxy measure for time of surgical procedure, with scores of 0.3 or less considered to represent early surgery, scores of 0.4 or 0.5 considered to represent medium surgery, and scores of 0.6 or more considered to represent late surgery for ERM. Patients were either pseudophakic at the time of vitrectomy or underwent combined phaco-vitrectomy for symptomatic ERM. RESULTS: Evaluation of parameter coefficients indicated that controlling for other factors, a delay of the surgical procedure from a state of early to medium corresponded to an increase (ie, disbenefit) of 0.074 units in post-operative logMAR score (95% confidence interval -0.001-0.15). A delay of the surgical procedure from a state of early to late corresponded to an increase (ie, disbenefit) of 0.21 units in post-operative logMAR score (95% confidence interval 0.13-0.29). Mean post-operative VA for early surgery was 0.16, out of which 36.2% of patients had a LogMAR score of 0.1 or better. This is in comparison to 17.2% in late ERM (those with a pre-operative logMAR score of 0.6 or more). CONCLUSION: We conclude that early surgery is associated with a lower (ie, better) post-operative logMAR score. Vitrectomy for early symptomatic ERM, in carefully selected patients, is beneficial in preserving excellent vision and allows quicker visual rehabilitation. PMID- 24406415 TI - The role of antibiotics in the prevention of post-intravitreal anti-VEGF endophthalmitis: primum non nocere! PMID- 24406416 TI - Role of lens vault in subtypes of angle closure in Iranian subjects. AB - PURPOSE: The purpose of this study is to quantify anterior chamber (AC) parameters and to determine the proportion of eyes with exaggerated lens vault (LV) in different subtypes of angle closure disease using anterior segment optical coherence tomography (AS-OCT). PATIENTS AND METHODS: In this prospective study, 115 eyes of 115 Iranian patients with angle closure disease were included and categorized into three groups: (1) fellow eyes of acute angle closure (AAC; 40 eyes); (2) primary angle closure glaucoma (PACG; 39 eyes); and (3) primary angle closure suspect (PACS; 36 eyes). Complete ophthalmic examination including gonioscopy, A-scan biometry, and AS-OCT were performed. Angle parameters, LV, and iris thickness (IT) were measured using AS-OCT. An exaggerated LV was defined as LV more than one-third the distance between the corneal endothelium and a line drawn to connect the nasal and temporal scleral spurs. RESULTS: Fellow eyes of AAC had the shallower AC (P=0.01), greater iris curvature (I-curve; P=0.01), and higher LV (P=0.02) as compared with PACS and PACG eyes. There was no statistically significant difference in the mean IT at 750 MUm from scleral spur among the three groups (P=0.45). Exaggerated LV was found in 67.5, 35.9, and 40% of fellow eyes of AAC, PACG, and PACS, respectively, (P=0.008) with an odds ratio of 1.92 (P=0.005) for fellow vs PACG and 1.68 (P=0.01) for fellow vs PACS. CONCLUSIONS: Exaggerated LV is highly prevalent in fellow eyes of AAC. These eyes have shallower AC depth, greater I-curve, and higher LV when compared with PACG and PACS. PMID- 24406417 TI - Macular thickness measurements with frequency domain-OCT for quantification of axonal loss in chronic papilledema from pseudotumor cerebri syndrome. AB - PURPOSE: To evaluate the ability of frequency domain-optical coherence tomography (FD-OCT)-measured macular thickness parameters to differentiate between eyes with resolved chronic papilledema and healthy eyes and to evaluate the correlation between FD-OCT measures and visual field (VF) loss on standard automated perimetry (SAP). METHODS: Fifty-two eyes from 29 patients suffering from pseudotumor cerebri syndrome (PTC) and 62 eyes from 31 normal controls underwent FD-OCT scanning and ophthalmic evaluation including VF with SAP. All patients had previously been submitted to treatment of PTC and had clinically resolved papilledema and stable VF for at least 6 months before the study. Macular and peripapillary retinal nerve fiber layer (RNFL) thickness measurements were determined for both groups. Comparisons were made using Generalized Estimated Equations. Correlations between FD-OCT and VF measurements were verified. RESULTS: In eyes with resolved papilledema, the macular thickness parameters corresponding to the inner and outer superior, temporal, inferior and nasal segments, average macular thickness and most RNFL thickness measurements were significantly reduced when compared with controls. The discrimination ability was similar for macular thickness measurements and RNFL thickness measurements. Both sets of OCT measurements correlated well with VF sensitivity loss. CONCLUSIONS: Eyes with resolved chronic papilledema show a significant reduction in macular thickness, which is well correlated with the severity of VF loss. Macular thickness measurements can potentially be used to estimate and monitor the amount of ganglion cell loss in eyes with papilledema from patients with PTC. PMID- 24406418 TI - Microincision cataract surgery combined with vitrectomy: a case series. AB - AIM: The objective of this study was to present the results of combined phacovitrectomy using 1.8 mm microincision cataract surgery (MICS) with special emphasis on the anterior segment complications in this group. METHODS: Retrospective, single-centre case series involving consecutive patients undergoing phacovitrectomy in a single centre in the United Kingdom during a 6 month period. RESULTS: A total of 52 eyes underwent combined MICS and pars plana vitrectomy. Intraoperative complications included posterior capsule rupture (n=2), minor iris trauma during phacoemulsification (n=1), iatrogenic retinal tears (n=2), and entry site break (n=1). Postoperatively two cases had significant inflammation, one of which resulted in 360 degrees posterior synaechiea, iris bombe, and raised intraocular pressure. Other complications included mild posterior synaechiae (n=2), posterior capsular opacification (n=3), cystoid macular oedema (n=1), and hyphaema (n=1), which spontaneously resolved. There were no cases of intraocular lens decentration. Two patients who underwent surgery for retinal detachment repair subsequently redetached. Among those having surgery for macular hole, non-closure was seen in one patient and one patient developed a retinal detachment. CONCLUSION: In conclusion, sub-2 mm MICS is a safe and effective technique in dealing with vitreoretinal disorders necessitating cataract surgery at the same time. PMID- 24406419 TI - Interval censoring and competing risks when reporting results of glaucoma surgery. PMID- 24406420 TI - Incidental folliculotropic mycosis fungoides in a blepharoplasty specimen performed for dermatochalasis. PMID- 24406421 TI - Retinal and choroidal thickness evaluation by SD-OCT in adults with obstructive sleep apnea-hypopnea syndrome (OSAS). AB - OBJECTIVE: To assess the macular retina and choroidal thickness change in patients with obstructive sleep apnea-hypopnea syndrome (OSAS) with no significant symptoms and pathological changes in the fundus using spectral domain optical coherence tomography. METHODS: This prospective, observational case control study consisted of 53 eyes of 53 patients with OSAS and 12 eyes of 12 age matched controls. Macular and choroidal thicknesses were measured by optical coherence tomography. RESULTS: The foveal and nasal macular thicknesses were significantly different between four groups (P=0.001, P=0.016). The foveal thickness of the control group was significantly thinner than that of the severe group (P=0.000). The nasal macular thickness of the control group was significantly thinner than that of the severe group (P=0.008). A significant correlation was found between oxygen desaturation index (ODI) and macular center thickness (r=0.357, R(2)=0.127, P=0.004), with an ODI coefficient of 0.457 (P=0.004). Similarly, a significant correlation was found between ODI and nasal macular thickness (r=0.265, R(2)=0.070, P=0.033), with an ODI coefficient of 0.233 (P=0.033). The subfoveal choroidal thickness was significantly different among the groups (F=3.657, P=0.017). The subfoveal choroidal thickness of the severe group was significantly thinner than that of the control group, mild group, and moderate group (P=0.023, 0.006, and 0.036, respectively). The choroidal thickness 1 mm nasal to the fovea was significantly different between the groups after correcting for age and diopter (F=3.411, P=0.023). The choroidal thickness 1 mm nasal to the fovea was significantly thinner in the severe group compared with the control group and mild group (P=0.013 and 0.010, respectively). Choroidal thickness was significantly correlated with diopter (r=0.520, R(2)=0.270, P<0.001), with a coefficient of 0.327 (P<0.001), and with ODI (r=0.520, R(2)=0.165, P=0.001), with a coefficient of -0.370 (P=0.001). CONCLUSIONS: OSAS patients showed decreased foveal and nasal macular thickness, similar to the subfoveal and nasal choroidal thickness. These findings suggest that, because of intermittent hypoxia, OSAS might change the retinal and choroidal blood supply. PMID- 24406423 TI - Is oral chemotherapy prescription safe for patients? A cross-sectional survey. AB - BACKGROUND: Oral chemotherapies are increasingly prescribed. Yet wide variations in prescription practices and in monitoring of toxicity have been underlined despite existing guidelines. There is little recent information available as regard to these practices. We aimed to obtain exhaustive information on oral chemotherapy prescription practices and safety monitoring in French hospitals. METHODS: A cross-sectional multicentre survey was carried out to collect information on drug prescription, administration and surveillance: prescribing practices, coordination and monitoring of adherence, safety monitoring and side effects occurrence prevention. Participants were a large sample of the French oncologists prescribing oral chemotherapy (20%). RESULTS: One hundred and fifty seven oncologists from 112 hospitals (public, comprehensive cancer centres and private) replied (23.7% of cancer hospitals). The majority (56.1%) of the prescriptions were hand-written on a blank sheet. Eighty-four physicians (53.5%) included dose information and 36 (23%) declared having no monitoring procedures for adherence. Only 84 responders (54%) provided education material at first prescription of oral chemotherapy in way to limit avoidable side-effects. Sixty one (39%) responders stated that they recalled at least one serious adverse event in the previous year declared in their centre. CONCLUSIONS: In this 2012 study, the majority of prescribers followed no standards in prescription writing, safety monitoring and toxicity prevention. The implementation of the international recommendations for oral chemotherapy administration should be considered as a top priority-for both prescribers and health authorities-as regards to the dynamic of development of these molecules and their potential side-effects. PMID- 24406422 TI - Molecular pathogenesis and management strategies of ectopia lentis. AB - Ectopia lentis (EL) is a condition that can either herald underlying systemic conditions, or be isolated. The recent expansion in the genetics of these conditions has furthered the understanding of the underlying molecular aetiology. It is becoming apparent that novel genes, and in particular the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family, are important in ocular development. The common link in these genes seems to be EL. The clinical management of EL is challenging. In particular, the options for addressing surgically induced aphakia in the context of an ectopic capsule are varied. Little evidence exists to direct management of these issues. This review summarises the molecular pathogenesis of EL and conditions associated with it, using the genetic aetiology as a framework. Furthermore, it summarises some of the issues involved in its clinical management. PMID- 24406424 TI - Cancer risk in amyloidosis patients in Sweden with novel findings on non-Hodgkin lymphoma and skin cancer. AB - BACKGROUND: Systemic amyloidoses include immunoglobulin light chain (AL) amyloidosis, serum amyloid (AA)-related amyloidosis and senile systemic amyloidosis (SSA). AL amyloidosis is associated with myeloma, and we showed recently that transthyretin-related hereditary amyloidosis was related to non Hodgkin lymphoma (NHL). In SSA, amyloids constitute wild-type transthyretin. We wanted to analyze cancer risks in amyloidosis, particularly in SSA. PATIENTS AND METHODS: Nonhereditary amyloidosis patients were identified from the Swedish Hospital Discharge and Outpatients Registers from years 1997 through 2010. Their cancer risk was assessed based on the Swedish Cancer Registry using standardized incidence ratio (SIR) between amyloidosis patients and the remaining population. To gain information about amyloidosis subtypes, we used the Swedish Prescribed Drug Register from years 2005 through 2010 to find out the specific medication prescribed. RESULTS: Among 1400 identified amyloidosis patients, cancer risk was increased for myeloma, NHL and squamous cell skin cancer. Myeloma and skin cancers were diagnosed 7-8 years earlier than in the population, whereas NHL was diagnosed in elderly patients. The SIR was 204 for myeloma in patients who received AL amyloidosis medication, and it was 17.22 in patients receiving rheumatoid arthritis medication, suggesting AA amyloidosis. In remaining patients, including SSA, NHL risk was 14.78, including lymphoplasmacytic lymphoma and Waldenstrom macroglobulinemia (51.41) and diffuse large B-cell lymphoma (18.69). In these patients, endometrial cancer (7.04) and cancer of unknown primary site (6.56) were also increased. CONCLUSIONS: SSA is likely to be a main cause of NHL in the elderly population. The present findings suggest a novel mechanism for amyloidosis-related cancer, highlighting the role of chronic stimulation by amyloid. PMID- 24406425 TI - The prognosis of incurable cachectic cancer patients on home parenteral nutrition: a multi-centre observational study with prospective follow-up of 414 patients. AB - BACKGROUND: The role of home parenteral nutrition (HPN) in incurable cachectic cancer patients unable to eat is extremely controversial. The aim of this study is to analyse which factors can influence the outcome. PATIENTS AND METHODS: We studied prospectively 414 incurable cachectic (sub)obstructed cancer patients receiving HPN and analysed the association between patient or clinical characteristics and surviving status. RESULTS: Median weight loss, versus pre disease and last 6-month period, was 24% and 16%, respectively. Median body mass index was 19.5, median KPS was 60, median life expectancy was 3 months. Mean/median survival was 4.7/3.0 months; 50.0% and 22.9% of patients survived 3 and 6 months, respectively. At the multivariable analysis, the variables significantly associated with 3- and 6-month survival were Glasgow Prognostic Score (GPS) and KPS, and GPS, KPS and tumour spread, respectively. By the aggregation of the significant variables, it was possible to dissect several classes of patients with different survival probabilities. CONCLUSIONS: The outcome of cachectic incurable cancer patients on HPN is not homogeneous. It is possible to identify groups of patients with a >=6-month survival (possibly longer than that allowed in starvation). The indications for HPN can be modulated on these clinical/biochemical indices. PMID- 24406426 TI - Photo-tunable multicolour fluorescence imaging based on self-assembled fluorogenic nanoparticles. AB - Non-fluorescent nanoparticles resulting from the self-assembly of a new perylene diimide behave as fluorogenic probes for biological cells under physiological conditions giving a dosage-dependent green or red fluorescence and showing very low cytotoxicity. The emission colour can be tuned by photo-irradiation to achieve multicolour labelling. PMID- 24406427 TI - Are the anatomical sites for vaccine administration selected judiciously? AB - Route of vaccine administration plays an important role in the development of immune response. Antigen administered via different anatomical sites interacts with diverse subsets of antigen presenting cells. Diverse population of antigen presenting cells directs a drastically different immune response. Initially, the recommended routes for vaccine administration were also selected on the basis of clinical trials conducted for the drug molecules. However, physicochemical and pharmaceutical behaviors of proteins (antigens) and chemical compounds are entirely different. Most of the commercial vaccines are injected in the arm or in the scapular region (deltoid muscle). Vaccine administered to these conventional anatomical sites has failed to induce desired immune response due to lack of optimum level of antigen presenting cells. In this review, we have discussed the importance of the selection of anatomical sites for vaccine administration. Mere selection of an optimum site for vaccine administration may drastically change the immune response of the current marketed formulations without any alteration in their existing production plans. PMID- 24406428 TI - Maleylated-BSA suppresses lipopolysaccharide-induced IL-6 production by activating the ERK-signaling pathway in murine RAW264.7 cells. AB - Macrophages are well known for their ability to induce diverse beneficial immune responses, especially in the defense against pathogens. However, an excessive activation of macrophages may cause harmful inflammation. In this context, the suppression of excessive macrophage activation would be a promising therapeutic strategy for treating inflammatory diseases. We have previously found that maleylated-bovine serum albumin (maleylated-BSA) suppresses the production of inflammatory mediators in murine macrophages. However, the immunosuppressive effects and underlying mechanism(s) of maleylated-BSA remain unclear. Here, we report that pretreatment with maleylated-BSA strongly inhibited the production of interleukin 6 (IL-6) induced by bacterial lipopolysaccharide (LPS) in murine RAW264.7 cells. This inhibitory effect of maleylated-BSA on LPS-induced IL-6 production was eliminated by treatment with an extracellular signal-regulated kinase (ERK) inhibitor, U0126, indicating the involvement of ERK pathways. Taken together, we have shown that maleylated-BSA suppresses LPS-induced production of IL-6 via the activation of an ERK signaling pathway in murine macrophages. The findings of this study imply the possibility of a novel therapeutic strategy for inflammatory diseases. PMID- 24406429 TI - Microdissection and transcriptional profiling: a window into the pathobiology of preclinical prion disease. AB - Prion diseases share common features on a sub-cellular level with many neurodegenerative diseases including Alzheimer disease; the most prevalent neurodegenerative disease world-wide. The most obvious similarity is the accumulation of misfolded forms of the host proteins which forms aggregates in the brains of patients. Remarkably, one of the earliest pathological changes detected in degenerating brain tissue, well before clinical symptoms are observed, is synaptic dysfunction and loss. This pathology was recently shown to be reversible in early stages of mouse prion disease suggesting that synaptic regeneration and reestablishment of neuronal function is possible. Determination of the molecular events that underlie synapse degeneration and how this eventually results in neuronal loss is therefore a research priority that may contribute to the search for new therapeutic interventions for neurodegenerative disorders. Functional genomic studies using unbiased whole genome expression analyses represent one method that can provide insights into these perplexing processes. However, transcriptional profiles from brain tissues are representative of a heterogeneous mixture of cell types that effectively mask the expression of low abundance transcripts, or molecular changes that occur only in a small population of affected neurons. One method that was recently applied to address these challenges was laser capture microdissection which was used to effectively isolate the CA1 neuronal rich region of the hippocampus prior to RNA extraction. Profiling of both mRNAs and microRNAs revealed previously unidentified neuronal-specific genes and expression signatures that are relevant to understanding the pathophysiological processes involved in preclinical stages of prion disease. In this review we will highlight these molecular signatures and discuss their implications with respect to prion-induced neurodegeneration. PMID- 24406430 TI - Effects of oxidative modification on gel properties of isolated porcine myofibrillar protein by peroxyl radicals. AB - AAPH-derived (2,2'-azobis (2-amidinopropane) dihydrochloride) peroxyl radicals were selected as representative free radicals of lipid peroxidation to investigate the effects of oxidative modifications on isolated porcine myofibrillar protein structures as well as their rheological and gelling properties. Incubation of myofibrillar protein with increasing concentrations of AAPH resulted in a gradual increase (p<0.05) in carbonyl content and SH->S-S conversion. Results from SDS-PAGE indicated that medium (~1 mM) and relatively high (>3 mM) concentrations of AAPH induced aggregation of myosin and denaturation of myosin, troponin and tropomyosin, respectively. These structural changes resulted in changes on gelation of myofibrillar protein. Low level protein oxidation (AAPH<=0.5 mM) had no remarkable effect (p>0.05) on the viscoelastic pattern of myofibrillar protein gelation. Moderate oxidative modification (AAPH~1mM) enhanced the water-holding capacity (WHC) and texture properties of gels, while further oxidation (AAPH>3mM) significantly reduced the gel quality. PMID- 24406432 TI - Emergence in China of human disease due to avian influenza A(H10N8)--cause for concern? AB - In December 2013, China reported the first human case of avian influenza A(H10N8). A 73-year-old female with chronic diseases who had visited a live poultry market succumbed with community-acquired pneumonia. While human infections with avian influenza viruses are usually associated with subtypes prevalent in poultries, A(H10N8) isolates were mostly found in migratory birds and only recently in poultries. Although not possible to predict whether this single intrusion by A(H10N8) is an accident or the start of another epidemic like the preceding A(H7N9) and A(H5N1), several features suggest that A(H10N8) is a potential threat to humans. Recombinant H10 could attach to human respiratory epithelium, and A(H10N4) virus could cause severe infections in minks and chickens. A(H10N8) viruses contain genetic markers for mammalian adaptation and virulence in the haemagglutinin (A135T, S138A[H3 numbering]), M1(N30D, T215A), NS1(P42S) and PB2(E627K) protein. Studies on this human A(H10N8) isolate will reveal its adaptability to humans. Clinicians should alert the laboratory to test for A(H5,6,7,9,10) viruses in patients with epidemiological exposure in endemic geographical areas especially when human influenza A(H1,3) and B are negative. Vigilant virological and serological surveillance for A(H10N8) in human, poultry and wild bird is important for following the trajectory of this emerging influenza virus. PMID- 24406431 TI - Aberrant CDK4 amplification in refractory rhabdomyosarcoma as identified by genomic profiling. AB - Rhabdomyosarcoma (RMS) is the most commonly occurring type of soft tissue tumor in children. However, it is rare in adults, and therefore, very little is known about the most appropriate treatment strategy for adult RMS patients. We performed genomic analysis of RMS cells derived from a 27-year-old male patient whose disease was refractory to treatment. A peritoneal seeding nodule from the primary tumor, pleural metastases, malignant pleural effusion, and ascites obtained during disease progression, were analyzed. Whole exome sequencing revealed 23 candidate variants, and 10 of 23 mutations were validated by Sanger sequencing. Three of 10 mutations were present in both primary and metastatic tumors, and 3 mutations were detected only in metastatic specimens. Comparative genomic hybridization array analysis revealed prominent amplification in the 12q13-14 region, and more specifically, the CDK4 proto-oncogene was highly amplified. ALK overexpression was observed at both protein and RNA levels. However, an ALK fusion assay using NanoString technology failed to show any ALK rearrangements. Little genetic heterogeneity was observed between primary and metastatic RMS cells. We propose that CDK4, located at 12q14, is a potential target for drug development for RMS treatment. PMID- 24406433 TI - Reconciliation of classification systems defining molecular subtypes of colorectal cancer: interrelationships and clinical implications. AB - Recently we published two independent studies describing novel gene expression based classifications of colorectal cancer (CRC). Notably, each study stratified CRC into a different number of subtypes: one reported 3 subtypes, whereas the second highlighted 5. Given that each ascribed clinical significance, distinctive biology, and therapeutic prognosis to the different subtypes, we sought to reconcile this apparent incongruity in subtype stratification of CRC, and to interrelate the results. To do so, we each evaluated the other's data sets and analytical methods and discovered that the subtypes and their classifiers are, in fact, clearly related to each other; indeed, the 5 subtype outcomes can be coalesced into the same three. In addition to presenting this clarification, we briefly discuss how both classification methods can be viewed within the broader literature on CRC subtypes, and potentially applied. PMID- 24406434 TI - Tricyclic antidepressants for management of residual symptoms in inflammatory bowel disease. AB - BACKGROUND: Tricyclic antidepressants (TCAs) have efficacy in treating irritable bowel syndrome (IBS). Some clinicians use TCAs to treat residual symptoms in inflammatory bowel disease (IBD) patients already on decisive IBD therapy or with quiescent inflammation, although this strategy has not been formally studied. GOALS: The aim of this study was to examine the efficacy of TCA therapy in IBD patients with residual symptoms, despite controlled inflammation, in a retrospective cohort study. STUDY: Inclusion required initiation of TCA for persistent gastrointestinal symptoms. IBD patients had inactive or mildly active disease with persistent symptoms despite adequate IBD therapy as determined by their physician. Symptom response was compared with IBS patients. Established Likert scales were used to score baseline symptom severity (0=no symptoms, 3=severe symptoms) and TCA response (0=no improvement; 3=complete satisfaction). RESULTS: Eighty-one IBD [41.3+/-1.7 y, 56F; 58 Crohn's disease/23 ulcerative colitis (UC)] and 77 IBS (46.2+/-1.7 y, 60F) patients were initiated on a TCA therapy. Baseline symptom scores (IBD, 2.06+/-0.03; IBS, 2.12+/-0.04; P=0.15) and symptom response to TCA therapy (IBD, 1.46+/-0.09; IBS, 1.30+/-0.09; P=0.2) were similar in both the groups. At least moderate improvement (Likert score >=2) on TCA was achieved by comparable proportions of patients (59.3% IBD vs. 46% IBS; P=0.09). Within IBD, response was better with UC than Crohn's disease (1.86+/ 0.13 vs. 1.26+/-0.11, respectively, P=0.003). CONCLUSIONS: In a clinical practice setting, TCA use led to moderate improvement of residual gastrointestinal symptoms in IBD patients for whom escalation of IBD therapy was not planned. UC patients demonstrated higher therapeutic success. IBD symptom responses were similar to IBS patients. PMID- 24406435 TI - Clinical significance of hepatitis B virus precore and core promoter variants in Korean patients with chronic hepatitis B. AB - BACKGROUND/AIM: We aimed to clarify the clinical significance of precore (preC)/core promoter (CP) variants of hepatitis B virus (HBV) in chronic hepatitis B (CHB) patients. METHODS: We assessed serum HBeAg, HBV DNA levels, alanine transferase (ALT) levels, and progression of liver fibrosis in 226 Korean CHB patients, presumed to be infected with genotype C HBV, to analyze HBV variants in the preC region (G1896A) and CP regions (A1762T, G1764A). RESULTS: CP and preC variants were more frequently found in HBeAg-negative patients than in HBeAg-positive patients (P<0.05). HBeAg-positive patients with CP variants had higher ALT levels and more advanced fibrosis scores (all P<0.01) than those without variants; those with preC variant had lower HBV DNA levels (P=0.009), with no significant difference in ALT levels and fibrosis scores. However, no significant correlation was found between HBV variants and clinicopathologic findings in HBeAg-negative patients. Furthermore, multivariate analysis revealed that (1) progression of liver fibrosis (>=F2) was associated with older age in both HBeAg-positive and HBeAg-negative patients (P<0.05) and with CP variants in the HBeAg-positive group (P=0.007), and (2) HBV DNA levels were positively correlated with ALT levels, irrespective of HBeAg (P<0.05), whereas they were negatively correlated with the presence of preC variant in the HBeAg-positive group (P=0.004). CONCLUSIONS: In HBeAg-positive CHB patients infected with genotype C HBV, preC variant was associated with enhanced host immune response with lower HBV DNA levels, whereas CP variants were associated with severe liver damage and liver fibrosis progression. PMID- 24406436 TI - Making sense of serologies: are they useful in indeterminate colitis? PMID- 24406438 TI - Concurrent working memory task decreases the Stroop interference effect as indexed by the decreased theta oscillations. AB - Working memory (WM) tasks may increase or decrease the interference effect of concurrently performed cognitive control tasks. However, the neural oscillatory correlates of this modulation effect of WM on the Stroop task are still largely unknown. In the present study, behavioral and electroencephalographic (EEG) data were recorded from 32 healthy participants during their performance of the single Stroop task and the same task with a concurrent WM task. We observed that the Stroop interference effect represented in both response times (RTs) and theta band event-related spectral perturbation (ERSP) magnitude reduced under the dual task condition compared with the single-task condition. The reduction of interference in theta-band ERSP was further positively correlated with interference reduction in RTs, and was mainly explained by the source in the left middle frontal gyrus. In conclusion, the present study suggests that the effect of concurrent WM tasks on the reduction of the Stroop interference effect can be indexed by EEG oscillations in theta-band rhythm in the centro-frontal regions and this modulation was mediated by the reduced cognitive control under the concurrent WM task. PMID- 24406437 TI - Connexin36 identified at morphologically mixed chemical/electrical synapses on trigeminal motoneurons and at primary afferent terminals on spinal cord neurons in adult mouse and rat. AB - Morphologically mixed chemical/electrical synapses at axon terminals, with the electrical component formed by gap junctions, is common in the CNS of lower vertebrates. In mammalian CNS, evidence for morphologically mixed synapses has been obtained in only a few locations. Here, we used immunofluorescence approaches to examine the localization of the neuronally expressed gap junction forming protein connexin36 (Cx36) in relation to the axon terminal marker vesicular glutamate transporter-1 (vglut1) in the spinal cord and the trigeminal motor nucleus (Mo5) of rat and mouse. In adult rodents, immunolabeling for Cx36 appeared exclusively as Cx36-puncta, and was widely distributed at all rostro caudal levels in most spinal cord laminae and in the Mo5. A high proportion of Cx36-puncta was co-localized with vglut1, forming morphologically mixed synapses on motoneurons, in intermediate spinal cord lamina, and in regions of medial lamina VII, where vglut1-containing terminals associated with Cx36 converged on neurons adjacent to the central canal. Unilateral transection of lumbar dorsal roots reduced immunolabeling of both vglut1 and Cx36 in intermediate laminae and lamina IX. Further, vglut1-terminals displaying Cx36-puncta were contacted by terminals labeled for glutamic acid decarboxylase65, which is known to be contained in presynaptic terminals on large-diameter primary afferents. Developmentally, mixed synapses begin to emerge in the spinal cord only after the second to third postnatal week and thereafter increase to adult levels. Our findings demonstrate that axon terminals of primary afferent origin form morphologically mixed synapses containing Cx36 in broadly distributed areas of adult rodent spinal cord and Mo5. PMID- 24406439 TI - Diurnal variations in brain iron concentrations in BXD RI mice. AB - Under normal and dietary iron deficiency conditions, the BXD recombinant inbred (RI) strains of mice show large variations in regional brain iron concentration, particularly in the ventral midbrain (VMB). In a study utilizing just one of the BXD strains, diurnal changes in subregional brain iron concentration were found, which were dependent on the brain region and sex of the mice. The focus of this study was to determine if diurnal changes in VMB can be found across other BXD RI strains and whether a diurnal effect would be common to all strains or variable across strains similar to the large strain variability in iron concentrations determined during the first part of the light phase. Eight RI (BXD type) strains of mice of both sexes were selected for this study. Mice were sacrificed at postnatal day 120: half in the light phase (LP) and half in the dark phase (DP) of the light-dark cycle. Iron concentrations were determined in VMB, which was the primary region of interest, and five other brain regions. Exploratory analysis was also done on liver and spleen iron concentrations to assess for diurnal changes. Three strains showed clear diurnal variation in iron in the VMB and the others strains showed diurnal variations in other regions. These changes were not equally apparent in both sexes. Exploratory analysis also found strain*sex-dependent diurnal differences in spleen and liver iron. In conclusion, significant brain-regional-specific diurnal changes in total iron concentrations were found in a selection of BXD RI mice. Sex and strain are functional determinates of which regions will be affected and in what direction the affect will be. The study provides an animal model for future work into determining the biological and genetic basis of circadian influences on VMB iron homeostasis. PMID- 24406440 TI - Voxel-based morphometry study of the insular cortex in female patients with current and remitted depression. AB - OBJECTIVE: Women are more prone to major depressive disorders (MDDs) and the incidence of MDD in women is almost twice that of men. Insular cortex abnormalities are a common finding in neuroanatomical studies of patients with MDD. However, it remains largely unclear whether female MDD patients at different clinical stages show morphologic changes in a specific subregion of the insular cortex. Additionally, it is not understood if any subregion changes can be used as a state or trait marker of MDD, and whether the diagnostic performance of any marker is sufficient to identify MDD. METHODS: Nineteen right-handed current MDD (cMDD) female patients and 19 remitted MDD (rMDD) patients, as well as 19 healthy controls matched for age and educational level, were recruited into the study. By means of voxel-based morphometry (VBM), we investigated gray matter volume abnormalities in insular subregions among the three groups and further conducted region-of-interest (ROI)-based receiver operating characteristic (ROC) analyses. The data from these investigations were correlated with clinical data to confirm the effectiveness of the identified changes in the subregions in differentiating the three groups. RESULTS: Both the cMDD and rMDD groups showed significantly decreased gray matter volumes in the left dorsal anterior insula compared to the healthy controls. The cMDD groups also showed decreased gray matter volumes in the right dorsal anterior insula relative to healthy controls. Further ROC comparisons demonstrated that the left dorsal anterior insula can effectively differentiate cMDD and rMDD groups from healthy controls. CONCLUSIONS: Our findings suggest that the volume changes in the left dorsal anterior insular cortex may be a trait-related marker of vulnerability to MDD and that the right dorsal anterior insular cortex may involve pathological changes of MDD. PMID- 24406441 TI - Dose-dependent influence of short-term intermittent ethanol intoxication on cerebral neurochemical changes in rats detected by ex vivo proton nuclear magnetic resonance spectroscopy. AB - The aim of this study was to quantitatively assess the effects of short-term intermittent ethanol intoxication on cerebral metabolite changes among sham controls (CNTL), low-dose ethanol (LDE)-exposed, and high-dose ethanol (HDE) exposed rats, which were determined with ex vivo high-resolution spectra. Eight week-old male Wistar rats were divided into three groups. Twenty rats in the LDE (n=10) and the HDE (n=10) groups received ethanol doses of 1.5 and 2.5 g/kg, respectively, through oral gavage every 8h for 4days. At the end of the 4-day intermittent ethanol exposure, one-dimensional ex vivo 500-MHz 1H nuclear magnetic resonance spectra were acquired from 30 samples of the frontal cortex region (from the three groups). Normalized total N-acetylaspartate (tNAA: NAA+NAAG [N-acetylaspartyl-glutamate]), GABA, and glutathione (GSH) levels were significantly lower in the frontal cortex of the HDE-exposed rats than that of the LDE-exposed rats. Moreover, compared to the CNTL group, the LDE rats exhibited significantly higher normalized GABA levels. The six pairs of normalized metabolite levels were positively (+) or negatively (-) correlated in the rat frontal cortex as follows: tNAA and GABA (+), tNAA and aspartate (Asp) (+), myo-Inositol (mIns) and Asp (-), mIns and alanine (+), mIns and taurine (+), and mIns and tNAA (-). Our results suggested that short-term intermittent ethanol intoxication might result in neuronal degeneration and dysfunction, changes in the rate of GABA synthesis, and oxidative stress in the rat frontal cortex. Our ex vivo(1)H high-resolution magic angle spinning nuclear magnetic resonance spectroscopy results suggested some novel metabolic markers for the dose dependent influence of short-term intermittent ethanol intoxication in the frontal cortex. PMID- 24406442 TI - Increased depression-like behaviors with dysfunctions in the stress axis and the reward center by free access to highly palatable food. AB - This study was conducted to examine the behavioral consequences of unlimited consumption of highly palatable food (HPF) and investigate its underlying neural mechanisms. Male Sprague-Dawley rats had free access to chocolate cookie rich in fat (HPF) in addition to ad libitum chow and the control group received chow only. Rats were subjected to behavioral tests during the 2nd week of food condition; i.e. ambulatory activity test on the 8th, elevated plus maze test (EPM) on the 10th and forced swim test (FST) on the 14th day of food condition. After 8 days of food condition, another group of rats were placed in a restraint box and tail bloods were collected at 0, 20, 60, and 120 time points during 2h of restraint period, used for the plasma corticosterone assay. At the end of restraint session, rats were sacrificed and the tissue sections of the nucleus accumbens (NAc) were processed for c-Fos immunohistochemistry. Ambulatory activities and the scores of EPM were not significantly affected by unlimited cookie consumption. However, immobility duration during FST was increased, and swim decreased, in the rats received free cookie access compared with control rats. Stress-induced corticosterone increase was exaggerated in cookie-fed rats, while the stress-induced c-Fos expression in the NAc was blunted, compared to control rats. Results suggest that free access to HPF may lead to the development of depression-like behaviors in rats, likely in relation with dysfunctions in the hypothalamic-pituitary-adrenal axis and the reward center. PMID- 24406443 TI - Functional characterization of rare variants in human dopamine receptor D4 gene by genotype-phenotype correlations. AB - Next generation sequencing technologies have facilitated a notable shift from common disease common variant hypothesis to common disease rare variant, as also witnessed in recent literature on schizophrenia. Dopamine receptor D4 (DRD4), a G protein-coupled receptor is associated with psychiatric disorders and has high affinity for atypical antipsychotic clozapine. We investigated the functional role of rare genetic variants in DRD4 which may have implications for translational medicine. CHO-K1 cells independently expressing four rare non synonymous variants of DRD4 namely R237L, A281P, S284G located in the third cytosolic loop and V194G, located in the fifth transmembrane domain were generated. Their genotype-phenotype correlations were evaluated using [3H]spiperone binding, G-protein activation and molecular dynamics-simulation studies. A281P and S284G were functionally similar to wildtype (WT). With R237L, potency of dopamine and quinpirole reduced ~sixfold and threefold respectively compared to WT; [3H]spiperone binding studies showed a reduction in total number of binding sites (~40%) but not binding affinity, in silico docking studies revealed that binding of both dopamine and spiperone to R237L was structurally similar to WT. Of note, V194G variant failed to inhibit forskolin-stimulated adenylate cyclase activity and phosphorylate extracellular signal-regulated kinase; showed significant reduction in binding affinity (K(d)=2.16 nM) and total number of binding sites (~66%) compared to WT in [3H]spiperone binding studies; and ligand docking studies showed that binding of dopamine and spiperone is superficial due to probable structural alteration. Transmembrane variant V194G in DRD4.4 results in functional alteration warranting continuing functional analysis of rare variants. PMID- 24406444 TI - Modeling and simulation of the water gradient within a Nafion membrane. AB - The perfluorinated sulfonic acid membrane (Nafion) shows among ionomers high water uptake and cationic conductivity. These properties allow Nafion to be used in nanocomposite actuators, sensors and fuel cells. In situ experiments have shown that there is a water gradient within the Nafion membrane. The water gradient causes the alteration of other physical properties within the thickness of the membrane and has a drastic impact on the performance of the devices made of the Nafion membrane. Deriving closed-form equations and using molecular dynamics (MD) simulation results, we bridge Nafion properties at the atomic scale and the macroscopic behavior of the membrane within a hierarchical multi-scale model. Multiple discrete simulation cells are selected across the thickness of the membrane with a wide range of water contents as representative volume elements (RVEs). The present framework is able to quantitatively predict the macroscopic properties of Nafion with the nanometric resolution regarding the water gradient across the membrane. PMID- 24406445 TI - An insight into the role of the surfactant CTAB in the formation of microporous molecular sieves. AB - Quaternary ammonium salts are well-known zeolite structure-directing agents. However, cationic surfactants with quaternary ammonium head groups are known to fail to function as SDAs of zeolites because their long surfactant chains disrupt the ordered growth of the zeolite crystals. In this study, we found that ZSM-5 and silicalite-1 can be formed very easily with appropriate synthesis compositions over a large temperature range of 100-200 degrees C. The (13)C CP/MAS data for surfactants in ZSM-5 combined with elemental analysis indicated that the surfactants were in more rigid, isolated environments and did not undergo decomposition. The surfactant head groups can serve as structure directing agents for zeolites, and the long chains become isolated and occupy the micropores. Our findings provide a new insight into the molecular factors governing the formation of inorganic-organic microporous materials, which opens up new possibilities for the elaborate fabrication of mesoporous zeolites. PMID- 24406446 TI - Heart failure in HIV infection: focus on the role of atherosclerosis. AB - PURPOSE OF REVIEW: Since the advent of highly active antiretroviral treatment, accelerated atherosclerosis resulting in coronary artery disease (CAD) has become an area of increasing concern among patients infected with HIV. As CAD has replaced myocarditis and opportunistic infection as the most common cause of heart failure in this population, it is necessary to re-evaluate the specific risks of cardiovascular disease in HIV-infected patients taking into consideration the processes driving atherogenesis. RECENT FINDINGS: Recent data illustrating that atazanavir is not associated with an increased risk of CAD argue against a class-wide association of protease inhibitors in HIV treatment and adverse cardiovascular outcomes. C-C chemokine receptor-type 5 has been identified as a potential target for pharmacological therapy to manage the process of atherosclerosis while simultaneously having an antiretroviral effect. Additionally, as the use of statins has recently been associated with new-onset diabetes in the general population, further investigation of this risk in HIV infected patients is necessary. SUMMARY: HIV-infected patients have an increased risk of CAD and subsequently heart failure. This is likely because of a confluence of several factors including: conventional risk factors, HIV-specific processes driving inflammation, coagulatory pathway and endothelial dysfunction. The benefits of antiretroviral drugs in terms of overall survival rates outweigh the risks of dyslipidemia. The focus of the management of cardiovascular risk remains in the domains of primary and secondary prevention. More accurate risk stratification, which accounts for HIV-specific risk factors, is now increasingly warranted. PMID- 24406447 TI - The prognostic role of right ventricular function in left ventricular disease in the setting of cardiac resynchronization therapy. AB - PURPOSE OF REVIEW: Cardiac resynchronization therapy (CRT) offers a new therapeutic approach for treating patients with ventricular dyssynchrony and moderate-to-severe heart failure (HF). The impact of right ventricular dysfunction on global cardiac function remains imperfectly understood despite increasing research on right ventricular function as it pertains to long-term outcomes in HF. In this article, we aim to review the prognostic role of right ventricular function in the setting of CRT. RECENT FINDINGS: Right ventricular dysfunction has emerged as a strong prognostic predictor of poor clinical outcomes in HF patients with CRT. The presence of right ventricular dysfunction at baseline is associated with poor prognosis and CRT response. Preliminary data indicate that CRT may have a positive influence on right ventricular remodeling and function. SUMMARY: CRT guidelines continue to be optimized on the basis of emerging data. The prognostic role of right ventricular dyssynchrony and right ventricular response to CRT will further contribute to the understanding of this topic and the identification of HF populations that will benefit from this therapy. As the impact of right ventricular function on global cardiopulmonary function remains imperfectly understood, ongoing research on right ventricular function in HF patients with CRT and its implication for long-term outcome is required. It is, however, clear that right ventricular function is a prognostic marker of response to CRT and adverse long-term outcome. Conversely, recent data indicate that CRT may in turn influence right ventricular remodeling and function. PMID- 24406448 TI - Brain natriuretic peptide: a biomarker for all cardiac disease? AB - PURPOSE OF REVIEW: To evaluate new development in the utility of brain natriuretic peptide and N-Terminal brain natriuretic peptide (BNP/NT-Pro-BNP) in the management of various cardiovascular diseases. The determination of plasma BNP levels has an established role in the discrimination of pulmonary oedema from other causes of acute dyspnoea, and there is increasing evidence of the utility of BNP/NT-Pro-BNP assay both as a prognostic tool in chronic heart failure and as a means of guiding therapy in heart failure patients aged below 70 years. RECENT FINDINGS: Findings have substantially extended the clinical utility of BNP/NT-Pro BNP assay. In heart failure with preserved left ventricular ejection fraction, BNP elevation may also facilitate diagnosis, although its precise utility is uncertain.In the acute catecholamine-induced myocardial inflammatory condition of Tako-Tsubo cardiomyopathy (TTC), BNP/NT-Pro-BNP elevations are marked and persist for at least 3 months, despite the absence of pulmonary oedema. In TTC, BNP/NT Pro-BNP therefore serves as an ancillary diagnostic measure as well as a marker of recovery. Among other conditions in which BNP assay may provide prognostic information are atrial fibrillation (in which the extent of elevation predicts thromboembolic risk) and pulmonary hypertension. SUMMARY: BNP/NT-Pro-BNP assay has widespread utility as an adjunct to cardiovascular disease diagnosis and management. PMID- 24406449 TI - Infection and noncardiovascular death in the elderly-Heart failure's dirty little secret. PMID- 24406450 TI - Microscopic and macroscopic characterization of the charging effects in SiC/Si nanocrystals/SiC sandwiched structures. AB - Microscopic charge injection into the SiC/Si nanocrystals/SiC sandwiched structures through a biased conductive AFM tip is subsequently characterized by both electrostatic force microscopy and Kelvin probe force microscopy (KPFM). The charge injection and retention characteristics are found to be affected by not only the band offset at the Si nanocrystals/SiC interface but also the doping type of the Si substrate. On the other hand, capacitance-voltage (C-V) measurements investigate the macroscopic charging effect of the sandwiched structures with a thicker SiC capping layer, where the charges are injected from the Si substrates. The calculated macroscopic charging density is 3-4 times that of the microscopic one, and the possible reason is the underestimation of the microscopic charging density caused by the averaging effect and detection delay in the KPFM measurements. PMID- 24406452 TI - Endoscopic resection of gastric neoplasm in solid-organ transplant recipients. AB - BACKGROUND: The aim of this study was to investigate the feasibility and safety of endoscopic resection of gastric neoplasm in solid-organ transplant (SOT) recipients. METHODS: Between January 1994 and December 2011, the results of endoscopic resection of 17 lesions in 15 consecutive patients who had previously undergone SOT at Asan Medical Center were retrospectively evaluated. We compared clinical outcomes of this group with 1:5 matched non-SOT patients treated by endoscopic resection. RESULTS: Of the 6,491 patients who underwent SOT during the study periods, 30 patients (0.46%) with 31 lesions were diagnosed with gastric cancer, and eight patients (0.12%) with nine lesions were diagnosed with gastric adenoma. Among them, 15 patients with 17 lesions were treated by endoscopic resection, and 19 patients with 20 lesions have undergone gastrectomy. In endoscopically resected SOT group, the median duration between transplantation and endoscopic treatment was 41 months (range, 5-196 months). En bloc and complete resection were achieved in 13 (76.5%) and 15 (88.2%) lesions. Four lesions (23.5%) experienced bleeding, which was successfully managed endoscopically. When compared with post-endoscopic resection bleeding rate of non SOT group (5.9%, [5/85]), there was no significant difference in multivariable analysis (P=0.083). CONCLUSIONS: In endoscopic resection for gastric neoplasm of SOT recipients, only manageable complications were noted in some patients, and graft dysfunctions or perforations did not occur. To avoid surgical resection with its associated perioperative mortality and morbidity, endoscopic resection for gastric neoplasm in SOT recipients is recommended as a feasible treatment with high efficacy and safety. PMID- 24406453 TI - Glomerular inflammation correlates with endothelial injury and with IL-6 and IL 1beta secretion in the peripheral blood. AB - BACKGROUND: Transplant glomerulitis is an active form of glomerular injury associated with suboptimal graft outcome, inadequate histologic reproducibility, and poorly understood pathogenesis. Using a modified pathologic schema where glomerular inflammation is defined by the presence of five or more leukocytes per glomerulus, we sought to assess the reproducibility of transplant glomerulitis and to prospectively investigate the pathogenesis of glomerular inflammation. METHODS: Our cohort includes 59 kidney transplant recipients who underwent 60 "for cause" allograft biopsies. In addition to light microscopy, the majority of the biopsies were assessed using immunohistochemistry, immunofluorescence, and electron microscopy studies. Biopsies were classified as noninflamed (n=21), inflamed (borderline changes or above) without glomerulitis (n=21), and transplant glomerulitis (n=18). Peripheral blood was collected on the day of biopsy and cytokines secreted by peripheral blood mononuclear cells (PBMCs) were measured ex vivo. RESULTS: Our modified schema had higher inter-observer agreement for detecting glomerulitis than that of the current Banff schema. Biopsies with glomerulitis showed ultrastructural signs of glomerular capillary wall remodeling. In contrast to other anatomic compartments, intraglomerular leukocytes in glomerulitis group consisted largely of monocytes. Patients with glomerulitis had high levels of IL-6 and IL-1beta secreted by PBMCs. Furthermore, the percentage of inflamed glomeruli and the number of intraglomerular monocytes showed independent association with IL-6 and IL-1beta levels, which tended to correlate with subsequent estimated glomerular filtration rate decline. CONCLUSIONS: Inter-observer reproducibility of transplant glomerulitis can be improved by using more stringent histologic criteria. Glomerular inflammation correlates with endothelial injury, monocyte influx, and IL-6 and IL-beta secretion by circulating immune cells. PMID- 24406454 TI - Oxidative stress in kidney transplantation: malondialdehyde is an early predictive marker of graft dysfunction. AB - BACKGROUND: Oxidative stress is one of the most important components of the ischemia-reperfusion process after kidney transplantation (KTx) and increases with graft dysfunction. METHODS: This prospective study was conducted on 40 consecutive KTx recipients to evaluate time-dependent changes in oxidative stress related parameters within the first week after KTx and to assess their performance in predicting delayed graft function (DGF=dialysis requirement during initial posttransplant week) and graft function at 1 year. Blood samples were collected before (day 0) and after KTx (days 1, 2, 4, and 7). Total antioxidant capacity, plasma levels of malondialdehyde (MDA), and activities of glutathione peroxidase, glutathione reductase and superoxide dismutase were measured. Multivariable linear mixed and linear regression models, receiver-operating characteristic (ROC), and areas under ROC curves (AUC-ROC) were used. RESULTS: At all time points after KTx, mean MDA levels were significantly higher in patients developing DGF (n=18). Shortly after KTx (8-12 hr), MDA values were higher in DGF recipients (on average, +0.16 MUmol/L) and increased further on following day, contrasting with prompt functioning recipients. Day 1 MDA levels accurately predicted DGF (AUC-ROC=0.90), with a performance higher than SCr (AUC-ROC=0.73) and similar to cystatin C (AUC-ROC=0.91). Multivariable analysis revealed that MDA levels on day 7 represented an independent predictor of 1-year graft function. Antioxidant enzyme activities were not significantly changed during the study period and were not predictors of 1-year graft function. CONCLUSIONS: Increased MDA levels on day 1 after KTx might be an early prognostic indicator of DGF, and levels on day 7 might represent a useful predictor of 1-year graft function. PMID- 24406455 TI - Treatment with anti-TNF alpha protects against the neuropathy induced by the proteasome inhibitor bortezomib in a mouse model. AB - Bortezomib (BTZ), a proteasome inhibitor, is an effective anti-neoplastic drug used in the treatment of multiple myeloma and mantle cell lymphoma. However, it can induce a reversible peripheral neuropathy that may lead to treatment discontinuation. The mechanism through which BTZ exerts toxic effects in peripheral neurons is not clear. Release of proinflammatory cytokines after nerve damage can induce neurodegeneration, but the effects of BTZ on cytokine expression in neurons are unknown, although BTZ modulates the expression of cytokines, such as TNF-alpha and IL-6, in tumor cells. The aim of this study was to evaluate the expression and the role of these cytokines on the course of BTZ induced neuropathy in mice. IL-6, TNF-alpha, TGF-beta1 and IL-1beta were up regulated in dorsal root ganglia but TNF-alpha and IL-6 increased faster and higher. Then, we studied the potential neuroprotective effect of selective antibodies anti-TNF-alpha and anti-IL-6 on the evolution of the neuropathy. Treatment with anti-TNF-alpha but not with anti-IL-6 significantly prevented the decrease of sensory nerve action potentials amplitude and the loss of myelinated and unmyelinated fibers. We conclude that monoclonal antibodies directed against TNF-alpha may be a suitable neuroprotective therapy against the neurotoxicity induced by BTZ. PMID- 24406456 TI - Whole cell biotransformation for reductive amination reactions. AB - Whole cell biotransformation systems with enzyme cascading increasingly find application in biocatalysis to complement or replace established chemical synthetic routes for production of, e.g., fine chemicals. Recently, we established an Escherichia coli whole cell biotransformation system for reductive amination by coupling a transaminase and an amino acid dehydrogenase with glucose catabolism for cofactor recycling. Transformation of 2-keto-3-methylvalerate to l isoleucine by E. coli cells was improved by genetic engineering of glucose metabolism for improved cofactor regeneration. Here, we compare this system with different strategies for cofactor regeneration such as cascading with alcohol dehydrogenases, with alternative production hosts such as Pseudomonas species or Corynebacterium glutamicum, and with improving whole cell biotransformation systems by metabolic engineering of NADPH regeneration. PMID- 24406457 TI - Noninvasive prenatal diagnosis in a fetus at risk for methylmalonic acidemia. AB - PURPOSE: Prenatal diagnosis of fetal Mendelian disorders can benefit from noninvasive approaches using fetal cell-free DNA in maternal plasma. Detecting metabolic disorders before birth can result in immediate treatment postpartum in order to optimize outcome. METHODS: We developed a mathematical model and an experimental methodology to analyze the case of a fetus with a 25% risk of inheriting two known mutations in MUT that cause methylmalonic acidemia. To accomplish this, we measured allelic counts at the mutation sites and the fetal fraction from high minor-allele-frequency single-nucleotide polymorphism positions. RESULTS: By counting linked alleles, the test was able to distinguish 11 positive markers from the negative controls and thereby determine whether or not the mutations carried by the parents were inherited by the fetus. For a homozygous fetus, the Z-score of the mutation site was 5.97, whereas the median Z score of all the linked alleles was 4.56 when all negative (heterozygous) controls had a Z-score <2.5. CONCLUSION: The application of this methodology for diagnosing methylmalonic acidemia shows that this is a cost-effective and noninvasive approach to diagnosing known mutations related to Mendelian disorders in the fetus. PMID- 24406458 TI - Predictive genetic testing experience for myocilin primary open-angle glaucoma using the Australian and New Zealand Registry of Advanced Glaucoma. AB - PURPOSE: Predictive genetic testing of relatives of known myocilin (MYOC) gene mutation carriers is an appropriate strategy to identify individuals at risk for glaucoma. It is likely to prevent irreversible blindness in this high-risk group because this treatable condition might otherwise be diagnosed late. The Australian and New Zealand Registry of Advanced Glaucoma has established genetic testing protocols for known glaucoma genes, including MYOC. METHODS: Through the Australian and New Zealand Registry of Advanced Glaucoma, we investigated the experience of 40 unaffected individuals who had undergone predictive genetic testing for MYOC mutations through questionnaires. RESULTS: The main motivations for being tested were (i) to make appropriate interventions and (ii) to reduce uncertainty. All our respondents perceived strong benefits, either medical or emotional, in being tested. However, different concerns were raised by the respondents that need to be addressed during counseling. Greater family awareness was reported by the majority of the respondents, and the ability to provide information to children was a strong motivation for being tested. CONCLUSION: This study provides valuable information on the personal and familial impacts of having predictive genetic testing for glaucoma, which will help health professionals to better address the issues faced by patients and provide them adequate support. PMID- 24406459 TI - Assessing the necessity of confirmatory testing for exome-sequencing results in a clinical molecular diagnostic laboratory. AB - PURPOSE: Sanger sequencing is currently considered the gold standard methodology for clinical molecular diagnostic testing. However, next-generation sequencing has already emerged as a much more efficient means to identify genetic variants within gene panels, the exome, or the genome. We sought to assess the accuracy of next-generation sequencing variant identification in our clinical genomics laboratory with the goal of establishing a quality score threshold for confirmatory Sanger-based testing. METHODS: Confirmation data for reported results from 144 sequential clinical exome-sequencing cases (94 unique variants) and an additional set of 16 variants from comparable research samples were analyzed. RESULTS: Of the 110 total single-nucleotide variants analyzed, 103 variants had a quality score >=Q500, 103 (100%) of which were confirmed by Sanger sequencing. Of the remaining seven variants with quality scores